HOLMES RYAN (US)
MAITY SOHAM (US)
COMBS ANDREW (US)
BUESKING ANDREW (US)
PAWLEY SARAH (US)
WO2021202964A1 | 2021-10-07 | |||
WO2023060262A1 | 2023-04-13 | |||
WO2023078401A1 | 2023-05-11 | |||
WO2023081209A1 | 2023-05-11 |
US5023252A | 1991-06-11 | |||
US4992445A | 1991-02-12 | |||
US5001139A | 1991-03-19 | |||
US5451233A | 1995-09-19 | |||
US5040548A | 1991-08-20 | |||
US5061273A | 1991-10-29 | |||
US5496346A | 1996-03-05 | |||
US5292331A | 1994-03-08 | |||
US5674278A | 1997-10-07 | |||
US3657744A | 1972-04-25 | |||
US4739762A | 1988-04-26 | |||
US5195984A | 1993-03-23 | |||
US5879382A | 1999-03-09 | |||
US6344053B1 | 2002-02-05 |
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What is claimed: 1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is aryl, a 3-8 membered cycloalkyl ring, a 5-7 membered heteroaryl ring comprising 1-4 heteroatoms selected from N, O, and S, or a 5-7 membered heterocyclic group comprising 1-4 heteroatoms selected from N, O, and S; W is a 5-10 membered heteroaryl ring comprising 1-4 heteroatoms selected from N, O, and S, or a 5-12 membered heterocyclic group comprising 1-4 heteroatoms selected from N, O, and S, C1-C8 alkyl, haloalkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkenyl, NRcRd, ORb, or SRb; wherein each group is optionally substituted by 1-6 Rf groups; Y is CR2 or N; n is 1, 2, 3, 4 or 5; m is 1, 2 or 3; L is a bond, O, S, NRa or C1-C6 alkylene; R1 is H, D, ORa, C1-C8 alkoxide, C1-C8 alkyl, haloalkyl, -C3-C8 cycloalkyl, -C3-C10 cycloalkenyl, aryl, or heteroaryl; wherein said C1-C8 alkoxide, C1-C8 alkyl, haloalkyl, C3-C8 cycloalkyl, -C3-C10 cycloalkenyl, aryl, and heteroaryl are optionally substituted by 1-6 Rf groups; each R2 and R5 is independently H, D, halogen, C1-C8 alkoxide, C1-C8 alkyl, haloalkyl, - OH, -CN, -NO2, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, -ORa, -SRa, -NRcRd, -NRaRc, -C(O)Rb, -OC(O)Rb, - C(O)ORb, -C(O)NRcRd, -S(O)Rb, -S(O)2NRcRd, -S(O)(=NRb)Rb, -SF5, -P(O)RbRb, - P(O)(ORb)(ORb), -B(ORc)(ORd), -S(O)2Rb, -C(O)NRbORb, -S(O)2ORb, -OS(O)2ORb, or - OPO(ORb)(ORb); wherein said C1-C8 alkyl is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -ORa, -SRa, -NRaRd, or NRcRd; each R3 and R4 is independently H, D, halogen, C1-C8 alkoxide, C1-C8 alkyl, haloalkyl, or CN; wherein said C1-C8 alkyl is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -ORa, -SRa, -NRaRd, or NRcRd; or R3 and R4 together with the atom to which they are attached are combined to form a C3-C7 cycloalkyl or C4-C8 heterocycloalkyl; each Ra is independently H, D, -C(O)Rb, -C(O)ORc, -C(O)NRcRd, -C(=NRb)NRbRc, - C(=NORb)NRbRc, -C(=NCN)NRbRc, -P(ORc)2, -P(O)RcRb, -P(O)ORcORb, -S(O)Rb, -S(O)NRcRd, -S(O)2Rb, -S(O)2NRcRd, SiRb3, -C1-C10alkyl, -C2-C10 alkenyl, -C2-C10 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl; each Rb, is independently H, D, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl; each Rc or Rd is independently H, D, -C1-C10 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -OC1- C6alkyl, -O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; or Rc and Rd, together with the atom to which they are both attached, form a monocyclic or multicyclic heterocycloalkyl, or a monocyclic or multicyclic heterocyclo-alkenyl group. Re is C3-C8 cycloalkyl, heterocycloalkyl wherein the heterocycloalkyl is attached to (C1- C6-alkyl) through a carbon atom or a sulfur atom of the heterocycloalkyl group, cycloalkenyl, heterocycloalkenyl wherein the heterocycloalkenyl is attached to (C1-C6-alkyl) through a carbon atom or a sulfur atom of the heterocycloalkenyl group, aryl, or heteroaryl, and each C3-C8 cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl is optionally substituted by 1-6 Rf groups; each Rf is independently H, D, oxo, halogen, C1-C8 alkoxide, C1-C8 alkyl, haloalkyl, -OH, -CN, -NO2, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, -ORa, -SRa, -NRcRd, -NRaRc, -C(O)Rb, -OC(O)Rb, - C(O)ORb, -C(O)NRcRd, -S(O)Rb, -S(O)2NRcRd, -S(O)(=NRb)Rb, -SF5, -P(O)RbRb, - P(O)(ORb)(ORb), -B(ORc)(ORd), -S(O)2Rb, -C(O)NRbORb, -S(O)2ORb, -OS(O)2ORb, or - OPO(ORb)(ORb); wherein said C1-C8 alkyl is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -ORa, -SRa, -NRaRd, or NRcRd. 2. The compound of claim 1, wherein ring A is aryl. 3. The compound of claim 2, wherein the aryl is a phenyl ring. 4. The compound of claim 1, wherein ring A is a 5-7 membered heteroaryl ring comprising 1-4 heteroatoms selected from N, O, and S. 5. The compound of any one of the preceding claims, wherein W is a 5-12 membered heterocyclic group comprising 1-4 heteroatoms selected from N, O, and S optionally substituted by 1-6 Rf groups. 6. The compound of any one of the preceding claims, wherein the 5-12 membered heterocyclic group is an isoindoline group optionally substituted by 1-6 Rf groups. 7. The compound of any one of claims 1-4, wherein W is NRcRd. 8. The compound of any one of the preceding claims, wherein Y is N. 9. The compound of any one of the preceding claims, wherein n is 1. 10. The compound of any one of claims 1-8, wherein n is 2. 11. The compound of any one of claims 1-8, wherein n is 3. 12. The compound of any one of claims 1-8, wherein n is 4. 13. The compound of any one of claims 1-8, wherein n is 5. 14. The compound of any one of the preceding claims, wherein m is 1. 15. The compound of any one of claims 1-13, wherein m is 2. 16. The compound of any one of claims 1-13, wherein m is 3. 17. The compound of any one of the preceding claims, wherein L is NRa. 18. The compound of any one of the preceding claims, wherein L is NH. 19. The compound of any one of the preceding claims, wherein R1 is H or C1-C8 alkyl optionally substituted by 1-6 Rf groups. 20. The compound of claim 19, wherein R1 is H. 21. The compound of claim 19, wherein R1 is C1-C8alkyl optionally substituted by 1-6 Rf groups. 22. The compound of claim 21, wherein R1 is methyl. 23. The compound of any one of the preceding claims, wherein at least one R2 is H. 24. The compound of any one of claims 1-22, wherein at least one R2 is C1-C8 alkyl, CF3, Br, F, CN or CHF2. 25. The compound of claim 24, wherein at least one R2 is methyl or CF3. 26. The compound of any one of the preceding claims, wherein R3 is H. 27. The compound of any one of claims 1-25, wherein R3 is C1-C8 alkyl. 28. The compound of claim 27, wherein R3 is methyl. 29. The compound of any one of the preceding claims, wherein R4 is H. 30. The compound of any one of claims 1-28, wherein R4 is C1-C8 alkyl. 31. The compound of claim 30, wherein R4 is methyl. 32. The compound of any one of the preceding claims, wherein at least one R5 is H. 33. The compound of any one of claims 1-31, wherein at least one R5 is -CO2H. 34. The compound of any one of the preceding claims, in the form of a pharmaceutically acceptable salt. 35. The compound of claim 1, that is a compound of formula (II) , or a pharmaceutically acceptable salt or stereoisomer thereof. 36. The compound of claim 1, that is a compound of formula (III) , or a pharmaceutically acceptable salt or stereoisomer thereof. 37. The compound of claim 1, that is a compound of formula (IV) , or a pharmaceutically acceptable salt or stereoisomer thereof. 38. The compound of claim 1, that is a compound of formula (V) , or a pharmaceutically acceptable salt or stereoisomer thereof. 39. The compound of claim 1, that is a compound of formula (VI) , or a pharmaceutically acceptable salt or stereoisomer thereof. 40. The compound of claim 1 that is: 2-((1-(2-(isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino) benzoic acid; 2-((1-(2-(5-fluoroisoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl) amino)benzoic acid; 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl) amino)benzoic acid; or a pharmaceutically acceptable salt thereof. 41. The compound of claim 1 that is: 2-((1-(2-(isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino) benzamide; 2-((1-(2-(isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)- N-methoxybenzamide; 2-((1-(2-(isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino) benzenesulfonamide; 2-((1-(2-(isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)- N-methylbenzenesulfonamide; 2-(isoindolin-2-yl)-3,6-dimethyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl) quinazolin-4(3H)-one; 8-(1-((2-(1H-tetrazol-5-yl)phenyl)amino)ethyl)-2-(isoindolin-2-yl)-3,6- dimethylquinazolin-4(3H)-one; N-hydroxy-2-((1-(2-(isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl) amino)benzamide; 8-(1-((2,4-difluoro-3-hydroxyphenyl)amino)ethyl)-2-(isoindolin-2-yl)-3,6-dimethyl- quinazolin-4(3H)-one; 2-(isoindolin-2-yl)-3,6-dimethyl-8-(1-((2-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)amino) ethyl)quinazolin-4(3H)-one; 2-((1-(2-(isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)thio) benzoic acid; 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-5-cyano-3,6-dimethyl-4-oxo-3,4-dihydro- quinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-(isoindolin-2-yl)-3-methyl-4-oxo-6-(trifluoromethyl)-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid; 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-methyl-4-oxo-6-(trifluoromethyl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl) ethyl)amino)benzoic acid; 2-((1-(2-(isoindolin-2-yl)-6-methyl-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-8-yl) ethyl)amino)benzoic acid; 2-((1-(2-(isoindolin-2-yl)-3-(2-methoxyethyl)-6-methyl-4-oxo-3,4-dihydroquinazolin-8- yl) ethyl)amino)benzoic acid; 2,3-difluoro-6-((1-(3-(3-fluoropropyl)-2-(isoindolin-2-yl)-6-methyl-4-oxo-3,4-dihydro- quinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-(isoindolin-2-yl)-3-isopropyl-6-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl) amino)benzoic acid; 2-((1-(2-(isoindolin-2-yl)-6-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino) benzoic acid; 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl) ethyl)amino)-4-cyanobenzoic acid; 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl) ethyl)amino)benzoic acid; 2-((1-(3,6-dimethyl-4-oxo-2-(1H-pyrazol-5-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino) benzoic acid; 2-((1-(2-amino-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-(isoindolin-2-yl)-3-isopropyl-6-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl) amino)benzoic acid; 3-((1-(2-(isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino) picolinic acid; 2-((1-(2-(isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)- 6-methoxybenzoic acid; 2-((1-(2-(isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)- 5-(trifluoromethyl)benzoic acid; 5-cyano-2-((1-(2-(isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl) amino)benzoic acid; 4-fluoro-2-((1-(2-(isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl) amino)benzoic acid; 5-chloro-2-((1-(2-(isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl) amino)benzoic acid; 4-((1-(2-(isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)- 1-methyl-1H-pyrazole-3-carboxylic acid; 2,3-difluoro-6-((1-(2-(isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl) ethyl)amino)benzoic acid; 2-((1-(2-(isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino) nicotinic acid; 2-((1-(2-(4,4-difluoropiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid; 2-((1-(5-acrylamido-2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-[1-[2-(5-azaspiro[2.4]heptan-5-yl)-3,6-dimethyl-4-oxoquinazolin-8-yl]ethylamino] benzoic acid; 2-[1-(2-methoxy-3,6-dimethyl-4-oxoquinazolin-8-yl)ethylamino]benzoic acid; 2-((1-(2-hydroxy-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-[1-(3,6-dimethyl-2-methylsulfanyl -4-oxoquinazolin-8-yl)ethylamino]benzoic acid; 2-((1-(2-(4-cyanopiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl) amino)benzoic acid; 3-fluoro-2-((1-(2-(isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl) amino)benzoic acid; 2-((1-(2-(4-acetylpiperazin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl) amino)benzoic acid; 2-[[1-[2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxoquinazolin-8-yl]-2,2,2- trifluoroethyl]amino]benzoic acid; ((1-(3-((1r,3r)-3-Hydroxycyclobutyl)-2-(isoindolin-2-yl)-6-methyl-4-oxo-3,4-dihydro- quinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-fluoro-3-methyl-4-oxo-3,4-dihydro- quinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(6-cyano-2-(isoindolin-2-yl)-3-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl) amino)benzoic acid; 2-[1-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-3,6-dimethyl-4-oxoquinazolin-8-yl]ethyl- amino]benzoic acid 2-[1-[3,6-dimethyl-4-oxo-2-(3-phenylpyrrolidin-1-yl)quinazolin-8-yl]ethylamino] benzoic acid; 2-[1-[3,6-dimethyl-4-oxo-2-(3-phenylpyrrolidin-1-yl)quinazolin-8-yl]ethylamino] benzoic acid; 2-[1-[2-(dimethylamino)-3,6-dimethyl-4-oxoquinazolin-8-yl]ethylamino]benzoic acid; 2-((1-(2-(azepan-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino) benzoic acid; 2-((1-(2-(1,1-dioxidothiomorpholino)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl) ethyl)amino)benzoic acid; 2-((1-(2-(4-hydroxypiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl) ethyl)amino)benzoic acid; or a pharmaceutically acceptable salt thereof. 42. The compound of claim 1 that is: 2-((1-(2-((1R,5S,6s)-6-((methoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-((1R,5S,6s)-6-(((benzyloxy)carbonyl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)- 3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(3,6-dimethyl-4-oxo-2-((1R,5S,6s)-6-(((2,2,2-trifluoroethoxy)carbonyl)amino)-3- azabicyclo[3.1.0]hexan-3-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(3,6-dimethyl-2-((1R,5S,6s)-6-(((2-morpholinoethoxy)carbonyl)amino)-3- azabicyclo[3.1.0]hexan-3-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-((1R,5S,6s)-6-(((4-methoxyphenoxy)carbonyl)amino)-3-azabicyclo[3.1.0]hexan- 3-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-((1R,5S,6s)-6-((cyclopropoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)- 3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(3,6-dimethyl-4-oxo-2-((1R,5S,6s)-6-((((tetrahydrofuran-2-yl)methoxy)carbonyl) amino)-3-azabicyclo[3.1.0]hexan-3-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-(5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-3,6-dimethyl-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-((3aR,6aR)-5-acetylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3,6-dimethyl-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-(5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; methyl 2-[1-[2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-methyl-4-oxo-6-(trideuteriomethyl) quinazolin-8-yl]ethylamino]benzoate; 2-((1-(2-(isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)- 4-methylbenzoic; 2-((1-(6-bromo-2-(isoindolin-2-yl)-3-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl) amino)benzoic acid; 2-[1-[3,6-dimethyl-4-oxo-2-(1-prop-2-enoylpyrrolidin-2-yl)quinazolin-8-yl]ethylamino] benzoic acid; 2-((1-(2-(isoindolin-2-yl)-3-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino) benzoic acid; 2-[1-[2-(1-fluorosulfonylpyrrolidin-2-yl)-3,6-dimethyl-4-oxoquinazolin-8-yl]ethyl- amino]benzoic acid; 2-((1-(6-bromo-2-(4,4-difluoropiperidin-1-yl)-3-methyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid; 2-((1-(3-((1r,3r)-3-cyanocyclobutyl)-2-(isoindolin-2-yl)-6-methyl-4-oxo-3,4-dihydro- quinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-cyclopropyl-3-methyl-4-oxo-3,4-dihydro- quinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-methoxy-3-methyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-ethyl-3-methyl-4-oxo-3,4-dihydroquinazolin- 8-yl)ethyl)amino)benzoic acid; 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-(difluoromethyl)-3-methyl-4-oxo-3,4- dihydro-quinazolin-8-yl)ethyl)amino)benzoic acid; 3-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)-6-(trifluoromethyl)picolinic acid; 2-((1-(2-((1R,5S,6R)-6-(isopropyl(methyl)carbamoyl)-3-azabicyclo[3.1.0]hexan-3-yl)- 3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-((1R,5S,6R)-6-(cyclobutyl(methyl)carbamoyl)-3-azabicyclo[3.1.0]hexan-3-yl)- 3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-((1R,5S,6R)-6-(methoxy(methyl)carbamoyl)-3-azabicyclo[3.1.0]hexan-3-yl)- 3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-((1R,5S,6R)-6-((2,2-difluoroethyl)(methyl)carbamoyl)-3-azabicyclo[3.1.0] hexan-3-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(3,6-dimethyl-2-((1R,5S,6R)-6-((S)-2-methylpyrrolidine-1-carbonyl)-3-azabicyclo [3.1.0]hexan-3-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(3,6-dimethyl-2-((1R,5S,6R)-6-((S)-3-methylmorpholine-4-carbonyl)-3-azabicyclo [3.1.0]hexan-3-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-((1R,5S,6R)-6-((2-methoxyethyl)(methyl)carbamoyl)-3-azabicyclo[3.1.0]hexan- 3-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(3,6-dimethyl-2-((1R,5S,6R)-6-(methyl(pyridin-3-yl)carbamoyl)-3- azabicyclo[3.1.0] hexan-3-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(3,6-dimethyl-2-((1R,5S,6R)-6-(methylcarbamoyl)-3-azabicyclo[3.1.0]hexan-3-yl)- 4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-((1R,5S,6R)-6-(dimethylcarbamoyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-(4-(cyclopentanecarbonyl)piperazin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydro- quinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-(4-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)piperazin-1-yl)-3,6-dimethyl-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-(4-(2-methoxyacetyl)piperazin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin- 8-yl)ethyl)amino)benzoic acid; 2-((1-(3,6-dimethyl-2-(4-(6-methylnicotinoyl)piperazin-1-yl)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-5-fluoro-3,6-dimethyl-4-oxo-3,4-dihydro- quinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)-2,2-difluoroethyl)amino)benzoic acid; 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)propyl)amino)benzoic acid; 2-((1-(3-(3,3-bis(hydroxymethyl)cyclobutyl)-2-(isoindolin-2-yl)-6-methyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-(2-azabicyclo[2.2.1]heptan-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid; 2-((1-(2-(2-azabicyclo[2.2.1]heptan-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid; 2-((1-(2-(2-azabicyclo[2.2.1]heptan-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid; 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-(difluoromethyl)-6-methyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-methyl-4-oxo-3-(2,2,2-trifluoroethyl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-methyl-3-(methyl-d3)-4-oxo-3,4-dihydro- quinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-chloro-3-methyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-[1-[2-(7,7-difluoro-2-azaspiro[3.3]heptan-2-yl)-3,6-dimethyl-4-oxoquinazolin-8- yl]ethyl-amino]benzoic acid; 2-[1-[3,6-dimethyl-2-[2-[(2-methylpropan-2-yl)oxycarbonylamino]-7-azaspiro[3.5] nonan-7-yl]-4-oxoquinazolin-8-yl]ethylamino]benzoic acid; 2-[1-[3,6-dimethyl-2-[2-[(2-methylpropan-2-yl)oxycarbonyl]-2,7-diazaspiro[3.5]nonan- 7-yl]-4-oxoquinazolin-8-yl]ethylamino]benzoic acid; 2-[1-[2-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-3,6-dimethyl-4-oxoquinazolin-8- yl]ethyl-amino]benzoic acid; 2-[1-[3,6-dimethyl-2-[3-[(2-methylpropan-2-yl)oxycarbonylamino]pyrrolidin-1-yl]-4- oxoquinazolin-8-yl]ethylamino]benzoic acid; 2-[1-[2-(7-azabicyclo[2.2.1]heptan-7-yl)-3,6-dimethyl-4-oxoquinazolin-8-yl]ethyl- amino] benzoic acid; 2-[1-[2-(3-azabicyclo[3.2.0]heptan-3-yl)-3,6-dimethyl-4-oxoquinazolin-8-yl]ethyl- amino] benzoic acid; 2-[1-[3,6-dimethyl-4-oxo-2-[rac-(3aR,6aS)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c] pyrrol-2-yl]quinazolin-8-yl]ethylamino]benzoic acid; 2-((1-(3,6-dimethyl-4-oxo-2-(4-azaspiro[2.4]heptan-4-yl)-3,4-dihydroquinazolin-8- yl)ethyl) amino)benzoic acid; 2-((1-(2-(2,2-dimethylpyrrolidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl) amino)benzoic acid; 2-((1-(2-(3-azabicyclo[3.1.1]heptan-3-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid; 2-((1-(2-(2-azabicyclo[2.1.1]hexan-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid; 5-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)-2-(methylthio)pyrimidine-4-carboxylic acid; 3-[1-[2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxoquinazolin-8-yl]ethyl- amino]-6-methoxypyridine-2-carboxylic acid; 3-[1-[2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxoquinazolin-8-yl]ethyl- amino]-6-methylpyridine-2-carboxylic acid; 2-[1-[2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxoquinazolin-8-yl]ethyl- amino]-6-fluorobenzoic acid; 2-[1-[2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxoquinazolin-8-yl]ethyl- amino]-5-methoxybenzoic acid; 2-[1-[2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxoquinazolin-8-yl]ethyl- amino]-5-fluorobenzoic acid; 3-[1-[2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxoquinazolin-8-yl]ethyl- amino]-6-methylsulfanylpyridine-2-carboxylic acid; 4-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)-6-fluoronicotinic acid; 4-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)-6-chloropyridazine-3-carboxylic acid; or a pharmaceutically acceptable salt thereof. 43. A pharmaceutical composition comprising a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 44. A method of treating a disease or disorder associated with modulation of phosphoinositide 3 -kinase (PI3K), comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-42 or a pharmaceutical composition of claim 43. 45. The method of claim 44, wherein the PI3K is PI3Kα. 46. The method of claim 44 or claim 45, wherein the PI3K associated with the disease or disorder has a H1047R mutation. 47. The method of any one of claims 44-46, wherein the disease or disorder is a cancer. 48. The method of claim 47, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, cervical cancer, bladder cancer, esophageal cancer, pancreatic cancer, bone cancer, hepatobiliary cancer, medulloblastoma, kidney cancer or prostate cancer. 49. The method of any one of claims 44-46, wherein the disease or disorder is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome), or PIK3CA-related overgrowth syndrome (PROS). 50. A method of inhibiting phosphoinositide 3-kinase (PI3K), comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1- 42 or a pharmaceutical composition of claim 43. 51. A method of treating cancer or a disorder, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1- 42 or a pharmaceutical composition of claim 43. 52. The method of claim 51, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer. 53. The method of claim 51, wherein the cancer is breast cancer. 54. The method of claim 51, wherein the disorder is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) or PIK3CA-related overgrowth syndrome (PROS). 55. The method of claim 51, wherein the disorder is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome). 56. The method of claim 51, wherein the disorder is PIK3CA-related overgrowth syndrome (PROS). 57. A method of degrading a phosphoinositide 3-kinase (PI3K) protein comprising contacting the PI3K protein with a compound of any one of claims 1-42 or a pharmaceutical composition of claim 43. 58. The method of claim 57, wherein the PI3K is PI3Kα. |
[00238] Compounds of Formula (I) can be prepared from optionally protected compounds 1-2 as shown in Scheme II. Reaction of compounds 1-2 with compounds 2-1 under standard reductive amination conditions (e.g., reducing agent such as, sodium triacetoxyborohydride and optionally an acid, such as acetic acid) can provide compounds 2-2. Alternatively, compounds 2-2 can be converted to compounds 2-5 under reductive condition (e.g., in the presence of a suitable reducing agent, such as sodium borohydride). Alcohols 2-5 can be transformed to compounds 2-6 where Lg 2 is halogen (e.g., Cl, Br, or I) under standard deoxygenative halogenation conditions (e.g., thionyl chloride, phosphorous tribromide, or triphenylphosphine and iodine) or a pseudohalogen (e.g., OTf, OTs, or OMs) under sulfonylation standard conditions (e.g., in the presence of a sulfonylating agent, such as methanesulfonyl chloride, p- toluenesulfonyl chloride, or trifluoromethanesulfonic anhydride, and a base, such as triethylamine). Alkylation of compounds 2-6 with nucleophiles 2-1 optionally in the presence of a base (e.g., triethylamine) can provide compounds 2-2. Alternatively, compounds 1-2 can be reacted with compounds 2-3 under standard reductive amination conditions (e.g., reducing agent such as, sodium triacetoxyborohydride and optionally an acid, such as acetic acid) to provide compounds 2-4. Scheme II [00239] Intermediates for the synthesis of compounds of Formula (I) can be prepared as shown in Scheme III. Compounds 3-1 where Lg 3 is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be coupled with an amine 3-2 under standard amide bond formation conditions such as in the presence of an amide coupling reagent (e.g., N,N’-cabonyldiimidazole or HATU and a base (e.g., diisopropylethylamine) to provide compounds 3-3. Anilines 3-3 can be converted to heterocycles 3-4 under standard acylation conditions (e.g., in the presence of N,N’- cabonyldiimidazole or triphosgene and a suitable base, such as 1,8-diazabicyclo[5.4.0]undec-7- ene). Diones 3-4 can be halogenated with suitable reagents, such as phosphoryl chloride or phosphoryl bromide, to provide compounds 3-5 where X 2 is halogen (e.g., Cl or Br). Reaction of halides 3-5 with a compounds 3-6 under standard nucleophilic aromatic substitution conditions, such as in the presence of a suitable base (e.g., N,N-diisoproylethylamine), or under standard Buchwald-Hartwig coupling conditions (e.g., palladium catalyst such as, XPhos Pd G3, and a base, such as Cs2CO3 or K3PO4) can afford compounds 3-7. Scheme III
[00240] Intermediates for the synthesis of compounds of Formula (I) can be prepared as shown in Scheme IV. Reaction of compounds 4-1 where Lg 4 is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) with nitrites 4-2 where R e is C3-C8 alkyl in the presence of an acid (e.g., HCl) can provide oximes 4-3. Acylation of oximes 4-3 with an acyl chloride 4-4 where R f is C1-C8 alkyl, such as acetyl chloride, optionally in the presence of a base, such as triethylamine can afford compounds 4-5. Compounds 4-5 can be converted to an ester 4-6 where R g is C1-C8 alkyl by Beckmann fragmentation in the presence of a base (e.g., diethylamine) in a suitable solvent (e.g., methanol). Treatment of compounds 4-6 with an amine 3-2 can afford compounds 4-7. Alkylation of compounds 4-7 with an electrophile 4-8 where Lg 5 is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) in the presence of a base (e.g.triethylamine or K2CO3) can afford compounds 4-9 where R h is H, D, -C1-C10 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl or two R h , together with the atom to which they are both attached, form a monocyclic or multicyclic heterocycloalkyl, or a monocyclic or multicyclic heterocyclo-alkenyl group. Scheme IV
[00241] Intermediates for the synthesis of compounds of Formula (I) can be prepared as shown in Scheme V. Beckmann rearrangement of compounds 4-5 in the presence of an activating reagent (e.g., phosphorous pentachloride) can provide compounds 5-1. Reaction of compounds 5-1 with electrophiles 5-2 where Lg 6 is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) under standard conditions (e.g., base, such as triethylamine or K2CO3) can afford compounds 5-3. Reaction of compounds 5-3 with a compound 5-4 under standard nucleophilic aromatic substitution conditions in the presence of a suitable base (e.g., N,N- diisopropylethylamine, K2CO3, KHMDS, or NaH) or Buchwald-Hartwig coupling under standard conditions (e.g., palladium catalyst such as, XPhos Pd G3, and a base, such as Cs2CO3 or K3PO4) can afford compounds 5-5. Scheme V
[00242] Compounds of Formula (I) can be prepared from optionally protected 2-6 as shown in Scheme VI. Alkylation of compounds 2-6 with an anthranilic acid derivative 6-1 where j is 1, 2, 3, or 4 optionally in the presence of a base (e.g., triethylamine) can provide compounds 6-2. Scheme VI [00243] Intermediates for the synthesis of compounds of Formula (I) can be prepared as shown in Scheme VII. Reaction of heterocycles 3-4 with amines 3-6 in the presence of an amide coupling reagent (e.g., (benzotriazol-1-yl-oxy)tri-pyrrolidinophosphonium hexafluorophosphate or bromotripyrrolidinophosphonium hexafluorophosphate) and a base (e.g., 1,8- diazabicyclo[5.4.0] undec-7-ene) can provide compound 3-7. Scheme VII [00244] Intermediates for the synthesis of compounds of Formula (I) can be prepared as shown in Scheme VIII. Anilines 3-3 can be converted to heterocycles 8-1 under standard conditions (e.g., in the presence of 1,1-thiocarbonyldiimidazole or carbon disulfide and a base (e.g., potassium tert-butoxide or KOH)). Reaction of heterocycles 8-1 with electrophiles 8-2 where Lg 7 is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) and R i is C1-C8 alkyl under standard conditions (e.g., base, such as triethylamine or K2CO3) can afford compounds 8- 3. Oxidation of compounds 8-3 using a standard oxidant (e.g., m-chloroperoxybenzoic acid) can provide sulfones 8-4. Reaction of sulfones 8-4 with nucleophiles 5-4 under standard nucleophilic aromatic substitution conditions in the presence of a suitable base (e.g., N,N- diisopropylethylamine, K2CO3, KHMDS, or NaH) can afford compounds 1-1. [00245] Intermediates for the synthesis of compounds of Formula (I) can be prepared as shown in Scheme IX. Preparation of intermediates 9-8 from benzoic acids 9-1 can be achieved by methods analogous to those described in Y. Tamura, et al. J. Org. Chem.1985, 50, 2273–2277, the disclosure of which is incorporated herein by reference to its entirety. Phenols 9-1 can be protected under standard conditions to provide compounds 9-2 where PG 1 is a suitable phenol protecting group including but not limited to those described in Wuts and Greene, p.246–287. Compounds 9-2 can be transformed to heterocycles 9-3 by acid chloride formation under standard conditions (e.g., thionyl chloride), subsequent amide formation with 2-amino-2-methyl- 1-propanol, and then condensation under standard conditions, such as in the presence of a dehydrating agent (e.g., thionyl chloride). Alkylation of compounds 9-3 in the presence of a base (e.g., butyllithium) with electrophiles 9-4 where Lg 8 is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can provide compounds 9-5. Reaction of compounds 9-5 in the presence of a base (e.g., butyllithium) with carbonate 9-6 where R j is C1-C8 alkyl can provide esters 9-7. Hydrolysis of compounds 9-7 under standard conditions (e.g., in the presence of aq. HCl or a aq. NaOH) can provide carboxylic acids 9-8. [00246] Intermediates 9-8 can be transformed into heterocycles 9-10 by urea formation with amines 9-9 under standard conditions such as in the presence of a dehydrating agent (e.g., acetic anhydride). Diones 9-10 can be deoxygenatively halogenated with suitable reagents, such as phosphoryl chloride or phosphoryl bromide, to provide compounds 9-11 where X 3 is halogen (e.g., Cl or Br). Reaction of halides 9-11 with a compound 5-4 under standard nucleophilic aromatic substitution conditions, such as in the presence of a suitable base (e.g., N,N- diisoproylethylamine or K2CO3), or under standard Buchwald-Hartwig coupling conditions (e.g., in the presence of a palladium catalyst such as, XPhos Pd G3 or Pd2(dba)3, and a base, such as KOtBu, Cs2CO3, or K3PO4, and optionally a ligand, such as rac-BINAP) can afford compounds 9-12. Deprotections of compounds 9-12 under standard conditions including but not limited to those described in Wuts and Greene, p.246–287 can provide phenols 9-13. Sulfonylation of compounds 9-13 using a standard sulfonylating agent (e.g., methanesulfonyl chloride, p- toluenesulfonyl chloride, or trifluoromethanesulfonic anhydride) and a base (e.g., triethylamine or K2CO3) can provide intermediates 9-14 where Lg 9 is pseudohalogen (e.g., OMs, OTs, or OTf). Scheme IX
[00247] Compounds of Formula (I) can be prepared from optionally protected 2-6 as shown in Scheme X. Alkylation of optionally protected compounds 10-1 with compounds 2-6 optionally in the presence of a base (e.g., triethylamine) and subsequent optional deprotection can provide compounds 10-2. Scheme X [00248] Compounds of Formula (I) can be prepared from as shown in Scheme XI. Annulation of amino acids 11-1 where ring B is an aryl or a 5-7 membered heteroaryl ring comprising 1-4 heteroatoms selected from N, O, and S with triphosgene affords bicycles 11-2. Reaction of compounds 11-2 with alcohols 2-6 under standard Mitsunobu conditions, such as in the presence of an azodicarboxylate (e.g., diisopropyl azodicarboxylate) and a phosphine (e.g., triphenylphosphine), can afford compounds 11-3. Hydrolysis under standard conditions, such as in the presence of a base (e.g., K2CO3 or NaOH) or an acid (e.g., HCl) or upon workup, can afford compounds 11-4. Scheme XI [00249] Intermediates for the synthesis of compounds of Formula (I) can be prepared as from benzoic acids 12-1 as shown in Scheme XII. Benzoic acids 12-1 can be transformed into hydroxamic acids 12-2 by acid chloride formation under standard conditions, such as in the presence of thionyl chloride, and subsequent acylation of hydroxyl amine in the presence of suitable base (e.g., triethylamine). Acylation of hydroxamic acids 12-2 with acid chlorides 12-3 where R z is a C1-C6 alkyl group in the presence of suitable base (e.g., triethylamine) can afford compounds 12-4. Compounds 12-4 can react with an alkyne 12-5 where R y is C1-C8 alkyl, haloalkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycloalkenyl wherein each group is optionally substituted by 1-6 R f groups via metal- catalyzed C–H activation in the presence of a metal catalyst (e.g., pentmathylcyclopentadienylrhodium(III) chloride dimer) and a base (e.g., cesium acetate) to provide bicyclic heterocycles 12-6. Selective alkylation of compounds 12-6 with electrophiles 5- 2 in the presence of base (e.g., cesium carbonate) can provide compounds 12-7. [00250] Intermediates for the synthesis of compounds of Formula (I) can be prepared as shown in Scheme XIII. Reaction of compounds 3-3 with aldehydes 13-1, where W 1 is W and wherein this group is connected to the aldehyde functional group through a carbon atom, under standard conditions, such as in the presence of a Lewis acid and an oxidant (e.g., FeCl3 or TFA and air), can afford quinazolin-4(3H)-ones 13-2. Alternatively, amide coupling of anilines 3-3 with carboxylic acids 13-3, where W 1 is W and wherein this group is connected to the carboxylic acid functional group through a carbon atom, under standard conditions, such as in the presence of a peptide coupling reagent (e.g., EDC or HATU) and a base (e.g., 4-dimethylaminopyridine or triethylamine) can provide amides 13-4. Cyclization of compounds 13-4 under various conditions, such as in the presence of an acid (e.g., p-toluenesulfonic acid or sulfuric acid), in the presence of a base (e.g., cesium carbonate or sodium hydroxide), in the presence of a dehydrating agent (e.g., acetic anhydride), or in the presence of I2 and hexamethyldisilazane, can provide quinazolin-4(3H)-ones 13-2. Scheme XIII
Example 1: 2-((1-(2-(isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroqui nazolin-8-yl)ethyl) amino)benzoic acid [00251] Step 1.2-amino-3-bromo-N,5-dimethylbenzamide [00252] To a solution of 2-amino-3-bromo-5-methylbenzoic acid (2.00 g, 8.69 mmol) in THF (20.0 mL) was added 1,1'-carbonyldiimidazole (1.55 g, 9.56 mmol), and the resulting reaction mixture was stirred at room temperature for 12 h. Then methylamine (6.50 mL, 13 mmol, 2.0 M in THF) was added, and the reaction mixture was stirred for 4 h. The reaction was diluted with ethyl acetate (20.0 mL), and the organic layer was washed with water and brine, dried over Na2SO4, and concentrated. The crude material, which contained the title compound, was carried forward without further purification. LC-MS calc. for C9H12BrN2O [M+H] + : m/z = 243.0, 245.0; Found: 242.9, 244.9. [00253] Step 2.8-bromo-3,6-dimethylquinazoline-2,4(1H,3H)-dione [00254] To a solution of 2-amino-3-bromo-N,5-dimethylbenzamide (500 mg, 2.06 mmol) in THF (10.0 mL) was added 1,1'-carbonyldiimidazole (500 mg, 3.09 mmol) and 1,8-diazabicyclo [5.4.0]undec-7-ene (0.614 mL, 4.11 mmol). The mixture was refluxed for 16 h. The reaction mixture was cooled to room temperature and poured into a mixture of ice water (5.0 mL) and sat. NH4Cl (aq.) (5.0 ml). The suspension was stirred for 10 min, and then the solid was collected by filtration to afford the title compound (495 mg, 1.84 mmol, 89.4% yield) as a white solid. LC- MS calc. for C10H10BrN2O2 [M+H] + : m/z = 269.0, 271.0; Found: 269.0, 271.0. [00255] Step 3.8-bromo-2-chloro-3,6-dimethylquinazolin-4(3H)-one [00256] N,N-diisopropylethylamine (0.64 mL, 3.68 mmol) was added dropwise to a mixture of 8-bromo-3,6-dimethylquinazoline-2,4(1H,3H)-dione (495 mg, 1.84 mmol) in phosphorous oxychloride (12.4 mL, 132 mmol) at room temperature. The heterogeneous mixture was heated at 95 °C for 16 h. The reaction was cooled to room temperature and then concentrated. The brown sticky solution was dissolved with toluene (2.0 mL) and concentrated. The brown residue was cooled with an ice bath, and ice was added to the flask.5 N NaOH (aq.) was added until the mixture was basic (pH > 9). The aqueous mixture was extracted with EtOAc (3.0 x 5 mL). The combined organic layers were washed with brine (2.0 x 5 mL), dried over Na2SO4, filtered, and concentrated. The crude material, which contained the title compound, was carried forward without further purification. LC-MS calc. for C10H9BrClN2O [M+H] + : m/z = 287.0, 289.0; Found: 286.8, 288.8. [00257] Step 4.8-bromo-2-(isoindolin-2-yl)-3,6-dimethylquinazolin-4(3H)-o ne [00258] To a mixture of isoindoline (0.12 mL, 1.04 mmol) and 8-bromo-2-chloro-3,6- dimethyl-quinazolin-4(3H)-one (200 mg, 0.696 mmol) in THF (5.0 mL) was added N,N- diisopropylethyl-amine (0.24 mL, 1.39 mmol). The mixture was heated at 50 °C for 4 h. The reaction mixture was concentrated. The crude material was suspended in water, and the solid was collected by filtration to afford the title compound (260 mg, 0.702 mmol, quantitative yield). LC- MS calc. for C18H17BrN3O [M+H] + : m/z = 370.1, 372.1; Found: 370.0, 372.0. [00259] Step 5.8-acetyl-2-(isoindolin-2-yl)-3,6-dimethylquinazolin-4(3H)- one [00260] 8-bromo-2-(isoindolin-2-yl)-3,6-dimethylquinazolin-4(3H)-one (260 mg, 0.702 mmol), 1-ethoxyvinyltri-n-butyltin (0.36 mL, 1.05 mmol), and bis(triphenylphosphine)palladium(II) dichloride (98.6 mg, 0.14 mmol) were dissolved in 1,4- dioxane (3.0 mL), and then the reaction mixture was heated at 100 °C for 6 h. The reaction mixture was cooled to room temperature and 6 N HCl (aq.) (0.2 ml) was added. The reaction was heated at 50 °C for 1 h. The crude product was purified by silica gel chromatography (0–100% EtOAc/hexane) to afford the title compound (205 mg, 0.615 mmol, 87.6% yield). LC-MS calc. for C20H20N3O2 [M+H] + : m/z = 334.2; Found: 334.1. [00261] Step 6.8-(1-hydroxyethyl)-2-(isoindolin-2-yl)-3,6-dimethylquinazo lin-4(3H)-one [00262] To the solution of 8-acetyl-2-(isoindolin-2-yl)-3,6-dimethylquinazolin-4(3H)-on e (205 mg, 0.615 mmol) in methanol (5.0 mL) was added sodium borohydride (69.8 mg, 1.84 mmol) at 0 °C. The mixture was warmed to room temperature and stirred for 2 h. The reaction was quenched with 0.5 M HCl (aq.) (2.0 mL), and the reaction mixture was extracted with EtOAc (3.0 x 3 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The crude material, which contained the title compound, was carried forward without further purification. LC-MS calc. for C20H22N3O2 [M+H] + : m/z = 336.2; Found: 336.1. [00263] Step 7.2-((1-(2-(isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroq uinazolin-8-yl)ethyl) amino)benzoic acid [00264] To a solution of 8-(1-hydroxyethyl)-2-(isoindolin-2-yl)-3,6-dimethylquinazoli n- 4(3H)-one (44.0 mg, 0.131 mmol) in DCM (1 mL) was added phosphorus tribromide (0.01 mL, 0.1 mmol) at 0°C dropwise. The mixture was stirred at room temperature for 1 h. The reaction was diluted with water (1.0 mL), and the two phases were separated. The organic layer was washed with sat. NaHCO3 (aq.) (1.0 mL) and brine (1.0 mL), dried over Na2SO4, filtered, and concentrated. To the crude residue was added a solution of anthranilic acid (36.0 mg, 0.262 mmol) in DMF (1.0 mL). The mixture was stirred at 80 °C for 4 h. The reaction mixture was cooled to room temperature, and the crude reaction was purified by prep-HPLC on a CSH Flouro-Phenyl column (43–53% MeCN/0.1% TFA (aq.)) to afford the title compound as a TFA salt (10.8 mg, 0.02 mmol, 10% yield). 1 H NMR (400 MHz, CDCl3) δ 9.71 (s, 1H, br), 7.97 (d, J = 8.3 Hz, 1H), 7.91 (s, 1H), 7.54 (s, 1H), 7.20 – 7.30 (m, 5H), 6.75 (t, J = 7.6 Hz, 1H), 6.63 (d, J = 8.5 Hz, 1H), 5.33 (q, J = 7.1 Hz, 1H), 5.07 (d, J = 13.4 Hz, 2H), 4.95 (d, J = 13.2 Hz, 2H), 3.74 (s, 3H), 2.41 (s, 3H), 1.73 (d, J = 6.7 Hz, 3H). LC-MS calc. for C27H27N4O3 [M+H] + : m/z = 455.2; Found: 455.1. Example 2: 2-((1-(2-(5-fluoroisoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-di hydroquinazolin-8- yl) ethyl)amino)benzoic acid [00265] The title compound was synthesized by procedures analogous to those outlined in Example 1. 1 H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H, br), 7.96 (dd, J = 8.0, 1.6 Hz, 1H), 7.90 (s, 1H), 7.54 (d, J = 2.1 Hz, 1H), 7.26 (m, 2H), 7.00 (dd, J = 13.4, 8.0 Hz, 2H), 6.72 (t, J = 7.5 Hz, 1H), 6.60 (d, J = 8.5 Hz, 1H), 5.39 (q, J = 6.7 Hz, 1H), 5.09 – 4.83 (m, 4H), 3.71 (s, 3H), 2.40 (s, 3H), 1.72 (d, J = 6.7 Hz, 3H). LCMS calc. for C27H26FN4O3 [M+H] + : 473.2; Found: 473.1. Example 3: 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4 - dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [00266] The title compound was synthesized by procedures analogous to those outlined in Example 1. LCMS calc. for C26H33N4O3 [M+H] + : 449.2; Found: 449.2. Examples 4 - 9 [00267] Examples 4 - 9 listed in Tables 1 and 2 were synthesized according to procedures analogous to Example 1. All examples in this table were prepared as the TFA salt. Table 1. Examples 4 - 9 Table 2. Examples 4 - 9
Example 10: N-Hydroxy-2-((1-(2-(isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzamide [00268] Thionyl chloride (3.2 µL, 0.044 mmol) was added to a solution of crude 2-((1-(2- (isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8 -yl)ethyl)amino)benzoic acid (10 mg, Example 1, Step 7) in DCM (1.0 mL), and the resulting mixture was stirred for 15 min. Then hydroxylamine hydrochloride (7.6 mg, 0.11 mmol) and triethylamine (2.0 µL, 0.11 mmol) were added sequentially, and the reaction was stirred for 1 h. The reaction mixture was concentrated, and the crude residue was purified by prep-HPLC on CSH Phenyl-Hexyl column (38–58% MeCN/0.1% TFA (aq.)) to afford the title compound as a TFA salt (2.7 mg). LC-MS calc. for C27H28N5O3 [M+H] + : m/z = 470.2; Found: 470.1. Example 11: 8-(1-((2,4-difluoro-3-hydroxyphenyl)amino)ethyl)-2-(isoindol in-2-yl)-3,6- dimethylquinazolin-4(3H)-one [00269] Step 1.8-(1-((2,4-difluoro-3-methoxyphenyl)amino)ethyl)-2-(isoind olin-2-yl)-3,6- dimethylquinazolin-4(3H)-one [00270] The title compound was synthesized by procedures analogous to those outlined in Example 1, Step 7, substituting 2,4-difluoro-3-methoxyaniline for anthranilic acid, and was isolated as a TFA saltLC-MS calc. for C27H27F2N4O2 [M+H] + : m/z = 477.2; Found: 477.2. [00271] Step 2.8-(1-((2,4-difluoro-3-hydroxyphenyl)amino)ethyl)-2-(isoind olin-2-yl)-3,6- dimethylquinazolin-4(3H)-one [00272] Boron tribromide (0.016 mL, 0.16 mmol) was added to a solution of 8-(1-((2,4- difluoro-3-methoxyphenyl)amino)ethyl)-2-(isoindolin-2-yl)-3, 6-dimethylquinazolin-4(3H)- one(19 mg, 0.033 mmol) (from Step 1) in DCM (0.65 mL), and the resulting mixture was stirred for 18 h. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by prep-HPLC on CSH C-18 column (47–67 MeCN/0.1% TFA (aq.)) to afford the title compound as a TFA salt (2.6 mg, 5.5 µmol, 14% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 1.9 Hz, 1H), 7.54 (d, J = 2.1 Hz, 1H), 7.44 – 7.37 (m, 2H), 7.36 – 7.27 (m, 2H), 6.63 – 6.47 (m, 1H), 5.89 (td, J = 9.1, 4.8 Hz, 1H), 5.25 (q, J = 6.7 Hz, 1H), 5.12 – 4.95 (m, 4H), 3.61 (s, 3H), 2.31 (s, 3H), 1.51 (d, J = 6.7 Hz, 3H). LC-MS calc. for C26H25F2N4O2 [M+H] + : m/z = 463.2; Found: 463.1. Example 12: 2-(isoindolin-2-yl)-3,6-dimethyl-8-(1-((2-(2,2,2-trifluoro-1 - hydroxyethyl)phenyl) amino)ethyl)quinazolin-4(3H)-one [00273] Step 1.1-(2-aminophenyl)-2,2,2-trifluoroethan-1-ol [00274] Trimethyl(trifluoromethyl)silane (0.29 mL, 2.0 mmol) was added to a solution of 2- nitrobenzaldehyde (200 mg, 1.3 mmol) and sodium acetate (220 mg, 2.7 mmol) in DMF (2.6 mL) at 0 ºC. The resulting reaction mixture was stirred at 0 ºC for 1 h before being diluted with DCM (10 mL) and water (25 mL). The two phases were separated, and the aqueous layer was extracted by DCM (20 mL × 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude residue was dissolved in methanol (13 mL), and then palladium on carbon (140 mg, 0.13 mmol, 10 wt.%) was added to the solution. The reaction mixture was stirred under an atmosphere of H2 for 18 h. The mixture was diluted with DCM and filtered through a pad of Celite®. The filtrate was concentrated. The crude material was used in the next step without further purification. LC-MS calc. for C8H9F3NO [M+H] + : m/z = 192.1; Found: 192.0. [00275] Step 2.2-(isoindolin-2-yl)-3,6-dimethyl-8-(1-((2-(2,2,2-trifluoro -1- hydroxyethyl)phenyl) amino)ethyl)quinazolin-4(3H)-one [00276] The title compound was synthesized by procedures analogous to those outlined in Example 1, Step 7. LC-MS calc. for C28H28F3N4O2 [M+H] + : m/z = 509.2; Found: 509.2. Example 13: 2-((1-(2-(isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroqui nazolin-8- yl)ethyl)thio)benzoic acid [00277] The title compound was synthesized by procedures analogous to those outlined in Example 1, Step 7, substituting 2-mercaptobenzoic acid for anthranilic acid. 1 H NMR (400 MHz, DMSO-d6) δ 7.79 (dd, J = 7.7, 1.6 Hz, 1H), 7.73 – 7.68 (m, 2H), 7.53 (d, J = 8.1 Hz, 1H), 7.37 – 7.24 (m, 5H), 7.13 (td, J = 7.5, 1.0 Hz, 1H), 5.59 (q, J = 7.1 Hz, 1H), 5.07 – 4.89 (m, 4H), 3.60 (s, 3H), 2.35 (s, 3H), 1.65 (d, J = 7.0 Hz, 3H). LC-MS calc. for C27H26N3O3S [M+H] + : m/z = 472.2; Found: 472.1. Example 14: 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-5-cyano-3,6-dimethy l-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [00278] Step 1.6-amino-2-bromo-3-methylbenzoic acid [00279] Hydrogen peroxide (4.8 mL, 47 mmol, 35 wt.% in water) was added dropwise to a solution of 4-bromo-5-methyl-1H-indole-2,3-dione (5.0 g, 21 mmol) in NaOH (21 mL, 3N (aq.)), and the reaction mixture was stirred for 18 h. The reaction mixture was adjusted to pH ~5 using 1N HCl (aq.), and the mixture was concentrated. The resulting residue was suspended in methanol (100 mL) and filtered, and the filtrate was concentrated. The crude solid was used in the next step without further purification. LC-MS calc. for C8H9BrNO2 [M+H] + : m/z = 230.0, 232.0; Found: 229.9, 231.9. [00280] Step 2.6-amino-2-bromo-N,3-dimethylbenzamide [00281] Crude 6-amino-2-bromo-3-methylbenzoic acid, 1-[bis(dimethylamino)methylene]-1H- 1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (12 g, 31 mmol), triethylamine (15 mL, 100 mmol), and methylamine hydrochloride (2.1 g, 31 mmol) were dissolved in DCM (70 mL), and the solution was stirred at room temperature for 1 h. The mixture was diluted with water (100 mL) and DCM (100 mL). The two phases were separated, and the aqueous layer was extracted by DCM (100 mL × 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude residue was used without further purification. LC-MS calc. for C9H12BrN2O [M+H] + : m/z = 243.0, 245.0; Found: 242.9, 244.9. [00282] Step 3.2-amino-6-bromo-3-iodo-N,5-dimethylbenzamide [00283] N-Iodosuccinimide (5.2 g, 23 mmol) was added to a mixture of crude 6-amino-2- bromo-N,3-dimethylbenzamide and sodium acetate (2.4 g, 29 mmol) in glacial acetic acid (42 mL), and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with water (200 mL) and DCM (200 mL). The two phases were separated, and the aqueous layer was extracted by DCM (100 mL × 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude residue was used without further purification. LC-MS calc. for C9H11BrINO2 [M+H] + : m/z = 368.9, 370.9; Found: 368.9, 370.9. [00284] Step 4.5-bromo-8-iodo-3,6-dimethylquinazoline-2,4(1H,3H)-dione . [00285] Triphosgene (6.2 g, 21 mmol) was added to a solution of crude 2-amino-6-bromo-3- iodo-N,5-dimethylbenzamide in THF (70 mL), and the reaction mixture was stirred at room temperature for 18 hours. The reaction was diluted with water (100 mL) and DCM (200 mL). The two phases were separated, and the aqueous layer was extracted by DCM (100 mL × 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude residue was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.99 (bs, 1H), 7.90 (s, 1H), 3.44 (s, 3H), 2.45 (s, 3H). [00286] Step 5.5-bromo-2-chloro-8-iodo-3,6-dimethylquinazolin-4(3H)-one [00287] The title compound was synthesized by procedures analogous to those outlined in Example 1, Step 3. LC-MS calc. for C10H8BrClIN2O [M+H] + : m/z = 412.9, 414.9; Found: 412.9, 414.8. [00288] Step 6. 2-(3-azabicyclo[3.1.0]hexan-3-yl)-5-bromo-8-iodo-3,6-dimethy lquinazolin- 4(3H)-one [00289] The title compound was synthesized by procedures analogous to those outlined in Example 1, Step 4, substituting 3-azabicyclo[3.1.0]hexane for isoindoline. LC-MS calc. for C15H16BrIN3O [M+H] + : m/z = 459.9, 461.9; Found: 459.8, 461.9. [00290] Step 7.8-acetyl-2-(3-azabicyclo[3.1.0]hexan-3-yl)-5-bromo-3,6-dim ethylquinazolin- 4(3H)-one [00291] 2-(3-azabicyclo[3.1.0]hexan-3-yl)-5-bromo-8-iodo-3,6-dimethy lquinazolin-4(3H)-one (1.3 g, 2.8 mmol), Tributyl(1-ethoxyvinyl)tin (1.1 g, 3.1 mmol), and bis(triphenylphosphine) palladium(II) dichloride (200 mg, 0.28 mmol) were dissolved in 1,4-dioxane (28 mL). The reaction vessel was sealed, and the reaction mixture degassed with N2 and heated to 80 ºC for 18 h. The reaction mixturew was cooled to room temperature, and several drops of 6N HCl (aq.) were added. After heating at 50 ºC for 1 h, the reaction mixture was cooled to room temperature and diluted with water (50 mL) and DCM (100 mL). The two phases were separated, and the aqueous layer was extracted by DCM (100 mL × 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0–100% EtOAc/hexanes) to afford the title compound (400 mg, 1.1 mmol, 38% yield). LC-MS calc. for C17H19BrN3O2 [M+H] + : m/z = 376.1, 378.1; Found: 376.0, 378.0. [00292] Step 8.2-(3-azabicyclo[3.1.0]hexan-3-yl)-5-bromo-8-(1-hydroxyethy l)-3,6- dimethylquinazolin-4(3H)-one [00293] The title compound was synthesized by procedures analogous to those outlined in Example 1, Step 6. LC-MS calc. for C17H21BrN3O2 [M+H] + : m/z = 378.1, 380.1; Found: 378.1, . . [00294] Step 9. tert-butyl 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-5-bromo-3,6-dimethy l-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate [00295] The title compound was synthesized by procedures analogous to those outlined in Example 1, Step 7, substituting tert-butyl 2-aminobenzoate for anthranilic acid. 1 H NMR (400 MHz, DMSO-d6) δ 8.19 (bs, 1H), 7.74 (dd, J = 8.0, 1.6 Hz, 1H), 7.51 (s, 1H), 7.29 – 7.10 (m, 1H), 6.50 (t, J = 7.5 Hz, 1H), 6.42 (d, J = 8.5 Hz, 1H), 5.30 (bs, 1H), 4.00 (d, J = 10.6 Hz, 1H), 3.86 (d, J = 10.5 Hz, 1H), 3.60 – 3.44 (m, 2H), 3.38 (s, 3H), 2.33 (s, 3H), 1.65 – 1.58 (m, 2H), 1.57 (s, 9H), 1.55 (d, J = 6.7 Hz, 3H), 0.67 – 0.53 (m, 1H), 0.35 – 0.23 (m, 1H). LC-MS calc. for C28H34BrN4O3 [M+H] + : m/z = 553.2, 555.2; Found: 553.1, 555.0. [00296] Step 10. tert-butyl 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-5-cyano-3,6-dimethy l-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate [00297] tert-Butyl 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-5-bromo-3,6-dimethy l-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate (5.0 mg, 9.0 µmol), zinc cyanide (4.1 mg, 45 µmol), and tetrakis(triphenylphosphine)palladium(0) (2.1 mg, 1.8 µmol) were dissolved in DMF (0.30 mL). The reaction vessel was sealed, and the reaction mixture was degassed with N2 and heated at 100 ºC for 18 h. The reaction mixture was cooled to room temperature and diluted with water (10 mL) and DCM (10 mL). The two phases were separated, and the aqueous layer was extracted by DCM (10 mL × 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by prep-HPLC on CSH C-18 column (75–100% MeCN/0.1% TFA (aq.)) to afford the title compound as a TFA salt (3.0 mg, 6.0 µmol, 54% yield). LC-MS calc. for C29H34N5O3 [M+H] + : m/z = 500.3; Found: 500.2. [00298] Step 11.2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-5-cyano-3,6-dime thyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [00299] TFA (50 µL, 0.65 mmol) was added to a solution of tert-butyl 2-((1-(2-(3- azabicyclo[3.1.0]hexan-3-yl)-5-cyano-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl) amino)benzoate (3.0 mg, 6.0 µmol) in DCM (0.20 mL) and the reaction mixture was stirred for 18 h. The reaction mixture was concentrated, and the crude residue was purified by prep-HPLC on CSH C-18 column (59–79% MeCN/0.1% TFA (aq.)) to afford the title compound as a TFA salt (1.0 mg, 1.8 µmol, 38% yield). LC-MS calc. for C25H26N5O3 [M+H] + : m/z = 444.2; Found: 444.1. Examples 15 - 21 [00300] Examples 15 - 21 listed in Tables 3 and 4 were synthesized according to procedures analogous to Example 1. All examples in this table were prepared as the TFA salt. Table 3. Examples 15 - 21
Table 4. Examples 15 - 21 Example 22: 2-((1-(2-(isoindolin-2-yl)-6-methyl-4-oxo-3,4-dihydroquinazo lin-8- yl)ethyl)amino)benzoic acid [00301] Step 1.2-((1-(2-(isoindolin-2-yl)-3-(4-methoxybenzyl)-6-methyl-4- oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [00302] The title compound was synthesized by procedures analogous to those outlined in Example 1, substituting (4-methoxyphenyl)methanamine for methylamine in Step 1. LC-MS calc. for C34H33N4O4 [M+H] + : m/z = 561.2; Found: 561.2. [00303] Step 2.2-((1-(2-(isoindolin-2-yl)-6-methyl-4-oxo-3,4-dihydroquina zolin-8-yl)ethyl) amino)benzoic acid [00304] A solution of 2-((1-(2-(isoindolin-2-yl)-3-(4-methoxybenzyl)-6-methyl-4-ox o-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (5.0 mg, 0.010 mmol) in TFA (1 mL) was stirred at 45 °C for 2 h. The reaction mixture was cooled to room temperature and concentrated,and the crude residue was purified by prep-HPLC on CSH C-18 column (40–60% MeCN/0.1% TFA (aq.)) to afford the title compound as a TFA salt (1.1 mg, 2.5 µmol, 28% yield). LC-MS calc. for C26H25N4O3 [M+H] + : m/z = 441.2; Found: 441.2. Example 23: 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo- 3,4-dihydro- quinazolin-8-yl)ethyl)amino)-4-cyanobenzoic acid [00305] Step 1.2-(3-azabicyclo[3.1.0]hexan-3-yl)-8-(1-hydroxyethyl)-3,6-d imethylquinazolin- 4(3H)-one [00306] The title compound was synthesized by procedures analogous to those outlined in Example 1, Steps 1–6, substituting 3-azabicyclo[3.1.0]hexane for isoindoline in Step 4. LC-MS calc. for C17H22N3O2 [M+H] + : m/z = 300.2; Found: 300.1. [00307] Step 2. Methyl 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo- 3,4- dihydroquinazolin-8-yl)ethyl)amino)-4-cyanobenzoate [00308] To a solution of 2-(3-azabicyclo[3.1.0]hexan-3-yl)-8-(1-hydroxyethyl)-3,6-dim ethyl- quinazolin-4(3H)-one (20 mg, 0.07 mmol) in DCM (1 mL) was added methanesulfonyl chloride (0.01 mL, 0.08 mmol) and triethylamine dropwise (0.02 mL, 0.1 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h and slowly warmed to room temperature over 4 h. Then, methyl 2- amino-4-cyanobenzoate (17.6 mg, 0.100 mmol), and triethylamine (0.02 mL, 0.1 mmol) were added. The mixture was stirred 16 h. The reaction mixture was concentrated and purified by prep-HPLC on CSH Flouro-Phenyl column (53–73% MeCN/0.1% TFA (aq.)) to afford the title compound as a TFA salt (5.0 mg, 11 µmol, 16% yield). LC-MS calc. for C26H28N5O3 [M+H] + : m/z = 458.2; Found: 458.1. [00309] Step 3.2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-ox o-3,4-dihydro- quinazolin-8-yl)ethyl)amino)-4-cyanobenzoic acid [00310] To a solution of methyl 2-[1-[2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4- oxoquinazolin-8-yl]ethylamino]-4-cyanobenzoate (5.0 mg, 0.011 mmol) in 1,4-dioxane (0.5 mL) and water (0.5 mL) was added LiOH (1.3 mg, 0.055 mmol). The mixture was stirred at 40 °C for 14 h. The mixture was adjusted to pH 2 with 1 M HCl and extracted with EtOAc (2.0 x 2 mL). The combined organic layers were washed with brine (2.0 mL), dried over Na2SO4, filtered, and concentrated. The crude residue was purified by prep-HPLC on CSH Flouro-Phenyl column (42– 62% MeCN/0.1% TFA (aq.)) to afford the title compound as a TFA salt (2.1 mg, 3.8 µmol, 35% yield). LC-MS calc. for C25H26N5O3 [M+H] + : m/z = 444.2; Found: 444.2. Example 24: 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo- 3,4-dihydro- quinazolin-8-yl)ethyl)amino)benzoic acid (isomer 1) [00311] Step 1. Methyl 2-(((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo -3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate (isomer 1) [00312] The title compound was synthesized by procedures analogous to those outlined in Example 1, substituting methyl 2-aminobenzoate for anthranilic acid in Step 7. The isomers were separated using chiral prep-HPLC on a Lux iA3 column (30 mL/min, 88:6:6 hexane/IPA/MeOH) to afford two isomers: isomer 1 (tR = 2.83 min) and isomer 2 (tR = 3.29 min). Isomer 1: LC-MS calc. for C25H29N4O3 [M+H] + : m/z = 433.2; Found: 433.2. [00313] Step 2.2-((-1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-o xo-3,4-dihydro- quinazolin-8-yl)ethyl)amino)benzoic acid (isomer 1) [00314] To a solution of methyl 2-((-1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo - 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (isomer 1) (50.0 mg, 0.116 mmol) in 1,4- dioxane (1.0 mL) and water (1.0 mL) was added LiOH (13.8 mg, 0.578 mmol). The mixture was stirred at 90 °C for 2 h. The mixture was adjusted to pH 2 with 1N HCl and was extracted with EtOAc (2.0 x 2 mL). The combined organic layers were washed with brine (2.0 mL), dried over Na2SO4, filtered, and concentrated to afford the title compound (23.2 mg, 55.4 µmol, 48.0% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.40 (s, 1H), 7.77 (dd, J = 7.9, 1.7 Hz, 1H), 7.66 (dd, J = 2.1, 1.0 Hz, 1H), 7.41 (d, J = 2.1 Hz, 1H), 7.17 (ddd, J = 8.7, 7.1, 1.7 Hz, 1H), 6.53 – 6.42 (m, 2H), 5.36 (m, 1H), 3.99 (d, J = 10.5 Hz, 1H), 3.82 (d, J = 10.5 Hz, 1H), 3.57 – 3.44 (m, 2H), 3.43 (s, 3H), 2.29 (s, 3H), 1.65 – 1.52 (m, 5H), 0.59 (td, J = 7.6, 4.5 Hz, 1H), 0.37 (q, J = 4.2 Hz, 1H). LC-MS calc. for C24H27N4O3 [M+H] + : m/z = 419.2; Found: 419.1. Example 25: 2-((1-(3,6-dimethyl-4-oxo-2-(1H-pyrazol-5-yl)-3,4-dihydroqui nazolin-8-yl) ethyl)amino)benzoic acid [00315] Step 1.8-bromo-3,6-dimethyl-2-(1H-pyrazol-5-yl)quinazolin-4(3H)-o ne [00316] A mixture of 2-amino-3-bromo-N,5-dimethylbenzamide (250 mg, 1.03 mmol), 1H- pyrazole-5-carbaldehyde (98.8 mg, 1.03 mmol), and iron(III) chloride (111 mg, 0.689 mmol) in water (5.0 mL) was heated at 100 °C for 24 h. Then reaction mixture was cooled to room temperature. The resulting solid was collected by filtration to afford the title compound (310 mg, 0.702 mmol, 94.4% yield). LC-MS calc. for C13H12BrN4O [M+H] + : m/z = 319.0, 321.0; Found: 319.0, 321.0. [00317] Step 2.8-bromo-3,6-dimethyl-2-(1-((2-(trimethylsilyl)ethoxy)methy l)-1H-pyrazol-5- yl)quinazolin-4(3H)-one [00318] To a solution of 8-bromo-3,6-dimethyl-2-(1H-pyrazol-5-yl)quinazolin-4(3H)-one (310 mg, 0.971 mmol) in THF (8 mL) was added NaH (58.3 mg, 1.46 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 h. Then, = 2-(trimethylsilyl)ethoxymethyl chloride (0.19 mL, 1.1 mmol) was added dropwise. The resulting mixture was warmed to room temperature and stirred overnight. The reaction was quenched with water, and the mixture was extracted with EtOAc (2.0 x 3 mL). The combined organic layers were washed with brine (2.0 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography (0–50% EtOAc/hexane) to afford the title compound (140 mg, 0.312 mmol, 32.1% yield). LC- MS calc. for C19H26BrN4O2Si [M+H] + : m/z = 449.1, 451.1; Found: 449.0, 451.0. [00319] Step 3.8-acetyl-3,6-dimethyl-2-(1-((2-(trimethylsilyl)ethoxy)meth yl)-1H-pyrazol-5- yl)quinazolin-4(3H)-one [00320] The title compound was synthesized by procedures analogous to those outlined in Example 1, Step 5. LC-MS calc. for C21H29N4O3Si [M+H] + : m/z = 413.2; Found: 413.2. [00321] Step 4.8-(1-hydroxyethyl)-3,6-dimethyl-2-(1-((2-(trimethylsilyl)e thoxy)methyl)-1H- pyrazol-5-yl)quinazolin-4(3H)-one [00322] The title compound was synthesized by procedures analogous to those outlined in Example 1, Step 6. LC-MS calc. for C21H31N4O3Si [M+H] + : m/z = 415.2; Found:415.2. [00323] Step 5.2-((1-(3,6-dimethyl-4-oxo-2-(1H-pyrazol-5-yl)-3,4-dihydroq uinazolin-8-yl) ethyl)amino)benzoic acid [00324] The title compound was synthesized by procedures analogous to those outlined in Example 1, Step 7. Deprotection of SEM group occurred spontaneously in this step. LC-MS calc. for C22H22N5O3 [M+H] + : m/z = 404.1; Found:404.1. Example 26: 2-((1-(2-amino-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl )ethyl)amino) benzoic acid [00325] Step 1.2-((1-(2-(bis(4-methoxybenzyl)amino)-3,6-dimethyl-4-oxo-3, 4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [00326] The title compound was synthesized by procedures analogous to those outlined in Example 1, substituting bis(4-methoxybenzyl)amine for isoindoline in Step 4. LC-MS calc. for C35H37N4O5 [M+H] + : m/z = 593.3; Found: 593.3. [00327] Step 2.2-((1-(2-amino-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino) benzoic acid [00328] A solution of 2-[1-[2-[bis[(4-methoxyphenyl)methyl]amino]-3,6-dimethyl-4- oxoquinazolin-8-yl]ethylamino]benzoic acid (5.0 mg, 8.4 µmol) in TFA (1 mL) was stirred at 45 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated, and the crude residue was concentrated purified by prep-HPLC on a CSH Flouro-Phenyl column (18- 38% MeCN/0.1% TFA (aq.)) to afford the title compound as a TFA salt (1.1 mg, 2.4 µmol, 28% yield). LC-MS calc. for C19H21N4O3 [M+H] + : m/z = 353.2; Found: 353.1. Example 27: 2-((1-(2-(isoindolin-2-yl)-3-isopropyl-6-methyl-4-oxo-3,4-di hydroquinazolin- 8-yl)ethyl)amino)benzoic acid (isomer 1) [00329] Step 1. Methyl 2-((1-(2-(isoindolin-2-yl)-3-isopropyl-6-methyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate (isomer 1) [00330] The title compound was synthesized by procedures analogous to those outlined in Example 1, substituting propan-2-amine for methylamine in Step 1 and methyl 2-aminobenzoate for anthranilic acid in Step 7. The isomers were separated using chiral prep-HPLC on a Lux iA3 column (30 mL/min, 98:2 hexane/EtOH) to afford two isomers: isomer 1 (tR = 2.51 min) and isomer 2 (tR = 3.43 min). Isomer 1: LC-MS calc. for C30H33N4O3 [M+H] + : m/z = 497.3; Found: 497.3. [00331] Step 2.2-((1-(2-(isoindolin-2-yl)-3-isopropyl-6-methyl-4-oxo-3,4- dihydroquinazolin- 8-yl)ethyl)amino)benzoic acid (isomer 1) [00332] To a solution of methyl 2-((1-(2-(isoindolin-2-yl)-3-isopropyl-6-methyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate (isomer 1) (5.0 mg, 0.010 mmol) in 1,4-dioxane (0.5 mL) and water (0.5 mL) was added LiOH (1.2 mg, 0.050 mmol). The mixture was stirred at 90 °C for 2 h. The mixture was adjusted to pH 2 with 1N HCl and was extracted with EtOAc (1x 2 mL). The combined organic layers were washed with brine (1.0 mL), dried over Na2SO4, filtered, and concentrated to afford the title compound (4.3 mg, 8.9 µmol, 89% yield). LC-MS calc. for C24H27N4O3 [M+H] + : m/z = 483.2; Found: 483.2. Example 28: 3-((1-(2-(isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroqui nazolin-8- yl)ethyl)amino)picolinic acid [00333] The title compound was synthesized by procedures analogous to those outlined in Example 1, Step 7 except that Step 7 was carried out at 110 °C in DMF. LC-MS calc. for C26H26N5O3 [M+H] + : m/z = 456.2; Found: 456.1. Examples 29 - 36 [00334] Examples 29 - 36 listed in Tables 5 and 6 were synthesized according to procedures analogous to Example 1 or Example 28. All examples in this table were prepared as the TFA salt. Table 5. Examples 29 - 36
Table 6. Examples 29 - 36
Example 37: 2-((1-(2-(4,4-difluoropiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4 - dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (isomer 1) [00335] Step 1. Methyl 2-((1-(2-(4,4-difluoropiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4 - dihydroquinazolin-8-yl)ethyl)amino)benzoate (isomer 1) [00336] The title compound was synthesized by procedures analogous to those outlined in Example 24. The isomers were separated using chiral prep-HPLC on an i-Amylose-3 column (30 mL/min, 80:10:10 Hexanes/IPA/MeOH) to afford two isomers: isomer 1 (tR = 1.90 min) and isomer 2 (tR = 2.74 min). Isomer 1: LC-MS calc. for C25H29F2N4O3 [M+H] + : m/z = 471.2; Found: 471.1. [00337] Step 2.2-((1-(2-(4,4-difluoropiperidin-1-yl)-3,6-dimethyl-4-oxo-3 ,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (isomer 1) [00338] To a solution of methyl 2-((1-(2-(4,4-difluoropiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4 - dihydroquinazolin-8-yl)ethyl)amino)benzoate (45.0 mg, 0.0956 mmol) in dioxane (2.0 mL) and water (2.0 mL) was added lithium hydroxide (32.1 mg, 0.765 mmol). The mixture was stirred at 90 °C for 2 h. The mixture was acidified with acetic acid and purified by prep HPLC on a CSH Phenyl-Hexyl column (52–66% MeCN/0.1% TFA (aq.)) to afford the title compound as a TFA salt (26.0 mg, 0.0456 mmol, 48% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.77 (dd, J = 7.9, 1.7 Hz, 1H), 7.74 – 7.70 (m, 1H), 7.48 (d, J = 2.1 Hz, 1H), 7.26 – 6.95 (m, 2H), 6.52 – 6.44 (m, 2H), 5.39 (q, J = 6.6 Hz, 1H), 3.51 (s, 3H), 3.39 (t, J = 5.7 Hz, 4H), 2.32 (s, 3H), 2.19 (d, J = 18.8 Hz, 4H), 1.55 (d, J = 6.7 Hz, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -95.17, -74.61. LC-MS calc. for C24H27F2N4O3 [M+H] + : m/z = 457.2; Found: 457.1. Example 38: 2-((1-(5-acrylamido-2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-di methyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [00339] Step 1. tert-butyl 2-((1-(5-acrylamido-2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-di methyl- 4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate [00340] tert-Butyl-2-[1-[2-(3-azabicyclo[3.1.0]hexan-3-yl)-5-bromo-3 ,6-dimethyl-4- oxoquinazolin-8-yl]ethylamino]benzoate (35.0 mg, 0.0632 mmol) (Example 14, Step 9), prop-2- enamide (27.0 mg, 0.379 mmol), K3PO4 (40.3 mg, 0.190 mmol), copper(I) iodide (6.0 mg, 0.032 mmol) and N1,N2-dimethylethane-1,2-diamine (6.81 uL, 0.0632 mmol) were added to a 4 mL scintillation vial.1,4-Dioxane (1.0 mL) was added, the vial was capped, and the reaction mixture was flushed with N2. After stirring at 100 °C overnight, the reaction mixture was cooled to room temperature, concentrated, diluted with water, and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with brine, concentrated, and purified by prep HPLC on a CSH C18 column (75–100% MeCN/0.1% TFA (aq.)) to afford the title compound as a TFA salt (15.0 mg, 0.0228 mmol). LC-MS calc. for C31H37N5NaO4 [M+Na] + : m/z = 566.3; Found: 566.1. [00341] Step 2.2-((1-(5-acrylamido-2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6- dimethyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [00342] A solution of tert-butyl 2-((1-(5-acrylamido-2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoa te (8.0 mg, 0.015 mmol) in DCM (0.5 mL) and TFA (0.5 mL) was stirred overnight. The reaction mixture was concentrated and purified by prep HPLC on a CSH C18 column (75–100% MeCN/0.1% TFA (aq.)) to afford the title compound as a TFA salt (1.0 mg, 2.0 µmol, 14% yield). LC-MS calc. for C27H29N5NaO4 [M+Na] + : m/z = 510.2; Found: 510.1. Example 39: 2-[1-[2-(5-azaspiro[2.4]heptan-5-yl)-3,6-dimethyl-4-oxoquina zolin-8-yl]ethyl- amino]benzoic acid [00343] Step 1: 2-(5-azaspiro[2.4]heptan-5-yl)-8-bromo-3,6-dimethylquinazoli n-4-one [00344] To a solution of 8-bromo-2-chloro-3,6-dimethylquinazolin-4-one (80.0 mg, 0.278 mmol) in THF (2 mL) was added diisopropylethylamine (0.145 mL, 0.835 mmol) and 5- azaspiro[2.4] heptane (0.0614 mL, 0.556 mmol). The resulting mixture was stirred overnight. The mixture was concentrated, and the crude product was directly purified by silica gel chromatography (0 –30% EtOAc/heptane) to afford the tile compound (93.1 mg, 0.267 mmol, 96.1% yield) as a white solid. 1 H NMR (300 MHz, CDCl3) δ 7.89 (dd, J = 2.1, 1.0 Hz, 1H), 7.73 (d, J = 2.0 Hz, 1H), 3.77 (t, J = 6.8 Hz, 2H), 3.54 (s, 3H), 3.50 (s, 2H), 2.39 (s, 3H), 1.90 (t, J = 6.8 Hz, 2H), 0.65 (d, J = 2.4 Hz, 4H). LC-MS calc. for C16H19BrN3O [M+H] + : m/z= 348.1/350.1; Found 347.8/349.8. [00345] Step 2: 8-acetyl-2-(5-azaspiro[2.4]heptan-5-yl)-3,6-dimethylquinazol in-4-one [00346] To a solution of 2-(5-azaspiro[2.4]heptan-5-yl)-8-bromo-3,6-dimethylquinazoli n-4- one (93.0 mg, 0.267 mmol) in 1,4-dioxane (2 mL) was added bis(triphenylphosphine)palladium(II) dichloride (37.5 mg, 0.0534 mmol). The resulting mixture was purged with N2 (3x). Tributyl(1-ethoxyvinyl)tin (0.226 mL, 0.668 mmol) was added, and the mixture was stirred at 100 °C for 5 h. The mixture was cooled to room temperature and quenched with sat. KF (aq.) (5 mL), and the mixture was stirred for 2 h. The reaction mixture was diluted with water (5 mL) and EtOAc (10 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was diluted with 1N HCl (3 mL) and THF (3 mL). The reaction was stirred for 2 h. The aqueous layer was adjusted to pH ~8–9 with sat. NaHCO3 and further diluted with EtOAc (10 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography (10–40% EtOAc/heptane) to afford the title compound (59.6 mg, 0.191 mmol, 71.7% yield) as a white solid. 1 H NMR (300 MHz, CDCl3) δ 8.12 (dd, J = 2.3, 1.1 Hz, 1H), 7.84 (d, J = 2.3 Hz, 1H), 3.74 (t, J = 6.8 Hz, 2H), 3.56 (s, 3H), 3.44 (s, 2H), 2.85 (s, 3H), 2.42 (s, 3H), 1.90 (t, J = 6.8 Hz, 2H), 0.66 (s, 4H). LC-MS calc. for C18H22N3O2 [M+H] + : m/z= 312.2; Found 312.2. [00347] Step 3: 2-(5-azaspiro[2.4]heptan-5-yl)-8-(1-hydroxyethyl)-3,6-dimeth ylquinazolin-4- one [00348] To a solution of 8-acetyl-2-(5-azaspiro[2.4]heptan-5-yl)-3,6-dimethylquinazol in-4-one (52.0 mg, 0.167 mmol) in methanol (2 mL) was added sodium borohydride (12.6 mg, 0.334 mmol). The resulting mixture was stirred for 2 h. The reaction was quenched with water (5 mL), and the reaction mixture was diluted with EtOAc (5 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified by silica gel chromatography (10–60% EtOAc/heptane) to afford the title compound (50.0 mg, 0.160 mmol, 95.5% yield) as a white solid. 1 H NMR (300 MHz, CDCl3) δ 7.85 (dd, J = 2.1, 1.0 Hz, 1H), 7.28 (d, J = 2.1 Hz, 1H), 5.84 (d, J = 6.7 Hz, 1H), 5.10 (t, J = 6.5 Hz, 1H), 3.79 – 3.64 (m, 2H), 3.55 (s, 3H), 3.47 (d, J = 9.7 Hz, 1H), 3.37 (d, J = 9.7 Hz, 1H), 2.40 (s, 3H), 1.91 (ddt, J = 14.3, 12.1, 6.3 Hz, 2H), 1.62 (d, J = 6.6 Hz, 3H), 0.66 (s, 4H). LC-MS calc. for C18H24N3O2 [M+H] + : m/z= 314.2; Found 314.2. [00349] Step 4: 2-(5-azaspiro[2.4]heptan-5-yl)-8-(1-bromoethyl)-3,6-dimethyl quinazolin-4- one [00350] To a solution of 2-(5-azaspiro[2.4]heptan-5-yl)-8-(1-hydroxyethyl)-3,6-dimeth yl- quinazolin-4-one (25.0 mg, 0.0798 mmol) in DCM (1 mL) was added phosphorus tribromide (0.0227 mL, 0.239 mmol). The resulting mixture was stirred at 35 °C for 2 h. The reaction was quenched with sat. NaHCO3 solution (10 mL), and the reaction mixture was diluted with EtOAc (10 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to afford the title compound (30.0 mg, 0.0797 mmol, >99%) as a colorless oil. The crude product was used in the next step directly without further purification. [00351] Step 5: 2-[1-[2-(5-azaspiro[2.4]heptan-5-yl)-3,6-dimethyl-4-oxoquina zolin-8-yl]ethyl- amino]benzoic acid [00352] To a solution of 2-(5-azaspiro[2.4]heptan-5-yl)-8-(1-bromoethyl)-3,6- dimethylquinazolin-4-one (30.0 mg, 0.0797 mmol) in DCM (1 mL) was added anthranilic acid (54.7 mg, 0.399 mmol) and diisopropylethylamine (0.0694 mL, 0.399 mmol). The mixture was stirred overnight. The reaction mixture was directly purified by prep-HPLC on C18 column (20– 100% MeCN/0.1% TFA (aq.)) to afford the title compound as a TFA salt (19.0 mg, 0.0438 mmol, 44.2% yield), a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.53 (s, 1H), 8.35 (s, 1H), 7.77 (dd, J = 7.9, 1.7 Hz, 1H), 7.66 (dd, J = 2.1, 1.0 Hz, 1H), 7.40 (d, J = 2.1 Hz, 1H), 7.18 (ddd, J = 8.6, 7.2, 1.8 Hz, 1H), 6.53 – 6.41 (m, 2H), 5.35 (q, J = 6.6 Hz, 1H), 3.76 (td, J = 6.8, 1.8 Hz, 2H), 3.54 (d, J = 10.2 Hz, 1H), 3.52 - 3.46 (m, 4H), 2.29 (s, 3H), 1.97 – 1.76 (m, 2H), 1.55 (d, J = 6.6 Hz, 3H), 0.69 – 0.55 (m, 4H). LC-MS calc. for C25H29N4O3 [M+H] + : m/z= 433.2; Found 433.1. Example 41: 2-[1-(2-methoxy-3,6-dimethyl-4-oxoquinazolin-8-yl)ethylamino ]benzoic acid [00353] Step 1: 8-bromo-2-methoxy-3,6-dimethylquinazolin-4-one [00354] To a solution of 8-bromo-2-chloro-3,6-dimethylquinazolin-4-one (200 mg, 0.696 mmol) in methanol (4 mL) was added sodium methoxide (113 mg, 2.09 mmol). The resulting mixture was stirred overnight. Additional sodium methoxide (0.042 mL, 0.209 mmol, 5 N in MeOH) was added, and the mixture was stirred overnight. The reaction was quenched with sat. NH4Cl solution (20 mL), and the reaction mixture was diluted with EtOAc (20 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified by silica gel chromatography (0–30% EtOAc/heptane) to afford the title compound (147 mg, 0.518 mmol, 74.4% yield) as a white solid. tR = 6.6 min (C18 column; 5– 95% MeCN/0.1% TFA (aq.) for 1 min, 5–95% MeCN/0.1% TFA (aq.) over 4 min, 95% MeCN/0.1% TFA (aq.) for 5 min; 1 mL/ min). [00355] Step 2: 8-acetyl-2-methoxy-3,6-dimethylquinazolin-4-one [00356] The title compound was synthesized by procedures analogous to Example 39, Step 2. LC-MS calc. for C13H15N2O3 [M+H] + : m/z=247.1; Found 247.1. [00357] Step 3: 8-(1-hydroxyethyl)-2-methoxy-3,6-dimethylquinazolin-4-one [00358] The title compound was synthesized by procedures analogous to Example 39, Step 3. LC-MS calc. for C13H16N2NaO3 [M+Na] + : m/z=271.1; Found 271.1. [00359] Step 4: 2-[1-(2-methoxy-3,6-dimethyl-4-oxoquinazolin-8-yl)ethylamino ]benzoic acid [00360] To a solution of 8-(1-hydroxyethyl)-2-methoxy-3,6-dimethylquinazolin-4-one (31.2 mg, 0.126 mmol) in DCM (3 mL) was added methanesulfonyl chloride (0.0290 mL, 0.375 mmol) and triethylamine (0.0710 mL, 0.509 mmol). The mixture was stirred at 35 °C for 0.5 h. The reaction mixture was cooled to room temperature and diluted with water (3 mL). The layers were separated, and the aqueous phase was extracted with DCM (3 x 3 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and redissolved in DCM (6 mL). To the mixture was added anthranilic acid (86.0 mg, 0.627 mmol) and triethylamine (0.125 mL, 0.897 mmol). After stirring at 35 °C for 2 h and then 30 °C for 2 d, the mixture was concentrated and purified by prep-HPLC on C18 column (10–90% MeCN/0.1% TFA (aq.)) to afford the title compound as a TFA salt (1.7 mg, 0.0043 mmol, 3.4% yield), a white solid. 1 H NMR (300 MHz, CD3OD) δ 7.88 (dd, J = 8.0, 1.7 Hz, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.52 (d, J = 2.1 Hz, 1H), 7.13 (ddd, J = 8.7, 7.1, 1.7 Hz, 1H), 6.58 – 6.36 (m, 2H), 5.48 (q, J = 6.7 Hz, 1H), 4.18 (s, 3H), 3.53 (s, 3H), 2.35 (s, 3H), 1.63 (d, J = 6.7 Hz, 3H). LC-MS calc. for C20H22N3O4 [M+H] + : m/z=368.2; Found 368.0. Example 42: 2-((1-(2-hydroxy-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino) benzoic acid [00361] To a solution of 8-(1-hydroxyethyl)-2-methoxy-3,6-dimethylquinazolin-4-one (31.2 mg, 0.126 mmol) in DCM (2 mL) was added phosphorus tribromide (0.0360 mL, 0.379 mmol). The mixture was stirred at 40 °C for 1 h. The reaction mixture was diluted with sat. NaHCO3 (aq.) (2 mL) and extracted with DCM (3 x 3 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was redissolved in DCM (3 mL). Anthranilic acid (81.4 mg, 0.594 mmol) and triethylamine (0.0900 mL, 0.646 mmol) were added. Upon stirring at 35 °C for 2 h, the mixture was concentrated and purified by prep-HPLC on a C18 column (20–70% MeCN/0.1 TFA (aq.)) to afford the title compound as a TFA salt (14 mg, 0.039 mmol, 31% yield), a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.79 (s, 1H), 10.97 (s, 1H), 8.33 (d, J = 5.6 Hz, 1H), 7.81 (dd, J = 8.0, 1.7 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.39 (d, J = 2.1 Hz, 1H), 7.22 (ddd, J = 8.7, 7.1, 1.7 Hz, 1H), 6.55 (t, J = 7.5 Hz, 1H), 6.31 (d, J = 8.4 Hz, 1H), 5.24-5.20 (m, , 1H), 3.29 (s, 3H), 2.25 (s, 3H), 1.42 (d, J = 6.3 Hz, 3H). LC-MS calc. for C19H20N3O4 [M+H] + : m/z= 354.1; Found 354.1. Example 43: 2-[1-(3,6-dimethyl-2-methylsulfanyl -4-oxoquinazolin-8- yl)ethylamino]benzoic acid [00362] Step 1: 8-bromo-3,6-dimethyl-2-sulfanylidene-1H-quinazolin-4-one [00363] To a solution of 2-amino-3-bromo-N,5-dimethylbenzamide (10.0 g, 41.1 mmol) in THF (100 mL) was added 1,1’-thiocarbonyldiimidazole (11.0 g, 61.7 mmol) and 1,8- diazabicyclo[5.4.0] undec-7-ene (12.5 g, 82.3 mmol. The resulting mixture was stirred at 70 °C for 27 h. The reaction mixture was cooled to 0 °C and diluted with sat. NH4Cl solution. The resulting solid was collected by filtration, triturated with water (3x), and dried by co-evaporating with toluene to afford the title compound (10.8 g, 37.9 mmol, 92.1% yield) as a brown solid. LC- MS calc. for C10H10BrN2OS [M+H] + : m/z= 285.0; Found 285.4. [00364] Step 2: 8-bromo-3,6-dimethyl-2-methylsulfanylquinazolin-4-one [00365] To a solution of 8-bromo-3,6-dimethyl-2-sulfanylidene-1H-quinazolin-4-one (10.8 g, 37.9 mmol) in THF (108 mL) was added iodomethane (8.06 g, 56.8 mmol) and triethylamine (7.66 g, 75.8 mmol) at 0 °C. The resulting mixture was stirred for 18 h at room temperature. The mixture was poured into water. The resulting solid was collected by filtration, washed with water (3x), and co-evaporated with toluene (3x) to afford the title compound (10.0 g, 33.4 mmol, 88.3% yield) as a brown solid. LC-MS calc. for C11H12BrN2OS [M+H] + : m/z= 299.0; Found 299.5. [00366] Step 3: 8-acetyl-3,6-dimethyl-2-methylsulfanylquinazolin-4-one [00367] To a solution of 8-bromo-3,6-dimethyl-2-methylsulfanylquinazolin-4-one (10.0 g, 33.4 mmol) in 1,4-dioxane (120 mL) was added tributyl(1-ethoxyvinyl)tin (18.1 mL, 53.5 mmol) and bis-(triphenylphosphine)palladium(II) dichloride (4.69 g, 6.68 mmol). The reaction was stirred at 100 °C for 18 h. The reaction mixture was cooled to 0 °C, and 1 N HCl was added to acidify to pH 2–3. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was filtered. The layers were separated, and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (20% EtOAc/hexanes) to afford the title compound (4.93 g, 18.8 mmol, 56.2% yield) as a yellow solid. LC-MS calc. for C13H15N2O2S [M+H] + : m/z= 263.1; Found 263.5. [00368] Step 4: 8-(1-hydroxyethyl)-3,6-dimethyl-2-methylsulfanylquinazolin-4 -one [00369] The title compound was synthesized by procedures analogous to Example 39, Step 3. LC-MS calc. for C13H17N2O2S [M+H] + : m/z= 265.1; Found 265.5. [00370] Step 5: Methyl 2-[1-(3,6-dimethyl-2-methylsulfanyl-4-oxoquinazolin-8-yl)eth ylamino] benzoate [00371] The title compound was synthesized by procedures analogous to Example 41, Step 4. LC-MS calc. for C21H24N3O3S [M+H] + : m/z= 398.2; Found 398.1. [00372] Step 6: 2-[1-(3,6-dimethyl-2-methylsulfanyl -4-oxoquinazolin-8-yl)ethylamino]benzoic acid [00373] To a solution of methyl 2-[1-(3,6-dimethyl-2-methylsulfanyl-4-oxoquinazolin-8- yl)ethyl-amino]benzoate (20.0 mg, 0.0503 mmol) in methanol (1 mL), THF (1 mL), and water (0.5 mL) was added NaOH (20.1 mg, 0.503 mmol). After stirring at 50 °C for 7 h, the reaction mixture was cooled to 0 °C, and 1N HCl was added to adjust to pH 2–3. The mixture was extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by prep-HPLC on a C18 column (50–100% MeCN/0.1% TFA (aq.)) to afford the title compound as a TFA salt (16 mg, 0.042 mmol, 83% yield), a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 8.43 (s, 1H), 7.77 (dd, J = 8.0, 1.6 Hz, 2H), 7.52 (d, J = 2.0 Hz, 1H), 7.18 (ddd, J = 8.7, 7.1, 1.8 Hz, 1H), 6.49 (t, J = 7.5 Hz, 1H), 6.43 (d, J = 8.5 Hz, 1H), 5.45 (q, J = 7.0 Hz, 1H), 3.52 (s, 3H), 2.68 (s, 3H), 2.33 (s, 3H), 1.58 (d, J = 6.7 Hz, 3H). LC-MS calc. for C20H20N3O3S [M-H]-: m/z= 384.1; Found 384.1. Example 44: 2-((1-(2-(4-cyanopiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihy droquinazolin-8- yl)ethyl)amino)benzoic acid [00374] Step 1: Methyl 2-((1-(3,6-dimethyl-2-(methylsulfonyl)-4-oxo-3,4-dihydroquin azolin-8- yl)ethyl)amino)benzoate [00375] To a solution of methyl 2-[1-(3,6-dimethyl-2-methylsulfanyl-4-oxoquinazolin-8- yl)ethyl-amino]benzoate (110 mg, 0.277 mmol, Example 43, Step 5) in DCM (5 mL) was added 3-chloro-perbenzoic acid (95.5 mg, 0.553 mmol) at 0 °C. Upon stirring at 40 °C for 4 h, the mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with sat. NaHCO3 (aq.) and brine (2 x 30 mL), dried over Na2SO4, filtered, and concentrated to afford the title compound (150 mg), which was used to the next step directly without further purification. LC- MS calc. for C21H24N3O5S [M+H] + : m/z= 430.1; Found 430.7. [00376] Step 2: Methyl 2-((1-(2-(4-cyanopiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihy dro- quinazolin-8-yl)ethyl)amino)benzoate [00377] To a solution of methyl 2-[1-(3,6-dimethyl-2-methylsulfonyl-4-oxoquinazolin-8- yl)ethyl-amino]benzoate (15.0 mg, 0.0349 mmol) in THF (2 mL) was added N,N- diisopropylethylamine (13.5 mg, 0.105 mmol) and piperidine-4-carbonitrile (3.85 mg, 0.0349 mmol) at 35 °C under a nitrogen atmosphere. The reaction was stirred at 70 °C for 14 h. The crude material was purified by prep-HPLC on a C18 column (20–80% MeCN/0.1% TFA (aq.)) to afford the title compound as a TFA salt (10 mg, 0.022 mmol, 62% yield). LC-MS calc. for C26H29N5NaO3 [M+Na] + : m/z = 462.2; Found 462.5. [00378] Step 3: 2-((1-(2-(4-cyanopiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihy droquinazolin-8- yl)ethyl)amino)benzoic acid [00379] To a solution of methyl 2-[1-[2-(4-cyanopiperidin-1-yl)-3,6-dimethyl-4- oxoquinazolin-8-yl]ethylamino]benzoate (10.0 mg, 0.0218 mmol) in methanol (1 mL), THF (1 mL), and water (0.3 mL) was added NaOH (2.61 mg, 0.0653 mmol). The mixture was stirred at 40 °C for 4 h. The mixture was acidified to pH 5–6 with 1N HCl, concentrated, and purified by prep-HPLC on a C18 column (10–90% MeCN/0.1% TFA (aq.)) to afford the title compound as a TFA salt (4.4 mg, 0.0098 mmol, 45% yield). LC-MS calc. for C25H28N5O3 [M+H] + : m/z= 446.2; Found 446.0. Example 45: 3-fluoro-2-((1-(2-(isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-d ihydroquinazolin- 8-yl)ethyl)amino)benzoic acid [00380] Step 1: 8-fluoro-1-(1-(2-(isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-di hydroquinazolin-8- yl)ethyl)-2H-benzo[d][1,3]oxazine-2,4(1H)-dione [00381] To a solution of 8-fluoro-1H-3,1-benzoxazine-2,4-dione (19.4 mg, 0.107 mmol) and triphenylphosphine (28.2 mg, 0.107 mmol) in THF (1 mL) was added diisopropyl azodicarboxylate (21.1 µL, 0.107 mmol) at 0 °C. The mixture was stirred for 10 min.2-(1,3- Dihydroisoindol-2-yl)-8-(1-hydroxyethyl)-3,6-dimethylquinazo lin-4-one (20.0 mg, 0.0596 mmol) was added. After stirring for 4 h, the mixture was concentrated and purified by prep- HPLC on a C18 column (10–80% MeCN/0.1% TFA (aq.)) to afford the title compound as the TFA salt (17 mg, 0.034 mmol, 57% yield) as a colorless solid. LC-MS calc. for C28H24FN4O4 [M+H] + : m/z= 499.2; Found 499.0. [00382] Step 2: 3-fluoro-2-((1-(2-(isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-d ihydroquinazolin- 8-yl)ethyl)amino)benzoic acid [00383] To a suspension of 1-[1-[2-(1,3-dihydroisoindol-2-yl)-3,6-dimethyl-4-oxoquinazo lin- 8-yl]ethyl]-8-fluoro-3,1-benzoxazine-2,4-dione (10.0 mg, 0.0201 mmol, from Step 1) in MeCN (0.5 mL) was added 2 N NaOH (5 drops). The mixture was stirred for 30 min. To the mixture was added 2 N HCl (0.5 mL). The mixture was diluted with MeCN and purified by prep-HPLC on a C18 column (10–70% MeCN/0.1% TFA (aq.)) to afford the title compound as a TFA salt (2.3 mg, 0.0049 mmol, 24% yield), a colorless solid. LC-MS calc. for C27H26FN4O3 [M+H]+: m/z= 473.2; Found 473.0. Example 46: 2-((1-(2-(4-acetylpiperazin-1-yl)-3,6-dimethyl-4-oxo-3,4-dih ydroquinazolin-8- yl)ethyl)amino)benzoic acid [00384] Step 1: tert-butyl 4-(8-(1-hydroxyethyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazol in-2- yl)piperazine-1-carboxylate [00385] The title compound was synthesized by procedures analogous to Example 39, Steps 1- 3. LC-MS calc. for C21H31N4O4 [M+H] + : m/z= 403.2; Found 403.2. [00386] Step 2: tert-butyl 4-(8-(1-((2-(methoxycarbonyl)phenyl)amino)ethyl)-3,6-dimethy l-4- oxo-3,4-dihydroquinazolin-2-yl)piperazine-1-carboxylate [00387] The title compound was synthesized by procedures analogous to Example 41, Step 4. 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (dd, J = 8.0, 4.0 Hz, 1H), 7.71-7.69 (m, 1H), 7.64 (d, J = 8.0, 1H), 7.49 (d, J = 4.0, 1H), 7.32 (d, J = 4.0, 1H), 6.56 (d, J = 8.0, 1H ), 6.49 (t, J = 8.0, 1H), 5.37 – 5.32 (m, 1H), 3.80 (s, 3H), 3.53 – 3.50 (m, 4H), 3.48 (s, 3H), 3.20 – 3.15 (m, 4H), 2.31 (s, 3H), 1.57 (d, J = 8.0, 3H), 1.40 (s, 9H). LC-MS calc. for C29H38N5O5 [M+H] + : m/z= 536.3; Found 536.1. [00388] Step 3: methyl 2-((1-(3,6-dimethyl-4-oxo-2-(piperazin-1-yl)-3,4-dihydroquin azolin-8- yl) ethyl)amino)benzoate [00389] To a solution of tert-butyl4-[8-[1-(2-methoxycarbonylanilino)ethyl]-3,6-dimet hyl-4- oxoquinazolin-2-yl]piperazine-1-carboxylate (160 mg, 0.299 mmol) in DCM (2 mL) was added TFA (0.4 mL, 5.23 mmol). The reaction mixture was stirred at 35 °C for 2 h. The mixture was acidified to pH 5–6 with 1 N HCl and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated. The crude material was purified by prep-HPLC on a C18 column (10–90% MeCN/0.1% TFA (aq.)) to afford the title compound as a TFA salt (120 mg, 0.276 mmol, 92.2% yield), a yellow solid. LC- MS calc. for C24H30N5O3 [M+H] + : m/z= 436.2; Found 436.2. [00390] Step 4: methyl 2-((1-(2-(4-acetylpiperazin-1-yl)-3,6-dimethyl-4-oxo-3,4-dih ydro- quinazolin-8-yl)ethyl)amino)benzoate [00391] To a solution of methyl 2-[1-(3, 6-dimethyl-4-oxo-2-piperazin-1-ylquinazolin-8- yl)ethyl-amino] benzoate (30.0 mg, 0.0689 mmol, from Step 3) in DCM (10 mL) was added triethylamine (0.0200 mL, 0.207 mmol) and acetic anhydride (7.74 mg, 0.0758 mmol). The mixture was stirred at 40 °C for 14 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by prep-HPLC on a C18 column (10–90% MeCN/0.1% TFA (aq.)) to afford the title compound as a TFA salt (20 mg, 0.042 mmol, 61% yield), a yellow solid. LC- MS calc. for C26H32N5O4 [M+H] + : m/z= 478.3; Found 478.9. [00392] Step 5: 2-((1-(2-(4-acetylpiperazin-1-yl)-3,6-dimethyl-4-oxo-3,4-dih ydroquinazolin-8- yl)ethyl)amino)benzoic acid [00393] To a solution of methyl 2-[1-[2-(4-acetylpiperazin-1-yl)-3,6-dimethyl-4- oxoquinazolin-8-yl]ethylamino]benzoate (20.0 mg, 0.0419 mmol, from Step 4) in methanol (1 mL), THF (0.5 mL), and water (0.5 mL) was added lithium hydroxide (7.03 mg, 0.168 mmol). The mixture was stirred at 40 °C for 14 h. The reaction mixture was acidified to pH 5–6 with 1N HCl, concentrated, and purified by prep-HPLC on a C18 column (10–90% MeCN/0.1% TFA (aq.)) to afford the title compound as a TFA salt (4.0 mg, 0.0079 mmol, 19% yield), a white solid. LC-MS calc. for C25H30N5O4 [M+H] + : m/z= 464.2; Found 464.2. Example 47: 2-[[1-[2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxoq uinazolin-8-yl]- 2,2,2-trifluoroethyl]amino]benzoic acid [00394] Step 1: 2-(3-azabicyclo[3.1.0]hexan-3-yl)-8-bromo-3,6-dimethylquinaz olin-4-one [00395] The title compound was synthesized by procedures analogous to Example 39, Step 1. 1 H NMR (300 MHz, CDCl3) δ 7.89 (dd, J = 2.0, 1.0 Hz, 1H), 7.73 (d, J = 2.0 Hz, 1H), 3.89 – 3.86 (m, 2H), 3.58 – 3.54 (m, 2H), 3.49 (s, 3H), 2.39 (s, 3H), 0.93 – 0.81 (m, 2H), 0.67 – 0.60 (m, 1H), 0.46 – 0.42 (m, 1H). LC-MS calc. for C15H16BrN3O [M+H] + : m/z= 334.1; Found 334.6. [00396] Step 2: 2-(3-azabicyclo[3.1.0]hexan-3-yl)-8-ethenyl-3,6-dimethylquin azolin-4-one [00397] To a solution of 2-(3-azabicyclo[3.1.0]hexan-3-yl)-8-bromo-3,6-dimethylquinaz olin- 4-one (200 mg, 0.598 mmol) in 1,4-dioxane (0.9 mL) and water (0.1 mL) was added 4,4,5,5- tetra-methyl-2-vinyl-1,3,2-dioxaborolane (0.205 mL, 1.20 mmol), potassium carbonate (248 mg, 1.80 mmol), and tetrakis(triphenylphosphine)palladium(0) (138 mg, 0.120 mmol). The resulting mixture was sparged with N2 (3x) and stirred at 100 °C for 2 h. The reaction mixture was cooled to room temperature and diluted with water (20 mL) and EtOAc (20 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography (0–40% EtOAc/heptane) to afford the title compound (164 mg, 0.581 mmol, 97.1% yield) as a yellow liquid. 1 H NMR (300 MHz, CDCl 3 ) δ 7.93 – 7.85 (m, 1H), 7.66 (d, J = 2.1 Hz, 1H), 7.55 (dd, J = 17.9, 11.2 Hz, 1H), 5.89 (dd, J = 17.9, 1.6 Hz, 1H), 5.36 (dd, J = 11.2, 1.5 Hz, 1H), 3.81 – 3.78 (m 2H), 3.53 – 3.49 (m, 2H), 3.50 (s, 3H), 2.42 (s, 3H), 0.93 – 0.81 (m, 2H), 0.65 – 0.58 (m, 1H), 0.51 – 0.47 (m, 1H). LC- MS calc. for C17H20N3O [M+H] + : m/z = 282.2; Found 282.2. [00398] Step 3: 2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxoquinazol ine-8- carbaldehyde [00399] To a solution of 2-(3-azabicyclo[3.1.0]hexan-3-yl)-8-ethenyl-3,6-dimethylquin azolin- 4-one (172 mg, 0.611 mmol) in 1,4-dioxane (3 mL) and water (1 mL) was added osmium teteraoxide (0.620 mL, 0.0611 mmol, 2.5 wt.% in tert-butanol). The resulting mixture was stirred for 10 min.4-Methylmorpholine N-oxide (71.6 mg, 0.611 mmol) was added, and the reaction mixture was stirred at 35 °C for 1 h. Sodium periodate (131 mg, 0.611 mmol) was added, and the reaction was stirred at room temperature for 1 h. The reaction mixture was diluted with sat. Na2SO3 (aq.) (10 mL) and EtOAc (10 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified by silica gel chromatography (0–40% EtOAc/heptane) to afford the title compound (144 mg, 0.508 mmol, 83.1% yield) as a light brown solid. 1 H NMR (300 MHz, CDCl3) δ 10.98 (s, 1H), 8.19 (dd, J = 2.2, 0.9 Hz, 1H), 8.07 – 7.96 (m, 1H), 3.92 – 3.88 (m, 2H), 3.58 – 3.53 (m, 2H), 3.52 (s, 3H), 2.44 (s, 3H), 0.93 – 0.81 (m, 2H), 0.69 – 0.62 (m, 1H), 0.44 – 0.39 (m, 1H). LC- MS calc. for C16H18N3O2 [M+H] + : m/z= 284.1; Found 284.2. [00400] Step 4: 2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-8-(2,2,2-trif luoro-1- hydroxyethyl )quinazolin-4-on [00401] To a solution of 2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxoquinazol ine-8- carbaldehyde (72.0 mg, 0.254 mmol) in THF (1.5 mL) was added cesium fluoride (57.9 mg, 0.381 mmol) and trimethyl(trifluoromethyl)silane (58.5 ^L, 0.381 mmol). The resulting mixture was stirred for 3 min. The reaction was quenched with 1 N HCl (0.5 mL), and the mixture was stirred for 0.5 h. The reaction mixture was diluted with sat. NaHCO3 (5 mL), water (5 mL), and EtOAc (5 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified by silica gel chromatography (10–60% EtOAc/heptane) to afford the title compound (95.5 mg, 0.270 mmol, quantitative) as a white solid. 1 H NMR (300 MHz, CDCl3) δ 7.98 (s, 1H), 7.34 (s, 1H), 5.35 (s, 1H), 5.11 (q, J = 7.7 Hz, 1H), 3.88 – 3.85 (m, 1H), 3.68 – 3.65 (m, 1H), 3.56 – 3.41 (m, 2H) and 3.51 (s, 3H), 2.43 (s, 3H), 0.91 – 0.81 (m, 2H), 0.70 – 0.63 (m, 1H), 0.47 – 0.43 (m, 1H). LC- MS calc. for C17H19F3N3O2 [M+H] + : m/z= 354.1; Found 354.1. [00402] Step 5: 2-[[1-[2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxoq uinazolin-8-yl]- 2,2,2-trifluoroethyl]amino]benzoic acid [00403] The title compound was synthesized by procedures analogous to Example 41, Step 4. 1 H NMR (300 MHz, DMSO-d6) δ 13.04 (s, 1H), 9.03 (d, J = 9.0 Hz, 1H), 7.85 – 7.81 (m, 2H), 7.58 (s, 1H), 7.38 – 7.32 (m, 1H), 6.80 (d, J = 8.5 Hz, 1H), 6.71 – 6.66 (m, 1H), 6.40 – 6.35 (m, 1H), 4.08 – 4.06 (m, 1H), 3.80 – 3.77 (m, 1H), 3.59 – 3.47 (m, 2H), 3.42 (s, 3H), 2.36 (s, 3H), 2.00 – 1.97 (m, 1H), 1.53 – 1.37 (m, 1H), 0.63 – 0.57 (m, 1H), 0.33 – 0.29 (m, 1H). LC-MS calc. for C24H24F3N4O3 [M+H]+: m/z= 473.2; Found 473.1. Example 48: ((1-(3-((1r,3r)-3-hydroxycyclobutyl)-2-(isoindolin-2-yl)-6-m ethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [00404] Step 1: 2-Amino-3-bromo-N-(3-hydroxycyclobutyl)-5-methylbenzamide [00405] To a solution of 2-amino-3-bromo-5-methylbenzoic acid (500 mg, 2.17 mmol) in THF (5 mL) was added 1,1’-carbonyldiimidazole (388 mg, 2.39 mmol). The reaction mixture was stirred for 17 h.3-Aminocyclobutan-1-ol hydrochloride (403 mg, 3.26 mmol) and triethylamine (330 mg, 3.26 mmol) were added. The mixture was stirred for 3 h. The reaction mixture was diluted with water and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (30% petroleum ether/EtOAc) to afford the title compound (380 mg, 1.27 mmol, 58.4% yield), a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 6.7 Hz, 1H), 7.35 (m, 2H), 6.12 (m, 2H), 4.99 (s, 1H), 4.39 – 4.25 (m, 2H), 2.27 – 2.20 (m, 2H), 2.17 (s, 3H), 2.15 – 2.08 (m, 2H). LC-MS calc. for C12H16BrN2O2 [M+H] + : m/z= 299.0; Found 299.5. [00406] Step 2: 2-amino-3-bromo-N-[3-[tert-butyl(dimethyl)silyl]oxycyclobuty l]-5-methyl- benzamide [00407] To a solution of 2-amino-3-bromo-N-(3-hydroxycyclobutyl)-5-methylbenzamide (200 mg, 0.67 mmol) in DCM (4 mL) was added imidazole (91 mg, 1.3 mmol). The mixture was cooled to 0 °C, and tert-butyldimethylsilyl chloride (120 mg, 0.82 mmol) was added in portions. The resulting mixture was stirred at 45 °C for 5 h. The reaction mixture was concentrated and purified by silica gel chromatography (6% EtOAc/hexanes) to afford the title compound (190 mg, 0.459 mmol, 68.7% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 6.6 Hz, 1H), 7.38 – 7.32 (m, 2H), 6.12 (s, 2H), 4.55 – 4.48 (m, 1H), 4.29 (m, 1H), 2.33 – 2.25 (m, 2H), 2.23 – 2.12 (m, 5H), 0.85 (s, 9H), 0.01 (s, 6Hf). LC-MS calc. for C18H30BrN2O2Si [M+H] + : m/z= 413.1; Found 413.7. [00408] Step 3: 8-bromo-3-[3-[tert-butyl(dimethyl)silyl]oxycyclobutyl]-6-met hyl-2- sulfanylidene-1H-quinazolin-4-one [00409] To a solution of 2-amino-3-bromo-N-[3-[tert-butyl(dimethyl)silyl]oxycyclobuty l]-5- methylbenzamide (190 mg, 0.46 mmol) in THF (4 mL) was added 1,1'-thiocarbonyldiimidazole (160 mg, 0.92 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (210 mg, 1.38 mmol). The reaction was stirred at 70 °C for 16 h. The reaction mixture was cooled to 0 °C, and the reaction quenched with sat. NH4Cl (aq.). The resulting precipitate was collected by filtration and rinsed with water. The crude material was purified by silica gel chromatography (5% EtOAc/hexanes) to give the title compound (160 mg, 0.351 mmol, 76.4% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.69 – 10.62 (m, 1H), 7.86 (s, 1H), 7.77 (s, 1H), 6.36 – 6.29 (m, 1H), 4.72 (m, 1H), 3.07 – 3.00 (m, 2H), 2.34 (s, 3H), 2.25 (m, 2H), 0.87 (s, 9H), 0.03 (s, 6H). LC-MS calc. for C19H28BrN2O2SSi [M+H] + : m/z= 455.1; Found 455.6. [00410] Step 4: 8-bromo-3-[3-[tertbutyl(dimethyl)silyl]oxycyclobutyl]-6-meth yl-2-methyl- sulfanylquinazolin-4-one [00411] To a solution of 8-bromo-3-[3-[tert-butyl(dimethyl)silyl]oxycyclobutyl]-6-met hyl-2- sulfanylidene-1H-quinazolin-4-one (40 mg, 0.092 mmol) in THF (2 mL) was added iodomethane (18 mg, 0.13 mmol) and triethylamine (18 mg, 0.18 mmol) at 0 °C. The resulting mixture was stirred at 30 °C for 21 h. The reaction mixture was concentrated, and the crude material was purified by prep-TLC (10:1 hexanes/EtOAc) to afford the title compound (25 mg, 0.053 mmol, 61% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.92 (m, 1H), 7.83 (m, 1H), 5.10 (m, J = 9.5, 6.6, 2.9, 0.9 Hz, 1H), 4.79 – 4.75 (m, 1H), 3.17 – 3.10 (m, 2H), 2.62 (s, 3H), 2.38 (s, 3H), 2.33 (m, 2H), 0.87 (s, 9H), 0.04 (s, 6H). LC-MS calc. for C20H30BrN2O2SSi [M+H] + : m/z=469.1; Found 469.6. [00412] Step 5: 8-bromo-3-((1r,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobuty l)-6-methyl-2- (methylsulfonyl)quinazolin-4(3H)-one [00413] The title compound was synthesized by procedures analogous to Example 44, Step 2. 1 H NMR (400 MHz, DMSO-d6) δ 8.08 (dd, J = 4.0, 1.6 Hz, 1H), 7.97 (dd, J = 4.0, 1.6 Hz, 1H), 5.69 – 5.58 (m, 1H), 4.80 – 4.75 (m, 1H), 3.64 (s, 3H), 3.26 – 3.20 (m, 2H), 2.46 (s, 3H), 2.30 – 2.23 (m, 2H), 0.87 (s, 9H), 0.03 (s, 6H). LC-MS calc. for C20H30BrN2O4SSi [M+H] + : m/z = 501.1; Found 501.7. [00414] Step 6: 8-bromo-3-((1r,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobuty l)-2-(isoindolin-2- yl)-6-methylquinazolin-4(3H)-one [00415] To a solution of 8-bromo-3-[3-[tert-butyl(dimethyl)silyl]oxycyclobutyl]-6-met hyl-2- methylsulfonylquinazolin-4-one (65 mg, 0.13 mmol) in THF (5 mL) was added N,N-diisopropyl- ethylamine (50 mg, 0.39 mmol) and isoindoline hydrochloride (30 mg, 0.19 mmol). The mixture was stirred at 50 °C for 14 h. The mixture was cooled to room temperature, diluted with water (20 mL), and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The crude material was purified by prep-TLC (20% EtOAc/petroleum ether) to afford the title compound (65 mg, 0.12 mmol, 93% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.81 (dd, J = 4.0, 1.6 Hz, 1H), 7.75 (dd, J = 4.0, 1.6 Hz, 1H), 7.39 – 7.37 (m, 2H), 7.29 – 7.27 (m, 2H), 5.03 – 4.99 (m, 1H), 4.90 (s, 4H), 4.69 – 4.65 (m, 1H), 2.86 – 2.80 (m, 2H), 2.46 – 2.43 (m, 2H), 2.34 (s, 3H), 0.87 (s, 9H), 0.03 (s, 6H). LC-MS calc. for C27H35BrN3O2Si [M+H] + : m/z= 540.2; Found 540.8. [00416] Step 7: 8-acetyl-3-((1r,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobut yl)-2-(isoindolin-2- yl)-6-methylquinazolin-4(3H)-one [00417] The title compound was synthesized by procedures analogous to Example 39, Step 2. Rf = 0.3 (5:1 petroleum ether/EtOAc). [00418] Step 8: 3-((1r,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-8-(1- hydroxyethyl)-2- (isoindolin-2-yl)-6-methylquinazolin-4(3H)-one [00419] The title compound was synthesized by procedures analogous to Example 39, Step 3. The crude material was purified by prep-TLC (3:1 petroleum ether/EtOAc) to afford the title compound (15 mg, 0.030 mmol, 36% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.64 (d, J = 1.3 Hz, 1H), 7.60 (d, J = 2.1 Hz, 1H), 7.39 – 7.37 (m, 2H), 7.29 – 7.27 (m, 2H), 5.40 – 5.38 (m, 1H), 5.05 – 5.01 (m, 2H), 4.89 (d, J = 12.0, 2H), 4.76 (d, J = 12.0, 2H), 4.72 – 4.70 (m, 1H), 2.90 – 2.85 (m, 2H), 2.46 – 2.40 (m, 2H), 2.36 (s, 3H), 1.36 (d, J = 4.0, 3H), 0.87 (s, 9H), 0.03 (s, 6H). LC-MS calc. for C29H40N3O3Si [M+H] + : m/z= 506.3; Found 506.9. [00420] Step 9: Methyl 2-((1-(3-((1r,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl )-2- (isoindolin-2-yl)-6-methyl-4-oxo-3,4-dihydroquinazolin-8-yl) ethyl)amino)benzoate [00421] The title compound was synthesized by procedures analogous to Example 41, Step 4. LC-MS calc. for C37H47N4O4Si [M+H] + : m/z= 639.3; Found 639.5. [00422] Step 10: Methyl 2-((1-(3-((1r,3r)-3-hydroxycyclobutyl)-2-(isoindolin-2-yl)-6 -methyl-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate [00423] To a solution of methyl 2-[1-[3-[3-[tert-butyl(dimethyl)silyl]oxycyclobutyl]-2-(1,3- dihydroisoindol-2-yl)-6-methyl-4-oxoquinazolin-8-yl]ethylami no]benzoate (19.0 mg, 0.030 mmol) in THF (1 mL) was added tetrabutylammonium fluoride (0.06 mL, 0.06 mmol, 1 N in THF). The reaction mixture was stirred at 40 °C for 14 h. The reaction was quenched with water (20 mL), and the mixture extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by prep-TLC (50% petroleum ether/EtOAc) to afford the title compound (15 mg, 0.029 mmol, 96% yield) as a yellow solid. LC- MS calc. for C31H32N4NaO4 [M+Na] + : m/z= 547.2; Found 547.8. [00424] Step 11: 2-((1-(3-((1r,3r)-3-Hydroxycyclobutyl)-2-(isoindolin-2-yl)-6 -methyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [00425] The title compound was synthesized by procedures analogous to Example 43, Step 6. 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.74 (dd, J = 8.1, 1.7 Hz, 1H), 7.63 (dd, J = 2.1, 1.0 Hz, 1H), 7.41-7.35 (m, 3H), 7.29 – 7.27 (m, 2H), 7.14 – 7.11 (m, 1H), 6.47 – 6.44 (m, 2H), 5.37 – 5.33 (m, 1H), 5.10 – 5.06 (m, 1H), 4.95 (d, J = 12.0 Hz, 2H), 4.83 (d, J = 12.0 Hz, 2H), 4.36 – 4.33 (m, 1H), 2.83 – 2.78 (m, 2H), 2.41 – 2.37 (m, 2H), 2.27 (s, 3H), 1.55 (d, J = 4.0 Hz, 3H). LC-MS calc. for C30H31N4O4 [M+H] + : m/z= 511.2; Found 511.1. Example 49: 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-fluoro-3-methyl-4 -oxo-3,4-dihydro- quinazolin-8-yl)ethyl)amino)benzoic acid [00426] The title compound was synthesized by procedures analogous to Example 1, Step 1–4; Example 39, Step 2–3; Example 41, Step 4; and Example 43, Step 6. LC-MS calc. for C23H23FN4NaO3 [M+Na] + : m/z= 445.1; Found 445.7. Example 50: 2-((1-(6-cyano-2-(isoindolin-2-yl)-3-methyl-4-oxo-3,4-dihydr oquinazolin-8- yl)ethyl)amino)benzoic acid [00427] Step 1: 2-amino-5-bromo-3-iodobenzoic acid [00428] To a suspension of 2-amino-5-bromobenzoic acid (15.0 g, 69.4 mmol) in DCM (200 mL) was added N-iodosuccinimide (34.4 g, 153 mmol). The mixture was stirred overnight, and then heated at 40 °C for 6 h. The mixture was cooled to room temperature and 5% Na2S2O3 solution (aq.) (50 mL) was added. The reaction mixture was stirred for 1 h. The resulting solid was collected by filtration, washed with water, and dried to give the title compound (17.0 g, 49.7 mmol, 71.6% yield) as a dark solid. LC-MS calc. for C7H6BrINO2 [M+H] + : m/z= 341.9, 343.9; Found 341.8, 343.7. [00429] Step 2: 6-Bromo-8-iodo-3-methylquinazoline-2,4(1H,3H)-dione [00430] The title compound was synthesized by procedures analogous to Example 14, Steps 2 and 4. LC-MS calc. for C9H7BrIN2O2 [M+H] + : m/z= 380.9; Found 380.7. [00431] Step 3: 6-Bromo-8-iodo-2-(isoindolin-2-yl)-3-methylquinazolin-4(3H)- one [00432] The title compound was synthesized by procedures analogous to Example 1, Step 3–4. LC-MS calc. for C17H14BrIN3O [M+H] + m/z= 481.9; Found 481.7. [00433] Step 4: 6-Bromo-8-(1-hydroxyethyl)-2-(isoindolin-2-yl)-3-methylquina zolin-4(3H)-one [00434] The title compound was synthesized by procedures analogous to Example 39, Step 2– 3. LC-MS calc. for C19H19BrN3O2 [M+H] + m/z= 401.1, 403.1; Found 401.9, 403.2. [00435] Step 5: 1-(1-(6-bromo-2-(isoindolin-2-yl)-3-methyl-4-oxo-3,4-dihydro quinazolin-8- yl)ethyl)-2H-benzo[d][1,3]oxazine-2,4(1H)-dione [00436] The title compound was synthesized by procedures analogous to Example 45, Step 1. LC-MS calc. for C27H22BrN4O4 [M+H] + m/z= 545.1, 547.1; Found 544.8, 546.8. [00437] Step 6: 2-((1-(6-cyano-2-(isoindolin-2-yl)-3-methyl-4-oxo-3,4-dihydr oquinazolin-8- yl)ethyl)amino)benzoic acid [00438] A mixture of 1-[1-[6-bromo-2-(1,3-dihydroisoindol-2-yl)-3-methyl-4-oxoqui nazolin- 8-yl]ethyl]-3,1-benzoxazine-2,4-dione (11.0 mg, 0.0202 mmol), tris(dibenzylideneacetone)- dipalladium(0) (1.85 mg, 0.00202 mmol), zinc (1.32 mg, 0.0202 mmol), zinc cyanide (4.74 mg, 0.0403 mmol), and 1,1'-bis(diphenylphosphino)ferrocene (2.24 mg, 0.00403 mmol) in DMF (1 mL) was heated at 100 °C overnight under a N2 atmosphere. The mixture was cooled to room temperature, filtered, and purified by prep-HPLC on a C18 column (10–70% MeCN/0.1% TFA (aq.)) to afford the TFA salt of the title compound (1.3 mg, 0.0028 mmol, 14% yield), a brown solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.71 (s, 1H), 8.43 (d, J = 6.7 Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H), 7.84 – 7.75 (m, 2H), 7.47 – 7.37 (m, 2H), 7.37 – 7.30 (m, 2H), 7.18 (ddd, J = 8.6, 7.1, 1.7 Hz, 1H), 6.58 – 6.47 (m, 1H), 6.41 (d, J = 8.5 Hz, 1H), 5.46 – 5.32 (m, 1H), 5.18 (m, 4H), 3.65 (s, 3H), 1.61 (d, J = 6.6 Hz, 3H). LC-MS calc. for C27H24N5O3 [M+H] + m/z= 466.2; Found 466.0. Examples 51 - 57 [00439] Examples 51 - 57 listed in Table 7 were synthesized according to procedures analogous to Example 41, Step 4 (Method A), Example 39, Step 4–5 (Method B), or Example 44 (Method C). The appropriate starting materials for Methods A and B can be prepared according to procedures analogous to Example 1, Steps 1–6. All examples in this table were prepared as the TFA salt. Table 7. Examples 51 – 57 Table 8. Examples 51-57 Example 58: 2-((1-(2-((1R,5S,6s)-6-((methoxycarbonyl)amino)-3-azabicyclo [3.1.0]hexan-3- yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amin o)benzoic acid [00440] Step 1. tert-Butyl ((1R,5S,6s)-3-(8-bromo-3,6-dimethyl-4-oxo-3,4-dihydroquinazo lin- 2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate [00441] The title compound was synthesized by procedures analogous to those outlined in Example 74, Step 1. LC-MS calc. for C20H26BrN4O3 [M+H] + m/z= 451.1; Found 451.0. [00442] Step 2. tert-butyl ((1R,5S,6s)-3-(8-(1-hydroxyethyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)carbam ate [00443] The title compound was synthesized by procedures analogous to those outlined in Example 1, Steps 5–6. LC-MS calc. for C22H31N4O4 [M+H] + m/z= 415.2; Found 415.1. [00444] Step 3. tert-Butyl 2-((1-(2-((1R,5S,6s)-6-((tert-butoxycarbonyl)amino)-3-azabic yclo [3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin- 8-yl)ethyl)amino)benzoate [00445] The title compound was synthesized by procedures analogous to those outlined in Example 23, Step 2. LC-MS calc. for C33H44N5O5 [M+H] + m/z= 590.3; Found 590.3. [00446] Step 4. tert-Butyl 2-((1-(2-((1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)- 3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoa te [00447] To a solution of tert-butyl 2-((1-(2-((1R,5S,6s)-6-((tert-butoxycarbonyl)amino)-3- azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo-3,4-dihydroq uinazolin-8- yl)ethyl)amino)benzoate in DCM (2 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 1.5 h. The mixture was concentrated and purified by prep-HPLC (15–60% MeCN/0.1% TFA (aq)) to afford the title compound (76.0 mg, 0.155 mmol, 41.3% yield), a colorless solid. LC-MS calc. for C28H36N5O3 [M+H] + m/z= 490.3; Found 490.1. [00448] Step 5. tert-Butyl 2-((1-(2-((1R,5S,6s)-6-((methoxycarbonyl)amino)-3- azabicyclo[3.1.0] hexan-3-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoate [00449] To a solution of tert-butyl 2-((1-(2-((1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3- yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amin o)benzoate (38 mg, 0.070 mmol) in DCM (2 mL) was added methoxycarbonyl methyl carbonate (9.1 mg, 0.070 mmol) and triethylamine (0.020 mL, 0.16 mmol). The mixture was stirred at room temperature for 2 h. The mixture was quenched with water (5 mL). The organic phase was separated, and the aqueous phase was extracted with DCM (3 x 10 mL). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated. The crude material was purified by silica gel chromatography (20–80% EtOAc/heptane) to afford the title compound (42.5 mg, 0.0776 mmol, quantitative yield), a white solid. LC-MS calc. for C30H38N5O5 [M+H] + m/z= 548.3; Found 548.2. [00450] Step 6.2-((1-(2-((1R,5S,6s)-6-((Methoxycarbonyl)amino)-3-azabicyc lo[3.1.0]hexan-3- yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amin o)benzoic acid [00451] The title compound was synthesized by procedures analogous to those outlined in Example 38, Step 2. 1 H NMR (300 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.67 (s, 1H), 7.42 (s, 2H), 7.16 (s, 1H), 6.45 (t, J = 7.6 Hz, 2H), 5.35 (d, J = 12.8 Hz, 1H), 4.02 (d, J = 10.6 Hz, 2H), 3.84 (d, J = 10.7 Hz, 2H), 3.51 (s, 3H), 3.43 (s, 3H), 2.29 (s, 3H), 1.99 (s, 1H), 1.74 (s, 2H), 1.55 (d, J = 6.5 Hz, 3H). LC-MS calc. for C26H30N5O5 [M+H] + m/z= 492.2; Found 492.1. Examples 59 – 64 [00452] Examples 59 – 64 listed in Tables 9 and 10 were synthesized according to procedures analogous to Example 58. All examples in this table were prepared as the TFA salt. Table 9. Examples 59 – 64
Table 10. Examples 59 – 64 Example 65: 2-((1-(2-(5-(tert-Butoxycarbonyl)-2,5-diazabicyclo[2.2.1]hep tan-2-yl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoi c acid [00453] Step 1.8-Acetyl-3,6-dimethylquinazoline-2,4(1H,3H)-dione [00454] To a nitrogen sparged solution of 8-bromo-3,6-dimethyl-1H-quinazoline-2,4-dione (1.00 g, 3.72 mmol) in 1,4-dioxane (35 mL) was added tetrakis(triphenylphosphine)palladium(0) (859 mg, 0.743 mmol) and tributyl(1-ethoxyvinyl)tin (1.88 mL, 5.57 mmol). The reaction was stirred at 100 °C overnight. The reaction mixture was cooled to 50 °C, 6 N HCl (2 mL) was added, and was stirred for 1 h. The reaction mixture was cooled to room temperature and purified directly by silica gel chromatography (0–100% EtOAc/hexanes) to afford the title compound (961 mg, 4.14 mmol, 98.0% yield) as a white solid. LC-MS calc. for C12H13N2O3 [M+H] + : m/z = 233.1; Found: 232.9. [00455] Step 2. tert-Butyl 5-(8-acetyl-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-2 ,5- diazabicyclo[2.2.1]heptane-2-carboxylate [00456] To a solution of 8-acetyl-3,6-dimethyl-1H-quinazoline-2,4-dione (150 mg, 0.646 mmol) in MeCN (3.25 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.290 mL, 1.94 mmol) and bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (361 mg, 0.775 mmol). The reaction was stirred for 1 h. tert-Butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (192 mg, 0.969 mmol) was added, and the reaction mixture was stirred at 60 °C overnight. The reaction mixture was cooled to room temperature and diluted with water and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated. The crude material was purified by silica gel chromatography (0–100% EtOAc/hexanes) to afford tert-butyl 5-(8- acetyl-3,6-dimethyl-4-oxoquinazolin-2-yl)-2,5-diazabicyclo[2 .2.1]heptane-2-carboxylate (61 mg, 0.15 mmol, 23% yield) as a yellow solid. LC-MS calc. for C22H29N4O4 [M+H] + : m/z = 413.2; Found: 413.0. [00457] Step 3. tert-Butyl 5-(8-(1-hydroxyethyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazol in-2- yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate [00458] The title compound was synthesized by procedures analogous to those outlined in Example 1, Step 6. LC-MS calc. for C22H31N4O4 [M+H] + : m/z = 415.2; Found: 415.1. [00459] Step 4.2-[1-[3,6-Dimethyl-2-[5-[(2-methylpropan-2-yl)oxycarbonyl] -2,5-diazabicyclo [2.2.1]heptan-2-yl]-4-oxoquinazolin-8-yl]ethylamino]benzoic acid [00460] The title compound was synthesized by procedures analogous to those outlined in Example 41, Step 4. LC-MS calc. for C29H36N5O5 [M+H] + : m/z = 534.3; Found: 534.0. Example 66: 2-((1-(2-((3aR,6aR)-5-Acetylhexahydropyrrolo[3,4-c]pyrrol-2( 1H)-yl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoi c acid [00461] The title compound was synthesized by procedures analogous to Example 46, Steps 1– 5, substituting tert-butyl (3as,6as)-rel-octahydropyrrolo[3,4-c]pyrrole-2-carboxylate hemioxalate (Astatech, cat# P15553) for 1-Boc-piperazine. LC-MS calc. for C27H32N5O4 [M+H] + : m/z = 490.2; Found: 490.1. Example 67: 2-((1-(2-(5,7-Dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3,6-dim ethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (isomer 1) [00462] Step 1: 8-Bromo-2-(5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3,6- dimethylquinazolin-4(3H)-one [00463] The title compound was synthesized by procedures analogous to those outlined in Example 65, Step 2. LC-MS calc. for C17H16BrN4O [M+H] + : m/z= 371.0; Found 371.4. [00464] Step 2: 2-(5,7-Dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-8-(1-hydroxyet hyl)-3,6- dimethylquinazolin-4(3H)-one [00465] The title compound was synthesized by procedures analogous to those outlined in Example 1, Step 5–6. 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (dd, J = 4.0, 1.6 Hz, 1H), 7.81 (dd, J = 4.0, 1.2 Hz, 1H), 7.68 – 7.66 (m, 1H), 7.63 – 7.62 (m, 1H), 7.31 (dd, J = 8.0, 4.0 Hz, 1H), 5.46 – 5.40 (m, 1H), 5.12 – 5.08 (m, 2H), 5.04 – 4.97 (m, 2H), 4.94 – 4.84 (m, 2H), 3.57 (s, 3H), 2.37 (s, 3H), 1.38 (d, J = 8.0 Hz, 3H). LC-MS calc. for C19H21N4O2 [M+H] + : m/z= 337.1; Found 337.5. [00466] Step 3: Methyl 2-((1-(2-(5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3,6-dim ethyl-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (isomer 1) [00467] The title compound was synthesized by procedures analogous to those outlined in Example 23, Step 2. The isomers were separated by chiral prep-HPLC on a Lux i-Amylose-3 column (60:20:20 hexane/IPA/MeOH) to afford two isomers: isomer 1 (tR = 5.89 min) and isomer 2 (tR = 6.88 min). Isomer 1: LC-MS calc. for C27H28N5O3 [M+H] + : m/z= 470.2; Found 470.6. [00468] Step 4: Methyl (S)-2-((1-(2-(5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3,6 -dimethyl- 4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (isomer 1) [00469] The title compound was synthesized by procedures analogous to those outlined in Example 24, Step 2. LC-MS calc. for C26H26N5O3 [M+H] + m/z= 456.2; Found 456.1. Example 68: Methyl 2-[1-[2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-methyl-4-oxo-6-(tr ideuterio- methyl)quinazolin-8-yl]ethylamino]benzoate (isomer 1) [00470] Step 1: 8-Acetyl-2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-methyl-6-(4,4,5 ,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)quinazolin-4-one [00471] To a solution of 8-acetyl-2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-bromo-3- methylquinazolin-4-one (1.50 g, 4.14 mmol) in 1,4-dioxane (4 mL) was added bis(pinacolato)diboron (1.58 g, 6.21 mmol), [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.34 g, 0.41 mmol) and potassium acetate (1.22 g, 12.4 mmol). The resulting mixture was subjected to vacuum-nitrogen cycle 3 times. The resulting mixture was stirred at 90 °C overnight. The reaction mixture was cooled to room temperature and diluted with water (100 mL) and EtOAc (100 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was further purified by silica gel chromatography (5–30% EtOAc/heptane) to afford the title compound as a beige solid (1.81 g, 4.40 mmol, >99%). 1 H NMR (300 MHz, CDCl3) δ 8.74 (d, J = 1.6 Hz, 1H), 8.34 (d, J = 1.6 Hz, 1H), 3.89 (d, J = 10.3 Hz, 2H), 3.60 – 3.48 (m, 5H), 2.81 (s, 3H), 1.62 (dd, J = 4.0, 1.9 Hz, 2H), 1.34 (s, 12H), 0.68 – 0.62 (m, 1H), 0.42 – 0.37 (m, 1H). LC-MS calc. for C22H29BN3O4 [M+H] + m/z= 410.2; Found 409.9. [00472] Step 2: 8-Acetyl-2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-methyl-6-(tride uteriomethyl) quinazolin-4-one [00473] To a solution of 8-acetyl-2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-methyl-6-(4,4,5 ,5- tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-one (1.6 g, 3.91 mmol) in THF (30 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II ), complex with dichloromethane (0.641 g, 0.782 mmol), potassium carbonate (1.62 g, 11.7 mmol) and water (0.210 mL, 11.7 mmol). The resulting mixture was subjected to vacuum-nitrogen cycle 3 times. CD3I (0.729 mL, 11.7 mmol) was added to the mixture. The resulting solution was stirred at room temperature for 1 h. To the mixture was added water (150 mL) and EtOAc (150 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (150 mL x 2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (0–60% EtOAc/heptane) to afford the title compound as a white solid (1.0 g, 3.4 mmol, 85% yield). 1 H NMR (300 MHz, CDCl3) δ 8.11 (d, J = 2.3 Hz, 1H), 7.84 (d, J = 2.3 Hz, 1H), 3.82 (d, J = 10.2 Hz, 2H), 3.55 - 3.49(m, 5H), 2.85 (s, 3H), 1.66 – 1.60 (m, 2H), 0.69 – 0.58 (m, 1H), 0.48 – 0.41 (m, 1H). LC-MS calc. for C17H17D3N3O2 [M+H] + m/z= 301.2; Found 301.1. [00474] Step 3: 2-(3-Azabicyclo[3.1.0]hexan-3-yl)-8-(1-hydroxyethyl)-3-methy l-6- (trideuteriomethyl)quinazolin-4-one [00475] The title compound was synthesized by procedures analogous to those outlined in Example 1, Step 6. 1 H NMR (300 MHz, CDCl3) δ 7.85 (d, J = 2.1 Hz, 1H), 7.33 – 7.28 (m, 1H), 5.69 (d, J = 6.8 Hz, 1H), 5.16 – 5.05 (m, 1H), 3.77 (dd, J = 13.7, 10.1 Hz, 2H), 3.60 - 3.42 (m, 5H), 1.66 - 1.57 (m, 5H), 0.70 – 0.59 (m, 1H), 0.49 – 0.42 (m, 1H). LC-MS calc. for C17H19D3N3O2 [M+H] + m/z= 303.2; Found 303.4. [00476] Step 4: Methyl 2-[1-[2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-methyl-4-oxo-6- (trideuteriomethyl)quinazolin-8-yl]ethylamino]benzoate (isomer 1) [00477] The title compound was synthesized by procedures analogous to those outlined in Example 1, Step 7, substituting methyl 2-aminobenzoate for anthranilic acid. The isomers were separated using chiral prep-HPLC on a Lux i-Amylose-3 column (85:7.5:7.5 hexane/IPA/MeOH) to afford two isomers: isomer 1 (tR = 2.47 min) and isomer 2 (tR = 2.85 min). Isomer 1: LC-MS calc. for C25H26D3N4O3 [M+H] + m/z= 436.2; Found 436.8. [00478] Step 5.2-[[Rac-(1R)-1-[2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-methyl -4-oxo-6- (trideuteriomethyl)quinazolin-8-yl]ethyl]amino]benzoic acid (isomer 1) [00479] The title compound was synthesized by procedures analogous to those outlined in Example 24, Step 2. LC-MS calc. for C24H24D3N4O3 [M+H] + m/z= 422.2; Found 422.1. Example 69: 2-((1-(2-(Isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroqui nazolin-8- yl)ethyl)amino)-4-methylbenzoic [00480] To a solution of 8-(1-hydroxyethyl)-2-(isoindolin-2-yl)-3,6-dimethylquinazoli n- 4(3H)-one (80 mg, 0.24 mmol) in DCM (3.0 mL) was added phosphorus tribromide (196 mg, 0.72 mmol) and stirred at 40 °C for 2 h. To the mixture was added triethylamine (170 mg,1.68 mmol) and 2-amino-4-methylbenzoic acid (254 mg, 1.68mmol). The mixture was stirred at 40 °C for 12 h. The mixture was quenched with water (10 mL) and extracted with DCM (10 mL x 2), The combined organic phases were concentrated in reduce pressure and purified by prep- HPLC on a C18 column (10-100% MeCN/0.1% TFA (aq)) to afford the title compound (9.1 mg, 7.8% yield), a white solid. LC-MS calc. for C28H27N4O3 [M-H]- m/z= 467.2; Found 467.9. Example 70: 2-((1-(6-Bromo-2-(isoindolin-2-yl)-3-methyl-4-oxo-3,4-dihydr oquinazolin-8- yl)ethyl)amino)benzoic acid [00481] Step 1: 1-(1-(6-Bromo-2-(isoindolin-2-yl)-3-methyl-4-oxo-3,4-dihydro quinazolin-8- yl)ethyl)-2H-benzo[d][1,3]oxazine-2,4(1H)-dione [00482] To a solution of isatoic anhydride (48.2 mg, 0.295 mmol) and triphenylphosphine (77.4 mg, 0.295 mmol) in THF (2 mL) was added diisopropyl azodicarboxylate (58.1 mL, 0.295 mmol) at 0 °C. The mixture was stirred for 10 min.6-bromo-2-(1,3-dihydroisoindol-2-yl)-8-(1- hydroxyethyl)-3-methylquinazolin-4-one (66 mg, 0.16 mmol) was added. The mixture was stirred for 4 h. To the mixture was added saturated aqueous NaHCO3 (2 mL). The organic phase was separated, and the aqueous phase was extracted with EtOAc (3 x 3 mL). The combined organic phases were dried over Na2SO4, concentrated, and purified by silica gel chromatography (0–30% EtOAc/heptane) to afford the title compound (55 mg, 0.10 mmol, 62% yield), a colorless solid. LC-MS calc. for C27H22BrN4O4 [M+H] + m/z= 545.0; Found 544.9. [00483] Step 2: 2-((1-(6-Bromo-2-(isoindolin-2-yl)-3-methyl-4-oxo-3,4-dihydr oquinazolin-8- yl)ethyl)amino)benzoic acid [00484] To a solution of 1-[1-[6-bromo-2-(1,3-dihydroisoindol-2-yl)-3-methyl-4- oxoquinazolin-8-yl]ethyl]-3,1-benzoxazine-2,4-dione (12 mg, 0.022 mmol) in DMSO (1 mL) was added 2 N NaOH (5 drops). The mixture was stirred for 0.5 h. The mixture was acidified with 1 N HCl to pH~5, diluted with MeCN, and purified by prep-HPLC on a C18 column (10– 70% MeCN/0.1% TFA (aq)) to afford the title compound (2.4 mg, 0.0046 mmol, 21% yield), a colorless solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.74 (s, 1H), 8.41 (s, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.80 (dd, J = 7.9, 1.7 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.45 – 7.36 (m, 2H), 7.36 – 7.29 (m, 2H), 7.18 (ddd, J = 8.7, 7.1, 1.7 Hz, 1H), 6.52 (t, J = 7.5 Hz, 1H), 6.41 (d, J = 8.5 Hz, 1H), 5.51 – 5.29 (m, 1H), 5.11 (q, J = 14.0 Hz, 4H), 3.63 (s, 3H), 1.60 (d, J = 6.6 Hz, 3H). LC- MS calc. for C26H24BrN4O3 [M+H] + m/z= 519.1; Found 519.0. Example 71: 2-[1-[3,6-Dimethyl-4-oxo-2-(1-prop-2-enoylpyrrolidin-2-yl)qu inazolin-8- yl]ethylamino]benzoic acid [00485] To a solution of 2-[1-(3,6-dimethyl-4-oxo-2-pyrrolidin-2-ylquinazolin-8- yl)ethylamino]benzoic acid (8.4 mg, 0.013 mmol) in DCM (1 mL) was added triethylamine (11.1 µL, 0.0794 mmol) and acrylic anhydride (1.11 µL, 0.00927 mmol). The resulting mixture was stirred for 0.5 h. Additional portions of triethylamine (11.1 µL, 0.0794 mmol) and acrylic anhydride (1.11 µL, 0.00927 mmol) were added and the mixture was stirred for 1 h. The mixture was concentrated under reduced pressure and purified by prep-HPLC on C18 column (20–100% MeCN/0.1% TFA (aq)) to afford the title compound (2.3 mg, 0.0046 mmol, 35% yield), a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.68 (s, 1H), 8.39 - 8.37 (m, 1H), 7.86 – 7.69 (m, 2H), 7.49 - 7.45 (m, 1H), 7.11 – 6.91 (m, 1H), 6.70 - 6.65 (m, 1H), 6.53 – 6.39 (m, 1H), 6.24 - 6.18 (m, 1H), 6.14 – 5.98 (m, 1H), 5.67 – 5.51 (m, 1H), 5.49 – 5.21 (m, 2H), 3.97 – 3.75 (m, 2H), 3.66 - 3.62 (m, 3H), 2.35 - 2.32 (m, 3H), 2.24 – 1.89 (m, 4H), 1.47 - 1.42 (m, 3H). LC-MS calc. for C26H29N4O4 [M+H] + m/z= 461.2; Found 461.1. Example 72: 2-((1-(2-(Isoindolin-2-yl)-3-methyl-4-oxo-3,4-dihydroquinazo lin-8- yl)ethyl)amino)benzoic acid [00486] To a suspension of 2-[1-[6-bromo-2-(1,3-dihydroisoindol-2-yl)-3-methyl-4- oxoquinazolin-8-yl]ethylamino]benzoic acid (10 mg, 0.019 mmol) and sodium bicarbonate (3 mg, 0.04 mmol) in DCM (1 ml) was added 10% Pd/C (2.0 mg, 0.098 mmol). Methanol (3 mL) was added. The mixture was stirred under a hydrogen atmosphere for 1 h. The mixture was filtered, concentrated, and purified by prep-HPLC on a C18 column (10–70% MeCN/0.1% TFA (aq)) to afford the title compound (5 mg, 0.01 mmol, 60% yield), a colorless solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.43 (s, 1H), 7.88 (dd, J = 7.9, 1.5 Hz, 1H), 7.77 (dd, J = 8.0, 1.7 Hz, 1H), 7.56 (dd, J = 7.4, 1.6 Hz, 1H), 7.47 – 7.36 (m, 2H), 7.36 – 7.28 (m, 2H), 7.22 – 7.08 (m, 2H), 6.53 – 6.38 (m, 2H), 5.46 (q, J = 6.6 Hz, 1H), 5.09 (q, J = 13.7 Hz, 4H), 3.62 (s, 3H), 1.59 (d, J = 6.6 Hz, 3H). LC-MS calc. for C26H25N4O3 [M+H] + m/z= 441.2; Found 441.0. Example 73: 2-[1-[2-(1-Fluorosulfonylpyrrolidin-2-yl)-3,6-dimethyl-4-oxo quinazolin-8- yl]ethylamino]benzoic acid [00487] Step 1: tert-Butyl 2-[[2-bromo-4-methyl-6-(methylcarbamoyl)phenyl]carbamoyl] pyrrolidine-1-carboxylate [00488] To a solution of 2-amino-3-bromo-N,5-dimethylbenzamide (900 mg, 3.70 mmol) in DCM (18 mL) was added 1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid (1.59 g, 7.40 mmol) followed by the addition of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.42 g, 7.40 mmol) and 4-(dimethylamino)pyridine (1.81 g, 14.8 mmol). The resulting mixture was stirred for 48 h. The mixture was quenched with 1 N HCl (50 mL) and diluted with EtOAc (50 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (30–100% EtOAc/heptane) to afford the title compound (390 mg, 0.89 mmol, 24% yield), a white solid. 1 H NMR (300 MHz, CDCl3) δ 8.52 (s, 1H), 7.54 – 7.43 (m, 1H), 7.33 (s, 1H), 6.61 (s, 1H), 4.44 (s, 1H), 3.61 – 3.38 (m, 2H), 2.90 (d, J = 4.9 Hz, 3H), 2.32 (s, 4H), 2.03 – 1.87 (m, 2H), 1.71 (d, J = 9.1 Hz, 1H), 1.49 (s, 9H). LC-MS calc. for C19H27BrN3O4 [M+H] + m/z= 440.1/442.1; Found 439.9/441.9. [00489] Step 2: tert-Butyl 2-(8-bromo-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2- yl)pyrrolidine-1-carboxylate [00490] To a solution of tert-butyl 2-[[2-bromo-4-methyl-6- (methylcarbamoyl)phenyl]carbamoyl] pyrrolidine-1-carboxylate (370 mg, 0.840 mmol) in DCM (7 mL) was added iodine (320 mg, 1.26 mmol). The reaction was stirred until all iodine was dissolved. The reaction mixture was cooled to 0 °C and [dimethyl- (trimethylsilylamino)silyl]methane (0.264 mL, 1.26 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 7 h. The reaction mixture was diluted with DCM (30 mL) 10% aq. Na2S2O3 (30 mL). The layers were separated, and the aqueous layer was extracted with DCM (30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was purified by silica gel chromatography (0– 100% EtOAc/heptane) to afford the title compound (211 mg, 0.499 mmol, 59.0% yield), a beige solid. LC-MS calc. for C19H25BrN3O3 [M+H] + m/z= 422.1/424.1; Found 422.0/424.0. [00491] Step 3: tert-Butyl 2-[8-(1-hydroxyethyl)-3,6-dimethyl-4-oxoquinazolin-2- yl]pyrrolidine-1-carboxylate [00492] The title compound was synthesized by procedures analogous to those outlined in Example 39, Step 2-3. LC-MS calc. for C21H30N3O4 [M+H] + m/z= 388.2; Found 388.2. [00493] Step 4: 2-[1-(3,6-Dimethyl-4-oxo-2-pyrrolidin-2-ylquinazolin-8-yl)et hylamino]benzoic acid [00494] The title compound was synthesized by procedures analogous to those outlined in Example 41, Step 4. LC-MS calc. for C23H27N4O3 [M+H] + m/z= 407.2; Found 407.0. [00495] Step 5: 2-[1-[2-(1-Fluorosulfonylpyrrolidin-2-yl)-3,6-dimethyl-4-oxo quinazolin-8- yl]ethylamino]benzoic acid [00496] To a solution of 2-[1-(3,6-dimethyl-4-oxo-2-pyrrolidin-2-ylquinazolin-8- yl)ethylamino]benzoic acid (18.4 mg, 0.0290 mmol) in MeCN (1 mL) was added triethylamine (0.0121 mL, 0.0870 mmol) followed by 1-(fluorosulfonyl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate (9.52 mg, 0.0290 mmol). The resulting mixture was stirred for 1 h. Additional portions of triethylamine (0.012 mL, 0.087 mmol) and 1-(fluorosulfonyl)-2,3- dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate (9.5 mg, 0.029 mmol) were added and the mixture was stirred for 1 h. The mixture was concentrated and purified by prep-HPLC on a C18 column (20–80% MeCN/0.1% TFA (aq)) to afford the title compound (3.3 mg, 0.0068 mmol, 22% yield), a white solid. LC-MS calc. for C23H26FN4O5S [M+H] + m/z= 489.2; Found 489.1. Example 74: 2-((1-(6-Bromo-2-(4,4-difluoropiperidin-1-yl)-3-methyl-4-oxo -3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [00497] Step 1: 6-Bromo-2-(4,4-difluoropiperidin-1-yl)-8-iodo-3-methylquinaz olin-4(3H)-one [00498] To a suspension of 6-bromo-2-chloro-8-iodo-3-methylquinazolin-4-one (795 mg, 1.99 mmol) and 4,4-difluoropiperidine hydrochloride (565 mg, 3.58 mmol) in THF (20 mL) was added N,N-diisopropylethylamine (1.39 mL, 7.96 mmol). The mixture was stirred at 60 °C for 4 h. The mixture was cooled to room temperature and diluted with water (20 mL) and EtOAc (20 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, concentrated, and purified by silica gel chromatography (0–50% EtOAc/heptane) to afford the title compound (870 mg, 1.8 mmol, 91% yield), a colorless solid. LC-MS calc. for C14H14BrF2IN3O [M+H] + m/z= 483.9; Found 483.7. [00499] Step 2: 6-Bromo-2-(4,4-difluoropiperidin-1-yl)-8-(1-hydroxyethyl)-3- methylquinazolin-4(3H)-one [00500] The title compound was synthesized by procedures analogous to those outlined in Example 39, Steps 2–3. LC-MS calc. for C16H19BrF2N3O2 [M+H] + m/z= 402.1; Found 401.9. [00501] Step 3: 2-((1-(6-Bromo-2-(4,4-difluoropiperidin-1-yl)-3-methyl-4-oxo -3,4-dihydro- quinazolin-8-yl)ethyl)amino)benzoic acid Example 75: 2-((1-(3-((1r,3r)-3-Cyanocyclobutyl)-2-(isoindolin-2-yl)-6-m ethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [00502] Step 1: Methyl 2-((1-(2-(isoindolin-2-yl)-6-methyl-3-((1s,3s)-3-((4-nitrobe nzoyl)oxy) cyclobutyl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)ben zoate [00503] To a solution of 4-nitrobenzoic acid (71 mg, 0.42 mmol), methyl 2-[1-[2-(1,3- dihydroisoindol-2-yl)-3-(3-hydroxycyclobutyl)-6-methyl-4-oxo quinazolin-8- yl]ethylamino]benzoate (150 mg, 0.286 mmol) and tri-n-butylphosphine (87 mg, 0.43 mmol) in THF (3 mL) was added a solution of di-tert-butyl azodicarboxylate (99 mg, 0.43 mmol) in THF (1 mL) dropwise. The reaction was refluxed under a nitrogen atmosphere for 48 h. The mixture was concentrated and purified by silica gel column chromatography (2% EtOAc/hexanes) to afford the title compound (60 mg, 0.089 mmol, 31% yield) as a light-yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 8.0 Hz, 2H), 8.30 – 8.28 (m, 1H), 8.26 (d, J = 8.0 Hz, 2H), 7.75 (dd, J = 8.0, 4.0 Hz, 1H), 7.72 – 7.71 (m, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.38 – 7.35 (m, 2H), 7.30 – 7.26 (m, 2H), 7.19 – 7.15 (m, 1H), 6.53 (d, J = 8.0 Hz, 1H), 6.51 – 6.47 (m, 1H), 5.63 – 5.57 (m, 1H), 5.41 – 5.34 (m, 1H), 5.29 – 5.21 (m, 1H), 4.94 (q, J = 12.0 Hz, 4H), 3.76 (s, 3H), 3.23 – 3.14 (m, 2H), 2.94 – 2.82 (m, 2H), 2.30 (s, 3H), 1.57 (d, J = 4.0 Hz, 3H). LC-MS calc. for C38H36N5O7 [M+H]+: m/z= 674.2; Found 673.5. [00504] Step 2: Methyl 2-((1-(3-((1s,3s)-3-hydroxycyclobutyl)-2-(isoindolin-2-yl)-6 -methyl-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate [00505] To a solution of methyl 2-[1-[2-(1,3-dihydroisoindol-2-yl)-6-methyl-3-[3-(4- nitrobenzoyl)oxycyclobutyl]-4-oxoquinazolin-8-yl]ethylamino] benzoate (130 mg, 0.193 mmol) in THF (8 mL) and MeOH (2 mL) was added a solution of Na2CO3 (62 mg, 0.59 mmol) in water (2 mL). The reaction was stirred at 25 °C for 2 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (25 mL x 2). The combined organic layers were washed with brine (20 mL), dried over by Na2SO4, filtered and concentrated. The crude material was purified by prep-TLC (50% EtOAc/hexanes) to give the title compound (82 mg, 0.16 mmol, 81% yield), a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 4.0 Hz, 1H), 7.74 (dd, J = 4.0, 1.2 Hz, 1H), 7.64 (dd, J = 1.2, 0.4 Hz, 1H), 7.40 (d, J = 4.0 Hz, 1H), 7.39 – 7.37 (m, 2H), 7.29 – 7.27 (m, 2H), 7.18 – 7.15 (m, 1H), 6.52 (d, J = 4.0 Hz, 1H), 6.49 – 6.46 (m, 1H), 5.38 – 5.34 (m, 1H), 5.11 – 5.06 (m, 1H), 5.04 (d, J = 4.0 Hz, 1H), 4.94 (q, J = 12.0 Hz, 4H), 4.37 – 4.33 (m, 1H), 3.75 (s, 3H), 2.84 – 2.79 (m 2H), 2.40 – 2.38 (m, 1H), 2.34 – 2.30 (m, 1H), 2.27 (s, 3H), 1.55 (d, J = 4.0 Hz, 3H). LC-MS calc. for C31H33N4O4 [M+H] + : m/z= 525.2; Found 525.1. [00506] Step 3: Methyl 2-((1-(2-(isoindolin-2-yl)-6-methyl-3-((1s,3s)-3-((methylsul fonyl)oxy) cyclobutyl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)ben zoate [00507] To a solution of methyl 2-[1-[2-(1,3-dihydroisoindol-2-yl)-3-(3-hydroxycyclobutyl)-6 - methyl-4-oxoquinazolin-8-yl]ethylamino]benzoate (15.8 mg, 0.0247 mmol) in DCM (1 mL) was added triethylamine (20.7 mL, 0.148 mmol) and methanesulfonyl chloride (3.83 mL, 0.0495 mmol). The mixture was stirred for 0.5 h. The mixture was quenched with water (1 mL). The organic phase was separated, and the aqueous phase was extracted with DCM (3 x 1 mL). The combined organic phases were dried over Na2SO4 and concentrated. The crude product was used directly in the next step without any further purification. LC-MS calc. for C32H35N4O6S [M+H] + : m/z= 603.2; Found 603.1. [00508] Step 4: 2-((1-(3-((1r,3r)-3-Cyanocyclobutyl)-2-(isoindolin-2-yl)-6-m ethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [00509] To a solution of methyl 2-[1-[2-(1,3-dihydroisoindol-2-yl)-6-methyl-3-(3- methylsulfonyloxycyclobutyl)-4-oxoquinazolin-8-yl]ethylamino ]benzoate (15 mg, 0.025 mmol) in DMF (1 mL) was added sodium cyanide (9.68 mg, 0.198 mmol). The mixture was heated to 125 °C for 24 h. The mixture was cooled to room temperature, filtered, and purified by prep- HPLC on a C18 column (10–70% MeCN/0.1% TFA (aq)) to afford the title compound (3.9 mg, 0.0075 mmol, 30% yield), a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.67 (br, 1H), 8.41 (s, 1H), 7.77 (dd, J = 8.1, 1.6 Hz, 1H), 7.68 (d, J = 2.1 Hz, 1H), 7.46 – 7.38 (m, 3H), 7.34 – 7.27 (m, 2H), 7.13 (td, J = 7.7, 1.7 Hz, 1H), 6.47 (t, J = 7.8 Hz, 2H), 5.45 – 5.30 (m, 1H), 5.30 – 5.12 (m, 1H), 5.00 (d, J = 13.8 Hz, 2H), 4.85 (d, J = 13.9 Hz, 2H), 3.61 – 3.55 (m, 1H), 3.16 – 2.99 (m, 2H), 2.98 – 2.70 (m, 2H), 2.30 (s, 3H), 1.56 (d, J = 6.6 Hz, 3H). LC-MS calc. for C31H30N5O3 [M+H] + m/z= 520.2; Found 520.0. Example 76: 2-((1-(2-(3-Azabicyclo[3.1.0]hexan-3-yl)-6-cyclopropyl-3-met hyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [00510] Step 1: 2-(3-Azabicyclo[3.1.0]hexan-3-yl)-6-bromo-8-iodo-3-methylqui nazolin-4(3H)- one [00511] The title compound was synthesized by procedures analogous to those outlined in Example 74, Step 1. LC-MS calc. for C 14 H 14 BrIN 3 O [M+H] + : m/z= 445.9; Found 445.8. [00512] Step 2: 2-(3-Azabicyclo[3.1.0]hexan-3-yl)-6-bromo-8-(1-hydroxyethyl) -3- methylquinazolin-4(3H)-one [00513] The title compound was synthesized by procedures analogous to those outlined in Example 39, Steps 2–3. LC-MS calc. for C16H19BrN3O2 [M+H] + : m/z= 364.1; Found 363.9. [00514] Step 3: 1-(1-(2-(3-Azabicyclo[3.1.0]hexan-3-yl)-6-bromo-3-methyl-4-o xo-3,4- dihydroquinazolin-8-yl)ethyl)-2H-benzo[d][1,3]oxazine-2,4(1H )-dione [00515] The title compound was synthesized by procedures analogous to those outlined in Example 70, Step 1. LC-MS calc. for C24H22BrN4O4 [M+H] + : m/z= 509.0; Found 508.9. [00516] Step 4: 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-cyclopropyl-3-met hyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [00517] A solution of 1-[1-[2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-bromo-3-methyl-4- oxoquinazolin-8-yl]ethyl]-3,1-benzoxazine-2,4-dione (13.8 mg, 0.0271 mmol), cyclopropylboronic acid (11.6 mg, 0.135 mmol), potassium carbonate (22.5 mg, 0.163 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II ) (1.98 mg, 2.71 mmol) in 1,4- dioxane (0.8 mL) and water (0.2 mL) was heated to 100 °C under a nitrogen atmosphere for 6 h. The mixture was cooled to room temperature, filtered, and purified by prep-HPLC on a C18 column (10–80% MeCN/0.1% TFA (aq)) to afford the title compound (5.5 mg, 0.012 mmol, 46% yield), a colorless solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.68 (br, 1H), 8.42 (br, 1H), 7.79 (dd, J = 7.9, 1.7 Hz, 1H), 7.51 (d, J = 2.2 Hz, 1H), 7.35 (d, J = 2.2 Hz, 1H), 7.20 (ddd, J = 8.6, 7.1, 1.7 Hz, 1H), 6.56 – 6.44 (m, 2H), 5.36 (q, J = 6.7 Hz, 1H), 4.00 (d, J = 10.5 Hz, 1H), 3.83 (d, J = 10.5 Hz, 1H), 3.51 (dd, J = 19.6, 10.3 Hz, 2H), 3.43 (s, 3H), 2.05 – 1.87 (m, 1H), 1.63 (dd, J = 7.2, 3.7 Hz, 2H), 1.57 (d, J = 6.6 Hz, 3H), 0.97 – 0.89 (m, 2H), 0.67 – 0.48 (m, 3H), 0.38 (q, J = 4.2 Hz, 1H). LCMS calc. for C26H29N4O3 [M+H] + m/z= 445.2; Found 444.9. Example 77: 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-methoxy-3-methyl- 4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [00518] Step 1: 8-Acetyl-2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-hydroxy-3-methy lquinazolin- 4(3H)-one [00519] To a solution of 8-acetyl-2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-methyl-6-(4,4,5 ,5- tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-one (100 mg, 0.24 mmol) in acetone (3 mL) was added a solution of Oxone (93 mg, 0.61 mmol) in water (1 mL). The reaction was stirred for 1 h. The mixture was extracted with EtOAc (3 x 3 mL) and the combined organic layers were dried over MgSO4, concentrated, and purified by silica gel chromatography (10–90% EtOAc/heptane) to afford the title compound (65 mg, 0.22 mmol, 89% yield), a yellow solid. LC-MS calc. for C16H18N3O3 [M+H] + m/z= 300.1; Found 300.4. [00520] Step 2: 8-Acetyl-2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-methoxy-3-methy lquinazolin- 4(3H)-one [00521] To a solution of 8-acetyl-2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-hydroxy-3- methylquinazolin-4-one (63 mg, 0.21 mmol) in DCM (1 mL), acetone (3 mL), and MeOH (2 mL) was added potassium carbonate (291 mg, 2.10 mmol) and iodomethane (197 mL, 3.16 mmol). The mixture was stirred at 35 °C for 2 days. The mixture was filtered, concentrated, and purified by silica gel chromatography (0–60% EtOAc/heptane) to afford the title compound (37 mg, 0.12 mmol, 56% yield), a colorless solid. LC-MS calc. for C17H20N3O3 [M+H] + m/z= 314.1; Found 314.3. [00522] Step 3: 2-(3-Azabicyclo[3.1.0]hexan-3-yl)-8-(1-hydroxyethyl)-6-metho xy-3- methylquinazolin-4(3H)-one [00523] The title compound was synthesized by procedures analogous to those outlined in Example 1, Steps 6. LC-MS calc. for C17H22N3O3 [M+H] + m/z= 316.1; Found 316.3. [00524] Step 4: 2-((1-(2-(3-Azabicyclo[3.1.0]hexan-3-yl)-6-methoxy-3-methyl- 4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [00525] The title compound was synthesized by procedures analogous to those outlined in Example 41, Step 4. 1 H NMR (300 MHz, DMSO-d6) δ 12.73 (s, 1H), 8.41 (s, 1H), 7.80 (dd, J = 8.0, 1.7 Hz, 1H), 7.28 (d, J = 3.0 Hz, 1H), 7.23 – 7.13 (m, 2H), 6.57 – 6.46 (m, 1H), 6.42 (d, J = 8.5 Hz, 1H), 5.46 – 5.27 (m, 1H), 3.96 (d, J = 10.4 Hz, 1H), 3.82 (d, J = 10.4 Hz, 1H), 3.75 (s, 3H), 3.56 – 3.48 (m, 2H), 3.45 (s, 3H), 1.66 – 1.60 (m, 2H), 1.57 (d, J = 6.6 Hz, 3H), 0.60 (td, J = 7.6, 4.5 Hz, 1H), 0.42 (q, J = 4.1 Hz, 1H). LC-MS calc. for C24H27N4O4 [M+H] + m/z= 435.2; Found 435.4. Example 78: 2-((1-(2-(3-Azabicyclo[3.1.0]hexan-3-yl)-6-ethyl-3-methyl-4- oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [00526] Step 1: 2-((1-(2-(3-Azabicyclo[3.1.0]hexan-3-yl)-3-methyl-4-oxo-6-vi nyl-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [00527] A solution of 1-[1-[2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-bromo-3-methyl-4- oxoquinazolin-8-yl]ethyl]-3,1-benzoxazine-2,4-dione (16.7 mg, 0.0328 mmol), [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.4 mg, 3.3 mmol), potassium carbonate (13.6 mg, 0.0984 mmol), and vinylboronic acid pinacol ester (11.2 mL, 0.0656 mmol) in 1,4-dioxane (0.75 mL) and water (0.25 mL) was heated to 100 °C under a nitrogen atmosphere for 3 h. The mixture was cooled to room temperature, filtered, concentrated, and purified by prep-HPLC on a C18 column (10–80% MeCN/0.1% TFA (aq)) to afford the title compound (7.5 mg, 0.017 mmol, 53% yield), a colorless solid. LC-MS calc. for C25H27N4O3 [M+H] + m/z= 431.2; Found 431.3. [00528] Step 2: 2-((1-(2-(3-Azabicyclo[3.1.0]hexan-3-yl)-6-ethyl-3-methyl-4- oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [00529] To a solution of 2-[1-[2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-ethenyl-3-methyl-4 - oxoquinazolin-8-yl]ethylamino]benzoic acid (7.5 mg, 0.017 mmol) in DCM (0.5 mL) added 10% Pd/C (10 mg, 0.094 mmol) and methanol (3 mL). The mixture was stirred under a hydrogen atmosphere for 6 h. The mixture was filtered and concentrated to afford the title compound (4.4 mg, 0.010 mmol, 58% yield), a colorless solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.69 (br, 1H), 8.44 (br, 1H), 7.79 (dd, J = 8.1, 1.6 Hz, 1H), 7.69 (d, J = 2.1 Hz, 1H), 7.46 (d, J = 2.1 Hz, 1H), 7.25 – 7.13 (m, 1H), 6.55 – 6.44 (m, 2H), 5.44 – 5.27 (m, 1H), 4.01 (d, J = 10.5 Hz, 1H), 3.84 (d, J = 10.5 Hz, 1H), 3.58 – 3.49 (m, 2H), 3.44 (s, 3H), 2.61 (q, J = 7.5 Hz, 2H), 1.67 – 1.60 (m, 2H), 1.58 (d, J = 6.7 Hz, 3H), 1.12 (t, J = 7.5 Hz, 3H), 0.61 (td, J = 7.7, 4.6 Hz, 1H), 0.38 (q, J = 4.2 Hz, 1H). LC-MS calc. for C25H29N4O3 [M+H] + m/z= 433.2; Found 433.3. Example 79: 2-((1-(2-(3-Azabicyclo[3.1.0]hexan-3-yl)-6-(difluoromethyl)- 3-methyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [00530] Step 1: 2-Amino-3-bromo-5-chloro-N-methylbenzamide [00531] To a solution of 2-amino-3-bromo-5-chlorobenzoic acid (10.0 g, 39.9 mmol) and 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridi nium 3-oxid hexafluorophosphate (18.2 g, 47.9 mmol) in DMF (200 mL) was added triethylamine (16.7 mL, 120 mmol). The mixture was stirred for 5 min. To the mixture was added methylamine (2 N in THF, 31.9 mL, 63.9 mmol). The mixture was stirred for 2 h. The mixture was poured into ice water (300 mL) to give a suspension. The resulting solid was collected by filtration, then redissolved in EtOAc (300 mL), washed with brine, dried over Na2SO4, and concentrated to afford the title compound (9.1 g, 34 mmol, 86% yield), a colorless solid. LC-MS calc. for C8H9BrClN2O [M+H] + m/z= 262.9; Found 263.2. [00532] Step 2: 8-Bromo-6-chloro-3-methylquinazoline-2,4(1H,3H)-dione [00533] To a solution of 2-amino-3-bromo-5-chloro-N-methylbenzamide (9.1 g, 34 mmol) in THF (100 mL) was added triphosgene (4.1 g, 14 mmol). The mixture was heated to 60 °C for 1 h. The reaction was cooled to room temperature and water (30 mL) was added at 0 °C. The mixture was stirred for 30 min. The solid was collected by filtration to give the title compound (9.9 g, 34 mmol, 99% yield), a colorless solid. LC-MS calc. for C9H7BrClN2O2 [M+H] + m/z= 288.9; Found 289.3. [00534] Step 3: 2-(3-Azabicyclo[3.1.0]hexan-3-yl)-8-bromo-6-chloro-3-methylq uinazolin- 4(3H)-one [00535] The title compound was synthesized by procedures analogous to those outlined in Example 65, Step 2. LC-MS calc. for C14H14BrClN3O [M+H] + m/z= 354.0; Found 354.2. [00536] Step 4: 8-Acetyl-2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-chloro-3-methyl quinazolin- 4(3H)-one [00537] The title compound was synthesized by procedures analogous to those outlined in Example 32, Step 2. LC-MS calc. for C 16 H 17 ClN 3 O 2 [M+H] + m/z= 318.1; Found 318.3. [00538] Step 5: (8-Acetyl-2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-methyl-4-oxo-3 ,4- dihydroquinazolin-6-yl)boronic acid [00539] A mixture of 8-acetyl-2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-chloro-3-methyl quinazolin- 4-one (100 mg, 0.31 mmol), bis(pinacolato)diboron (95.9 mg, 0.380 mmol), XPhos (CAS 564483-18-7, 9.0 mg, 0.0189 mmol), palladium(II) acetate (4.24 mg, 0.0189 mmol) and potassium acetate (93 mg, 0.94 mmol) in 1,4-dioxane (3 mL) was heated to 85 °C under a nitrogen atmosphere for 16 h. The mixture was cooled to room temperature, filtered, and concentrated. The crude material was purified by silica gel chromatography (0–70% EtOAc/heptane). The material was dissolved in acetone (8 mL) and a suspension of sodium periodate (200 mg, 0.94 mmol) and ammonium acetate (73 mg, 0.94 mmol) in water (3 mL) was added. The reaction was stirred for 16 h. The mixture was extracted with EtOAc (2 x 20 mL) and the combined organic layers were dried over MgSO4, filtered, and concentrated. The crude material was purified by silica gel chromatography (0–10% MeOH/DCM) to afford the title compound (20 mg, 0.061 mmol, 19% yield), a colorless solid. LC-MS calc. for C16H19BN3O4 [M+H] + m/z= 328.1; Found 328.3. [00540] Step 6: 8-Acetyl-2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-(difluoromethyl )-3-methyl- quinazolin-4(3H)-one [00541] To a mixture of bis(triphenylphosphine)palladium(II) dichloride (3.22 mg, 0.00459 mmol), XantPhos (3.98 mg, 0.00688 mmol, CAS 161265-03-8), potassium carbonate (50.7 mg, 0.367 mmol), tris(acetylacetonato)iron(III) (1.13 mg, 0.00321 mmol) and hydroquinone (20.2 mg, 0.183 mmol) under a nitrogen atmosphere was added a mixture of [8-acetyl-2-(3- azabicyclo[3.1.0]hexan-3-yl)-3-methyl-4-oxoquinazolin-6-yl]b oronic acid (15 mg, 0.046 mmol), ethyl 2-bromo-2,2-difluoroacetate (24 mL, 0.18 mmol) and styrene (2.11 mL, 0.0183 mmol) in 1,4-dioxane (1.5 mL). The mixture was heated to 80 °C for 16 h. The mixture was cooled to room temperature, filtered, and purified by prep-HPLC on a C18 column (10–70% MeCN/0.1% TFA (aq)) to afford the title compound (7.5 mg, 0.023 mmol, 49% yield), a light purple solid. LC-MS calc. for C17H18F2N3O2 [M+H] + m/z= 334.1; Found 334.3. [00542] Step 7: 2-(3-Azabicyclo[3.1.0]hexan-3-yl)-6-(difluoromethyl)-8-(1-hy droxyethyl)-3- methylquinazolin-4(3H)-one [00543] The title compound was synthesized by procedures analogous to those outlined in Example 1, Step 6. LC-MS calc. for C17H20F2N3O2 [M+H] + m/z= 336.1; Found 336.3. [00544] Step 8: 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-(difluoromethyl)- 3-methyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [00545] The title compound was synthesized by procedures analogous to those outlined in Example 41, Step 4. LC-MS calc. for C24H25F2N4O3 [M+H] + m/z= 455.1; Found 455.2. Example 80: 3-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo- 3,4-dihydro- quinazolin-8-yl)ethyl)amino)-6-(trifluoromethyl)picolinic acid [00546] To a solution of 2-(3-azabicyclo[3.1.0]hexan-3-yl)-8-(1-hydroxyethyl)-3,6- dimethylquinazolin-4-one (33 mg, 0.11 mmol) in DCM (7 mL) was added phosphorus tribromide (60 mg, 0.22 mmol). The reaction was stirred for 2.5 h. Sat. aq. NaHCO3 (5 mL) was added followed by EtOAc (5 mL). The resulting layers were separated, and the aqueous layer was extracted by EtOAc (2 x 5 mL). The combined organic layers were washed by brine, dried over anhydrous MgSO4, filtered, and concentrated. The material was dissolved in DCM (3 mL) and methyl 3-amino-6-(trifluoromethyl)pyridine-2-carboxylate (50 mg, 0.23 mmol) was added. The reaction mixture was stirred at 40 °C overnight. The mixture was concentrated, and the crude material was dissolved in THF (1 mL) and methanol (1 mL). Lithium hydroxide monohydrate (47.3 mg, 1.13 mmol) was added. The mixture was heated to 45 °C for 45 min. The mixture was concentrated and dissolved in EtOAc (7 mL), washed with water (2 x 5 mL), concentrated, and purified by prep-HPLC on a C18 column (20–100% MeCN/0.1% TFA (aq)) to afford the title compound (18 mg, 0.032 mmol, 27% yield), a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.76 (d, J = 7.0 Hz, 1H), 7.69 (d, J = 9.1 Hz, 2H), 7.51 (d, J = 1.9 Hz, 1H), 7.13 (d, J = 9.0 Hz, 1H), 5.42 – 5.33 (m, 1H), 3.97 (d, J = 10.5 Hz, 1H), 3.82 (d, J = 10.4 Hz, 1H), 3.51 (t, J = 10.3 Hz, 2H), 3.43 (s, 3H), 2.32 (s, 3H), 1.63 (t, J = 7.2 Hz, 5H), 0.58 (dd, J = 12.2, 7.6 Hz, 1H), 0.36 (dd, J = 8.2, 4.0 Hz, 1H). LC-MS calc. for C24H25F3N5O3 [M+H] + m/z= 488.1; Found 488.3. Example 81: 2-((1-(2-((1R,5S,6R)-6-(Isopropyl(methyl)carbamoyl)-3- azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo-3,4-dihydroq uinazolin-8- yl)ethyl)amino)benzoic acid [00547] Step 1. methyl (1R,5S,6R)-3-(8-acetyl-3,6-dimethyl-4-oxo-3,4-dihydroquinazo lin-2-yl)- 3-azabicyclo[3.1.0]hexane-6-carboxylate [00548] The title compound was synthesized by procedures analogous to Example 65, Step 2. LC-MS calc. for C19H22N3O4 [M+H] + : m/z= 356.1; Found 356.1. [00549] Step 2. Methyl (1R,5S,6R)-3-(8-(1-((2-(tert-butoxycarbonyl)phenyl)amino)eth yl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-3-azabicyclo[3.1. 0]hexane-6-carboxylate [00550] The title compound was synthesized by procedures analogous to Example 14, Steps 8 and 9. LC-MS calc. for C30H37N4O5 [M+H] + : m/z= 533.2; Found 533.1. [00551] Step 3. (1R,5S,6R)-3-(8-(1-((2-(tert-butoxycarbonyl)phenyl)amino)eth yl)-3,6-dimethyl- 4-oxo-3,4-dihydroquinazolin-2-yl)-3-azabicyclo[3.1.0]hexane- 6-carboxylic acid [00552] The title compound was synthesized by procedures analogous to Example 23, Step 3. LC-MS calc. for C29H35N4O5 [M+H] + : m/z= 519.2; Found 519.1. [00553] Step 4.2-((1-(2-((1R,5S,6R)-6-(Isopropyl(methyl)carbamoyl)-3- azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo-3,4-dihydroq uinazolin-8- yl)ethyl)amino)benzoic acid [00554] To a solution of (1R,5S,6R)-3-(8-(1-((2-(tert-butoxycarbonyl)phenyl)amino)eth yl)- 3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-3-azabicyclo[ 3.1.0]hexane-6-carboxylic acid (15.1 mg, 0.024 mmol, TFA salt) in DCM (1 mL) was added triethylamine (9.91 µL, 0.071 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b] pyridinium 3-oxid hexafluorophosphate (9.92 mg, 0.026 mmol). The resulting mixture was stirred for 15 min. N- Isopropylmethylamine (5.21 mg, 0.071 mmol) was added, and the reaction was stirred for 30 min. Progress of the reaction was monitored by LCMS. Upon completion of the reaction, the reaction mixture was concentrated and to the concentrated crude reaction mixture was added trifluoroacetic acid (1 mL). The reaction mixture was stirred for 3 h. The crude material was diluted with MeCN (5 mL) and water (5 mL) and was purified by prep-HPLC on a C18 column (10–90% MeCN/0.1% TFA (aq.)) to afford the title compound as a TFA salt (6.10 mg, 0.012 mmol, 48.9% yield), a white solid. LC-MS calc. for C29H36N5O4 [M+H] + : m/z= 518.2; Found 518.0. Examples 82 – 90 [00555] Examples 82 – 90 listed in Tables 11 and 12 were synthesized according to procedures analogous to Example 81. All examples in this table were prepared as the TFA salt. Table 11. Examples 82 – 90 Table 12. Examples 82 – 90
Examples 91 – 92 [00556] Examples 91 – 92 listed in Tables 13 and 14 were synthesized according to procedures analogous to Example 46. All examples in this table were prepared as the TFA salt. Table 13. Examples 91 – 92 Table 14. Examples 91 – 92 Example 93: 2-((1-(2-(4-(2-Methoxyacetyl)piperazin-1-yl)-3,6-dimethyl-4- oxo-3,4-dihydro- quinazolin-8-yl)ethyl)amino)benzoic acid [00557] Step 1. tert-Butyl 4-(8-(1-hydroxyethyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazol in-2- yl)piperazine-1-carboxylate [00558] The title compound was synthesized by procedures analogous to Example 39, Steps 1– 3. LC-MS calc. for C21H31N4O4 [M+H] + : m/z= 403.2; Found 403.2 [00559] Step 2. tert-Butyl 4-(8-(1-((2-(tert-butoxycarbonyl)phenyl)amino)ethyl)-3,6-dim ethyl- 4-oxo-3,4-dihydroquinazolin-2-yl)piperazine-1-carboxylate [00560] To a solution of tert-butyl 4-[8-(1-hydroxyethyl)-3,6-dimethyl-4-oxoquinazolin-2- yl]piperazine-1-carboxylate (230 mg, 0.571 mmol) in DCM (6 mL) was added triethylamine (0.398 mL, 2.86 mmol). The reaction mixture was cooled to 0 °C, and methane sulfonyl chloride (0.053 mL, 0.69 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. A solution of tert-butyl-2-aminobenzoate (133 mg, 0.686 mmol) in DCM (1 mL) was added. The reaction mixture was stirred at 40 °C overnight and then cooled to room temperature. The reaction mixture was diluted with water (10 mL), and the layers were separated. The aqueous layer was extracted with DCM (2 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The crude material was purified by silica gel chromatography (0–80% EtOAc/hexane) to afford the title compound (130 mg, 0.225 mmol, 39.4% yield) as an off-white solid. LC-MS calc. for C32H44N5O5 [M+H] + : m/z= 578.3; Found 578.1. [00561] Step 3.2-((1-(3,6-Dimethyl-4-oxo-2-(piperazin-1-yl)-3,4-dihydroqu inazolin-8- yl)ethyl)amino)benzoic acid [00562] To a solution of tert-butyl 4-(8-(1-((2-(tert-butoxycarbonyl)phenyl)amino)ethyl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)piperazine-1-carbo xylate (130 mg, 0.225 mmol) in DCM (2 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred for 4h. The reaction mixture was diluted with water (10 mL), and the layers were separated. The aqueous layer was extracted with DCM (2 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The crude material was purified by prep-HPLC on a C18 column (10–90% MeCN/0.1% TFA (aq.)) to afford the title compound as a TFA salt (60.0 mg, 0.112 mmol, 49.8% yield), a white solid. LC-MS calc. for C23H28N5O3 [M+H] + : m/z= 422.2; Found 422.2. [00563] Step 4.2-((1-(2-(4-(2-Methoxyacetyl)piperazin-1-yl)-3,6-dimethyl- 4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [00564] To a solution of methoxy acetic acid (6.41 mg, 0.071 mmol) in DCM (1 mL) was added triethylamine (29.8 µL, 0.214 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b] pyridinium 3-oxid hexafluorophosphate (29.8 mg, 0.078 mmol). The resulting mixture was stirred for 15 min.2-((1-(3,6-dimethyl-4-oxo-2-(piperazin-1-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino) benzoic acid (30.0 mg, 0.056 mmol, TFA salt) was added, and the reaction was stirred for 30 min. The reaction mixture was diluted with water (10 mL), and the layers were separated. The aqueous layer was extracted with DCM (2 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The crude material was purified by prep-HPLC on a C18 column (10–90% MeCN/0.1% TFA (aq.)) to afford the title compound as a TFA salt (11.7 mg, 0.019 mmol, 34.4% yield), a white solid. LC-MS calc. for C26H32N5O5 [M+H] + : m/z= 494.2; Found 494.0. Example 94: 2-((1-(3,6-Dimethyl-2-(4-(6-methylnicotinoyl)piperazin-1-yl) -4-oxo-3,4- dihydro-quinazolin-8-yl)ethyl)amino)benzoic acid [00565] The title compound was synthesized according to procedures analogous to those outlined in Example 93. LC-MS calc. for C30H33N6O4 [M+H] + : m/z= 541.3; Found 541.1. Example 95: 2-((1-(2-(3-Azabicyclo[3.1.0]hexan-3-yl)-5-fluoro-3,6-dimeth yl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (isomer 1) [00566] Step 1.2-(3-Azabicyclo[3.1.0]hexan-3-yl)-5-fluoro-8-(1-hydroxyeth yl)-3,6- dimethylquinazolin-4(3H)-one [00567] The title compound was synthesized by procedures analogous to those outlined in Example 14, Steps 2-8. LC-MS calc. for C17H21FN3O2 [M+H] + : m/z = 318.2; Found: 318.1. [00568] Step 2. Methyl 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-5-fluoro-3,6-dimeth yl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (isomer 1) [00569] The title compound was synthesized by procedures analogous to those outlined in Example 24, Step 1. The isomers were separated using chiral prep-HPLC on a Lux i-Amylose-3 column (30 mL/min, 85:7.5: 7.5 hexane/IPA/MeOH) to afford two isomers: isomer 1 (tR = 2.54 min) and isomer 2 (tR = 2.88 min). Isomer 1: LC-MS calc. for C25H28FN4O3 [M+H] + : m/z = 451.2; Found: 451.1. [00570] Step 4.2-((1-(2-(3-Azabicyclo[3.1.0]hexan-3-yl)-5-fluoro-3,6-dime thyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (isomer 1) [00571] The title compound was synthesized by procedures analogous to those outlined in Example 24, Step 2. 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (broad s, 1H), 7.77 (dd, J = 8.0, 1.7 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.17 (ddd, J = 8.7, 7.1, 1.8 Hz, 1H), 6.49 (t, J = 7.5 Hz, 1H), 6.42 (d, J = 8.5 Hz, 1H), 5.28 (q, J = 6.6 Hz, 1H), 4.03 – 3.97 (m, 2H), 3.58 – 3.44 (m, 2H), 3.38 (s, 3H), 2.16 (d, J = 2.2 Hz, 3H), 1.62 – 1.59 (m, 2H), 1.52 (d, J = 6.7 Hz, 3H), 0.62 – 0.57 (m, 1H), 0.33 – 0.30 (m, 1H). LC-MS calc. for C24H26FN4O3 [M+H] + : m/z = 437.2; Found: 437.1. Example 96: 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo- 3,4-dihydro- quinazolin-8-yl)-2,2-difluoroethyl)amino)benzoic acid [00572] Step 1.2-(3-Azabicyclo[3.1.0]hexan-3-yl)-8-(2,2-difluoro-1-hydrox yethyl)-3,6- dimethylquinazolin-4(3H)-one [00573] (Difluoromethyl)trimethylsilane (18 µL, 0.13 mmol) was added to a solution of 2-(3- azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo-3,4-dihydroq uinazoline-8-carbaldehyde (Example 47, Step 3) (25 mg, 0.090 mmol) and cesium fluoride (20 mg, 0.13 mmol) in THF (0.90 mL), and the reaction mixture was stirred for 24 h. The reaction mixture was then heated to 70 ºC for 24 h. The reaction mixture was cooled to room temperature and diluted with water and DCM. The two phases were separated, and the aqueous layer was extracted with DCM (10 mL x 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude residue containing the title compound was used without further purification (20 mg, 0.060 mmol, 68% yield). LC-MS calc. for C17H20F2N3O2 [M+H] + : m/z = 336.1; Found = 336.1. [00574] Step 2.2-((1-(2-(3-Azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-ox o-3,4- dihydroquinazolin-8-yl)-2,2-difluoroethyl)amino)benzoic acid [00575] Methanesulfonyl chloride (2.8 µL, 0.04 mmol) was added to a solution of 2-(3- azabicyclo[3.1.0]hexan-3-yl)-8-(2,2-difluoro-1-hydroxyethyl) -3,6-dimethylquinazolin-4(3H)-one (6.0 mg, 0.02 mmol) and triethylamine (7.5 µL, 0.05 mmol) in DCM (0.60 mL), and the reaction mixture was stirred for 1 h. Then anthranilic acid (3.7 mg, 0.03 mmol) was added, and the reaction mixture was stirred for 18 h. The reaction mixture was diluted with water and DCM, and the resulting two phases were separated. The aqueous layer was extracted with DCM (5 mL x 2), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by prep-HPLC on a C18 column (56-76% MeCN/0.1%TFA (aq.)) to afford the title compound as a TFA salt (2.2 mg, 4.8 µmol, 22% yield). LC-MS calc. for C24H25F2N4O3 [M+H] + : m/z = 455.2; Found = 455.1. Example 97: 2-((1-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo- 3,4-dihydro- quinazolin-8-yl)propyl)amino)benzoic acid [00576] Step 1.2-(3-Azabicyclo[3.1.0]hexan-3-yl)-8-(1-hydroxypropyl)-3,6- dimethylquinazolin-4(3H)-one [00577] Ethylmagnesium bromide solution (35 µL, 0.11 mmol, 3.0 M in diethyl ether) was added to a solution of 2-(3-azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazoline-8-carbaldehyde (Example 47, Step 3) (25 mg, 0.09 mmol) in THF (0.90 mL) at 0 ºC, and the reaction mixture was stirred at 0 ºC for 15 min. The reaction mixture was diluted with sat. NH4Cl (aq.) and DCM; then the resulting two phases were separated. The aqueous layer was extracted with DCM (5 mL x 2), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material containing the title compound was used without further purification. LC-MS calc. for C18H24N3O2 [M+H] + : m/z = 314.2; Found = 314.1. [00578] Step 2.2-((1-(2-(3-Azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-ox o-3,4-dihydro- quinazolin-8-yl)propyl)amino)benzoic acid [00579] The title compound was synthesized by procedures analogous to those outlines in Example 96, Step 2. 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (bs, 1H), 7.76 (dd, J = 7.8, 1.7 Hz, 1H), 7.66 (s, 1H), 7.38 (d, J = 2.1 Hz, 1H), 7.24 – 7.02 (m, 1H), 6.54 – 6.30 (m, 2H), 5.24 – 5.13 (m, 1H), 4.01 (d, J = 10.5 Hz, 1H), 3.81 (d, J = 10.5 Hz, 1H), 3.59 – 3.51 (m, 1H), 3.50 – 3.44 (m, 1H), 3.43 (s, 3H), 2.29 (s, 3H), 2.01 – 1.78 (m, 2H), 1.67 – 1.57 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H), 0.64 – 0.50 (m, 1H), 0.41 – 0.32 (m, 1H). LC-MS calc. for C25H29N4O3 [M+H] + : m/z = 433.2; Found = 433.1. Example 98: 2-((1-(3-(3,3-Bis(hydroxymethyl)cyclobutyl)-2-(isoindolin-2- yl)-6-methyl-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [00580] Step 1.8-Acetyl-2-(isoindolin-2-yl)-6-methyl-3-(2-oxaspiro[3.3]he ptan-6- yl)quinazolin-4(3H)-one [00581] The title compound was synthesized by procedures analogous to those outlines in Example 1, Steps 1-2, substituting 2-oxaspiro[3.3]heptan-6-amine for methylamine in Step 1; Example 65, Step 2, substituting isoindoline hydrochloride for tert-butyl 2,5- diazabicyclo[2.2.1]heptane-2-carboxylate; and Example 1, Step 5, substituting 10% H2SO4 (aq.) for 6N HCl (aq.). LC-MS calc. for C25H26N3O3 [M+H] + : m/z = 416.2; Found = 416.1. [00582] Step 2.8-(1-Hydroxyethyl)-2-(isoindolin-2-yl)-6-methyl-3-(2-oxasp iro[3.3]heptan-6- yl)quinazolin-4(3H)-one [00583] The title compound was synthesized by procedures analogous to those outlines in Example 1, Step 6. LC-MS calc. for C25H28N3O3 [M+H] + : m/z = 418.2; Found = 418.1. [00584] Step 3.2-((1-(3-(3,3-Bis(hydroxymethyl)cyclobutyl)-2-(isoindolin- 2-yl)-6-methyl-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [00585] The title compound was synthesized by procedures analogous to those outlines in Example 41, Step 4 except the displacement was performed at 45 ºC for 18 h to afford the product as an ammonium salt. LC-MS calc. for C32H35N4O5 [M+H] + : m/z = 555.3; Found = 555.2. Example 99: 2-((1-(2-(2-Azabicyclo[2.2.1]heptan-2-yl)-3,6-dimethyl-4-oxo -3,4-dihydro- quinazolin-8-yl)ethyl)amino)benzoic acid (Isomer 2) [00586] Step 1.2-(2-Azabicyclo[2.2.1]heptan-2-yl)-8-bromo-3,6-dimethylqui nazolin-4(3H)- one [00587] The title compound was synthesized by procedures analogous to those outlined in Example 1, Step 4, substituting 2-azabicyclo[2.2.1]heptane hydrochloride (CAS#: 63838-50-6) for isoindoline. LC-MS calc. for C16H19BrN3O [M+H] + : m/z = 348.1, 350.1; Found = 348.0, 350.0. [00588] Step 2.8-Acetyl-2-(2-azabicyclo[2.2.1]heptan-2-yl)-3,6-dimethylqu inazolin-4(3H)-one (Isomer 1 and Isomer 2) [00589] The title compound was synthesized from procedures analogous to those outlined in Example 1, Step 5. The crude product was purified by prep-HPLC on a C18 column (12.9- 32.9% MeCN/0.1%TFA (aq.)) to afford the title compound as a TFA salt. LC-MS calc. for C18H22N3O2 [M+H] + : m/z = 312.2; Found = 312.1. The isomers were separated using chiral prep-HPLC on a Lux Cellulose-4 column (30 mL/min, 80:10:10 hexane/IPA/MeOH) to afford two isomers: isomer 1 (tR= 6.15) and isomer 2 (tR= 6.87). [00590] Step 3.2-(2-Azabicyclo[2.2.1]heptan-2-yl)-8-(1-hydroxyethyl)-3,6- dimethylquinazolin-4(3H)-one (Isomer 1 and Isomer 2) [00591] The title compounds were synthesized from 8-acetyl-2-(2-azabicyclo[2.2.1]heptan-2- yl)-3,6-dimethylquinazolin-4(3H)-one (Isomer 1) by procedures analogous to those outlined in Example 1, Step 6 to afford a mixture of isomers 1 and 2. LC-MS calc. for C18H24N3O2 [M+H] + : m/z = 314.2; Found = 314.1. [00592] Step 4.2-((1-(2-(2-Azabicyclo[2.2.1]heptan-2-yl)-3,6-dimethyl-4-o xo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (Isomer 2) [00593] The title compound was synthesized from a mixture of 2-(2-azabicyclo[2.2.1]heptan- 2-yl)-8-(1-hydroxyethyl)-3,6-dimethylquinazolin-4(3H)-one (Isomer 1and Isomer 2; Example 99, Step 3) by procedures analogous to those outlined in Example 96, Step 2. The isomers were separated on prep-HPLC on a CSH-FP column (31.4-51.4% MeCN/0.1% TFA (aq.)) to afford two isomers: isomer 1 (tR= 4.07) and isomer 2 (tR= 4.56). Isomer 1: LC-MS calc. for C25H29N4O3 [M+H] + : m/z = 433.2; Found = 433.2. Isomer 2: LC-MS calc. for C25H29N4O3 [M+H] + : m/z = 433.2; Found = 433.1. Example 100.2-((1-(2-(2-Azabicyclo[2.2.1]heptan-2-yl)-3,6-dimethyl-4 -oxo-3,4-dihydro- quinazolin-8-yl)ethyl)amino)benzoic acid (Isomer 3) Example 101.2-((1-(2-(2-Azabicyclo[2.2.1]heptan-2-yl)-3,6-dimethyl-4 -oxo-3,4-dihydro- quinazolin-8-yl)ethyl)amino)benzoic acid (Isomer 4) [00594] Step 1.2-(2-Azabicyclo[2.2.1]heptan-2-yl)-8-(1-hydroxyethyl)-3,6- dimethylquinazolin-4(3H)-one (Isomer 3 and Isomer 4) [00595] The title compounds were synthesized from 8-acetyl-2-(2-azabicyclo[2.2.1]heptan-2- yl)-3,6-dimethylquinazolin-4(3H)-one (Isomer 2) (Example 99, Step 2) by procedures analogous to those outlined in Example 1, Step 6 to afford a mixture of isomers 3 and 4. LC-MS calc. for C18H24N3O2 [M+H] + : m/z = 314.2; Found = 314.1. [00596] Step 2.2-((1-(2-(2-Azabicyclo[2.2.1]heptan-2-yl)-3,6-dimethyl-4-o xo-3,4-dihydro- quinazolin-8-yl)ethyl)amino)benzoic acid (Isomer 3) and 2-((1-(2-(2-azabicyclo[2.2.1]heptan-2- yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amin o)benzoic acid (Isomer 4) [00597] The title compounds were synthesized from a mixture of 2-(2- azabicyclo[2.2.1]heptan-2-yl)-8-(1-hydroxyethyl)-3,6-dimethy lquinazolin-4(3H)-one (Isomer 3 and Isomer 4; Example 100, Step 1) by procedures analogous to those outlined in Example 96, Step 2. The isomers were separated on prep-HPLC on a CSH-FP column (28.9-48.9% MeCN/0.1% TFA (aq.)) to afford two isomers: isomer 3 (t R = 4.57) and isomer 4 (t R = 5.07). Isomer 3: LC-MS calc. for C25H29N4O3 [M+H] + : m/z = 433.2; Found = 433.2. Isomer 4: LC- MS calc. for C25H29N4O3 [M+H] + : m/z = 433.1; Found = 433.1. Example 102: 2-((1-(2-(3-Azabicyclo[3.1.0]hexan-3-yl)-3-(difluoromethyl)- 6-methyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [00598] Step 1.2-(3-Azabicyclo[3.1.0]hexan-3-yl)-8-bromo-3-(4-methoxybenz yl)-6- methylquinazolin-4(3H)-one [00599] The title compound was synthesized by procedures analogous to those outlined in Example 1, Step 1-4, substituting (4-methoxyphenyl)methanamine for methylamine in Step 1 and substituting 3-azabicyclo[3.1.0]hexane hydrochloride for isoindoline in Step 4. LC-MS calc. for C22H23BrN3O2 [M+H] + : m/z = 440.1, 442.1; Found: 440.1, 442.1. [00600] Step 2.2-(3-Azabicyclo[3.1.0]hexan-3-yl)-8-bromo-6-methylquinazol in-4(3H)-one [00601] A solution of 2-(3-azabicyclo[3.1.0]hexan-3-yl)-8-bromo-3-[(4- methoxyphenyl)methyl]-6-methylquinazolin-4-one (220 mg, 0.50 mmol) in TFA (3 mL) was stirred at 45 °C for 2 h. The reaction mixture was cooled to room temperature and concentrated. The crude material, which contained the title compound, was carried forward without further purification. LC-MS calc. for C14H15BrN3O [M+H] + : m/z = 320.0, 322.0; Found: 319.9, 321.9. [00602] Step 3.2-(3-Azabicyclo[3.1.0]hexan-3-yl)-8-bromo-3-(difluoromethy l)-6- methylquinazolin-4(3H)-one [00603] To a solution of 2-(3-azabicyclo[3.1.0]hexan-3-yl)-8-bromo-6-methyl-3H-quinaz olin- 4-one (120 mg, 0.38 mmol) in diglyme (2.0 mL) was added sodium tert-butoxide (79 mg, 0.83 mmol). The solution was stirred at -15 °C for 10 min. (Bromodifluoromethyl)trimethylsilane (0.07 mL, 0.5 mmol) was added dropwise. The resulting solution was stirred at -15 °C for 1 h. The reaction mixture was warmed to room temperature and diluted with EtOAc (5 mL) and brine (5 mL). The organic phase was collected, and the aqueous phase was extracted again with EtOAc (2 x 5 mL). The combined organic layer was washed with brine (6 x 5 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (0–100% EtOAc/hexanes) to afford the title compound (55 mg, 0.15 mmol, 40% yield). LC-MS calc. for C15H15BrF2N3O [M+H] + : m/z = 370.0, 372.0; Found: 370.0, 372.0. [00604] Step 4.2-((1-(2-(3-Azabicyclo[3.1.0]hexan-3-yl)-3-(difluoromethyl )-6-methyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [00605] The title compound was synthesized by procedures analogous to those outlined in Example 1, Step 5-7. LC-MS calc. for C24H25F2N4O3 [M+H] + : m/z = 455.2; Found:455.1. Example 103: 2-((1-(2-(3-Azabicyclo[3.1.0]hexan-3-yl)-6-methyl-4-oxo-3-(2 ,2,2- trifluoroethyl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzo ic acid [00606] The title compound was synthesized by procedures analogous to those outlined in Example 1, Step 1-7, substituting 2,2,2-trifluoroethylamine hydrochloride for methylamine in Step 1. LCMS calc. for C25H26F3N4O3 [M+H] + : 487.2; Found: 487.1. Example 104: 2-((1-(2-(3-Azabicyclo[3.1.0]hexan-3-yl)-6-methyl-3-(methyl- d3)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (isomer 2) [00607] Step 1.2-(3-Azabicyclo[3.1.0]hexan-3-yl)-8-(1-hydroxyethyl)-6-met hyl-3-(methyl- d3)quinazolin-4(3H)-one [00608] The title compound was synthesized by procedures analogous to those outlined in Example 1, Step 1-6, substituting methyl-d3-amine hydrochloride for methylamine in Step 1 and substituting 3-azabicyclo[3.1.0]hexane hydrochloride for isoindoline in Step 4. LC-MS calc. C17H19D3N3O2 [M+H] + m/z= 303.2; Found 303.0. [00609] Step 2.1-(1-(2-(3-Azabicyclo[3.1.0]hexan-3-yl)-6-methyl-3-(methyl -d3)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2H-benzo[d][1,3]oxazine-2,4(1H )-dione [00610] To a solution of isatoic anhydride (572 mg, 3.51 mmol) and triphenylphosphine (919 mg, 3.51 mmol) in THF (5 mL) was added diisopropyl azodicarboxylate (690 uL, 3.51 mmol) at 0 °C.2-(3-Azabicyclo[3.1.0]hexan-3-yl)-8-(1-hydroxyethyl)-6-m ethyl-3- (trideuteriomethyl)quinazolin-4-one (530 mg, 1.75 mmol) in THF (3 mL) was added. The mixture was stirred at 0 °C for 15 min and warmed up to room temperature over 30 min. The mixture was concentrated and purified by prep-HPLC on C18 column (10-60% MeCN/0.05% TFA (aq))) to afford the title compound (390 mg, 0.87 mmol, 50% yield), a colorless solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.05 (dd, J = 7.8, 1.6 Hz, 1H), 7.87 – 7.74 (m, 3H), 7.69 (d, J = 8.6 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 6.32 – 6.16 (m, 1H), 3.49 – 3.43 (m, 2H), 3.17 – 3.04 (m, 2H), 2.43 (s, 3H), 1.89 (d, J = 7.0 Hz, 3H), 1.43 – 1.34 (m, 1H), 1.34 – 1.27 (m, 1H), 0.38 (td, J = 7.7, 4.7 Hz, 1H), 0.00 (q, J = 4.2 Hz, 1H). LCMS calc. for C25H22D3N4O4 [M+H] + m/z= 448.2; Found 447.9. [00611] Step 3.1-(1-(2-(3-Azabicyclo[3.1.0]hexan-3-yl)-6-methyl-3-(methyl -d3)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2H-benzo[d][1,3]oxazine-2,4(1H )-dione (isomer 2) [00612] The isomers were separated using chiral prep-HPLC on a Lux iA1 column (30 mL/min, 60:20:20 hexane/IPA/MeOH) to afford two isomers: isomer 1 (tR = 2.97 min) and isomer 2 (tR = 3.88 min). Isomer 2: LC-MS calc. for C25H22D3N4O4 [M+H] + m/z= 448.2; Found 447.9. [00613] Step 4.2-((1-(2-(3-Azabicyclo[3.1.0]hexan-3-yl)-6-methyl-3-(methy l-d3)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (isomer 2) [00614] The title compound was synthesized by procedures analogous to those outlined in Example 45, Step 2. 1 H NMR (400 MHz, DMSO) δ 7.78 (dd, J = 7.9, 1.7 Hz, 1H), 7.66 (dd, J = 2.1, 0.9 Hz, 1H), 7.42 (d, J = 2.1 Hz, 1H), 7.17 (ddd, J = 8.6, 7.1, 1.7 Hz, 1H), 6.54 – 6.43 (m, 2H), 5.36 (q, J = 6.6 Hz, 1H), 3.99 (d, J = 10.5 Hz, 1H), 3.82 (d, J = 10.5 Hz, 1H), 3.59 – 3.29 (m, 2H), 2.29 (s, 3H), 1.61 (dt, J = 7.3, 3.4 Hz, 2H), 1.55 (d, J = 6.7 Hz, 3H), 0.59 (td, J = 7.6, 4.6 Hz, 1H), 0.37 (q, J = 4.1 Hz, 1H). LC-MS calc. for C24H24D3N4O3 [M+H] + m/z= 422.2; Found 422.2. Example 105: 2-((1-(2-(3-Azabicyclo[3.1.0]hexan-3-yl)-6-chloro-3-methyl-4 -oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (isomer 2) [00615] Step 1.1-(1-(2-(3-Azabicyclo[3.1.0]hexan-3-yl)-6-chloro-3-methyl- 4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2H-benzo[d][1,3]oxazine-2,4(1H )-dione [00616] The title compound was synthesized by procedures analogous to those outlined in Example 104, Step 1-2, substituting methyl-d3-amine hydrochloride for methylamine in Step 1 and substituting 3-azabicyclo[3.1.0]hexane hydrochloride for isoindoline in Step 4. LCMS calc. for C24H22ClN4O4 [M+H] + m/z= 465.1; Found 465.3. [00617] Step 2.1-(1-(2-(3-Azabicyclo[3.1.0]hexan-3-yl)-6-chloro-3-methyl- 4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2H-benzo[d][1,3]oxazine-2,4(1H )-dione (isomer 2) [00618] The isomers were separated using chiral prep-HPLC on a Lux iA1 column (25 mL/min, 65:17.5:17.5 hexane/IPA/MeOH) to afford two isomers: isomer 1 (tR = 3.42 min) and isomer 2 (tR = 4.40 min). Isomer 2: LC-MS calc. for C24H22ClN4O4 [M+H] + m/z= 465.1; Found 465.3. [00619] Step 3.2-((1-(2-(3-Azabicyclo[3.1.0]hexan-3-yl)-6-chloro-3-methyl -4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (isomer 2) [00620] The title compound was synthesized by procedures analogous to those outlined in Example 45, Step 2. 1 H NMR (400 MHz, DMSO) δ 8.39 (s, 1H), 7.84 – 7.76 (m, 2H), 7.51 (d, J = 2.6 Hz, 1H), 7.19 (ddd, J = 8.7, 7.1, 1.8 Hz, 1H), 6.52 (t, J = 7.3 Hz, 1H), 6.40 (d, J = 8.5 Hz, 1H), 5.33 (q, J = 6.8 Hz, 1H), 4.04 (d, J = 10.6 Hz, 1H), 3.89 (d, J = 10.6 Hz, 1H), 3.55 (dd, J = 23.6, 10.5 Hz, 2H), 3.43 (s, 3H), 1.62 (dd, J = 7.1, 3.4 Hz, 2H), 1.57 (d, J = 6.7 Hz, 3H), 0.67 – 0.55 (m, 1H), 0.32 (q, J = 4.2 Hz, 1H). LC-MS calc. for C23H24ClN4O3 [M+H] + m/z= 439.2; Found 439.1. Examples 106 – 117 [00621] Examples 106 – 117 listed in Tables 15 and 16 were synthesized according to procedures analogous to Example 41, [Step 4] (Method A), Example 69, (Method B), or Example 67 (Method C). The appropriate starting materials for Methods A, B, and C can be prepared according to procedures analogous to those described herein. All examples in this table were prepared as the TFA salt unless otherwise noted. Table 15. Examples 106 – 117
Table 16. Examples 106 – 117
Examples 118 – 126 [00622] Examples 118- 126 listed in Tables 17 and 18 were synthesized according to procedures analogous to Example 41, [Step 4] (Method A) or Example 28 (Method B). All examples in this table were prepared as the TFA salt unless otherwise noted. Table 17. Examples 118 – 126
Table 18. Examples 118 – 126
Example A: PI3K Pathway Activation Assay [00623] The inhibitory activity of compounds was evaluated by measuring phosphorylation of AKT on Ser473 as a readout of the PI3K pathway using HTRF (CisBio catalog number: 64AKSPE). These studies were conducted in the T-47D (heterozygous PIK3CA H1047R) and SKBR3 (PIK3CA WT) cell lines. Cells were maintained in a 37°C incubator at 5% CO2 in the following media: T-47D: RPMI 1640, ATCC© Modification (Gibco, A10491-01) supplemented with 10% v/v FBS (Gibco, 26140-079), 1% penicillin streptomycin (Gibco, 15140-122), and 7.4 ug/mL insulin (MilliporeSigma, I9278); SKBR3: McCoy’s 5a (Modified) Medium (Gibco, 16600-082) supplemented with 10% v/v FBS (Gibco, 26140-079). Cells were seeded in 384- well plates at a density of 4,000 cells/well. Compounds dissolved in DMSO were added using a digital dispense (D300E, Tecan) 10-point serial dilution. After two hours of treatment, cells were lysed for thirty minutes and then incubated with detection reagents per HTRF kit material and manufacturer’s instructions. Fluorescence signal was measured with a multimode plate reader (Envision 2105, Perkin Elmer). Fluorescent signal was normalized to background and DMSO controls to obtain percent inhibition/activity for each compound. The results are summarized in Table 19. Table 19. IC50 Values
[00624] In Table 9, a “+” denotes an IC50 value of > 10000 nM; a “++” denotes an IC50 value of 500 nM < IC50 ≤ 10000 nM; a “+++” denotes an IC50 value of < 500 nM. [00625] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.