BUELL JOHN (US)
PHAM PHUONGLY (US)
SPEVAK WAYNE (US)
WAL MARK VANDER (US)
HAN XINPING (US)
ZHANG CHAO (US)
GUO ZUOJUN (US)
WALLESHAUSER JACK (US)
ZHANG YING (US)
RANK STEVEN (US)
OGAWA YASUYUKI (US)
SHI SONGYUAN (US)
WO2020146613A1 | 2020-07-16 | |||
WO2017172979A1 | 2017-10-05 | |||
WO2021168193A1 | 2021-08-26 |
CN102887895B | 2016-08-24 | |||
EP2966079A1 | 2016-01-13 | |||
US20040077595A1 | 2004-04-22 | |||
US4150949A | 1979-04-24 | |||
US4626513A | 1986-12-02 | |||
US4568649A | 1986-02-04 | |||
EP0154734A1 | 1985-09-18 |
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What is claimed is: 1. A compound having Formula I: or a pharmaceutically acceptable salt, a solvate, a tautomer, a stereoisomer, or a deuterated analog thereof, wherein: R1 is bridged heterocycloalkyl substituted with 0-4 T1 and 1 G; R2 is alkyl substituted with 0-5 R4 and 0-2 J, aryl substituted with 0-4 R4 and 0-1 J, arylalkyl substituted with 0-4 R4 and 0-1 J, heteroaryl substituted with 0-5 R4 and 0-1 J, heteroarylalkyl substituted with 0-5 R4 and 0-1 J, heterocycloalkyl substituted with 0-5 R4 and 0-1 J, heterocycloalkylalkyl substituted with 0-5 R4 and 0-1 J, bridged heterocycloalkyl substituted with 0-5 R4 and 0-1 J, bridged heterocycloalkylalkyl substituted with 0-5 R4 and 0-1 J, cycloalkyl substituted with 0-5 R4 and 0-1 J; cycloalkylalkyl substituted with 0-5 R4 and 0-1 J, or 6-11 membered heterocyclic spiro ring substituted with 0-5 R4 and 0-1 J; provided that when R2 is alkyl substituted with 0-5 R4 and 0-2 J, X is not -[C(R10)2]1-6; R3 is aryl, heteroaryl, -N(H)-heteroaryl, or heterocycloalkyl, wherein R3 is substituted with 0-4 R5 and 0-1 M; each R4 is independently alkyl, halogen, hydroxyl, CN, haloalkyl, hydroxyalkyl, C1-C6cyanoalkyl, or alkoxy, provided that when R4 is attached to a nitrogen atom, R4 is not halogen or CN; each R5 is independently alkyl, alkynyl, alkoxy, halogen, hydroxyl, CN, haloalkyl, C1-C6cyanoalkyl, C 2-C4alkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, or hydroxyalkyl, provided that when R5 is attached to a nitrogen atom, R5 is not halogen or CN; each R6 is independently H, alkyl, haloalkyl, or hydroxyalkyl; each R7 is independently H, halogen, alkyl, alkenyl, alkynyl, CN, haloalkyl, hydroxyalkyl, cycloalkyl, -C(O)OR10, or alkoxy optionally substituted with 1-3 halogens; each R8 is independently alkyl, halogen, hydroxyl, -NH2, -N(H)alkyl, -N(alkyl)2, CN, SH, haloalkyl, or hydroxyalkyl, provided that when R8 is attached to nitrogen, R8 is not halogen, hydroxyl, -NH2, -N(H)alkyl, -N(alkyl)2, or CN; each R9 is independently halogen, hydroxyl, CN, haloalkyl, or hydroxyalkyl; each R10 is independently H, N(H)2, alkyl, hydroxyalkyl, or haloalkyl; R11 is cycloalkyl substituted with 0-4 R4 and 0-1 J; each J is independently is -N(R10)2, -NO2, -SO2N(R10)2, -NH-SO2R10, -NHC(O)N(R10)2, -C(O)N(R10)2, -C(O)C(R10)2-aryl, -C(O)OCH2-aryl, -alkyl-N(R10)2, -alkyl-NHC(O)alkyl, -alkyl-NHC(O)OCH2-phenyl, -C(O)-alkylene-OH, -OC(O)R10, heterocycloalkyl substituted with 0-1 hydroxy and 0-1 halo, or -C(O)OR10; provided that when J is N(R10)2, -NO2, or -SO2N(R10)2, J is not attached to a nitrogen atom; M is -C(O)R10, -C(O)NH2, -N(H)C(O)CH3, -N(H)SO2-alkyl,NO2, -C1-C3alkyl-C(O)OR10, or -N(R10)2, provided that M is not attached to a nitrogen atom; X is absent, -[C(R10)2]1-6-, -[C[(R10)2]0-4-O-, -O-[C(R10)2]1-4-, C2-C6 alkenylene, -NR6-[C(R10)2]0-4-, or -[C(R10)2]0-4-NR6-;each Z is independently CR7 or N; G is L1-L2-T2 provided that: when Formula I is , then G is not hydrogen; each T1 is independently alkyl, halogen, hydroxyl, haloalkyl, or hydroxyalkyl, provided that when T1 is attached to nitrogen, T1 is not halogen or hydroxyl; T2 is H, CN, -C(NH)N(H)CN, -C(NH)OCH3, -C(O)OR10, -N(R10)2, -OR10, -C(O)N(R10)2, -SO2N(R10)2, -SO2R10, -N(R10)-SO2N(R10)2, -N(R10)-C(O)-N(R10)2, -N(R10)-SO2(R10), -N(R10)-C(O)O(R10), -P(O)(R10)2, -N(R10)C(O)-alkyl, -O-C(O)-alkyl, -C(=NR10)N(R10)2, cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, carbocyclic spiro ring, aryl, or heteroaryl, wherein T2 is substituted with 0-4 R8 and 0-1 R11 provided that when L1 and L2 are both absent, T2 is not CN, -N(R10)-SO2N(R10)2, -N(R10)-C(O)-N(R10)2, N(R10)2, -OR10, -N(R10)C(O)-alkyl, or -O-C(O)-alkyl, and provided that when L1 and L2 taken together are -C(O), -C(O)C(O)N(H)-, -C(O)O-, -C(O)N(H)-, -S(O)2-, -alkylene-C(O)N(H)-, -alkylene-C(O)-, -SO2-, or -SO2NH-, T2 is not CN, -N(R10)-SO2N(R10)2, -N(R10)-C(O)-N(R10)2, -C(O)OR10, -N(R10)2, -OR10, -C(O)N(R10)2, -SO2N(R10)2, -N(R10)C(O)-alkyl, -O-C(O)-alkyl, -C(NH)OCH3, or -C(=NR10)N(R10)2; L1 is absent, -C(O)-, -C(O)C(O)N(H)-, -C(O)O-, -C(O)N(H)-, -C(O)N(H)-O-, -alkylene- C(O)N(H)-, -alkylene-C(O)-, -SO2-, or -SO2N(H)-, provided that when L1 is -C(O)N(H)-O-, T2 is H; and L2 is absent, alkylene substituted with 0-4 R9, -C2-C4alkenylene, or C3-C6alkenylene substituted with 0-4 R9, provided that when L1 is -C(O)- and L2 is absent, T2 is not H. 2. The compound according to claim 1, wherein: X is absent, -[C (R10)2]1-4-, -(CH2)0-3-O-, O-[C (R10)2]1-3-, C3-C4 alkenylene, or -NR6-; R1 is a 6-9 membered bridged heterocycloalkyl having at least one nitrogen atom, wherein R1 is substituted with 0-4 T1 and 1 G; R2 is C1-C6alkyl substituted with 0-5 R4 and 0-2 J, phenyl substituted with 0-4 R4 and 0-1 J, -C0-C6alkyl-phenyl substituted with 0-4 R4 and 0-1 J, 5-10 membered heteroaryl substituted with 0-5 R4 and 0-1 J, -C0-C6alkyl-5-10 membered heteroaryl substituted with 0-5 R4 and 0-1 J, -C0-C6alkyl-4-10 membered heterocycloalkyl substituted with 0-5 R4 and 0-1 J, or -C0-C6alkyl-C3-C10cycloalkyl substituted with 0-5 R4 and 0-1 J, provided that when R2 is C1-C6alkyl substituted with 0-5 R4 and 0-2 J, X is not-C[(R10)2]1-3; R3 is phenyl, naphthyl, 5-10 membered heteroaryl, or 5-10 membered heterocycloalkyl, wherein R3 is substituted with 0-4 R5 and 0-1 M; each R4 is independently C1-C6alkyl, halogen, hydroxyl, CN, C1-C6haloalkyl, C1- C6hydroxyalkyl, C1-C6cyanoalkyl, or C1-C6alkoxy, provided that when R4 is attached to a nitrogen atom, R4 is not halogen, or CN; each R5 is independently C1-C6alkyl, C1-C6alkynyl, C1-C6alkoxy, halogen, hydroxyl, CN, C1-C6haloalkyl, C1-C6cynoalkyl, or C1-C6hydroxyalkyl, provided that when R5 is attached to a nitrogen atom, R5 is not halogen or CN; each R6 is independently H, C1-C6alkyl, C1-C6haloalkyl, or C1-C6hydroxyalkyl; each R7 is independently H, halogen, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, CN, C1-C4haloalkyl, C1-C4hydroxyalkyl; C3-C4cycloalkyl, -C(O)OR10, or C1-C4alkoxy optionally substituted with 1-3 halogens; each R8 is independently C1-C6alkyl, halogen, hydroxyl, -NH2, -N(H)C1-C6alkyl, -N(C1- C6alkyl)2, CN, C1-C6haloalkyl, or C1-C6hydroxyalkyl, provided that when R8 is attached to nitrogen, R8 is not halogen, hydroxyl, -NH2, -N(H)C1-C6alkyl, -N(C1-C6alkyl)2, or CN; each R9 is independently halogen, hydroxyl, CN, C1-C6haloalkyl, or C1-C6hydroxyalkyl; each R10 is independently H, -N(H)2, C1-C6alkyl, or C1-C6lhaloalkyl; R11 is C3-C6cycloalkyl substituted with 0-3 R4 and 0-1 J; each J is independently is -N(R10)2, -SO2N(R10)2, -C(O)N(R10)2, or -C(O)OR10; provided that when J is -N(R10)2 or -SO2N(R10)2, J is not attached to a nitrogen atom; each T1 is independently C1-C6alkyl, halogen, hydroxyl, C1-C6haloalkyl, or C1-C6hydroxyalkyl, provided that when T1 is attached to nitrogen, T1 is not halogen or hydroxyl; T2 is H, CN, -C(O)OR10, -N(R10)2, -OR10, -C(O)N(R10)2, -SO2N(R10)2, -SO2R10, -N(R10)C(O)-C1- C6alkyl, -O-C(O)-C1-C6alkyl, -C(=NH)NH2, C3-C6cycloalkyl, 4-10 membered heterocycloalkyl, 5-9 membered bridged heterocycloalkyl, 6-9 membered heterocyclic spiro ring, 6-9 membered carbocyclic spiro ring, phenyl, naphthyl, or 5-10 membered heteroaryl, wherein T2 is substituted with 0-4 R8 and 0-1 R11; provided that when L1 and L2 are both absent, T2 is not CN, -N(R10)2, -OR10, -N(R10)C(O)-C1-C6alkyl, or -O-C(O)-C1-C6alkyl, and provided that when L1 and L2 taken together are -C(O)-, -C(O)C(O)N(H)-, -C(O)O-, -C(O)N(H)-, -C(O)N(H)-O-, -C1-C6alkyelene-C(O)N(H)-, -C1-C6alkylene-C(O)-, -SO2-, or -SO2NH-, T2 is not CN, -C(O)OR10, C1-C6alkoxy, N(R10)2, -OR10, -C(O)N(R10)2, -SO2N(R10)2, -N(R10)C(O)-C1-C6alkyl, -O-C(O)- C1-C6alkyl, or -C(=NH)NH2; L1 is absent, -C(O)-, -C(O)C(O)N(H)-, -C(O)O-, -C(O)N(H)-, -C1-C6alkyelene-C(O)N(H)-, -C1-C6alkylene-C(O)-, -SO2-, or -SO2N(H)- provided that when L1 is -C(O)N(H)-O-, T2 is H; L2 is absent, C1-C6alkylene substituted with 0-2 R9, or C3-C6alkenylene substituted with 0-4 R9, provided that when L1 is -C(O)- and L2 is absent, T2 is not H; and M is -C(O)NH2, -NH2C(O)CH3, -N(H)SO2- C1-C3alkyl, or -NH2, provided that M is not attached to a nitrogen atom. 3. The compound according to any of the preceding claims having one of the following formulae: , or a pharmaceutically acceptable salt, a solvate, a tautomer, a stereoisomer, or a deuterated analog thereof. 4. The compound according to claim 3 having Formula IIB or IID, or a pharmaceutically acceptable salt, a solvate, a tautomer, a stereoisomer, or a deuterated analog thereof. 5. The compound according to any of the preceding claims having one of the following formulae: , or a pharmaceutically acceptable salt, a solvate, a tautomer, a stereoisomer, or a deuterated analog thereof, wherein each R7 is independently H, F, Cl, C1-C3alkyl, or C1-C3haloalkyl. 6. The compound according to any of the preceding claims having one of the following formulae: or a pharmaceutically acceptable salt, a solvate, a tautomer, a stereoisomer, or a deuterated analog thereof. 7. The compound according to any of the preceding claims, wherein: R1 is a 7-9 membered bridged heterocycloalkyl having at least one nitrogen atom, wherein R1 is substituted with 0-3 T1 and 1 G; R2 is -C0-C5alkyl-4-10 membered heterocycloalkyl substituted with 0-4 R4 and 0-1 J; -C0-C5alkyl-5-10 membered heteroaryl substituted with 0-3 R4 and 0-1 J; or C1-C6alkyl substituted with 1-2 J groups; R3 is phenyl, naphthyl, 5-10 membered heteroaryl, or 5-10 membered heterocycloalkyl, wherein the naphthyl, 5-10 membered heteroaryl, and 5-10 membered heterocycloalkyl are each substituted with 0-4 R5, and wherein the phenyl is substituted with 0-4 R5 and 0-1M; each R4 is independently C1-C5alkyl, halogen, hydroxyl, CN, C1-C5haloalkyl, C1- C5hydroxyalkyl, C1-C5cyanoalkyl, or C1-C5alkoxy, provided that when R4 is attached to a nitrogen atom, R4 is not halogen, hydroxyl, or CN; each R5 is independently C1-C5alkyl, C1-C5alkynyl, C1-C5alkoxy, halogen, hydroxyl, CN, C1-C5haloalkyl, C1-C5cynoalkyl, or C1-C5hydroxyalkyl each R8 is independently C1-C5alkyl, halogen, hydroxyl, -NH2, -N(H)C1-C5alkyl, -N(C1- C5alkyl)2, CN, C1-C5haloalkyl, or C1-C5hydroxyalkyl, provided that when R8 is attached to nitrogen, R8 is not halogen, hydroxyl, -NH2, -N(H)C1-C5alkyl, -N(C1-C5alkyl)2, or CN; each R9 is independently halogen, hydroxyl, CN, C1-C5haloalkyl, or C1-C5hydroxyalkyl; each R10 is independently H, C1-C5alkyl, or C1-C5haloalkyl; each T1 is independently C1-C5alkyl, halogen, hydroxyl, C1-C5haloalkyl, or C1-C5hydroxyalkyl, provided that when T1 is attached to nitrogen, T1 is not halogen or hydroxyl; T2 is H, CN, -C(O)OR10, C1-C5alkoxy, N(R10)2, -C(O)N(R10)2, -SO2N(R10)2, -SO2R10, -N(R10)C(O)-C1-C5alkyl, -O-C(O)-C1-C5alkyl, C3-C6cycloalkyl, 4-10 membered heterocycloalkyl, 7-9 membered bridged heterocycloalkyl, phenyl, naphthyl, or 5-10 membered heteroaryl, wherein T2 substituted with 0-4 R8, provided that when L1 and L2 are both absent, T2 is not CN, C1-C5alkoxy, N(R10)2, -N(R10)C(O)-C1-C5alkyl, or -O-C(O)-C1-C5alkyl, and provided that when L1 and L2 taken together are -C(O)-, -C(O)N(H)-, -C1-C5alkyelene-C(O)N(H)-, -C1-C5alkylene-C(O)-, -SO2-, or -SO2NH, T2 is not CN, -C(O)OR10, C1-C5alkoxy, N(R10)2, -C(O)N(R10)2, -SO2N(R10)2, -N(R10)C(O)-C1-C5alkyl, or -O-C(O)-C1-C5alkyl; L1 is absent, -C(O)-, -C(O)N(H)-, -C1-C5alkyelene-C(O)N(H)-, -C1-C5alkylene-C(O)-, -SO2-, or -SO2N(H)-; and L2 is absent, or C1-C5alkylene substituted with 0-4 R9, provided that when L1 is -C(O)- and L2 is absent, T2 is not H; and M is -C(O)NH2, -NH2C(O)CH3, -N(H)SO2CH3, or -NH2, provided that M is not attached to a nitrogen atom. 8. The compound according to any of the preceding claims, wherein: R1 is a 7-9 membered bridged heterocycloalkyl having at least one nitrogen atom, wherein R1 is substituted with 0-2 T1 and 1 G; R2 is 5-10 membered heterocyloalkyl-C1-C4alkyl substituted with 0-3 R4 or C1-C5alkyl substituted with 1-2 J groups; R3 is phenyl, naphthyl, 5-10 membered heteroaryl, or a 5-10 membered heterocycloalkyl, wherein the naphthyl, 5-10 membered heteroaryl, and 5-10 membered heterocycloalkyl are each substituted with 0-3 R5, and wherein the phenyl is substituted with 0-4 R5 and 0-1M; each R4 is independently C1-C4alkyl, halogen, hydroxyl, CN, C1-C4haloalkyl, C1- C4hydroxyalkyl, or C1-C4alkoxy, provided that when R4 is attached to a nitrogen atom, R4 is not halogen, hydroxyl, or CN; each R5 is independently C1-C4alkyl, C1-C4alkynyl, halogen, hydroxyl, CN, C1-C4haloalkyl, C1-C4cynoalkyl, or C1-C4hydroxyalkyl; each R8 is independently C1-C4alkyl, halogen, hydroxyl, -NH2, -N(H)C1-C4alkyl, -N(C1- C4alkyl)2, CN, C1-C4haloalkyl, or C1-C4hydroxyalkyl, provided that when R8 is attached to nitrogen, R8 is not halogen, hydroxyl, -NH2, -N(H)C1-C5alkyl, -N(C1-C5alkyl)2, or CN; each R9 is independently halogen, hydroxyl, CN, C1-C4haloalkyl, or C1-C4hydroxyalkyl; each R10 is independently H, C1-C4alkyl, or C1-C4haloalkyl; each T1 is independently C1-C4alkyl halogen hydroxyl, C1-C4haloalkyl, or C1-C4hydroxyalkyl, provided that when T1 is attached to nitrogen, T1 is not halogen or hydroxyl; T2 is H, CN, -C(O)OR10, C1-C4alkoxy, -N(R10)2, -C(O)N(R10)2, SO2N(R10)2, -SO2R10, -N(R10)C(O)- C1-C4alkyl, -O-C(O)-C1-C4alkyl, C3-C6cycloalkyl, 4-6 membered heterocycloalkyl, 7-8 membered bridged heterocycloalkyl, phenyl, naphthyl, or 5-6 membered heteroaryl, wherein T2 is substituted with 0-4 R8, provided that when L1 and L2 are both absent, T2 is not CN, C1-C4alkoxy, N(R10)2, -N(R10)C(O)-C1-C4alkyl, or -O-C(O)-C1-C4alkyl, and provided that when L1 and L2 taken together are -C(O)-, -C(O)N(H)-, -S(O)2-, C1-C4alkyelene-C(O)N(H)-, or -C1-C4alkylene-C(O)-, T2 is not CN, -C(O)OR10, C1-C4alkoxy, -N(R10)2, -C(O)N(R10)2, SO2N(R10)2, -N(R10)C(O)-C1-C4alkyl, or -O-C(O)-C1-C4alkyl; L1 is absent, -C(O)-, -C(O)N(H)-, -S(O)2-, -SO2N(H)-, C1-C4alkyelene-C(O)N(H)-, -C1-C4alkylene-C(O)-, or -C1-C4alkylene-C(O)-; and L2 is absent, or C1-C4alkylene substituted with 0-2 R9, provided that when L1 is -C(O)- and L2 is absent, T2 is not H. 9. The compound according to any one of claims 1-8, wherein R1 is 7-9 membered bridged piperazine or piperidine substituted with 0-2 T1 and 1 G. 10. The compound according to any one of claims 1-8, wherein R1 is one of the following formulae: 11. The compound according to claim 10, wherein R1 is formula (a) or (b). 13. The compound according to any of the preceding claims, wherein R2 is one of the following formulae and R4 is H, Cl, or F: 14. The compound according to any one of the preceding claims, wherein R3 is one of the following formulae: . 15. The compound according to any one of the preceding claims, wherein R3 is: and R5a is hydrogen, halo, or ethynyl. 16. The compound according to any one of the preceding claims, wherein R3 is: and R5a is hydrogen, halo, or ethynyl. 17. The compound according to any of the preceding claims wherein: L1 is –C(O)N(H)-, -C(O)-, -C1-C3alkylene, -SO2-, -SO2N(H)-, or -C1-C3alkylene-C(O)-; L2 is absent or C1-C3alkylene; and T2 is one of the following formulae: 18. The compound according to any one of the preceding claims, wherein: L1 is –C(O)N(H)- or -C(O)-; and L2 is absent, -CH2- or -CH2-CH2-. 19. The compound according to any one of claims 1-16, wherein: L1 is absent; L2 is absent; and T2 is H. 20. The compound according to any one of claims 1-16, wherein G is -CH2-C(H)(OH)-CH2-OH, -C(O)N(H)CH2COOH, -S(O)2(CH2)2OCH3, -C(O)CH2-SO2CH3, -C(O)CH2-SO2-NH2, -C(O)C(H)(CH3)-SO2-NH2, -C(O)(CH2)2-SO2-NH2, -C(O)CH2-SO2-N(CH3)2, -SO2N(H)(CH2)2CH3, -SO2N(H)(CH2)2N(CH3)2, -SO2(CH2)3N(CH3)2, -C(O)CH2CH(OH)CH2NH2, -C(O)CH2C(OH)(CH3)3, -C(O)CH2CH2OH, -C(O)CH(CH3)OH, -C(O)CH(OH)(CH2)OH, -C(O)CH2N(H)C(O)CH3, -C(O)NH2, -C(O)N(H)CH2C(O)OCH2CH3, -C(O)CH2NH2, -C(O)CH2CN, -C(O)(CH2)2CN, -C(O)CH2NHCH3, -C(O)CH2CH3, -C(O)CH2N(CH3)2, -C(O)CH2CH2CH2N(CH3)2, -C(O)N(H)CH2C(CH3)2OH, -C(O)N(H)CH2C(O)NH2, -C(O)CH2C(O)OH, -C(O)(CH2)2C(O)OH, -C(O)CH2OC(O)CH3, -C(O)CH2OH, -C(O)(CH2)2C(O)OCH3, or one of the following Formulae: 21. The compound according to claim 20, wherein G is -CH2-C(H)(OH)-CH2-OH, -C(O)N(H)CH2COOH, -S(O)2(CH2)2OCH3, -C(O)CH2-SO2CH3, -C(O)CH2-SO2-NH2, -C(O)C(H)(CH3)-SO2-NH2, -C(O)(CH2)2-SO2-NH2, -C(O)CH2-SO2-N(CH3)2, -SO2N(H)(CH2)2CH3, -SO2N(H)(CH2)2N(CH3)2, -SO2(CH2)3N(CH3)2, -C(O)CH2CH(OH)CH2NH2, -C(O)CH2C(OH)(CH3)3, -C(O)CH2CH2OH, -C(O)CH(CH3)OH, -C(O)CH(OH)(CH2)OH, -C(O)CH2N(H)C(O)CH3, -C(O)NH2, -C(O)N(H)CH2C(O)OCH2CH3, -C(O)CH2NH2, -C(O)CH2CN, -C(O)(CH2)2CN, -C(O)CH2NHCH3, -C(O)CH2CH3, -C(O)CH2N(CH3)2, -C(O)CH2CH2CH2N(CH3)2, -C(O)N(H)CH2C(CH3)2OH, -C(O)N(H)CH2C(O)NH2, -C(O)CH2C(O)OH, -C(O)(CH2)2C(O)OH, -C(O)CH2OC(O)CH3, -C(O)CH2OH, or -C(O)(CH2)2C(O)OCH3. 22. The compound according to claim 20, wherein G is one of formulae (a), (b), (c), (d), (e), (h), (i), (j), (k), (l), (m), (p), (q), (r), (s), (t), (u), (v), (w), (z), (ad), (ae), (af), (ag), (ah), (aj), (ak), (al), (am), (at), (av), (aw), (ax), or (bg). 23. The compound according to claim 20, wherein G is one of formulae (d), (f), (n), (o), (x), (ai), (an), (ao), (ap), (aq), (ar), (as), (au), (ay), (az), (ba), (bb), (bc), (bd), (be), (bf), (bi), or (bj). 24. The compound according to any one of claim 21-23, wherein R2 is and R4 is H, Cl, or F. 25. A compound selected from Table IA or Table IB, or a pharmaceutically acceptable salt thereof. 26. A pharmaceutical composition comprising a compound in any one of the preceding claims, and a pharmaceutically acceptable carrier. 27. The pharmaceutical composition of Claim 26, further comprising a second pharmaceutical agent. 28. A method for treating a subject with a disease or condition mediated by KRAS, said method comprising administering to the subject an effective amount of a compound in one of Claims 1-25, or a pharmaceutically acceptable salt, a solvate, a tautomer, a stereoisomer, or a deuterated analog thereof, or a pharmaceutical composition in one of Claims 26-27. 29. The method for treating according to Claim 28, wherein the disease or condition is a neoplastic disorder, a cancer, an age-related disease, an inflammatory disorder, a cognitive disorder or a neurodegenerative disease. 30. The method of claim 29, wherein the disease or condition is pancreatic cancer, colorectal cancer, malignant solid tumor, rectal carcinoma, endometrial endometriod carcinoma, appendix carcinoma, mucinous adenocarcinoma, cholangiocarcinoma, extrahepatic cholangiocarcinoma, bladder cancer, bladder urothelial carcinoma, lung cancer, ampulla of vater carcinoma, ovarian cancer, gastric adenocarcinoma, malignant small intestinal neoplasm, poorly differentiated adenocarcinoma, acute myeloid leukemia, breast cancer, breast invasive ductal carcinoma, ampulla vater pancreatobiliary type adenocarcinoma, glioma, multiple myeloma, myelodysplastic syndrome, or small intestine carcinoma. 31. The method according to any one of Claim 28-30, further comprising administering one or more additional therapeutic agents. 32. The method according to claim 31, wherein the one or more additional therapeutic agents is one or more of i) an alkylating agent selected from adozelesin, altretamine, bizelesin, busulfan, carboplatin, carboquone, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven, lomustine, mechlorethamine, melphalan, oxaliplatin, piposulfan, semustine, streptozocin, temozolomide, thiotepa, and treosulfan; ii) an antibiotic selected from bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, mitoxantrone, neocarzinostatin, pentostatin, and plicamycin; iii) an antimetabolite selected from the group consisting of azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, ftorafur, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed, thioguanine, and trimetrexate; iv) an immunotherapy agent selected from a PD-1 or PD-L1 inhibitor; v) a hormone or hormone antagonist selected from the group consisting of enzalutamide, abiraterone, anastrozole, androgens, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprolide, magestrol, raloxifene, tamoxifen, and toremifene; vi) a taxane selected from DJ-927, docetaxel, TPI 287, paclitaxel and DHA- paclitaxel; vii) a retinoid selected from alitretinoin, bexarotene, fenretinide, isotretinoin, and tretinoin; viii) an alkaloid selected from etoposide, homoharringtonine, teniposide, vinblastine, vincristine, vindesine, and vinorelbine; ix) an antiangiogenic agent selected from AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide, and thalidomide; x) a topoisomerase inhibitor selected from amsacrine, edotecarin, exatecan, irinotecan, SN-38 (7-ethyl-10-hydroxy-camptothecin), rubitecan, topotecan, and 9-aminocamptothecin; xi) a kinase inhibitor selected from erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib, sorafenib, sunitinib malate, AEE-788, AG-013736, AMG 706, AMN107, BMS-354825, BMS-599626, UCN-01 (7-hydroxystaurosporine), vemurafenib, dabrafenib, trametinib, cobimetinib selumetinib and vatalanib; xii) a targeted signal transduction inhibitor selected from bortezomib, geldanamycin, and rapamycin; xiii) a biological response modifier selected from imiquimod, interferon-α and interleukin-2; xiv) an IDO inhibitor; and xv) a chemotherapeutic agent selected from 3- AP (3-amino-2-carboxyaldehyde thiosemicarbazone), altrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, elesclomol, eribulin mesylate (E7389), ixabepilone, lonidamine, masoprocol, mitoguanazone, oblimersen, sulindac, testolactone, tiazofurin, a mTOR inhibitor, a PI3K inhibitor, a Cdk4 inhibitor, an Akt inhibitor, a Hsp90 inhibitor, a farnesyltransferase inhibitor or an aromatase inhibitor (anastrozole letrozole exemestane); xvi) a Mek inhibitor; xvii) a tyrosine kinase inhibitor; xviii) a c-Kit mutant inhibitor, xix) an EGFR inhibitor, a PD-1 inhibitor, or xx) an epigenetic modulator. |
[0121] Embodiment 10(b) of this disclosure relates to the compound according to any one of Embodiments 1(b), 2(b), 3, 4, 5 , 6, 7(b), or 8(b), wherein R 1 is one of the following formulae:
Embodiment 10(c) relates to the compound of Embodiment 10(a) wherein G is H. Embodiment 10(d) relates to the compound of Embodiment 10(a) wherein G is not H. Embodiment 10(e) relates to the compound of Embodiment 10(b) wherein G is H. Embodiment 10(f) relates to the compound of Embodiment 10(b) wherein G is not H. [0122] Embodiment 11(a) of this disclosure relates to the compound according to Embodiment 10(a), wherein R 1 is formula (a) or (b). [0123] Embodiment 11(b) of this disclosure relates to the compound according to Embodiment 10(b), wherein R 1 is formula (a) or (b). [0124] Embodiment 11(c) relates to the compound of Embodiment 11(a) wherein G is H. [0125] Embodiment 11(d) relates to the compound of Embodiment 11(a) wherein G is not H. [0126] Embodiment 11(e) relates to the compound of Embodiment 11(b) wherein G is H. [0127] Embodiment 11(f) relates to the compound of Embodiment 11(b) wherein G is not H. [0128] Embodiment 12(a) of this disclosure relates to the compound according to any one of Embodiments 1(a), 2(a), 3, 4, or 5 , wherein R 2 is one of the following formulae:
[0129] Embodiment 12(b) of this disclosure relates to the compound according to any one of Embodiments 1(b), 2(b), 3, 4, or 5 , wherein R 2 is one of the following formulae:
Embodiment 12(c) relates to the compound of Embodiment 12(a) wherein G is H. Embodiment 12(d) relates to the compound of Embodiment 12(a) wherein G is not H. Embodiment 12(e) relates to the compound of Embodiment 12(b) wherein G is H. Embodiment 12(f) relates to the compound of Embodiment 12(b) wherein G is not H. [0130] Embodiment 13 of this disclosure relates to the compound according to any of 1(a), 1(b), 2(a), 2(b), 3, 4, 5, 6, 7(a), 7(b), 8(a), 8(b), 9, 10(a), 10(b), 11(a), 11(b), 12(a), or 12(b), wherein R 2 is one of the following formulae: . Embodiment 13(a) relates to the compound of Embodiment 13 wherein G is H. Embodiment 13(b) relates to the compound of Embodiment 13 wherein G is not H. [0131] Embodiment 14(a) of this disclosure relates to the compound according to any one of Embodiments 1(a), 2(a), 3, 4, 5, 6, 7(a), 8(a), 9, 10(a), 11(a), 12(a), or 13, wherein R 3 is one of the following formulae: [0132] Embodiment 14(b) of this disclosure relates to the compound according to any one of Embodiments 1(b), 2(b), 3, 4, 5, 6, 7(b), 8(b), 9, 10(b), 11(b), 12(b), or 13, wherein R 3 is one of the following formulae: Embodiment 14(c) relates to the compound of Embodiment 14(a) wherein G is H. Embodiment 14(d) relates to the compound of Embodiment 14(a) wherein G is not H. Embodiment 14(e) relates to the compound of Embodiment 14(b) wherein G is H. Embodiment 14(f) relates to the compound of Embodiment 14(b) wherein G is not H. [0133] Embodiment 15(a) of this disclosure relates to the compound according to Embodiments 1(a), 2(a), 3, 4, 5, 6, 7(a), 8(a), 9, 10(a), 11(a), 12(a), 13, or 14(a), wherein R 3 is [0134] Embodiment 15(b) of this disclosure relates to the compound according to Embodiments 1(b), 2(b), 3, 4, 5, 6, 7(b), 8(b), 9, 10(b), 11(b), 12(b), 13, or 14(b), wherein R 3 is Embodiment 15(c) relates to the compound of Embodiment 15(a) wherein G is H. Embodiment 15(d) relates to the compound of Embodiment 15(a) wherein G is not H. Embodiment 15(e) relates to the compound of Embodiment 15(b) wherein G is H. Embodiment 15(f) relates to the compound of Embodiment 15(b) wherein G is not H. [0135] Embodiment 16(a) of this disclosure relates to the compound according to any of Embodiments 1(a), 2(a), 3, 4, 5, 6, 7(a), 8(a), 9, 10(a), 11(a), 12(a), 13, 14(a), or 15(a), wherein R 3 is: [0136] Embodiment 16(b) of this disclosure relates to the compound according to any of Embodiments 1(b), 2(b), 3, 4, 5, 6, 7(b), 8(b), 9, 10(b), 11(b), 12(b), 13, 14(b), or 15(b), wherein R 3 is: Embodiment 16(c) relates to the compound of Embodiment 16(a) wherein G is H. Embodiment 16(d) relates to the compound of Embodiment 16(a) wherein G is not H. Embodiment 16(e) relates to the compound of Embodiment 16(b) wherein G is H. Embodiment 16(f) relates to the compound of Embodiment 16(b) wherein G is not H. [0137] Embodiment 17(a) of this disclosure relates to the compound according to any of Embodiments 1(a), 2(a), 3, 4, 5, 6, 7(a), 8(a), 9, 10(a), 11(a), 12(a), 13, 14(a), 15(a) or 16(a) wherein: L 1 is –C(O)N(H)-, -C(O)-, -C 1 -C 3 alkylene, -SO 2 -, -SO 2 N(H)-, or -C 1 -C 3 alkylene-C(O)-; L 2 is absent or C 1 -C 3 alkylene; and T 2 is one of the following formulae: [0138] Embodiment 17(b) of this disclosure relates to the compound according to any of Embodiments 1(b), 2(b), 3, 4, 5, 6, 7(b), 8(b), 9, 10(b), 11(b), 12(b), 13, 14(b), 15(b), or 16(b) wherein: L 1 is –C(O)N(H)-, -C(O)-, or C 1 - C 3 alkylene; L 2 is absent or C 1 -C 3 alkylene; and T 2 is one of the following formulae:
[0139] Embodiment 17(c) of this disclosure relates to the compound according to Embodiments 17(b) wherein: L 1 is –C(O)N(H)-, -C(O)-, or C 1 -C 3 alkylene; L 2 is absent or C 1 -C 3 alkylene; and T 2 is one of the following formulae:
[0140] Embodiment 18(a) of this disclosure relates to the compound according to any one of Embodiments 1(a), 2(a), 3, 4, 5, 6, 7(a), 8(a), 9, 10(a), 11(a), 12(a), 13, 14(a), 15(a), 16(a), or 17(a), wherein: L 1 is –C(O)N(H)- or -C(O)-; and L 2 is absent, -CH 2 -, or -CH 2 -CH 2 -. Embodiment 18(b) of this disclosure relates to the compound according to any one of Embodiments 1(b), 2(b), 3, 4, 5, 6, 7(b), 8(b), 9, 10(b), 11(b), 12(b), 13, 14(b), 15(b), 16(b), or 17(b), wherein: L 1 is –C(O)N(H)- or -C(O)-;and L 2 is absent. [0141] Embodiment 19(a) of this disclosure relates to the compound according to any one of Embodiments 1(a), 2(a), 3, 4, 5, 6, 7(a), 8(a), 9, 10(a), 11(a), 12(a), 13, 14(a), 15(a), 16(a), 17(a), or 18(a),wherein: L 1 is absent; L 2 is absent; and T 2 is H. Embodiment 19(b) of this disclosure relates to the compound according to any one of Embodiments 1(b), 2(b), 3, 4, 5, 6, 7(b), 8(b), 9, 10(b), 11(b), 12(b), 13, 14(b), 15(b), 16(b), 17(b), or 18(b),wherein: L 1 is absent; L 2 is absent; and T 2 is H. Embodiment 20(a) of this disclosure relates to the compound according to any one of Embodiments 1(a), 2(a), 3, 4, 5, 6, 7(a), 8(a), 9, 10(a), 11(a), 12(a), 13, 14(a), 15(a), or 16(a), wherein G is: -C(O)N(H)CH 2 COOH, -S(O) 2 (CH 2 ) 2 OCH 3 , -C(O)CH 2 -SO 2 CH 3 , -C(O)CH 2 -SO 2 -NH 2 , -C(O)C(H)(CH 3 )-SO 2 -NH 2 , -C(O)(CH 2 ) 2 -SO 2 -NH 2 , -C(O)CH 2 -SO 2 -N(CH 3 ) 2 , -SO 2 N(H)(CH 2 ) 2 CH 3 , -SO 2 N(H)(CH 2 ) 2 N(CH 3 ) 2 , -SO 2 (CH 2 ) 3 N(CH 3 ) 2 , -C(O)CH 2 CH(OH)CH 2 NH 2 , -C(O)CH 2 C(OH)(CH 3 ) 3 , -C(O)CH 2 CH 2 OH, -C(O)CH(CH 3 )OH, -C(O)CH(OH)(CH 2 )OH, -C(O)CH 2 N(H)C(O)CH 3 , -C(O)NH 2 , -C(O)N(H)CH 2 C(O)OCH 2 CH 3 , -C(O)CH 2 NH 2 , -C(O)CH 2 CN, -C(O)(CH 2 ) 2 CN, -C(O)CH 2 NHCH 3 , -C(O)CH 2 CH 3 , -C(O)CH 2 N(CH 3 ) 2 , -C(O)CH 2 CH 2 CH 2 N(CH 3 ) 2 , -C(O)N(H)CH 2 C(CH 3 ) 2 OH, -C(O)N(H)CH 2 C(O)NH 2 , -C(O)CH 2 C(O)OH, -C(O)(CH 2 ) 2 C(O)OH, -C(O)CH 2 OC(O)CH 3 , -C(O)CH 2 OH, -C(O)(CH 2 ) 2 C(O)OCH 3 , or one of the following Formulae:
[0142] Embodiment 20(b) of this disclosure relates to the compound according to any one of Embodiments 1(b), 2(b), 3, 4, 5, 6, 7(b), 8(b), 9, 10(b), 11(b), 12(b), 13, 14(b), 15(b), or 16(b), wherein G is: C(O)N(H)CH 2 COOH, -S(O) 2 (CH 2 ) 2 OCH 3 , -C(O)(CH 2 ) 2 -SO 2 -NH 2 , -SO 2 N(H)(CH 2 ) 2 CH 3 , -C(O)CH 2 CH(OH)CH 2 NH 2 , -C(O)CH 2 CH 2 OH, -C(O)CH 2 N(H)C(O)CH 3 , -C(O)NH 2 , -C(O)N(H)CH 2 C(O)OCH 2 CH 3 , -C(O)CH 2 NH 2 , -C(O)CH 2 NHCH 3 , -C(O)CH 2 CH 3 , -C(O)CH 2 N(CH 3 ) 2 , -C(O)CH 2 CH 2 CH 2 N(CH 3 ) 2 , -C(O)N(H)CH 2 C(CH 3 ) 2 OH, -C(O)N(H)CH 2 C(O)NH 2 , -C(O)(CH 2 ) 2 C(O)OH, -C(O)CH 2 OC(O)CH 3 , -C(O)CH 2 OH, -C(O)(CH 2 ) 2 C(O)OCH 3 , or one of the following Formulae:
Embodiment 21(a) of this disclosure relates to the compound according to Embodiment 20(b), wherein G is -C(O)N(H)CH 2 COOH, -S(O) 2 (CH 2 ) 2 OCH 3 , -C(O)CH 2 -SO 2 CH 3 , -C(O)CH 2 -SO 2 -NH 2 , -C(O)C(H)(CH 3 )-SO 2 -NH 2 , -C(O)(CH 2 ) 2 -SO 2 -NH 2 , -C(O)CH 2 -SO 2 -N(CH 3 ) 2 , -SO 2 N(H)(CH 2 ) 2 CH 3 , -SO 2 N(H)(CH 2 ) 2 N(CH 3 ) 2 , -SO 2 (CH 2 ) 3 N(CH 3 ) 2 , -C(O)CH 2 CH(OH)CH 2 NH 2 , -C(O)CH 2 C(OH)(CH 3 ) 3 , -C(O)CH 2 CH 2 OH, -C(O)CH(CH 3 )OH, -C(O)CH(OH)(CH 2 )OH, -C(O)CH 2 N(H)C(O)CH 3 , -C(O)NH 2 , -C(O)N(H)CH 2 C(O)OCH 2 CH 3 , -C(O)CH 2 NH 2 , -C(O)CH 2 CN, -C(O)(CH 2 ) 2 CN, -C(O)CH 2 NHCH 3 , -C(O)CH 2 CH 3 , -C(O)CH 2 N(CH 3 ) 2 , -C(O)CH 2 CH 2 CH 2 N(CH 3 ) 2 , -C(O)N(H)CH 2 C(CH 3 ) 2 OH, -C(O)N(H)CH 2 C(O)NH 2 , -C(O)CH 2 C(O)OH, -C(O)(CH 2 ) 2 C(O)OH, -C(O)CH 2 OC(O)CH 3 , -C(O)CH 2 OH, or -C(O)(CH 2 ) 2 C(O)OCH 3 . [0143] Embodiment 21(b) of this disclosure relates to the compound according to Embodiment 20(b), wherein G is -C(O)N(H)CH 2 COOH, -S(O) 2 (CH 2 ) 2 OCH 3 , -C(O)(CH 2 ) 2 -SO 2 -NH 2 , -SO 2 N(H)(CH 2 ) 2 CH 3 , -C(O)CH 2 CH(OH)CH 2 NH 2 , -C(O)CH 2 CH 2 OH, -C(O)CH 2 N(H)C(O)CH 3 , -C(O)NH 2 , -C(O)N(H)CH 2 C(O)OCH 2 CH 3 , C(O)CH 2 NH 2 , -C(O)CH 2 CH 3 , -C(O)CH 2 N(CH 3 ) 2 , -C(O)N(H)CH 2 C(CH 3 ) 2 OH, -C(O)(CH 2 ) 2 C(O)OH, -C(O)CH 2 OC(O)CH 3 , -C(O)CH 2 OH or -C(O)(CH 2 ) 2 C(O)OCH 3 . Embodiment 22(a) of this disclosure relates to the compound according to Embodiment 20(a), wherein G is one of formulae (a), (b), (c), (d), (e), (h), (i), (j), (k), (l), (m), (p), (q), (r), (s), (t), (u), (v), (w), (z), (ad), (ae), (af), (ag), (ah), (aj), (ak), (al), (am), (at), (av), (aw), (ax), or (bg). Embodiment 22(b) of this disclosure relates to the compound according to Embodiment 20(b), wherein G is one of formulae (a), (b), (c), (d), (e), (h), (i), (j), (k), (l), (m), (p), (q), (r), (s), (t), (u), (v), (w), (z), (ad), (ae), (af), (ag), (ah), (aj), (ak), (al) or (am). Embodiment 23(a) of this disclosure relates to the compound according to Embodiment 20(a), wherein G is one of formulae (d), (f), (n), (o), (x), (ai), (an), (ao), (ap), (aq), (ar), (as), (au), (ay), (az), (ba), (bb), (bc), (bd), (be), (bf), (bi), or (bj). Embodiment 23(b) of this disclosure relates to the compound according to Embodiment 20(b), wherein G is one of formulae (d), (f), (n), (o), (x), (ai) or (an). [0144] Embodiment 24(a) of this disclosure relates to the compound according to any one of Embodiments 21(a), 22(a), or 23(a), wherein R 2 is Embodiment 24(b) of this disclosure relates to the compound according to any one of Embodiments 21(b), 22(b), or 23(b), wherein R 2 is [0145] Embodiment 25 of this disclosure relates to the compound according to Embodiment 1 selected from Table IA, or a pharmaceutically acceptable salt thereof. Embodiment 25(a) relates to the compound of Embodiment 25 wherein G is H. Embodiment 25(b) relates to the compound of Embodiment 25 wherein G is not H. [0146] Embodiment 1(ii) of this disclosure relates to a compound having Formula I: or a pharmaceutically acceptable salt, a solvate, a tautomer, a stereoisomer, or a deuterated analog thereof, wherein: R 1 is bridged heterocycloalkyl substituted with 0-4 T 1 and 1 G; R 2 is alkyl substituted with 0-5 R 4 and 0-2 J, aryl substituted with 0-4 R 4 and 0-1 J, arylalkyl substituted with 0-4 R 4 and 0-1 J, heteroaryl substituted with 0-5 R 4 and 0-1 J, heteroarylalkyl substituted with 0-5 R 4 and 0-1 J, heterocycloalkyl substituted with 0-5 R 4 and 0-1 J, heterocycloalkylalkyl substituted with 0-5 R 4 and 0-1 J, bridged heterocycloalkyl substituted with 0-5 R 4 and 0-1 J, bridged heterocycloalkylalkyl substituted with 0-5 R 4 and 0-1 J, cycloalkyl substituted with 0-5 R 4 and 0-1 J; cycloalkylalkyl substituted with 0-5 R 4 and 0-1 J, or 6-11 membered heterocyclic spiro ring substituted with 0-5 R 4 and 0-1 J; provided that when R 2 is alkyl substituted with 0-5 R 4 and 0-2 J, X is not -[C(R 10 ) 2 ] 1-6 ; R 3 is aryl, heteroaryl, -N(H)-heteroaryl, or heterocycloalkyl, wherein R 3 is substituted with 0-4 R 5 and 0-1 M; each R 4 is independently alkyl, halogen, hydroxyl, CN, haloalkyl, hydroxyalkyl, C 1 -C 6 cyanoalkyl, or alkoxy, provided that when R 4 is attached to a nitrogen atom, R 4 is not halogen or CN; each R 5 is independently alkyl, alkynyl, alkoxy, halogen, hydroxyl, CN, haloalkyl, C 1 -C 6 cyanoalkyl, C 2 -C 4 alkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, or hydroxyalkyl, provided that when R 5 is attached to a nitrogen atom, R 5 is not halogen or CN; each R 6 is independently H, alkyl, haloalkyl, or hydroxyalkyl; each R 7 is independently H, halogen, alkyl, alkenyl, alkynyl, CN, haloalkyl, hydroxyalkyl, cycloalkyl, -C(O)OR 10 , or alkoxy optionally substituted with 1-3 halogens; each R 8 is independently alkyl, halogen, hydroxyl, -NH 2 , -N(H)alkyl, -N(alkyl) 2 , CN, SH, haloalkyl, or hydroxyalkyl, provided that when R 8 is attached to nitrogen, R 8 is not halogen, hydroxyl, -NH 2 , -N(H)alkyl, -N(alkyl) 2 , or CN; each R 9 is independently halogen, hydroxyl, CN, haloalkyl, or hydroxyalkyl; each R 10 is independently H, N(H) 2 , alkyl, hydroxyalkyl, or haloalkyl; R 11 is cycloalkyl substituted with 0-4 R 4 and 0-1 J; each J is independently is -N(R 10 ) 2 , -NO 2 , -SO 2 N(R 10 ) 2 , -NH-SO 2 R 10 , -NHC(O)N(R 10 ) 2 , -C(O)N(R 10 ) 2 , -C(O)C(R 10 ) 2 -aryl, -C(O)OCH 2 -aryl, -alkyl-N(R 10 ) 2 , -alkyl-NHC(O)alkyl, -alkyl-NHC(O)OCH 2 -phenyl, -C(O)-alkylene-OH, -OC(O)R 10 , heterocycloalkyl substituted with 0-1 hydroxy and 0-1 halo, or -C(O)OR 10 ; provided that when J is N(R 10 ) 2 , -NO 2 , or -SO 2 N(R 10 ) 2 , J is not attached to a nitrogen atom; M is -C(O)R 10 , -C(O)NH 2 , -N(H)C(O)CH 3 , -N(H)SO 2 -alkyl, NO 2 , -C 1- C 3 alkyl-C(O)OR 10 , or -N(R 10 ) 2, provided that M is not attached to a nitrogen atom; X is absent, -[C(R 10 ) 2 ] 1-6 -, -[C[(R 10 ) 2 ] 0-4 -O-, -O-[C(R 10 ) 2 ] 1-4 -, C 2 -C 6 alkenylene, -NR 6 -[C(R 10 ) 2 ] 0-4 - , or -[C(R 10 ) 2 ] 0-4 -NR 6 -;each Z is independently CR 7 or N; G is L 1 -L 2 -T 2 provided that: when Formula I is , then G is not hydrogen; each T 1 is independently alkyl, halogen, hydroxyl, haloalkyl, or hydroxyalkyl, provided that when T 1 is attached to nitrogen, T 1 is not halogen or hydroxyl; T 2 is H, CN, -C(NH)N(H)CN, -C(NH)OCH 3 , -C(O)OR 10 , -N(R 10 ) 2 , -OR 10 , -C(O)N(R 10 ) 2 , -SO 2 N(R 10 ) 2 , -SO 2 R 10 , -N(R 10 )-SO 2 N(R 10 ) 2 , -N(R 10 )-C(O)-N(R 10 ) 2 , -N(R 10 )-SO 2 (R 10 ), -N(R 10 )-C(O)O(R 10 ), -P(O)(R 10 ) 2 , -N(R 10 )C(O)-alkyl, -O-C(O)-alkyl, -C(=NR 10 )N(R 10 ) 2 , cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, carbocyclic spiro ring, aryl, or heteroaryl, wherein T 2 is substituted with 0-4 R 8 and 0-1 R 11 provided that when L 1 and L 2 are both absent, T 2 is not CN, -N(R 10 )-SO 2 N(R 10 ) 2 , -N(R 10 )-C(O)-N(R 10 ) 2 , N(R 10 ) 2 , -OR 10 , -N(R 10 )C(O)-alkyl, or -O-C(O)-alkyl, and provided that when L 1 and L 2 taken together are -C(O), -C(O)C(O)N(H)-, -C(O)O-, -C(O)N(H)-, -S(O) 2 -, -alkylene-C(O)N(H)-, -alkylene-C(O)-, -SO 2 -, or -SO 2 NH-, T 2 is not CN, -N(R 10 )-SO 2 N(R 10 ) 2, -N(R 10 ) -C(O)-N(R 10 ) 2 , -C(O)OR 10 , -N(R 10 ) 2 , -OR 10 , -C(O)N(R 10 ) 2 , -SO 2 N(R 10 ) 2 , -N(R 10 )C(O)-alkyl, -O-C(O)-alkyl, -C(NH)OCH 3 , or -C(=NR 10 )N(R 10 ) 2 ; L 1 is absent, -C(O)-, -C(O)C(O)N(H)-, -C(O)O-, -C(O)N(H)-, -C(O)N(H)-O-, -alkylene- C(O)N(H)-, -alkylene-C(O)-, -SO 2 -, or -SO 2 N(H)-, provided that when L 1 is -C(O)N(H)-O-, T 2 is H; and L 2 is absent, alkylene substituted with 0-4 R 9 , -C 2 -C 4 alkenylene, or C 3 -C 6 alkenylene substituted with 0-4 R 9 , provided that when L 1 is -C(O)- and L 2 is absent, T 2 is not H. Embodiment 1(ii)(a) relates to Embodiment 1(ii) wherein G is H. Embodiment 1(ii)(b) relates to Embodiment 1(ii) wherein G is not H. Embodiment 1(ii)(c) relates to Embodiment 1(ii) or 1(ii)(b) wherein G is not alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. Embodiment 1(ii)(d) relates to Embodiment 1(ii) wherein G has one of the following Formulae:
Embodiment 1(ii)(e) relates to Embodiment 1(ii) wherein G is cyanoalkylcarbonyl (-C(O)- alkyl-CN), -alkylene-N(R 10 )-C(O)O(R 10 ) substituted with 0-1 R 8 , -alkylene-NH 2 with 0-1 R 8 , -alkylene-N(R 10 )C(O)-alkyl substituted with 1 R 8 , -C(O)-C 2 -C 4 alkenylene, -C 2 -C 4 alkenylene-C(O)N(R 10 ) 2 , -alkylene-N(R 10 )-SO 2 (R 10 ), -alkylene-N(R 10 )-C(O)-N(R 10 ) 2 , -alkylene-C(O)-N(R 10 ) 2 , -alkylene-C(O)OR 10 , -C(O)-NH 2 , -SO 2 N(R 10 ) 2 , -C(O)-alkylene-P(O)(R 10 ) 2 . [0147] Embodiment 1(iii) relates to any one of Embodiments 1(ii), 1(ii)(a), 1(ii)(b), 1(ii)(c), 1(ii)(d), or 1(ii)(e) wherein R 2 is not cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated 5-6 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O, or partially unsaturated 8-10 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O. [0148] Embodiment 1(iv) relates to any one of Embodiments 1(ii), 1(ii)(a), 1(ii)(b), 1(ii)(c), 1(ii)(d), or 1(ii)(e) wherein R 2 is saturated 7-9 membered heterocycloalkyl comprising at least one nitrogen. [0149] Embodiment 1(v) relates to any one of Embodiments 1(ii), 1(ii)(a), 1(ii)(b), 1(ii)(c), 1(ii)(d), or 1(ii)(e) wherein R 2 is: that is substituted with 0-3 R 4 , provided that G is not alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. [0150] Embodiment 1(vi) relates to Embodiment 1(ii) wherein each Z is CR 7 . [0151] Embodiment 1(vii) relates to Embodiment 1(ii) wherein when G is H, then R 2 is that is substituted with 0-3 R 4 . [0152] Embodiment 2(ii) of this disclosure relates to the compound of Embodiment 1(ii), wherein: X is absent, -[C (R 10 ) 2 ] 1-4 -, -(CH 2 ) 0-3 -O-, O-[C (R 10 ) 2 ] 1-3 -, C 3 -C 4 alkenylene, or -NR 6 - R 1 is a 6-9 membered bridged heterocycloalkyl having at least one nitrogen atom, wherein R 1 is substituted with 0-4 T 1 and 1 G; R 2 is C 1 -C 6 alkyl substituted with 0-5 R 4 and 0-2 J, phenyl substituted with 0-4 R 4 and 0-1 J, -C 0 -C 6 alkyl-phenyl substituted with 0-4 R 4 and 0-1 J, 5-10 membered heteroaryl substituted with 0-5 R 4 and 0-1 J, -C 0 -C 6 alkyl-5-10 membered heteroaryl substituted with 0-5 R 4 and 0-1 J, -C 0 -C 6 alkyl-4-10 membered heterocycloalkyl substituted with 0-5 R 4 and 0-1 J, or -C 0 -C 6 alkyl-C 3 -C 10 cycloalkyl substituted with 0-5 R 4 and 0-1 J, provided that when R 2 is C 1 -C 6 alkyl substituted with 0-5 R 4 and 0-2 J, X is not-C[(R 10 ) 2 ] 1-3 ; R 3 is phenyl, naphthyl, 5-10 membered heteroaryl, or 5-10 membered heterocycloalkyl, wherein R 3 is substituted with 0-4 R 5 and 0-1 M; each R 4 is independently C 1 -C 6 alkyl, halogen, hydroxyl, CN, C 1 -C 6 haloalkyl, C 1 - C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, or C 1 -C 6 alkoxy, provided that when R 4 is attached to a nitrogen atom, R 4 is not halogen, or CN; each R 5 is independently C 1 -C 6 alkyl, C 1 -C 6 alkynyl, C 1 -C 6 alkoxy, halogen, hydroxyl, CN, C 1 -C 6 haloalkyl, C 1 -C 6 cynoalkyl, or C 1 -C 6 hydroxyalkyl, provided that when R 5 is attached to a nitrogen atom, R 5 is not halogen or CN; each R 6 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 hydroxyalkyl; each R 7 is independently H, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, CN, C 1 -C 4 haloalkyl, C 1 -C 4 hydroxyalkyl; C 3 -C 4 cycloalkyl, -C(O)OR 10 , or C 1 -C 4 alkoxy optionally substituted with 1-3 halogens; each R 8 is independently C 1 -C 6 alkyl, halogen, hydroxyl, -NH 2 , -N(H)C 1 -C 6 alkyl, -N(C 1 - C 6 alkyl) 2 , CN, C 1 -C 6 haloalkyl, or C 1 -C 6 hydroxyalkyl, provided that when R 8 is attached to nitrogen, R 8 is not halogen, hydroxyl, -NH 2 , -N(H)C 1 -C 6 alkyl, -N(C 1 -C 6 alkyl) 2 , or CN; each R 9 is independently halogen, hydroxyl, CN, C 1 -C 6 haloalkyl, or C 1 -C 6 hydroxyalkyl; each R 10 is independently H, -N(H) 2 , C 1 -C 6 alkyl, or C 1 -C 6 lhaloalkyl; R 11 is C 3 -C 6 cycloalkyl substituted with 0-3 R 4 and 0-1 J; each J is independently is -N(R 10 ) 2 , -SO 2 N(R 10 ) 2 , -C(O)N(R 10 ) 2 , or -C(O)OR 10 ; provided that when J is -N(R 10 ) 2 or -SO 2 N(R 10 ) 2 , J is not attached to a nitrogen atom; each T 1 is independently C 1 -C 6 alkyl, halogen, hydroxyl, C 1 -C 6 haloalkyl, or C 1 -C 6 hydroxyalkyl, provided that when T 1 is attached to nitrogen, T 1 is not halogen or hydroxyl; T 2 is H, CN, -C(O)OR 10 , -N(R 10 ) 2 , -OR 10 , -C(O)N(R 10 ) 2 , -SO 2 N(R 10 ) 2 , -SO 2 R 10 , -N(R 10 )C(O)-C 1 - C 6 alkyl, -O-C(O)-C 1 -C 6 alkyl, -C(=NH)NH 2 , C 3 -C 6 cycloalkyl, 4-10 membered heterocycloalkyl, 5-9 membered bridged heterocycloalkyl, 6-9 membered heterocyclic spiro ring, 6-9 membered carbocyclic spiro ring, phenyl, naphthyl, or 5-10 membered heteroaryl, wherein T 2 is substituted with 0-4 R 8 and 0-1 R 11 ; provided that when L 1 and L 2 are both absent, T 2 is not CN, -N(R 10 ) 2 , -OR 10 , -N(R 10 )C(O)-C 1 -C 6 alkyl, or -O-C(O)-C 1 -C 6 alkyl, and provided that when L 1 and L 2 taken together are -C(O)-, -C(O)C(O)N(H)-, -C(O)O-, -C(O)N(H)-, -C(O)N(H)-O-, -C 1 -C 6 alkyelene-C(O)N(H)-, -C 1 -C 6 alkylene-C(O)-, -SO 2 -, or -SO 2 NH-, T 2 is not CN, -C(O)OR 10 , C 1 -C 6 alkoxy, N(R 10 ) 2 , -OR 10 , -C(O)N(R 10 ) 2 , -SO 2 N(R 10 ) 2 , -N(R 10 )C(O)-C 1 -C 6 alkyl, -O-C(O)- C 1 -C 6 alkyl, or -C(=NH)NH 2 ; L 1 is absent, -C(O)-, -C(O)C(O)N(H)-, -C(O)O-, -C(O)N(H)-, -C 1 -C 6 alkyelene-C(O)N(H)-, -C 1 -C 6 alkylene-C(O)-, -SO 2 -, or -SO 2 N(H)- provided that when L 1 is -C(O)N(H)-O-, T 2 is H; L 2 is absent, C 1 -C 6 alkylene substituted with 0-2 R 9 , or C 3 -C 6 alkenylene substituted with 0-4 R 9 , provided that when L 1 is -C(O)- and L 2 is absent, T 2 is not H; and M is -C(O)NH 2 , -NH 2 C(O)CH 3 , -N(H)SO 2 - C 1 -C 3 alkyl, or -NH 2 , provided that M is not attached to a nitrogen atom. Embodiment 2(ii)(a) relates to Embodiment 2(ii) wherein G is H. Embodiment 2(ii)(b) relates to Embodiment 2(ii) wherein G is not H. Embodiment 2(ii)(c) relates to Embodiment 2(ii) wherein G is not hydrogen, alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. [0153] Embodiment 2(iii) relates to any one of Embodiments 2(ii), 2(ii)(a), 2(ii)(b), or 2(ii)(c) wherein R 2 is not cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated 5-6 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O, or partially unsaturated 8-10 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O. [0154] Embodiment 2(iv) relates to any one of Embodiments 2(ii), 2(ii)(a), 2(ii)(b), or 2(ii)(c) wherein R 2 is saturated 7-9 membered heterocycloalkyl comprising at least one nitrogen. [0155] Embodiment 2(v) relates to any one of Embodiments 2(ii), 2(ii)(a), 2(ii)(b), or 2(ii)(c) wherein R 2 is that is substituted with 0-3 R 4 , provided that G is not alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. [0156] Embodiment 2(vi) relates to Embodiment 2(ii) wherein each Z is CR 7 . [0157] Embodiment 2(vii) relates to Embodiment 2(ii) wherein when G is H, then R 2 is that is substituted with 0-3 R 4 . [0158] Embodiment 3(ii) of this disclosure relates to the compound of any one of Embodiments 1(ii), 1(ii)(a), 1(ii)(b), 1(ii)(c), 1(ii)(d), 1(ii)(e), 2(ii), 2(ii)(a), 2(ii)(b), or 2(ii)(c) having one of the following formulae: , , or a pharmaceutically acceptable salt, a solvate, a tautomer, a stereoisomer, or a deuterated analog thereof. Embodiment 3(ii)(a) relates to Embodiment 3(ii) wherein G is H, provided that when the compound has the Formula (IIB), R 7 is not H. Embodiment 3(ii)(b) relates to Embodiment 3(ii) wherein G is not H. Embodiment 3(ii)(c) relates to Embodiment 3(ii) wherein G is not hydrogen, alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-Alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. Embodiment 3(ii)(d) relates to Embodiment 3(ii) wherein G has one of the following Formulae:
Embodiment 3(ii)(e) relates to Embodiment 3(ii) wherein G is cyanoalkylcarbonyl (-C(O)- alkyl-CN), -alkylene-N(R 10 )-C(O)O(R 10 ) substituted with 0-1 R 8 , -alkylene-NH 2 with 0-1 R 8 , -alkylene-N(R 10 )C(O)-alkyl substituted with 1 R 8 , -C(O)-C 2 -C 4 alkenylene, -C 2 -C 4 alkenylene-C(O)N(R 10 ) 2 , -alkylene-N(R 10 )-SO 2 (R 10 ), -alkylene-N(R 10 )-C(O)-N(R 10 ) 2 , -alkylene-C(O)-N(R 10 ) 2 , -alkylene-C(O)OR 10 , -C(O)-NH 2 , -SO 2 N(R 10 ) 2 , -C(O)-alkylene-P(O)(R 10 ) 2 . [0159] Embodiment 3(iii) relates to any one of Embodiments 3(ii), 3(ii)(a), 3(ii)(b), 3(ii)(c), 3(ii)(d), or 3(ii)(e) wherein R 2 is not cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated 5-6 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O, or partially unsaturated 8-10 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O. [0160] Embodiment 3(iv) relates to any one of Embodiments 3(ii), 3(ii)(a), 3(ii)(b), 3(ii)(c), 3(ii)(d), or 3(ii)(e) wherein R 2 is saturated 7-9 membered heterocycloalkyl comprising at least one nitrogen. [0161] Embodiment 3(v) relates to any one of Embodiments 3(ii), 3(ii)(a), 3(ii)(b), 3(ii)(c), 3(ii)(d), or 3(ii)(e) wherein R 2 is that is substituted with 0-3 R 4 , provided that G is not alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. [0162] Embodiment 3(vi) relates to Embodiment 3(ii) wherein when G is H, then R 2 is that is substituted with 0-3 R 4 . [0163] Embodiment 4(ii) of this disclosure relates to the compound of Embodiment 3(ii) having Formula IIB or IID, or a pharmaceutically acceptable salt, a solvate, a tautomer, a stereoisomer, or a deuterated analog thereof. Embodiment 4(ii)(a) relates to Embodiment 4(ii) wherein G is H, provided that when the compound has the Formula (IIB), R 7 is not H. Embodiment 4(ii)(b) relates to Embodiment 4(ii) wherein G is not H. Embodiment 4(ii)(c) relates to Embodiment 4(ii) wherein G is not hydrogen, alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-Alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. Embodiment 4(ii)(d) relates to Embodiment 4(ii) wherein G has one of the following Formulae:
Embodiment 4(ii)(e) relates to Embodiment 4(ii) wherein G is cyanoalkylcarbonyl (-C(O)- alkyl-CN), -alkylene-N(R 10 )-C(O)O(R 10 ) substituted with 0-1 R 8 , -alkylene-NH 2 with 0-1 R 8 , -alkylene-N(R 10 )C(O)-alkyl substituted with 1 R 8 , -C(O)-C 2 -C 4 alkenylene, -C 2 -C 4 alkenylene-C(O)N(R 10 ) 2 , -alkylene-N(R 10 )-SO 2 (R 10 ), -alkylene-N(R 10 )-C(O)-N(R 10 ) 2 , -alkylene-C(O)-N(R 10 ) 2 , -alkylene-C(O)OR 10 , -C(O)-NH 2 , -SO 2 N(R 10 ) 2 , -C(O)-alkylene-P(O)(R 10 ) 2 . [0164] Embodiment 4(iii) relates to any one of the Embodiments 4(ii), 4(ii)(a), 4(ii)(b), 4(ii)(c), 4(ii)(d), or 4(ii)(e) wherein R 2 is not cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated 5-6 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O, or partially unsaturated 8- 10 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O. [0165] Embodiment 4(iv) relates to any one of the Embodiments 4(ii), 4(ii)(a), 4(ii)(b), 4(ii)(c), 4(ii)(d), or 4(ii)(e) wherein R 2 is saturated 7-9 membered heterocycloalkyl comprising at least one nitrogen. [0166] Embodiment 4(v) relates to any one of the Embodiments 4(ii), 4(ii)(a), 4(ii)(b), 4(ii)(c), 4(ii)(d), or 4(ii)(e) wherein R 2 is that is substituted with 0-3 R 4 , provided that G is not alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. [0167] Embodiment 4(vi) relates to Embodiment 4(ii) having the Formula of (IID): . Embodiment 4(vi)(a) relates to Embodiment 4(vi) wherein G is H. Embodiment 4(vi)(b) relates to Embodiment 4(vi) wherein G is not H. [0168] Embodiment 4(vii) relates to any one of the Embodiments 4(vi), 4(vi)(a), or 4(vi)(b) wherein R 2 is not cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated 5-6 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O, or partially unsaturated 8-10 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O. [0169] Embodiment 4(viii) relates to any one of the Embodiments 4(vi), 4(vi)(a), or 4(vi)(b) wherein R 2 is saturated 7-9 membered heterocycloalkyl comprising at least one nitrogen. [0170] Embodiment 4(ix) relates to any one of the Embodiments 4(vi), 4(vi)(a), or 4(vi)(b) wherein R 2 is that is substituted with 0-3 R 4 , provided that G is not alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. [0171] Embodiment 4(x) relates to Embodiment 4(ii) wherein when G is H, then R 2 is that is substituted with 0-3 R 4 . [0172] Embodiment 5(ii) of this disclosure relates to the compound according to the compound of any one of Embodiments 1(ii), 2(ii), 3(ii), or 4(ii) having one of the following formulae: , or a pharmaceutically acceptable salt, a solvate, a tautomer, a stereoisomer, or a deuterated analog thereof, wherein each R 7 is independently H, F, Cl, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl. Embodiment 5(ii)(a) relates to Embodiment 5(ii) wherein G is H, provided that when the compound has the Formula (IIIA), R 7 is not H. Embodiment 5(ii)(b) relates to Embodiment 5(ii) wherein G is not H. Embodiment 5(ii)(c) relates to Embodiment 5(ii) wherein G is not hydrogen, alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-Alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. Embodiment 5(ii)(d) relates to Embodiment 5(ii) wherein G has one of the following Formulae:
Embodiment 5(ii)(e) relates to Embodiment 5(ii) wherein G is cyanoalkylcarbonyl (-C(O)- alkyl-CN), -alkylene-N(R 10 )-C(O)O(R 10 ) substituted with 0-1 R 8 , -alkylene-NH 2 with 0-1 R 8 , -alkylene-N(R 10 )C(O)-alkyl substituted with 1 R 8 , -C(O)-C 2 -C 4 alkenylene, -C 2 -C 4 alkenylene-C(O)N(R 10 ) 2 , -alkylene-N(R 10 )-SO 2 (R 10 ), -alkylene-N(R 10 )-C(O)-N(R 10 ) 2 , -alkylene-C(O)-N(R 10 ) 2 , -alkylene-C(O)OR 10 , -C(O)-NH 2 , -SO 2 N(R 10 ) 2 , -C(O)-alkylene-P(O)(R 10 ) 2 . [0173] Embodiment 5(iii) relates to any one of the Embodiments 5(ii), 5(ii)(a), 5(ii)(b), 5(ii)(c), 5(ii)(d), or 5(ii)(e) wherein R 2 is not cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated 5-6 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O, or partially unsaturated 8- 10 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O. [0174] Embodiment 5(iv) relates to any one of the Embodiments 5(ii), 5(ii)(a), 5(ii)(b), 5(ii)(c), 5(ii)(d), or 5(ii)(e) wherein R 2 is saturated 7-9 membered heterocycloalkyl comprising at least one nitrogen. [0175] Embodiment 5(v) relates to any one of the Embodiments 5(ii), 5(ii)(a), 5(ii)(b), 5(ii)(c), 5(ii)(d), or 5(ii)(e) wherein R 2 is that is substituted with 0-3 R 4 , provided that G is not alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. [0176] Embodiment 5(vi) relates to Embodiment 5(ii) having the Formula of (IIIB): , Embodiment 5(vi)(a) relates to Embodiment 5(vi) wherein G is H. Embodiment 5(vi)(b) relates to Embodiment 5(vi) wherein G is not H. [0177] Embodiment 5(vii) relates to any one of the Embodiments 5(vi), Embodiments 5(vi)(a), or 5(vi)(b) wherein R 2 is not cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated 5-6 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O, or partially unsaturated 8-10 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O. [0178] Embodiment 5(viii) relates to any one of the Embodiments 5(vi), Embodiments 5(vi)(a), or 5(vi)(b) wherein R 2 is saturated 7-9 membered heterocycloalkyl comprising at least one nitrogen. [0179] Embodiment 5(ix) relates to any one of the Embodiments 5(vi), Embodiments 5(vi)(a), or 5(vi)(b) wherein R 2 is that is substituted with 0-3 R 4 , provided that G is not alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. [0180] Embodiment 5(x) relates to Embodiment 5(ii) wherein when G is H, then R 2 is that is substituted with 0-3 R 4 . [0181] Embodiment 6(ii) of this disclosure relates to the compound according to any one of Embodiments 1(ii), 2(ii), 3(ii), 4(ii), or 5(ii) having one of the following formulae:
or a pharmaceutically acceptable salt, a solvate, a tautomer, a stereoisomer, or a deuterated analog thereof. Embodiment 6(ii)(a) relates to Embodiment 6(ii) wherein G is H. Embodiment 6(ii)(b) relates to Embodiment 6(ii) wherein G is not H. Embodiment 6(ii)(c) relates to Embodiment 6(ii) wherein G is not hydrogen, alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. Embodiment 6(ii)(d) relates to Embodiment 6(ii) wherein G has one of the following Formulae:
Embodiment 6(ii)(e) relates to Embodiment 6(ii) wherein G is cyanoalkylcarbonyl (-C(O)- alkyl-CN), -alkylene-N(R 10 )-C(O)O(R 10 ) substituted with 0-1 R 8 , -alkylene-NH 2 with 0-1 R 8 , -alkylene-N(R 10 )C(O)-alkyl substituted with 1 R 8 , -C(O)-C 2 -C 4 alkenylene, -C 2 -C 4 alkenylene-C(O)N(R 10 ) 2 , -alkylene-N(R 10 )-SO 2 (R 10 ), -alkylene-N(R 10 )-C(O)-N(R 10 ) 2 , -alkylene-C(O)-N(R 10 ) 2 , -alkylene-C(O)OR 10 , -C(O)-NH 2 , -SO 2 N(R 10 ) 2 , -C(O)-alkylene-P(O)(R 10 ) 2 . [0182] Embodiment 6(iii) relates to any one of Embodiments 6(ii), 6(ii)(a), 6(ii)(b), 6(ii)(c), 6(ii)(d), or 6(ii)(e) wherein R 2 is not cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated 5-6 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O, or partially unsaturated 8-10 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O. [0183] Embodiment 6(iv) relates to any one of Embodiments 6(ii), 6(ii)(a), 6(ii)(b), 6(ii)(c), 6(ii)(d), or 6(ii)(e) wherein R 2 is saturated 7-9 membered heterocycloalkyl comprising at least one nitrogen. [0184] Embodiment 6(v) relates to any one of Embodiments 6(ii), 6(ii)(a), 6(ii)(b), 6(ii)(c), 6(ii)(d), or 6(ii)(e) wherein R 2 is that is substituted with 0-3 R 4 , provided that G is not alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. [0185] Embodiment 6(vi) relates to Embodiment 6(ii) wherein when G is H, then R 2 is that is substituted with 0-3 R 4 . [0186] Embodiment 7(ii) of this disclosure relates to the compound according to any one of Embodiments 1(ii), 2(ii), 3(ii), 4(ii), 5(ii), or 6(ii) wherein: R 1 is a 7-9 membered bridged heterocycloalkyl having at least one nitrogen atom, wherein R 1 is substituted with 0-3 T 1 and 1 G; R 2 is -C 0 -C 5 alkyl-4-10 membered heterocycloalkyl substituted with 0-4 R 4 and 0-1 J; -C 0 -C 5 alkyl-5-10 membered heteroaryl substituted with 0-3 R 4 and 0-1 J; or C 1 -C 6 alkyl substituted with 1-2 J groups; R 3 is phenyl, naphthyl, 5-10 membered heteroaryl, or 5-10 membered heterocycloalkyl, wherein the naphthyl, 5-10 membered heteroaryl, and 5-10 membered heterocycloalkyl are each substituted with 0-4 R 5 , and wherein the phenyl is substituted with 0-4 R 5 and 0-1M; each R 4 is independently C 1 -C 5 alkyl, halogen, hydroxyl, CN, C 1 -C 5 haloalkyl, C 1 - C 5 hydroxyalkyl, C 1 -C 5 cyanoalkyl, or C 1 -C 5 alkoxy, provided that when R 4 is attached to a nitrogen atom, R 4 is not halogen, hydroxyl, or CN; each R 5 is independently C 1 -C 5 alkyl, C 1 -C 5 alkynyl, C 1 -C 5 alkoxy, halogen, hydroxyl, CN, C 1 -C 5 haloalkyl, C 1 -C 5 cynoalkyl, or C 1 -C 5 hydroxyalkyl each R 8 is independently C 1 -C 5 alkyl, halogen, hydroxyl, -NH 2 , -N(H)C 1 -C 5 alkyl, -N(C 1 - C 5 alkyl) 2 , CN, C 1 -C 5 haloalkyl, or C 1 -C 5 hydroxyalkyl, provided that when R 8 is attached to nitrogen, R 8 is not halogen, hydroxyl, -NH 2 , -N(H)C 1 -C 5 alkyl, -N(C 1 -C 5 alkyl) 2 , or CN; each R 9 is independently halogen, hydroxyl, CN, C 1 -C 5 haloalkyl, or C 1 -C 5 hydroxyalkyl; each R 10 is independently H, C 1 -C 5 alkyl, or C 1 -C 5 haloalkyl; each T 1 is independently C 1 -C 5 alkyl, halogen, hydroxyl, C 1 -C 5 haloalkyl, or C 1 -C 5 hydroxyalkyl, provided that when T 1 is attached to nitrogen, T 1 is not halogen or hydroxyl; T 2 is H, CN, -C(O)OR 10 , C 1 -C 5 alkoxy, N(R 10 ) 2 , -C(O)N(R 10 ) 2 , -SO 2 N(R 10 ) 2 , -SO 2 R 10 , -N(R 10 )C(O)-C 1 -C 5 alkyl, -O-C(O)-C 1 -C 5 alkyl, C 3 -C 6 cycloalkyl, 4-10 membered heterocycloalkyl, 7-9 membered bridged heterocycloalkyl, phenyl, naphthyl, or 5-10 membered heteroaryl, wherein T 2 substituted with 0-4 R 8 , provided that when L 1 and L 2 are both absent, T 2 is not CN, C 1 -C 5 alkoxy, N(R 10 ) 2 , -N(R 10 )C(O)-C 1 -C 5 alkyl, or -O-C(O)-C 1 -C 5 alkyl, and provided that when L 1 and L 2 taken together are -C(O)-, -C(O)N(H)-, -C 1 -C 5 alkyelene-C(O)N(H)-, -C 1 -C 5 alkylene-C(O)-, -SO 2 -, or -SO 2 NH, T 2 is not CN, -C(O)OR 10 , C 1 -C 5 alkoxy, N(R 10 ) 2 , -C(O)N(R 10 ) 2 , -SO 2 N(R 10 ) 2 , -N(R 10 )C(O)-C 1 -C 5 alkyl, or -O-C(O)-C 1 -C 5 alkyl; L 1 is absent, -C(O)-, -C(O)N(H)-, -C 1 -C 5 alkyelene-C(O)N(H)-, -C 1 -C 5 alkylene-C(O)-, -SO 2 -, or -SO 2 N(H)-; and L 2 is absent, or C 1 -C 5 alkylene substituted with 0-4 R 9 , provided that when L 1 is -C(O)- and L 2 is absent, T 2 is not H; and M is -C(O)NH 2 , -NH 2 C(O)CH 3 , -N(H)SO 2 CH 3 , or -NH 2 , provided that M is not attached to a nitrogen atom. Embodiment 7(ii)(a) relates to Embodiment 7(ii) wherein G is H. Embodiment 7(ii)(b) relates to Embodiment 7(ii) wherein G is not H. Embodiment 7(ii)(c) relates to Embodiment 7(ii) wherein G is not hydrogen, alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. Embodiment 7(ii)(d) relates to Embodiment 7(ii) wherein G has one of the following Formulae:
Embodiment 7(ii)(e) relates to Embodiment 7(ii) wherein G is cyanoalkylcarbonyl (-C(O)- alkyl-CN), -alkylene-N(R 10 )-C(O)O(R 10 ) substituted with 0-1 R 8 , -alkylene-NH 2 with 0-1 R 8 , -alkylene-N(R 10 )C(O)-alkyl substituted with 1 R 8 , -C(O)-C 2 -C 4 alkenylene, -C 2 -C 4 alkenylene-C(O)N(R 10 ) 2 , -alkylene-N(R 10 )-SO 2 (R 10 ), -alkylene-N(R 10 )-C(O)-N(R 10 ) 2 , -alkylene-C(O)-N(R 10 ) 2 , -alkylene-C(O)OR 10 , -C(O)-NH 2 , -SO 2 N(R 10 ) 2 , -C(O)-alkylene-P(O)(R 10 ) 2 . [0187] Embodiment 7(iii) relates to any one of Embodiments 7(ii), 7(ii)(a), 7(ii)(b), 7(ii)(c), 7(ii)(d), or 7(ii)(e) wherein R 2 is saturated 7-9 membered heterocycloalkyl comprising at least one nitrogen. [0188] Embodiment 7(iv) relates to any one of Embodiments 7(ii), 7(ii)(a), 7(ii)(b), 7(ii)(c), 7(ii)(d), or 7(ii)(e) wherein R 2 is that is substitut 4 ed with 0-3 R , provided that G is not alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. [0189] Embodiment 7(v) relates to Embodiment 7(ii) wherein when G is H, then R 2 is that is substituted with 0-3 R 4 . [0190] Embodiment 8(ii) of this disclosure relates to the compound according to any of Embodiments 1(ii), 2(ii), 3(ii), 4(ii), 5(ii), 6(ii), or 7(ii), wherein: R 1 is a 7-9 membered bridged heterocycloalkyl having at least one nitrogen atom, wherein R 1 is substituted with 0-2 T 1 and 1 G; R 2 is 5-10 membered heterocyloalkyl-C 1 -C 4 alkyl substituted with 0-3 R 4 or C 1 -C 5 alkyl substituted with 1-2 J groups; R 3 is phenyl, naphthyl, 5-10 membered heteroaryl, or a 5-10 membered heterocycloalkyl, wherein the naphthyl, 5-10 membered heteroaryl, and 5-10 membered heterocycloalkyl are each substituted with 0-3 R 5 , and wherein the phenyl is substituted with 0-4 R 5 and 0-1M; each R 4 is independently C 1 -C 4 alkyl, halogen, hydroxyl, CN, C 1 -C 4 haloalkyl, C 1 - C 4 hydroxyalkyl, or C 1 -C 4 alkoxy, provided that when R 4 is attached to a nitrogen atom, R 4 is not halogen, hydroxyl, or CN; each R 5 is independently C 1 -C 4 alkyl, C 1 -C 4 alkynyl, halogen, hydroxyl, CN, C 1 -C 4 haloalkyl, C 1 -C 4 cynoalkyl, or C 1 -C 4 hydroxyalkyl; each R 8 is independently C 1 -C 4 alkyl, halogen, hydroxyl, -NH 2 , -N(H)C 1 -C 4 alkyl, -N(C 1 - C 4 alkyl) 2 , CN, C 1 -C 4 haloalkyl, or C 1 -C 4 hydroxyalkyl, provided that when R 8 is attached to nitrogen, R 8 is not halogen, hydroxyl, -NH 2 , -N(H)C 1 -C 5 alkyl, -N(C 1 -C 5 alkyl) 2 , or CN; each R 9 is independently halogen, hydroxyl, CN, C 1 -C 4 haloalkyl, or C 1 -C 4 hydroxyalkyl; each R 10 is independently H, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl; each T 1 is independently C 1 -C 4 alkyl halogen hydroxyl, C 1 -C 4 haloalkyl, or C 1 -C 4 hydroxyalkyl, provided that when T 1 is attached to nitrogen, T 1 is not halogen or hydroxyl; T 2 is H, CN, -C(O)OR 10 , C 1 -C 4 alkoxy, -N(R 10 ) 2 , -C(O)N(R 10 ) 2 , SO 2 N(R 10 ) 2 , -SO 2 R 10 , -N(R 10 )C(O)- C 1 -C 4 alkyl, -O-C(O)-C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl, 7-8 membered bridged heterocycloalkyl, phenyl, naphthyl, or 5-6 membered heteroaryl, wherein T 2 is substituted with 0-4 R 8 , provided that when L 1 and L 2 are both absent, T 2 is not CN, C 1 -C 4 alkoxy, N(R 10 ) 2 , -N(R 10 )C(O)-C 1 -C 4 alkyl, or -O-C(O)-C 1 -C 4 alkyl, and provided that when L 1 and L 2 taken together are -C(O)-, -C(O)N(H)-, -S(O) 2 -, C 1 -C 4 alkyelene-C(O)N(H)-, or -C 1 -C 4 alkylene-C(O)-, T 2 is not CN, -C(O)OR 10 , C 1 -C 4 alkoxy, -N(R 10 ) 2 , -C(O)N(R 10 ) 2 , SO 2 N(R 10 ) 2 , -N(R 10 )C(O)-C 1 -C 4 alkyl, or -O-C(O)-C 1 -C 4 alkyl; L 1 is absent, -C(O)-, -C(O)N(H)-, -S(O) 2 -, -SO 2 N(H)-, C 1 -C 4 alkyelene-C(O)N(H)-, -C 1 -C 4 alkylene-C(O)-, or -C 1 -C 4 alkylene-C(O)-; and L 2 is absent, or C 1 -C 4 alkylene substituted with 0-2 R 9 , provided that when L 1 is -C(O)- and L 2 is absent, T 2 is not H. Embodiment 8(ii)(a) relates to Embodiment 8(ii) wherein G is H. Embodiment 8(ii)(b) relates to Embodiment 8(ii) wherein G is not H. Embodiment 8(ii)(c) relates to Embodiment 8(ii) wherein G is not hydrogen, alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-Alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. Embodiment 8(ii)(d) relates to Embodiment 8(ii) wherein G has one of the following Formulae:
Embodiment 8(ii)(e) relates to Embodiment 8(ii) wherein G is cyanoalkylcarbonyl (-C(O)- alkyl-CN), -alkylene-N(R 10 )-C(O)O(R 10 ) substituted with 0-1 R 8 , -alkylene-NH 2 with 0-1 R 8 , -alkylene-N(R 10 )C(O)-alkyl substituted with 1 R 8 , -C(O)-C 2 -C 4 alkenylene, -C 2 -C 4 alkenylene-C(O)N(R 10 ) 2 , -alkylene-N(R 10 )-SO 2 (R 10 ), -alkylene-N(R 10 )-C(O)-N(R 10 ) 2 , -alkylene-C(O)-N(R 10 ) 2 , -alkylene-C(O)OR 10 , -C(O)-NH 2 , -SO 2 N(R 10 ) 2 , -C(O)-alkylene-P(O)(R 10 ) 2 . [0191] Embodiment 8(iii) relates to any one of Embodiments 8(ii), 8(ii)(a), 8(ii)(b), 8(ii)(c), 8(ii)(d), or 8(ii)(e) wherein R 2 is saturated 7-9 membered heterocycloalkyl comprising at least one nitrogen. [0192] Embodiment 8(iv) relates to any one of Embodiments 8(ii), 8(ii)(a), 8(ii)(b), 8(ii)(c), 8(ii)(d), or 8(ii)(e) wherein R 2 is that is substituted with 0-3 R 4 , provided that G is not alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. [0193] Embodiment 8(v) relates to Embodiment 8(ii) wherein when G is H, then R 2 is that is substituted with 0-3 R 4 . [0194] Embodiment 9(ii) of this disclosure relates to the compound according to any one of Embodiments 1(ii), 2(ii), 3(ii), 4(ii), 5(ii), 6(ii), 7(ii), or 8(ii), wherein R 1 is 7-9 membered bridged piperazine or piperidine substituted with 0-2 T 1 and 1 G. Embodiment 9(ii)(a) relates to Embodiment 9(ii) wherein G is H. Embodiment 9(ii)(b) relates to Embodiment 9(ii) wherein G is not H. Embodiment 9(ii)(c) relates to Embodiment 9(ii) wherein G is not hydrogen, alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-Alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. Embodiment 9(ii)(d) relates to Embodiment 9(ii) wherein G has one of the following Formulae:
Embodiment 9(ii)(e) relates to Embodiment 9(ii) wherein G is cyanoalkylcarbonyl (-C(O)- alkyl-CN), -alkylene-N(R 10 )-C(O)O(R 10 ) substituted with 0-1 R 8 , -alkylene-NH 2 with 0-1 R 8 , -alkylene-N(R 10 )C(O)-alkyl substituted with 1 R 8 , -C(O)-C 2 -C 4 alkenylene, -C 2 -C 4 alkenylene-C(O)N(R 10 ) 2 , -alkylene-N(R 10 )-SO 2 (R 10 ), -alkylene-N(R 10 )-C(O)-N(R 10 ) 2 , -alkylene-C(O)-N(R 10 ) 2 , -alkylene-C(O)OR 10 , -C(O)-NH 2 , -SO 2 N(R 10 ) 2 , -C(O)-alkylene-P(O)(R 10 ) 2 . [0195] Embodiment 9(iii) relates to any one of Embodiments 9(ii), 9(ii)(a), 9(ii)(b), 9(ii)(c), 9(ii)(d), or 9(ii)(e) wherein R 2 is that is substituted with 0-3 R 4 , provided that G is not alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. [0196] Embodiment 9(iv) relates to Embodiment 9(ii) wherein when G is H, then R 2 is that is substituted with 0-3 R 4 . [0197] Embodiment 10(ii) of this disclosure relates to the compound according to any one of Embodiments 1(ii), 2(ii), 3(ii), 4(ii), 5(ii), 6(ii), 7(ii), or 8(ii), wherein R 1 is one of the following formulae: Embodiment 10(ii)(a) relates to Embodiment 10(ii) wherein G is H. Embodiment 10(ii)(b) relates to Embodiment 10(ii) wherein G is not H. Embodiment 10(ii)(c) relates to Embodiment 10(ii) wherein G is not hydrogen, alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-Alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. Embodiment 10(ii)(d) relates to Embodiment 10(ii) wherein G has one of the following Formulae:
Embodiment 10(ii)(e) relates to Embodiment 10(ii) wherein G is cyanoalkylcarbonyl (-C(O)- alkyl-CN), -alkylene-N(R 10 )-C(O)O(R 10 ) substituted with 0-1 R 8 , -alkylene-NH 2 with 0-1 R 8 , -alkylene-N(R 10 )C(O)-alkyl substituted with 1 R 8 , -C(O)-C 2 -C 4 alkenylene, -C 2 -C 4 alkenylene-C(O)N(R 10 ) 2 , -alkylene-N(R 10 )-SO 2 (R 10 ), -alkylene-N(R 10 )-C(O)-N(R 10 ) 2 , -alkylene-C(O)-N(R 10 ) 2 , -alkylene-C(O)OR 10 , -C(O)-NH 2 , -SO 2 N(R 10 ) 2 , -C(O)-alkylene-P(O)(R 10 ) 2 . [0198] Embodiment 10(iii) relates to any one of Embodiments 10(ii), 10(ii)(a), 10(ii)(b), 10(ii)(c), 10(ii)(d), or 10(ii)(e) wherein R 2 is not cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated 5-6 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O, or partially unsaturated 8- 10 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O. [0199] Embodiment 10(iv) relates to any one of Embodiments 10(ii), 10(ii)(a), 10(ii)(b), 10(ii)(c), 10(ii)(d), or 10(ii)(e) wherein R 2 is saturated 7-9 membered heterocycloalkyl comprising at least one nitrogen. Embodiment 10(v) relates to any one of Embodiments 10(ii), 10(ii)(a), 10(ii)(b), 10(ii)(c), 10(ii)(d), or 10(ii)(e) wherein that is substituted with 0-3 R 4 , provided that G is not alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. [0200] Embodiment 11(ii) of this disclosure relates to the compound according to Embodiment 10(ii), wherein R 1 is formula (a) or (b). Embodiment 11(ii)(a) relates to Embodiment 11(ii) wherein G is H. Embodiment 11(ii)(b) relates to Embodiment 11(ii) wherein G is not H. [0201] Embodiment 11(iii) relates to Embodiment 11(ii) wherein R 2 is not cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated 5-6 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O, or partially unsaturated 8-10 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O. [0202] Embodiment 11(iv) relates to any one of Embodiments 11(ii), 11(ii)(a), or 11(ii)(b) wherein R 2 is saturated 7-9 membered heterocycloalkyl comprising at least one nitrogen. [0203] Embodiment 11(v) relates to any one of Embodiments 11(ii), 11(ii)(a), or 11(ii)(b) wherein R 2 is that is substituted with 0-3 R 4 , provided that G is not alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. [0204] Embodiment 11(vi) relates to the compound of Embodiment 11(ii) wherein R 1 has the Formula (a). [0205] Embodiment 11(vii) relates to Embodiment 1(ii) wherein when G is H, then R 2 is that is substituted with 0-3 R 4 .
[0206] Embodiment 12(ii) of this disclosure relates to the compound according to any one of Embodiments 1(ii), 2(ii), 3(ii), 4(ii), or 5(ii), wherein R 2 is one of the following formulae:
Embodiment 12(ii)(a) relates to Embodiment 12(ii) wherein G is H. Embodiment 12(ii)(b) relates to Embodiment 12(ii) wherein G is not H. Embodiment 12(ii)(c) relates to Embodiment 12(ii) wherein G is not hydrogen, alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-Alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl.
Embodiment 12(ii)(d) relates to Embodiment 12(ii) wherein G has one of the following Formulae:
Embodiment 12(ii)(e) relates to Embodiment 12(ii) wherein G is cyanoalkylcarbonyl (-C(O)- alkyl-CN), -alkylene-N(R 10 )-C(O)O(R 10 ) substituted with 0-1 R 8 , -alkylene-NH 2 with 0-1 R 8 , -alkylene-N(R 10 )C(O)-alkyl substituted with 1 R 8 , -C(O)-C 2 -C 4 alkenylene, -C 2 -C 4 alkenylene-C(O)N(R 10 ) 2 , -alkylene-N(R 10 )-SO 2 (R 10 ), -alkylene-N(R 10 )-C(O)-N(R 10 ) 2 , -alkylene-C(O)-N(R 10 ) 2 , -alkylene-C(O)OR 10 , -C(O)-NH 2 , -SO 2 N(R 10 ) 2 , -C(O)-alkylene-P(O)(R 10 ) 2 . [0207] Embodiment 12(iii) relates to Embodiment 12(ii) wherein when G is H, then R 2 is that is substituted with 0-3 R 4 . [0208] Embodiment 13(ii) of this disclosure relates to the compound according to any of 1(ii), 2(ii), 3(ii), 4(ii), 5(ii), 6(ii), 7(ii), 8(ii), 9(ii), 10(ii), 11(ii), or 12(ii), wherein R 2 is one of the following formulae and R 4 is H, Cl, or F: . Embodiment 13(ii)(a) relates to Embodiment 13(ii) wherein G is H. Embodiment 13(ii)(b) relates to Embodiment 13(ii) wherein G is not H. Embodiment 13(ii)(c) relates to Embodiment 13(ii) wherein G is not hydrogen, alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-Alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. Embodiment 13(ii)(d) relates to Embodiment 13(ii) wherein G has one of the following Formulae:
Embodiment 13(ii)(e) relates to Embodiment 13(ii) wherein G is cyanoalkylcarbonyl (-C(O)- alkyl-CN), -alkylene-N(R 10 )-C(O)O(R 10 ) substituted with 0-1 R 8 , -alkylene-NH 2 with 0-1 R 8 , -alkylene-N(R 10 )C(O)-alkyl substituted with 1 R 8 , -C(O)-C 2 -C 4 alkenylene, -C 2 -C 4 alkenylene-C(O)N(R 10 ) 2 , -alkylene-N(R 10 )-SO 2 (R 10 ), -alkylene-N(R 10 )-C(O)-N(R 10 ) 2 , -alkylene-C(O)-N(R 10 ) 2 , -alkylene-C(O)OR 10 , -C(O)-NH 2 , -SO 2 N(R 10 ) 2 , -C(O)-alkylene-P(O)(R 10 ) 2 . [0209] Embodiment 13(iii) relates to the compound of Embodiment 13(ii) wherein R 4 is H and R 2 has the following formula: . [0210] Embodiment 13(iv) relates to the compound of Embodiment 13(ii) wherein R 4 is F and R 2 has the following formula: . [0211] Embodiment 13(v) relates to the compound of Embodiment 13(ii) wherein R 4 is Cl and R 2 has the following formula: . [0212] Embodiment 14(ii) of this disclosure relates to the compound according to any one of Embodiments 1(ii), 2(ii), 3(ii), 4(ii), 5(ii), 6(ii), 7(ii), 8(ii), 9(ii), 10(ii), 11(ii), 12(ii), or 13(ii), wherein R 3 is one of the following formulae:
. Embodiment 14(ii)(a) relates to Embodiment 14(ii) wherein G is H. Embodiment 14(ii)(b) relates to Embodiment 14(ii) wherein G is not H. Embodiment 14(ii)(c) relates to Embodiment 14(ii) wherein G is not hydrogen, alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-Alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. Embodiment 14(ii)(d) relates to Embodiment 14(ii) wherein G has one of the following Formulae:
Embodiment 14(ii)(e) relates to Embodiment 14(ii) wherein G is cyanoalkylcarbonyl (-C(O)- alkyl-CN), -alkylene-N(R 10 )-C(O)O(R 10 ) substituted with 0-1 R 8 , -alkylene-NH 2 with 0-1 R 8 , -alkylene-N(R 10 )C(O)-alkyl substituted with 1 R 8 , -C(O)-C 2 -C 4 alkenylene, -C 2 -C 4 alkenylene-C(O)N(R 10 ) 2 , -alkylene-N(R 10 )-SO 2 (R 10 ), -alkylene-N(R 10 )-C(O)-N(R 10 ) 2 , -alkylene-C(O)-N(R 10 ) 2 , -alkylene-C(O)OR 10 , -C(O)-NH 2 , -SO 2 N(R 10 ) 2 , -C(O)-alkylene-P(O)(R 10 ) 2 . [0213] Embodiment 14(iii) relates to Embodiment 14(ii) wherein R 2 is not cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated 5-6 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O, or partially unsaturated 8-10 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O. [0214] Embodiment 14(iv) relates to Embodiment 14(ii) wherein R 2 is saturated 7-9 membered heterocycloalkyl comprising at least one nitrogen. [0215] Embodiment 14(v) relates to Embodiment 14(ii) wherein R 2 is . [0216] Embodiment 15(ii) of this disclosure relates to the compound according to Embodiments 1(ii), 2(ii), 3(ii), 4(ii), 5(ii), 6(ii), 7(ii), 8(ii), 9(ii), 10(ii), 11(ii), 12(ii), 13(ii), or 14(ii), wherein R 3 is and R 5a is hydrogen, halo, or ethynyl. Embodiment 15(ii)(a) relates to Embodiment 15(ii) wherein G is H. Embodiment 15(ii)(b) relates to Embodiment 15(ii) wherein G is not H. Embodiment 15(ii)(c) relates to Embodiment 15(ii) wherein G is not hydrogen, alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-Alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. Embodiment 15(ii)(d) relates to Embodiment 15(ii) wherein G has one of the following Formulae:
Embodiment 15(ii)(e) relates to Embodiment 15(ii) wherein G is cyanoalkylcarbonyl (-C(O)- alkyl-CN), -alkylene-N(R 10 )-C(O)O(R 10 ) substituted with 0-1 R 8 , -alkylene-NH 2 with 0-1 R 8 , -alkylene-N(R 10 )C(O)-alkyl substituted with 1 R 8 , -C(O)-C 2 -C 4 alkenylene, -C 2 -C 4 alkenylene-C(O)N(R 10 ) 2 , -alkylene-N(R 10 )-SO 2 (R 10 ), -alkylene-N(R 10 )-C(O)-N(R 10 ) 2 , -alkylene-C(O)-N(R 10 ) 2 , -alkylene-C(O)OR 10 , -C(O)-NH 2 , -SO 2 N(R 10 ) 2 , -C(O)-alkylene-P(O)(R 10 ) 2 . [0217] Embodiment 15(iii) relates to Embodiment 15(ii) wherein R 2 is not cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated 5-6 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O, or partially unsaturated 8-10 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O. [0218] Embodiment 15(iv) relates to Embodiment 15(ii) wherein R 2 is saturated 7-9 membered heterocycloalkyl comprising at least one nitrogen. [0219] Embodiment 15(v) relates to Embodiment 15(ii) wherein R 2 is that is substituted with 0-3 R 4 , provided that G is not alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. [0220] Embodiment 15(vi) relates to the compound of Embodiment 15(ii) wherein R 3 is [0221] Embodiment 15(vii) relates to Embodiment 15(vi) wherein R 2 is not cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated 5-6 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O, or partially unsaturated 8-10 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O. [0222] Embodiment 15(viii) relates to Embodiment 15(vi) wherein R 2 is saturated 7-9 membered heterocycloalkyl comprising at least one nitrogen. [0223] Embodiment 15(ix) relates to Embodiment 15(vi) wherein R 2 is that is substituted with 0-3 R 4 , provided that G is not alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. [0224] Embodiment 15(x) relates to the compound of Embodiment 15(ii) wherein R 3 is [0225] Embodiment 15(xi) relates to Embodiment 15(x) wherein R 2 is not cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated 5-6 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O, or partially unsaturated 8-10 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O. [0226] Embodiment 15(xii) relates to Embodiment 15(x) wherein R 2 is saturated 7-9 membered heterocycloalkyl comprising at least one nitrogen. [0227] Embodiment 15(xiii) relates to Embodiment 15(x) wherein R 2 is that is substituted with 0-3 R 4 , provided that G is not alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. [0228] Embodiment 15(xiv) relates to the compound of Embodiment 15(ii) wherein R 3 is [0229] Embodiment 15(xv) relates to Embodiment 15(xiv) wherein R 2 is not cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated 5-6 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O, or partially unsaturated 8-10 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O. [0230] Embodiment 15(xvi) relates to Embodiment 15(xiv) wherein R 2 is saturated 7-9 membered heterocycloalkyl comprising at least one nitrogen. [0231] Embodiment 15(xvii) relates to Embodiment 15(xiv) wherein R 2 is that is substituted with 0-3 R 4 , provided that G is not alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. [0232] Embodiment 15(xviii) relates to the compound of Embodiment 15(ii) wherein R 3 is [0233] Embodiment 15(xix) relates to Embodiment 15(xviii) wherein R 2 is not cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated 5-6 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O, or partially unsaturated 8-10 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O. [0234] Embodiment 15(xx) relates to Embodiment 15(xviii) wherein R 2 is saturated 7-9 membered heterocycloalkyl comprising at least one nitrogen. [0235] Embodiment 15(xxi) relates to Embodiment 15(xvii) wherein R 2 is that is substituted with 0-3 R 4 , provided that G is not alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. [0236] Embodiment 16(ii) of this disclosure relates to the compound according to any of Embodiments 1(ii), 2(ii), 3(ii), 4(ii), 5(ii), 6(ii), 7(ii), 8(ii), 9(ii), 10(ii), 11(ii), 12(ii), 13(ii), or 14(ii), wherein R 3 is: and R 5a is hydrogen, halo, or ethynyl. Embodiment 16(ii)(a) relates to Embodiment 16(ii) wherein G is H. Embodiment 16(ii)(b) relates to Embodiment 16(ii) wherein G is not H Embodiment 16(ii)(c) relates to Embodiment 16(ii) wherein G is not hydrogen, alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-Alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. Embodiment 16(ii)(d) relates to Embodiment 16(ii) wherein G has one of the following Formulae:
Embodiment 16(ii)(e) relates to Embodiment 16(ii) wherein G is cyanoalkylcarbonyl (-C(O)- alkyl-CN), -alkylene-N(R 10 )-C(O)O(R 10 ) substituted with 0-1 R 8 , -alkylene-NH 2 with 0-1 R 8 , -alkylene-N(R 10 )C(O)-alkyl substituted with 1 R 8 , -C(O)-C 2 -C 4 alkenylene, -C 2 -C 4 alkenylene-C(O)N(R 10 ) 2 , -alkylene-N(R 10 )-SO 2 (R 10 ), -alkylene-N(R 10 )-C(O)-N(R 10 ) 2 , -alkylene-C(O)-N(R 10 ) 2 , -alkylene-C(O)OR 10 , -C(O)-NH 2 , -SO 2 N(R 10 ) 2 , -C(O)-alkylene-P(O)(R 10 ) 2 . [0237] Embodiment 16(iii) relates to Embodiment 16(ii) wherein R 2 is not cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated 5-6 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O, or partially unsaturated 8-10 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O. [0238] Embodiment 16(iv) relates to Embodiment 16(ii) wherein R 2 is saturated 7-9 membered heterocycloalkyl comprising at least one nitrogen. [0239] Embodiment 16(v) relates to Embodiment 16(ii) wherein R 2 is that is substituted with 0-3 R 4 , provided that G is not alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. [0240] Embodiment 16(vi) relates to the compound of Embodiment 16(ii) wherein R 3 is [0241] Embodiment 16(vii) relates to Embodiment 16(vi) wherein R 2 is not cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated 5-6 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O, or partially unsaturated 8-10 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O. [0242] Embodiment 16(viii) relates to Embodiment 16(vi) wherein R 2 is saturated 7-9 membered heterocycloalkyl comprising at least one nitrogen. [0243] Embodiment 16(ix) relates to Embodiment 16(vi) wherein that is substituted with 0-3 R 4 , provided that G is not alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. [0244] Embodiment 16(x) relates to the compound of Embodiment 16(ii) wherein R 3 is [0245] Embodiment 16(xi) relates to Embodiment 16(x) wherein R 2 is not cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated 5-6 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O, or partially unsaturated 8-10 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O. [0246] Embodiment 16(xii) relates to Embodiment 16(x) wherein R 2 is saturated 7-9 membered heterocycloalkyl comprising at least one nitrogen. [0247] Embodiment 16(xiii) relates to Embodiment 16(x) wherein R 2 is that is substituted with 0-3 R 4 , provided that G is not alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. [0248] Embodiment 16(xiv) relates to the compound of Embodiment 16(ii) wherein R 3 is [0249] Embodiment 16(xv) relates to Embodiment 16(xiv) wherein R 2 is not cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated 5-6 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O, or partially unsaturated 8-10 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O. [0250] Embodiment 16(xvi) relates to Embodiment 16(xiv) wherein R 2 is saturated 7-9 membered heterocycloalkyl comprising at least one nitrogen. [0251] Embodiment 16(xvii) relates to Embodiment 16(xiv) wherein R 2 is that is substituted with 0-3 R 4 , provided that G is not alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. [0252] Embodiment 16(xviii) relates to the compound of Embodiment 16(ii) wherein R 3 is [0253] Embodiment 16(xix) relates to Embodiment 16(xviii) wherein R 2 is not cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated 5-6 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O, or partially unsaturated 8-10 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O. [0254] Embodiment 16(xx) relates to Embodiment 16(xviii) wherein R 2 is saturated 7-9 membered heterocycloalkyl comprising at least one nitrogen. [0255] Embodiment 16(xxi) relates to Embodiment 16(xviii) wherein R 2 is that is substituted with 0-3 R 4 , provided that G is not alkyl, hydroxyalkyl, alkenyl, benzyl, alkoxyalkyl, alkylaminoalkyl (e.g. -alkylene-N(R 10 ) 2 ), alkylcarbonyl (e.g. -C(O)-alkyl), alkylcarbonylaminoalkyl (e.g. -alkylene-N-C(O)-R 10 ), cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, heterocyclic spiro ring, aryl, or heteroaryl. [0256] Embodiment 17(ii) of this disclosure relates to the compound according to any of Embodiments 1(ii), 2(ii), 3(ii), 4(ii), 5(ii), 6(ii), 7(ii), 8(ii), 9(ii), 10(ii), 11(ii), 12(ii), 13(ii), 14(ii), 15(ii), or 16(ii), wherein: L 1 is –C(O)N(H)-, -C(O)-, -C 1 -C 3 alkylene, -SO 2 -, -SO 2 N(H)-, or -C 1 -C 3 alkylene-C(O)-; L 2 is absent or C 1 -C 3 alkylene; and T 2 is one of the following formulae:
Embodiment 17(ii)(a) relates to Embodiment 17(ii) wherein R 2 is not cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated 5-6 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O, or partially unsaturated 8-10 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O. Embodiment 17(ii)(b) relates to Embodiment 17(ii) wherein R 2 is saturated 7-9 membered heterocycloalkyl comprising at least one nitrogen. Embodiment 17(ii)(c) relates to Embodiment 17(ii) wherein R 2 is that is substituted with 0-3 R 4 . [0257] Embodiment 17(iii) of this disclosure relates to the compound according to Embodiments 17(ii) wherein: L 1 is –C(O)N(H)-, -C(O)-, or C 1 -C 3 alkylene; L 2 is absent or C 1 -C 3 alkylene; and T 2 is one of the following formulae:
Embodiment 17(iii)(a) relates to Embodiment 17(iii) wherein R 2 is not cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated 5-6 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O, or partially unsaturated 8-10 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O. Embodiment 17(iii)(b) relates to Embodiment 17(iii) wherein R 2 is saturated 7-9 membered heterocycloalkyl comprising at least one nitrogen. Embodiment 17(iii)(c) relates to Embodiment 17(iii) wherein R 2 is that is substituted with 0-3 R 4 . [0258] Embodiment 18(ii) of this disclosure relates to the compound according to any one of Embodiments 1(ii), 2(ii), 3(ii), 4(ii), 5(ii), 6(ii), 7(ii), 8(ii), 9(ii), 10(ii), 11(ii), 12(ii), 13(ii), 14(ii), 15(ii), 16(ii), or 17(ii), wherein: L 1 is –C(O)N(H)- or -C(O)-; and L 2 is absent, -CH 2 - or -CH 2 -CH 2 -. Embodiment 18(ii)(a) relates to Embodiment 18(ii) wherein R 2 is not cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated 5-6 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O, or partially unsaturated 8-10 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O. Embodiment 18(ii)(b) relates to Embodiment 18(ii) wherein R 2 is saturated 7-9 membered heterocycloalkyl comprising at least one nitrogen. Embodiment 18(ii)(c) relates to Embodiment 18(ii) wherein R 2 is that is substituted with 0-3 R 4 . [0259] Embodiment 19(ii) of this disclosure relates to the compound according to any one of Embodiments 1(ii), 2(ii), 3(ii), 4(ii), 5(ii), 6(ii), 7(ii), 8(ii), 9(ii), 10(ii), 11(ii), 12(ii), 13(ii), 14(ii), 15(ii), or 16(ii) wherein: L 1 is absent; L 2 is absent; and T 2 is H. Embodiment 19(ii)(a) relates to Embodiment 19(ii) wherein R 2 is not cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated 5-6 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O, or partially unsaturated 8-10 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O. Embodiment 19(ii)(b) relates to Embodiment 19(ii) wherein R 2 is saturated 7-9 membered heterocycloalkyl comprising at least one nitrogen. Embodiment 19(ii)(c) relates to Embodiment 19(ii) wherein R 2 is that is substituted with 0-3 R 4 . [0260] Embodiment 20(ii) of this disclosure relates to the compound according to any one of 1(ii), 2(ii), 3(ii), 4(ii), 5(ii), 6(ii), 7(ii), 8(ii), 9(ii), 10(ii), 11(ii), 12(ii), 13(ii), 14(ii), 15(ii), or 16(ii), wherein G is: -CH 2 -C(H)(OH)-CH 2 -OH, -C(O)N(H)CH 2 COOH, -S(O) 2 (CH 2 ) 2 OCH 3 , -C(O)CH 2 - SO 2 CH 3 , -C(O)CH 2 -SO 2 -NH 2 , -C(O)C(H)(CH 3 )-SO 2 -NH 2 , -C(O)(CH 2 ) 2 -SO 2 -NH 2 , -C(O)CH 2 -SO 2 -N(CH 3 ) 2 , -SO 2 N(H)(CH 2 ) 2 CH 3 , -SO 2 N(H)(CH 2 ) 2 N(CH 3 ) 2 , -SO 2 (CH 2 ) 3 N(CH 3 ) 2 , -C(O)CH 2 CH(OH)CH 2 NH 2 , -C(O)CH 2 C(OH)(CH 3 ) 3 , -C(O)CH 2 CH 2 OH, -C(O)CH(CH 3 )OH, -C(O)CH(OH)(CH 2 )OH, -C(O)CH 2 N(H)C(O)CH 3 , -C(O)NH 2 , -C(O)N(H)CH 2 C(O)OCH 2 CH 3 , -C(O)CH 2 NH 2 , - C(O)CH 2 CN, -C(O)(CH 2 ) 2 CN, -C(O)CH 2 NHCH 3 , -C(O)CH 2 CH 3 , -C(O)CH 2 N(CH 3 ) 2 , -C(O)CH 2 CH 2 CH 2 N(CH 3 ) 2 , -C(O)N(H)CH 2 C(CH 3 ) 2 OH, -C(O)N(H)CH 2 C(O)NH 2 , -C(O)CH 2 C(O)OH, -C(O)(CH 2 ) 2 C(O)OH, -C(O)CH 2 OC(O)CH 3 , -C(O)CH 2 OH, -C(O)(CH 2 ) 2 C(O)OCH 3 , or one of the following Formulae:
Embodiment 20(ii)(a) relates to Embodiment 20(ii) wherein R 2 is not cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated 5-6 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O, or partially unsaturated 8-10 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O. Embodiment 20(ii)(b) relates to Embodiment 20(ii) wherein R 2 is saturated 7-9 membered heterocycloalkyl comprising at least one nitrogen. Embodiment 20(ii)(c) relates to Embodiment 20(ii) wherein R 2 is that is substituted with 0-3 R 4 . [0261] Embodiment 21(ii) of this disclosure relates to the compound according to Embodiment 20(ii), wherein G is -CH 2 -C(H)(OH)-CH 2 -OH, - C(O)N(H)CH 2 COOH, -S(O) 2 (CH 2 ) 2 OCH 3 , -C(O)CH 2 -SO 2 CH 3 , -C(O)CH 2 -SO 2 -NH 2 , -C(O)C(H)(CH 3 )- SO 2 -NH 2 , -C(O)(CH 2 ) 2 -SO 2 -NH 2 , -C(O)CH 2 -SO 2 - N(CH 3 ) 2 , -SO 2 N(H)(CH 2 ) 2 CH 3 , -SO 2 N(H)(CH 2 ) 2 N(CH 3 ) 2 , -SO 2 (CH 2 ) 3 N(CH 3 ) 2 , - C(O)CH 2 CH(OH)CH 2 NH 2 , -C(O)CH 2 C(OH)(CH 3 ) 3 , -C(O)CH 2 CH 2 OH, -C(O)CH(CH 3 )OH, - C(O)CH(OH)(CH 2 )OH, -C(O)CH 2 N(H)C(O)CH 3 , -C(O)NH 2 , -C(O)N(H)CH 2 C(O)OCH 2 CH 3 , - C(O)CH 2 NH 2 , -C(O)CH 2 CN, -C(O)(CH 2 ) 2 CN, -C(O)CH 2 NHCH 3 , -C(O)CH 2 CH 3 , -C(O)CH 2 N(CH 3 ) 2 , - C(O)CH 2 CH 2 CH 2 N(CH 3 ) 2 , -C(O)N(H)CH 2 C(CH 3 ) 2 OH, -C(O)N(H)CH 2 C(O)NH 2 , -C(O)CH 2 C(O)OH, - C(O)(CH 2 ) 2 C(O)OH, -C(O)CH 2 OC(O)CH 3 , -C(O)CH 2 OH, or -C(O)(CH 2 ) 2 C(O)OCH 3 . Embodiment 21(ii)(a) relates to Embodiment 21(ii) wherein R 2 is not cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated 5-6 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O, or partially unsaturated 8-10 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O. Embodiment 21(ii)(b) relates to Embodiment 21(ii) wherein R 2 is saturated 7-9 membered heterocycloalkyl comprising at least one nitrogen. Embodiment 21(ii)(c) relates to Embodiment 21(ii) wherein R 2 is that is substituted with 0-3 R 4 . [0262] Embodiment 22(ii) of this disclosure relates to the compound according to Embodiment 20(ii), wherein G is one of formulae (a), (b), (c), (d), (e), (h), (i), (j), (k), (l), (m), (p), (q), (r), (s), (t), (u), (v), (w), (z), (ad), (ae), (af), (ag), (ah), (aj), (ak), (al), (am), (at), (av), (aw), (ax), or (bg). Embodiment 22(ii)(a) relates to Embodiment 22(ii) wherein R 2 is not cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated 5-6 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O, or partially unsaturated 8-10 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O. Embodiment 22(ii)(b) relates to Embodiment 22(ii) wherein R 2 is saturated 7-9 membered heterocycloalkyl comprising at least one nitrogen. Embodiment 22(ii)(c) relates to Embodiment 22(ii) wherein R 2 is that is substituted with 0-3 R 4 . . [0263] Embodiment 23(ii) of this disclosure relates to the compound according to Embodiment 20(ii), wherein G is one of formulae (d), (f), (n), (o), (x), (ai), (an), (ao), (ap), (aq), (ar), (as), (au), (ay), (az), (ba), (bb), (bc), (bd), (be), (bf), (bi), or (bj). Embodiment 23(ii)(a) relates to Embodiment 23(ii) wherein R 2 is not cyanoalkyl, alkylcarbonylaminoalkyl, alkylaminocarbonyl, alkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated 5-6 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O, or partially unsaturated 8-10 membered heterocycloalkyl with at least one heteroatom selected from the group consisting of N, S and O. Embodiment 23(ii)(b) relates to Embodiment 23(ii) wherein R 2 is saturated 7-9 membered heterocycloalkyl comprising at least one nitrogen. Embodiment 23(ii)(c) relates to Embodiment 23(ii) wherein R 2 is that is substituted with 0-3 R 4 . [0264] Embodiment 24(ii) of this disclosure relates to the compound according to any one of Embodiments 21(ii), 22(ii), or 23(ii), wherein R 2 is and R 4 is H, Cl, or F. [0265] Embodiment 24(iii) relates to the compound of Embodiment 24(ii) wherein R 4 is H and R 2 has the following formula: . [0266] Embodiment 24(iv) relates to the compound of Embodiment 24(ii) wherein R 4 is F and R 2 has the following formula: . [0267] Embodiment 24(v) relates to the compound of Embodiment 24(ii) wherein R 4 is Cl and R 2 has the following formula: . [0268] Embodiment 25(ii) of this disclosure relates to the compound according to Embodiment 1(ii) selected from Table IA, or a pharmaceutically acceptable salt thereof. Embodiment 25(ii)(a) relates to the compound of Embodiment 25(ii) wherein G is H. Embodiment 25(ii)(b) relates to the compound of Embodiment 25(ii) wherein G is not H. [0269] Embodiment 25(iii) of this disclosure relates to the compound according to Embodiment 1(ii) selected from Table IB, or a pharmaceutically acceptable salt thereof. Embodiment 25(iii)(a) relates to the compound of Embodiment 25(iii) wherein G is H. Embodiment 25(iii)(b) relates to the compound of Embodiment 25(iii) wherein G is not H. Embodiment 25(iv) relates to Embodiment 25(ii) wherein R 2 is that is substituted with 0-3 R 4 .. [0270] Additionally, the formulae described in this disclosure are intended to include hydrated or solvated as well as unhydrated or unsolvated forms of the identified structures. For example, the indicated compounds include both hydrated and non-hydrated forms. Other examples of solvates include the structures in combination with a suitable solvent, such as isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, or ethanolamine. [0271] Additionally, the formulae described in this disclosure are intended to include hydrated or solvated as well as unhydrated or unsolvated forms of the identified structures. For example, the indicated compounds include both hydrated and non-hydrated forms. Other examples of solvates include the structures in combination with a suitable solvent, such as isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, or ethanolamine. III. Formulations and Administration [0272] Embodiment 26 of this disclosure relates to a pharmaceutical composition comprising a compound in any one of Embodiments 1-25, including any subembodiments thereof (such as those indicated with designations “(a)”, “(b)”, “(ii)”, “(iii)”, “(iv)”, “(v)”, or “(vi)”, “(vii)”, “(viii)”, “(ix)”, “(x)”, etc.), and a pharmaceutically acceptable carrier. [0273] Embodiment 27 of this disclosure relates to a pharmaceutical composition of Embodiment 26, further comprising a second pharmaceutical agent. [0274] Suitable dosage forms, in part, depend upon the use or the route of administration, for example, oral, transdermal, transmucosal, inhalant, or by injection (parenteral). Such dosage forms should allow the compound to reach target cells. Other factors are well known in the art, and include considerations such as toxicity and dosage forms that retard the compound or composition from exerting its effects. Techniques and formulations generally may be found in The Science and Practice of Pharmacy, 21 st edition, Lippincott, Williams and Wilkins, Philadelphia, PA, 2005 (hereby incorporated by reference herein). [0275] Compounds of the present disclosure (i.e. any of the compounds described in Embodiments 1-25, including any of the subembodiments thereof) can be formulated as pharmaceutically acceptable salts. [0276] Carriers or excipients can be used to produce compositions. The carriers or excipients can be chosen to facilitate administration of the compound. Examples of carriers include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose, or sucrose, or types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols and physiologically compatible solvents. Examples of physiologically compatible solvents include sterile solutions of water for injection (WFI), saline solution, and dextrose. [0277] The compounds can be administered by different routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, transmucosal, rectal, transdermal, or inhalant. In some embodiments, the compounds can be administered by oral administration. For oral administration, for example, the compounds can be formulated into conventional oral dosage forms such as capsules, tablets, and liquid preparations such as syrups, elixirs, and concentrated drops. [0278] For inhalants, compounds of the disclosure may be formulated as dry powder or a suitable solution, suspension, or aerosol. Powders and solutions may be formulated with suitable additives known in the art. For example, powders may include a suitable powder base such as lactose or starch, and solutions may comprise propylene glycol, sterile water, ethanol, sodium chloride and other additives, such as acid, alkali and buffer salts. Such solutions or suspensions may be administered by inhaling via spray, pump, atomizer, or nebulizer, and the like. The compounds of the disclosure may also be used in combination with other inhaled therapies, for example corticosteroids such as fluticasone propionate, beclomethasone dipropionate, triamcinolone acetonide, budesonide, and mometasone furoate; beta agonists such as albuterol, salmeterol, and formoterol; anticholinergic agents such as ipratropium bromide or tiotropium; vasodilators such as treprostinal and iloprost; enzymes such as DNAase; therapeutic proteins; immunoglobulin antibodies; an oligonucleotide, such as single or double stranded DNA or RNA, siRNA; antibiotics such as tobramycin; muscarinic receptor antagonists; leukotriene antagonists; cytokine antagonists; protease inhibitors; cromolyn sodium; nedocril sodium; and sodium cromoglycate. [0279] Pharmaceutical preparations for oral use can be obtained, for example, by combining the active compounds with solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose (CMC), and/or polyvinylpyrrolidone (PVP: povidone). If desired, disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid, or a salt thereof such as sodium alginate. [0280] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain, for example, gum arabic, talc, poly- vinylpyrrolidone, carbopol gel, polyethylene glycol (PEG), and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dye-stuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. [0281] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin (“gelcaps”), as well as soft, sealed capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols (PEGs). In addition, stabilizers may be added. [0282] Alternatively, injection (parenteral administration) may be used, e.g., intramuscular, intravenous, intraperitoneal, and/or subcutaneous. For injection, the compounds of the disclosure are formulated in sterile liquid solutions, such as in physiologically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution. In addition, the compounds may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms can also be produced. [0283] Administration can also be by transmucosal, topical, transdermal, or inhalant means. For transmucosal, topical or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives. In addition, detergents may be used to facilitate permeation. Transmucosal administration, for example, may be through nasal sprays or suppositories (rectal or vaginal). [0284] The topical compositions of this disclosure are formulated as oils, creams, lotions, ointments, and the like by choice of appropriate carriers known in the art. Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohol (greater than C 12 ). In another embodiment, the carriers are those in which the active ingredient is soluble. Emulsifiers, stabilizers, humectants and antioxidants may also be included as well as agents imparting color or fragrance, if desired. Creams for topical application are formulated from a mixture of mineral oil, self-emulsifying beeswax and water in which mixture the active ingredient, dissolved in a small amount solvent (e.g. an oil), is admixed. Additionally, administration by transdermal means may comprise a transdermal patch or dressing such as a bandage impregnated with an active ingredient and optionally one or more carriers or diluents known in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. [0285] The amounts of various compounds to be administered can be determined by standard procedures taking into account factors such as the compound IC 5 0, the biological half-life of the compound, the age, size, and weight of the subject, and the indication being treated. The importance of these and other factors are well known to those of ordinary skill in the art. Generally, a dose will be between about 0.01 and 50 mg/kg, or 0.1 and 20 mg/kg of the subject being treated. Multiple doses may be used. [0286] The compounds of the disclosure may also be used in combination with other therapies for treating the same disease. Such combination use includes administration of the compounds and one or more other therapeutics at different times, or co-administration of the compound and one or more other therapies. In some embodiments, dosage may be modified for one or more of the compounds of the disclosure or other therapeutics used in combination, e.g., reduction in the amount dosed relative to a compound or therapy used alone, by methods well known to those of ordinary skill in the art. [0287] It is understood that use in combination includes use with other therapies, drugs, medical procedures etc., where the other therapy or procedure may be administered at different times (e.g. within a short time, such as within hours (e.g.1, 2, 3, 4-24 hours), or within a longer time (e.g.1-2 days, 2-4 days, 4-7 days, 1-4 weeks)) than a compound of the present disclosure, or at the same time as a compound of the disclosure. Use in combination also includes use with a therapy or medical procedure that is administered once or infrequently, such as surgery, along with a compound of the disclosure administered within a short time or longer time before or after the other therapy or procedure. In some embodiments, the present disclosure provides for delivery of compounds of the disclosure and one or more other drug therapeutics delivered by a different route of administration or by the same route of administration. The use in combination for any route of administration includes delivery of compounds of the disclosure and one or more other drug therapeutics delivered by the same route of administration together in any formulation, including formulations where the two compounds are chemically linked in such a way that they maintain their therapeutic activity when administered. In one aspect, the other drug therapy may be co-administered with one or more compounds of the disclosure. Use in combination by co-administration includes administration of co-formulations or formulations of chemically joined compounds, or administration of two or more compounds in separate formulations within a short time of each other (e.g. within an hour, 2 hours, 3 hours, up to 24 hours), administered by the same or different routes. Co-administration of separate formulations includes co-administration by delivery via one device, for example the same inhalant device, the same syringe, etc., or administration from separate devices within a short time of each other. Co-formulations of compounds of the disclosure and one or more additional drug therapies delivered by the same route includes preparation of the materials together such that they can be administered by one device, including the separate compounds combined in one formulation, or compounds that are modified such that they are chemically joined, yet still maintain their biological activity. Such chemically joined compounds may have a linkage that is substantially maintained in vivo, or the linkage may break down in vivo, separating the two active components. IV. Methods of Use [0288] The methods and compounds will typically be used in therapy for human subjects. However, they may also be used to treat similar or identical indications in other animal subjects. [0289] In certain embodiments, the patient is 60 years or older and relapsed after a first line cancer therapy. In certain embodiments, the patient is 18 years or older and is relapsed or refractory after a second line cancer therapy. In certain embodiments, the patient is 60 years or older and is primary refractory to a first line cancer therapy. In certain embodiments, the patient is 70 years or older and is previously untreated. In certain embodiments, the patient is 70 years or older and is ineligible and/or unlikely to benefit from cancer therapy. [0290] In certain embodiments, the therapeutically effective amount used in the methods provided herein is at least 10 mg per day. In certain embodiments, the therapeutically effective amount is 10, 50, 90, 100, 135, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200, 2500 mg per day. In other embodiments, the therapeutically effective amount is 10, 50, 90, 100, 135, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200, 2500, 3000, 3500, 4000, 4500, 5000 mg per day or more. In certain embodiments, the compound is administered continuously. [0291] In certain embodiments, provided herein is a method for treating a diseases or condition mediated by KRAS by administering to a mammal having a disease or condition at least 10, 50, 90, 100, 135, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200, 2500, 3000, 3500, 4000, 4500, 5000 mg per day of any of the compounds described in a compound in one of Embodiments 1-36, or a pharmaceutically acceptable salt, deuterated analog, a tautomer or a stereoisomer thereof, and wherein the compound is administered on an empty stomach. [0292] Embodiment 28 or this disclosure relates to a method for treating a subject with a disease or condition mediated by KRAS, said method comprising administering to the subject an effective amount of a compound in one of Embodiments 1-25 (including any subembodiments thereof), or a pharmaceutically acceptable salt, a solvate, a tautomer, a stereoisomer, or a deuterated analog thereof, or a pharmaceutical composition in one of Embodiments 26-27. [0293] Embodiment 29 or this disclosure relates the method for treatment of a disease or condition according to Embodiment 28, wherein the disease or condition is a neoplastic disorder, a cancer, an age-related disease, an inflammatory disorder, a cognitive disorder or a neurodegenerative disease. [0294] Embodiment 30 or this disclosure relates the method of Embodiment 29, wherein the disease or condition is pancreatic cancer (e.g., pancreatic carcinoma, pancreatic ductal adenocarcinoma, pancreatic adenocarcinoma, pancreatic adenosquamous carcinoma, pancreatic neuroendocrine neoplasm), colorectal cancer, (e.g., colorectal carcinoma, colorectal adenocarcinoma, colorectal mucinous adenocarcinoma, colorectal neuroendocrine carcinoma, malignant colorectal neoplasm) malignant solid tumor, rectal carcinoma (e.g., rectal adenocarcinoma), endometrial endometriod carcinoma, appendix carcinoma, mucinous adenocarcinoma, cholangiocarcinoma, extrahepatic cholangiocarcinoma, bladder cancer, bladder urothelial carcinoma, lung cancer (e.g., lung adenocarcinoma, non-small cell lung cancer, small cell lung carcinoma, squamous cell lung carcinoma), ampulla of vater carcinoma, ovarian cancer (e.g., ovarian mucinous adenocarcinoma, ovarian serous adenocarcinoma, low grade ovarian serous adenocarcinoma), gastric adenocarcinoma, malignant small intestinal neoplasm, poorly differentiated adenocarcinoma, acute myeloid leukemia, breast cancer, breast invasive ductal carcinoma, ampulla vater pancreatobiliary type adenocarcinoma, glioma, multiple myeloma, myelodysplastic syndrome, or small intestine carcinoma. [0295] Embodiment 30(a) or this disclosure relates the method of Embodiment 30, wherein the disease or condition is pancreatic cancer, colorectal cancer, malignant solid tumor, rectal carcinoma, lung cancer, acute myeloid leukemia, glioma, multiple myeloma, or myelodysplastic syndrome. [0296] Embodiment 30(b) or this disclosure relates the method of Embodiment 30(a), wherein the disease or condition is pancreatic carcinoma, pancreatic ductal adenocarcinoma, pancreatic adenocarcinoma, colorectal carcinoma, colorectal adenocarcinoma, malignant colorectal neoplasm, malignant solid tumor, rectal adenocarcinoma, lung adenocarcinoma, non-small cell lung cancer, small cell lung carcinoma, squamous cell lung carcinoma, acute myeloid leukemia, glioma, multiple myeloma, or myelodysplastic syndrome. [0297] Embodiment 30(c) or this disclosure relates the method of Embodiment 29, wherein the disease or condition is mediated by KRAS G12D. [0298] Embodiment 30(d) or this disclosure relates the method of Embodiment 30(c), wherein the disease or condition is pancreatic ductal adenocarcinoma colorectal carcinoma, pancreatic carcinoma, pancreatic adenocarcinoma, malignant colorectal neoplasm patients, malignant colorectal neoplasm, rectal carcinoma, lung adenocarcinoma, non-small cell lung carcinoma, colorectal carcinoma, malignant solid tumor, acute myeloid leukemia, squamous cell lung carcinoma, small cell lung carcinoma, glioma, myelodysplastic syndrome, breast cancer, gastric carcinoma, ovarian carcinoma, multiple myeloma patients, hepatocellular carcinoma, head and neck squamous cell carcinoma, glioblastoma or thyroid gland undifferentiated carcinoma. Embodiment 30(e) or this disclosure relates the method of Embodiment 29, wherein the disease or condition is mediated by KRAS G12V. Embodiment 30(f) or this disclosure relates the method of Embodiment 30(e), wherein the disease or condition is pancreatic ductal adenocarcinoma, pancreatic ductal adenocarcinoma, colorectal adenocarcinoma patients, colorectal carcinoma, rectal adenocarcinoma, pancreatic carcinoma, pancreatic adenocarcinoma, malignant colorectal neoplasm, lung adenocarcinoma, non-small cell lung carcinoma, colorectal carcinoma, malignant solid tumor, acute myeloid leukemia, squamous cell lung carcinoma, small cell lung carcinoma, glioma, myelodysplastic syndrome or multiple myeloma. V. Combination Therapy [0299] KRAS modulators may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of cancer. In one embodiment, the composition includes any one or more compound(s) as described herein along with one or more compounds that are therapeutically effective for the same disease indication, wherein the compounds have a synergistic effect on the disease indication. In one embodiment, the composition includes any one or more compound(s) as described herein effective in treating a cancer and one or more other compounds that are effective in treating the same cancer, further wherein the compounds are synergistically effective in treating the cancer. [0300] Embodiment 31 or this disclosure relates the method according to any one of Embodiments 28-30, further comprising administering one or more additional therapeutic agents. [0301] Embodiment 32 or this disclosure relates the method according to Embodiment 31, wherein the one or more additional therapeutic agents is one or more of i) an alkylating agent selected from adozelesin, altretamine, bizelesin, busulfan, carboplatin, carboquone, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven, lomustine, mechlorethamine, melphalan, oxaliplatin, piposulfan, semustine, streptozocin, temozolomide, thiotepa, and treosulfan; ii) an antibiotic selected from bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, mitoxantrone, neocarzinostatin, pentostatin, and plicamycin; iii) an antimetabolite selected from the group consisting of azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5- fluorouracil, ftorafur, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed, thioguanine, and trimetrexate; iv) an immunotherapy agent selected from a PD-1 or PD-L1 inhibitor; v) a hormone or hormone antagonist selected from the group consisting of enzalutamide, abiraterone, anastrozole, androgens, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprolide, magestrol, raloxifene, tamoxifen, and toremifene; vi) a taxane selected from DJ-927, docetaxel, TPI 287, paclitaxel and DHA-paclitaxel; vii) a retinoid selected from alitretinoin, bexarotene, fenretinide, isotretinoin, and tretinoin; viii) an alkaloid selected from etoposide, homoharringtonine, teniposide, vinblastine, vincristine, vindesine, and vinorelbine; ix) an antiangiogenic agent selected from AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide, and thalidomide; x) a topoisomerase inhibitor selected from amsacrine, edotecarin, exatecan, irinotecan, SN- 38 (7-ethyl-10-hydroxy-camptothecin), rubitecan, topotecan, and 9-aminocamptothecin; xi) a kinase inhibitor selected from erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib, sorafenib, sunitinib malate, AEE-788, AG-013736, AMG 706, AMN107, BMS-354825, BMS-599626, UCN-01 (7- hydroxystaurosporine), vemurafenib, dabrafenib, trametinib, cobimetinib selumetinib and vatalanib; xii) a targeted signal transduction inhibitor selected from bortezomib, geldanamycin, and rapamycin; xiii) a biological response modifier selected from imiquimod, interferon-α and interleukin-2; xiv) an IDO inhibitor; and xv) a chemotherapeutic agent selected from 3-AP (3-amino-2-carboxyaldehyde thiosemicarbazone), altrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, elesclomol, eribulin mesylate (E7389), ixabepilone, lonidamine, masoprocol, mitoguanazone, oblimersen, sulindac, testolactone, tiazofurin, a mTOR inhibitor, a PI3K inhibitor, a Cdk4 inhibitor, an Akt inhibitor, a Hsp90 inhibitor, a farnesyltransferase inhibitor or an aromatase inhibitor (anastrozole letrozole exemestane); xvi) a Mek inhibitor; xvii) a tyrosine kinase inhibitor; xviii) a c-Kit mutant inhibitor, xix) an EGFR inhibitor, a PD-1 inhibitor, or xx) an epigenetic modulator. [0302] In another embodiment, the present disclosure provides a method of treating a cancer in a subject in need thereof by administering to the subject an effective amount of a composition including any one or more compound(s) as described herein in combination with one or more other therapies or medical procedures effective in treating the cancer. Other therapies or medical procedures include suitable anticancer therapy (e.g. drug therapy, vaccine therapy, gene therapy, photodynamic therapy) or medical procedure (e.g. surgery, radiation treatment, hyperthermia heating, bone marrow or stem cell transplant). In one embodiment, the one or more suitable anticancer therapies or medical procedures is selected from treatment with a chemotherapeutic agent (e.g. chemotherapeutic drug), radiation treatment (e.g. x-ray, .gamma.-ray, or electron, proton, neutron, or .alpha. particle beam), hyperthermia heating (e.g. microwave, ultrasound, radiofrequency ablation), Vaccine therapy (e.g. AFP gene hepatocellular carcinoma vaccine, AFP adenoviral vector vaccine, AG-858, allogeneic GM-CSF-secretion breast cancer vaccine, dendritic cell peptide vaccines), gene therapy (e.g. Ad5CMV-p53 vector, adenovector encoding MDA7, adenovirus 5-tumor necrosis factor alpha), photodynamic therapy (e.g. aminolevulinic acid, motexatin lutetium), surgery, or bone marrow and stem cell transplantation. [0303] Embodiment 32(a) of this disclosure relates to the method according to Embodiment 32, wherein the one or more additional therapeutic agents is a PD-1 inhibitor selected from pembrolizumab, nivolumab and emiplimab. [0304] Embodiment 32(a)(1) of this disclosure relates to the method according to Embodiment 32(a), wherein the PD-1 inhibitor is pembrolizumab. [0305] Embodiment 32(a)(2) of this disclosure relates to the method according to Embodiment 32(a), wherein the PD-1 inhibitor is nivolumab. [0306] Embodiment 32(a)(3) of this disclosure relates to the method according to Embodiment 32(a), wherein the PD-1 inhibitor is emiplimab. [0307] Embodiment 32(b) of this disclosure relates to the method according to Embodiment 32, wherein the one or more additional therapeutic agents is a PD-L1 inhibitor selected from atezolizumab, avelumab and durvalumab. [0308] Embodiment 32(b)(1) of this disclosure relates to the method according to Embodiment 32(b), wherein the PD-L1 inhibitor is atezolizumab. [0309] Embodiment 32(b)(2) of this disclosure relates to the method according to Embodiment 32(b), wherein the PD-L1 inhibitor is avelumab. [0310] Embodiment 32(b)(3) of this disclosure relates to the method according to Embodiment 32(b), wherein the PD-L1 inhibitor is durvalumab. [0311] Embodiment 32(c) of this disclosure relates the method according to Embodiment 31, wherein the additional therapeutic agents is a CTLA-4 inhibitor. [0312] Embodiment 32(c)(1) of this disclosure relates the method according to Embodiment 32(c), wherein the CTLA-4 inhibitor is ipilimumab. VI. Kits [0313] In another aspect, the present disclosure provides kits that include one or more compounds as described in any one of a compound in one of Embodiments 1-25 (including any subembodiments thereof), or a pharmaceutically acceptable salt, a solvate, a tautomer, a stereoisomer, or a deuterated analog thereof, or a pharmaceutical composition in one of Embodiments 26-27. In some embodiments, the compound or composition is packaged, e.g., in a vial, bottle, flask, which may be further packaged, e.g., within a box, envelope, or bag. The compound or composition may be approved by the U.S. Food and Drug Administration or similar regulatory agency for administration to a mammal, e.g., a human. The compound or composition may be approved for administration to a mammal, e.g., a human, for a KRAS mediated disease or condition. The kits described herein may include written instructions for use and/or other indication that the compound or composition is suitable or approved for administration to a mammal, e.g., a human, for a KRAS mediated disease or condition. The compound or composition may be packaged in unit dose or single dose form, e.g., single dose pills, capsules, or the like. VII. Binding Assays [0314] The methods of the present disclosure can involve assays that are able to detect the binding of compounds to a target molecule. Such binding is at a statistically significant level, with a confidence level of at least 90%, or at least 95, 97, 98, 99% or greater confidence level that the assay signal represents binding to the target molecule, i.e., is distinguished from background. In some embodiments, controls are used to distinguish target binding from non-specific binding. A large variety of assays indicative of binding are known for different target types and can be used for this disclosure. [0315] Binding compounds can be characterized by their effect on the activity of the target molecule. Thus, a “low activity” compound has an inhibitory concentration (IC 5 0) or effective concentration (EC 5 0) of greater than 1 μM under standard conditions. By “very low activity” is meant an IC 5 0 or EC 5 0 of above 100 μM under standard conditions. By “extremely low activity” is meant an IC 5 0 or EC 5 0 of above 1 mM under standard conditions. By “moderate activity” is meant an IC 5 0 or EC 5 0 of 200 nM to 1 μM under standard conditions. By “moderately high activity” is meant an IC 5 0 or EC 5 0 of 1 nM to 200 nM. By “high activity” is meant an IC 5 0 or EC 5 0 of below 1 nM under standard conditions. The IC 5 0 or EC 5 0 is defined as the concentration of compound at which 50% of the activity of the target molecule (e.g. enzyme or other protein) activity being measured is lost or gained relative to the range of activity observed when no compound is present. Activity can be measured using methods known to those of ordinary skill in the art, e.g., by measuring any detectable product or signal produced by occurrence of an enzymatic reaction, or other activity by a protein being measured. [0316] By “background signal” in reference to a binding assay is meant the signal that is recorded under standard conditions for the particular assay in the absence of a test compound, molecular scaffold, or ligand that binds to the target molecule. Persons of ordinary skill in the art will realize that accepted methods exist and are widely available for determining background signal. [0317] By “standard deviation” is meant the square root of the variance. The variance is a measure of how spread out a distribution is. It is computed as the average squared deviation of each number from its mean. For example, for the numbers 1, 2, and 3, the mean is 2 and the variance is: σ 2 = (1-2) 2 + (2-2) 2 + (3-2) 2 = 0.667. 3 Surface Plasmon Resonance [0318] Binding parameters can be measured using surface plasmon resonance, for example, with a BIAcore ® chip (Biacore, Japan) coated with immobilized binding components. Surface plasmon resonance is used to characterize the microscopic association and dissociation constants of reaction between an sFv or other ligand directed against target molecules. Such methods are generally described in the following references which are incorporated herein by reference. Vely F. et al., (2000) BIAcore ® analysis to test phosphopeptide-SH2 domain interactions, Methods in Molecular Biology.121:313-21; Liparoto et al., (1999) Biosensor analysis of the interleukin-2 receptor complex, Journal of Molecular Recognition.12:316-21; Lipschultz et al., (2000) Experimental design for analysis of complex kinetics using surface plasmon resonance, Methods.20(3):310-8; Malmqvist., (1999) BIACORE: an affinity biosensor system for characterization of biomolecular interactions, Biochemical Society Transactions 27:335-40; Alfthan, (1998) Surface plasmon resonance biosensors as a tool in antibody engineering, Biosensors & Bioelectronics.13:653-63; Fivash et al., (1998) BIAcore for macromolecular interaction, Current Opinion in Biotechnology.9:97-101; Price et al.; (1998) Summary report on the ISOBM TD-4 Workshop: analysis of 56 monoclonal antibodies against the MUC 1 mucin. Tumour Biology 19 Suppl 1:1-20; Malmqvist et al, (1997) Biomolecular interaction analysis: affinity biosensor technologies for functional analysis of proteins, Current Opinion in Chemical Biology.1:378-83; O’Shannessy et al., (1996) Interpretation of deviations from pseudo-first-order kinetic behavior in the characterization of ligand binding by biosensor technology, Analytical Biochemistry.236:275-83; Malmborg et al., (1995) BIAcore as a tool in antibody engineering, Journal of Immunological Methods.183:7-13; Van Regenmortel, (1994) Use of biosensors to characterize recombinant proteins, Developments in Biological Standardization.83:143-51; and O’Shannessy, (1994) Determination of kinetic rate and equilibrium binding constants for macromolecular interactions: a critique of the surface plasmon resonance literature, Current Opinions in Biotechnology.5:65-71. [0319] BIAcore ® uses the optical properties of surface plasmon resonance (SPR) to detect alterations in protein concentration bound to a dextran matrix lying on the surface of a gold/glass sensor chip interface, a dextran biosensor matrix. In brief, proteins are covalently bound to the dextran matrix at a known concentration and a ligand for the protein is injected through the dextran matrix. Near infrared light, directed onto the opposite side of the sensor chip surface is reflected and also induces an evanescent wave in the gold film, which in turn, causes an intensity dip in the reflected light at a particular angle known as the resonance angle. If the refractive index of the sensor chip surface is altered (e.g. by ligand binding to the bound protein) a shift occurs in the resonance angle. This angle shift can be measured and is expressed as resonance units (RUs) such that 1000 RUs is equivalent to a change in surface protein concentration of 1 ng/mm 2 . These changes are displayed with respect to time along the y- axis of a sensorgram, which depicts the association and dissociation of any biological reaction. High Throughput Screening (HTS) Assays [0320] HTS typically uses automated assays to search through large numbers of compounds for a desired activity. Typically HTS assays are used to find new drugs by screening for chemicals that act on a particular enzyme or molecule. For example, if a chemical inactivates an enzyme it might prove to be effective in preventing a process in a cell which causes a disease. High throughput methods enable researchers to assay thousands of different chemicals against each target molecule very quickly using robotic handling systems and automated analysis of results. [0321] As used herein, “high throughput screening” or “HTS” refers to the rapid in vitro screening of large numbers of compounds (libraries); generally tens to hundreds of thousands of compounds, using robotic screening assays. Ultra-high-throughput Screening (uHTS) generally refers to the high-throughput screening accelerated to greater than 100,000 tests per day. [0322] To achieve high-throughput screening, it is advantageous to house samples on a multicontainer carrier or platform. A multicontainer carrier facilitates measuring reactions of a plurality of candidate compounds simultaneously. Multi-well microplates may be used as the carrier. Such multi- well microplates, and methods for their use in numerous assays, are both known in the art and commercially available. [0323] Screening assays may include controls for purposes of calibration and confirmation of proper manipulation of the components of the assay. Blank wells that contain all of the reactants but no member of the chemical library are usually included. As another example, a known inhibitor (or activator) of an enzyme for which modulators are sought, can be incubated with one sample of the assay, and the resulting decrease (or increase) in the enzyme activity used as a comparator or control. It will be appreciated that modulators can also be combined with the enzyme activators or inhibitors to find modulators which inhibit the enzyme activation or repression that is otherwise caused by the presence of the known the enzyme modulator. Measuring Enzymatic and Binding Reactions During Screening Assays [0324] Techniques for measuring the progression of enzymatic and binding reactions, e.g., in multicontainer carriers, are known in the art and include, but are not limited to, the following. [0325] Spectrophotometric and spectrofluorometric assays are well known in the art. Examples of such assays include the use of colorimetric assays for the detection of peroxides, as described in Gordon, A. J. and Ford, R. A., (1972) The Chemist's Companion: A Handbook Of Practical Data, Techniques, And References, John Wiley and Sons, N.Y., Page 437. [0326] Fluorescence spectrometry may be used to monitor the generation of reaction products. Fluorescence methodology is generally more sensitive than the absorption methodology. The use of fluorescent probes is well known to those skilled in the art. For reviews, see Bashford et al., (1987) Spectrophotometry and Spectrofluorometry: A Practical Approach, pp.91-114, IRL Press Ltd.; and Bell, (1981) Spectroscopy In Biochemistry, Vol. I, pp.155-194, CRC Press. [0327] In spectrofluorometric methods, enzymes are exposed to substrates that change their intrinsic fluorescence when processed by the target enzyme. Typically, the substrate is nonfluorescent and is converted to a fluorophore through one or more reactions. As a non-limiting example, SMase activity can be detected using the Amplex ® Red reagent (Molecular Probes, Eugene, OR). In order to measure sphingomyelinase activity using Amplex ® Red, the following reactions occur. First, SMase hydrolyzes sphingomyelin to yield ceramide and phosphorylcholine. Second, alkaline phosphatase hydrolyzes phosphorylcholine to yield choline. Third, choline is oxidized by choline oxidase to betaine. Finally, H 2 O 2 , in the presence of horseradish peroxidase, reacts with Amplex ® Red to produce the fluorescent product, Resorufin, and the signal therefrom is detected using spectrofluorometry. [0328] Fluorescence polarization (FP) is based on a decrease in the speed of molecular rotation of a fluorophore that occurs upon binding to a larger molecule, such as a receptor protein, allowing for polarized fluorescent emission by the bound ligand. FP is empirically determined by measuring the vertical and horizontal components of fluorophore emission following excitation with plane polarized light. Polarized emission is increased when the molecular rotation of a fluorophore is reduced. A fluorophore produces a larger polarized signal when it is bound to a larger molecule (i.e. a receptor), slowing molecular rotation of the fluorophore. The magnitude of the polarized signal relates quantitatively to the extent of fluorescent ligand binding. Accordingly, polarization of the “bound” signal depends on maintenance of high affinity binding. [0329] FP is a homogeneous technology and reactions are very rapid, taking seconds to minutes to reach equilibrium. The reagents are stable, and large batches may be prepared, resulting in high reproducibility. Because of these properties, FP has proven to be highly automatable, often performed with a single incubation with a single, premixed, tracer-receptor reagent. For a review, see Owicki et al., (1997), Application of Fluorescence Polarization Assays in High-Throughput Screening, Genetic Engineering News, 17:27. [0330] FP is particularly desirable since its readout is independent of the emission intensity (Checovich, W. J., et al., (1995) Nature 375:254-256; Dandliker, W. B., et al., (1981) Methods in Enzymology 74:3-28) and is thus insensitive to the presence of colored compounds that quench fluorescence emission. FP and FRET (see below) are well-suited for identifying compounds that block interactions between sphingolipid receptors and their ligands. See, for example, Parker et al., (2000) Development of high throughput screening assays using fluorescence polarization: nuclear receptor- ligand-binding and kinase/phosphatase assays, J Biomol Screen 5:77-88. [0331] Fluorophores derived from sphingolipids that may be used in FP assays are commercially available. For example, Molecular Probes (Eugene, OR) currently sells sphingomyelin and one ceramide fluorophores. These are, respectively, N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s- indacene- 3-pentanoyl)sphingosyl phosphocholine (BODIPY® FL C 5 -sphingomyelin); N-(4,4-difluoro- 5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene- 3-dodecanoyl)sphingosyl phosphocholine (BODIPY® FL C 1 2-sphingomyelin); and N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene- 3- pentanoyl)sphingosine (BODIPY ® FL C 5 -ceramide). U.S. Patent No.4,150,949, (Immunoassay for gentamicin), discloses fluorescein-labelled gentamicins, including fluoresceinthiocarbanyl gentamicin. Additional fluorophores may be prepared using methods well known to the skilled artisan. [0332] Exemplary normal-and-polarized fluorescence readers include the POLARION ® fluorescence polarization system (Tecan AG, Hombrechtikon, Switzerland). General multiwell plate readers for other assays are available, such as the VERSAMAX ® reader and the SPECTRAMAX ® multiwell plate spectrophotometer (both from Molecular Devices). [0333] Fluorescence resonance energy transfer (FRET) is another useful assay for detecting interaction and has been described. See, e.g., Heim et al., (1996) Curr. Biol.6:178-182; Mitra et al., (1996) Gene 173:13-17; and Selvin et al., (1995) Meth. Enzymol.246:300-345. FRET detects the transfer of energy between two fluorescent substances in close proximity, having known excitation and emission wavelengths. As an example, a protein can be expressed as a fusion protein with green fluorescent protein (GFP). When two fluorescent proteins are in proximity, such as when a protein specifically interacts with a target molecule, the resonance energy can be transferred from one excited molecule to the other. As a result, the emission spectrum of the sample shifts, which can be measured by a fluorometer, such as a fMAX multiwell fluorometer (Molecular Devices, Sunnyvale Calif.). [0334] Scintillation proximity assay (SPA) is a particularly useful assay for detecting an interaction with the target molecule. SPA is widely used in the pharmaceutical industry and has been described (Hanselman et al., (1997) J. Lipid Res.38:2365-2373; Kahl et al., (1996) Anal. Biochem. 243:282-283; Undenfriend et al., (1987) Anal. Biochem.161:494-500). See also U.S. Patent Nos. 4,626,513 and 4,568,649, and European Patent No.0,154,734. One commercially available system uses FLASHPLATE ® scintillant-coated plates (NEN Life Science Products, Boston, MA). [0335] The target molecule can be bound to the scintillator plates by a variety of well-known means. Scintillant plates are available that are derivatized to bind to fusion proteins such as GST, His6 or Flag fusion proteins. Where the target molecule is a protein complex or a multimer, one protein or subunit can be attached to the plate first, then the other components of the complex added later under binding conditions, resulting in a bound complex. [0336] In a typical SPA assay, the gene products in the expression pool will have been radiolabeled and added to the wells, and allowed to interact with the solid phase, which is the immobilized target molecule and scintillant coating in the wells. The assay can be measured immediately or allowed to reach equilibrium. Either way, when a radiolabel becomes sufficiently close to the scintillant coating, it produces a signal detectable by a device such as a TOPCOUNT NXT ® microplate scintillation counter (Packard BioScience Co., Meriden Conn.). If a radiolabeled expression product binds to the target molecule, the radiolabel remains in proximity to the scintillant long enough to produce a detectable signal. [0337] In contrast, the labeled proteins that do not bind to the target molecule, or bind only briefly, will not remain near the scintillant long enough to produce a signal above background. Any time spent near the scintillant caused by random Brownian motion will also not result in a significant amount of signal. Likewise, residual unincorporated radiolabel used during the expression step may be present, but will not generate significant signal because it will be in solution rather than interacting with the target molecule. These non-binding interactions will therefore cause a certain level of background signal that can be mathematically removed. If too many signals are obtained, salt or other modifiers can be added directly to the assay plates until the desired specificity is obtained (Nichols et al., (1998) Anal. Biochem. 257:112-119). General Synthesis [0338] The compounds may be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of typical compounds described herein may be accomplished as described in the following examples. If available, reagents may be purchased commercially, e.g., from Sigma Aldrich or other chemical suppliers. [0339] The compounds of this disclosure can be prepared from readily available starting materials using, for example, the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. [0340] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in Wuts, P. G. M., Greene, T. W., & Greene, T. W. (2006). Greene’s protective groups in organic synthesis. Hoboken, N.J., Wiley-Interscience, and references cited therein. [0341] The compounds of this disclosure may contain one or more asymmetric or chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, supercritical fluid chromathography, chiral seed crystals, chiral resolving agents, and the like. [0342] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd’s Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989) organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March’s Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). [0343] It will also be appreciated that in each of the schemes, the addition of any substituent may result in the production of a number of isomeric products (including, but not limited to, enantiomers or one or more diastereomers) any or all of which may be isolated and purified using conventional techniques. When enantiomerically pure or enriched compounds are desired, chiral chromatography and/or enantiomerically pure or enriched starting materials may be employed as conventionally used in the art or as described in the Examples. [0344] Compounds of the present disclosure may be synthesized in accordance with the general reaction schemes and/or examples described below. The general schemes may be altered by substitution of the starting materials with other materials having similar structures to result in corresponding products. The structure of the desired product will generally make apparent to a person of skill in the art the required starting materials. Intermediate 3 [0345] Step 1: ((4-bromonaphthalen-2-yl)oxy)(tert-butyl)dimethylsilane (2) [0346] To a solution of 4-bromonaphthalen-2-ol (1, 5.00 g, 22.4 mmol) in 200 mL DCM was added tert-butyl-chloro-dimethyl-silane (5.07 g, 33.6 mmol, 1.5 eq.). The reaction mixture was stirred at ambient temp until all solids dissolved, then imidazole (4.58 g, 67.2 mmol, 3.0 eq.) was added portion- wise to the reaction mixture at ambient temperature while stirring. After 30 min., the reaction mixture was filtered to remove solids, diluted with 150 mL DCM, washed with water and brine, dried over MgSO4, and concentrated onto silica and was purified by silica gel chromatography eluting with EtOAc/Hexane (product eluted ~0-5% EtOAc/Hexane). The desired fractions were combined and concentrated to give 4-bromonaphthalen-2-yl)oxy)(tert-butyl)dimethylsilane (2, 7.36 g). [0347] Step 2: tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2- yl)naphthalen-2-yl)oxy)silane (3) [0348] To a solution of ((4-bromonaphthalen-2-yl)oxy)(tert-butyl)dimethylsilane (2, 3.00 g, 8.89 mmol) in 30 mL dioxane was added of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.71 g, 10.7 mmol, 1.2 eq.), potassium acetate (1.75 g, 17.8 mmol, 2.0 eq.), and Pd2(PPh3) 2 Cl 2 (0.62 g, 0.889 mmol, 0.1 eq.). The flask was fitted with reflux condenser and stirred under N2 in a 100 ºC pre-heated oil bath. After 2 hr, the reaction mixture was cooled to ambient temp, diluted with 150 mL DCM, filtered to remove insoluble material. The filtrate was washed with water and brine, dried over MgSO4, and concentrated. The concentrate was dissolved in ~70 mL DCM and evaporated onto silica and was purified by silica gel chromatography eluting with eluting 0-15% EtOAc/hexane (product eluted ~10% EtOAc/hexane). The desired fractions were concentrated to give tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2-yl)naphthalen-2- yl)oxy)silane (3, 1.98 g). Intermediate 6 [0349] Step 1: Synthesis of ((4-bromonaphthalen-2-yl)oxy)(tert-butyl)dimethylsilane (5) [0350] 4-bromonaphthalen-2-ol (4, 5 g, 22.41 mmol) and tert-butyl-chloro-dimethyl-silane (5.07 g, 33.62 mmol) were dissolved in DCM (200 ml). After stirring for 5 minutes at room temperature, imidazole (4.58 g, 67.24 mmol) was added and the reaction was stirred for 30 minutes. The reaction became cloudy with imidazole salts which were filtered off. The reaction was evaporated on to silica gel and purified by normal phase flash column chromatography to give ((4-bromonaphthalen-2-yl)oxy)(tert- butyl)dimethylsilane (5, 7.17 g). [0351] Step 2: Synthesis of tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n- 2-yl)naphthalen-2-yl)oxy)silane (6) [0352] ((4-bromonaphthalen-2-yl)oxy)(tert-butyl)dimethylsilane (5, 7.17 g, 21.26 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (8.1 g, 31.88 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (1.56 g, 2.13 mmol), potassium acetate (3.13 g, 31.88 mmol), and dioxane (200 ml) were combined in a 500 ml pressure vial. The vial was purged with nitrogen, sealed, and stirred vigorously at 100 °C for 6 hours. The reaction was poured over brine and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated on to silica gel. The product was isolated by normal phase flash column to give tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2-yl)naphthalen-2-yl)oxy)silane (6, 7.01 [0353] Step 1: tert-butyl 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3-oxa-7,9- diazabicyclo[3.3.1]nonane-9-carboxylate (8) [0354] To a solution of 7-bromo-2,4,6-trichloro-8-fluoro-quinazoline (7, 200 mg, 0.605 mmol) in 3 mL dioxane was added tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate (166 mg, 0.726 mmol, 1.2 eq.) and DIPEA (320 uL, 1.84 mmol, 3.0 eq.). The reaction mixture was allowed to stir at ambient temp. After 2 hr., the reaction mixture was diluted with 20 mL DCM, washed with water, ammonium chloride, and brine, dried over MgSO 4 , and concentrated. The crude material was dissolved in DCM and evaporated onto silica and purified by silica gel column chromatography eluting with 0-15% EtOAc/DCM (product eluted ~5-8% EtOAc/DCM). The desired fractions were pooled and concentrated to give tert-butyl 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3-oxa-7,9- diazabicyclo[3.3.1]nonane-9-carboxylate (8, 145 mg). MS (ESI) [M+H + ] + = 522.8. [0355] Step 2: tert-butyl 7-(7-bromo-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]non ane-9-carboxylate (9) [0356] To a solution of tert-butyl 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3-oxa-7,9- diazabicyclo[3.3.1]nonane-9-carboxylate (8, 140 mg, 0.268 mmol) in 2 mL DMSO was added [(2S)-1- methylpyrrolidin-2-yl]methanol (156 mg, 1.35 mmol, 5 eq) and potassium fluoride (32 mg, 0.55 mmol, 2.0 eq). The reaction was stirred in a 120 ºC pre-heated oil bath for 3.5 hr., at which time the reaction mixture was cooled to ambient temp., diluted with 25 mL EtOAc, washed with water and brine, dried over MgSO 4 , and concentrated. The residue was dissolved in DCM and evaporated onto silica and was purified by silica gel column chromatography eluting with 0-30% MeOH/EtOAc (product elutes ~5% MeOH/EtOAc). The desired fractions were pooled and concentrated to give tert-butyl 7-(7-bromo-6- chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quin azolin-4-yl)-3-oxa-7,9- diazabicyclo[3.3.1]nonane-9-carboxylate (9, 70 mg, 40% yield). MS (ESI) [M+H + ] + = 601.8. [0357] Step 3: tert-butyl 7-(7-(3-((tert-butyldimethylsilyl)oxy)naphthalen-1-yl)-6-chl oro-8- fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4- yl)-3-oxa-7,9- diazabicyclo[3.3.1]nonane-9-carboxylate (10) [0358] To a solution of tert-butyl 7-(7-bromo-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]non ane-9-carboxylate (9, 70 mg, 0.107 mmol) in 2 mL dioxane and 0.5 mL H 2 O was added tert-butyl-dimethyl-[[4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2-naphthyl]oxy]silane (3, 66 mg, 0.172 mmol, 1.6 eq,), solid Na 2 CO 3 (36 mg, 0.34 mmol, 3.2 eq.), and Pd(PPh3)4 (15 mg, 0.013 mmol, 0.1 eq.). The reaction mixture was stirred in a 90 ºC pre-heated oil bath. After 2 hr., the reaction mixture was cooled to ambient temp, diluted with 25 mL DCM and washed with water. The DCM phase was concentrated, dissolved in 4 mL of ~25% H 2 O/MeCN, and purified by RP-HPLC, eluting with 10-100% MeCN/H 2 O (0.1% TFA). The desired fractions were pooled, frozen, and lyophilized to give tert-butyl 7-(7-(3-((tert- butyldimethylsilyl)oxy)naphthalen-1-yl)-6-chloro-8-fluoro-2- (((S)-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]non ane-9-carboxylate (10, 40 mg). MS (ESI) [M+H + ] + = 778.5. [0359] Step 4: 4-(4-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)-6-chloro-8-fl uoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)naphthalen-2-o l (P-0040). [0360] To a solution of tert-butyl 7-[7-[3-[tert-butyl(dimethyl)silyl]oxy-1-naphthyl]-6-chloro- 8- fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-4 -yl]-3-oxa-7,9-diazabicyclo[3.3.1]nonane- 9-carboxylate (10, 39 mg, 0.50 mmol) in 0.5 mL MeOH was added 3 ml of 4N HCl/dioxane. The reaction mixture stirred at ambient temp. After for 90 min, the reaction mixture was concentrated to a yellow residue, dissolved in 2 mL H 2 O and purified by RP silica gel column chromatography eluting with MeCN/H 2 O (0.1% formic acid). The desired fractions were pooled, frozen, and lyophilized to white solid: 4-(4-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)-6-chloro-8-fl uoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)quinazolin-7-yl)naphthalen-2-ol (P-0040, 18 mg) as a bis-HCl salt. MS (ESI) [M+H + ] + = 564.0. Example 2 [0361] 4-(4-(3,9-diazabicyclo[4.2.1]nonan-3-yl)-6-chloro-8-fluoro-2 -(((S)-1- methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)naphthalen-2-o l (P-0046). [0362] All synthetic steps were performed as detailed in Example 1, by substitution of tert-butyl 3,9-diazabicyclo[4.2.1]nonane-9-carboxylate in synthetic Step 1 to afford 4-(4-(3,9- diazabicyclo[4.2.1]nonan-3-yl)-6-chloro-8-fluoro-2-(((S)-1-m ethylpyrrolidin-2-yl)methoxy)quinazolin-7- yl)naphthalen-2-ol (P-0046). MS (ESI) [M+H + ] + = 563.0. Example 3 [0363] 4-(4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-6-chloro-8-fluoro-2 -(((S)-1- methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)naphthalen-2-o l (P-0030). [0364] All synthetic steps were performed as detailed in Example 1, by substitution of tert-butyl 2,5-diazabicyclo[2.2.2]octane-2-carboxylate in synthetic Step 1 to afford 4-(4-(2,5- diazabicyclo[2.2.2]octan-2-yl)-6-chloro-8-fluoro-2-(((S)-1-m ethylpyrrolidin-2-yl)methoxy)quinazolin-7- yl)naphthalen-2-ol (P-0030). MS (ESI) [M+H + ] + = 548.3. Example 4 [0365] Step 1: tert-butyl (1R,5S)-3-(7-bromo-2-chloroquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (11) [0366] To a solution of 7-bromo-2,4-dichloro-quinazoline (10, 500 mg, 1.80 mmol) in 7 mL dioxane was added tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (460 mg, 2.17 mmol, 1.2 eq.) and DIEA (1.0 mL, 5.7 mmol, 3.2 eq.). The reaction was purged with N2 and allowed to stir at ambient temp. After overnight stir, the reaction mixture was diluted with 40 mL DCM, washed with water and brine, dried over MgSO4, and concentrated. The resulting reaction mixture was dissolved in DCM, evaporated onto silica and was purified by silica gel column chromatography eluting with 0-30% EtOAc/DCM (product eluted at ~10% EtOAc/DCM). The desired fractions were pooled and concentrated to give tert-butyl (1R,5S)-3-(7-bromo-2-chloroquinazolin-4-yl)-3,8-diazabicyclo [3.2.1]octane-8- carboxylate (11, 578 mg). LCMS MS (ESI) [M+H + ] + = 454.7. [0367] Step 2: tert-butyl (1R,5S)-3-(7-(3-((tert-butyldimethylsilyl)oxy)naphthalen-1-y l)-2- chloroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbo xylate (12) [0368] To a solution of tert-butyl (1R,5S)-3-(7-bromo-2-chloroquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (11, 1.83 g, 4.03 mmol) in 28 mL dioxane and 7 mL H 2 O was added , tert-butyl-dimethyl-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro lan-2-yl)-2-naphthyl]oxy]silane (3, 2.02 g, 5.26 mmol, 1.3 eq.), solid K 2 CO 3 (1.96 g, 14.2 mmol, 3.5 eq), and Pd(PPh 3 ) 4 (933 mg (0.807 mmol, 0.2 eq.). The reaction mixture was stirred in a 80 ºC pre-heated oil bath. After 1 hr., the reaction mixture was cooled to ambient temp, diluted with 200 mL DCM, washed with water and brine, dried over MgSO 4 , and concentrated. The crude material was dissolved in DCM, evaporated onto silica and purified by silica gel column chromatography, eluting with 0-25% EtOAc/Hexane (the product eluted at ~10% EtOAc/hexane). The desired fractions were pooled and concentrated to give tert-butyl (1R,5S)-3- (7-(3-((tert-butyldimethylsilyl)oxy)naphthalen-1-yl)-2-chlor oquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (12, 1.86 g). MS (ESI) [M+H + ] + = 632.1. [0369] Step 3: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((1-methy lazetidin-2- yl)methoxy)quinazolin-7-yl)naphthalen-2-ol (P-0086). [0370] To a solution of tert-butyl (1R,5S)-3-(7-(3-((tert-butyldimethylsilyl)oxy)naphthalen-1- yl)-2-chloroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8 -carboxylate (12, 100 mg, 0.158 mmol) in 1.0 mL dioxane was added (1-methylazetidin-2-yl)methanol (160 mg, 1.59 mmol, 10 eq.), solid K2CO3 (220 mg, 1.59 mmol, 10 eq.) and RuPhos Pd G4 catalyst (40 mg, 0.047 mmol, 0.3 eq.). The reaction mixture was stirred under N2 in a 95 ºC pre-heated sand bath. After 30 min, the reaction mixture was filtered to remove insoluble material, concentrated, dissolved in DCM, and evaporated onto silica. The product was purified by silica gel column chromatography, eluting with EtOAc/DCM to remove most by-product peaks, then MeOH/EtOAc to elute protected product (protected product eluted ~15% MeOH/EtOAc). The desired fractions were pooled and concentrated, and then dissolved in 0.5 mL MeOH and 3 mL of 4N HCl/dioxane. The reaction mixture was stirred at ambient temp for 1 hr., at which time the reaction mixture was concentrated, dissolved in 2 mL of ~10%MeCN/H 2 O, and purified by RP-flash silica gel column chromatography eluting with MeCN/H 2 O (0.1% formic acid). The desired fractions were pooled, frozen, and lyophilized to give 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 2-((1-methylazetidin-2-yl)methoxy)quinazolin-7-yl)naphthalen -2-ol (P-0086, 21 mg, 24% yield) as a bis- HCl salt. MS (ESI) [M+H + ] + = 482.2. Example 5 [0371] Step 1: 3-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-hydro xynaphthalen-1- yl)quinazolin-2-yl)amino)-N,N-dimethylpropanamide (P-0058). [0372] To a solution of tert-butyl (1R,5S)-3-(7-(3-((tert-butyldimethylsilyl)oxy)naphthalen-1- yl)-2-chloroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8 -carboxylate (12, 50 mg, 0.079 mmol) (10) in 0.5 mL dioxane was added 3-amino-N,N-dimethyl-propanamide (173 mg, 1.49 mmol, 19 eq.), and solid K 2 CO 3 (214 mg, 1.55 mmol, 20 eq.). The reaction mixture was stirred under N2 in a pre-heated 100 ºC oil bath. After 1 hr., the reaction mixture was cooled to ambient temp and filtered over glass fiber pad to remove insoluble material. To the filtrate was added 0.3 mL MeOH and 2 mL of 2N HCl/dioxane. After stirring at ambient temp for 1 hr., the reaction mixture was concentrated to residue, dissolved in 4 mL of ~10% MeCN/H 2 O and purified by prep-RP HPLC, eluting with H 2 O/MeCN (0.1% TFA). The desired fractions were pooled, frozen, and lyophilized. The lyophilized product was dissolved in MeOH and passed through a 200 mg SPE-HCO 3 column for neutralization. The filtrate was concentrated and dried overnight in vacuum oven (50 ºC) to give 3-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3- hydroxynaphthalen-1-yl)quinazolin-2-yl)amino)-N,N-dimethylpr opanamide (P-0058, 9.1 mg). MS (ESI) [M+H + ] + = 497.6. Example 6 [0373] Step 1: 4-(benzyloxy)-7-bromo-2-chloro-8-fluoroquinazoline (14) [0374] To a solution of 7-bromo-2,4-dichloro-quinazoline (13, 2.00 g, 7.20 mmol) in 15 mL of t-butanol and 5 mL THF was added benzyl alcohol (0.92 mL, 8.9 mmol , 1.3 eq.). The suspension was stirred under N2 followed by addition of crushed KOH (418 mg, 7.43 mmol, 1.1 eq.) in one portion. The suspension stirred at ambient temp. After 2 hr., the reaction mixture was diluted with 200 mL EtOAc, washed with water and ammonium chloride. The organic layer was concentrated, dissolved in DCM, and evaporated onto silica. The product was purified by RP silica gel column chromatography eluting with MeCN/H 2 O (0.1% formic acid). The desired fractions were pooled, concentrated to ~50 mL, frozen, and lyophilized to give 4-(benzyloxy)-7-bromo-2-chloro-8-fluoroquinazoline (14, 1.73 g). MS (ESI) [M+H + ] + = 368.8. [0375] Step 2: 4-(benzyloxy)-7-(3-((tert-butyldimethylsilyl)oxy)naphthalen- 1-yl)-2-chloro- 8-fluoroquinazoline (15) [0376] To a solution of 4-(benzyloxy)-7-bromo-2-chloro-8-fluoroquinazoline (14, 1.28 g, 3.58 mmol) in 32 mL dioxane and 8 mL H 2 O, was added tert-butyl-dimethyl-[[4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2-naphthyl]oxy]silane (3, 1.35 g, 3.48 mmol, 1.0 eq.), solid K 2 CO 3 (1.29 g, 12.2 mmol, 3.5 eq.) and Pd(PPh 3 ) 4 (0.81 g, 0.70 mmol, 0.2 eq.). The reaction mixture was stirred under N 2 in an 80 ºC pre-heated oil bath. After 1 hr, the reaction mixture was cooled to ambient temp, diluted with 200 mL DCM, washed with water and brine, dried over MgSO 4 , and concentrated. The crude material was dissolved in DCM, evaporated onto silica and purified by silica gel column chromatography eluting with EtOAc/hexane (the product eluted at 10-15% EtOAc/hexane). The fractions containing desired product were pooled and concentrated to give 4-(benzyloxy)-7-(3-((tert- butyldimethylsilyl)oxy)naphthalen-1-yl)-2-chloro-8-fluoroqui nazoline (15, 0.34g). MS (ESI) [M+H + ] + = 545.2. [0377] Step 3: (S)-4-(benzyloxy)-7-(3-((tert-butyldimethylsilyl)oxy)naphtha len-1-yl)-8- fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)quinazoline (16) [0378] To a solution of 4-(benzyloxy)-7-(3-((tert-butyldimethylsilyl)oxy)naphthalen- 1-yl)-2- chloro-8-fluoroquinazoline (15, 340 mg, 0.624 mmol) in 4 mL dioxane was added [(2S)-1- methylpyrrolidin-2-yl]methanol (362 mg, 3.14 mmol, 5 eq.), solid K2CO3 (518 mg, 3.75 mmol, 6 eq.), and RuPhos Pd G4 catalyst (106 mg, 0.125 mmol, 0.2 eq.). The reaction mixture was stirred under N2 in a 90 ºC oil bath. After 1 hr, the reaction mixture was filtered to remove insoluble material, concentrated to a residue, dissolved in DCM, and concentrated onto silica. The product was purified by silica gel column chromatography eluting with EtOAc/DCM (product eluted at 70% EtOAc/DCM). The desired fractions were pooled and concentrated to give (S)-4-(benzyloxy)-7-(3-((tert- butyldimethylsilyl)oxy)naphthalen-1-yl)-8-fluoro-2-((1-methy lpyrrolidin-2-yl)methoxy)quinazoline (16, 236 mg). MS (ESI) [M+H + ] + = 625.1. [0379] Step 4: (S)-7-(3-((tert-butyldimethylsilyl)oxy)naphthalen-1-yl)-8-fl uoro-2-((1- methylpyrrolidin-2-yl)methoxy)quinazolin-4-ol (17) [0380] A solution of (S)-4-(benzyloxy)-7-(3-((tert-butyldimethylsilyl)oxy)naphtha len-1-yl)-8- fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)quinazoline (16, 202mg, 0.627 mmol) in 15 mL THF and 100 mL MeOH was passed through an HCube hydrogenator at 60 ºC using Pd/C cartridge. After one pass, LCMS indicated ~90% conversion to desired hydroxy and ~10% remaining O-Bn start material. The material was concentrated to give (S)-7-(3-((tert-butyldimethylsilyl)oxy)naphthalen-1-yl)-8-fl uoro-2- ((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-ol (17, 171 mg). MS (ESI) [M+H + ] + = 535.0. [0381] Step 5: 4-(4-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro- 2-(((S)-1- methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)naphthalen-2-o l (P-0115). [0382] To solution of (S)-7-(3-((tert-butyldimethylsilyl)oxy)naphthalen-1-yl)-8-fl uoro-2-((1- methylpyrrolidin-2-yl)methoxy)quinazolin-4-ol (17, 81 mg, 0.15 mmol) in 5 mL DCM was added DIPEA (0.20 mL, 1.15 mmol). The reaction mixture was purged with N2 and stirred in -40 ºC bath. While stirring cold, triflic anhydride (35 uL, 0.21 mmol, 1.4 eq.) was added dropwise. After ~20 min, a solution of 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (69 mg, 0.46 mmol, 3 eq.) and DIPEA (0.3 mL, 1.72 mmol) in 3 mL DCM was added slowly to the cold (-40 ºC) stirring triflate solution. Following addition, the cold bath was removed and the reaction allowed to warm to ambient temp. After 1 hr., the reaction was concentrated. To the residue was added 3 mL of 4N HCl/dioxane and 0.5 mL MeOH and the reaction mixture stirred at ambient temp. After 1 hr., the reaction mixture was concentrated, dissolved in 4 ml of ~75% MeCN/H 2 O, and injected onto prep-LC for purification, eluting with MeCN/H 2 O (0.1% TFA). The desired fractions were pooled, frozen, and lyophilized to give 4-(4-((1R,5S)-8-oxa-3- azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((S)-1-methylpyrrol idin-2-yl)methoxy)quinazolin-7- yl)naphthalen-2-ol (P-0115, 11.0 mg) as TFA salt. MS (ESI) [M+H + ] + = 515.1. Intermediate 18 [0383] Step 1: Tert-butyl (1R,5S)-3-(7-bromo-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (18) [0384] Tert-butyl (1R,5S)-3-(7-bromo-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (11, 1.51 g, 3.33 mmol), hexahydro-1h-pyrrolizin-7a-ylmethanol (1.41 g, 9.98 mmol), KF (0.39 g, 6.66 mmol), and DMSO (50 ml) were combined in a 100 ml round bottom flask. The reaction was stirred at 120 °C for 24 hours in an oil bath. The reaction was diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered and then evaporated on to silica gel. The product was isolated by reverse phase flash column chromatography (120g, C 1 8, water:ACN) to give tert-butyl (1R,5S)-3-(7- bromo-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazo lin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (18, 0.554 g). Intermediate 20 [0385] Step 1: Tert-butyl (1R,5S)-3-(7-(3-((tert-butyldimethylsilyl)oxy)naphthalen-1-y l)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl )-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (19) [0386] Tert-butyl (1R,5S)-3-(7-bromo-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (18, 0.48 g, 0.86 mmol), tert- butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y l)naphthalen-2-yl)oxy)silane (3, 0.5 g, 1.29 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (0.06 g, 0.09 mmol), 2.5M potassium carbonate (1.03 ml), and dioxane (7 ml) were combined in a 20 ml microwave vial. The vial was sealed and stirred under nitrogen atmosphere at 100 °C for 6 hours. The reaction was poured over brine and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated on to silica gel. The product was isolated by reverse phase flash column chromatography (40g, C 1 8) to give tert-butyl (1R,5S)-3-(7-(3-((tert-butyldimethylsilyl)oxy)naphthalen- 1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazo lin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (19, 0.503 g). [0387] Step 2: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-((tert- butyldimethylsilyl)oxy)naphthalen-1-yl)-2-((tetrahydro-1H-py rrolizin-7a(5H)- yl)methoxy)quinazoline (20) [0388] Tert-butyl (1R,5S)-3-(7-(3-((tert-butyldimethylsilyl)oxy)naphthalen-1-y l)-2-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabi cyclo[3.2.1]octane-8-carboxylate (19, 0.5 g, 0.68 mmol) was dissolved in DCM (50 ml). The reaction was cooled to 0 °C and a mixture of TFA (2.52 ml, 33.97 mmol) in DCM (7.5ml) was added slowly and the reaction was stirred at 0 °C for 6 hours. The reaction was evaporated to dryness without submerging in a water bath. The reaction was then diluted with ethyl acetate (100 ml) and washed with saturated sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, filtered and then evaporated to dryness to give 4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-7-(3-((tert-butyldimethylsily l)oxy)naphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazoline (20, 0.437 g). Example 7 [0389] Step 1: 2-(1,1-dioxidoisothiazolidin-2-yl)-1-((1R,5S)-3-(7-(3-hydrox ynaphthalen-1- yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazoli n-4-yl)-3,8-diazabicyclo[3.2.1]octan- 8-yl)ethan-1-one (P-0092). [0390] Tert-butyl-[[4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1,2 ,3,5,6,7-hexahydropyrrolizin- 8-ylmethoxy)quinazolin-7-yl]-2-naphthyl]oxy]-dimethyl-silane (20, 0.03 g, 0.05 mmol), 2-(1,1-dioxo- 1,2-thiazolidin-2-yl)acetic acid (0.04 g, 0.24 mmol), HATU (0.02 g, 0.14 mmol), DMF (2 ml), and DIEA (0.04 ml, 0.24 mmol) were combined in a 20 ml scintillation vial and the stirred at room temperature for 2 hours. The reaction was treated with TFA (0.07 ml, 1.0 mmol) and heated to 60 °C for 2 hours. The reaction was then concentrated, diluted with 95/5 water/ACN and purified by reverse phase flash column chromatography to give 2-(1,1-dioxidoisothiazolidin-2-yl)-1-((1R,5S)-3-(7-(3-hydrox ynaphthalen-1-yl)- 2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4- yl)-3,8-diazabicyclo[3.2.1]octan-8- yl)ethan-1-one (P-0092, 0.008 g). MS (ESI) [M+H + ] + = 683.65. Example 8 [0391] Step 1: (1R,5S)-3-(7-(3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-py rrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)-N-(1H-pyrazol-4-yl)-3,8-d iazabicyclo[3.2.1]octane-8- carboxamide (P-0126). [0392] Tert-butyl-[[4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1,2 ,3,5,6,7-hexahydropyrrolizin- 8-ylmethoxy)quinazolin-7-yl]-2-naphthyl]oxy]-dimethyl-silane (20, 0.03 g, 0.05 mmol) was dissolved in dioxane (2 ml) and DIEA (0.04 ml, 0.24 mmol) and stirred at room temperature. bis(trichloromethyl) carbonate (0.01 g, 0.024 mmol) in DCM (1 ml) was added dropwise and the reaction was stirred for 60 minutes. Formation of the amide chloride intermediate was confirmed by LCMS in MeOH. To the reaction mixture was added tert-butyl 4-aminopyrazole-1-carboxylate (0.01 ml, 0.07 mmol) and K2CO3 (0.02 g, 0.14 mmol) and the reaction was heated to 70 °C for 2 hours. The reaction was then cooled to room temperature, filtered to remove solids, then treated with 4M HCl (1.2 ml) in dioxane and stirred at room temperature for 2 hours. The de-protected product was isolated by prep-HPLC to give (1R,5S)-3- (7-(3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7 a(5H)-yl)methoxy)quinazolin-4-yl)-N-(1H- pyrazol-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide (P-0126, 0.012 g). MS (ESI) [M+H + ] + = 631.20. Example 9 [0393] 2-((1R,5S)-3-(7-(3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H -pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-y l)-1-(piperidin-4-yl)ethan-1-one (P- 0138) Tert-butyl-[[4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1,2 ,3,5,6,7-hexahydropyrrolizin-8- ylmethoxy)quinazolin-7-yl]-2-naphthyl]oxy]-dimethyl-silane (20, 0.03 g, 0.05 mmol) was dissolved in THF (2 ml) and TEA (0.03 ml, 0.24 mmol). tert-butyl 4-(2-bromoacetyl)piperidine-1- carboxylate (0.02 ml, 0.07 mmol) was added and the reaction was stirred at 70 °C for 2 hours. The reaction was cooled to room temperature, treated with 4M HCl (0.59 ml), and stirred for 30 minutes at 70 °C. The product was isolated by prep-HPLC to give 2-((1R,5S)-3-(7-(3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H - pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyc lo[3.2.1]octan-8-yl)-1-(piperidin-4- yl)ethan-1-one (P-0138, 0.014 g. MS (ESI) [M+H + ] + = 647.30. Example 10 [0394] Step 1: 4-(4-((1R,5S)-8-((2-methoxyethyl)sulfonyl)-3,8-diazabicyclo[ 3.2.1]octan-3- yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazoli n-7-yl)naphthalen-2-ol (P-0139) Tert-butyl-[[4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1,2 ,3,5,6,7-hexahydropyrrolizin-8- ylmethoxy)quinazolin-7-yl]-2-naphthyl]oxy]-dimethyl-silane (20, 0.03 g, 0.06 mmol), 2- methoxyethanesulfonyl chloride (0.01 g, 0.07 mmol), THF (2 ml), and DIEA (0.02 ml, 0.12 mmol) were combined in a 20 ml scintillation vial was stirred at room temperature for 2 hours. TFA (0.21 ml, 2.88 mmol) was added and the reaction was heated to 70 °C for 2 hours. The product was isolated by prep- HPLC to give 4-(4-((1R,5S)-8-((2-methoxyethyl)sulfonyl)-3,8-diazabicyclo[ 3.2.1]octan-3-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl )naphthalen-2-ol (P-0139, 0.009 g). MS (ESI) [M+H + ] + = 644.25. Example 11 [0395] Step 1: Tetrahydrofuran-3-yl (1R,5S)-3-(7-(3-hydroxynaphthalen-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl )-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (P-0098). [0396] Tert-butyl-[[4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1,2 ,3,5,6,7-hexahydropyrrolizin- 8-ylmethoxy)quinazolin-7-yl]-2-naphthyl]oxy]-dimethyl-silane (0.03 g, 0.06 mmol), tetrahydrofuran-3-yl carbonochloridate (20, 0.01 g, 0.06 mmol), THF (2 ml), and DIEA (0.02 ml, 0.12 mmol) were combined in a 20 ml scintillation vial was stirred at room temperature for 2 hours. TFA (0.21 ml, 2.88 mmol) was added and the reaction was heated to 70 °C for 2 hours. The product was isolated by prep-HPLC to give tetrahydrofuran-3-yl (1R,5S)-3-(7-(3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-py rrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (P-0098, 0.021 g). MS (ESI) [M+H + ] + = 636.25. Example 12 [0397] Step 1: tert-Butyl 3-(7-bromo-2,6-dichloro-8-fluoro-quinazolin-4-yl)-3,8- diazabicyclo [3.2.1]octane-8-carboxylate (21) [0398] To a solution of 7-bromo-2,4,6-trichloro-8-fluoro-quinazoline (7, 500 mg, 1.51 mmol), DIEA (587 mg, 4.54 mmol) in dioxane (5 mL), was added tert-butyl 3,8-diazabicyclo[3.2.1]octane-8- carboxylate (386 mg, 1.82 mmol) at room temperature, and then the reaction mixture was stirred at room temperature for 2 hrs. The reaction mixture was diluted with CH 2 Cl 2 (10 mL) and washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was washed with hexane-ethyl acetate, and collected by filtration to give tert-butyl 3-(7-bromo-2,6-dichloro-8-fluoro- quinazolin-4-yl)-3,8-diazabicyclo[3.2.1] octane-8-carboxylate (21, 700 mg). [0399] Step 2: Tert-butyl 3-[7-bromo-6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2- yl]methoxy] quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (22) [0400] To a solution of tert-butyl 3-(7-bromo-2,6-dichloro-8-fluoro-quinazolin-4-yl)-3,8- diazabicyclo [3.2.1]octane-8-carboxylate (21, 500 mg, 0.99 mmol), KF (115 mg, 1.98 mmol) in DMSO (4 mL), was added [(2S)-1-methylpyrrolidin-2-yl] methanol (341 mg, 2.96 mmol) at room temperature, and then the reaction mixture was stirred at 100 ºC for 5 hours. [0401] The reaction mixture was diluted with ethyl acetate (10 mL) and washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (pre packed column, 24 g, MeOH/ ethyl acetate = 0 to 10%) to give tert-butyl 3-[7-bromo-6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-y l]methoxy]quinazolin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (22, 300 mg). MS (ESI) [M+H + ] + = 586.21. [0402] Step 3: Tert-Butyl 3-[7-[3-[tert-butyl(dimethyl)silyl]oxy-1-naphthyl]-6-chloro- 8- fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-4 -yl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (23) [0403] To a solution of tert-butyl 3-[7-bromo-6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2- yl]methoxy]quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (22, 85 mg, 0.145 mmol), tert- butyl-dimethyl-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-2-naphthyl]oxy]silane (3, 168 mg, 0.436 mmol) and Na2CO3 (46.2 mg, 0.436 mmol) in dioxane (2 mL) and H 2 O (0.5 mL), was added Pd(PPh3)4 (16.8 mg, 0.015 mmol) at room temperature, and then the reaction mixture was stirred at 90 ºC for 3 hrs. The reaction mixture was diluted with CH 2 Cl 2 (10 mL) and washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified with silica gel column chromatography (MeOH / ethyl acetate = 0 to 10%) to give tert-butyl 3-[7-[3-[tert- butyl(dimethyl)silyl]oxy-1-naphthyl]-6-chloro-8-fluoro-2-[[( 2S)-1-methylpyrrolidin-2- yl]methoxy]quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (23, 100 mg). MS (ESI) [M+H]+ = 762.49. [0404] Step 4: Tert-butyl 3-[7-[3-[tert-butyl(dimethyl)silyl]oxy-1-naphthyl]-8-fluoro- 2- [[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6-vinyl-quinazolin-4 -yl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (24) [0405] To a solution of tert-butyl 3-[7-[3-[tert-butyl(dimethyl)silyl]oxy-1-naphthyl]-6-chloro- 8- fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-4 -yl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (23, 56 mg, 0.073 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (33.9 mg, 0.22 mmol) and Na 2 CO 3 (23.4 mg, 0.22 mmol) in dioxane (2 mL) and H 2 O (0.5 mL), was added SPhos Pd G4 (6.5 mg, 0.007 mmol) at room temperature and the reaction mixture was stirred at 90 ºC for 1 hr. The reaction mixture was diluted with CH 2 Cl 2 (10 mL), washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified with silica gel column chromatography (MeOH / ethyl acetate = 0 to 10%) to give tert-butyl 3-[7-[3-[tert-butyl(dimethyl) silyl]oxy-1-naphthyl]-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2 -yl]methoxy]-6-vinyl-quinazolin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (24, 35 mg). MS (ESI) [M+H]+ = 754.6. [0406] Step 5: 4-[4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-[[(2S)-1 - methylpyrrolidin-2-yl]methoxy]-6-vinyl-quinazolin-7-yl]napht halen-2-ol (P-0036). [0407] To a solution of tert-butyl 3-[7-[3-[tert-butyl(dimethyl)silyl]oxy-1-naphthyl]-8-fluoro- 2- [[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6-vinyl-quinazolin-4 -yl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (24, 35 mg, 0.046 mmol) in MeOH (0.5 mL), was added 4M HCl in dioxane (1.5 mL) and the reaction was stirred at room temperature for 1 hr. [0408] After the reaction was quenched with aqueous NaHCO3, the reaction mixture was extracted with CH 2 Cl 2 -IPA (3:1, 10 mL). The extract was washed with brine, dried over anhydrous Na2SO4, and filtered and concentrated in vacuo. The residue was purified with reverse phase column chromatography (0.5% HCO 2 H in CH 3 CN/0.5% HCO 2 H in H 2 O = 0 to 100%) to give 4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-[[(2S)-1-methylpyr rolidin-2-yl]methoxy]-6-vinyl-quinazolin-7- yl]naphthalen-2-ol (P-0036, 13 mg). MS (ESI) [M+H + ] + = 540.3. Example 13 [0409] Step 1: tert-Butyl 3-(7-bromo-2-chloro-8-fluoro-6-iodo-quinazolin-4-yl)-3,8- diazabicyclo [3.2.1]octane-8-carboxylate (26) [0410] To a solution of 7-bromo-2,4-dichloro-8-fluoro-6-iodo-quinazoline (25, 880 mg, 2.09 mmol), DIEA (809 mg, 6.26 mmol) in dioxane (10 mL), was added tert-butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate (487 mg, 2.30 mmol) at room temperature, and then the reaction mixture was stirred at room temperature for 2 hrs. The reaction mixture was diluted with CH 2 Cl 2 (10 mL) and washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was washed with hexane:ethyl acetate (9:1) and collected by filtration to give tert-butyl 3-(7- bromo-2-chloro-8-fluoro-6-iodo-quinazolin-4-yl)-3,8-diazabic yclo [3.2.1]octane-8-carboxylate (26, 1,180 mg). [0411] Step 2: Tert-butyl 3-[7-bromo-8-fluoro-6-iodo-2-[[(2S)-1-methylpyrrolidin-2-yl] methoxy]quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-car boxylate (27) [0412] To a solution of tert-butyl 3-(7-bromo-2-chloro-8-fluoro-6-iodo-quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (26, 1180 mg, 1.97 mmol), KF (229 mg, 3.95 mmol) in DMSO (10 mL), was added [(2S)-1-methylpyrrolidin-2-yl]methanol (1140 mg, 9.87 mmol) at room temperature, and then the reaction mixture was stirred at 120 ºC for 5 hours. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/ CH 2 Cl 2 = 0 to 10%) to give tert-butyl 3-[7-bromo-8-fluoro-6-iodo-2-[[(2S)-1-methylpyrrolidin-2- yl]methoxy]quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (25, 600 mg). MS (ESI) [M+H + ] + = 678.06. [0413] Step 3: Phenyl 7-bromo-4-(8-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octa n-3-yl)- 8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin e-6-carboxylate (28) [0414] To a solution of tert-butyl 3-[7-bromo-8-fluoro-6-iodo-2-[[(2S)-1-methylpyrrolidin-2- yl]methoxy]quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (27, 50 mg, 0.074 mmol), phenyl formate (27.1 mg, 0.222 mmol), DBU (33.8 mg, 0.222 mmol) and Xantphos (42.8 mg, 0.074 mmol) in CH 3 CN (1 mL), was added Pd(OAc) 2 (8.3 mg, 0.037 mmol) at room temperature, and the reaction mixture was stirred at 90 ºC for 2 hrs. The reaction mixture was diluted with CH 2 Cl 2 (10 mL) and washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH / CH 2 Cl 2 = 0 to 20%) to give phenyl 7-bromo-4-(8-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octa n-3-yl)-8-fluoro-2-[[(2S)-1- methylpyrrolidin-2-yl]methoxy]quinazoline-6-carboxylate (28, 25 mg). MS (ESI) [M+H + ] + = 670.2. [0415] Step 4: Phenyl 4-(8-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octan-3-yl)- 7-[3-[tert- butyl(dimethyl)silyl]oxy-1-naphthyl]-8-fluoro-2-[[(2S)-1-met hylpyrrolidin-2-yl]methoxy] quinazoline-6-carboxylate (29) [0416] To a solution of phenyl 7-bromo-4-(8-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octa n- 3-yl)-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quin azoline-6-carboxylate (28, 17 mg, 0.025 mmol), tert-butyl-dimethyl-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro lan-2-yl)-2-naphthyl]oxy]silane (3, 29.2 mg, 0.076 mmol) and Na 2 CO 3 (8.1 mg, 0.076 mmol) in dioxane (2 mL) and H 2 O (0.5 mL), was added Pd(PPh 3 ) 4 (2.9 mg, 0.003 mmol) at room temperature and the reaction mixture was stirred at 90 ºC for 1 hr. The reaction mixture was diluted with CH 2 Cl 2 (10 mL) and washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH / CH 2 Cl 2 = 0 to 10%) to provide phenyl 4-(8-tert-butoxycarbonyl-3,8- diazabicyclo[3.2.1]octan-3-yl)-7-[3-[tert-butyl(dimethyl)sil yl]oxy-1-naphthyl]-8-fluoro-2-[[(2S)-1- methylpyrrolidin-2-yl]methoxy]quinazoline-6-carboxylate (29, 21 mg). [0417] Step 5: Phenyl 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(3-hydroxy- 1- naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazoli ne-6-carboxylate (30) [0418] To a solution of phenyl 4-(8-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octan-3-yl)- 7- [3-[tert-butyl(dimethyl)silyl]oxy-1-naphthyl]-8-fluoro-2-[[( 2S)-1-methylpyrrolidin-2- yl]methoxy]quinazoline-6-carboxylate (29, 18 mg, 0.021 mmol) in MeOH (0.5 mL), was added 4M HCl in dioxane (1.5 mL). The reaction mixture was stirred at room temperature for 1 hr. [0419] The reaction mixture was concentrated down to give phenyl 4-(3,8-diazabicyclo [3.2.1] octan-3-yl)-8-fluoro-7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-met hylpyrrolidin-2-yl]methoxy] quinazoline- 6-carboxylate (30, 13mg). [0420] Step 6: 4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(3-hydroxy- 1-naphthyl)-2- [[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazoline-6-carboxy lic acid (P-0024). [0421] To a solution of phenyl 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(3-hydroxy- 1- naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazoli ne-6-carboxylate (30, 13.5 mg, 0.021 mmol) in MeOH (1 mL), was added 1M NaOH (0.5 mL) at room temperature, and the reaction mixture was stirred at 60 ºC for 1 hour. The reaction mixture was allowed to room temperature, and then the reaction mixture was neutralized with 1M HCl. The reaction mixture was concentrated in vacuo, and the residue was purified with reverse phase column chromatography (0.5% HCO 2 H in CH 3 CN/0.5% HCO 2 H in H 2 O = 0 to 100%) to give 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(3-hydroxy- 1-naphthyl)-2- [[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazoline-6-carboxy lic acid (P-0024, 9 mg). MS (ESI) [M+H + ] + = 558.3. Example 14 [0422] Step 1: Tert-butyl 3-[7-[3-[tert-butyl(dimethyl)silyl]oxy-1-naphthyl]-8-fluoro- 6- (hydroxyl methyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin- 4-yl]-3,8- diazabicyclo[3.2.1] octane-8-carboxylate (31) [0423] To a solution of phenyl 4-(8-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octan-3-yl)- 7- [3-[tert-butyl(dimethyl)silyl]oxy-1-naphthyl]-8-fluoro-2-[[( 2S)-1-methylpyrrolidin-2-yl]methoxy] quinazoline-6-carboxylate (29, 20 mg, 0.024 mmol) in THF (2 mL), was added slowly LAH (2 M in THF, 0.24 mL, 0.047 mmol) at 0 ºC and the reaction mixture was stirred at 0 ºC for 1 hour. [0424] After the reaction was quenched with 1N NaOH solution, the reaction mixture was diluted with CH 2 Cl 2 (10 mL) and washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford tert-butyl 3-[7-[3-[tert-butyl(dimethyl)silyl]oxy-1-naphthyl]-8- fluoro-6-(hydroxymethyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]me thoxy]quinazolin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (31, 17mg). [0425] Step 2: 4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-6-(hydroxy methyl)-2-[[(2S)- 1-methylpyrrolidin-2-yl]methoxy]quinazolin-7-yl]naphthalen-2 -ol (P-0056) [0426] To a solution of tert-butyl 3-[7-[3-[tert-butyl(dimethyl)silyl]oxy-1-naphthyl]-8-fluoro- 6- (hydroxymethyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]qui nazolin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (31, 17 mg, 0.022 mmol) in MeOH (0.5 mL), was added 4M HCl in dioxane (1.5 mL) and the reaction was stirred at room temperature for 1 hr. [0427] After the reaction was quenched with aqueous NaHCO3, the reaction mixture was extracted with CH 2 Cl 2 -IPA (3:1, 10 mL). The extract was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by reverse phase column chromatography (0.5% HCO 2 H in CH 3 CN/0.5% HCO 2 H in H 2 O = 0 to 100%) to give 4-[4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-6-(hydroxymethyl)-2- [[(2S)-1-methylpyrrolidin-2- yl]methoxy]quinazolin-7-yl]naphthalen-2-ol (P-0056, 7mg). MS (ESI) [M+H + ] + = 544.3. Intermediate 33 [0428] Step 1: 7-bromo-2,4-dichloro-8-fluoroquinazoline (13) [0429] To a stirred solution of 7-bromo-8-fluoroquinazoline-2,4(1H,3H)-dione (31, 780 mg, 3.01 mmol) in POCl 3 (14 mL), diisopropylethylamine (1.61 mL, 9.03 mmol) was added at room temperature. The reaction mixture was then stirred at 150 ºC for 3 hours. Upon completion, the reaction mixture was cooled to room temperature, poured onto crushed ice, extracted with 20 ml ethyl acetate, and washed with water and brine. The organic layer was dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (AcOEt / Hexane = 0 to 10%) to give 7-bromo-2,4-dichloro-8-fluoroquinazoline (13, 580 mg). [0430] Step 2: Tert-butyl 3-(7-bromo-2-chloro-8-fluoro-quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (32) [0431] To a solution of 7-bromo-2,4-dichloro-8-fluoroquinazoline (13, 300 mg, 1.01 mmol) in dioxane (3 mL), DIEA (0.54 mL, 3.04 mmol) was added, followed by tert-butyl (1R,5S)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (237 mg, 1.16 mmol). The reaction mixture was stirred at room temperature for 2 hrs. After LC-MS showed completion, the reaction mixture was diluted with CH 2 Cl 2 (10 mL) and washed twice with water and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography with Hexane:EtOAc (9:1) to provide tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8-dia zabicyclo[3.2.1]octane- 8-carboxylate (32, 450 mg). [0432] Step 3: Tert-butyl 3-[7-bromo-8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8- ylmethoxy)quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-c arboxylate (33) [0433] To a solution of tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (32, 200 mg, 0.424 mmol) in DMSO (4 mL), KF (49 mg, 0.848 mmol) was added at room temperature, followed by (tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (299 mg, 2.12 mmol). The reaction mixture was stirred at 120 ºC for 5 hours. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/ CH 2 Cl 2 = 0 to 20%) to give tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl )-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (32, 130 mg). Example 15 [0434] Step 1: (1R,5S)-3-(8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-((tetrahy dro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyc lo[3.2.1]octane-8-carboxylate (34) [0435] To a solution of compound tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyc lo[3.2.1]octane-8-carboxylate (33, 280 mg, 0.139 mmol) and (2-fluoro-6-hydroxyphenyl)boronic acid (64.9 mg, 0.416 mmol) in 2 mL dioxane, Na 2 CO 3 (73.5 mg, 0.694 mmol) and H 2 O (0.5 mL) was added, followed by RuPhos Pd Gen4 (11.8 mg, 0.014 mmol). The reaction mixture was stirred at 90 ºC for 2 hours. After LCMS showed completion, the reaction mixture was cooled down to room temperature and diluted with CH 2 Cl 2 (10 mL). Then the reaction mixture was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH / CH 2 Cl 2 = 0 to 80%) to give tert-butyl (1R,5S)-3-(8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-((tetrahy dro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyc lo[3.2.1]octane-8-carboxylate (34, 50 mg, 59.2%). [0436] Step 2: 2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- ((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-3-fluorophenol (P-0049). [0437] To a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl )-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (34, 35 mg, 0.082 mmol) in MeOH (0.5 mL), 4M HCI in dioxane (1.5 mL) was added and the reaction was stirred at room temperature for 1 hr. After the reaction was quenched with saturated NaHCO3 solution, the reaction mixture was extracted with CH 2 Cl 2 :IPA (3:1, 10 mL). The extract was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by reverse phase column chromatography (0.5% HCO 2 H in CH 3 CN/0.5% HCO 2 H in H 2 O = 0 to 100%) to give 2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- ((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-3-fluorophenol (P-004915 mg). MS (ESI) [M+H + ] + = 508.2. Example 16 [0438] Step 1: Tert-butyl 3-[7-[3-[tert-butyl(dimethyl)silyl]oxy-1-naphthyl]-8-fluoro- 2- [[(2S)-1-methylpyrrolidin-2-yl]methoxy]pyrido[4,3-d]pyrimidi n-4-yl]-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (35) [0439] To a solution of tert-butyl 3-[7-bromo-8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8- ylmethoxy)quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-c arboxylate (33, 50 mg, 0.087 mmol) and tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2-yl)naphthalen-2-yl)oxy)silane (3, 100 mg, 0.26 mmol) in 2 mL dioxane, Na2CO3 (27.6 mg, 0.26 mmol) and H 2 O (0.5 mL) was added, followed by Pd(PPh3)4 (10 mg, 0.009 mmol). The reaction mixture was stirred at 90 ºC for 2 hours. After LCMS showed completion, the reaction mixture was cooled down to room temperature and diluted with CH 2 Cl 2 (10 mL). Then the reaction mixture was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH / CH 2 Cl 2 = 0 to 50%) to provide tert-butyl 3-[7-[3-[tert-butyl(dimethyl)silyl]oxy-1-naphthyl]-8- fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]pyrido[4,3-d ]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylatt (35, 50 mg). [0440] Step 2: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- ((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol (P-0048). [0441] To a solution of tert-butyl 3-[7-[3-[tert-butyl(dimethyl)silyl]oxy-1-naphthyl]-8-fluoro- 2- [[(2S)-1-methylpyrrolidin-2-yl]methoxy]pyrido[4,3-d]pyrimidi n-4-yl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylatt (35, 98 mg, 0.134 mmol) in MeOH (0.5 mL), 4M HCI in dioxane (1.5 mL) was added and the reaction was stirred at room temperature for 1 hr. After the reaction was quenched with saturated NaHCO3 solution, the reaction mixture was extracted with CH 2 Cl 2 :IPA (3:1, 10 mL). The extract was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by reverse phase column chromatography (0.5% HCO 2 H in CH 3 CN/0.5% HCO 2 H in H 2 O = 0 to 100%) to provide 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- ((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol (P-0048, 25 mg, 69.8% yield). MS (ESI) [M+H + ] + = 540.2.
[0442] Step 1: 4,6-dichloro-5-fluoro-pyridine-3-carbonyl chloride (37) [0443] To a solution of 4,6-dichloro-5-fluoronicotinic acid (36, 1 g, 4.67 mmol) in CH 2 Cl 2 (20 mL), oxalyl chloride (0.45 mL, 5.24 mmol) was added slowly and then DMF (35 mg, 0.476 mmol) was added at room temperature. The reaction mixture was stirred at 50 ºC for 2 hours. The reaction mixture was concentrated in vacuo and then azeotroped with toluene to give 4,6-dichloro-5-fluoronicotinoyl chloride (37, 1.08 g). [0444] Step 2: 4,6-dichloro-5-fluoro-N-(methylsulfanylcarbonimidoyl)pyridin e-3- carboxamide (38) [0445] To a solution of 2-methylisothiourea sulfuric acid (3.29 g, 11.8 mmol) in 1M NaOH aq. (15 ml), a solution of 4,6-dichloro-5-fluoronicotinoyl chloride (37, 1.08 g, 4.73 mmol) in diethyl ether (4 mL) was slowly added at 0 ºC, and the reaction mixture was stirred for 1 hour at 0 ºC. The solid precipitate were collected by filtration and dried to give methyl (4,6-dichloro-5- fluoronicotinoyl)carbamimidothioate (38, 520 mg). [0446] Step 3: 7-chloro-8-fluoro-2-methylsulfanyl-3H-pyrido[4,3-d]pyrimidin -4-one (39) [0447] Methyl (4,6-dichloro-5-fluoronicotinoyl)carbamimidothioate (38, 520 mg, 1.84 mmol) was dissolved in DMF (4 mL) and the reaction mixture was stirred at 120 ºC for 2 hours. The reaction mixture was cooled to room temperature and water (20 mL) was added. The solid precipitate was filtered and dried under vacuo to give 7-chloro-8-fluoro-2(methylthio)pyrido[4,3-d]pyrimidin-4(3H)- one (39, 320 mg, 70.6% yield). [0448] Step 4: Tert-butyl 3-(7-chloro-8-fluoro-2-methylsulfanyl-pyrido[4,3-d]pyrimidin -4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40) [0449] To a solution of 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H) -one (39, 160 mg, 0.651 mmol) in 5 mL CH 2 Cl 2 , was added DIEA (421 mg, 3.26 mmol). Then Tf2O (0.16 mL, 0.977 mmol) was added dropwise at 0 ºC. The reaction mixture was stirred at 0 ºC for 30 min, followed by the addition of tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. The reaction mixture was warmed up to room temperature and stirred for 30 min. The reaction mixture was diluted with CH 2 Cl 2 (10 mL) and washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/ Hexane = 0 to 30%) to give tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyri midin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40, 210 mg). [0450] Step 5: Tert-butyl 3-[7-[3-[tert-butyl(dimethyl)silyl]oxy-1-naphthyl]-8-fluoro- 2- methylsulfanyl-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo [3.2.1]octane-8-carboxylate (41) [0451] To a solution of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylat e (40, 210 mg, 0.477 mmol) and tert- butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y l)naphthalen-2-yl)oxy)silane (3, 367 mg, 0.955 mmol) in 4 mL dioxane, Na 2 CO 3 (152 mg, 1.43 mmol) and H 2 O (1 mL) was added, followed by Pd(PPh 3 ) 4 (55 mg, 0.048 mmol). The reaction mixture was stirred at 90 ºC for 2 hrs. After LCMS showed completion, the reaction mixture was cooled down to room temperature and diluted with CH 2 Cl 2 (10 mL). Then the reaction mixture was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc / Hexane = 0 to 30%) to give tert-butyl (1R,5S)-3-(7-(3-((tert-butyldimethylsilyl)oxy)naphthalen-1-y l)-8- fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazab icyclo[3.2.1]octane-8-carboxylate (41, 283 mg). [0452] Step 6: Tert-butyl 3-[7-[3-[tert-butyl(dimethyl)silyl]oxy-1-naphthyl]-8-fluoro- 2- methylsulfinyl-pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo [3.2.1]octane-8-carboxylate (42) [0453] To a solution of tert-butyl (1R,5S)-3-(7-(3-((tert-butyldimethylsilyl)oxy)naphthalen-1- yl)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (41, 90 mg, 0.136 mmol) in CH 2 Cl 2 (2 mL), mCPBA (33.5 mg, 0.150 mmol, 77%) was added at 0 ºC and then the reaction mixture was stirred for 30 min at 0 ºC. The reaction was quenched with saturated Na2S2O3 aq. (5 mL) and then the reaction mixture was diluted with CH 2 Cl 2 (10 mL) and concentrated in vacuo to give tert-butyl (1R,5S)-3-(7-(3-((tert-butyldimethylsilyl)oxy)naphthalen-1-y l)-8-fluoro-2- (methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicycl o[3.2.1]octane-8-carboxylate (42, 92 mg). [0454] Step 7: Tert-butyl 3-[7-[3-[tert-butyl(dimethyl)silyl]oxy-1-naphthyl]-8-fluoro- 2- [[(2S)-1-methylpyrrolidin-2-yl]methoxy]pyrido[4,3-d]pyrimidi n-4-yl]-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (43) [0455] To a solution of tert-butyl (1R,5S)-3-(7-(3-((tert-butyldimethylsilyl)oxy)naphthalen-1- yl)-8-fluoro-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (42, 92 mg, 0.136 mmol) and (S)-(1-methylpyrrolidin-2-yl)methanol (31.3 mg, 0.271 mmol) in THF (2 mL), sodium hydride (11 mg, 60% in mineral oil, 0.271 mmol) was added at 0 ºC and the reaction mixture was stirred for 30 min at 0 ºC. Upon completion, the reaction mixture was quenched with saturated NH4Cl aq. (2 mL), and the reaction mixture was extracted with EtOAc. The extract was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give tert-butyl (1R,5S)-3- (7-(3-((tert-butyldimethylsilyl)oxy)naphthalen-1-yl)-8-fluor o-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2 .1]octane-8-carboxylate (43, 98 mg). [0456] Step 8: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((S)-1- methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)na phthalen-2-ol (P-0026). [0457] To a solution of tert-butyl (1R,5S)-3-(7-(3-((tert-butyldimethylsilyl)oxy)naphthalen-1- yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[ 4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (43, 98 mg, 0.134 mmol) in MeOH (0.5 mL), 4M HCI in dioxane (1.5 mL) was added, and the reaction was stirred at room temperature for 1 hr. After the reaction was quenched with saturated NaHCO 3 solution, the reaction mixture was extracted with CH 2 Cl 2 :IPA (3:1, 10 mL). The extract was washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by reverse phase column chromatography (0.5% HCO 2 H in CH 3 CN/0.5% HCO 2 H in H 2 O = 0 to 100%) to provide 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[ 4,3-d]pyrimidin-7-yl)naphthalen-2-ol (P- 0026, 10 mg). MS (ESI) [M+H + ] + = 515.3.
Example 17 [0458] Step 1 : Tert-butyl 3-[2-[[(2S)-1-benzyloxycarbonylpyrrolidin-2-yl]methoxy]-8- fluoro-7-(3-hydroxy-1-naphthyl)quinazolin-4-yl]-3,8-diazabic yclo[3.2.1]octane-8-carboxylate (45): [0459] In a 50 mL flask were added tert-butyl 3-[7-[3-[tert-butyl(dimethyl)silyl]oxy-1- naphthyl]-2-chloro-8-fluoro-quinazolin-4-yl]-3,8-diazabicycl o[3.2.1]octane-8-carboxylate (1, 1.0 g, 1.54 mmol), benzyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.81 g, 7.70 mmol), potassium carbonate (44, 28 g, 9.24 mmol), and RuPhos Pd G4 (393 mg, 0.462 mmol). DMF (6 mL) was added and the mixture was stirred at 95 ºC for 1 hour. The reaction was directly purified by reverse phase chromatography (150 g C 1 8 column, 0-100% MeCN in water with 0.1% formic acid). This purification provided tert-butyl 3-[2-[[(2S)-1-benzyloxycarbonylpyrrolidin-2-yl]methoxy]-8-fl uoro-7-(3-hydroxy-1- naphthyl)quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-ca rboxylate (45, 590 mg). LCMS (M+H)+ = 734.4. [0460] Step 2 : Tert-butyl 3-[8-fluoro-7-(3-hydroxy-1-naphthyl)-2-[[(2S)-pyrrolidin-2- yl]methoxy]quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (46): [0461] Tert-butyl 3-[2-[[(2S)-1-benzyloxycarbonylpyrrolidin-2-yl]methoxy]-8-fl uoro-7-(3- hydroxy-1-naphthyl)quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]o ctane-8-carboxylate (45, 0.59 g, 0.804 mmol) was dissolved in 20 mL of ethyl acetate and palladium on carbon (10% Pd by weight, 100 mg) was added. The reaction mixture was subjected to hydrogen atmosphere (~1 ATM, balloon) for 30 minutes at room temperature. The solution was filtered through celite and concentrated under reduced pressure to give tert-butyl 3-[8-fluoro-7-(3-hydroxy-1-naphthyl)-2-[[(2S)-pyrrolidin-2- yl]methoxy]quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (46, 482 mg). MS (ESI) [M+H + ] + = 600.3. [0462] Step 3 Tert-butyl 3-[2[[(2S)-1-[3-(benzyloxycarbonylamino)propyl]pyrrolidin-2- yl]methoxy]-8-fluoro-7-(3-hydroxy-1-naphthyl)quinazolin-4-yl ]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (47): [0463] Tert-butyl 3-[8-fluoro-7-(3-hydroxy-1-naphthyl)-2-[[(2S)-pyrrolidin-2- yl]methoxy]quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (46, 0.135 g, 0.225 mmol) was dissolved in dichloromethane (3 mL) and acetic acid (0.2 mL). Benzyl (3-oxopropyl)carbamate (56 mg, 0.27 mmol) and sodium triacetoxyborohydride (57 mg, 0.27 mmol) were added and the reaction was stirred at room temperature for 15 minutes. The reaction was concentrated and dissolved in 1 mL of DMF and 0.2 mL of water. This solution was directly purified by reverse phase chromatography (50 g C 1 8 column, 0-80% MeCN in water with 0.1% formic acid) to provide tert-butyl 3-[2-[[(2S)-1-[3- (benzyloxycarbonylamino)propyl]pyrrolidin-2-yl]methoxy]-8-fl uoro-7-(3-hydroxy-1- naphthyl)quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-ca rboxylate (47, 95 mg). MS (ESI) [M+H + ] + = 791.3. [0464] Step 4 : Tert-butyl 3-[2-[[(2S)-1-(3-aminopropyl)pyrrolidin-2-yl]methoxy]-8-fluo ro- 7-(3-hydroxy-1-naphthyl)quinazolin-4-yl]-3,8-diazabicyclo[3. 2.1]octane-8-carboxylate (48): [0465] Tert-butyl 3-[2-[[(2S)-1-[3-(benzyloxycarbonylamino)propyl]pyrrolidin-2 -yl]methoxy]- 8-fluoro-7-(3-hydroxy-1-naphthyl)quinazolin-4-yl]-3,8-diazab icyclo[3.2.1]octane-8-carboxylate (47, 62 mg, 0.078 mmol) was dissolved in 10 mL of ethanol and palladium on carbon (10% Pd by weight, 50 mg) was added. The reaction mixture was subjected to hydrogen atmosphere (~1 ATM, balloon) for 30 minutes at room temperature. The solution was filtered through celite and concentrated under reduced pressure to give tert-butyl 3-[2-[[(2S)-1-(3-aminopropyl)pyrrolidin-2-yl]methoxy]-8-fluo ro-7-(3- hydroxy-1-naphthyl)quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]o ctane-8-carboxylate (48, 51 mg). MS (ESI) [M+H + ] + = 657.3. [0466] Step 5 : N-[3-[(2S)-2-[[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluor o-7-(3-hydroxy-1- naphthyl)quinazolin-2-yl]oxymethyl]pyrrolidin-1-yl]propyl]ac etamide (P-0476): [0467] Tert-butyl 3-[2-[[(2S)-1-(3-aminopropyl)pyrrolidin-2-yl]methoxy]-8-fluo ro-7-(3- hydroxy-1-naphthyl)quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]o ctane-8-carboxylate (48, 29 mg, 0.044 mmol) was dissolved in dichloromethane and triethylamine (35 mg, 0.44 mmol) and acetyl chloride (45 mg, 0.44 mmol) were added. The mixture was stirred at room temperature for 15 minutes. The reaction was concentrated and dissolved in 5 mL of TFA. This solution was left at room temperature for 4 days. The reaction was directly purified by reverse phase chromatography (50 g C 1 8 column, 0-50% MeCN in water with 0.1% formic acid). This purification provided N-[3-[(2S)-2-[[4-(3,8-diazabicyclo[3.2.1]octan- 3-yl)-8-fluoro-7-(3-hydroxy-1-naphthyl)quinazolin-2-yl]oxyme thyl]pyrrolidin-1-yl]propyl]acetamide (P- 0476, 12 mg). MS (ESI) [M+H + ] + = 599.3. [0468] Step 6 : Benzyl N-[3-[(2S)-2-[[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluor o-7-(3- hydroxy-1-naphthyl)quinazolin-2-yl]oxymethyl]pyrrolidin-1-yl ]propyl]carbamate (P-0477): [0469] Tert-butyl 3-[2-[[(2S)-1-[3-(benzyloxycarbonylamino)propyl]pyrrolidin-2 -yl]methoxy]- 8-fluoro-7-(3-hydroxy-1-naphthyl)quinazolin-4-yl]-3,8-diazab icyclo[3.2.1]octane-8-carboxylate (47, 33 mg, 0.042 mmol) was dissolved in 1 mL of trifluoroacetic acid and left to stand at room temperature for 15 minutes. The reaction was concentrated to give benzyl N-[3-[(2S)-2-[[4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(3-hydroxy-1-napht hyl)quinazolin-2-yl]oxymethyl]pyrrolidin- 1-yl]propyl]carbamate (P-0477, 29 mg). MS (ESI) [M+H + ] + = 691.3. [0470] Step 7 : 4-[2-[[(2S)-1-(3-aminopropyl)pyrrolidin-2-yl]methoxy]-4-(3,8 - diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-quinazolin-7-yl]naph thalen-2-ol (P-0478): Tert-butyl 3-[2-[[(2S)-1-(3-aminopropyl)pyrrolidin-2-yl]methoxy]-8-fluo ro-7-(3-hydroxy-1- naphthyl)quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-ca rboxylate (48, 22 mg, 0.033 mmol) was dissolved in 1 mL of trifluoroacetic acid and left to stand at room temperature for 15 minutes. The reaction was concentrated to give 4-[2-[[(2S)-1-(3-aminopropyl)pyrrolidin-2-yl]methoxy]-4-(3,8 - diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-quinazolin-7-yl]naph thalen-2-ol (P-0478, 19.5 mg). MS (ESI) [M+H + ] + = 557.3. Example 18 [0471] Step 1: Tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (32) [0472] To a solution of 7-bromo-2,4-dichloro-8-fluoro-quinazoline (13, 300 mg, 1.01 mmol) in dioxane (3 mL), DIPEA (393 mg, 3.04 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (237 mg, 1.16 mmol) were added. After stirring for 2 hours at room temperature, the reaction was quenched by the addition of H 2 O, and the resulting was diluted with CH 2 Cl 2 . The layers were separated, and the aqueous layer was extracted with CH 2 Cl 2 . The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (32, 450 mg). MS (ESI) [M+H] + = 471.10. [0473] Step 2: Tert-butyl (1R,5S)-3-(7-(3-((tert-butyldimethylsilyl)oxy)naphthalen-1-y l)-2- chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan e-8-carboxylate (44) [0474] To a solution of tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (32, 3.3 g, 7 mmol) in dioxane/H 2 O (4/1, 50 mL), tert-butyl- dimethyl-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2 -naphthyl]oxy]silane (3.2 g, 8.4 mmol), Na2CO3 (2.2 g, 21 mmol) and [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II ) (511 mg, 0.7 mmol) were added at room temperature. After stirring for 3 hours at 90 °C, the reaction mixture was concentrated and purified with normal phase chromatography to afford tert-butyl (1R,5S)-3-(7-(3-((tert- butyldimethylsilyl)oxy)naphthalen-1-yl)-2-chloro-8-fluoroqui nazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (44, 2.5 g). [0475] Step 3: Tert-butyl (1R,5S)-3-(7-(3-((tert-butyldimethylsilyl)oxy)naphthalen-1-y l)-2- (3-(dimethylamino)azetidin-1-yl)-8-fluoroquinazolin-4-yl)-3, 8-diazabicyclo[3.2.1]octane-8- carboxylate (49) [0476] To a solution of tert-butyl (1R,5S)-3-(7-(3-((tert-butyldimethylsilyl)oxy)naphthalen-1- yl)-2-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1 ]octane-8-carboxylate (44, 100 mg, 0.15 mmol) in MeCN (3 mL), N,N-dimethylazetidin-3-amine hydrochloride (400 mg, 0.3 mmol) and N-ethyl- N-isopropyl-propan-2-amine (100 mg, 0.77 mmol) were added. After stirring for 1 hour at 110 °C under microwave condition, the reaction mixture was concentrated and purified with reverse phase C 1 8 column chromatography to afford tert-butyl (1R,5S)-3-(7-(3-((tert-butyldimethylsilyl)oxy)naphthalen-1-y l)-2-(3- (dimethylamino)azetidin-1-yl)-8-fluoroquinazolin-4-yl)-3,8-d iazabicyclo[3.2.1]octane-8-carboxylate (49, 700 mg). [0477] Step 4: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(3- (dimethylamino)azetidin-1-yl)-8-fluoroquinazolin-7-yl)naphth alen-2-ol (P-0794) [0478] To a solution of tert-butyl (1R,5S)-3-(7-(3-((tert-butyldimethylsilyl)oxy)naphthalen-1- yl)-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoroquinazolin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (49, 20 mg, 0.03 mmol) in CH 2 Cl 2 (10 mL), 4 N HCl in dioxane (1 mL) was added. After stirring for 2 hours at 75 °C, the reaction mixture was concentrated under reduced pressure and washed with EtOAc to afford 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(3-(dimet hylamino)azetidin-1- yl)-8-fluoroquinazolin-7-yl)naphthalen-2-ol (P-0794, 22.6 mg). MS (ESI) [M+H] + = 499.55. Example 19a [0479] Step 1: 5-(2-(4-Fluorophenyl)acetyl)-2,2-dimethyl-1,3-dioxane-4,6-di one (51) [0480] To a solution of p-fluorophenylacetic acid (50, 50 g, 324 mmol), 2,2-dimethyl-1,3- dioxane-4,6-dione (51.4 g, 357 mmol) and DMAP (3.37 g, 27.6 mmol) in MeCN, DIPEA (90.1 g, 697 mmol) was slowly added below 45 °C under nitrogen atmosphere. After that, 2,2-dimethylpropanoyl chloride (43 g, 357 mmol) was added dropwise while still maintaining below 45 °C. After stirring for 3 hours at 45 °C, the reaction mixture was cooled to 0 °C, and 1 M HCl was added. After additional stirring for 2 hours at 0 °C, precipitate was formed. Filtration of the precipitate gave yellow solid, and the crude product was washed with the solution of MeCN/H 2 O (1/4) to afford 5-[2-(4-fluorophenyl)acetyl]-2,2- dimethyl-1,3-dioxane-4,6-dione (51, 100 g). MS (ESI) [M+H] + = 281.10. [0481] Step 2: Tert-butyl 4-(4-fluorophenyl)-3-oxobutanoate (52) [0482] A mixture of 5-[2-(4-fluorophenyl)acetyl]-2,2-dimethyl-1,3-dioxane-4,6-di one (51, 96.3 g, 344 mmol) in t-BuOH (289 mL) was stirred for 1 hour at 90 °C. After cooled to room temperature, the reaction mixture was concentrated under reduced pressure. The crude product was washed with petroleum ether to afford tert-butyl 4-(4-fluorophenyl)-3-oxobutanoate (52, 49.9 g). MS (ESI) [M+H] + = 253.12. [0483] Step 3: 4-(4-Fluorophenyl)-3-oxobutanoic acid (53) [0484] To a solution of tert-butyl 4-(4-fluorophenyl)-3-oxobutanoate (52, 52.5 g, 208 mmol) in CH 2 Cl 2 (105 mL), TFA (105 mL) was added dropwise at room temperature. After stirring for overnight at room temperature, the resulting mixture was concentrated under reduced pressure. The reaction was quenched by the addition of saturated aqueous NaHCO 3 , and the resulting mixture was diluted with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure to afford 4-(4-fluorophenyl)-3-oxobutanoic acid (53, 16.9 g). MS (ESI) [M+H] + = 197.05. [0485] Step 4: 7-Fluoronaphthalene-1,3-diol (54) [0486] A mixture of 4-(4-fluorophenyl)-3-oxobutanoic acid (53, 16.9 g, 86.2 mmol) in CF 3 SO 3 H (188 mL) was stirred overnight at room temperature. The reaction was quenched by the addition of saturated aqueous NaHCO 3 , and the resulting mixture was diluted with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 7-fluoronaphthalene-1,3-diol (54, 11.3 g). MS (ESI) [M+H] + = 179.00. [0487] Step 5: 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (55) [0488] To a solution of 7-fluoronaphthalene-1,3-diol (54, 11.3 g, 63.4 mmol) and (2- bromoethynyl)triisopropylsilane (17.4 g, 66.6 mmol) in 1,4-dioxane (113 mL), dichloro(p-cymene) ruthenium(II) dimer (3.88 g, 6.34 mmol) and potassium acetate (12.5 g, 127 mmol) were added at room temperature. After stirring for 2 hours at 110 °C under nitrogen atmosphere, the resulting mixture was filtered, and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 7-fluoro-8-[2- (triisopropylsilyl)ethynyl]naphthalene-1,3-diol (55, 18.3 g). MS (ESI) [M+H] + = 395.20. [0489] Step 6: 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)na phthalen-1-ol (56) [0490] To a solution of 7-fluoro-8-[2-(triisopropylsilyl)ethynyl]naphthalene-1,3-dio l (55, 18.3 g, 51 mmol) in CH 2 Cl 2 (190 mL), chloromethyl methyl ether (6.16 g, 76.6 mmol) and DIPEA (19.8 g, 153 mmol) were added dropwise at 0 °C. After stirring for 3 hours at room temperature, the reaction was quenched by the addition of NH3 . H 2 O, and the resulting mixture was diluted with CH 2 Cl 2 . The layers were separated, and the aqueous layer was extracted with CH 2 Cl 2 . The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-ol (56, 13.1 g). MS (ESI) [M+H] + = 403.20. [0491] Step 7: 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)na phthalen-1-yl trifluoromethanesulfonate (57) [0492] To a stirred solution of 7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl) ethynyl]naphthalen-1-ol (56, 13.1 g, 32.5 mmol) in CH 2 Cl 2 (130 mL), DIPEA (12.6 g, 97.6 mmol) and Tf 2 O (13.8 g, 48.8 mmol) were added dropwise at −40 °C under nitrogen atmosphere. After stirring for 1 hour at −40 °C under nitrogen atmosphere, the reaction was quenched by the addition of H 2 O at 0 °C. The resulting mixture was extracted with CH 2 Cl 2 and the combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1- yl trifluoromethanesulfonate (57, 9.9 g). MS (ESI) [M+H] + = 535.20. [0493] Step 8: ((2-Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-d ioxaborolan- 2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (58) [0494] To a solution of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)na phthalen- 1-yl trifluoromethanesulfonate (57, 5 g, 9.35 mmol) and bis(pinacolato)diboron (7.12 g, 28.1 mmol) in toluene (50 mL), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II ), complex with dichloromethane (760 mg, 0.94 mmol) and potassium acetate (2.75 g, 28.1 mmol) were added at room temperature under nitrogen atmosphere. After stirring for 4 hours at 130 °C under nitrogen atmosphere, the resulting mixture was filtered, and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to afford ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-d ioxaborolan-2-yl)naphthalen-1- yl)ethynyl)triisopropylsilane (58, 2.41 g). MS (ESI) [M+H] + = 513.40. Example 19b [0495] Step 1 : Tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabi cyclo[3.2.1]octane-8-carboxylate (59) [0496] To a solution of tert-butyl 3-(7-bromo-2-chloro-8-fluoro-quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (32, 2 g, 4.24 mmol) and [(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methanol (1.35 g, 8.48 mmol) in DMSO (20 mL), KF (500 mg, 8.61 mmol) was added. After stirring for overnight at 90 °C under nitrogen, and run the additional stirring for 6 hours at 120 °C. The reaction was filtered, concentrated, and purified with reverse phase C 1 8 column chromatography to afford tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyc lo[3.2.1]octane-8-carboxylate (59, 1.2 g). [0497] Step 2: Tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (60) [0498] To a solution of (1R,5S)-3-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyc lo[3.2.1]octane-8-carboxylate (59, 200 mg, 0.33 mmol) and {2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2- yl)naphthalen-1-yl] ethynyl}triisopropylsilane (58, 207 mg, 0.4 mmol.) in dioxane/H 2 O (5/1, 6 mL), CataCXium A Pd G 2 (23 mg, 0.03 mmol), CataCXium (12 mg, 0.03 mmol) and Cs 2 CO 3 (219 mg, 0.67 mmol) were added at room temperature under nitrogen atmosphere. After stirring for overnight at 90 °C under nitrogen atmosphere, the reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was diluted with EtOAc, and washed with H 2 O. The organic layer was concentrated under reduced pressure, and the residue was purified by prep-TLC to afford tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triis opropylsilyl)ethynyl)naphthalen-1-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methox y)quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (60, 210 mg). MS (ESI) [M+H] + = 900.46. [0499] Step 3: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin- 7-yl)-6-fluoro-5- ((triisopropylsilyl)ethynyl)naphthalen-2-ol (61) [0500] 4 M HCl in dioxane (10 mL) was added to tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1- yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyc lo[3.2.1]octane-8-carboxylate (60, 200 mg, 0.22 mmol) at room temperature. After stirring for 2 hours at room temperature, the reaction mixture was concentrated under reduced pressure to afford 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)meth oxy)quinazolin-7-yl)-6-fluoro-5- ((triisopropylsilyl)ethynyl)naphthalen-2-ol (61, 150 mg). MS (ESI) [M+H] + = 738.39. [0501] Step 4: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin- 7-yl)-5-ethynyl-6-fluoronaphthalen- 2-ol (P-0815) [0502] To a solution of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazoli n-7-yl)-6-fluoro-5- ((triisopropylsilyl)ethynyl)naphthalen-2-ol (61, 20 mg, 0.0270 mmol) in DMF (0.5 mL), CsF (41 mg, 0.27 mmol) was added at room temperature. After stirring for overnight at room temperature, the reaction mixture was filtered and washed with DMF. The filtrate was concentrated under reduced pressure. The crude product was purified by prep-HPLC to afford 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol (P-0815, 4.1 mg). MS (ESI) [M+H] + = 600.30. Example 20 [0503] Step 1: Tert-butyl ((S)-3-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen -1- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7 a(5H)-yl)methoxy)quinazolin-4-yl)- 3,8-diazabicyclo[3.2.1]octan-8-yl)-2-hydroxypropyl)carbamate (P-0817) [0504] To a solution of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazoli n-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (P-0815, 20 mg, 0.03 mmol) and tert-butyl (S)-(oxiran-2-ylmethyl)carbamate (6 mg, 0.03 mmol) in t- BuOH (0.4 mL), DIPEA (9 mg, 0.06 mmol) was added at room temperature. After stirring for 3 hours at 80 °C, the reaction was cooled to room temperature and concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep C 1 8 OBD Column, 30x50 mm, 5 μm, 13 nm; Mobile Phase A: water (10 mmol/L, NH4HCO3), Mobile Phase B: MeCN; Flow rate: 60 mL/min; Gradient: 5% B to 5% B in 2 min, 5% B to 18% B in 2.5 min, 18% B to 50% B in 9.5 min, 50% B; wave Length: 220 nm; RT1 (min): 9.4) to afford tert-butyl ((S)-3-((1R,5S)-3- (7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyc lo[3.2.1]octan-8-yl)-2- hydroxypropyl)carbamate (P-0817, 6.4 mg). MS (ESI) [M+H] + = 773.35. Example 21a [0505] Step 1: 3-Bromo-1H-indole-4-carbonitrile (63) [0506] To a solution of 1H-indole-4-carbonitrile (62, 960 mg, 6.4 mmol) in 15 mL dioxane, 1,3- dibromo-5,5-dimethyl-imidazolidine-2,4-dione (1.00 g, 3.5 mmol) in 5 mL dioxane was added dropwise at 0 °C. After stirring for 10 min at room temperature, the reaction was quenched by the addition of saturated aqueous NaHCO 3 , and the resulting mixture was diluted with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO 4 , and concentrated under reduced pressure. The residue was isolated via 40 g silica column, eluting with EtOAc/hexanes (product eluted ~30% EtOAc). The fractions identified by TLC (20% EtOAc/hexane; bromo product Rf ~0.2) were pooled and concentrated to afford the 3-bromo-1H-indole-4-carbonitrile (63, 1.35 g). MS (ESI) [M+H] + = 222.9. [0507] Step 2: 3-Bromo-1-(triisopropylsilyl)-1H-indole-4-carbonitrile (64) [0508] To a solution of 3-bromo-1H-indole-4-carbonitrile (63, 1.35 g, 6.13 mmol) in 20 mL THF, NaH (60% in mineral oil, 316 mg, 7.97 mmol) was added portion-wise as a solid in 0 to 5°C. After stirring for over 10 min at 0 to 5 °C, triisopropylsilyl chloride (1.43 g, 7.36 mmol) in 5 mL THF was added dropwise. After stirring for 10 min at 0 to 5 °C, the reaction was quenched by the addition of saturated aqueous NH4Cl/H 2 O (1/1), and the resulting was diluted with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was isolated via 40 g silica, eluting with EtOAc/hexane (product elutes ~15% EtOAc). Fractions identified as product by TLC (20% EtOAc/hexane; product Rf~0.7) to afford 3-bromo-1-(triisopropylsilyl)-1H-indole- 4-carbonitrile (64, 2.52 g). MS (ESI) [M+H] + = 378.95. [0509] Step 3: 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(triisopro pylsilyl)-1H- indole-4-carbonitrile (65) [0510] To a cooled (−78 °C) solution of 3-bromo-1-(triisopropylsilyl)-1H-indole-4-carbonitrile (64, 1.26 g, 3.34 mmol) in 50 mL THF was added dropwise n-BuLi (2.5 M in hexanes, 2.2 mL, 5.5 mmol). After stirring for 1 hour at −78 °C, the reaction mixture was treated with an Pinacolborane (1.28 g, 10.1 mmol) in 5 mL THF. After stirring for 30 min, the reaction was quenched by addition of 5 mL of MeOH, and the resulting mixture was diluted with EtOAc. The combined organic layers were washed with saturated aqueous NH4Cl, and the resulting was diluted with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was isolated via 40 g silica, eluting with EtOAc/hexane (product eluted ~10% EtOAc/hexane). The fractions identified by TLC (20% EtOAc/hexane; product Rf ~0.5) were pooled and concentrated to afford 3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1-(triisopropylsilyl)-1H-indole-4-c arbonitrile (65, 0.68 g). MS (ESI) [M+H + ] + = 425.15. Example 21b [0511] Step 4: Tert-butyl (1R,5S)-3-(7-(4-cyano-1-(triisopropylsilyl)-1H-indol-3-yl)-8 - fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinaz olin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (65) [0512] Tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a( 5H)- yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (33, 80 mg, 0.13 mmol), 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(triisopropy lsilyl)-1H-indole-4-carbonitrile (65, 91 mg, 0.20 mmol), Na 2 CO 3 (52 mg, 0.49 mmol) and Pd(PPh 3 ) 4 (26 mg, 0.02 mmol) were dissolved in 1.6 mL dioxane and 0.4 mL water (2 mL of 20% H 2 O/dioxane). After stirring for 1 hour at 80° C, the reaction mixture was cooled to room temperature, filtered to remove solids, and concentrated to residue. The residue was dissolved in 2 mL DMSO and the Boc/des-Tips product isolated via 13 g flash C 1 8, eluting with MeCN/H 2 O (0.1% formic acid). The fractions containing Boc/des-Tips product were pooled frozen, and lyophilized to afford tert-butyl (1R,5S)-3-(7-(4-cyano-1-(triisopropylsilyl)-1H-indol-3-yl)-8 -fluoro- 2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (66, 57 mg). [0513] Step 5: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- ((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-1H-indole-4-ca rbonitrile (P-0666) [0514] To a tert-butyl (1R,5S)-3-(7-(4-cyano-1-(triisopropylsilyl)-1H-indol-3-yl)-8 -fluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl )-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (66, 57 mg, 0.07 mmol), 50% TFA in CH 2 Cl 2 (2 mL) was added. After stirring for 30 min at room temperature, the reaction mixture was concentrated to residue, dissolved in 4 mL H 2 O, and product isolated via prep-LC, eluting with MeCN/H 2 O (0.1% TFA). Fractions containing product were pooled, frozen, and lyophilized to afford 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl )-1H-indole-4-carbonitrile (P-0666, 43 mg). MS (ESI) [M+H] + = 538.60. Example 22 [0515] Step 1: Tert-butyl (1R,5S)-3-(7-(3-((tert-butyldimethylsilyl)oxy)naphthalen-1-y l)-8- fluoro-2-(3-methoxy-2,2-dimethyl-3-oxopropoxy)quinazolin-4-y l)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (2) [0516] The mixture of tert-butyl (1R,5S)-3-(7-(3-((tert-butyldimethylsilyl)oxy)naphthalen-1-y l)- 2-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]oct ane-8-carboxylate (44, 90 mg, 0.13 mmol), methyl 3-hydroxy-2,2-dimethylpropanoate (36.6 mg, 0.27 mmol), anhydrous Cs2CO3 (90.4 mg, 0.27 mmol) and PdRuPhos G4 catalyst (11.9 mg, 0.01 mmol) were purged with N2 gas and then added 2 mL dioxane. After stirring for 1 hour at 90 °C, 1 mL water and 1 mL MeOH were added to the reaction mixture. After additional stirring for 30 min at room temperature, removed solvent under reduced pressure and the residue was purified by RP-HPLC to afford tert-butyl (1R,5S)-3-(7-(3-((tert- butyldimethylsilyl)oxy)naphthalen-1-yl)-8-fluoro-2-(3-methox y-2,2-dimethyl-3-oxopropoxy)quinazolin- 4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (67, 58 mg). [0517] Step 2: 3-((4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2. 1]octan-3-yl)-8- fluoro-7-(3-hydroxynaphthalen-1-yl)quinazolin-2-yl)oxy)-2,2- dimethylpropanoic acid (68) [0518] To a solution of afford tert-butyl (1R,5S)-3-(7-(3-((tert- butyldimethylsilyl)oxy)naphthalen-1-yl)-8-fluoro-2-(3-methox y-2,2-dimethyl-3-oxopropoxy)quinazolin- 4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (67, 58 mg, 0.07 mmol) in 2 mL MeOH/THF (1/1), 1 N LiOH in H 2 O (1 mL) were added. After stirring for 4 hours at room temperature, the reaction mixture through a short silica pad with 30% MeOH in CH 2 Cl 2 . Concentrated the filtrate under reduced pressure and purified the residue by RP-HPLC to afford 3-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8- fluoro-7-(3-hydroxynaphthalen-1-yl)quinazolin-2-yl)oxy)-2,2- dimethylpropanoic acid (68, 30 mg). [0519] Step 3: 3-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7 -(3- hydroxynaphthalen-1-yl)quinazolin-2-yl)oxy)-2,2-dimethylprop anoic acid (P-0647) [0520] To a solution of 3-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7 -(3- hydroxynaphthalen-1-yl)quinazolin-2-yl)oxy)-2,2-dimethylprop anoic acid (68, 30 mg, 0.04 mmol) in CH 2 Cl 2 (1 mL), 0.2 mL TFA was added. After stirring for 1 hour at room temperature, the reaction was concentrated under reduced pressure. The residue was purified by RP-HPLC to afford 3-((4-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(3-hydroxynaphthal en-1-yl)quinazolin-2-yl)oxy)-2,2- dimethylpropanoic acid (P-0647, 19 mg). MS (ESI) [M+H] + = 517.60. Example 23 [0521] Step 1: Tert-butyl (1R,5S)-3-(8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy )- 7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicycl o[3.2.1]octane-8-carboxylate (69) [0522] A mixture of tert-butyl (1R,5S)-3-(7-(3-((tert-butyldimethylsilyl)oxy)naphthalen-1-y l)-2- chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan e-8-carboxylate (44, 90 mg, 0.13 mmol), cyclopropane-1,1-diyldimethanol (28.3 mg, 0.27 mmol), anhydrous Cs2CO3 (90.4 mg, 0.27 mmol) and PdRuPhos G4 catalyst (11.9 mg, 0.01 mmol) was purged with N2 gas and then added 2 mL dioxane. After stirring for 1 hour at 90 °C, 1 mL water and 1 mL MeOH were added to the reaction mixture. After additional stirring for 30 min at room temperature, the reaction was concentrated under reduced pressure. The residue was purified by RP-HPLC to afford tert-butyl (1R,5S)-3-(8-fluoro-2-((1- (hydroxymethyl)cyclopropyl)methoxy)-7-(3-hydroxynaphthalen-1 -yl)quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (69, 52 mg). [0523] Step 2: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- ((1 (hydroxymethyl)cyclopropyl)methoxy)quinazolin-7-yl)naphthale n-2-ol (3) [0524] To a solution of tert-butyl (1R,5S)-3-(8-fluoro-2-((1- (hydroxymethyl)cyclopropyl)methoxy)-7-(3-hydroxynaphthalen-1 -yl)quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (69, 52 mg, 0.08 mmol) in CH 2 Cl 2 (1 mL), 0.2 mL TFA was added. After stirring for 1 hour at room temperature, the reaction was concentrated under reduced pressure. The residue was purified by RP-HPLC to afford 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3- yl)-8-fluoro-2-((1 (hydroxymethyl)cyclopropyl)methoxy)quinazolin-7-yl)naphthale n-2-ol (P-0614, 44 mg). MS (ESI) [M+H] + = 501.60. Example 24 [0525] Step 1: 4-(4-((1R,5S)-8-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl) -3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-py rrolizin-7a(5H)- yl)methoxy)quinazolin-7-yl)-5-fluoronaphthalen-2-ol (2) [0526] To a mixture of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl )-5-fluoronaphthalen-2-ol (P-0501, 60 mg, 0.10 mmol), (S)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (140 mg, 1.08 mmol), formic acid (0.5 mg, 0.01 mmol) in THF (2 mL) was added at room temperature. After stirring for 1 hour at 40°C, NaBH4 (12 mg, 0.32 mmol) was added in portions at room temperature. After stirring for overnight at room temperature, the reaction was quenched by addition of saturated aqueous NH4Cl (5 mL) at room temperature, and the resulting mixture was diluted with EtOAc. The aqueous layer was extracted with EtOAc, and the combined organic layer was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 19x150 mm, 5 μm; Mobile Phase A: water (10 mmol/L, NH 4 HCO 3 ), Mobile Phase B: MeCN; Flow rate: 25 mL/min; Gradient: 34% B to 61% B in 7 min, 61% B; wave Length: 220 nm; RT1(min): 6.45) to afford 4-(4-((1R,5S)-8-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl) -3,8-diazabicyclo[3.2.1]octan-3-yl)- 8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quin azolin-7-yl)-5-fluoronaphthalen-2-ol (70, 12.1 mg). MS (ESI) [M+H] + = 672. [0527] Step 2: (R)-3-((1R,5S)-3-(8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1 -yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl )-3,8-diazabicyclo[3.2.1]octan-8- yl)propane-1,2-diol [0528] To a solution of 4-(4-((1R,5S)-8-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl) -3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-py rrolizin-7a(5H)-yl)methoxy)quinazolin-7- yl)-5-fluoronaphthalen-2-ol (70, 12 mg, 0.01 mmol) in 0.3 mL dioxane, 4 M HCl in dioxane (0.3 mL) was added at room temperature. After stirring for 1 hour at room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with hexane (0.5 mL) to afford (R)-3-((1R,5S)-3-(8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1 -yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]oc tan-8-yl)propane-1,2-diol (P-0501, 10.1 mg). MS (ESI) [M+H] + = 632.15. [0529] All compounds in Tables IA and IB listed below can be made according to the synthetic examples described in this disclosure, and by making any necessary substitutions of starting materials that the skilled artisan would be able to obtain either commercially or otherwise. TABLE IA
TABLE IB
Biological Examples Biological Test Methods [0530] The compounds of disclosure were tested using the following assays: KRAS binding disruption assay [0531] Compound binding to G12D or G12C-mutant KRAS was indirectly measured in a proximity-based binding disruption assays using AlphaScreen technology from Perkin Elmer. Binding of Flag-tagged G12D or G12C-mutant KRAS to biotinylated KRpep-2d analogues or to biotinylated RAF1- RBD was detected using the AlphaScreen FLAG (M2) kit. Compound binding disrupts the interaction of KRpep-2d or RAF1-RBD with KRAS, leading to a decrease in Alpha signal. [0532] G12D or G12C-mutant human KRAS (amino acid residues 1-188) with FLAG tag and human RAF1-RBD (amino acid residues 51-131) with Avi-Tag were purified from E. coli. All assay components were prepared in 20 mM HEPES (pH 7.5), 100 mM NaCl, 5 mM MgCl 2 , 0.01% Tween-20, and 0.01% BSA. Biotinylated analogues of KRpep-2d were custom synthesized. The binding disruption assays were performed using 5-20 nM of mutant KRAS and 5-20 nM of either biotinylated KRpep-2d analogue or RAF1-RBD.19 µL of KRAS protein and 4 µL of biotinylated KRpep-2d or RAF1-RBD were added to the wells of a 384-well plate containing 1µL of various concentrations of test compound or DMSO vehicle.16 wells containing KRAS, biotinylated KRpep-2d or RAF1-RBD, and 5% DMSO served as high controls.16 wells containing KRAS only and 5% DMSO served as low controls. Binding reactions were incubated for 1 hour at 25ºC, then Anti-Flag Acceptor and Streptavidin Donor Alpha beads were added at a final concentration of 10 µg/mL for an additional hour at room temperature. Alpha signal was read out on a Perkin Elmer Envision HTS instrument. The percentage inhibition at individual compound concentrations relative to high and low controls was calculated. The data were analyzed by using nonlinear regression to generate IC 5 0 values. Various compounds in Table IA were tested using this assay and were found to be active. KRAS binding competition assay [0533] Compound binding to G12V-mutant KRAS was indirectly measured in a proximity- based competition assay using AlphaScreen technology from Perkin Elmer. Binding of Flag-tagged G12V-mutant KRAS to biotinylated KRpep-2d analogues was detected using the AlphaScreen FLAG (M2) kit. Compound binding disrupts the interaction of KRpep-2d with KRAS, leading to a decrease in Alpha signal. [0534] G12V-mutant human KRAS (amino acid residues 1-188) with FLAG tag was purified from E. coli. All assay components were prepared in 20 mM HEPES (pH 7.5), 100 mM NaCl, 5 mM MgCl2, 0.01% Tween-20, and 0.01% BSA. Biotinylated analogues of KRpep-2d were custom synthesized. The binding competition assays were performed using 10 nM of mutant KRAS and 10 nM of biotinylated KRpep-2d analogue.19 µL of KRAS protein and 4 µL of biotinylated KRpep-2d were added to the wells of a 384-well plate containing 1µL of various concentrations of test compound or DMSO vehicle.16 wells containing KRAS, biotinylated KRpep-2d, and 5% DMSO served as high controls.16 wells containing KRAS only and 5% DMSO served as low controls. Binding reactions were incubated for 1 hour at 25ºC, then Anti-Flag Acceptor and Streptavidin Donor Alpha beads were added at a final concentration of 10 µg/mL for an additional hour at room temperature. Alpha signal was read out on a Perkin Elmer Envision HTS instrument. The percentage inhibition at individual compound concentrations relative to high and low controls was calculated. The data were analyzed by using nonlinear regression to generate IC 50 values. Various compounds in Table IA were tested using this assay and were found to be active. Phospho-ERK and growth inhibition in AGS KRASG12D cells [0535] Cellular activity of inhibitors was assessed in the AGS cell line that is heterozygous for KRASG12D. AGS cells were maintained and assayed in F-12K medium supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin at 37 ºC in a humidified incubator supplied with 5% CO 2 . Phospho-ERK levels were detected using AlphaScreen technology from Perkin Elmer. The phospho- ERK assays were performed as follows. Cells were seeded in a 96-well plate in 50 µL of culture media at a density of 5x10 4 cells per well. Compound at a maximal concentration of 5 mM was serially diluted 1:3 in DMSO for an 8-point titration. A 1 μL aliquot of each dilution point was added to 249 μL culture media.50 μL of diluted compound was added to each well, providing 10 µM compound at the maximum concentration point.4 wells containing cells treated with 0.2% DMSO served as high controls, and 4 wells containing cells treated with 1 μM PD0325901, a MEK inhibitor, served as low controls. After 2 hours of incubation, media was removed from the wells. Cells were lysed in 50 µL of AlphaLISA lysis buffer supplemented with protease and phosphatase inhibitors. The lysates were then transferred to a 384- well plate. Anti-mouse IgG Acceptor Alpha beads were added for a final concentration of 10 µg/mL, and anti-phospho-ERK and biotinylated anti-ERK antibodies were added for a final concentration of 0.02nM and 0.625nM, respectively, for 4 hours at room temperature. After the antibody and Acceptor bead incubation, Streptavidin Donor Alpha beads were added for a final concentration of 10 µg/mL for an additional 2 hours at room temperature. Alpha signal was read out on a Perkin Elmer Envision HTS instrument. The percentage inhibition at individual compound concentrations relative to high and low controls was calculated. The data were analyzed by using nonlinear regression to generate IC 5 0 values. Various compounds in Table IA were tested using this assay and were found to be active. [0536] G Growth inhibition assays were performed as follows. Cells were seeded in U-bottom, ultra-low attachment spheroid 96-well plates in 75 µL of culture media at a density of 10 3 cells per well. Compound at a maximal concentration of 5 mM was serially diluted 1:3 in DMSO for an 8-point titration. A 1 μL aliquot of each dilution point was added to 249 μL culture media.75 μL of diluted compound was added to each well, providing 10 µM compound at the maximum concentration point.8 wells containing cells treated with 0.2% DMSO served as high controls. After 5 days of treatment, cell viability was measured using 50 μL of CellTiter-Glo® 3D from Promega. Following incubation of the plate at room temperature for 10 minutes, luminescent signal was read on a Tecan plate reader. The percentage inhibition at individual concentrations relative to high controls was calculated. The data were analyzed by using nonlinear regression to generate IC 50 values. Various compounds in Table IA were tested using this assay and were found to be active. [0537] The following Table 2 provides data, where available, indicating biochemical and/or cell inhibitory activity for exemplary compounds as described herein in Table IA. In Table 2 below, activity is provided as follows: +++ = 0.0001 µM < IC 50 ≤10 µM; ++ = 10 µM < IC 50 ≤100 µM; + = 100 µM < IC 50 ≤1000 µM. Blank cells of Table 2 and compounds not listed in Table 2 indicate test results that are not yet available, and do not indicate any level of activity or potency. TABLE 2
[0538] It has been observed that the compounds of this disclosure exhibit an unexpectedly higher potency for KRAS G12D solely because of the unique structural distinction of having a bridged heterocycloalkyl at the R 1 variable. Table 3 below provides side-by-side comparisons of representative compounds of this disclosure to the non-bridged versions of these compounds at the R1 variable. TABLE 3 It has been observed that when comparing structurally similar compounds from the art, such as those listed in Table 4 from WO 2017/172979, to compounds of this disclosure, that the compounds of this disclosure having the structurally unique bridged heterocycloalkyl at the R 1 variable exhibit an unexpectedly higher potency for KRAS G12D. Table 4 below provides side-by-side comparisons of structurally similar compounds in WO 2017/172979 that do not contain such a bridge to compounds in this disclosure that do contain this bridge. TABLE 4 [0539] Other embodiments of this disclosure relate to compounds that exhibit an unexpectedly higher potency for KRAS G12V solely because of the unique structural distinction of having a bridged heterocycloalkyl at the R 1 variable vs the same compounds that do not. Other embodiments of this disclosure relate to compounds that exhibit a higher potency for KRAS G12D over KRAS G12C. Other embodiments of this disclosure relate to compounds that exhibit a higher potency for KRAS G12D over KRAS G12V. Other embodiments of this disclosure relate to compounds that exhibit a higher potency for KRAS G12V over KRAS G12C. Other embodiments of this disclosure relate to compounds that exhibit a higher potency for KRAS G12V over KRAS G12D. [0540] All patents and other references cited herein are indicative of the level of skill of those skilled in the art to which the disclosure pertains, and are incorporated by reference in their entireties, including any tables and figures, to the same extent as if each reference had been incorporated by reference in its entirety individually. [0541] One skilled in the art would readily appreciate that the present disclosure is well adapted to obtain the ends and advantages mentioned, as well as those inherent therein. The methods, variances, and compositions described herein as presently representative of the embodiments described herein are exemplary and are not intended as limitations on the scope of the disclosure. Changes therein and other uses will occur to those skilled in the art, which are encompassed within the spirit of the disclosure, are defined by the scope of the claims. [0542] It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the present disclosure described herein without departing from the scope and spirit of the disclosure. For example, variations can be made to provide additional compounds of the compounds of this disclosure and/or various methods of administration can be used. Thus, such additional embodiments are within the scope of the present disclosure and the following claims. [0543] The present disclosure illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically described herein. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the disclosure claimed. Thus, it should be understood that although the present disclosure has been specifically described by the embodiments and optional features, modification and variation of the concepts herein described may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this disclosure as defined by the appended claims. [0544] In addition, where features or aspects of the disclosure are described in terms grouping of alternatives, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the groups described herein. [0545] Also, unless indicated to the contrary, where various numerical values are provided for embodiments, additional embodiments are described by taking any 2 different values as the endpoints of a range. Such ranges are also within the scope of the present disclosure. [0546] Thus, additional embodiments are within the scope of the disclosure and within the following claims.