HUNTER DAVID (US)
EL MARROUNI ABDELLATIF (US)
ROECKER ANTHONY (US)
SHAW ANTHONY (US)
SHIPE WILLIAM (US)
WANG CHENG (US)
WANG DEPING (US)
ZHANG YUNLONG (US)
CONVERSO ANTONELLA (US)
HUNTER DAVID N (US)
EL MARROUNI ABDELLATIF (US)
ROECKER ANTHONY J (US)
SHAW ANTHONY W (US)
SHIPE WILLIAM D (US)
WANG CHENG (US)
WANG DEPING (US)
ZHANG YUNLONG (US)
US20010044540A1 | 2001-11-22 | |||
US20030092722A1 | 2003-05-15 | |||
US20080176830A1 | 2008-07-24 | |||
US4764512A | 1988-08-16 |
WHAT IS CLAIMED IS: 1. A compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: R1 is O or S; R2 is -H or -C1-8alkyl unsubstituted or substituted with 1 to 17 of F; R3 is halo or -C1-8alkyl unsubstituted or substituted with 1 to 17 of F; R4 is -H, halo, or -C1-8alkyl; R5 is -H or halo; R6 is -H or halo; and R7 is a 6-membered ring selected from (a) phenyl and (b) heteroaryl comprised of carbon atoms and 1, 2 or 3 nitrogen atoms, wherein one of the nitrogen atoms may optionally be in the form of an N-oxide, wherein the heteroaryl ring is attached by a carbon atom in the ring to the adjacent carbon atom in -C(R6)-; and wherein the 6-membered ring is unsubstituted or substituted with one or more substituents up to the maximum number allowed by valence, independently selected at each occurrence from: (i) halo, (ii) -CN, (iii) -NR8aR9a, (iv) -S(O)2NR8bR9b,(v) -C(O)NR8cR9c, (vi) -S(O)2C1-8alkyl, and (vii) oxo (=O), (viii) -C1-8alkyl unsubstituted or substituted with 1 to 8 substituents independently selected at each occurrence from -OH and halo, (ix) -O-(C1-8alkyl) unsubstituted or substituted with 1 to 8 substituents independently selected at each occurrence from -OH and halo, and (x) -C3-6cycloalkyl unsubstituted or substituted with 2 to 5 substituents independently selected at each occurrence from -OH and halo; and R8a, R8b, R8c, R9a, R9b and R9c are each independently selected at each occurence from -H and - C1-8alkyl unsubstituted or substituted with 1 to 8 substituents independently selected at each occurrence from -OH and halo. 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is (i) -H, or (ii) an alkyl group selected from -C1-6alkyl, -C1-5alkyl, -C1-4alkyl, or -C1- 3alkyl, wherein the alkyl group is unsubstituted or substituted with one or more of -F up to the maximum number allowed by valence. 3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein R3 is (i) halo or (ii) an alkyl group selected from -C1-6alkyl, -C1-5alkyl, -C1-4alkyl, or - C1-3alkyl, wherein the alkyl group is unsubstituted or substituted with one or more of halo up to the maximum number allowed by valence. 4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R4 is -H, halo or -C1-6alkyl. 5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein R5 is -H, F, Cl or Br. 6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R6 is -H, F, Cl or Br. 7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein R8a, R8b, R8c, R9a, R9b and R9c are each independently selected from -H or -C1-6alkyl unsubstituted or substituted with 1 to 6 substituents independently selected at each occurrence from -OH and halo. 8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof wherein R1 is O. 9. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof wherein R1 is S. 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R7 is a 6-membered ring selected from phenyl, pyridine, pyridinone, pyridine n-oxide, pyrimidine, pyrimidinone, pyrazine and triazine, unsubstituted or substituted with one or more substituents up to the maximum number allowed by valence, independently selected at each occurrence from: (i) halo, (ii) -CN, (iii) -NR8aR9a, (iv) -S(O)2NR8bR9b,(v) -C(O)NR8cR9c, (vi) -S(O)2C1-8alkyl, (vii) -C1-8alkyl unsubstituted or substituted with 1 to 8 substituents independently selected at each occurrence from -OH and halo, (viii) -O-(C1-8alkyl) unsubstituted or substituted with 1 to 8 substituents independently selected at each occurrence from -OH and halo, and (ix) -C3-6cycloalkyl unsubstituted or substituted with 2 to 5 substituents independently selected at each occurrence from -OH and halo; and R8a, R8b, R8c, R9a, R9b and R9c are each independently selected at each occurence from -H and - C1-8alkyl unsubstituted or substituted with 1 to 8 substituents independently selected at each occurrence from -OH and halo. 11. The compound of claim 1 or 10, or a pharmaceutically acceptable salt thereof wherein, R1 is O or S; R2 is -H or -C1-6alkyl unsubstituted or substituted with 1 to 13 of -F; R3 is halo or -C1-6alkyl; R4 is -H, -halo or C1-6alkyl; R5 is -H, -F or -Cl; R6 is -H , -F or -Cl; wherein the 6-membered ring of R7 is unsubstituted or substituted with one or more substituents up to the maximum number allowed by valence, independently selected at each occurrence from: (i) halo, (ii) -CN, (iii) -NR8aR9a, (iv) -S(O)2NR8bR9b,(v) -C(O)NR8cR9c, (vi) -S(O)2C1-6alkyl, (vii) -C1-6alkyl unsubstituted or substituted with 1 to 6 substituents independently selected at each occurrence from -OH and halo, and (viii) -O-(C1-6alkyl) unsubstituted or substituted with 1 to 6 substituents independently selected at each occurrence from -OH and halo; and R8a, R8b, R8c, R9a, R9b and R9c are each independently selected from -H or -C1-6alkyl unsubstituted or substituted with 1 to 6 substituents independently selected at each occurrence from -OH and halo. 12. The compound of claim 1 having Formula II or a pharmaceutically acceptable salt thereof. 13. The compound of claim 1, 10 or 12, or a pharmaceutically acceptable salt thereof, wherein R3 is halo or -C1-6alkyl. 14. The compound of claim 1, 10 or 12, or a pharmaceutically acceptable salt thereof, wherein R4 is is -H, halo or -C1-6alkyl. 15. The compound of claim 1, 10 or 12, or a pharmaceutically acceptable salt thereof, wherein R5 is -H, -F, -Cl or Br. 16. The compound of any one of claims 1, 10 or 12, or a pharmaceutically acceptable salt thereof, wherein R7 is selected from: Ra is -H, -C1-6alkyl or halo; Rb is -H, halo, -CN or -C1-6alkyl; Rc is (i) -H, (ii) -C1-6alkyl unsubstituted or substituted with -OH, (iii) -OC1-6alkyl unsubstituted or substituted with -OH; or (iv) -SO2NR8R9, (v) SO2-C1-3alkyl or (vi) -C(O)NR8R9; Rcn is -H or -C1-3alkyl; Rd is -H, -NR8R9 or -C1-6alkyl; Rdn is -H or -C1-3alkyl; and Re is -H, halo, -CN or -C(O)NR8R9. 17. The compound of claim 1 that is: or a pharmaceutically acceptable salt thereof. 18. A pharmaceutical composition comprising an effective amount of the compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 19. The pharmaceutical composition of claim 18 further comprising an effective amount of one or more additional nucleoside or nucleotide HIV reverse transcriptase inhibitors, nucleoside or nucleotide reverse transcriptase translocation inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV fusion inhibitors, HIV entry inhibitors, HIV maturation inhibitors, post-attachment inhibitors and latency reversing agents. 20. A method for the treatment or prophylaxis of infection by HIV, or for the treatment, prophylaxis or delay in the onset or progression of AIDS or ARC in a human subject in need thereof which comprises administering to the subject an effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof. 21. A method for eliciting GAG-POL dimerization in HIV-infected cells in a human subject in need thereof which comprises administering to the subject an effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof. 22. A method for selectively killing HIV infected GAG-POL expressing cells in a human subject which comprises administering to the subject an effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof. 23. A method for selectively killing HIV infected GAG-POL expressing cells without concomitant cytotoxicity to HIV naïve cells in a human subject which comprises administering to the human subject an effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof. 24. A method for augmenting the suppression of HIV viremia in a human subject whose viremia is being suppressed by administration of one or more compatible HIV antiviral agents, which comprises additionally administering to the subject an effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof. 25. The method of any one of claims 20 to 24 further comprising administering to the human subject an effective amount of one or more additional compatible HIV antiviral agents selected from nucleoside or nucleotide HIV reverse transcriptase inhibitors, nucleoside reverse transcriptase translocation inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV fusion inhibitors, HIV entry inhibitors, HIV maturation inhibitors, post- attachment inhibitors and latency reversing agents. 26. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, for use in a method for treatment or prophylaxis of infection by HIV, or for the treatment, prophylaxis or delay in the onset or progression of AIDS or ARC in a human subject. 27. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, for use in a method for eliciting GAG-POL dimerization in HIV-infected cells in a human subject. 28. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, for use in selectively killing HIV infected GAG-POL expressing cells in a human subject. 29. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, for use in selectively killing HIV infected GAG-POL expressing cells without concomitant cytotoxicity to HIV naïve cells in a human subject. 30. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, for use in augmenting the suppression of HIV viremia in a human subject whose viremia is being suppressed by administration of one or more compatible HIV antiviral agents. 31. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, for use in augmenting the suppression of HIV viremia in a human subject whose viremia is being suppressed by one or more compatible HIV antiviral agents. 32. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, for use in combination with one or more additional compatible HIV antiviral agent selected from nucleoside or nucleotide HIV reverse transcriptase inhibitors, nucleoside reverse transcriptase translocation inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV fusion inhibitors, HIV entry inhibitors, HIV maturation inhibitors, post- attachment inhibitors and latency reversing agents. 33. The compound according to any one of claims 1 to 17 for use in therapy. |
Scheme 2 depicts a method for preparing compounds of Formula I. Intermediate A is prepared with procedures illustrated in the Intermediate A section. Protection of the NH group followed by borylation provided the Bpin intermediate. Then, cross coupling Suzuki-Miyaura reaction using an appropriate 6-membered heterocyclic ring (Intermediate C) afforded the introduction of the C-ring. Alkylation with alkyl halides groups and deprotection provides compounds of Formula I. Synthesis of C is illustrated in the Intermediate C section. SCHEME 3 Scheme 3 depicts a method for preparing compounds of Formula I. Intermediate B is prepared with procedures illustrated in the Intermediate B section. An in situ Stille coupling or cross-electrophile mediated by Nickel using an appropriate 6-membered heterocyclic ring (Intermediate C) provides compounds of formula (4). Synthesis of C is illustrated in the Intermediate C section. Reactions sensitive to moisture or air were performed under nitrogen or argon using anhydrous solvents and reagents. Reactions performed using microwave irradiation were normally carried out using an Emrys Optimizer manufactured by Personal Chemistry, or an Initiator manufactured by Biotage. Concentration of solutions was carried out on a rotary evaporator under reduced pressure. The progress of reactions was determined by either analytical thin layer chromatography (TLC) usually performed with E. Merck pre-coated TLC plates, silica gel 60F-254, layer thickness 0.25 mm or analytical liquid chromatography-mass spectrometry (LC-MS). Typically, the analytical LC-MS system used consisted of a Waters ZQ ™ platform with electrospray ionization in positive ion detection mode with an Agilent 1100 series HPLC with autosampler. The column was commonly a Waters Xterra MS C18, 3.0 × 50 mm, 5 μm or a Waters Acquity UPLC ® BEH C181.0 x 50 mm, 1.7 μm. The flow rate was 1 mL/min, and the injection volume was 10 μL. UV detection was in the range 210–400 nm. The mobile phase consisted of solvent A (water plus 0.05% TFA) and solvent B (acetonitrile plus 0.05% TFA) with a gradient of 100% solvent A for 0.7 min changing to 100% solvent B over 3.75 min, maintained for 1.1 min, then reverting to 100% solvent A over 0.2 min. LC/MS determinations were carried out on a Waters Classing Aquity system equipped with TUV and MS detectors and a Waters SQD mass spectrometer, a Shimadzu 20 UV 254 and 220nM with Shimadzu 2010 or 2020 mass spectrometer, or an Agilent 1200 HPLC quipped with DAD/ELSD and G6110 MSD using one of the following conditions: 1) Ascentis Express C18 (3 x 50 mm) 2.7μm column using mobile phase containing A: 0.05% Trifluoroacetic acid in water and B: 0.05% Trifluoroacetic acid in acetonitrile with a gradient from 90:10 (A:B) to 5:95 (A:B) over 6 min at a flow rate of 1.8 mL/min, UV detection at 210 nm; 2) Aquity BEH C18, (1.0 x 50 mm) 1.7 μm column using mobile phase containing A: 0.05% Trifluoroacetic acid in water and B: 0.05% Trifluoroacetic acid in acetonitrile with a gradient from 90:10 (A:B) to 5:95 (A:B) over 2 min at a flow rate of 0.3 mL/min, UV detection at 215 nm; 3) Agilent YMC J'Sphere H-80 (3 x 50 mm) 5μm column using mobile phase containing A: 0.1% Trifluoroacetic acid in water and B: acetonitrile with a gradient from 95:5 (A:B) to 0:100 (A:B) over 3.6 min and 0:100 (A:B) for 0.4 min at a flow rate of 1.4 mL/min, UV detection at 254 and 220 nm and Agilent 1100 quadrupole mass spectrometer; 4) an Agilent TC-C18 (2.1 x 50 mm) 5μm column using mobile phase containing A: 0.0375% Trifluoroacetic acid in water and B: 0.01875% Trifluoroacetic acid in acetonitrile with a gradient from 90:10 (A:B) for 0.4 min to 90:10 to 0:100 (A:B) over 3 min and 10:90 (A:B) for 0.6 min at a flow rate of 0.8 mL/min, UV detection at 254 and 220 nm and Agilent 6110 quadrupole mass spectrometer. Preparative HPLC purifications were usually performed using either a mass spectrometry directed system or a non-mass guided system. Usually they were performed on a Waters Chromatography Workstation configured with LC-MS System consisting of: Waters ZQ ™ single quad MS system with Electrospray Ionization, Waters 2525 Gradient Pump, Waters 2767 Injecto /Collector, Waters 996 PDA Detector, the MS Conditions of: 150-750 amu, Positive Electrospray, Collection Triggered by MS, and a Waters SUNFIRE ® C-185 micron, 30 mm (id) x 100 mm column. The mobile phases consisted of mixtures of acetonitrile (10-100%) in water containing 0.1% TFA. Flow rates were maintained at 50 mL/min, the injection volume was 1800 μL, and the UV detection range was 210–400 nm. An alternate preparative HPLC system used was a Gilson Workstation consisting of: Gilson GX-281 Injector/Collector, Gilson UV/VIS-155 Detector, Gilson 333 and 334 Pumps, and equipped with a column selected from the following: Phenomenexd Synergi C18 (150mm x 30mm x 4 micron), YMC-Actus Pro C18 (150mm x 30mm x 5 micron), Xtimate C18 (150mm x 25mm x 5 micron), Boston Green ODS (150mm x 30mm x 5 micron), XSELECT C18 (150mm x 30mm x 5 micron), and Waters XSELECT C18 (150mm x 30mm x 5 micron). Conditions included either high pH (0-100% acetonitrile/water eluent comprising 0.1% v/v 10mM NH 4 HCO 3 or 0.05% NH 4 OH) or low pH (0-95% acetonitrile/water eluent comprising 0.1% v/v TFA). The injection volume ranged from 1000-8000 μL, and the UV detection range was 210– 400 nm. Mobile phase gradients were optimized for the individual compounds. Flash chromatography was usually performed using either a Biotage ® Flash Chromatography apparatus (Dyax Corp.), an ISCO CombiFlash® Rf apparatus, or an ISCO CombiFlash® Companion XL on silica gel (32-63 µm, 60 Å pore size) in pre-packed cartridges of the size noted. SFC chiral resolution was carried out on a Sepiate Prep SFC 100, Multigram II (MG II) , THAR80 prep SFC, or a Waters SFC (80, 200, or 350). Chiral preparative chromatography was conducted on one of of CHIRALPAK AS, of CHIRALPAK AD, CHIRALCEL ® OD, CHIRALCEL ® IA, CHIRALCEL ® OJ columns (20x250 mm) (Daicel Chemical Industries, Ltd.) or WHELK-O ® 1 (Regis Technologies, Inc.) with desired isocratic solvent systems identified on chiral analytical chromatography or by supercritical fluid (SFC) conditions. Proton or 1 H NMR was acquired using a Varian Unity-Inova 400 MHz NMR spectrometer equipped with a Varian 400 ATB PFG 5mm, Nalorac DBG 400-5 or a Nalorac IDG 400-5 probe, a Varian-400MHz MR spectrometer equipped with an Auto X ID PFG Probe 5mm, a Varian 400MHz VNMRS spectrometer equipped with a PFG 4Nuc Probe 5 mm, or a Bruker Avance III 500MHz spectrometer equipped with a PABBO Probe 5 mm in accordance with standard analytical techniques, unless specified otherwise, and results of spectral analysis are reported. 1 H NMR spectra were acquired in CDCl 3 solutions unless otherwise noted. Chemical shifts were reported in parts per million (ppm). Tetramethylsilane (TMS) was used as internal reference in CD 3 Cl solutions, residual CH 3 OH peak or TMS was used as internal reference in CD 3 OD solutions, and TMS was used as internal reference in DMSO-d6 solutions. Coupling constants (J) were reported in hertz (Hz). It is understood that a chiral center in a compound may exist in the "S" or "R" stereo- configuration, or as a mixture of both. Within a molecule, each bond drawn as a straight line from a chiral center encompasses each of the (R) and (S) stereoisomers as well as mixtures thereof unless otherwise noted. Final products in the Examples herein have the “S” stereoconfiguration at the chiral center noted with an asterisk* as shown below, except that in Examples 30 and 62, a last step stereoisomer separation afforded each of the S and R stereoisomers at the *chiral center. . The isomer mixture made in each of Examples 30 and 62 was separated in the last step, providing both an Isomer A (faster eluting isomer) and an Isomer B (slower eluting isomer), based on their observed elution order resulting from the separation as performed in the Example. Elution time and/or order of separated isomers may differ if performed under conditions different than those employed herein. “A” and “B” only refer to elution order resulting from the purification conditions as performed. An asterisk (*) may be used in the associated chemical structure drawings of the Example compounds to indicate a chiral center. A Intermediates Intermediate A01, Isomer A01-A and Isomer A01-B: (S)-7-bromo-4-(cyclopropylethynyl)-1-(4- methoxybenzyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1 H)-one AND (R)-7-bromo-4- (cyclopropylethynyl)-1-(4-methoxybenzyl)-4-(trifluoromethyl) -3,4-dihydroquinazolin-2(1H)-one Step 1: 1-(4-bromo-2-fluorophenyl)-2,2,2-trifluoroethanol: A solution of 4-bromo-2- fluorobenzaldehyde (40 g, 197 mmol) and trimethyl(trifluoromethyl)silane (30.8 g, 217 mmol) in THF (240 mL) was added TBAF (3.94 ml, 3.94 mmol) at 0 °C. The mixture was stirred for 3 h at 20 °C. Additional TBAF (39.4 ml, 39.4 mmol) was added. The mixture was stirred for 10 min. HCl (1M, 180 mL) was added and the mixture was stirred for 0.5 h. The mixture was diluted with H 2 O (600 mL) and extracted with EtOAc (400 mL x 2) and washed with brine and dried over Na 2 SO 4 , filtered and concentrated to give the title compound, which was used without further purification. Step 2: 1-(4-bromo-2-fluorophenyl)-2,2,2-trifluoroethanone: A mixture of 1-(4-bromo-2- fluorophenyl)-2,2,2-trifluoroethanol (51.7 g, 189 mmol) and DMP (161 g, 379 mmol) and NaHCO3 (47.7 g, 568 mmol) in DCM (510 mL) was stirred for 3 h at 20 °C. The mixture was washed with sat aq NaHCO3 sol (500 mL x 2), H2O (500 mL x 2) and brine (500 mL), and dried over Na 2 SO 4 , filtered and concentrated. The crude product was purified by flash chromatography (SiO 2 , 0-30% EtOAc/PE) to provide the title compound. Step 3: 1-(4-bromo-2-((4-methoxybenzyl)amino)phenyl)-2,2,2-trifluoro ethanone: A mixture of 1-(4- bromo-2-fluorophenyl)-2,2,2-trifluoroethanone (33 g, 122 mmol) and (4- methoxyphenyl)methanamine (33.4 g, 244 mmol) in toluene (330 ml) was stirred at 120 °C for 2 h. The mixture was washed with 10% citric acid aq sol (330 mL x 2) and brine (330 mL) and dried over Na2SO4 and filtered and concentrated. The crude product was purified by flash chromatography (SiO2, 0-30% EtOAc/PE) to the title compound. Step 4: 7-bromo-4-hydroxy-1-(4-methoxybenzyl)-4-(trifluoromethyl)-3, 4-dihydroquinazolin-2(1H)- one: To a solution of 1-(4-bromo-2-((4-methoxybenzyl)amino)phenyl)-2,2,2-trifluoro ethanone (100 g, 258 mmol) in AcOH (500 mL) and H2O (50 mL) was added sodium cyanate (100 g, 1546 mmol). The mixture was stirred at 60 °C for 4 h. The mixture was diluted with H 2 O (500 mL) and filtered to give the crude product. The crude product was diluted with sat aq NaHCO 3 sol (500 mL) and extracted with EtOAc (300 mL x 3), and the combined organic phase was washed with brine (900 mL), dried over Na 2 SO 4 , filtered and concentrated to give the title compound, which was used directly without further purification. Step 5: 7-bromo-1-(4-methoxybenzyl)-4-(trifluoromethyl)quinazolin-2( 1H)-one: To a solution of 7- bromo-4-hydroxy-1-(4-methoxybenzyl)-4-(trifluoromethyl)-3,4- dihydroquinazolin-2(1H)-one (98 g, 227 mmol) in toluene (700 mL). The mixture was stirred at 130 °C for 16 h, and was then concentrated to give the title product, which was used directly without further purification. Step 6: (S)-7-bromo-4-(cyclopropylethynyl)-1-(4-methoxybenzyl)-4-(tr ifluoromethyl)-3,4- dihydroquinazolin-2(1H)-one AND (R)-7-bromo-4-(cyclopropylethynyl)-1-(4-methoxybenzyl)-4- (trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one: To a solution of ethynylcyclopropane (5.32 g, 80.46 mmol) in toluene (260 mL), LiHMDS (66.9 ml, 66.9 mmol) was added at -5 °C. The mixture was heated to 85 °C for 15 min and then cooled to -15 °C. A solution of 7-bromo-1-(4- methoxybenzyl)-4-(trifluoromethyl)quinazolin-2(1H)-one (6 g, 13.4 mmol) in THF (520 ml) was added, and the mixture was stirred for 12 h at 20 °C. The reaction mixture was poured into an aq NH4Cl sol (1200 mL), extracted with EtOAc (3 x 600 mL). The combined organic phase was washed with brine (1800 mL), filtered and concentrated. The crude was purified by flash chromatography (SiO2, 0-30% EtOAc/PE) to give the title compound. The racemic mixture was resolved by prep SFC (IC-H column, 40% MeOH (0.1%NH3H2O)/CO2, 66 mL/min, 100 bar, 40 ℃) to provide Isomer A01-A (faster eluting) and Isomer A01-B (slower eluting). MS (ESI) m/z 479, 481 [M+1] for both. Intermediate A02: 7-bromo-6-chloro-4-(cyclopropylethynyl)-1-(4-methoxybenzyl)- 4- (trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one Step 1: 1-(4-bromo-5-chloro-2-((4-methoxybenzyl)amino)phenyl)-2,2,2- trifluoroethanone: To a mixture of 1-(4-bromo-2-((4-methoxybenzyl)amino)phenyl)-2,2,2-trifluoro ethanone (44 g, 113 mmol) in DMF (440 mL) was added NCS (15.9 g, 119 mmol) and the mixture was stirred at 50 °C for 1.5 h. The reaction was quenched with H 2 O (1 L), and the mixture was extracted with EtOAc (3 x 400 mL). The combined organic layer was washed with brine (1.2 L), dried over anhydrous Na2SO4, filtered and concentrated to give the title product, which was used directly without further purification. Step 2: 7-bromo-6-chloro-4-hydroxy-1-(4-methoxybenzyl)-4-(trifluorom ethyl)-3,4- dihydroquinazolin-2(1H)-one: To a solution of 1-(4-bromo-5-chloro-2-((4- methoxybenzyl)amino)phenyl)-2,2,2-trifluoroethanone (47 g, 111 mmol) in AcOH (400 mL) and H 2 O (40 mL) was added sodium cyanate (50.6 g, 778 mmol). The mixture was stirred at 60 °C for 3 h. The reaction was quenched into sat aq NaHCO 3 sol (500 mL), and the mixture was extracted with EtOAc (3 x 300 mL). The organic layers were washed with brine (900 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated. The mixture was purified by flash chromatography (SiO 2 , 0-30% EtOAc/PE) to afford the title compound. Step 3: 7-bromo-6-chloro-1-(4-methoxybenzyl)-4-(trifluoromethyl)quin azolin-2(1H)-one To a solution of 7-bromo-6-chloro-4-hydroxy-1-(4-methoxybenzyl)-4-(trifluorom ethyl)-3,4- dihydroquinazolin-2(1H)-one (7g, 15.03 mmol) in toluene (4 mL). The mixture was stirred at 120 °C for 16 h. The reaction was concentrated to give the title compound, which was used directly without further purification. Step 4: 7-bromo-6-chloro-4-(cyclopropylethynyl)-1-(4-methoxybenzyl)- 4-(trifluoromethyl)-3,4- dihydroquinazolin-2(1H)-one: To a solution of ethynylcyclopropane (6.20 g, 94 mmol) in toluene (350 ml), LiHMDS (78 mL, 78 mmol) was added at -5 °C. The mixture was heated at 85 °C for 15 min and then cooled to -15 °C. A solution of 7-bromo-6-chloro-1-(4-methoxybenzyl)-4- (trifluoromethyl)quinazolin-2(1H)-one (7 g, 15.64 mmol) in THF (700 mL) was added, and the mixture was stirred for 16 h at 20 °C. The reaction mixture was poured into a sat aq NH4Cl sol (1200 mL), extracted with EtOAc (3 x 600 mL). The combined organic phase was washed with brine (1800 mL), filtered and concentrated. The crude product was purified by HPLC (SiO 2 , 10-50% EtOAc:PE) to give the title compound. Intermediate A03: 7-bromo-4-(cyclopropylethynyl)-4-(trifluoromethyl)-3,4-dihyd roquinazolin- 2(1H)-one To a solution of intermediate A01-Isomer A (20 g, 41.7 mmol) in MeCN (60 mL) and H2O (20 mL) was added CAN (114 g, 209 mmol). The reaction was stirred at 40 °C for 1 h. The reaction was dissolved in H 2 O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layer was washed with water, dried over Na2SO4, filtered and concentrated to give the title compound, which was used in the next step without further purification. MS (ESI) m/z 359, 361 [M+1]. Intermediate A04: Isomer A04-A and Isomer A04-B: (S)-7-bromo-6-fluoro-4- (cyclopropylethynyl)-4-(trifluoromethyl)-3,4-dihydroquinazol in-2(1H)-one AND (R)-7-bromo-6- fluoro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-3,4-dihydr oquinazolin-2(1H)-one Step 1: methyl 2-amino-4-bromo-5-fluorobenzoate: To a solution of methyl 4-bromo-5-fluoro-2- nitrobenzoate (25 g, 90 mmol) in EtOH (375 ml) was added iron (40.2 g, 719 mmol) and NH4Cl (4.81 g, 90 mmol) in H 2 O (125 ml). The reaction mixture stirred at 70 °C for 16 h. The reaction mixture was quenched with H2O (200 mL) and extracted with EtOAc (300 mL x 2). The combined organics were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to afford the title compound, which was used directly without further purification. Step 2: methyl 4-bromo-2-((tert-butoxycarbonyl)amino)-5-fluorobenzoate:To a solution of methyl 2-amino-4-bromo-5-fluorobenzoate (20 g, 81 mmol) was added di-tert-butyl dicarbonate (88 g, 403 mmol) and stirred at 120 °C for 16 h. The reaction mixture was concentrated and the resulting residue was diluted with PE and cooled to 0 °C. The resulting precipitate was filtered and the solid was washed with 20 mL of cold PE and then, dried under vacuum to afford the title compound. Step 3: tert-butyl (5-bromo-4-fluoro-2-(hydroxymethyl)phenyl)carbamate: To a stirred solution of methyl 4-bromo-2-((tert-butoxycarbonyl)amino)-5-fluorobenzoate (13 g, 37.3 mmol) in THF (130 mL) was added LiAlH 4 (1.417 g, 37.3 mmol) at 0 °C and the resulting mixture was stirred at 0 °C for 1 h. The mixture was quenched by adding water (2 mL) and then sat aq Na2SO4 sol and the resulting mixture was stirred for 10 min. The mixture was filtered and extracted with EtOAc (100 mL x 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by prep MPLC (SiO2, 1-20% EtOAc:PE) to give the title product. MS (ESI) m/z 320, 322 [M+1]. Step 4: tert-butyl (5-bromo-4-fluoro-2-formylphenyl)carbamate: To a solution of tert-butyl (5- bromo-4-fluoro-2-(hydroxymethyl)phenyl)carbamate (10 g, 31.2 mmol) in DCM (200 ml) was added DMP (26.5 g, 62.5 mmol) at 15 °C for 1 h. The mixture was diluted with DCM (100 mL), filtered and the organic phase was concentrated. The crude product was diluted with EtOAc (10 mL) and PE (200 mL), filtered and the organic phase was concentrated to give the title product. Step 5: tert-butyl (5-bromo-4-fluoro-2-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)c arbamate: A solution of tert-butyl (5-bromo-4-fluoro-2-formylphenyl)carbamate (10 g, 31.4 mmol) and trimethyl(trifluoromethyl)silane (13.41 g, 94 mmol) in THF (200 ml) was added TBAF (1.644 g, 6.29 mmol) at 0 °C. The mixture was stirred for 0.5 h at 20 °C. TBAF (8.22 g, 31.4 mmol) was added. The mixture was stirred at 20 °C for 0.5 h. HCl (1M, 20 mL) was added and the mixture was diluted with H 2 O (50 mL) and extracted with EtOAc (150 mL x 2) and washed with brine (50 mL x 2) and dried over Na 2 SO 4 and filtered and concentrated. The residue was purified on flash chromatography (SiO2, 5% EtOAc/PE) to give the title compound. Step 6: tert-butyl (5-bromo-4-fluoro-2-(2,2,2-trifluoroacetyl)phenyl)carbamate: To a solution of tert-butyl (5-bromo-4-fluoro-2-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)c arbamate (6 g, 15.46 mmol) in DCM (60 ml) was added DMP (13.11 g, 30.9 mmol) at 20 °C for 1 h. The mixture was diluted with DCM, filtered and concentrated. The crude product was treated with EtOAc (5 mL) and PE (50 mL), filtered and concentrated to give the title product. Step 7: 1-(2-amino-4-bromo-5-fluorophenyl)-2,2,2-trifluoroethanone: To a vial containing tert- butyl (5-bromo-4-fluoro-2-(2,2,2-trifluoroacetyl)phenyl)carbamate (5g, 12.95 mmol) was added a 4 M HCl solution in EtOAc (3 mL) and stirred for 1 h at 20 °C. The solvent was removed under reduced pressure to give the crude product, which was purified by flash chromatography (SiO 2 , 2% EtOAc/PE) to afford the title product. Step 8: 7-bromo-6-fluoro-4-hydroxy-4-(trifluoromethyl)-3,4-dihydroqu inazolin-2(1H)-one: To a solution of 1-(2-amino-4-bromo-5-fluorophenyl)-2,2,2-trifluoroethanone (3 g, 10.49 mmol) in THF (30 ml) was added 4-dimethylaminopyridine (1.281 g, 10.49 mmol) and (trimethylsilyl)isocyanate (3.14 g, 27.3 mmol). The mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3 x 25 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by flash chromatography (SiO2, 3-100% EtOAc:PE) to afford the title product. Step 9: 7-bromo-6-fluoro-4-(trifluoromethyl)quinazolin-2(1H)-one: To a stirred solution of 7-bromo- 6-fluoro-4-hydroxy-4-(trifluoromethyl)-3,4-dihydroquinazolin -2(1H)-one (1.8 g, 5.47 mmol) in toluene (20 mL) under N2 and the resulting mixture was stirred at 120 °C for 23 h. The organic layer was concentrated to give the title product, which was used for the next step without further purification. Step 10: (S)-7-bromo-4-(cyclopropylethynyl)-6-fluoro-4-(trifluorometh yl)-3,4-dihydroquinazolin- 2(1H)-one AND (R)-7-bromo-4-(cyclopropylethynyl)-6-fluoro-4-(trifluorometh yl)-3,4- dihydroquinazolin-2(1H)-one: To a solution of ethynylcyclopropane (2.168 g, 32.8 mmol) in toluene (6 mL), LiHMDS (27.3 ml, 27.3 mmol) was added at -5 °C. The mixture was heated at 85 °C for 35 min and then cooled to -5 °C. A solution of 7-bromo-6-fluoro-4-(trifluoromethyl)quinazolin- 2(1H)-one (1.7 g, 5.47 mmol) in THF (12 ml) was added, and the mixture was stirred for 2 h at 20 °C. The reaction was quenched with a 1 M aq citric acid sol (5 ml) and diluted with EtOAc (35 mL). The organic layer was separated and dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by flash chromatography (SiO2, 50% EtOAc/PE) to give the title product, which was resolved by prep SFC (Chiralpak AS-H, 40% MeOH (0.1%NH 3 H 2 O)/CO 2 ; 70 g/min; 40 °C; 100 bar) to provide: Isomer A04-A (faster eluting) and Isomer A04-B (slower eluting) MS (ESI) m/z 377, 379 [M+1] for both. Intermediate A05, Isomer A05-A and Isomer A05-B: (S)-7-bromo-4-(cyclopropylethynyl)-4-(1,1- difluoroethyl)-3,4-dihydroquinazolin-2(1H)-one AND (R)-7-bromo-4-(cyclopropylethynyl)-4-(1,1- difluoroethyl)-3,4-dihydroquinazolin-2(1H)-one Step 1: (2-bromo-6-fluorophenyl)trimethylsilane: To a solution of 1-bromo-3-fluorobenzene (50 g, 286 mmol) and TMSCl (73.0 ml, 571 mmol) in THF (450 mL) was added LDA (286 mL, 571 mmol) at -70 °C. The reaction was stirred at -70 °C for 2 h. The reaction was hydrolyzed with aq 1M H2SO4 sol. The yellow organic phase was separated, and the water phase was extracted with EtOAc. The combined organic phase was concentrated to give the title compound, which was used without further purification. Step 2: 1-(4-bromo-2-fluoro-3-(trimethylsilyl)phenyl)-2,2-difluoropr opan-1-one: To a solution of 2,2,6,6-tetramethylpiperidine (18.86 g, 134 mmol) in THF (125 mL) was added nBuLi (53.4 ml, 134 mmol) at -20 °C. After 30 min of stirring at -20 o C, the mixture was cooled to -70 o C, and a solution of (2-bromo-6-fluorophenyl)trimethylsilane (30 g, 121 mmol) in THF (35 mL) was added. After 1 h of stirring at -70 o C, ethyl 2,2-difluoropropanoate (18.44 g, 134 mmol) was added dropwise. The mixture was then allowed to warm to 20 °C and stirred at 20 °C for another 1 h. Then, sat aq NH 4 Cl sol (300 mL) was added, and the mixture was extracted with EtOAc (3 x 300 mL). The combined organic layer was washed with brine (300 mL), dried over Na2SO4, filtered and concentrated to give the title compound, which was used without further purification. Step 3: 1-(4-bromo-2-fluorophenyl)-2,2-difluoropropan-1-one: To a solution of 1-(4-bromo-2- fluoro-3-(trimethylsilyl)phenyl)-2,2-difluoropropan-1-one (45 g, 133 mmol) in THF (200 mL) was added TBAF (34.7 g, 133 mmol) at 20 °C. The reaction was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated and the resulting residue was purified by flash chromatography (SiO2, 0-5% EtOAc/PE) to afford the title compound. Step 4: 1-(4-bromo-2-((4-methoxybenzyl)amino)phenyl)-2,2-difluoropro pan-1-one: To a solution of 1-(4-bromo-2-fluorophenyl)-2,2-difluoropropan-1-one (20 g, 74.9 mmol) in toluene (200 mL) were added (4-methoxyphenyl)methanamine (20.55 g, 150 mmol) and K2CO3 (12.42 g, 90 mmol). The reaction was stirred at 115 °C for 2 h. The reaction was concentrated and the residue was purified by flash chromatography (SiO 2 , 0-5% EtOAc/PE) to give the title product. Step 5: 7-bromo-4-(1,1-difluoroethyl)-4-hydroxy-1-(4-methoxybenzyl)- 3,4-dihydroquinazolin- 2(1H)-one: To a solution of 1-(4-bromo-2-((4-methoxybenzyl)amino)phenyl)-2,2- difluoropropan-1-one (20 g, 52.1 mmol) in AcOH (400 mL) was added sodium cyanate (33.8 g, 521 mmol). The reaction was stirred at 110 °C for 16 h. The reaction was adjusted to pH=8 with sat aq NaHCO3 sol and extracted with EtOAc (3 x 500 mL). The organic layer was washed with brine (500 mL), dried over Na 2 SO 4 , filtered and concentrated. The crude product was purified by flash chromatography (SiO2, 0-25% EtOAc/PE) to give the title compound. Step 6: 7-bromo-4-(1,1-difluoroethyl)-1-(4-methoxybenzyl)quinazolin- 2(1H)-one: To a solution of 7-bromo-4-(1,1-difluoroethyl)-4-hydroxy-1-(4-methoxybenzyl)- 3,4-dihydroquinazolin-2(1H)- one (10 g, 23.41 mmol) in MeCN (200 mL) was added phosphorus pentoxide (3.99 g, 28.1 mmol). The reaction was stirred at 90 °C under N2 for 3 h. The reaction was adjusted with sat aq NaHCO3 sol to pH=8 and extracted with EtOAc (3 x 500 mL). The organic layer was washed with brine (500 mL), dried over Na 2 SO 4 , filtered and concentrated to give the title product, which was used in the next step without further purification. Step 7: 7-bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-1-(4-me thoxybenzyl)-3,4- dihydroquinazolin-2(1H)-one: To a solution of ethynylcyclopropane (4.36 g, 66.0 mmol) in toluene (50 mL) was added LiHMDS (55.0 mL, 55.0 mmol) at 0 °C. The reaction was stirred at 85 °C for 15 min. Then, a solution of 7-bromo-4-(1,1-difluoroethyl)-1-(4-methoxybenzyl) quinazolin-2(1H)- one (9 g, 11.00 mmol) in THF (50.0 mL) was added to the reaction at 0 °C. The reaction was stirred at 15 °C for 0.5 h. The reaction was quenched with sat aq NH 4 Cl sol (100 mL). The residue was extracted with EtOAc (3 x 100 mL). The organic layer was washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated. The crude product was purified by flash chromatography (SiO2, 0-25% EtOAc/PE) to afford the title compound. Step 8: (S)-7-bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-3,4 -dihydroquinazolin-2(1H)-one AND (R)-7-bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-3,4 -dihydroquinazolin-2(1H)-one: To a mixture of 7-bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-1-(4-me thoxybenzyl)-3,4- dihydroquinazolin-2(1H)-one (3 g, 6.31 mmol) in MeCN (40 mL) and water (15 mL) was added CAN (17.30 g, 31.6 mmol). The reaction was stirred at 15 °C for 2 h. The reaction was extracted with EtOAc (3 x 50 mL). The organic layer was washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated. The crude product was purified by flash chromatography (SiO 2 , 0-25% EtOAc/PE) to give the title product. The racemic mixture was resolved by prep SFC (DAICEL CHIRALPAK AD, 45% MeOH (0.1%NH 3 H 2 O)/CO 2 , 65 mL/min, 40 °C, 100 bar) to afford: Isomer A05-A (faster eluting) and Isomer A05-B (slower eluting) MS (ESI) m/z 355, 357 [M+1] for both. Intermediate A06: 7-bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluor o-3,4- dihydroquinazolin-2(1H)-one Step 1: 5-bromo-4-fluoro-2-iodoaniline: To a solution of 3-bromo-4-fluoroaniline (100 g, 526 mmol) in AcOH (1 L) was added NIS (101 g, 447 mmol) at 25 °C. The mixture was stirred for 16 h at 25 °C. The reaction mixture was concentrated and the resulting crude was then dissolved in water (100 mL) and extracted with EtOAc (350 mLx2). The combined organic layer was washed with H 2 O (150 mLx2), sat aq NaHCO 3 sol (250 mL) and brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated. The resulting crude was purified by flash chromatography (SiO2, 0-2% EtOAc/PE) to give the title compound. Step 2: tert-butyl (5-bromo-4-fluoro-2-iodophenyl)carbamate: To a stirred solution of 5-bromo-4- fluoro-2-iodoaniline (60 g, 190 mmol) in DCM (80 mL) was added DMAP (1.160 g, 9.50 mmol). Then, Et3N (2.65 ml, 18.99 mmol) and di-tert-butyl dicarbonate (62.2 g, 285 mmol) were added. The mixture was stirred at 25 °C for 4 h. The reaction mixture was diluted with DCM (500 mL), washed with water (100 mL x 2), brine (50 mL), dried over Na2SO4, filtered and concentrated to give the title compound, which was used without further purification. Step 3: tert-butyl (5-bromo-2-(2,2-difluoropropanoyl)-4-fluorophenyl)carbamate: To a mixture of tert-butyl (5-bromo-4-fluoro-2-iodophenyl)carbamate (20 g, 33.7 mmol) and ethyl 2,2- difluoropropanoate (12.65 mL, 101 mmol) in THF (250 mL) was added dropwise isopropylmagnesium chloride-lithium chloride complex (64.7 mL, 84 mmol) at -70 °C over 30 min. The reaction mixture was stirred at -70 °C for 1 h. The mixture was quenched with sat aq NH 4 Cl sol (45 mL) and water (45 mL), and then extracted with EtOAc (80 mLx2). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated to give the title compound, which was used without further purification. Step 4: 1-(2-amino-4-bromo-5-fluorophenyl)-2,2-difluoropropan-1-one: A mixture of tert-butyl (5- bromo-2-(2,2-difluoropropanoyl)-4-fluorophenyl)carbamate (45 g, 118 mmol) in a solution of HCl in EtOAc (4 M, 200 mL) at 25 °C was stirred for 1 h. The formed precipitate was treated with EtOAc (400 mL) and concentrated to give the title compound. Step 5: 7-bromo-4-(1,1-difluoroethyl)-6-fluoro-4-hydroxy-3,4-dihydro quinazolin-2(1H)-one: To a solution of 1-(2-amino-4-bromo-5-fluorophenyl)-2,2-difluoropropan-1-one (6.7 g, 23.75 mmol) in THF (67 mL) was added DMAP (2.90 g, 23.75 mmol) and (trimethylsilyl)isocyanate (8.36 mL, 61.8 mmol). The resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with H 2 O (30 mL) and extracted into EtOAc (3x55 mL). The combined organic layer was dried over Na 2 SO 4 , filtered and concentrated. The crude was dissolved in THF (25 mL) and aq HCl (1M, 25 mL) and stirred at 25 °C for 2 h. The reaction mixture was concentrated and then purified by flash chromatography (SiO2; 30~80% EtOAc/PE) to give the title compound. Step 6: 7-bromo-4-(1,1-difluoroethyl)-6-fluoroquinazolin-2(1H)-one: A mixture of 7-bromo-4-(1,1- difluoroethyl)-6-fluoro-4-hydroxy-3,4-dihydroquinazolin-2(1H )-one (2 g, 6.15 mmol) in toluene (50 mL) was stirred under nitrogen at 140 °C for 16 h. The reaction mixture was concentrated to give the title product, which was used without further purification. Step 7: 7-bromo-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-6-fluor o-3,4-dihydroquinazolin- 2(1H)-one : To a solution of ethynylcyclopropane (3.31 mL, 39.1 mmol) in toluene (10 mL), LiHMDS (25.05 mL, 32.6 mmol) was added at -5 °C. The mixture was heated at 85 °C for 35 min and then cooled to -5 °C. A solution of 7-bromo-4-(1,1-difluoroethyl)-6-fluoroquinazolin-2(1H)- one (2 g, 6.51 mmol) in THF (20 mL) was added, and the mixture was stirred for 100 min at 25 °C. The reaction was quenched by the addition of sat aq NH4Cl sol (45 mL) and extracted with EtOAc (55 mLx2). The organic layers were combined and dried over Na 2 SO 4 , filtered, and concentrated to give the title compound, which was used without further purification. MS (ESI) m/z 373.0, 375.0 [M+1]. Intermediate A07: 7-bromo-6-chloro-4-(cyclopropylethynyl)-1-(4-methoxybenzyl)- 3-methyl-4- (trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one To a solution of intermediate A02 (500 mg, 0.973 mmol) in DMF (5 ml), NaH (97 mg, 2.433 mmol) and MeI (0.183 ml, 2.92 mmol) were sequentially added to the reaction solution at 15 °C. The resulting mixture was stirred at 50 °C for 2 h. The mixture was then diluted with H 2 O (50 mL), and then extracted with EtOAc (3 x 50 mL), washed with brine (3 x 50 mL), dried over Na2SO4, filtered, concentrated. The resulting residue was purified by flash chromatography (SiO2, 0-20% EtOAc/PE) to afford the title compound. MS (ESI) m/z 527, 529 [M+1]. B Intermediates Intermediate B01: (S)-4-(cyclopropylethynyl)-7-(4,4,5,5-tetramethyl-1,3,2-diox aborolan-2-yl)-4- (trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one A solution of intermediate A03, BisPin (255 mg, 1.002 mmol) and KOAc (246 mg, 2.506 mmol) in 1,4-dioxane (7 mL) was added Pd(PPh3)2Cl2 (29.3 mg, 0.042 mmol) under nitrogen, the mixture was stirred at 80 °C for 16 h under nitrogen. The mixture was diluted with water (30 mL) and EtOAc (30 mL), filtered and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (SiO2, 30% EtOAc/PE) to afford the title compound. MS (ESI) m/z 407 [M+1]. Intermediate B02 was prepared using a procedure analogous to that used for making Intermediate B01 except that Intermediate A03 was replaced by Intermediate A04-Isomer A. Intermediate B03: (S)-7-(chloromethyl)-4-(cyclopropylethynyl)-4-(trifluorometh yl)-3,4- dihydroquinazolin-2(1H)-one Step 1: (S)-4-(cyclopropylethynyl)-4-(trifluoromethyl)-7-vinyl-3,4-d ihydroquinazolin-2(1H)-one: A solution of intermediate A03 (6 g, 16.71 mmol) in 1,4-dioxane (120 mL) and water (12 mL) was added potassium trifluoro(vinyl)borate (3.36 g, 25.06 mmol), K2CO3 (6.93 g, 50.1 mmol), PdCl 2 (dppf) (1.222 g, 1.671 mmol) under N 2 and the resulting mixture was stirred for 1 h at 100 °C under N 2 . The reaction was cooled and then poured into H 2 O (500 mL), extracted with EtOAc (3 x 200 mL). The combined organic layer was filtered, concentrated, and purified by flash chromatography (SiO 2 , 0-30% EtOAc/PE) to afford the title compound. Step 2: (S)-4-(cyclopropylethynyl)-2-oxo-4-(trifluoromethyl)-1,2,3,4 -tetrahydroquinazoline-7- carbaldehyde: To a stirred solution of (S)-4-(cyclopropylethynyl)-4-(trifluoromethyl)-7-vinyl-3,4- dihydroquinazolin-2(1H)-one (5.49 g, 17.92 mmol) in 1,4-dioxane (100 mL) and H2O (50 mL) was added 2,6-lutidine (3.84 g, 35.8 mmol), potassium osmate(VI) dihydrate (1.321 g, 3.58 mmol). The resulting mixture was stirred for 10 min, then sodium periodate (11.50 g, 53.8 mmol) was added and the resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with H2O (500 mL) and extracted with EtOAc (3 x 300 mL). The combined organics were washed with brine (90 mL), dried over Na2SO4, filtered and concentrated, and then, purified by flash chromatography (SiO2, 0-30% EtOAc/PE) to afford the title compound. Step 3: (S)-4-(cyclopropylethynyl)-7-(hydroxymethyl)-4-(trifluoromet hyl)-3,4-dihydroquinazolin- 2(1H)-one: To a solution of (S)-4-(cyclopropylethynyl)-2-oxo-4-(trifluoromethyl)-1,2,3,4 - tetrahydroquinazoline-7-carbaldehyde (4.6 g, 14.92 mmol) in MeOH (50 mL) was added NaBH4 (0.226 g, 5.97 mmol) at 25°C under N 2 and the mixture was stirred at this temperature for 10 min. Water (250 mL) was added to the mixture and then extracted with EtOAc (3 x 150 mL). The combined organic phase was washed with brine (450 mL) and dried over Na2SO4, filtered and concentrated. The crude product was purified prep-HPLC (water: MeCN with 0.1%TFA) to give the title compound. Intermediate B04, B04-Isomer A and B04-Isomer B (S)-6-chloro-4-(cyclopropylethynyl)-7-(hydroxymethyl)-1-(4-m ethoxybenzyl)-4-(trifluoromethyl)- 3,4-dihydroquinazolin-2(1H)-one AND (R)-6-chloro-4-(cyclopropylethynyl)-7-(hydroxymethyl)-1- (4-methoxybenzyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin- 2(1H)-one Step 1: 6-chloro-4-(cyclopropylethynyl)-1-(4-methoxybenzyl)-4-(trifl uoromethyl)-7-vinyl-3,4- dihydroquinazolin-2(1H)-one: To a solution of Intermediate A02 (14 g, 27.3 mmol) and potassium trifluoro(vinyl)borate (5.48 g, 40.9 mmol) in 1,4-dioxane (140 ml) and water (14 mL) was added K 2 CO 3 (11.30 g, 82 mmol) and PdCl 2 (dppf) (1.994 g, 2.73 mmol), then the reaction mixture was stirred at 100 °C for 3 h under N2. The reaction was concentrated and purified by flash chromatography (SiO 2 ; 0-20% EtOAc/PE) to give the title compound. Step 2: 6-chloro-4-(cyclopropylethynyl)-7-(hydroxymethyl)-1-(4-metho xybenzyl)-4- (trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one: A solution of 6-chloro-4- (cyclopropylethynyl)-1-(4-methoxybenzyl)-4-(trifluoromethyl) -7-vinyl-3,4-dihydroquinazolin- 2(1H)-one (8.2 g, 17.79 mmol) in MeOH (30 mL) and DCM (150 ml) was bubbled with ozone (0.854 g, 17.79 mmol) for 0.5 h at -60 °C. NaBH(OAc)3 (22.63 g, 107 mmol) was added and the reaction mixture was stirred for 0.5 h at 20 o C. The reaction was dissolved in water (100 mL) and extracted with DCM (100 mL x 3). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to give the title product, which was used directly for the next step without purification. Step 3: (S)-6-chloro-4-(cyclopropylethynyl)-7-(hydroxymethyl)-4-(tri fluoromethyl)-3,4- dihydroquinazolin-2(1H)-one AND (R)-6-chloro-4-(cyclopropylethynyl)-7-(hydroxymethyl)-4- (trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one: To a solution of 6-chloro-4- (cyclopropylethynyl)-7-(hydroxymethyl)-1-(4-methoxybenzyl)-4 -(trifluoromethyl)-3,4- dihydroquinazolin-2(1H)-one (8.5 g, 18.28 mmol) in MeCN (200 ml) and H2O (70 ml) was added CAN (50.1 g, 91 mmol). The mixture was stirred for 16 h at 20 °C. The reaction was dissolved in H 2 O (100 mL) and extracted with EtOAc (150 mL x 3). The combined organic layer was washed with brine (200 mL), dried over Na 2 SO 4 , filtered and concentrated. The crude product was purified by prep-HPLC (water/MeCN with 0.1%TFA) to give the title compound, which was resolved by SFC (Chiralpak AD, 30% EtOH/CO 2 , 200 g/min, 40 ℃, 100 bar) to give: Isomer B04-A (faster eluting): 1 H-NMR (400 MHz, MeOH-d 4 ) δ ppm 7.44 (s, 1H), 7.14 (s, 1H), 4.71-4.60 (m, 2H), 1.53- 1.38 (m, 1H), 1.00-0.85 (m, 2H), 0.83-0.70 (m, 2H).; and Isomer B04-B (slower eluting): 1 H-NMR (400 MHz, MeOH-d4) δ ppm 7.44 (s, 1H), 7.14 (s, 1H), 4.71-4.62 (m, 2H), 1.45 (tt, J = 8.3, 4.9 Hz, 1H), 0.99-0.85 (m, 2H), 0.82-0.69 (m, 2H). The following intermediates were prepared using a procedure analogous to that used for making B04 using the noted starting intermediate in place of A02.
Intermediate B07: 6-chloro-4-(cyclopropylethynyl)-7-(hydroxymethyl)-3-methyl-4 - (trifluoromethyl)-3,4-dihydroquinazolin-2( -one Step 1: 6-chloro-4-(cyclopropylethynyl)-1-(4-methoxybenzyl)-3-methyl -4-(trifluoromethyl)-7-vinyl- 3,4-dihydroquinazolin-2 -one: To a solution of intermediate A07 (0.5 g, 1.23 mmol) in 1,4- dioxane (6 mL) and water (1.25 mL) were added CH 2 CHBF 3 K (0.25 g, 1.84 mmol), PdCl 2 (dppf) (90 mg, 0.123 mmol) and K2CO3 (0.51 g, 3.68 mmol). The reaction was stirred at 100 °C for 3 h under N 2 . Then, the reaction mixture was cooled and poured into water (15 mL), extracted with EtOAc (50 mL x 2). The combined organic phase was washed with brine (15 mL) and concentrated. The resulting residue was purified on flash chromatography (SiO2, 5-20% EtOAc/PE) to give the title compound. Step 2: 6-chloro-4-(cyclopropylethynyl)-1-(4-methoxybenzyl)-3-methyl -2-oxo-4-(trifluoromethyl)- 1,2,3,4-tetrahydroquinazoline-7-carbaldehyde: To a stirred solution of 6-chloro-4- (cyclopropylethynyl)-1-(4-methoxybenzyl)-3-methyl-4-(trifluo romethyl)-7-vinyl-3,4- dihydroquinazolin-2(1H)-one (350 mg, 0.737 mmol) in 1,4-dioxane (6 ml) and water (2 mL) was added 2,6-lutidine (158 mg, 1.47 mmol), potassium osmate (VI) dihydrate (54.3 mg, 0.15 mmol) and, then, sodium periodate (473 mg, 2.21 mmol). The resulting mixture was stirred for 10 min at 0 °C and the resulting mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated and diluted with EtOAc (20 mL), washed with water (10 mL), brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated to give the title compound, which was used directly. Step 3: 6-chloro-4-(cyclopropylethynyl)-7-(hydroxymethyl)-1-(4-metho xybenzyl)-3-methyl-4- (trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one: To a solution of 6-chloro-4- (cyclopropylethynyl)-1-(4-methoxybenzyl)-3-methyl-2-oxo-4-(t rifluoromethyl)-1,2,3,4- tetrahydroquinazoline-7-carbaldehyde (350 mg, 0.37 mmol) in MeOH (2 mL), NaBH4 (13.9 mg, 0.38 mmol) was added at 15 °C and stirred for 20 min. The reaction mixture was diluted with water (25 mL), and then extracted with EtOAc (35 mL x 2), washed with brine (15 mL), dried over Na2SO4, filtered and concentrated to give the title compound, which was used directly. Step 4: 6-chloro-4-(cyclopropylethynyl)-7-(hydroxymethyl)-3-methyl-4 -(trifluoromethyl)-3,4- dihydroquinazolin-2 -one: To a solution of 6-chloro-4-(cyclopropylethynyl)-7- (hydroxymethyl)-1-(4-methoxybenzyl)-3-methyl-4-(trifluoromet hyl)-3,4-dihydroquinazolin- 2(1H)-one (100 mg, 0.21 mmol) in MeCN (1.5 mL) and water (0.5 mL) was added CAN (572 mg, 1.04 mmol). The reaction was stirred at 20 °C for 20 h. The reaction mixture was diluted with water (5 mL), and then extracted with EtOAc (5 mL x 2), washed with brine (5 mL),dried over Na 2 SO 4 , filtered and concentrated. The resulting residue was purified by prep-TLC (SiO2, 50% EtOAc:PE) to afford the title compound. MS (ESI) m/z 359.1 [M+H]. Intermediate B08: (S)-7-(chloromethyl)-4-(cyclopropylethynyl)-4-(trifluorometh yl)-3,4- dihydroquinazolin-2(1H)-one To a solution of intermediate B03 (300 mg, 0.967 mmol) in anhydrous DCM (3 ml) was added DIPEA (1.013 ml, 5.80 mmol) and MsCl (0.151 ml, 1.934 mmol). The reaction was stirred at 20 °C for 16 h. The reaction was diluted with water (20 ml) and extracted with DCM (3 x 20 ml). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The crude product was purified by prep-TLC (SiO2, 50% EtOAc/PE) to afford the title compound. The following intermediates were prepared using a procedure analogous to that used for making B08 using the noted starting intermediate in place of B03. Intermediate B13: (S)-7-(chloromethyl)-4-(cyclopropylethynyl)-6,8-difluoro-4-( trifluoromethyl)- 3,4-dihydroquinazolin-2(1H)-one Step 1: (S)-4-(cyclopropylethynyl)-6,8-difluoro-7-(hydroxymethyl)-4- (trifluoromethyl)-3,4- dihydroquinazolin-2(1H)-one: To a solution of intermediate B05 (20 mg, 0.061 mmol) in anhydrous MeCN (0.6 ml) was added 1-fluoro-4-methyl-1,4-diazabicyclo[2.2.2]octane-1,4-diium tetrafluoroborate (19.49 mg, 0.061 mmol). The resulting mixture was stirred at 50 °C for 16 h. The reaction was then purified by HPLC (water/MeCN with 0.1% TFA) to give the title product. Step 2: (S)-7-(chloromethyl)-4-(cyclopropylethynyl)-6,8-difluoro-4-( trifluoromethyl)-3,4- dihydroquinazolin-2(1H)-one: To a solution of (S)-4-(cyclopropylethynyl)-6,8-difluoro-7- (hydroxymethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2( 1H)-one (10 mg, 0.061 mmol) in anhydrous DCM (0.5 ml) was added thionyl chloride (500 ^L, 6.85 mmol). The resulting mixture was stirred at 40 °C for 16 h. The reaction was concentrated to give the title compound, which was used without further purification. MS (ESI) m/z 364 [M+1]. Intermediate B14 was prepared using a procedure analogous to that used for making B03 except that Intermediate A03 was replaced by Intermediate A06. The racemic B14 product was separated by SFC (Chiralpak AD; 42% iPrOH(0.1%NH 3 H 2 O)/CO; 72 mL/min; 40 ℃;100 bar) to give: Isomer A (faster eluting) and Isomer B (slower eluting): MS (ESI) m/z 325.1 [M+1] for both. Intermediate B15: (S)-7-(chloromethyl)-4-(cyclopropylethynyl)-4-(1,1-difluoroe thyl)-6-fluoro-3,4- dihydroquinazolin-2(1H)-one Intermediate B15 was prepared using a procedure analogous to Intermediate B08 except that Intermediate B03 was replaced by Intermediate B14. MS (ESI) m/z 343 [M+1]. Intermediate B16: (S)-7-(chloromethyl)-4-(cyclopropylethynyl)-6-methyl-4-(trif luoromethyl)-3,4- dihydroquinazolin-2(1H)-one Step 1: (S)-6-bromo-4-(cyclopropylethynyl)-7-(hydroxymethyl)-4-(trif luoromethyl)-3,4- dihydroquinazolin-2(1H)-one: Intermediate B03 (2056 mg, 6.63 mmol) was dissolved in DMF (64 mL) and NBS (1179 mg, 6.63 mmol) was added and stirred at 25 °C for 16 h. The reaction mixture was diluted with sat aq NaHCO 3 sol (200 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated, and then, purified by MPLC (SiO2, 40-50% EtOAc/PE) to give the title compound. Step 2: (S)-4-(cyclopropylethynyl)-7-(hydroxymethyl)-6-methyl-4-(tri fluoromethyl)-3,4- dihydroquinazolin-2(1H)-one: To a mixture of (S)-6-bromo-4-(cyclopropylethynyl)-7- (hydroxymethyl)-4-(trifluoromethyl)-3,4-dihydro quinazolin-2(1H)-one (500 mg, 1.285 mmol), trimethylboroxine (0.539 ml, 3.85 mmol) and Cs 2 CO 3 (837 mg, 2.57 mmol) in 1,4-dioxane (25 mL) and water (2.5 mL) was added PdCl 2 (dppf) (94 mg, 0.128 mmol) under N 2 . The mixture was stirred at 80 °C for 3 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (30 mLx2). The combined organic layer was washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated. The resulting residue was purified by prep-HPLC (MeCN:water with 0.1% TFA) to give the title compound. Step 3: (S)-7-(chloromethyl)-4-(cyclopropylethynyl)-6-methyl-4-(trif luoromethyl)-3,4- dihydroquinazolin-2(1H)-one: To a mixture of (S)-4-(cyclopropylethynyl)-7-(hydroxymethyl)-6- methyl-4-(trifluoromethyl) -3,4-dihydroquinazolin-2(1H)-one (80 mg, 0.247 mmol), DIPEA (0.172 ml, 0.987 mmol) in DCM (10 mL) was added MsCl (0.029 mL, 0.371 mmol) under N 2 . The mixture was stirred at 25 °C for 16 h. The reaction was diluted with water (20 mL) and extracted with DCM (10 mLx2). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated. The resulting crude was purified by prep-TLC (SiO 2 , 50% EtOAc/PE) to give the title compound. Intermediate B17: (S)-7-(chloromethyl)-4-(cyclopropylethynyl)-3-methyl-4-(trif luoromethyl)-3,4- dihydroquinazolin-2(1H)-one Step 1: (S)-7-bromo-4-(cyclopropylethynyl)-1-(4-methoxybenzyl)-3-met hyl-4-(trifluoromethyl)-3,4- dihydroquinazolin-2(1H)-one: A solution of intermediate A01-Isomer A (1.05 g, 2.191 mmol) in anhydrous 1,4-dioxane (21.91 ml), was treated with NaH (0.175 g, 4.38 mmol). Then, CH3I (0.411 ml, 6.57 mmol) was added and stirred at 25 ^C. The mixture was quenched with sat aq NH4Cl sol, extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered and concentrated. The resulting residue was purified by flash chromatography (SiO 2 , 0-100% EtOAc:hexanes) to provide the title compound. Step 2: (S)-4-(cyclopropylethynyl)-1-(4-methoxybenzyl)-7-(((4-methox ybenzyl)oxy)methyl)-3- methyl-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one: A mixture of (S)-7-bromo-4- (cyclopropylethynyl)-1-(4-methoxybenzyl)-3-methyl-4-(trifluo romethyl)-3,4- dihydroquinazolin-2(1H)-one (500 mg, 1.014 mmol), potassium (4- methoxy)benzyloxymethyltrifluoroborate (575 mg, 2.230 mmol) and PdCl2(dppf) (83 mg, 0.101 mmol) in anhydrous 1,4-dioxane (10 mL), was treated with a 3 M Cs2CO3 aq sol (2027 µl, 6.08 mmol). The resulting mixture was irradiated at 150 °C in microwave oven for 30 min. The mixture was quenched with sat aq NH 4 Cl sol, extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified with flash chromatography (SiO2, 0-100% EtOAc/hexanes) to give the title compound. Step 3: (S)-4-(cyclopropylethynyl)-7-(hydroxymethyl)-1-(4-methoxyben zyl)-3-methyl-4- (trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one: A solution of (S)-4-(cyclopropylethynyl)-1-(4- methoxybenzyl)-7-(((4-methoxybenzyl)oxy)methyl)-3-methyl-4-( trifluoromethyl)-3,4- dihydroquinazolin-2(1H)-one (250 mg, 0.443 mmol) in DCM (8.8 mL) was treated with TFA (341 µl, 4.43 mmol), and stirred at 25 ^C for 30 min. The mixture was carefully quenched with sat aq NaHCO 3 sol, extracted with DCM. The organic layer was concentrated and the residue was purified with flash chromatography (SiO2, 0-100%, EtOAc/hexanes) to give the title compound. MS (ESI) m/z 445 [M+1]. Step 4: (S)-4-(cyclopropylethynyl)-7-(hydroxymethyl)-3-methyl-4-(tri fluoromethyl)-3,4- dihydroquinazolin-2(1H)-one: To a solution of (S)-4-(cyclopropylethynyl)-7-(hydroxymethyl)-1- (4-methoxybenzyl)-3-methyl-4-(trifluoromethyl)-3,4-dihydroqu inazolin-2(1H)-one (208 mg, 0.468 mmol) in MeCN (4 ml)/water(1 ml) was added CAN (1.03 g, 1.87 mmol). The reaction mixture was stirred at 25 ^C for 3 h. The mixture was diluted with EtOAc and washed with water. The organic layer was dried, concentrated, and purified by flash column (SiO 2 , 0-10% DCM/MeOH) to give the title compound. Step 5: (S)-7-(chloromethyl)-4-(cyclopropylethynyl)-3-methyl-4-(trif luoromethyl)-3,4- dihydroquinazolin-2(1H)-one: A mixture of (S)-4-(cyclopropylethynyl)-7-(hydroxymethyl)-3- methyl-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (83 mg, 0.256 mmol) and thionyl chloride (0.187 ml, 2.56 mmol) in DCM (1 ml) was stirred at 50 ^C for 2 h. The reaction mixture was concentrated to provide the title compound. C Intermediates Intermediate C01: 4-(Chloromethyl)benzenesulfonamide Step 1: 4-(hydroxymethyl)benzenesulfonamide: To a solution of 4-sulfamoylbenzoic acid (1 g, 4.9 mmol) in THF (20 mL) was added BH3.Me2S (1.5 g, 19.9 mmol) at 0 °C and stirred at 20 °C for 12 h. The reaction was quenched with MeOH and concentrated to afford the title product. Step 2: 4-(chloromethyl)benzenesulfonamide: To a solution of 4-(hydroxymethyl)benzene sulfonamide (200 mg, 1.07 mmol) in SOCl 2 (1ml, 13.70 mmol) was stirred at 50 °C for 30 h. The reaction was concentrated and the resulting residue was purified by prep-HPLC (water:MeCN with 0.1%TFA) to afford the title compound. MS (ESI) m/z 206 [M+1]. Intermediate C02: 4-(Chloromethyl)-3-fluorobenzenesulfonamide Step 1: 3-fluoro-4-vinylbenzenesulfonamide: To a solution of 4-bromo-3-fluorobenzene sulfonamide (1 g, 3.94 mmol) in 1,4-dioxane (16 mL) and water (4 mL) was added K2CO3 (1.63 g, 11.81 mmol), C 2 H 3 BF 3 K (0.68 g, 5.12 mmol) and PdCl 2 (dppf) (0.29 g, 0.394 mmol) under N 2 . The reaction was stirred at 100 °C for 1 h under N 2 . The mixture was filtered, concentrated and purified by flash column (SiO2, 30% EtOAc/PE) to provide the title compound. Step 2: 3-fluoro-4-(hydroxymethyl)benzenesulfonamide: To a solution of 3-fluoro-4- vinylbenzenesulfonamide (400 mg, 1.988 mmol) in DCM (5 mL) and MeOH (0.5 mL) was stirred at -70 °C under O3 for 15 min, then under O2 for 20 min. The reaction mixture was allowed to warm up to 25 °C and NaBH4 (372 mg, 9.84 mmol) was added. The resulting solution was stirred at 25 °C for 1.5 h. The reaction was concentrated and the resulting residue was purified by prep-TLC (SiO 2 , 50% EtOAc:PE) to afford the title compound. Step 3: 4-(chloromethyl)-3-fluorobenzenesulfonamide: To a solution of 3-fluoro-4- (hydroxymethyl)benzenesulfonamide (100 mg, 0.49 mmol) in DCM (2 mL) was added SOCl 2 (0.711 ml, 9.75 mmol). The reaction was stirred at 50 °C for 16 h. The solution was concentrated and the crude was purified by prep-TLC (50% EtOAc:PE) to provide the title compound. Intermediate C03: tert-Butyl (4-(chloromethyl)-5-fluoropyrimidin-2-yl)carbamate Step 1: 2-chloro-5-fluoro-4-vinylpyrimidine: To a solution of 2,4-dichloro-5-fluoropyrimidine (15 g, 90 mmol) and potassium trifluoro(vinyl)borate (13.24 g, 99 mmol) in 1,4-dioxane (150 ml) and water (30 ml) was added K 2 CO 3 (37.2 g, 270 mmol) and PdCl 2 (dppf) (6.57 g, 8.98 mmol), then the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was filtered through Celite ® and extracted with EtOAc (3 x 150 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated. The resulting residue was purified by flash chromatography (SiO2, 20% EtOAc/PE) to afford the title compound. MS (ESI) m/z 159.1 [M+1] Step 2: tert-butyl (5-fluoro-4-vinylpyrimidin-2-yl)carbamate: To a nitrogen purged suspension of 2- chloro-5-fluoro-4-vinylpyrimidine (3 g, 18.92 mmol) in 1,4-dioxane (10 ml) was added tert-butyl carbamate (4.43 g, 37.8 mmol), Cs 2 CO 3 (12.33 g, 37.8 mmol), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (1.09 g, 1.89 mmol) and tris(dibenzylideneacetone)dipalladium(0) (1.733 g, 1.892 mmol). The solution was stirred at 100 °C for 16 h under nitrogen atmosphere. The mixture was concentrated and purified by flash chromatography (SiO 2 , 20% EtOAc/PE(0.1% Et 3 N)) to afford the title compound. Step 3: tert-butyl (5-fluoro-4-formylpyrimidin-2-yl)carbamate: Ozone was bubbled into a solution of tert-butyl (5-fluoro-4-vinylpyrimidin-2-yl)carbamate (500 mg, 2.090 mmol) in DCM (10 ml) at - 78 °C for 15 minutes. After excess O 3 was purged by O 2 for 20 min. Sodium triacetoxyborohydride (439 mg, 2.073 mmol) was added and then, the reaction mixture was stirred at 0 °C for 0.5 h. The reaction mixture was quenched with water and sat aq NaHCO3 sol (20ml) and extracted with DCM (20 ml). The organic layer was washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The resulting residue was purified by prep-TLC (SiO 2 , 5% MeOH:DCM) to afford the title compound. Step 4: tert-butyl (4-(chloromethyl)-5-fluoropyrimidin-2-yl)carbamate: To a solution of tert-butyl (5-fluoro-4-(hydroxymethyl)pyrimidin-2-yl)carbamate (70 mg, 0.288 mmol) in DCM (0.5 ml) was added DIPEA (0.151 ml, 0.863 mmol) and MsCl (0.045 ml, 0.576 mmol). The reaction was stirred at 20 °C for 16 h. The reaction mixture was concentrated and purified by prep-TLC (SiO2, 30% EtOAc/PE) to provide the title compound. Intermediate C04: 2-Amino-4-(chloromethyl)benzenesulfonamide Step 1: 4-bromo-2-nitrobenzenesulfonic acid: To a solution of 4-bromo-1-fluoro-2-nitrobenzene (10 g, 45.5 mmol) in EtOH (120 ml) was added a mixture of sodium sulfite (14.32 g, 114 mmol) in EtOH (120 ml) and H 2 O (250 ml). The reaction mixture was stirred at 70 °C for 15 h. The reaction pH was adjusted to 1 with aq 2 M HCl sol (100 mL) then concentrated. The resulting residue was dissolved in brine (200 mL) and water (50 ml) and the resulting mixture was heated at 110 °C until the solid was fully dissolved. The mixture was cooled to 20 °C and the solid was collected by filtration, washed with water and dried to provide the title compound. Step 2: 4-bromo-2-nitrobenzenesulfonamide: To a solution of 4-bromo-2-nitrobenzenesulfonic acid (3 g, 10.64 mmol) and DMF (0.025 ml, 0.319 mmol) in toluene (50 ml) was dropwise added SOCl 2 (5.05 ml, 69.1 mmol). Then, the reaction was stirred at 115 °C for 4 h, cooled to 20 °C and concentrated. The residue was dissolved in toluene (4 ml) and cooled to -10 °C. NH 4 OH (1 ml, 10.64 mmol) in THF (10 ml) was added and the resulting mixture was stirred at -10 °C for 2 h. The reaction was adjusted to pH~4 with aq HCl sol (6 M, 2 mL). The reaction mixture was quenched with saturated NH 4 Cl (10 mL). The reaction mixture was extracted with EtOAc (3 x 10 ml). The organic layer was separated, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (SiO2, 0-30% EtOAc/PE) to afford the title compound. MS (ESI) m/z 303, 305 [M+1]. Step 3: 2-nitro-4-vinylbenzenesulfonamide: To a solution of 4-bromo-2-nitrobenzenesulfonamide (1.1 g, 3.91 mmol) in 1,4-dioxane (10 ml) and water (2 ml), was added K2CO3 (1.082 g, 7.83 mmol), C 2 H 3 BF 3 K (0.786 g, 5.87 mmol) and PdCl 2 (dppf) (0.286 g, 0.391 mmol). The reaction was stirred at 100 °C for 3 h under N 2 . The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3 x 25 ml). The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to dryness. The crude product was purified by flash silica gel chromatography (0-30% EtOAc/PE) to afford the title compound. MS (ESI) m/z 251 [M+1]. Step 4: 4-(hydroxymethyl)-2-nitrobenzenesulfonamide: To a solution of 2-nitro-4- vinylbenzenesulfonamide (800 mg, 3.51 mmol) in DCM (8 ml) and MeOH (0.8 ml) was stirred at - 70 °C under O3 for 15 min, then under O2 for 20 min. Then, NaBH4 (663 mg, 17.53 mmol) was added the reaction at -78 °C. The reaction was stirred at 20 °C for 1 h. The reaction mixture was quenched with sat aq NH 4 Cl sol (20 mL) and extracted with EtOAc (3 x 25 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by MPLC (5% EtOAc/PE) to afford the title compound. MS (ESI) m/z 233 [M+1]. Step 5: 2-amino-4-(hydroxymethyl)benzenesulfonamide: A mixture of 4-(hydroxymethyl)-2- nitrobenzenesulfonamide (200 mg, 0.861 mmol) and NH4Cl (230 mg, 4.31 mmol), iron (240 mg, 4.31 mmol) in ethanol (2 ml) and water (0.5 ml) was stirred at 80 °C for 3 h. The mixture was filtered through a pad of Celite ® and washed with 1:1 mixture of THF/EtOH (3 x 5 mL). The filtrate was concentrated and the residue was separated in 1:1 mixture of THF/EtOAc (5 mL) and water (10 mL), extracted with a 1:1 mixture of THF/EtOAc (3 x 5ml). The combined organic layer was dried over Na 2 SO 4 , filtered and concentrated to afford the title compound, which was used without further purification. MS (ESI) m/z 203 [M+1]. Step 6: 2-amino-4-(chloromethyl)benzenesulfonamide: To a solution of 2-amino-4- (hydroxymethyl)benzenesulfonamide (150 mg, 0.742 mmol) in DCM (1 ml) and 1,4-dioxane (0.5 ml) was added SOCl 2 (0.162 ml, 2.225 mmol) at 0 °C. Then, the reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was diluted with DCM (3 mL), then added to sat aq NaHCO3 sol (5 mL) at 0 °C, and then extracted with EtOAc (2 x 5 mL). The combined organic phase was dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by prep HPLC (water: MeCN with 0.1%TFA) to afford the title compound. MS (ESI) m/z 221 [M+1]. Intermediate C05: 5-(chloromethyl)-4-methoxy-2,6-dimethylpyrimidine Step 1: 1,3-diethyl 2-(1-hydroxyethyl)propanedioate: Into a 50-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 1,3-diethyl 2- acetylpropanedioate (5000 g, 24.73 mol) in AcOH (25 L) and followed by the addition of NaBH 4 (1220 g, 32.25 mol) in several batches at 0 o C over 1 h. The resulting solution was stirred at 0 o C for 3h, and then quenched with water (2 L), and extracted with DCM (3×5 L). The combined organic layer was concentrated and the residue was purified by column chromatography (SiO 2 , 50% EtOAc/hexanes) to afford the title compound. Step 2: 1,3-diethyl 2-[1-(acetyloxy)ethyl]propanedioate: Into a 50-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 1,3-diethyl 2- (1-hydroxyethyl)propanedioate (3800 g, 18.61 mol) in DCM (38 L), acetic anhydride (2280 g, 22.35 mol), TEA (3762 g, 37.18 mol), 4-dimethylaminopyridine (454 g, 3.72 mol). The resulting solution was stirred at 60 o C for 16 h, then quenched by the addition of water (4 L), and extracted with DCM (3×5 L). The combined organic layer was concentrated. The residue was purified by column chromatography (SiO2, 2% EtOAc/PE) to afford the title compound. Step 3: 1,3-diethyl 2-ethylidenepropanedioate: Into a 10-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1,3-diethyl 2-[1-(acetyloxy) ethyl]propanedioate (3200 g, 12.99 mol) and followed by dropwise addition of acetaldehyde (1716 g, 38.95 mol) with stirring at 80 o C over 40 min. The resulting solution was stirred at 80 o C for 16 h, then cooled to 20 °C and quenched by the addition of water (5 L), and then extracted with EtOAc (3×2 L). The combined organic layer was concentrated and purified by column chromatography (SiO2, 0.5% EtOAc/PE) to afford the title compound. Step 4: Ethyl 2,4-dimethyl-6-oxo-1,4,5,6-tetrahydropyrimidine-5-carboxylat e: Into a 50-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of ethanimidamide hydrochloride (1060 g, 11.21 mol) in ethanol (30 L), NaOEt (1380 g, 14.68 mol), and followed by dropwise addition of a solution of 1,3-diethyl 2-ethylidene propanedioate (1700 g, 9.13 mol) in ethanol (4 L) with stirring at 60 o C over 30 min. The resulting solution was stirred at 60 o C for 2 h, and then cooled to 20 °C. The mixture was filtered and concentrated to afford the title compound, which was used as is in the next step. Step 5: Ethyl 2,4-dimethyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate: Into a 50-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of ethyl 2,4-dimethyl-6-oxo-1,4,5,6-tetrahydropyrimidine-5-carboxylat e (2500 g, 12.61 mol) in 1,4-dioxane (25 L), potassium carbonate (7200 g, 52.09 mol), NBS (2300 g, 12.92 mol), BPO (78 g, 304.39 mmol). The resulting solution was stirred at 80 o C for 16 h. The reaction mixture was cooled down to 20 °C, and then quenched by the addition of water (10 L). The pH value of the solution was adjusted to 7 with aq HCl (12N). The resulting solution was extracted with DCM (3×5 L). The combined organic layer was concentrated and the residue was purified by column chromatography (SiO 2 , 5% MeOH/DCM) to afford the title compound. Step 6: Ethyl 4-chloro-2,6-dimethylpyrimidine-5-carboxylate: Into a 50-L 4-necked round-bottom flask purged with N 2 , was placed ethyl 2,4-dimethyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate (1100 g, 5.61 mol) and POCl 3 (11 L). The resulting solution was stirred at 80 o C for 5 h, and then concentrated to afford the title compound, which was used in the next step as is. Step 7: Ethyl 4-methoxy-2,6-dimethylpyrimidine-5-carboxylate: Into a 50-L 4-necked round-bottom flask purged with N 2 , was placed a solution of ethyl 4-chloro-2,6-dimethylpyrimidine-5- carboxylate (2000 g, 9.32 mol) in MeOH (20 L). The resulting solution was stirred at 20 o C for 2 h, and concentrated. The residue was dissolved in water (5 L) and extracted with DCM (3×2 L). The combined organic layer was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO 2 , 10% EtOAc/PE) to afford the title compound. Step 8: (4-methoxy-2,6-dimethylpyrimidin-5-yl)MeOH: Into a 10-L 4-necked round-bottom flask purged with N 2 , was placed a solution of ethyl 4-methoxy-2,6-dimethylpyrimidine-5-carboxylate (270 g, 1.28 mol) in THF (2.7 L) and followed by the addition of LiAlH 4 (54 g, 1.42 mol) in several batches at 0 o C over 30 min. The resulting solution was stirred at 0 o C for 2h, and then quenched by the addition of 15% NaOH sol (65 mL). After stirred for 1h, the mixture was filtered and concentrated to afford the title compound. Step 9: 5-(chloromethyl)-4-methoxy-2,6-dimethylpyrimidine: To a stirred solution of (4-methoxy- 2,6-dimethylpyrimidin-5-yl)methanol (1 g, 5.95 mmol) in DCM (15 mL) was added DIPEA (3.12 mL, 17.84 mmol) and MsCl (1.390 mL, 17.84 mmol) at 0 °C under N 2 . The resulting mixture was stirred at 15 °C for 2h and then, diluted with water (15mL) and extracted with DCM (3×20mL). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO 2 , 0-30% EtOAc/PE) to afford the title compound. MS (ESI) m/z 187 [M+1] Intermediate C06: 2-amino-4-bromonicotinonitrile Step 1: 4-bromo-2-fluoronicotinic acid: To a solution of 4-bromo-2-fluoropyridine (10 g, 56.8 mmol) in THF (120 ml) was added LDA (34.1 ml, 68.2 mmol) dropwise at -78°C under N 2 , and was stirred for 0.5 h at -78°C. The mixture was poured into CO 2 (100 g, 2272 mmol) and diluted with H2O (100 mL) and extracted with EtOAc (2x50 mL), the pH of the aq phase was adjusted with aq HCl (37%) to pH=6. The mixture was extracted with EtOAc (3x100 mL) and washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated to afford the title product. Step 2: 4-bromo-2-fluoronicotinamide: The 4-bromo-2-fluoronicotinic acid (3.37g, 15.32 mmol) was dissolved in 1,4-dioxane (30 mL) followed by the addition of pyridine (0.743 mL, 9.19 mmol), Boc 2 O (4.62 mL, 19.91 mmol) and ammonium bicarbonate (1.574 g, 19.91 mmol). The mixture was stirred at 15 °C for 12 h. The solution was concentrated and the crude was purified by prep-TLC (SiO2, 50% EtOAc:PE) to afford the title compound. Step 3: 4-bromo-2-fluoronicotinonitrile: To a solution of 4-bromo-2-fluoronicotinamide (2.27 g, 10.36 mmol) in THF (20 ml) was added TFAA (4.39 ml, 31.1 mmol) and Et 3 N (4.33 ml, 31.1 mmol). The reaction was stirred at 0 °C for 1 h. The mixture was poured into water (5 mL) and extracted with EtOAc (2 x 15 mL). The combined organic layer was washed with sat aq NaHCO 3 sol (15 mL), brine (15 mL) and dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by column chromatography (SiO2, 5-30% EtOAc/PE) to afford the title product. Step 4: 2-amino-4-bromonicotinonitrile: A solution of 4-bromo-2-fluoronicotinonitrile (200 mg, 0.995 mmol) in ammonia (1 ml) was stirred at 20 °C for 1 h. The solution was bubbled with N 2 to remove the ammonia, then extracted with EtOAc (2 x 5 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated to afford the title product. Intermediate C07: (6-(Chloromethyl)pyridin-3-yl)methanol Step 1: Methyl 6-(chloromethyl)nicotinate: Methyl 6-(hydroxymethyl)nicotinate (1000 mg, 5.98 mmol) was dissolved in DCE (30 mL) at 0 °C and DIPEA (2.3 mL, 13.16 mmol) was added followed by the addition of MsCl (513 µL, 6.58 mmol). The reaction was stirred for 16 h at 25 ^C. The reaction was concentrated and the residue was dissolved in EtOAc (50 mL) and washed with water (2 x 10 mL), brine (10 mL), dried over MgSO 4 , and concentrated. The residue was purified by flash chromatography (SiO 2 , 0-70% EtOAc:hexanes) to afford the title compound. Step 2: (6-(Chloromethyl)pyridin-3-yl)methanol: Methyl 6-(chloromethyl)nicotinate (1 g, 5.39 mmol) was dissolved in THF (24.49 ml) and the temperature was cooled to 0 °C, then a 2 M LiAlH4 sol in THF (1.47 mL, 5.88 mmol) was added dropwise. Upon completion of addition of LiAlH 4 , the resulting mixture was stirred at 0 °C for 30 min. The reaction was quenched with the slow addition of 0.22 mL of water followed by 0.22 mL of 15% aq NaOH. This mixture was stirred for 10 min, then 0.88 mL water were added and brought to ambient temperature and the reaction mixture was stirred for additional 15 min. The mixture was filtered and diluted with DCM (20 mL), dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (SiO2, 0-100% EtOAc:hexanes) to afford the title compound. Intermediate C08: 2-(Chloromethyl)-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy) pyridine Step 1: Methyl 5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)picolinate: Methyl 5- hydroxypicolinate (100 mg, 0.653 mmol) was dissolved in DMF (3265 µL) and Cs 2 CO 3 (319 mg, 0.980 mmol) and 2-(2-bromoethoxy)tetrahydro-2H-pyran (150 mg, 0.718 mmol) was added. The reaction mixture was stirred at 40 °C for 16 h, and then, diluted with EtOAc (50 mL) and washed with H 2 O (20 mL) and dried over MgSO 4 , filtered, and concentrated. The residue was purified by flash chromatography (SiO 2 , 0-100% EtOAc/hexanes) to afford the title compound. Step 2: (5-(2-((Tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-2-yl)met hanol: Methyl 5-(2- ((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)picolinate (95 mg, 0.338 mmol) was dissolved in THF (1535 µL) and chilled to 0 °C, then a 2 M LiAlH 4 sol in THF (77 µL, 0.154 mmol) was added dropwise. Then, the reaction was stirred at 0 °C for 30 min, and quenched with sat aq Rochelle salt sol. (10 drops). The mixture was dissolved in EtOAc (10 mL) and washed with water (2 x 5 mL), brine, dried over MgSO 4 , filtered and concentrated. The resulting crude was purified by flash chromatography (SiO 2 , 0-100% EtOAc:hexanes) to give the title compound. Step 3: 2-(Chloromethyl)-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy) pyridine: (5-(2- ((Tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-2-yl)methanol (2000 mg, 7.90 mmol) was dissolved in DCE (39.5 mL) and DIPEA (2.7 mL, 11.84 mmol) followed by the addition of MsCl (738 µL, 9.48 mmol) and stirred 16h. The solution was concentrated and purified by flash chromatography (SiO2, 0-100% EtOAc/hexanes) to give the title compound. Intermediate C09: 2-(Chloromethyl)-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy) isonicotinonitrile Step 1: 2-(((Tert-butyldimethylsilyl)oxy)methyl)-5-fluoroisonicotino nitrile: 5-Fluoro-2- (hydroxymethyl)isonicotinonitrile (2.0 g, 13.15 mmol) was dissolved in DCM (65.7 mL) and TBSCl (2.58 g, 17.09 mmol) and imidazole (1.343 g, 19.72 mmol) were added and stirred for 16 h at 25 ^C. The reaction was filtered and concentrated. The resulting crude was purified by flash chromatography (SiO2, 0-30% EtOAc/hexanes) to give the title compound. Step 2: 2-(((Tert-butyldimethylsilyl)oxy)methyl)-5-(2-((tetrahydro-2 H-pyran-2-yl)oxy)ethoxy) isonicotinonitrile: 2-((Tetrahydro-2H-pyran-2-yl)oxy)ethanol (1.405 g, 9.61 mmol) was dissolved in DMF (10 mL) and KOtBu (1.079 g, 9.61 mmol) was added and the resulting mixture was sonicated for 10 min. The reaction was cooled to 0 ^C, then, 2-(((tert-butyldimethylsilyl) oxy)methyl)-5- fluoroisonicotinonitrile (2.134 g, 8.01 mmol) was added in one portion. The resulting mixture was stirred for 30 min at 0 °C. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (2 x 10 mL). The organic layer was concentrated and purified by flash chromatography (SiO2, 0-100% EtOAc/hexanes) to give the title compound. Step 3: 2-(hydroxymethyl)-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy )isonicotinonitrile: 2- (((Tert-butyldimethylsilyl)oxy)methyl)-5-(2-((tetrahydro-2H- pyran-2-yl)oxy)ethoxy) isonicotinonitrile (2.26 g, 5.75 mmol) was dissolved in THF (28.8 mL) and a 1 M TBAF sol in THF (5.75 mL, 5.75 mmol) was added. The resulting reaction was stirred 1 h at 25 ^C. The mixture was diluted in EtOAc (50 mL) and washed with (2 x 10 mL), dried over MgSO 4 , filtered and concentrated. The resulting residue was purified by flash chromatography (SiO 2 , 0-100% (3:1 EtOAc:EtOH):hexanes) to give the title compound. Step 4: 2-(Chloromethyl)-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy) isonicotinonitrile: 2- (Hydroxymethyl)-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)i sonicotinonitrile (5 g, 17.97 mmol) was dissolved in DCE (90 mL) and DIPEA (6.90 mL, 39.5 mmol) was added and the reaction was cooled to 0 °C and MsCl (1.540 mL, 19.76 mmol) was added. The resulting mixture was stirred for 16h at 25 ^C. The reaction was concentrated, and the residue was dissolved in EtOAc (50 mL) and washed with water (2 x 20 mL), brine (20 mL), and dried over MgSO 4 , filtered and concentrated. The resulting residue was purified by flash chromatography (SiO 2 , 0-100% EtOAc/hexanes) to give the title compound. Intermediate C10: Tert-butyl (3-(((tert-butyldimethylsilyl)oxy)methyl)-6- (trimethylstannyl)pyridin-2-yl)carbamate Step 1: (2-Amino-6-chloropyridin-3-yl)methanol: Methyl 2-amino-6-chloronicotinate (1 g, 5.36 mmol) was dissolved in THF (25 ml) and chilled to 0 °C, then a 2 M LiAlH4 sol in THF (2.9 mL, 5.85 mmol) was added dropwise. Then, the reaction was stirred at 0 °C for 30 min. The reaction was quenched with 0.22 mL of H 2 O followed by 0.22 mL of an aq 15% NaOH sol, and then an additional 0.88 mL of water. The resulting mixture was stirred at 25 °C for 30 min, and then, filtered. The filtrate was diluted with DCM (20 mL), dried over MgSO 4 , filtered and concentrated. The residue was purified by flash chromatography (SiO2, 0-80% EtOAc/hexanes) to provide the title compound. Step 2: 3-(((Tert-butyldimethylsilyl)oxy)methyl)-6-chloropyridin-2-a mine: (2-Amino-6- chloropyridin-3-yl)methanol (773 mg, 4.87 mmol) was dissolved in DMF (2.5 mL) and imidazole (398 mg, 5.85 mmol) was added followed by the addition of TBSCl (735 mg, 4.87 mmol) and stirred at 25 °C for 16 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (2 x 20 mL), brine (20 mL) and dried over MgSO 4 , filtered and concentrated. The resulting residue was purified by flash chromatography (SiO2, 0-100% EtOAc/hexanes) to provide the title compound. Step 3: Tert-butyl (3-(((tert-butyldimethylsilyl)oxy)methyl)-6-chloropyridin-2- yl)carbamate: 3- (((Tert-butyldimethylsilyl)oxy)methyl)-6-chloropyridin-2-ami ne (992 mg, 3.64 mmol) was dissolved in THF (18 mL) and Boc2O (1688 µL, 7.27 mmol) followed by the addition of DMAP (4.44 mg, 0.036 mmol) and the resulting mixture was stirred at 25 °C for 16 h. The reaction was concentrated and the resulting residue was purified by flash chromatography (SiO2, 0-30% EtOAc/hexanes) to provide the title compound. MS (ESI) m/z 373 [M+1]. Step 4: Tert-butyl (3-(((tert-butyldimethylsilyl)oxy)methyl)-6-(trimethylstanny l)pyridin-2- yl)carbamate: A mixture of tert-butyl (3-(((tert-butyldimethylsilyl)oxy)methyl)-6-chloropyridin- 2-yl)carbamate (300 mg, 0.80 mmol), hexamethylditin (0.2 mL, 0.96 mmol), and Pd(PPh3)4 (93 mg, 0.080 mmol) in 1,4-dioxane (0.2 ml) was bubbled with N 2 for 2 min, then heated at 115 °C for 16 h. Then, the reaction was treated with a sat aq KF sol (3 mL) at 25 °C and stirred for 10 min. The mixture was filtered and the filtrate was diluted with EtOAc (10 mL) and washed with water (2 x 5 mL) and concentrated. The resulting crude was purified by flash chromatography (SiO2, 0-30% EtOAc/hexanes) to provide the title compound. Intermediate C11: 5-(chloromethyl)-4-methoxy-6-methylpyrimidine Step 1: (4,6-dichloro-2-methylpyrimidin-5-yl)methanol: A solution of 4,6-dichloro-2- methylpyrimidine-5-carbaldehyde 4,6-dichloropyrimidine-5-carbaldehyde (386 mg, 2.181 mmol) in MeOH (14 mL) was cooled to -78 °C, was then added a 25% sodium methoxide sol in MeOH (0.499 mL, 2.181 mmol) dropwise. The resulting mixture was allowed to warm to 25 °C and stirred for addition 30 min, and then cooled to 0 °C in an ice bath, then NaBH 4 (83 mg, 2.181 mmol) was added in portions slowly. The reaction was quenched with water and EtOAc. The layers were separated and the aqueous layer was further extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO 2 , 0-50% EtOAc/hexanes) to afford the title compound. Step 2: (4-methoxy-6-methylpyrimidin-5-yl)methanol: A stirred solution of (4-chloro-6- methoxypyrimidin-5-yl)methanol (168 mg, 0.962 mmol), PdCl 2 (dppf).DCM complex (39.3 mg, 0.048 mmol) and Cs2CO3 (941 mg, 2.89 mmol) in 1,4-dioxane (4.0 mL) and water (802 µL) was degassed and purged with N2, then trimethylboroxine (269 µL, 1.925 mmol) was added and heated at 100 °C for 18 h. The reaction mixture was cooled to 25 °C, filtered through Celite ® and concentrated. The residue was purified by flash chromatography (0-5% MeOH/DCM) to afford the title compound. Step 3: 5-(chloromethyl)-4-methoxy-6-methylpyrimidine: To a stirred solution of 4-methoxy-6- methylpyrimidin-5-yl)methanol (106 mg, 0.69 mmol) in DCE (1.0 mL), was added thionyl chloride (2.51 mL, 34.4 mmol) and stirred at 60 °C for 3 h. The reaction mixture was concentrated to afford the title compound, which was used without further purification. Intermediate C12: tert-butyl (6-(chloromethyl)pyridin-2-yl)carbamate Thionyl chloride (0.199 ml, 2.72 mmol) was added slowly to a solution of tert-butyl 6- (hydroxymethyl)pyridin-2-ylcarbonate (122 mg, 0.544 mmol) in DCM (2 ml) at 0 ^C. The resulting mixture was stirred at 0 ^C for 1 h, then at 25 ^C for another 1h. The reaction mixture was concentrated to provide the title compound, which was used without further purification. Intermediate C13: tert-butyl (6-(chloromethyl)-5-fluoropyridin-2-yl)carbamate Step 1: tert-butyl (5-fluoro-6-(hydroxymethyl)pyridin-2-yl)carbamate: A mixture of (6-chloro-3- fluoropyridin-2-yl)methanol (0.129 g, 0.798 mmol), tert-butyl carbamate (0.187 g, 1.597 mmol), K3PO4 (0.678 g, 3.19 mmol), and Brettphos Pd G3 (0.072 g, 0.080 mmol) in 1,4-dioxane (6 ml) was bubbled with N 2 for 5 min, then heated at 90 ℃ for 2 h. The reaction mixture was filtered and concentrated. The residue was purified by column chromatography (SiO 2 , 0-30% EtOAc:hexanes) to give the title compound. Step 2: tert-butyl (6-(chloromethyl)-5-fluoropyridin-2-yl)carbamate: Thionyl chloride (0.093 ml, 1.28 mmol) was added slowly to a solution of tert-butyl (4-fluoro-6-(hydroxymethyl)pyridin-2- yl)carbamate (62 mg, 0.256 mmol) in DCM (2 ml) at 0 ℃. The mixture was stirred at 0 ℃ for 0.5 h, then at 25 ℃ for 1h. The reaction mixture was concentrated to give the title compound, which was used without further purification. Intermediate C14: tert-butyl (4-(chloromethyl)-5-fluoropyridin-2-yl)carbamate Step 1: methyl 2-((tert-butoxycarbonyl)amino)-5-fluoroisonicotinate: To a nitrogen purged suspension solution of methyl 2-bromo-5-fluoroisonicotinate (1.5g, 6.41 mmol) in 1,4-dioxane (15 ml) was added tert-butyl carbamate (0.901 g, 7.69 mmol), Cs 2 CO 3 (2.92 g, 8.97 mmol), Xantphos (0.148 g, 0.256 mmol) and tris(dibenzylideneacetone)dipalladium (0) (0.117 g, 0.128 mmol). The solution was stirred at 100 °C for 2 h under nitrogen atmosphere. The mixture was filtered through Celite ® and diluted with water (30 mL) and extracted with EtOAc (20 mLx3). The combined organic layer was washed with water (20 mL), brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated to give the title compound, which was used without further purification. Step 2: tert-butyl (5-fluoro-4-(hydroxymethyl)pyridin-2-yl)carbamate: Methyl 2-((tert- butoxycarbonyl)amino)-5-fluoroisonicotinate (1.84 g, 6.81 mmol) and CaCl 2 (1.133 g, 10.21 mmol) was dissolved in EtOH (80 ml). The solution was cooled to 0 °C, then NaBH4 (0.775 g, 20.49 mmol) was gradually added. Then, the solution was stirred for 2h at 25 °C. The reaction mixture was quenched by water (100 mL), filtered through Celite ® , and extracted with EtOAc (50mLx3). The combined organic layer was washed with brine (150 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (SiO2, 25% EtOAc/PE) to give the title compound. Step 3:tert-butyl (4-(chloromethyl)-5-fluoropyridin-2-yl)carbamate: To a mixture of tert-butyl (5- fluoro-4-(hydroxymethyl)pyridin-2-yl)carbamate (170 mg, 0.702 mmol) and DIPEA (0.245 mL, 1.404 mmol) in DCM (1 mL) was added MsCl (0.109 mL, 1.404 mmol) at 0 °C. The mixture was stirred at 20 °C for 16h. The mixture was diluted with water (30 ml) and extracted with DCM (20 ml*2). The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by prep-TLC (SiO2, 25% EtOAc/PE) to give the title compound. Intermediates used to prepare each of Examples 1-63 that were not commercially available were prepared as described above and are noted in the INT column in each of Tables 1-8. EXAMPLE 1: (S)-4-(cyclopropylethynyl)-7-((6-methyl-2-oxo-1,2-dihydropyr idin-3-yl)methyl)- 4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one To a solution of intermediate B08 (15 mg, 0.046 mmol), (2-methoxy-6-methylpyridin-3- yl)boronic acid (11 mg, 0.068 mmol) and XPhos Pd G2 (4 mg, 0.004 mmol) in 1,4-dioxane (0.3 mL) was added an aq Cs 2 CO 3 solution (1.5 M, 0.09 mL, 0.137 mmol). The reaction was stirred at 80 °C for 18 h. The resulting mixture was passed through a diatomaceous earth filter and washed with EtOAc (8 mL), and concentrated to dryness. The residue was treated with pyridine hydrochloride (56 mg, 0.48 mmol) in DMA (0.2 mL). The resulting mixture was stirred at 110 °C for 1 h. The mixture was cooled down to room temperature and purified by prep HPLC (water:MeCN with 0.1% TFA) to afford the title compound. 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.59 (s, 1H), 8.28 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 6.9 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.71 (s, 1H), 5.94 (d, J = 6.9 Hz, 1H), 3.60 (s, 2H), 2.13 (s, 3H), 1.43 (td, J = 8.3, 4.2 Hz, 1H), 0.85 (dt, J = 7.6, 3.8 Hz, 2H), 0.74 – 0.64 (m, 2H). MS (ESI) m/z 402 [M+1]. The compounds in Table 1 were prepared in an analogous fashion to that described for Example 1. TABLE 1 EXAMPLE 4: (S)-4-(cyclopropylethynyl)-7-((1-methyl-6-oxo-1,6-dihydropyr idin-3-yl)methyl)- 4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one To a solution of intermediate B08 (15 mg, 0.046 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3- dioxolan-2-yl)pyridin-2(1H)-one (16 mg, 0.068 mmol) and PdCl 2 (dppf) (3.3 mg, 0.005 mmol) in 1,4-dioxane (0.4 mL) was added an aq Cs2CO3 sol (1.5 M, 0.08 mL, 0.114 mmol). The reaction was stirred at 80 °C for 18 h. The solution was purified by prep-HPLC (water:MeCN with 0.1% TFA) to afford the title compound. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.61 (s, 1H), 8.33 (s, 1H), 7.62 (d, J = 2.1 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.27 (dd, J = 9.3, 2.5 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.69 (s, 1H), 6.36 (d, J = 9.2 Hz, 1H), 3.64 (s, 2H), 3.40 (s, 3H), 1.44 (ddd, J = 13.2, 8.3, 5.0 Hz, 1H), 0.91 – 0.81 (m, 2H), 0.74 – 0.64 (m, 2H). MS (ESI) m/z 402 [M+1]. EXAMPLE 5: (S)-4-(cyclopropylethynyl)-7-((1-methyl-2-oxo-1,2-dihydropyr idin-4-yl)methyl)- 4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one Example 5 was prepared using a procedure analogous to Example 4 except that 1-methyl-5- (4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)pyridin-2(1H)-one was replaced by 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-o ne. 1 H NMR (500 MHz, DMSO- d6) δ ppm 9.61 (s, 1H), 8.33 (s, 1H), 7.62 (d, J = 2.1 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.27 (dd, J = 9.3, 2.5 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.69 (s, 1H), 6.36 (d, J = 9.2 Hz, 1H), 3.64 (s, 2H), 3.40 (s, 3H), 1.44 (ddd, J = 13.2, 8.3, 5.0 Hz, 1H), 0.91 – 0.81 (m, 2H), 0.74 – 0.64 (m, 2H). MS (ESI) m/z 402 [M+1]. EXAMPLE 6: (S)-4-((4-(cyclopropylethynyl)-2-oxo-4-(trifluoromethyl)-1,2 ,3,4- tetrahydroquinazolin-7-yl)methyl)-3-fluorobenzenesulfonamide To a mixture of intermediate B01 (30 mg, 0.074 mmol), PdCl2(dppf) (5.40 mg, 7.39 µmol), intermediate C02 (33.0 mg, 0.148 mmol) in 1,4-dioxane (0.8 mL) and water (0.2 mL) was added Cs 2 CO 3 (72.2 mg, 0.222 mmol). The reaction was stirred at 90 °C for 3 h under N 2 . The reaction mixture was filtered and purified by prep HPLC (water:MeCN with 0.05% NH4OH) to afford the title compound. 1 H NMR (400MHz, DMSO-d6) δ ppm 9.64 (s, 1H), 8.32 (s, 1H), 7.65 - 7.49 (m, 3H), 7.44 (s, 2H), 7.35 (d, J=7.8 Hz, 1H), 6.88 (d, J=7.9 Hz, 1H), 6.71 (s, 1H), 4.00 (s, 2H), 1.44 (br s, 1H), 0.85 (dd, J=3.1, 8.1 Hz, 2H), 0.69 (br s, 2H). MS (ESI) m/z 468 [M+1]. The compounds in Table 2 were prepared in an analogous fashion to that described for Example 6. TABLE 2
EXAMPLE 12: (S)-2-amino-4-((4-(cyclopropylethynyl)-2-oxo-4-(trifluoromet hyl)-1,2,3,4- tetrahydroquinazolin-7-yl)methyl)pyridin-1-ium 2,2,2-trifluoroacetate To a mixture of intermediate B01 (30 mg, 0.074 mmol), PdCl 2 (dppf) (5.40 mg, 7.39 µmol), 2- Boc-amino-4-bromomethylpyridine (33.0 mg, 0.148 mmol) in 1,4-dioxane (0.8 mL) and water (0.2 mL) was added Cs2CO3 (72.2 mg, 0.222 mmol). The reaction was stirred at 90 °C for 3 h under N 2 . The reaction mixture was filtered, treated with TFA (0.5 mL), and stirred for 30 min. The mixture was concentrated and purified by prep-HPLC (water:MeCN with 0.1% TFA) to afford the title compound. 1 H NMR (600 MHz, DMSO-d6) δ 9.73 (s, 1H), 8.38 (s, 1H), 7.95 (s, 2H), 7.85 (d, J = 6.5 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 6.92 (d, J = 7.4 Hz, 1H), 6.73 – 6.68 (m, 3H), 3.97 (s, 2H), 1.46 (m, 1H), 0.87 (m, 2H), 0.70 (m, 2H). MS (ESI) m/z 387 [M+1]. The compounds in Table 3 were prepared in an analogous fashion to that described for Example 12. TABLE 3 EXAMPLE 16: (S)-4-(cyclopropylethynyl)-7-((2-methyl-6-oxo-1,6-dihydropyr imidin-5- yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-o ne To a solution of intermediate B01 (21 mg, 0.052 mmol), 5-(chloromethyl)-4-methoxy-2- methylpyrimidine (16 mg, 0.078 mmol) and PdCl 2 (dppf) (3.8 mg, 0.005 mmol) in 1,4-dioxane (0.4 mL) was added an aq Cs2CO3 sol (1.5 M, 0.10 mL, 0.155 mmol). The reaction was stirred at 80 °C for 18 h. The resulting mixture was passed a diatomaceous earth filter, washed with EtOAc (8 mL), and concentrated to dryness. The residue was treated with pyridine hydrochloride (60 mg, 0.52 mmol) in DMA (0.2 mL). The mixture was stirred at 110 °C for 30 min. The solution was purified by prep HPLC (water:MeCN with 0.1% TFA) to afford the title compound. 1 H NMR (600 MHz, MeOH-d 4 ) δ 7.78 (s, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.80 (s, 1H), 3.75 (s, 2H), 1.40 (td, J = 8.7, 4.4 Hz, 1H), 0.88 (dd, J = 8.2, 3.2 Hz, 2H), 0.75 (d, J = 5.2 Hz, 2H). MS (ESI) m/z 403 [M+1]. The compounds in Table 4 were prepared in an analogous fashion to that described for Example 16. TABLE 4 EXAMPLE 20: (S)-4-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-2-oxo-1 ,2,3,4- tetrahydroquinazolin-7-yl)methyl)benzenesulfonamide Step 1: (S)-4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-7-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)-3,4-dihydroquinazolin-2(1H)-one: A mixture of intermediate A05-Isomer A (0.05 g, 0.141 mmol), BisPin (0.039 g, 0.155 mmol), KOAc (0.041 g, 0.422 mmol), PdCl 2 (PPh 3 ) 4 (9.88 mg, 0.014 mmol) in 1,4-dioxane (1 ml) was stirred at 90 °C for 24 h. EtOAc (5 mL) and water (5 mL) were added and the mixture was filtered through Celite ® . The organic layer was separated and concentrated to give the title compound, which was used without further purification. MS (ESI) m/z 403 [M+1]. Step 2: (S)-4-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-2-oxo-1 ,2,3,4-tetrahydroquinazolin- 7-yl)methyl)benzenesulfonamide: To a mixture of (S)-4-(cyclopropylethynyl)-4-(1,1- difluoroethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y l)-3,4-dihydroquinazolin-2(1H)- one (0.051 g, 0.127 mmol), PdCl2(dppf) (9.28 mg, 0.013 mmol), 4-bromomethyl benzenesulfonamide (33.0 mg, 0.148 mmol) in 1,4-dioxane (1 mL) and water (0.25 mL) was added Cs2CO3 (0.124 g, 0.380 mmol). The reaction was stirred at 90 °C for 16 h. The reaction mixture was filtered, concentrated and purified by prep HPLC (water:MeCN with 0.1% TFA) to afford the title compound. 1 H NMR (500 MHz, MeOH-d 4 ) δ ppm7.85 (d, J = 8.3 Hz, 2H), 7.42 (m, 3H), 6.91 (d, J = 8.0 Hz, 1H), 6.68 (s, 1H), 4.04 (s, 2H), 1.65 (t, J = 18.4 Hz, 3H), 1.39 (ddd, J = 13.3, 8.4, 5.0 Hz, 1H), 0.87 (dd, J = 8.4, 2.8 Hz, 2H), 0.83 – 0.69 (m, 2H). MS (ESI) m/z 446 [M+1]. EXAMPLE 21: (S)-4-(cyclopropylethynyl)-7-((2,4-dimethyl-6-oxo-1,6-dihydr opyrimidin-5- yl)methyl)-3-ethyl-4-(trifluoromethyl)-3,4-dihydroquinazolin -2(1H)-one Step 1: (S)-7-bromo-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1-((2 -(trimethylsilyl)ethoxy) methyl)-3,4-dihydroquinazolin-2(1H)-one: To an ice-cold solution of intermediate A03 (3 g, 8.35 mmol) in THF (84 mL) was added 60% NaH dispersion in mineral oil (0.368 g, 9.19 mmol). The resulting mixture was stirred at 0°C for 10 min, before addition of SEMCl (2.22 mL, 12.5 mmol). The reaction mixture was allowed to warm to room temperature and partitioned between EtOAc and water. The mixture was filtered through Celite and washed with EtOAc. The organic layer was separated and dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (SiO2, 0-60% EtOAc/hexanes) to afford the title compound. MS (ESI) m/z 489, 491 [M+1]. Step 2: (S)-4-(cyclopropylethynyl)-7-((4-methoxy-2,6-dimethylpyrimid in-5-yl)methyl)-4- (trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3,4-d ihydroquinazolin-2(1H)-one A mixture of BisPin (88 mg, 0.347 mmol), KOAc (78 mg, 0.797 mmol), (S)-7-bromo-4- (cyclopropylethynyl)-4-(trifluoromethyl)-1-((2-(trimethylsil yl)ethoxy)methyl)-3,4- dihydroquinazolin-2(1H)-one (130 mg, 0.266 mmol), and PdCl2(PPh3)4 (18.64 mg, 0.027 mmol) in 1,4-dioxane (2.7 mL) was flushed with N 2 , and then heated at 100 °C under N 2 for 2 h. Then, intermediate C05 (59.5 mg, 0.319 mmol), PdCl 2 (dppf)-DCM adduct (21.69 mg, 0.027 mmol) and an aq Cs2CO3 sol (3 M, 177 µL, 0.531 mmol) were added. The resulting mixture was flushed with N2, and heated at 100 °C for 1h. The mixture was passed through a Celite funnel and washed with DCM (2×). The filtrate was concentrated and the resulting residue was purified by flash chromatography (SiO2, 0-100% EtOAc/hexanes) to afford the title compound. MS (ESI) m/z 561.7 [M+1]. Step 3: (S)-4-(cyclopropylethynyl)-7-((2,4-dimethyl-6-oxo-1,6-dihydr opyrimidin-5-yl)methyl)-3- ethyl-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one: To a solution of (S)-4- (cyclopropylethynyl)-7-((4-methoxy-2,6-dimethylpyrimidin-5-y l)methyl)-4- (trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3,4-d ihydroquinazolin-2(1H)-one (29.3 mg, 0.052 mmol) in anhydrous 1,4-dioxane (500 µL), was added 60% NaH dispersion in mineral oil (6.27 mg, 0.157 mmol). After 10 min, iodoethane (40 µL, 0.388 mmol) was added dropwise. The resulting mixture was stirred at 25 ^C overnight. The mixture was quenched with sat aq NH4Cl sol and extracted with EtOAc (3×). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated. The residue was dissolved in MeCN (2 mL) and treated with pyridine hydrochloride (120 mg, 1.04 mmol), and irradiated at 120 °C in microwave oven for 30 min. The crude mixture was purified by prep HPLC (water:MeCN with 0.1% TFA) to afford the title compound. 1 H NMR (600 MHz, CDCl3) δ ppm 7.47 (d, J = 8.4 Hz, 1H), 7.30 (s, 1H), 6.94 (d, J = 8.1 Hz, 1H), 3.96(dd, J = 7.2, 13.8 Hz, 2H), 3.61 (dd, J = 7.1, 14.3 Hz, 2H), 2.67 (s, 3H), 2.65 (s, 3H), 1.41 – 1.36 (m, 1H), 1.17 (t, J = 6.7 Hz, 3H), 0.90 (d, J = 8.1 Hz, 2H), 0.79 (d, J = 4.9 Hz, 2H). MS (ESI) m/z 445.5 [M+1]. The compounds in Table 5 were prepared in an analogous fashion to that described for Example 21. TABLE 5
EXAMPLE 25: (S)-7-((2-aminopyrimidin-4-yl)methyl)-4-(cyclopropylethynyl) -4- (trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one A mixture of 4-chloropyrimidin-2-amine (628 mg, 4.87 mmol), hexamethylditin (1.0 ml, 5.25 mmol), and Pd(PPh3)4 (554 mg, 0.48 mmol) in 1,4-dioxane (6 ml) was bubbled with N2 for 2 min, then heated at 115 °C for 4 h. Intermediate B08 (1613 mg, 6.25 mmol), CuI (928 mg, 4.87 mmol) and Pd(PPh 3 ) 4 (563 mg, 0.487 mmol) were added to the reaction mixture. The resulting mixture was bubbled with N 2 for 2 min, then heated at 115 °C for 16 h. The reaction mixture was treated with KF and stirred for 30 min. The reaction mixture was filtered and concentrated and purified by column chromatography (SiO2, 0-8% DCM/MeOH) to give the title product. 1 H NMR (500 MHz, DMSO- d 6 ) δ 9.65 (s, 1H), 8.31 (s, 1H), 8.13 (d, J = 5.0 Hz, 1H), 7.35 (d, J = 7.9 Hz, 1H), 6.94 – 6.89 (m, 1H), 6.72 (s, 1H), 6.55 (s, 2H), 6.43 (d, J = 5.0 Hz, 1H), 3.76 (s, 2H), 1.45 (ddd, J = 13.2, 8.3, 5.0 Hz, 1H), 0.86 (dp, J = 9.3, 4.7 Hz, 2H), 0.70 (dq, J = 7.9, 4.5, 3.9 Hz, 2H). MS (ESI) m/z 388 [M+1]. The compounds in Table 6 were prepared in an analogous fashion to that described for Example 25. TABLE 6
EXAMPLE 35: (S)-7-((6-aminopyridin-2-yl)methyl)-4-(cyclopropylethynyl)-4 - (trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one A mixture of intermediate B01 (75 mg, 0.185 mmol), Na2CO3 (117 mg, 1.108 mmol), PdCl 2 (dppf) (13.51 mg, 0.018 mmol), and intermediate C12 (132 mg, 0.489 mmol) in 1,4- dioxane (2.5 mL) and water (750 µl) was placed in a vial, sealed and irradiated at 100 °C for 1h in microwave. The reaction mixture was diluted with EtOAc (5 ml) and washed with water (2 x 5 ml). The organic layer was dried over Na 2 SO 4 , concentrated, and purified by column chromatography (SiO 2 , 0-35% EtOAc/Hexane). The resulting oil was dissolved in DCM (0.5 ml) and treated with a 4 M solution of HCl in 1,4-dioxane (0.27 ml, 1.09 mmol). The reaction mixture was stirred at 25 °C for 2h. The reaction mixture was concentrated and purified by column chromatography (SiO 2 , 0-10% DCM/MeOH) to give the title compound. 1 H NMR (500 MHz, MeOH-d4) δ 7.87 (dd, J = 8.9, 7.3 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.00 (dd, J = 8.1, 1.7 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 6.77 (s, 1H), 6.74 (d, J = 7.3 Hz, 1H), 1.42 (ddd, J = 13.3, 8.3, 5.0 Hz, 1H), 0.98 – 0.87 (m, 2H), 0.76 (tt, J = 4.9, 2.2 Hz, 2H). MS (ESI) m/z 387 [M+1]. The compounds in Table 7 were prepared in an analogous fashion to that described for Example 35. TABLE 7 EXAMPLE 38: (S)-7-((2-aminopyrimidin-4-yl)methyl)-4-(cyclopropylethynyl) -6-fluoro-4- (trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one A mixture of intermediate B09 (504 mg, 1.45 mmol), 4-bromopyrimidin-2-amine (304 mg, 1.74 mmol), picolinimidamide hydrochloride (68.7 mg, 0.44 mmol), NaI (218 mg, 1.45 mmol), dichloro(dimethoxyethane)nickel (96 mg, 0.44 mmol) and zinc (238 mg, 3.63 mmol) in DMA (8 ml) was stirred at 25 °C for 1 h. The reaction mixture was filtered and purified by prep HPLC (water:MeCN with 0.05% NH 4 OH) to afford the title compound. 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.72 (s, 1H), 8.40 (s, 1H), 8.14 (d, J = 4.8 Hz, 1H), 7.17 (d, J = 9.6 Hz, 1H), 6.77 (d, J = 6.3 Hz, 1H), 6.57 (s, 2H), 6.41 (d, J = 4.9 Hz, 1H), 3.88 – 3.77 (m, 2H), 1.48 (tt, J = 8.4, 5.1 Hz, 1H), 0.88 (dd, J = 8.0, 2.8 Hz, 2H), 0.73 (s, 2H). MS (ESI) m/z 406 [M+1]. EXAMPLE 39: (S)-7-((2-aminopyrimidin-4-yl)methyl)-4-(cyclopropylethynyl) -3-methyl-4- (trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one A mixture of 4-chloropyrimidin-2-amine (19 mg, 0.16 mmol), hexamethylditin (0.03 ml, 0.16 mmol), and Pd(PPh 3 ) 4 (17 mg, 0.01 mmol) in 1,4-dioxane (0.5 ml) was bubbled with N 2 for 2 min, then heated at 115 °C for 4 h. The reaction mixture added to a mixture of intermediate B17 (45 mg, 0.131 mmol), CuI (25.0 mg, 0.131 mmol), and Pd(PPh3)4 (15.17 mg, 0.013 mmol) in 1,4-dioxane (2 ml). The resulting mixture was bubbled with N2 for 2 min, then heated at 115 °C for 2 h. The reaction mixture was treated with KF and stirred for 30 min. The reaction mixture was filtered and concentrated and purified by column chromatography (SiO2, 0-8% DCM/MeOH) to give the title product. 1 H NMR (500 MHz, CDCl3) δ 8.20 (s, 1H), 7.82 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 6.95 (d, J = 8.1 Hz, 1H), 6.58 (s, 1H), 6.45 (d, J = 5.0 Hz, 1H), 5.21 (s, 2H), 3.87 (s, 2H), 3.30 (s, 3H), 1.42 (ddd, J = 13.3, 8.3, 5.0 Hz, 1H), 0.96 – 0.89 (m, 2H), 0.86 – 0.80 (m, 2H). MS (ESI) m/z 402 [M+1]. EXAMPLE 40: (S)-7-((2-aminopyrimidin-4-yl)methyl)-4-(cyclopropylethynyl) -6-fluoro-3- methyl-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one Step 1: (S)-7-bromo-4-(cyclopropylethynyl)-6-fluoro-1-(4-methoxybenz yl)-4-(trifluoromethyl)- 3,4-dihydroquinazolin-2(1H)-one: A mixture of intermediate A04-Isomer A (2 g, 5.30 mmol), Cs2CO3 (2.073 g, 6.36 mmol) and PMBCl (0.794 ml, 5.83 mmol) in DMF (26.5 ml) was stirred at 25 ^C for 16h. The mixture was diluted with water, extracted with EtOAc (3x). The combined organic layer was dried over Na2SO4, filtered and concentrated. The resulting residue was purified by flash chromatography (SiO2, 0-100% EtOAc/hexanes) to provide the title compound. MS (ESI) m/z 497, 499 [M+1]. Step 2: (S)-7-bromo-4-(cyclopropylethynyl)-6-fluoro-1-(4-methoxybenz yl)-3-methyl-4- (trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one: A solution of (S)-7-bromo-4- (cyclopropylethynyl)-6-fluoro-1-(4-methoxybenzyl)-4-(trifluo romethyl)-3,4- dihydroquinazolin-2(1H)-one (580 mg, 1.17 mmol) in 1,4-dioxane (12 ml), was treated with NaH (93 mg, 2.33 mmol). Then, MeI (0.22 mL, 3.50 mmol) was added and the mixture stirred at 25 ^C for 16h. The mixture was quenched with aq sat NH 4 Cl sol and extracted with EtOAc (3x). The combined organic layer was dried over Na2SO4, filtered and concentrated. The resulting residue was purified by flash chromatography (SiO 2 , 0-100% EtOAc:hexanes) to provide the title compound. MS (ESI) m/z 511, 513 [M+1]. Step 3: (S)-4-(cyclopropylethynyl)-6-fluoro-1-(4-methoxybenzyl)-7-(( (4- methoxybenzyl)oxy)methyl)-3-methyl-4-(trifluoromethyl)-3,4-d ihydroquinazolin-2(1H)-one A mixture of (S)-7-bromo-4-(cyclopropylethynyl)-6-fluoro-1-(4-methoxybenz yl)-3-methyl-4- (trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (440 mg, 0.86 mmol), potassium (4- methoxy)benzyloxymethyltrifluoroborate (489 mg, 1.89 mmol) and PdCl 2 (dppf) (70 mg, 0.09 mmol) in 1,4-dioxane (10 mL), was treated with an aq 3 M Cs 2 CO 3 sol (1.7 mL, 5.16 mmol). The resulting mixture was irradiated at 150 °C in microwave oven for 30 min. The mixture was quenched with aq sat NH4Cl sol and extracted with EtOAc (3x). The combined organic layer was dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by flash chromatography (SiO2, 0-100% EtOAc/hexanes) to give the title compound. MS (ESI) m/z 583 [M+1]. Step 4: (S)-4-(cyclopropylethynyl)-6-fluoro-7-(hydroxymethyl)-1-(4-m ethoxybenzyl)-3-methyl- 4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one: A mixture of (S)-4-(cyclopropylethynyl)- 6-fluoro-1-(4-methoxybenzyl)-7-(((4-methoxybenzyl)oxy)methyl )-3-methyl-4- (trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (318 mg, 0.546 mmol) and HCl in 1,4- dioxane (4 M, 1.365 ml, 5.46 mmol) in DCM (1 ml) was stirred at 25 ^C for 3 h. The reaction mixture was concentrated and purified by flash chromatography (SiO 2 , 0-7% MeOH:DCM) to give the title compound. MS (ESI) m/z 463 [M+1]. Step 5: (S)-7-(chloromethyl)-4-(cyclopropylethynyl)-6-fluoro-1-(4-me thoxybenzyl)-3-methyl-4- (trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one: A mixture of (S)-4-(cyclopropylethynyl)-6- fluoro-7-(hydroxymethyl)-1-(4-methoxybenzyl)-3-methyl-4-(tri fluoromethyl)-3,4- dihydroquinazolin-2(1H)-one (230 mg, 0.497 mmol) and thionyl chloride (0.036 ml, 0.497 mmol) in DCM (1 ml) was stirred at 45 ^C for 16 h. The reaction mixture was concentrated to provide the title compound, which was used without further purification. Step 6: (S)-7-((2-aminopyrimidin-4-yl)methyl)-4-(cyclopropylethynyl) -6-fluoro-1-(4- methoxybenzyl)-3-methyl-4-(trifluoromethyl)-3,4-dihydroquina zolin-2(1H)-one: A mixture of 4- chloropyrimidin-2-amine (24 mg, 0.20 mmol), hexamethylditin (0.04 ml, 0.20 mmol), and Pd(PPh3)4 (21 mg, 0.01 mmol) in 1,4-dioxane (1 ml) was bubbled with N2 for 2 min, then heated at 115 °C for 4 h. The reaction mixture added to a mixture of (S)-7-(chloromethyl)-4- (cyclopropylethynyl)-6-fluoro-1-(4-methoxybenzyl)-3-methyl-4 -(trifluoromethyl)-3,4- dihydroquinazolin-2(1H)-one (26 mg, 0.05 mmol), CuI (10 mg, 0.05 mmol), and Pd(PPh3)4 (6.3 mg, 5.4 mmol) in 1,4-dioxane (2 ml). The resulting mixture was bubbled with N 2 for 2 min, then heated at 120 °C for 2 h. The reaction mixture was treated with KF and stirred for 30 min. The reaction mixture was filtered, concentrated and purified by column chromatography (SiO2, 0-8% MeOH/DCM) to give the title product. MS (ESI) m/z 522 [M+1]. Step 7: (S)-7-((2-aminopyrimidin-4-yl)methyl)-4-(cyclopropylethynyl) -6-fluoro-3-methyl-4- (trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one: A mixture of (S)-7-((2-aminopyrimidin-4- yl)methyl)-4-(cyclopropylethynyl)-1-(4-methoxybenzyl)-3-meth yl-4-(trifluoromethyl)-3,4- dihydroquinazolin-2(1H)-one (26 mg, 0.06 mmol) and CAN (51.8 mg, 0.09 mmol) in MeCN (0.8 ml)/water (0.2 ml) was stirred at 70 °C for 3 h. The reaction mixture was concentrated and the resulting residue was purified by HPLC (MeCN:water with 0.1% TFA). 1 H NMR (500 MHz, MeOH-d 4 ) δ ppm 8.21 (d, J = 6.2 Hz, 1H), 7.32 (d, J = 9.8 Hz, 1H), 6.85 (dd, J = 6.2, 3.0 Hz, 2H), 4.22 – 4.09 (m, 2H), 3.25 (s, 3H), 1.54 (ddd, J = 13.3, 8.4, 5.0 Hz, 1H), 0.99 (dq, J = 8.8, 3.1 Hz, 2H), 0.83 (ddd, J = 6.4, 4.9, 3.4 Hz, 2H). MS (ESI) m/z 420 [M+1]. EXAMPLE 41: (S)-2-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluorome thyl)-1,2,3,4- tetrahydroquinazolin-7-yl)methyl)-5-(hydroxymethyl)pyridin-1 -ium 2,2,2-trifluoroacetate
Aq K3PO4 (1.5M, 853 µL, 1.28 mmol) was added to a vial containing intermediate B02 (181 mg, 0.43 mmol), PdCl2(dppf) (31.2 mg, 0.043 mmol), intermediate C07 (101 mg, 0.64 mmol) in 1,4-dioxane (2.1 mL) under N 2 . The resulting mixture was stirred at 90 °C for 16 h. EtOAc (10 mL) was added and the mixture was filtered through Celite ® . The organic layer was concentrated, and the residue was purified by prep-HPLC (water:MeCN with 0.1% TFA) to afford the title compound. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.71 (s, 1H), 8.52 (s, 1H), 8.41 (s, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.17 (d, J = 9.7 Hz, 1H), 6.79 (d, J = 6.5 Hz, 1H), 4.55 (s, 2H), 4.17 (d, J = 5.1 Hz, 2H), 1.54 – 1.42 (m, 1H), 0.87 (dd, J = 8.2, 3.1 Hz, 2H), 0.72 (dt, J = 5.3, 3.1 Hz, 2H). MS (ESI) m/z 420 [M+1]. EXAMPLE 42: (S)-4-(cyclopropylethynyl)-6-fluoro-7-((5-(2-hydroxyethoxy)p yridin-2- yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-o ne Step 1: (S)-4-(cyclopropylethynyl)-7-((5-(2-((tetrahydro-2H-pyran-2- yl)oxy)ethoxy)pyridin-2- yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-o ne: Water (200 µl) was added to a vial containing intermediate B02 (80 mg, 0.189 mmol), intermediate C08 (77 mg, 0.283 mmol), PdCl2(dppf) (13.80 mg, 0.019 mmol) and K3PO4 (60 mg, 0.28 mmol) in 1,4-dioxane (800 µL) under N2. The mixture was stirred at 90 °C for 16h. EtOAc (10 mL) and water (2 mL) were added and the mixture was filtered through Celite ® . The organic layer was separated, concentrated, and the residue was purified with flash chromatography (SiO2, 0-100% (EtOAc:EtOH; 3:1)/hexanes) to provide the title compound. MS (ESI) m/z 534 [M+1]. Step 2: (S)-4-(cyclopropylethynyl)-6-fluoro-7-((5-(2-hydroxyethoxy)p yridin-2-yl)methyl)-4- (trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one: (S)-4-(cyclopropylethynyl)-7-((5-(2- ((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-2-yl)methyl)-4 -(trifluoromethyl)-3,4- dihydroquinazolin-2(1H)-one (30 mg, 0.056 mmol) was dissolved in MeOH (800 µL) and pTsOH . H2O (32.1 mg, 0.169 mmol) was added and the resulting mixture was stirred at 25 ^C for 1 h. The organic was concentrated and the residue was purified by prep-HPLC (water:MeCN with 0.05% NH4OH) to afford the title compound. 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.65 (s, 1H), 8.37 (s, 1H), 8.19 (d, J = 2.9 Hz, 1H), 7.35 (dd, J = 8.6, 3.0 Hz, 1H), 7.18 (dd, J = 39.2, 9.1 Hz, 2H), 6.75 (d, J = 6.5 Hz, 1H), 4.89 (t, J = 5.5 Hz, 1H), 4.02 (dt, J = 9.4, 5.4 Hz, 4H), 3.71 (q, J = 5.1 Hz, 2H), 1.56 – 1.38 (m, 1H), 0.95 – 0.83 (m, 2H), 0.72 (dt, J = 5.2, 3.1 Hz, 2H). MS (ESI) m/z 450 [M+1]. EXAMPLE 43: (S)-4-cyano-2-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(tri fluoromethyl)- Step 1: 2-(((S)-4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluorome thyl)-1,2,3,4- tetrahydroquinazolin-7-yl)methyl)-5-(2-((tetrahydro-2H-pyran -2- yl)oxy)ethoxy)isonicotinonitrile: In a vial, intermediate B02 (100 mg, 0.25 mmol), Cs2CO3 (241 mg, 0.74 mmol), PdCl 2 (dppf) (18.01 mg, 0.025 mmol), intermediate C09 (146 mg, 0.49 mmol) in 1,4-dioxane (0.8 mL) was stirred at 80 °C under N 2 for 16 h. EtOAc (2 mL) and water (2 mL) were added and the organic layer was separated and concentrated. The residue was purified by flash chromatography (SiO2, 0-100% EtOAc/hexanes) to give title compound. MS (ESI) m/z 541 [M+1]. Step 2: 2-((4-(Cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl )-1,2,3,4- tetrahydroquinazolin-7-yl)methyl)-5-(2-hydroxyethoxy)isonico tinonitrile: 2-(((S)-4- (Cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2, 3,4-tetrahydroquinazolin-7- yl)methyl)-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)isonic otinonitrile (45 mg, 0.08 mmol) was dissolved in MeOH (0.8 mL) and p-TsOH monohydrate (15.8 mg, 0.08 mmol). The reaction was stirred for 1h and then diluted with EtOAc (2 mL) and water (2 mL). The organic layer was separated and concentrated to give the title compound, which was used without further purification. MS (ESI) m/z 457 [M+1]. Step 3: (S)-4-cyano-2-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(tri fluoromethyl)-1,2,3,4- tetrahydroquinazolin-7-yl)methyl)-5-(2-hydroxyethoxy)pyridin e 1-oxide: (S)-2-((4- (cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluoromethyl)-1,2, 3,4-tetrahydroquinazolin-7- yl)methyl)-5-(2-hydroxyethoxy)isonicotinonitrile (25 mg, 0.055 mmol) was dissolved in DCM (0.8 mL) and m-CPBA (14.18 mg, 0.082 mmol) was added and stirred at 25 ^C for 16 h. The reaction was neutralized with a aq. sat. Na 2 SO 3 sol. The organic layer was separated and concentrated, and the residue was purified by prep-HPLC (water:MeCN with 0.05% NH 4 OH) to afford the title compound. 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.58 (s, 1H), 8.45 (s, 1H), 8.31 (s, 1H), 8.01 (s, 1H), 7.32 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 6.5 Hz, 1H), 6.72 (s, 1H), 4.27 – 4.17 (m, 2H), 4.01 (s, 2H), 3.81 – 3.67 (m, 2H), 1.47 – 1.39 (m, 1H), 0.86 (dd, J = 8.3, 3.0 Hz, 2H), 0.70 (dd, J = 7.3, 4.2 Hz, 2H). MS (ESI) m/z 473 [M+1]. EXAMPLE 44: (S)-4-((4-(cyclopropylethynyl)-2-thioxo-4-(trifluoromethyl)- 1,2,3,4- tetrahydroquinazolin-7-yl)methyl)benzenesulfonamide Step 1: (S)-4-((2-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)- 3,4-dihydroquinazolin-7- yl)methyl)benzenesulfonamide: A mixture of Example 9 (50 mg, 0.111 mmol) in POCl3 (1 mL, 10.73 mmol) containing Na2CO3 (17.69 mg, 0.167 mmol) was heated to 95 °C for 5h. The reaction was cooled to 25 ^C and concentrated to give the title compound, which was used without further purification. MS (ESI) m/z 468 [M+1]. Step 2: (S)-4-((4-(cyclopropylethynyl)-2-thioxo-4-(trifluoromethyl)- 1,2,3,4-tetrahydroquinazolin- 7-yl)methyl)benzenesulfonamide: A solution of (S)-4-((2-chloro-4-(cyclopropylethynyl)-4- (trifluoromethyl)-3,4-dihydroquinazolin-7-yl)methyl)benzenes ulfonamide (50 mg, 0.107 mmol) in ethanol (534 µL) containing thiourea (24.40 mg, 0.321 mmol) was heated to 95 °C for 5 h. The reaction was then concentrated and the residue was purified by prep HPLC (water:MeCN with 0.1% TFA) to afford the title compound. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 11.10 (s, 1H), 9.89 (s, 1H), 7.76 (d, J = 8.3 Hz, 2H), 7.48 – 7.37 (m, 3H), 7.29 (s, 2H), 7.01 (d, J = 8.1 Hz, 1H), 6.91 (s, 1H), 4.01 (s, 2H), 1.57 – 1.39 (m, 1H), 0.87 (dd, J = 8.3, 3.5 Hz, 2H), 0.83 – 0.64 (m, 2H). MS (ESI) m/z 466 [M+1]. EXAMPLE 45: (S)-7-((6-amino-5-(hydroxymethyl)pyridin-2-yl)methyl)-4- (cyclopropylethynyl)-4-(trifluoromethyl)-3,4-dihydroquinazol in- one Step 1: Tert-butyl (S)-(3-(((tert-butyldimethylsilyl)oxy)methyl)-6-((4-(cyclopr opylethynyl)-2- oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)me thyl)pyridin-2-yl)carbamate: A mixture of intermediate C10 (200 mg, 0.399 mmol), intermediate B08 (100 mg, 0.304 mmol), CuI (57.9 mg, 0.304 mmol), and Pd(PPh3)4 (35.2 mg, 0.030 mmol) in 1,4-dioxane (3 mL) was bubbled with N2 for 2 min, then heated at 110 °C for 16 h. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over Na 2 SO 4 , concentrated, and purified with flash chromatography (0-100%, (3:1 EtOAc:EtOH)/hexanes) to give the title compound. MS (ESI) m/z 631 [M+1]. Step 2: (S)-7-((6-amino-5-(hydroxymethyl)pyridin-2-yl)methyl)-4-(cyc lopropylethynyl)-4- (trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one: A mixture of tert-butyl (S)-(3-(((tert- butyldimethylsilyl)oxy)methyl)-6-((4-(cyclopropylethynyl)-2- oxo-4-(trifluoromethyl)- 1,2,3,4-tetrahydroquinazolin-7-yl)methyl)pyridin-2-yl)carbam ate (58 mg, 0.092 mmol) in TFA (460 µL): DCM (460 µL) was stirred for 16 h at 25 ^C. The reaction was concentrated and the residue was purified by prep HPLC (water:MeCN with 0.1% TFA) to afford the title compound. 1 H NMR (500 MHz, MeOH-d 4 ) δ ppm 7.42 (dd, J = 7.6, 4.4 Hz, 2H), 6.95 (d, J = 8.1 Hz, 1H), 6.74 (s, 1H), 6.54 (d, J = 7.4 Hz, 1H), 4.51 (s, 2H), 3.91 (s, 2H), 1.49 - 1.36 (m, 1H), 0.89 (dd, J = 8.4, 2.9 Hz, 2H), 0.76 (ddt, J = 6.9, 4.8, 2.2 Hz, 2H). MS (ESI) m/z 417 [M+1]. EXAMPLE 46: (S)-7-((6-amino-5-(hydroxymethyl)pyrazin-2-yl)methyl)-4- (cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-3,4-dihydr oquinazolin-2(1H)-one Step 1: (S)-tert-butyl (3-(((tert-butoxycarbonyl)oxy)methyl)-6-((4-(cyclopropylethy nyl)-6-fluoro- 2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl) methyl)pyrazin-2-yl)carbamate: A mixture of intermediate C10 (131 mg, 0.22 mmol), intermediate B08 (70 mg, 0.20 mmol), CuI (38 mg, 0.20 mmol), and Pd(PPh 3 ) 4 (23 mg, 0.02 mmol) in 1,4-dioxane (2 mL) was bubbled with N2 for 2 min, then heated at 110 °C for 16 h. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was separated and dried over Na 2 SO 4 , concentrated to isolate the title compound. Step 2: (S)-7-((6-amino-5-(hydroxymethyl)pyrazin-2-yl)methyl)-4-(cyc lopropylethynyl)-6- fluoro-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one: (S)-tert-butyl (3-(((tert- butoxycarbonyl)oxy)methyl)-6-((4-(cyclopropylethynyl)-6-fluo ro-2-oxo-4-(trifluoromethyl)- 1,2,3,4-tetrahydroquinazolin-7-yl)methyl)pyrazin-2-yl)carbam ate (149 mg, 0.203 mmol) was dissolved in DCM (1 mL):TFA (1 mL) for 16 h. The solution was concentrated and purified by reverse phase chromatography (MeCN:water with 0.1% TFA) to give the title compound. 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.66 (d, J = 21.5 Hz, 1H), 8.38 (d, J = 5.7 Hz, 1H), 7.87 - 7.66 (m, 2H), 7.54 (dd, J = 15.1, 6.6 Hz, 1H), 7.27 - 7.04 (m, 1H), 6.74 (d, J = 6.5 Hz, 1H), 4.46 (s, 2H), 4.05 - 3.80 (m, 2H), 1.59 - 1.38 (m, 1H), 0.87 (dd, J = 8.2, 2.8 Hz, 2H), 0.80 - 0.61 (m, 2H). MS (ESI) m/z 436 [M+1]. EXAMPLE 47: (S)-7-((2-aminopyrimidin-4-yl)methyl)-4-(cyclopropylethynyl) -4-(1,1- difluoroethyl)-6-fluoro-3,4-dihydroquinazolin-2(1H)-one A mixture of 4-chloropyrimidin-2-amine (100 mg, 4.87 mmol), hexamethylditin (0.14 ml, 0.69 mmol), and Pd(PPh 3 ) 4 (26.8 mg, 0.023 mmol) in 1,4-dioxane (3 ml) was heated under N 2 for 2 min at 105 °C for 16 h. The reaction mixture was added to a mixture of intermediate B15 (1613 mg, 6.25 mmol), CuI (3.7 mg, 0.02 mmol), and Pd(PPh3)4 (11.3 mg, 9.77 µmol) in 1,4-dioxane (1 ml). The resulting mixture heated at 105 °C for 16 h under N 2 . The mixture was purified by prep TLC(SiO2, 10% MeOH/EtOAc) to give the crude product, which was repurified by prep-HPLC (MeCN:water with 0.1%TFA) to give the title compound. 1 H NMR (400 MHz, MeCN-d3) δ ppm 0.68 - 0.75 (m, 2H), 0.82 - 0.90 (m, 2H), 1.31 - 1.43 (m, 1H), 1.68 (t, J = 18.8 Hz, 3H), 3.99 - 4.11 (m, 2H), 6.23 (br s, 1H), 6.71 (d, J = 6.0 Hz, 1H), 6.75 (d, J = 6.5 Hz, 1H), 7.26 (d, J = 10.0 Hz, 1H), 7.76 (br s, 1H), 8.14 (br s, 1H). MS (ESI) m/z 402.1 [M+1]. EXAMPLE 48: (S)-7-((2-amino-6-chloropyrimidin-4-yl)methyl)-4-(cyclopropy lethynyl)-4- (trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one A solution of intermediate B08 (40 mg, 0.122 mmol) and 4,6-dichloropyrimidin-2-amine (10 mg, 0.061 mmol) in DME (0.5 ml) was transferred into glove box and added 4,4'-di-tert-butyl- 2,2'-bipyridine (3.27 mg, 0.012 mmol), (TMS) 3 SiH (30.3 mg, 0.122 mmol) and (Ir[dF(CF3)ppy]2(dtbbpy))PF6 (1.365 mg, 1.217 µmol) and NiCl2(DME) (5.35 mg, 0.024 mmol) and Na2CO3 (25.8 mg, 0.243 mmol). The reaction mixture was bubbled with N2 and capped and taken out of glove box. Then, the vial was irradiated with Integrated Photoreactor, 34w LED blue light for 1 h at 25 °C. The residue was purified by prep HPLC (MeCN:water with 0.1%TFA) to give the title compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.66 (s, 1H), 8.33 (s, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.11 (br s, 2H), 6.92 (d, J=7.0 Hz, 1H), 6.71 (s, 1H), 6.59 (s, 1H), 3.78 (s, 2H), 1.53 - 1.39 (m, 1H), 0.95 - 0.81 (m, 2H), 0.78 - 0.55 (m, 2H). MS (ESI) 422.1 [M+1]. The compounds in Table 8 were prepared in an analogous fashion to that described for Example 48. Table 8
EXAMPLE 55: -2-amino-4-((4-(cyclopropylethynyl)-2-oxo-4-(trifluoromethyl )-1,2,3,4- tetrahydroquinazolin-7-yl)methyl)nicotinamide
To a solution of Example 50 (14 mg, 0.034 mmol) in EtOH (4.2 ml) was added KOH (477 mg, 1.702 mmol), the mixture was stirred at 100 °C for 8h. The solution was dried under a stream of N 2 gas and the resulting crude was purified by prep-HPLC (MeCN:water with 10 mM NH4HCO3) to give the title product. 1 H NMR (400 MHz, MeCN-d3) δ ppm 7.91 (d, J = 5.29 Hz, 1H), 7.83 (s, 1H), 7.43 (d, J = 8.16 Hz, 1H), 6.88 - 6.96 (m, 1H), 6.67 (s, 1H), 6.53 (s, 1H), 6.44 (d, J = 5.29 Hz, 1H), 6.40 (s, 1H), 6.32 (s, 1H), 5.15 (br s, 2H), 3.94 (s, 2H), 1.32 - 1.43 (m, 1H), 0.83 - 0.91 (m, 2H), 0.68 - 0.77 (m, 2H). MS (ESI) m/z 430.1 [M+1]. EXAMPLE 56: (S)-4-((4-(cyclopropylethynyl)-6-fluoro-2-oxo-4-(trifluorome thyl)-1,2,3,4- tetrahydroquinazolin-7-yl)methyl)nicotinonitrile To a solution of 4-bromonicotinonitrile (31.7 mg, 0.173 mmol) and intermediate B09 (50 mg, 0.144 mmol) in DMA (5 mL) was added NiCl 2 (DME) (7.92 mg, 0.036 mmol), picolinimidamide (17.5 mg, 0.144 mmol), manganese (32 mg, 0.58 mmol) and TBAI (12.2 mg, 0.033 mmol) in a dry glove box. The reaction was stirred at 80 °C for 2 h. The reaction mixture was quenched with water (20 mL). The reaction mixture was extracted with EtOAc (25mL x 3). The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by prep HPLC (MeCN:water with 0.1%TFA) to give the title compound. 1 H NMR (400 MHz, MeCN-d3) δ ppm 0.68 - 0.79 (m, 2H), 0.81 - 0.93 (m, 2H), 1.38 (tt, J = 8.3, 4.9 Hz, 1H), 4.20 (d, J = 2.1 Hz, 2H), 6.52 (br s, 1H), 6.72 (d, J = 6.4 Hz, 1H), 7.25 - 7.40 (m, 2H), 7.89 (br s, 1H), 8.69 (d, J = 5.2 Hz, 1H), 8.87 (s, 1H). MS (ESI) m/z 415.1 [M+1]. EXAMPLE 57: (S)-4-(cyclopropylethynyl)-6-fluoro-7-(pyridin-4-ylmethyl)-4 -(trifluoromethyl)- 3,4-dihydroquinazolin-2(1H)-one To a solution of intermediate B09 (30 mg, 0.09 mmol) and pyridin-4-ylboronic acid (13.83 mg, 0.112 mmol) was dissolved in water (0.15 mL) and 1,4-dioxane (1.5 mL), was added followed by Na2CO3 (27.5 mg, 0.260 mmol) and Pd(PPh3)4 (10.0 mg, 8.65 µmol) under N2, the mixture was stirred at 100 °C for 4 h. The organic layers were separated and concentrated. The crude was purified by prep-TLC (SiO 2 , 30% EtOAc/PE) to give the title compound. 1 H NMR (400 MHz, CD3OD) δ ppm 0.76 (br d, J=1.54 Hz, 2 H) 0.89 (br dd, J=7.72, 2.43 Hz, 2 H) 1.33 - 1.52 (m, 1 H) 3.89 - 4.20 (m, 2 H) 6.76 (d, J=6.39 Hz, 1 H) 7.25 (br d, J=9.70 Hz, 1 H) 7.29 (br d, J=4.85 Hz, 2 H) 8.44 (br d, J=3.53 Hz, 2 H). MS (ESI) m/z 390.1 [M+1]. EXAMPLE 58: (S)-7-((2-amino-5-fluoropyrimidin-4-yl)methyl)-4-(cyclopropy lethynyl)-4-(1,1- difluoroethyl)-3,4-dihydroquinazolin-2(1H)-one Step 1: (S)-7-((2-chloro-5-fluoropyrimidin-4-yl)methyl)-4-(cycloprop ylethynyl)-4-(1,1- difluoroethyl)-3,4-dihydroquinazolin-2(1H)-one: To a solution of 2,4-dichloro-5- fluoropyrimidine (77 mg, 0.46 mmol) and intermediate B11 (100 mg, 0.31 mmol) in DMA (3.6 mL) was added NiCl2(DME) (16.91 mg, 0.077 mmol), picolinimidamide (37.3 mg, 0.31 mmol), manganese (67.7 mg, 1.23 mmol) and TBAI (26.2 mg, 0.071 mmol) in the glovebox. The reaction was stirred at 70 °C for 2 h. The mixture was directly purified by prep-HPLC (MeCN:water with 0.1%TFA) to give the title compound. MS (ESI) m/z 421.1[M+H]. Step 2: (S)-tert-butyl (4-((4-(cyclopropylethynyl)-4-(1,1-difluoroethyl)-2-oxo-1,2, 3,4- tetrahydroquinazolin-7-yl)methyl)-5-fluoropyrimidin-2-yl)car bamate: To a solution of (S)-7-((2- chloro-5-fluoropyrimidin-4-yl)methyl)-4-(cyclopropylethynyl) -4-(1,1-difluoroethyl)-3,4- dihydroquinazolin-2(1H)-one (20 mg, 0.048 mmol) in toluene (2 mL) were added tert-butyl carbamate (6.68 mg, 0.057 mmol), Xphos Pd G3 (4.02 mg, 4.75 µmol) and NaOtBu (9.13 mg, 0.095 mmol). The reaction was stirred at 100 °C for 16 h. The reaction was purified by prep-TLC (SiO 2 , 50% EtOAc:PE) to give the title compound. Step 3: (S)-7-((2-amino-5-fluoropyrimidin-4-yl)methyl)-4-(cyclopropy lethynyl)-4-(1,1- difluoroethyl)-3,4-dihydroquinazolin-2(1H)-one: To a solution of (S)-tert-butyl (4-((4- (cyclopropylethynyl)-4-(1,1-difluoroethyl)-2-oxo-1,2,3,4-tet rahydroquinazolin-7-yl)methyl)- 5-fluoropyrimidin-2-yl)carbamate (12 mg, 0.024 mmol) in DCM (0.5 mL) was added TFA (0.05 mL). The reaction was stirred at 25 °C for 1 h. The reaction was purified by prep-HPLC (MeCN:water with 10 mM NH 4 HCO 3 ) to give the title compound. 1 H NMR (400 MHz, MeCN- d 3 ) δ = 8.09 (d, J = 1.9 Hz, 1H), 7.57 (br s, 1H), 7.42-7.40 (d, J = 7.9 Hz, 1H), 6.94-6.92 (d, J = 8.1 Hz, 1H), 6.69 (s, 1H), 6.06 (br s, 1H), 5.34 (br s, 2H), 3.92 (s, 2H), 1.68-1.58 (t, J = 18.8 Hz, 4H), 1.42 - 1.29 (m, 1H), 0.85-0.82 (dd, J = 2.9, 8.3 Hz, 2H), 0.70 (br s, 2H). MS (ESI) m/z 402.2 [M+1]. EXAMPLE 59: (S)-7-((2-aminopyrimidin-4-yl)methyl)-4-(cyclopropylethynyl) -6,8-difluoro-4- (trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one Example 59 was prepared using a procedure analogous to Example 56 except that intermediate B09 was replaced by intermediate B13 and 4-bromonicotinonitrile was replaced by 4- bromopyrimidin-2-amine. 1 H NMR (400 MHz, MeCN-d 3 ): δ ppm 0.75 - 0.79 (m, 2H), 0.90 - 0.98 (m, 2H), 1.40 - 1.44 (m, 1H), 4.10 (s, 2H), 6.60 (s, 1H), 6.68-6.69 (d, J = 5.2 Hz, 1H), 7.01 (s, 1H), 7.23-7.25 (d, J = 8.8 Hz, 1H), 7.86 (s, 1H), 8.14 (s, 1H). MS (ESI) m/z 424.1 [M+1]. EXAMPLE 60: Racemate, Isomer 60A and Isomer 60B: (S)-7-((R)-(2-aminopyrazin-4- yl)fluoromethyl)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluor omethyl)-3,4-dihydroquinazolin- 2(1H)-one AND (S)-7-((S)-(2-aminopyrazin-4-yl)fluoromethyl)-4-(cyclopropyl ethynyl)-6-fluoro- 4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one To the solution of Example 38 (15 mg, 0.037 mmol) in MeCN (2.5 ml) was added 1- chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (13.76 mg, 0.039 mmol) at 25 °C. Then the reaction was stirred at 50 °C for 5 h. The mixture was purified by prep- HPLC (MeCN:water with 0.1%TFA) to give the title products: Isomer 60A (faster eluting): 1 H NMR (400 MHz, MeCN-d3) δ ppm 0.74 - 0.82 (m, 2H), 0.90-0.92 (m, 2H), 1.37 - 1.47 (m, 1H), 6.55 (d, J = 44 Hz, 1H), 6.57 (s, 1 H), 6.89-6.91 (d, J = 5.2 Hz, 1H), 7.03-7.04 (d, J = 4.8 Hz, 1H), 7.39-7.42 (d, J = 10.0 Hz, 1H), 7.93 (br s, 1H), 8.34 - 8.36 (d, J = 6.0 Hz, 1H). MS (ESI) m/z 424.2 [M+1]; and Isomer 60B (slower eluting): 1 H NMR (400 MHz, MeCN -d 3 ) δ ppm 0.71 - 0.81 (m, 2H), 0.90-0.92 (m, 2H), 1.34 - 1.46 (m, 1H), 6.56 (d, J = 44 Hz, 1H), 6.57 (s, 1H), 25162 6.90-6.91 (d, J = 6.0 Hz, 1H), 7.04-7.05 (d, J = 5.6 Hz, 2H), 7.18-7.20 (d, J = 8.0 Hz, 1H), 7.39- 7.42 (d, J = 10.0 Hz, 1H), 7.97 (s, 1H), 8.34-8.35 (d, J = 5.60 Hz, 1H). MS (ESI) m/z 424.2 [M+1]. EXAMPLE 61: (S)-4-(cyclopropylethynyl)-7-((3-hydroxypyrazin-2-yl)methyl) -4- (trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one Step 1: (S)-7-((3-chloropyrazin-2-yl)methyl)-4-(cyclopropylethynyl)- 4-(trifluoromethyl)-3,4- dihydroquinazolin-2(1H)-one: A solution of intermediate B08 (60 mg, 0.183 mmol) and 2,3- dichloropyrazine (68.0 mg, 0.46 mmol) in DME (1 ml) was transferred into the glovebox and added 4,4'-di-tert-butyl-2,2'-bipyridine (2.94 mg, 0.011 mmol), (TMS)3SiH (45.4 mg, 0.183 mmol) and (Ir[dF(CF 3 )ppy] 2 (dtbbpy))PF 6 (6.1 mg, 5.5 µmol) and NiCl 2 (DME) (2.0 mg, 9.1 µmol) and Na2CO3 (38.7 mg, 0.36 mmol). The reaction mixture was bubbled with N2 and capped and taken out of glove box. Then, the vial was irradiated with Integrated Photoreactor, 34w LED blue light for 16 h at 25 °C. The residue was purified by prep HPLC (MeCN:water with 0.1%TFA) to give the title compound. Step 2 : (S)-4-(cyclopropylethynyl)-7-((3-hydroxypyrazin-2-yl)methyl) -4-(trifluoromethyl)-3,4- dihydroquinazolin-2(1H)-one: A solution of (S)-7-((3-chloropyrazin-2-yl)methyl)-4- (cyclopropylethynyl)-4-(trifluoromethyl)-3,4-dihydroquinazol in-2(1H)-one (5 mg, 0.012 mmol) in AcOH (1 ml) was stirred at 130 °C for 3 h under microwave irradiation. The reaction mixture was concentrated and the resulting crude was purified by prep HPLC (MeCN:water with 0.1% TFA) to give the title product. 1 H NMR (400 MHz, MeCN-d 3 ) δ ppm 0.70 - 0.71 (m, 2H), 0.84 - 0.88 (m, 2H), 1.33 - 1.37 (m, 1H), 3.97 (s, 2H), 6.32 (br s, 1H), 6.83 (s, 1H), 6.97-6.99 (d, J = 7.8 Hz, 1H), 7.07-7.08 (d, J = 4.3 Hz, 1H), 7.17 (d, J = 4.3 Hz, 1H), 7.41-7.43 (d, J = 7.7 Hz, 1H), 8.01 (br s, 1H). MS (ESI) m/z 389 [M+1]. EXAMPLE 62: Racemate, Isomer 62A and Isomer 62B: (S)-6-chloro-4-(cyclopropylethynyl)- 7-((2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-4-( trifluoromethyl)-3,4- dihydroquinazolin-2(1H)-one, AND (R)-6-chloro-4-(cyclopropylethynyl)-7-((2,4-dimethyl-6- oxo-1,6-dihydropyrimidin-5-yl)methyl)-4-(trifluoromethyl)-3, 4-dihydroquinazolin-2(1H)-one Step 1: 6-chloro-4-(cyclopropylethynyl)-1-(4-methoxybenzyl)-7-(4,4,5 ,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-4-(trifluoromethyl)-3,4-dihydroquinazolin -2(1H)-one: A solution of intermediate A02 (2.2 g, 4.28 mmol), BisPin (1.631 g, 6.42 mmol), and KOAc (1.261 g, 12.85 mmol) in 1,4-dioxane (44 mL) was added Pd(PPh3)2Cl2 (0.301 g, 0.428 mmol) under N2 and the resulting mixture was stirred at 80 °C for 5h under N2. The residue was purified by prep HPLC (MeCN:water with 0.05% HCl) to give the title compound. MS (ESI) m/z 434 [M+1]. Step 2: 6-chloro-4-(cyclopropylethynyl)-7-((4-methoxy-2,6-dimethylpy rimidin-5-yl)methyl)-1- (4-methoxybenzyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin- 2(1H)-one: To a solution of 6- chloro-4-(cyclopropylethynyl)-1-(4-methoxybenzyl)-7-(4,4,5,5 -tetramethyl-1,3,2- dioxaborolan-2-yl)-4-(trifluoromethyl)-3,4-dihydroquinazolin -2(1H)-one (800 mg, 1.671 mmol) in THF (8 mL) and water (0.8 mL) was added intermediate C05 (312 mg, 1.671 mmol), KOAc (710 mg, 3.34 mmol) and XPhos Pd G3 (263 mg, 0.334 mmol). The reaction was stirred at 100 °C for 3 h under N 2 . The mixture was purified by flash chromatography (SiO 2 , 0-30% EtOAc/PE) to give the title compound. MS (ESI) m/z 585.3 [M+1]. Step 3: 6-chloro-4-(cyclopropylethynyl)-7-((2,4-dimethyl-6-oxo-1,6-d ihydropyrimidin-5- yl)methyl)-1-(4-methoxybenzyl)-4-(trifluoromethyl)-3,4-dihyd roquinazolin-2(1H)-one: To a mixture of 6-chloro-4-(cyclopropylethynyl)-7-((4-methoxy-2,6-dimethylpy rimidin-5- yl)methyl)-1-(4-methoxybenzyl)-4-(trifluoromethyl)-3,4-dihyd roquinazolin-2(1H)-one (50 mg, 0.09 mmol) in DMF (2.5 mL) was added pyridine hydrochloride (50 mg, 0.43 mmol). The reaction was stirred at 100 °C for 2 h. The reaction was dissolved in water (10 mL) and extracted with EtOAc (10 mLx3). The organic layer was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to give the title product, which was used in the next step as is. Step 4: 6-chloro-4-(cyclopropylethynyl)-7-((2,4-dimethyl-6-oxo-1,6-d ihydropyrimidin-5- yl)methyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-o ne: To a stirred solution of 6- chloro-4-(cyclopropylethynyl)-7-((2,4-dimethyl-6-oxo-1,6-dih ydropyrimidin-5-yl)methyl)-1- (4-methoxybenzyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin- 2(1H)-one (50 mg, 0.09 mmol) in MeCN (1 mL) and water (0.33 mL) was added CAN (192 mg, 0.35 mmol) and the mixture was stirred at 40 °C for 1 h. The reaction was dissolved in water (10 mL) and extracted with EtOAc (10 mLx3). The organic layer was washed with brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated. The crude product was purified by prep-HPLC (MeCN:water with 0.1% TFA). The resulting racemic product was separated by SFC (DAICEL CHIRALPAK AS, 40% MeOH (0.1% NH 3 H 2 O)/ CO 2 , 70 mL/min, 40 ^C) to give: Isomer 62A (faster eluting): 1 H NMR (400 MHz, MeOH-d 4 ): δ ppm 7.48 (s, 1H), 6.52 (s, 1H), 3.93 (s, 2H), 2.40 (s, 3H), 2.23 (s, 3H), 1.38 - 1.50 (m, 1H), 0.90 - 0.94 (m, 2H), 0.78 (dq, J = 4.9, 3.3 Hz, 2H). MS (ESI) m/z 451.1 [M+1]; and Isomer 62B (slower eluting): 1 H NMR (400 MHz, MeOH-d4): δ ppm 7.48 (s, 1H), 6.51 (s, 1H), 4.10 (q, J = 7.1 Hz, 1H), 3.92 (s, 2H), 2.39 (s, 3H), 2.22 (s, 3H), 1.38 - 1.48 (m, 1H), 0.86 - 0.95 (m, 2H), 0.77 (dq, J = 4.9, 3.3 Hz, 2H). MS (ESI) m/z 451.1 [M+1] . EXAMPLE 63: (S)-4-(cyclopropylethynyl)-7-((2-(hydroxymethyl)-4-methyl-6- oxo-1,6- dihydropyrimidin-5-yl)methyl)-4-(trifluoromethyl)-3,4-dihydr oquinazolin-2(1H)-one Step 1: ethyl 2-(((S)-4-(cyclopropylethynyl)-2-oxo-4-(trifluoromethyl)-1,2 ,3,4- tetrahydroquinazolin-7-yl)methyl)-3-oxobutanoate: To a solution of intermediate B08 (100 mg, 0.304 mmol) and ethyl 3-oxobutanoate (396 mg, 3.04 mmol) and sodium ethoxide (31.1 mg, 0.456 mmol) in EtOH (2 mL) was stirred 80 °C for 16 h. The reaction mixture was concentrated and purified by prep-TLC (SiO2, 50% EtOAc/PE) to give the title compound. Step 2: (S)-4-(cyclopropylethynyl)-7-((2-(hydroxymethyl)-4-methyl-6- oxo-1,6- dihydropyrimidin-5-yl)methyl)-4-(trifluoromethyl)-3,4-dihydr oquinazolin-2(1H)-one: A mixture of ethyl 2-(((S)-4-(cyclopropylethynyl)-2-oxo-4-(trifluoromethyl)-1,2 ,3,4- tetrahydroquinazolin-7-yl)methyl)-3-oxobutanoate (50 mg, 0.118 mmol), 2- hydroxyacetamidamide hydrochloride (52.3 mg, 0.47 mmol) and K 2 CO 3 (48.8 mg, 0.35 mmol) in EtOH (1 mL) was stirred at 40 °C for 12 h. The reaction mixture was concentrated and purified by prep-HPLC (MeCN:water with 0.1%TFA) to give the title compound. 1 H NMR (400 MHz, MeOH-d 4 ) δ ppm 0.72 - 0.77 (m, 2H), 0.85 - 0.91 (m, 2H), 1.36 - 1.44 (m, 1H), 2.31 (s, 3H), 3.88 (s, 2H), 4.48 (s, 2H), 6.72 (s, 1H), 6.92 - 6.98 (d, J = 7.9 Hz, 1H), 7.40 (d, J = 7.9 Hz, 1H). MS (ESI) m/z 433.2 [M+1]. Determination of cell kill (HIV-TACK) activity: PBMCs derived from healthy donors were grown in complete media (RPMI 1640 with L-glutamine; 10% heat inactivated Fetal Bovine Serum; 100 U/mL Penicillin-Streptomycin) containing 5 µg/mL Phytohemagglutinin at about 2.5 x 106 cells/mL for 3 days at 5% CO2, 37°C, and 90% humidity. On day 4, PHA stimulated cells were washed and resuspended at about 20 x 106 cells/mL in complete media with IL-2 (10 U/mL) with VSV-G pseudotyped HIV virus stock (VSV- G/pNLG1-P2A-∆Env - 20 µg/mL p24) and incubated for 4 hours at 37°C, 5% CO2 and 90% humidity. VSV-G/pNLG1-P2A-∆Env is a VSV-G pseudotyped virus derived from pNL43 with egfp inserted 5’ of nef and eGFP expression driven off normal spliced RNA transcripts. Virus contained Vif truncated by 50 amino acids due to deletion of a single nucleotide causing a frameshift and does not express Nef due to a stop codon after gfp. HIV Env is not expressed due to a frameshift resulting in multiple stop codons. Infected cells were then washed with complete media plus 10U/mL IL-23- times with centrifuging at 200 x g for 3 minutes at 22°C. Cells were resuspended at 5 x 106 cells/mL in complete media plus 10 U/mL IL-2 and incubated overnight at 37°C, 5% CO2 and 90% humidity. For compound treatment infected PBMCs were diluted to 4 x 105 cells/mL with RPMI 1640 with L-glutamine, 50% Normal Human Serum (NHS), 100 U/mL Penicillin- Streptomycin plus IL-2 (10 U/mL) and 20,000 cells were transferred to each well in a 384-well poly-D-lysine coated compound plate containing compounds with final DMSO <0.5%. Compounds were tested with 10-point 3-fold titration. Plates were analyzed on an Acumen ex3 imager using the Blue Laser 488 nm and the number of GFP positive objects were collected with loss of GFP representing death of infected cells. Titration curves and EC50 values were calculated using a four- parameter logistic fit. Results are shown in Table 9. TABLE 9
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