Antibacterial compounds

Abstract

The invention relates to antibacterial and anti-mycobacterial drug compounds of formula I. It also relates to pharmaceutical formulations of antibacterial drug compounds. It also relates to uses of the derivatives in treating bacterial infections, and methods of treating bacterial infections. The invention is also directed to antibacterial drug compounds capable of treating bacterial infections that are currently hard to treat with existing drug compounds, e.g., those caused by resistant bacterial or mycobacterial strains.

Claims

1. A compound of formula (VII), or a pharmaceutically acceptable salt or N-oxide thereof: ##STR00251## wherein X.sup.1 is independently selected from N and CR.sup.5; X.sup.2 is independently selected from N and CR.sup.2; A is independently selected from O, S, NR.sup.6 and NOR.sup.6; Z.sup.1 is selected from O and S; R.sup.1 is independently selected from H, F, NR.sup.6R.sup.7, NR.sup.6NR.sup.6R.sup.7 and C.sub.1-C.sub.4-alkyl; R.sup.2 is independently selected from H, C.sub.1-C.sub.4-alkyl and halo; R.sup.3 is independently selected from (CR.sup.8R.sup.8).sub.nC.sub.3-C.sub.10 heterocycloalkyl, (CR.sup.8R.sup.8).sub.n-aryl, (CR.sup.8R.sup.8).sub.n-heteroaryl, and (CR.sup.8R.sup.8).sub.nC.sub.3-C.sub.10 cycloalkyl; wherein the aryl, heteroaryl, heterocycloalkyl or cycloalkyl group is optionally substituted with 1, 2 or 3 R.sup.15 groups; wherein R.sup.15 is independently at each occurrence selected from oxo, NR.sup.6, NOR.sup.6, C.sub.3-C.sub.5-heterocycloalkyl, halo, nitro, cyano, NR.sup.6R.sup.7, NR.sup.6S(O).sub.2R.sup.6, NR.sup.6CONR.sup.6R.sup.6, NR.sup.6CO.sub.2R.sup.6, OR.sup.6; SR.sup.6, SOR.sup.6, SO.sub.3R.sup.6, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.6, CO.sub.2R.sup.6C(O)R.sup.6, CONR.sup.6R.sup.6, C(O)NR.sup.6CR.sup.6R.sup.6C(O)OR.sup.6, C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-alkynyl, C.sub.1-C.sub.4 haloalkyl, CR.sup.6R.sup.6OR.sup.6, CR.sup.6R.sup.6NR.sup.7R.sup.6, and CR.sup.6CR.sup.6R.sup.6NR.sup.7R.sup.6; R.sup.4 is independently selected from C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.1-C.sub.8 haloalkyl, (CR.sup.8R.sup.8).sub.nC.sub.3-C.sub.6 cycloalkyl, (CR.sup.8R.sup.8).sub.nC.sub.3-C.sub.6 heterocycloalkyl, (CR.sup.8R.sup.8).sub.nC.sub.3-C.sub.6 halocycloalkyl, (CR.sup.8R.sup.8).sub.n-phenyl, and (CR.sup.8R.sup.8).sub.n-heteroaryl; R.sup.5 is independently selected from H, OC.sub.1-C.sub.8 alkyl, halo, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.1-C.sub.8 haloalkyl, OC.sub.1-C.sub.8 haloalkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 heterocycloalkyl, and C.sub.3-C.sub.6 halocycloalkyl; or R.sup.4 and R.sup.5 together form an alkylene or heteroalkylene chain of the form (CR.sup.8R.sup.8).sub.rW.sup.1(CR.sup.8R.sup.8).sub.sW.sup.2(CR.sup.8R.sup.8).sub.t and which is attached at its respective ends to the substitution point for R.sup.4 and R.sup.5 respectively; wherein W.sup.1 and W.sup.2 are each independently selected from a bond, O, S and NR.sup.9; wherein r, s, and t are each independently an integer selected from 0, 1 and 2 and wherein definitions of r, s, t, W.sup.1 and W.sup.2 are chosen such that the total length of the alkylene or heteroalkylene chain is 2, 3 or 4 atoms; R.sup.6, R.sup.9 and R.sup.13 are independently at each occurrence selected from H, C.sub.1-C.sub.4 alkyl, and C.sub.1-C.sub.4 haloalkyl; R.sup.7 and R.sup.14 are each independently at each occurrence selected from H, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, S(O).sub.2C.sub.1-C.sub.4alkyl, C(O)C.sub.1-C.sub.4 alkyl, C(O)OC.sub.1-C.sub.4 alkyl and CH.sub.2-phenyl; R.sup.8 is independently at each occurrence selected from H, Me, CF.sub.3 and F; R.sup.12 is independently at each occurrence selected from H, halo, nitro, cyano, NR.sup.13R.sup.14, NR.sup.13S(O).sub.2R.sup.13, NR.sup.13CONR.sup.13R.sup.13, NR.sup.13CO.sub.2R.sup.13, OR.sup.13; SR.sup.13, SOR.sup.13, SO.sub.3R.sup.13, SO.sub.2R.sup.13, SO.sub.2NR.sup.13R.sup.13, CO.sub.2R.sup.13C(O)R.sup.13, CONR.sup.13R.sup.13, C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-alkynyl, C.sub.1-C.sub.4 haloalkyl, CR.sup.13R.sup.13OR.sup.13, CR.sup.13R.sup.13OC(O)R.sup.13; and CR.sup.13R.sup.13NR.sup.13R.sup.14; and n is an integer independently selected at each occurrence from 0, 1, 2 and 3; and wherein each of said aryl, heteroaryl, C.sub.3-C.sub.10 heterocycloalkyl or C.sub.3-C.sub.10 cycloalkyl groups is monocyclic or bicyclic; and wherein when the R.sup.1, R.sup.2, R.sup.4, R.sup.6, R.sup.7, R.sup.9, and R.sup.15 groups are an alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl or heteroaryl group, said alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally substituted, where chemically possible, by 1 to 5 substituents which are each independently at each occurrence selected from oxo, NR.sup.a, NOR.sup.a, halo, nitro, cyano, NR.sup.aR.sup.a, NR.sup.aS(O).sub.2R.sup.a, NR.sup.aCONR.sup.aR.sup.a, NR.sup.aCO.sub.2R.sup.a, OR.sup.a; SR.sup.a, S(O)R.sup.a, S(O).sub.2OR.sup.a, S(O).sub.2R.sup.a, S(O).sub.2NR.sup.aR.sup.a, CO.sub.2R.sup.a C(O)R.sup.a, CONR.sup.aR.sup.a, C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-alkynyl, C.sub.1-C.sub.4 haloalkyl, CR.sup.bR.sup.bOR.sup.a, CR.sup.bR.sup.bNR.sup.aR.sup.a, and CR.sup.bCR.sup.bR.sup.bNR.sup.aR.sup.a; wherein R.sup.a is independently at each occurrence selected from H, C.sub.1-C.sub.4 alkyl and C.sub.1-C.sub.4 haloalkyl; and R.sup.b is independently at each occurrence selected from H, halogen, C.sub.1-C.sub.4 alkyl and C.sub.1-C.sub.4 haloalkyl.

2. The compound of claim 1, wherein Z.sup.1 is O.

3. The compound of claim 1, wherein R.sup.12 is independently at each occurrence selected from H, C.sub.1-C.sub.4-alkyl, CR.sup.13R.sup.13OR.sup.13, CR.sup.13R.sup.13OC(O)R.sup.13 and CR.sup.13R.sup.13NR.sup.13R.sup.14.

4. The compound of claim 1, wherein A is O.

5. The compound of claim 1, wherein R.sup.1 is H.

6. The compound of claim 1, wherein X.sup.2 is CR.sup.2.

7. The compound of claim 1, wherein X.sup.1 is CR.sup.5.

8. The compound of claim 7, wherein R.sup.5 is independently selected from Cl, OC.sub.1-C.sub.4 alkyl, and C.sub.1-C.sub.4 alkyl.

9. The compound of claim 7, wherein R.sup.4 and R.sup.5 together form an alkylene or heteroalkylene chain of the form O(CR.sup.8R.sup.8).sub.2 and which is attached at its respective ends to the substitution point for R.sup.4 and R.sup.5 respectively.

10. The compound of claim 1, wherein R.sup.4 is independently selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, cyclopropyl and halocyclopropyl.

11. The compound of claim 1, wherein R.sup.3 is selected from phenyl and 6- or 9-membered heteroaryl comprising at least one nitrogen.

12. The compound of claim 1, wherein R.sup.3 is ##STR00252## wherein R.sup.16 is R.sup.15; or wherein two R.sup.16 groups together with the carbon or carbons to which they are attached form a 3-6 membered cycloalkyl, a 3-6 membered heterocycloalkyl ring or a 6-membered aryl or heteroaryl ring; wherein where two R.sup.16 groups form a heterocycloalkyl ring, said heterocycloalkyl ring will comprise 1 or 2 heteroatoms selected from N, O and S in the ring system; wherein where two R.sup.16 groups form a cycloalkyl or heterocycloalkyl ring, said cycloalkyl or heterocycloalkyl ring is optionally substituted with one or two R.sup.15 groups; wherein R.sup.15 is independently selected from oxo, NOR.sup.6, NR.sup.6R.sup.7, OR.sup.6, C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-alkynyl, CR.sup.6R.sup.6NR.sup.6R.sup.7 and CR.sup.6CR.sup.6R.sup.6NR.sup.6R.sup.7; and m is an integer independently selected from 0, 1, 2 and 3.

13. The pharmaceutical formulation, comprising a compound of claim 1; and a pharmaceutically acceptable excipient.

14. The pharmaceutical formulation of claim 13, further comprising at least one other antibiotic.

15. The pharmaceutical formulation of claim 14, wherein the at least one other antibiotic is a fluoroquinolone antibiotic.

16. A method of treating a bacterial or mycobacterial infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (VII), or a pharmaceutically acceptable salt or N-oxide thereof: ##STR00253## wherein X.sup.1 is independently selected from N and CR.sup.5; X.sup.2 is independently selected from N and CR.sup.2; A is independently selected from O, S, NR.sup.6 and NOR.sup.6; Z.sup.1 is selected from O and S; R.sup.1 is independently selected from H, F, NR.sup.6R.sup.7, NR.sup.6NR.sup.6R.sup.7 and C.sub.1-C.sub.4-alkyl; R.sup.2 is independently selected from H, C.sub.1-C.sub.4-alkyl and halo; R.sup.3 is independently selected from (CR.sup.8R.sup.8).sub.nC.sub.3-C.sub.10 heterocycloalkyl, (CR.sup.8R.sup.8).sub.n-aryl, (CR.sup.8R.sup.8).sub.n-heteroaryl, and (CR.sup.8R.sup.8).sub.nC.sub.3-C.sub.10 cycloalkyl; wherein the aryl, heteroaryl, heterocycloalkyl or cycloalkyl group is optionally substituted with 1, 2 or 3 R.sup.15 groups; wherein R.sup.15 is independently at each occurrence selected from oxo, NR.sup.6, NOR.sup.6, C.sub.3-C.sub.5-heterocycloalkyl, halo, nitro, cyano, NR.sup.6R.sup.7, NR.sup.6S(O).sub.2R.sup.6, NR.sup.6CONR.sup.6R.sup.6, NR.sup.6CO.sub.2R.sup.6, OR.sup.6; SR.sup.6, SOR.sup.6, SO.sub.3R.sup.6, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.6, CO.sub.2R.sup.6C(O)R.sup.6, CONR.sup.6R.sup.6, C(O)NR.sup.6CR.sup.6R.sup.6C(O)OR.sup.6, C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-alkynyl, C.sub.1-C.sub.4 haloalkyl, CR.sup.6R.sup.6OR.sup.6, CR.sup.6R.sup.6NR.sup.7R.sup.6, and CR.sup.6CR.sup.6R.sup.6NRR.sup.6; R.sup.4 is independently selected from C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.1-C.sub.8 haloalkyl, (CR.sup.8R.sup.8).sub.nC.sub.3-C.sub.6 cycloalkyl, (CR.sup.8R.sup.8).sub.nC.sub.3-C.sub.6 heterocycloalkyl, (CR.sup.8R.sup.8).sub.nC.sub.3-C.sub.6 halocycloalkyl, (CR.sup.8R.sup.8).sub.n-phenyl, and (CR.sup.8R.sup.8).sub.n-heteroaryl; R.sup.5 is independently selected from H, OC.sub.1-C.sub.8 alkyl, halo, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.1-C.sub.8 haloalkyl, OC.sub.1-C.sub.8 haloalkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 heterocycloalkyl, and C.sub.3-C.sub.6 halocycloalkyl; or R.sup.4 and R.sup.5 together form an alkylene or heteroalkylene chain of the form (CR.sup.8R.sup.8).sub.rW.sup.1(CR.sup.8R.sup.8).sub.sW.sup.2(CR.sup.8R.sup.8).sub.t and which is attached at its respective ends to the substitution point for R.sup.4 and R.sup.5 respectively; wherein W.sup.1 and W.sup.2 are each independently selected from a bond, O, S and NR.sup.9; wherein r, s, and t are each independently an integer selected from 0, 1 and 2 and wherein definitions of r, s, t, W.sup.1 and W.sup.2 are chosen such that the total length of the alkylene or heteroalkylene chain is 2, 3 or 4 atoms; R.sup.6, R.sup.9 and R.sup.13 are independently at each occurrence selected from H, C.sub.1-C.sub.4 alkyl, and C.sub.1-C.sub.4 haloalkyl; R.sup.7 and R.sup.14 are each independently at each occurrence selected from H, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, S(O).sub.2C.sub.1-C.sub.4alkyl, C(O)C.sub.1-C.sub.4 alkyl, C(O)OC.sub.1-C.sub.4 alkyl and CH.sub.2-phenyl; R.sup.8 is independently at each occurrence selected from H, Me, CF.sub.3 and F; R.sup.12 is independently at each occurrence selected from H, halo, nitro, cyano, NR.sup.13R.sup.14, NR.sup.13S(O).sub.2R.sup.13, NR.sup.13CONR.sup.13R.sup.13, NR.sup.13CO.sub.2R.sup.13, OR.sup.13; SR.sup.13, SOR.sup.13, SO.sub.3R.sup.13, SO.sub.2R.sup.13, SO.sub.2NR.sup.13R.sup.13, CO.sub.2R.sup.13C(O)R.sup.13, CONR.sup.13R.sup.13, C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-alkynyl, C.sub.1-C.sub.4 haloalkyl, CR.sup.13R.sup.13OR.sup.13, CR.sup.13R.sup.13OC(O)R.sup.13; and CR.sup.13R.sup.13NR.sup.13R.sup.14; and n is an integer independently selected at each occurrence from 0, 1, 2 and 3; and wherein each of said aryl, heteroaryl, C.sub.3-C.sub.10 heterocycloalkyl or C.sub.3-C.sub.10 cycloalkyl groups is monocyclic or bicyclic; and wherein when the R.sup.1, R.sup.2, R.sup.4, R.sup.6, R.sup.7, R.sup.9, and R.sup.15 groups are an alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl or heteroaryl group, said alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally substituted, where chemically possible, by 1 to 5 substituents which are each independently at each occurrence selected from oxo, NR.sup.a, NOR.sup.a, halo, nitro, cyano, NR.sup.aR.sup.a, NR.sup.aS(O).sub.2R.sup.a, NR.sup.aCONR.sup.aR.sup.a, NR.sup.aCO.sub.2R.sup.a, OR.sup.a; SR.sup.a, S(O)R.sup.a, S(O).sub.2OR.sup.a, S(O).sub.2R.sup.a, S(O).sub.2NR.sup.aR.sup.a, CO.sub.2R.sup.aC(O)R.sup.a, CONR.sup.aR.sup.a, C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-alkynyl, C.sub.1-C.sub.4 haloalkyl, CR.sup.bR.sup.bOR.sup.a, CR.sup.bR.sup.bNR.sup.aR.sup.a, and CR.sup.bCR.sup.bR.sup.bNR.sup.aR.sup.a; wherein R.sup.a is independently at each occurrence selected from H, C.sub.1-C.sub.4 alkyl and C.sub.1-C.sub.4 haloalkyl; and R.sup.b is independently at each occurrence selected from H, halogen, C.sub.1-C.sub.4 alkyl and C.sub.1-C.sub.4 haloalkyl.

17. The method of claim 16, wherein the bacterial infection is caused by Gram negative bacteria.

18. The method of claim 16, wherein the bacterial infection is caused by a bacterial strain selected from Haemophilus spp., Moraxella spp., Legionella spp. and Neisseria spp.

19. The method of claim 18, wherein the bacterial infection is gonorrhoea.

20. The method of claim 16, wherein the bacterial infection is caused by Gram positive bacteria.

21. The method of claim 20, wherein the bacterial infection is caused by methicillin-resistant Staphylococcus aureus or methicillin-resistant Staphylococcus epidermidis.

22. The method of claim 16, wherein the bacterial infection is caused by mycobacteria.

23. The method of claim 22, wherein the mycobacterial infection is tuberculosis (TB).

24. The method of claim 16, wherein the bacterial infection is caused by a bacterial strain which is resistant to one or more fluoroquinolone antibiotics.

Description

EXPERIMENTAL

(1) Analytical Methods

(2) NMR spectra were obtained on a LC Bruker AV400 using a 5 mm QNP probe (Method A) or Bruker AVIII 400 Nanobay using a 5 mm BBFQ with z-gradients (Method B).

(3) MS was carried out on a Waters ZQ MS (Method A and B) or ACQ-SQD2#LCA081 (Method C) using H.sub.2O and ACN (0.1-0.05% formic acidhigh pH; 0.05% ammonialow pH). Wavelengths were 254 and 210 nM.

(4) Method A

(5) Column: Gemini NX C18, 5 m, 502 mm. Column flow rate was 1 mL/min. Injection volume 10 L

(6) TABLE-US-00002 Time (min) H.sub.2O % ACN % 0 95 5 4 5 95 4.45 5 95 4.5 95 5 5 STOP

(7) Method B

(8) Column: Waters XBridge C18, 5 m, 502.1 mm. Flow rate: 0.8 mL/min. Injection volume 10 L

(9) TABLE-US-00003 Time (min) H.sub.2O % ACN % 0 95 5 4 5 95 4.45 5 95 4.5 95 5 5 STOP

(10) Method C

(11) Column: ACQUITY UPLC BEH C18 1.7 m, 502.1 mm. Flow rate: 0.6 mL/min. Injection volume 2 L.

(12) TABLE-US-00004 Time (min) H.sub.2O % ACN % 0 95 5 0.30 95 5 2.00 5 95 2.60 95 5 3.00 STOP

(13) Method D

(14) Column: YMC-Triart C18 502 mm, 5 uM. Flow rate: 0.8 mL/min. Injection volume 5 L.

(15) TABLE-US-00005 % H.sub.2O:ACN Time 50 v/v + 1% (min) H.sub.2O % ACN % formic acid 0 95 0 5 4 0 95 5 4.4 0 95 5 4.5 95 5 0 4.5 STOP

(16) Method E

(17) Column YMC Triart-C18 502 mm, 5 uM Flow rate: 0.8 mL/min. Injection volume 5 L

(18) Mobile Phase A H2O, B MeCN C 1% formic in 50% H2O/50% MeCN

(19) TABLE-US-00006 Time (min) A B C 0 95 0 5 2.0 95 0 5 12.0 0 95 5 14.0 0 95 5 14.1 95 0 5

(20) Preparative HPLC was performed using a Waters 3100 Mass detector (Method A) or Waters 2767 Sample Manager (Method B) using H.sub.2O and ACN (0.1-0.05% formic acidhigh pH; 0.05% ammonialow pH).

(21) Method A

(22) Column: XBridge prep C18 5 M OBD 19100 mm. Flow rate: 20 mL/min.

(23) Method B

(24) Column: XBridge prep C18 5 M OBD 19100 mm. Flow rate: 20 mL/min.

Example 17-(4-amino-2,5-difluoro-phenyl)-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one A

(a) 3-bromo-N-(1-methoxycyclopropyl)-2-methyl-aniline

(25) ##STR00069##

(26) To a stirring solution of 3-bromo-2-methyl-aniline (14.6 mL, 118.25 mmol) in MeOH (200 mL) was added acetic acid (27.1 mL, 472.99 mmol). To the solution was added (1-ethoxycyclopropoxy)-trimethyl-silane (28.5 mL, 141.9 mmol) dropwise at room temperature and the resulting reaction mixture was heated to reflux overnight. After consumption of all starting material (monitored by LCMS) the mixture was concentrated in vacuo to obtain the title product as colourless oil in quantitative yield, which was used without further purification.

(27) LC-MS (Method A) 256.3/258.3 [M+H].sup.+; RT 2.85 min

(b) 3-bromo-N-cyclopropyl-2-methyl-aniline

(28) ##STR00070##

(29) To a solution of 3-bromo-N-(1-methoxycyclopropyl)-2-methyl-aniline (31.0 g, 121.03 mmol) in THF (50 mL) was added borane THF complex (242.1 mL, 242.06 mmol) dropwise at 0 C. over 20 min. The resulting mixture was allowed to warm to room temperature, stirred for 3 h and then refluxed for 18 h. After consumption of starting material (followed by LCMS), the reaction mixture was cooled to room temperature and carefully quenched with MeOH until bubbling stopped. Organic solvents were removed under reduced pressure. The residue was then poured into H.sub.2O (200 mL) and extracted with Et.sub.2O (350 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO.sub.4, filtered and concentrated in vacuo to give 3-bromo-N-cyclopropyl-2-methyl-aniline in quantitative yield. The product was used in the next step without further purification.

(30) LC-MS (Method A) 226.3/228.3 [M+H].sup.+; RT 3.07 min

(31) ##STR00071##

(32) A solution of 3-bromo-N-cyclopropyl-2-methyl-aniline (26.3 g, 116.32 mmol) and oxalyl chloride (22.5 mL, 261.71 mmol) in Et.sub.2O (150 mL) was heated to reflux for 18 h. After all starting material was consumed (followed by LCMS); the reaction mixture was concentrated under reduced pressure to remove excess oxalyl chloride. The residue was dissolved in DCM (250 mL) and the resultant solution was added dropwise to a stirring solution of aluminium trichloride (62.0 g, 465.26 mmol) in DCM (250 mL) at 00 C. The resulting reaction mixture was left to stir at the room temperature for 18 h before concentrating under reduced pressure. The residue was diluted with EtOAc, and carefully quenched with aqueous NaHCO.sub.3. Multiple extractions and washes of organic layers were combined, washed with brine and dried over MgSO.sub.4. The filtrate was concentrated in vacuo to give the crude product, which was purified by flash chromatography eluting with DCM to give 6-bromo-1-cyclopropyl-7-methyl-indoline-2,3-dione (6.87 g, 21%) as a bright orange solid.

(33) LC-MS (Method A) 280.3/282.3 [M+H].sup.+; RT 2.34 min

(d) 4-bromo-2-(cyclopropylamino)-3-methyl-benzoic acid

(34) ##STR00072##

(35) To a solution of 6-bromo-1-cyclopropyl-7-methyl-indoline-2,3-dione (790 mg, 2.82 mmol) in 2M aqueous NaOH (15 mL, 798.81 mmol) at 0 C., was added H.sub.2O.sub.2 (1.2 mL, 39.07 mmol) dropwise and the resulting reaction mixture was left to stir at room temperature for 2 h. After completion of the reaction, (monitored by LCMS), the reaction mixture was acidified to pH=4-5 with 2M aqueous HCl and then extracted with EtOAc (2300 mL). The combined organic layers were washed with brine (300 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give 4-bromo-2-(cyclopropylamino)-3-methyl-benzoic acid (760 mg, 99%) as a pale yellow-beige colour solid.

(36) LC-MS (Method A) 270.3/272.3 [M+H].sup.+; RT 2.29 min

(e) ethyl 5-[4-bromo-2-(cyclopropylamino)-3-methyl-phenyl]oxazole-4-carboxylate

(37) ##STR00073##

(38) To a solution of 4-bromo-2-(cyclopropylamino)-3-methyl-benzoic acid (530 mg, 1.96 mmol) in dry THF (15 mL) at room temperature under N.sub.2 was added triphosgene (348 mg, 1.17 mmol) in one portion. After stirring at room temperature for 3 h the solvent was carefully removed in vacuo. To the resulting residue under N.sub.2 was added dry THF (10 mL), followed by Et.sub.3N (2.18 mL, 15.7 mmol) dropwise. To the resulting mixture was added ethyl isocyanoacetate (0.32 mL, 2.94 mmol) in one portion and the reaction heated to 60 C. overnight. The reaction was cooled to room temperature and the solvent was removed under reduced pressure. The residue was then partitioned between EtOAc (20 mL) and brine (20 mL). 2M aqueous HCl was then added to adjust the aq. pH to around 3. The EtOAc layer was then separated, washed 4 times with H.sub.2O, dried over MgSO.sub.4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography eluting with 50% Petroleum ether (40-60)/EtOAc to afford ethyl 5-[4-bromo-2-(cyclopropylamino)-3-methyl-phenyl]oxazole-4-carboxylate (370 mg, 52%) as an off white solid.

(39) LC-MS (Method A) 365.3/367.3 [M+H].sup.+; RT 2.72 min

(f) 7-bromo-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one

(40) ##STR00074##

(41) To a solution of ethyl 5-[4-bromo-2-(cyclopropylamino)-3-methyl-phenyl]oxazole-4-carboxylate (370 mg, 1.01 mmol) in dry DMF (5 mL) was added NaH (60% dispersed in mineral oil) (61 mg, 1.52 mmol) in one portion. This was then heated to 100 C. for 1 h, after which time the reaction mixture was cooled to room temperature. EtOAc and H.sub.2O were added and the layers separated. The aq. layer was washed once with EtOAc and the combined organic extracts were washed a further 4 times with H.sub.2O to remove DMF. The combined organic extracts were dried over MgSO.sub.4, filtered, concentrated in vacuo and purified by flash chromatography using 50% Petroleum ether (40-60)/EtOAc as the eluent system to afford 7-bromo-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one (112 mg, 35%) as an off white solid.

(42) LC-MS (Method A) 319.3/321.3 [M+H].sup.+; RT 2.13 min

(g) 7-(4-amino-2,5-difluoro-phenyl)-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one A

(43) ##STR00075##

(44) A mixture of 7-bromo-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one (213 mg, 0.67 mmol), 2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (204 mg, 0.80 mmol), Cs.sub.2CO.sub.3 (326 mg, 1 mmol) and 1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (65 mg, 0.08 mmol) in toluene (3 mL), IPA (1 mL) and H.sub.2O (1 mL) was heated to 70 C. for 1.5 h. The reaction mixture was filtered through Celite and concentrated to dryness. The mixture was then redissolved in MeOH and purified by flash chromatography using a gradient eluent system of 100% Petroleum ether (40-60) to 100% EtOAc. The fractions containing the desired product were concentrated in vacuo and triturated with ice cold Et.sub.2O to give 7-(4-amino-2,5-difluoro-phenyl)-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one A as a yellow solid (41 mg, 17%).

(45) .sup.1H NMR (Method A) (CDCl.sub.3): ppm 8.07 (s, 1H), 7.76 (d, J=7.8 Hz 1H), 7.21 (d, J=7.2 Hz, 1H), 6.97-6.93 (m, 1H), 6.63-6.59 (m, 1H), 4.00 (s, 2H), 3.66-3.60 (m, 1H), 2.53 (s, 3H), 1.27-1.19 (m, 2H), 0.67-0.65 (m, 2H); LC-MS (Method A) 368.4 [M+H].sup.+; RT 2.10 min

Example 27-(4-amino-2,5-difluoro-phenyl)-5-ethyl-6-methyl-oxazolo[4,5-c]quinolin-4-one B

(a) 6-bromo-7-methyl-indoline-2,3-dione

(46) ##STR00076##

(47) A mixture of 3-bromo-2-methylaniline (10 mL, 60.52 mmol), chloral hydrate (14.86 g, 89.86 mmol) and anhydrous Na.sub.2SO.sub.4 (94.56 g, 665.74 mmol) in hydrochloric acid (6.4 mL, 211.24 mmol) and H.sub.2O (700 mL) was stirred vigorously at room temperature overnight. To the resulting mixture, hydroxylamine hydrochloride (5.86 g, 84.26 mmol) was added and the mixture was heated to reflux overnight. The reaction mixture was ice cooled, and the resulting precipitate was collected by vacuum filtration and washed copiously with H.sub.2O and dried under suction. The precipitate was re-dissolved in EtOAc (500 mL) and washed with H.sub.2O (300 mL) and brine (300 mL) then dried over MgSO.sub.4. The resulting filtrate was removed in vacuo to give 6-bromo-7-methyl-indoline-2,3-dione as a dark brown solid in quantitative yield, which was used directly in the next step without further purification.

(48) LC-MS 238.5/240.5 [M+H].sup.+; RT 1.84 min

(b) 6-bromo-1-ethyl-7-methyl-indoline-2,3-dione

(49) ##STR00077##

(50) Iodoethane (7.61 mL, 94.65 mmol) was added dropwise to a solution of 6-bromo-7-methyl-indoline-2,3-dione (11.36 g, 47.32 mmol) and anhydrous K.sub.2CO.sub.3 (7.85 g, 56.79 mmol) in dry DMF (20 mL) and the reaction mixture was heated to 100 C. After 1 h the reaction mixture was then diluted with EtOAc (100 mL) and H.sub.2O (100 mL) and the phases separated. The aqueous phase was extracted with EtOAc (270 mL) and the combined organic phases were washed with brine (200 mL) and dried over MgSO.sub.4. The resulting filtrate was removed in vacuo to give 6-bromo-1-ethyl-7-methyl-indoline-2,3-dione (11.2 g, 88% yield) as a brown crystalline solid which was used directly in the next step without further purification.

(51) LC-MS (Method A) 268.3/270.3 [M+H].sup.+; RT 2.32 min

(52) ##STR00078##

(53) Dropwise to a solution of 6-bromo-1-ethyl-7-methyl-indoline-2,3-dione (10.0 g, 37.3 mmol) in 2M aq. NaOH (100 mL) was added H.sub.2O.sub.2 (53.3 mL, 522.17 mmol) and the resulting reaction mixture was left to stir at room temperature for 2 h. The reaction mixture was diluted with DCM (150 mL) and the phases were separated. The aq. phase was acidified to pH 3 with 2M aqueous HCl and the resulting precipitate was filtered, collected and dried overnight in a heated desiccator at 40 C. to give 4-bromo-2-(ethylamino)-3-methyl-benzoic acid (5.2 g, 54% yield) as a pale yellow crystalline solid.

(54) LC-MS (Method A) 258.3/260.3 [M].sup.+; RT 1.25 min

(d) 7-bromo-1-ethyl-4-hydroxy-8-methyl-3-nitro-quinolin-2-one

(55) ##STR00079##

(56) To a solution of 4-bromo-2-(ethylamino)-3-methyl-benzoic acid (1.74 g, 6.74 mmol) in dry THF (20 mL) at room temperature under N.sub.2 atmosphere was added triphosgene (1.2 g, 4.03 mmol) in one portion. This was allowed to stir at room temperature for 3 h, after which time the solvent was carefully removed in vacuo (rotary evaporator was prohibited from reaching>40 C. vacuum was set at 1 mbar, and reached between 1-10 mbar) to give a thick red oil which was diluted with dry THF (10 mL) under a N.sub.2 atmosphere. To the resulting solution Et.sub.3N (7.5 mL, 53.93 mmol) was added dropwise, followed by the addition of ethyl nitroacetate (1.12 mL, 10.11 mmol) in one portion. The reaction mixture was heated to 60 C. overnight, after which time the solvent was removed in vacuo (maintaining bath temperature<40 C.). The residue was then partitioned between EtOAc (20 mL) and brine (20 mL). 2M aqueous HCl was then added to adjust the pH to around 3. The organic phase was separated, dried over Na.sub.2SO.sub.4, filtered and the solvent removed in vacuo to give 7-bromo-1-ethyl-4-hydroxy-8-methyl-3-nitro-quinolin-2-one as an orange solid in quantitative yield, which was used in the next step without further purification.

(57) LC-MS (Method A) 327.3/329.3 [M].sup.+; RT 2.08 min

(e) 3-amino-7-bromo-1-ethyl-4-hydroxy-8-methyl-quinolin-2-one

(58) ##STR00080##

(59) Sodium hydrosulfite (3.5 g, 20.1 mmol) was added to a stirred solution of 7-bromo-1-ethyl-4-hydroxy-8-methyl-3-nitro-quinolin-2-one (2.63 g, 8.04 mmol) in EtOH (20 mL) and H.sub.2O (4 mL) and heated to reflux for 1 h. The reaction mixture was filtered through filter paper and the solvent removed in vacuo. Purification by flash column chromatography eluting with 0-10% MeOH in DCM gave 3-amino-7-bromo-1-ethyl-4-hydroxy-8-methyl-quinolin-2-one (652 mg, 27%) as a yellow crystalline solid.

(60) LC-MS (Method A) 297.3/299.3 [M].sup.+; RT 1.77 min

(f) 7-bromo-5-ethyl-6-methyl-oxazolo[4,5-c]quinolin-4-one

(61) ##STR00081##

(62) To 3-amino-7-bromo-1-ethyl-4-hydroxy-8-methyl-quinolin-2-one (101 mg, 0.34 mmol) was added to triethyl orthoformate (5. mL, 0.34 mmol). The reaction mixture was heated to 105 C. for 2 h, then excess triethyl orthoformate was removed in vacuo. Column chromatography eluting with 30-70% EtOAc in Petroleum ether (40-60) gave 7-bromo-5-ethyl-6-methyl-oxazolo[4,5-c]quinolin-4-one in quantitative yield, which was used in the next step without further purification.

(63) LC-MS (Method A) 307.3/309.3 [M].sup.+; RT 2.15 min

(g) 7-(4-amino-2,5-difluoro-phenyl)-5-ethyl-6-methyl-oxazolo[4,5-c]quinolin-4-one B

(64) ##STR00082##

(65) A mixture of 7-bromo-5-ethyl-6-methyl-oxazolo[4,5-c]quinolin-4-one (82 mg, 0.27 mmol), 2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (81 mg, 0.32 mmol), Cs.sub.2CO.sub.3 (130 mg, 0.40 mmol) and 1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (43 mg, 0.05 mmol) in toluene (3 mL), IPA (1 mL) and H.sub.2O (1 mL) was heated to 70 C. for 1 h. The reaction mixture was then filtered through Celite and the solvent removed in vacuo. Purification by flash column chromatography eluting with 30-70% EtOAc in Petroleum ether (40-60) gave 7-(4-amino-2,5-difluoro-phenyl)-5-ethyl-6-methyl-oxazolo[4,5-c]quinolin-4-one B (13 mg, 13%) as a light purple crystalline solid.

(66) .sup.1H NMR (Method A) (CDCl.sub.3): ppm 8.09 (s, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 6.95 (1H, dd, J=11.0 Hz, 7.0 Hz, 1H), 6.61 (dd, J=11.0 Hz, 7.0 Hz, 1H), 4.55 (m, 2H), 3.99 (m, 2H), 2.45 (d, J=1.5 Hz, 3H), 1.32 (t, J=7.0 Hz, 3H); LC-MS (Method A) 356.4 [M+H].sup.+; RT 2.11 min

Example 37-(4-amino-2,5-difluoro-phenyl)-5-cyclopropyl-6-methyl-3H-oxazolo[4,5-c]quinoline-2,4-dione C

(a) 7-bromo-1-cyclopropyl-4-hydroxy-8-methyl-3-nitro-quinolin-2-one

(67) ##STR00083##

(68) To a solution of 4-bromo-2-(cyclopropylamino)-3-methyl-benzoic acid (18 g, 66.64 mmol) (prepared as described in Example 1 step (d)) in dry THF (360 mL) at room temperature under N.sub.2 atmosphere was added triphosgene (11.83 g, 39.85 mmol) in one portion. This was allowed to stir at room temperature for 3 h, after which time the solvent was carefully removed in vacuo (rotary evaporator was prohibited from reaching>40 C. Vacuum was set at 1 mbar, and reached between 1-10 mbar) to give a thick red oil which was diluted with dry THF (450 mL) under a N.sub.2 atmosphere. To the resulting solution Et.sub.3N (74.3 mL, 533.1 mmol) was added dropwise, followed by the addition of ethyl nitroacetate (11.1 mL, 99.96 mmol) in one portion. The reaction mixture was heated to 60 C. overnight, after which time the solvent was removed in vacuo. The residue was then partitioned between EtOAc (100 mL) and brine (100 mL). 2M aqueous HCl was then added to adjust the pH to around 3.

(69) The organic phase was separated, dried over Na.sub.2SO.sub.4, filtered and the solvent removed in vacuo to give an orange oil. Purification by flash column chromatography eluting initially with 50-100% EtOAc in Petroleum ether (40-60) switching to 5-10% MeOH in DCM gave 7-bromo-1-cyclopropyl-4-hydroxy-8-methyl-3-nitro-quinolin-2-one (6 g, 27%) as a yellow solid.

(70) LC-MS (Method B) 339.3.2/341.2 [M].sup.+; RT 1.60 min

(b) 7-(4-amino-2,5-difluoro-phenyl)-1-cyclopropyl-4-hydroxy-8-methyl-3-nitro-quinolin-2-one

(71) ##STR00084##

(72) A mixture of 7-bromo-1-cyclopropyl-4-hydroxy-8-methyl-3-nitro-quinolin-2-one (2.4 g, 7.08 mmol), 4-amino-2,5-difluorobenzeneboronic acid pinacol ester (1.99 g, 7.78 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (578 mg, 0.71 mmol), Cs.sub.2CO.sub.3 (6.92 g, 21.23 mmol) in 1,4-dioxane (40 mL) and H.sub.2O (4 mL). This was then heated to 70 C. for 2 h. The reaction mixture was then filtered through Celite and the solvent removed in vacuo. Purification by flash column chromatography eluting with 20-80% MeOH in DCM gave 7-(4-amino-2,5-difluoro-phenyl)-5-ethyl-6-methyl-oxazolo[4,5-c]quinolin-4-one (1.5 g, 55%) as a yellow crystalline solid.

(73) LC-MS (Method B) 388.4 [M+H].sup.+; RT 1.90 min

(74) ##STR00085##

(75) Sodium hydrosulfite (0.56 g, 3.23 mmol) was added to a stirred solution of 7-(4-amino-2,5-difluoro-phenyl)-1-cyclopropyl-4-hydroxy-8-methyl-3-nitro-quinolin-2-one (0.5 g, 1.29 mmol) in EtOH (5 mL) and H.sub.2O (1 mL) and stirred for 2 h at room temperature. A precipitate formed which was filtered off and washed with H.sub.2O (20 ml), followed by Et.sub.2O (20 mL). The grey solid was then kept under vacuum over night to give the desired product as a grey solid, which was used in the next step without further purification.

(76) LC-MS (Method B) 358.4 [M+H].sup.+; RT 1.62 min

(d) 7-(4-amino-2,5-difluoro-phenyl)-5-cyclopropyl-6-methyl-3H-oxazolo[4,5-c]quinoline-2,4-dione C

(77) ##STR00086##

(78) To a solution of 3-amino-7-(4-amino-2,5-difluoro-phenyl)-1-cyclopropyl-4-hydroxy-8-methyl-quinolin-2-one (100 mg, 0.28 mmol) in THF (10 mL) was added triphosgene (33 mg, 0.11 mmol) and allowed to stir at room temp for 4 h. To the reaction mixture was added H.sub.2O and the solvents were removed in vacuo. Purification by flash column chromatography eluting with 5-10% MeOH in DCM gave 7-(4-amino-2,5-difluoro-phenyl)-5-cyclopropyl-6-methyl-3H-oxazolo[4,5-c]quinoline-2,4-dione C as an olive solid (103 mg, 96% yield).

(79) .sup.1H NMR (Method B) (DMSO-d.sub.6): ppm 8.09 (s, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 6.95 (1H, dd, J=12.0 Hz, 8.0 Hz, 1H), 6.60 (dd, J=12.0 Hz, 8.0 Hz, 1H), 3.96 (bs, 2H), 3.58 (m, 1H), 2.52 (d, J=1.5 Hz, 3H), 1.29 (m, 2H), 0.68 (m, 2H); LC-MS (Method B) 384.4 [M+H].sup.+; RT 2.90 min

Example 47-(4-amino-2,5-difluoro-phenyl)-5-cyclopropyl-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one D

(a) 3-amino-7-bromo-1-cyclopropyl-4-hydroxy-8-methyl-quinolin-2-one

(80) ##STR00087##

(81) Using the method described in Example 2 step (e) and using 7-bromo-1-cyclopropyl-4-hydroxy-8-methyl-3-nitro-quinolin-2-one (prepared as described in Example 3 step (a)) 3-amino-7-bromo-1-cyclopropyl-4-hydroxy-8-methyl-quinolin-2-one was prepared as a pale brown solid and used in the next step without further purification.

(82) LC-MS (Method C) 308.9/310.8 [M+H].sup.+, RT 1.38 min

(b) N-(7-bromo-1-cyclopropyl-4-hydroxy-8-methyl-2-oxo-3-quinolyl)acetamide

(83) ##STR00088##

(84) Anhydrous Et.sub.3N (0.23 mL, 1.66 mmol) and acetyl chloride (0.07 mL, 0.99 mmol) were added dropwise to a solution of 3-amino-7-bromo-1-cyclopropyl-4-hydroxy-8-methyl-quinolin-2-one (205 mg, 0.66 mmol) in THF (5 mL). The mixture, sheltered from light, was refluxed for 5 h, cooled to room temperature and allowed to stir at room temperature overnight. It was then diluted with H.sub.2O (10 mL) and acidified with 6M aqueous HCl. The aqueous layer was extracted with EtOAc (220 mL). The combined organic layers were washed with aq. NaHCO.sub.3 (10 mL) and brine (10 mL), dried over Na.sub.2SO.sub.4, filtered and the solvent removed under vacuo to give N-(7-bromo-1-cyclopropyl-4-hydroxy-8-methyl-2-oxo-3-quinolyl)acetamide (101 mg, 43%) as a brown oil. The product used in the next step without further purification.

(85) LC-MS (Method C) 350.9/352.8 [M+H].sup.+, RT 1.81 min

(86) ##STR00089##

(87) Glacial acetic acid (1.0 mL, 17.47 mmol) and trifluoroacetic acid (1.0 mL, 13.07 mmol) were added to N-(7-bromo-1-cyclopropyl-4-hydroxy-8-methyl-2-oxo-3-quinolyl)acetamide (101 mg, 0.29 mmol) in a microwave vial. The solution was then irradiated with microwaves at 200 C. for 20 min, allowed to cool and solvent removed under vacuo. To the residue was added EtOAc (20 mL) and the solution washed with aq. NaHCO.sub.3 (5 mL) followed by brine (5 mL). The organic layer was then dried over Na.sub.2SO.sub.4, filtered and the solvent removed under vacuo. The resulting residue was purified by flash chromatography eluting with 6% MeOH/DCM to give 7-bromo-5-cyclopropyl-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one (36 mg, 38%) as a pale yellow solid.

(88) LC-MS (Method C) 332.9/334.8 [M+H].sup.+, RT 1.68 min

(d) 7-(4-amino-2,5-difluoro-phenyl)-5-cyclopropyl-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one D

(89) ##STR00090##

(90) A mixture of 7-bromo-5-cyclopropyl-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one (107 mg, 0.32 mmol), 4-amino-2,5-difluorobenzeneboronic acid pinacol ester (122 mg, 0.48 mmol), [1,1-bis(diphenylphosphino)ferrocene]Palladium(II) chloride dichloromethane complex (26 mg, 0.03 mmol) and Cs.sub.2CO.sub.3 (313 mg, 0.96 mmol) were dissolved in 1,2-dimethoxyethane (1.5 mL) and H.sub.2O (0.5 mL). The solution was then irradiated with microwaves at 120 C. for 20 min, allowed to cool and then diluted with EtOAc (50 mL). The resulting organics were washed with saturated aq. Na.sub.2CO.sub.3 (220 mL) followed by brine (20 mL). The organic layer was then separated, dried over Na.sub.2SO.sub.4, filtered and solvent removed under vacuo. The resulting residue was then purified by reverse phase mass directed auto-preparative HPLC (Method A) to give 7-(4-amino-2,5-difluoro-phenyl)-5-cyclopropyl-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one D (23 mg 19% yield) as a white solid.

(91) .sup.1H NMR (Method B) (CD.sub.3OD): ppm 7.78-7.81 (d, J=8.0 Hz, 1H), 7.28-7.30 (d, J=8.0, 1H), 6.95-6.99 (dd, J=11.3 Hz, 6.9 Hz, 1H), 6.66-6.71 (dd, J=11.3 Hz, 7.4 Hz, 1H), 3.63-3.66 (m, 1H), 2.70 (s, 3H), 2.57 (s, 3H), 1.27 (d, 2H), 0.61 (s, 2H); LC-MS (Method C) 382.2 [M+H].sup.+, RT 1.60 min

Example 57-(4-amino-2-fluoro-phenyl)-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one E

(92) ##STR00091##

(93) Prepared using 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and 7-bromo-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 1 step (f)) and a similar procedure to that described in Example 1 step (g)

(94) .sup.1H NMR (Method A) (CDCl.sub.3): ppm 8.07 (s, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.09 (m, 1H), 6.56 (m, 1H), 6.50 (m, 1H), 3.92 (s, 2H), 3.63 (m, 1H), 2.52 (m, 3H), 1.30-1.23 (m, 2H), 0.67 (s, 2H); LC-MS (Method D) 350.5 [M+H].sup.+; RT 1.97 min.

Example 67-(5-aminopyrazin-2-yl)-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one F

(a) 5-cyclopropyl-6-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-oxazolo[4,5-c]quinolin-4-one

(95) ##STR00092##

(96) To a solution of 7-bromo-5-cyclopropyl-6-dimethyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 1 step (f)) (1.64 g, 5.14 mmol) in 1,2-dimethoxyethane (30 mL) under N.sub.2 was added potassium acetate (1.51 g, 15.42 mmol), bis(pinacolato)diboron (1.70 g, 6.68 mmol) and [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (210 mg, 0.26 mmol). The resulting reaction mixture was heated to 75 C. for 72 h. On cooling the reaction mixture was partitioned between EtOAc (50 mL) and H.sub.2O (50 ml). The organic phase was separated and dried (MgSO.sub.4), filtered and evaporated in vacuo. The resulting residue was purified by flash chromatography using a gradient of 0-100% EtOAc in DCM to give 5-cyclopropyl-6-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazolo[4,5-c]quinolin-4-one (1.6 g, 85% yield) as a brown foam.

(97) LC-MS (Method D) 367.5 [M+H].sup.+; RT 2.83 min

(b) 7-(5-aminopyrazin-2-yl)-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one F

(98) ##STR00093##

(99) Prepared using 5-cyclopropyl-6-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazolo[4,5-c]quinolin-4-one and 5-bromo-2-pyrazinamin and a similar procedure to that described in Example 1 step (g)

(100) .sup.1H NMR (Method A) (CDCl.sub.3): b ppm 8.22 (d, J=1.5 Hz, 1H), 8.14 (d, J=1.5 Hz, 1H), 8.08 (s, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 4.71 (s, 2H), 3.65 (m, 1H), 2.64 (s, 3H), 1.34-1.21 (m, 2H), 0.70 (m, 2H); LC-MS (Method D) 334.4 [M+H].sup.+; RT 4.73 min.

Example 75-cyclopropyl-6-methyl-7-phenyl-oxazolo[4,5-c]quinolin-4-one G

(101) ##STR00094##

(102) Prepared using 4.4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane and 7-bromo-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 1 step (f)) and a similar procedure to that described in Example 1 step (g)

(103) .sup.1H NMR (Method A) (CDCl.sub.3): ppm 8.07 (s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.53-7.36 (m, 5H), 7.28 (d, J=8.0 Hz, 1H), 3.70-3.59 (m, 1H), 2.54 (s, 3H), 1.35-1.21 (m, 2H), 0.75-0.66 (m, 2H); LC-MS (Method D) 317.5 [M+H].sup.+; RT 7.04 min.

Example 84-(5-cyclopropyl-2,6-dimethyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)benzoic acid H

(104) ##STR00095##

(105) Prepared using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and 7-bromo-5-cyclopropyl-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 4 step (c)) and a similar procedure to that described in Example 4 step (d)

(106) .sup.1H NMR (Method B) (CD.sub.3OD): ppm 8.26-8.08 (m, 2H), 7.87 (d, J=8.0 Hz, 1H), 7.65-7.51 (m, 2H), 7.38 (d, J=8.0 Hz, 1H), 3.67 (m, 1H), 2.71 (s, 3H), 2.60 (s, 3H), 1.34 (m, 2H), 0.75-0.60 (m, 2H); LC-MS (Method C) 375.1 [M.sup.+ H.sup.+], RT 1.47 min

Example 97-[4-{aminomethyl)phenyl]-5-cyclopropyl-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one I

(107) ##STR00096##

(108) Prepared using 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanamine hydrochloride and 7-bromo-5-cyclopropyl-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 4 step (c)) and a similar procedure to that described in Example 4 step (d)

(109) .sup.1H NMR (Method B) (CD.sub.3OD): ppm 8.50 (br s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.71-7.47 (m, 4H), 7.33 (d, J=8.0 Hz, 1H), 4.21 (s, 2H), 3.65 (m, 1H), 2.70 (s, 3H), 2.57 (s, 3H), 1.37-1.28 (m, 2H), 0.66 (m, 2H); LC-MS (Method C) 360.4 [M.sup.+ H.sup.+], RT 1.15 min

Example 105-cyclopropyl-7-(1H-indazol-5-yl)-2,6-dimethyl-oxazolo{4,5-c]quinolin-4-one J

(110) ##STR00097##

(111) Prepared using 5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole and 7-bromo-5-cyclopropyl-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 4 step (c)) and a similar procedure to that described in Example 4 step (d)

(112) .sup.1H NMR (Method B) (DMSO-d.sub.6): ppm 13.20 (s, 1H), 8.20-8.14 (m, 1H), 7.83 (s, 1H), 7.76 (d, J=7.9 Hz, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.44 (dd, J=8.6, 1.6 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 3.58 (m, 1H), 2.65 (s, 3H), 2.50 (s, 3H) 1.35-1.18 (m, 2H), 0.65-0.47 (m, 2H); LC-MS (Method C) 371.1 [M.sup.+ H.sup.+], RT 1.71 min

Example 11tert-butyl 3-[4-(5-cyclopropyl-2,6-dimethyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)pyrazol-1-yl]azetidine-1-carboxylate K

(113) ##STR00098##

(114) Prepared using tert butyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]azetine-1-carboxylate and 7-bromo-5-cyclopropyl-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 4 step (c)) and a similar procedure to that described in Example 4 step (d)

(115) .sup.1H NMR (Method B) (CDCl.sub.3): ppm 7.77 (s, 1H), 7.70 (s, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.30 (d, J=8.1 Hz, 1H), 5.20-5.07 (m, 1H), 4.54-4.30 (m, 4H), 3.71-3.58 (m, 1H), 2.69 (s, 3H), 2.67 (s, 3H), 1.48 (s, 9H), 1.35-1.19 (m, 2H), 0.70-0.54 (m, 2H); LC-MS (Method C) 476.5 [M.sup.+ H.sup.+], RT 1.68 min

Example 127-[1-(azetidin-3-yl)pyrazol-4-yl]-5-cyclopropyl-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one L

(116) ##STR00099##

(117) Prepared from Example 11 by deprotection of the BOC group using the method described in Example 49 step (j)

(118) .sup.1H NMR (Method B) (CD.sub.3OD): ppm 8.56 (br s, 1H), 8.07 (s, 1H), 7.98 (s, 1H), 7.79 (d, J=8.1 Hz, 1H), 7.46 (d, J=8.1 Hz, 1H), 4.68-4.48 (m, 4H), 3.75-3.60 (m, 1H), 3.37 (m, 1H), 2.76 (s, 3H), 2.69 (s, 3H), 1.51-1.14 (m, 2H), 0.75-0.40 (m, 2H); LC-MS (Method C) 376.3 [M.sup.+ H.sup.+], RT 1.09 min

Example 137-(4-amino-3-fluoro-phenyl)-5-cyclopropyl)-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one M

(119) ##STR00100##

(120) Prepared using 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and 7-bromo-5-cyclopropyl-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 4 step (c)) and a similar procedure to that described in Example 4 step (d)

(121) .sup.1H NMR (Method B) (CD.sub.3OD): ppm 7.73 (d, J=8.1 Hz, 1H), 7.28 (d, J=7.9 Hz, 1H), 7.07-6.91 (m, 3H), 3.61 (m, 1H), 2.67 (s, 3H), 2.57 (s, 3H), 1.30 (m, 2H), 0.61 (m, 2H); LC-MS (Method C) 364.2 [M+H].sup.+; RT 1.92 min

Example 147-(2-aminopyrimidin-5-yl)-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one N

(122) ##STR00101##

(123) Prepared using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyrimidinamine and 7-bromo-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 1 step (f)) and a similar procedure to that described in Example 1 step (g)

(124) .sup.1H NMR (Method B) (CDCl.sub.3): ppm 8.44 (s, 2H), 8.11 (s, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.23 (d, J=7.5 Hz, 1H), 5.66 (br s, 2H), 3.66 (br s, 1H), 2.61 (s, 3H), 1.32 (m, 2H), 0.69 (m, 2H); LC-MS (Method C) 334.1 [M+H].sup.+; RT 1.14 min

Example 157-(1H-benzimidazol-5-yl)-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one O

(125) ##STR00102##

(126) Prepared using 5-cyclopropyl-6-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 6 step (a)) and tert butyl 5-bromobenzimidazole-1-carboxylate and a similar procedure to that described in Example 1 step (g), followed by deprotection of the BOC group using the method described in Example 49 step (j)

(127) .sup.1H NMR (Method A) (DMSO-d.sub.6): ppm 12.59 (s, 0.5H), 12.55 (s, 0.5H), 8.80 (s, 1H), 8.31 (d, J=2.3 Hz, 1H), 7.82 (d, J=8.1 Hz, 1H), 7.77 (d, J=8.4 Hz, 0.5H), 7.71 (m, 1H), 7.65 (d, J=8.9 Hz, 0.5H), 7.56 (s, 0.5H), 7.37 (d, J=8.1 Hz, 1H), 7.30 (d, J=8.4 Hz, 0.5H), 7.27 (d, J=8.4 Hz, 0.5H), 3.59 (m, 1H), 1.26 m, 2H), 0.58 (m, 2H); LC-MS (Method D) 357.4 [M+H].sup.+; RT 1.54 min

Example 167-(2-aminopyrimidin-5-yl)-5-cyclopropyl-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one P

(128) ##STR00103##

(129) Prepared using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyrimidinamine and 7-bromo-5-cyclopropyl-, 2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 4 step (c)) and a similar procedure to that described in Example 4 step (d)

(130) .sup.1H NMR (Method B) (CD.sub.3OD): ppm 8.41 (s, 2H), 7.85 (d, J=8.1 Hz, 1H), 7.35 (d, J=7.9 Hz, 1H), 3.66 (m, 1H), 2.70 (s, 3H), 2.65 (s, 3H), 1.33 (m, 2H), 0.84 (m, 2H); LC-MS (Method C) 348.1 [M+H].sup.+; RT 1.21 min

Example 174-(5-cyclopropyl)-2,6-dimethyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)benzenesulphonamide Q

(131) ##STR00104##

(132) Prepared using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulphonamide and 7-bromo-5-cyclopropyl-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 4 step (c)) and a similar procedure to that described in Example 4 step (d)

(133) .sup.1H NMR (Method A) (DMSO-d.sub.6): ppm 8.04-7.98 (m, 2H), 7.83 (d, J=8.0 Hz, 1H), 7.76-7.68 (m, 2H), 7.51 (s, 2H), 7.35 (d, J=8.0 Hz, 1H), 3.62 (dq, J=7.1, 4.0, 3.6 Hz, 1H), 2.71 (s, 3H), 2.54 (s, 3H), 1.33-1.26 (m, 2H), 0.64-0.53 (m, 2H); LC-MS (Method E) 410.4 [M+H].sup.+; RT 6.18 min

Example 185-cyclopropyl-7-(1H-indol-5-yl)-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one R

(134) ##STR00105##

(135) Prepared using indole-6-boronic acid pinacol ester and 7-bromo-5-cyclopropyl-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 4 step (c)) and a similar procedure to that described in Example 4 step (d)

(136) .sup.1H NMR (Method A) (DMSO-d.sub.6): ppm 11.15 (s, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.53 (s, 1H), 7.45 (d, J=8.3 Hz, 1H), 7.39-7.32 (m, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.10 (dd, J=8.4, 1.7 Hz, 1H), 6.47-6.43 (m, 1H), 3.50 (tt, J=6.8, 3.9 Hz, 1H), 2.58 (s, 3H), 1.22-1.15 (m, 2H), 0.52-0.45 (m, 2H); LC-MS (Method E) 370.4 [M+H].sup.+; RT 7.61 min.

Example 197-(4-amino-3,5-difluoro-phenyl)-5-methyl-oxazolo[4,5-c]quinolin-4-one S

(137) ##STR00106##

(138) Prepared using 5-cyclopropyl-6-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 6 step (a)) and 4-bromo-2,6-difluoroaniline and a similar procedure to that described in Example 1 step (g)

(139) .sup.1H NMR (Method A) (CDCl.sub.3): ppm 8.07 (s, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 6.95-6.84 (m, 1H), 3.88 (br s, 2H), 3.67-3.60 (m, 1H), 2.56 (s, 3H), 1.34-1.25 (m, 2H), 0.71-0.64 (m, 2H); LC-MS (Method A) 368.5 [M+H].sup.+; RT 2.48 min

Example 205-cyclopropyl-6-methyl-7-(1H-pyrazolo[3,4-b]pyridine-5-yl)oxazolo[4,5-c]quinolin-4-one T

(140) ##STR00107##

(141) Prepared using tert butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[3,4-b]pyridine-1-carboxylate and 7-bromo-5-cyclopropyl-, 6-methyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 1 step (f)) and a similar procedure to that described in Example 1, step (g), followed by deprotection of the BOC group using the method described in Example 49 step (j)

(142) .sup.1H NMR (Method A) (CDCl.sub.3): b ppm 8.67 (d, J=2.0 Hz, 1H), 8.21 (s, 1H), 8.16 (d, J=2.0 Hz, 1H), 8.11 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 3.71-3.63 (m, 1H), 2.59 (s, 3H), 1.39-1.31 (m, 2H), 0.78-0.70 (m, 2H); LC-MS (Method A) 358.5 [M+H].sup.+; RT 1.77 min

Example 217-(3-amino-1H-pyrazolo[3,4-b]pyridine-5-yl)-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one U

(143) ##STR00108##

(144) Prepared using tert butyl 3-[bis(tert-butoxycarbonyl)amino]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[3,4-b]pyridine-1-carboxylate and 7-bromo-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 1 step (f)) and a similar procedure to that described in Example 1 step (g), followed by deprotection of the BOC groups using the method described in Example 49 step (j)

(145) .sup.1H NMR (Method A) (CDCl.sub.3): ppm 10.15 (br s, 1H), 8.57 (d, J=2.0 Hz, 1H), 8.10 (s, 1H), 7.97 (d, J=2.0 Hz, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 4.29 (br s, 2H), 3.70-3.62 (m, 1H), 2.58 (s, 3H), 1.37-1.29 (m, 2H), 0.76-0.68 (m, 2H); LC-MS (Method A) 373.4 [M+H].sup.+; RT 1.58 min

Example 225-cyclopropyl-7-[2,5-difluoro-4-(1-hydroxyethyl)phenyl]-6-methyl-oxazolo[4,5-c]quinolin-4-one V

(146) ##STR00109##

(147) Prepared using 1-[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanol and 7-bromo-5-cyclopropyl-, 6-methyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 1 step (f)) and a similar procedure to that described in Example 1 step (g)

(148) .sup.1H NMR (Method B) (CDCl.sub.3): ppm 8.09 (s, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.37 (dd, J=9.9, 6.0 Hz, 1H), 7.22 (d, J=7.9 Hz, 1H), 7.00 (dd, J=9.9, 5.8 Hz, 1H), 5.27 (m, 1H), 3.63 (m, 1H), 2.52 (d, J=1.4 Hz, 3H), 1.58 (d, J=6.4 Hz, 3H), 1.24 (m, 2H), 0.66 (m, 2H); LC-MS (Method C) 397.1 [M+H].sup.+; RT 1.54 min

Example 237-(6-amino-3-pyridyl)-5-cyclopropyl-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one W

(149) ##STR00110##

(150) Prepared using 2-aminopyridine-5-boronic acid pinacol ester and 7-bromo-5-cyclopropyl-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 4 step (c)) and a similar procedure to that described in Example 4 step (d)

(151) .sup.1H NMR (Method B) (CD.sub.3OD): ppm 7.98 (dd, J=2.5, 0.8 Hz, 1H), 7.84-7.80 (m, 1H), 7.67 (dd, J=8.7, 2.4 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 6.78 (dd, J=8.7, 0.8 Hz, 1H), 3.65 (m, 1H), 2.69 (s, 3H), 2.62 (s, 3H), 1.31 (d, J=6.0 Hz, 2H), 0.65-0.60 (m, 2H); LC-MS (Method C) 347.2 [M+H].sup.+; RT 1.06 min

Example 244-(5-cyclopropyl)-2,6-dimethyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)-2,5-difluoro-benzonitrile X

(152) ##STR00111##

(153) Prepared using 2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile and 7-bromo-5-cyclopropyl-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 4 step (c)) and a similar procedure to that described in Example 4 step (d)

(154) .sup.1H NMR (Method B) (CDCl.sub.3): ppm 7.77 (d, J=7.9 Hz, 1H), 7.47 (dd, J=8.1, 5.1 Hz, 1H), 7.25-7.22 (m, 1H), 7.17 (d, J=8.0 Hz, 1H), 3.62 (m, 1H), 2.69 (s, 3H), 2.51 (d, J=1.5 Hz, 3H), 1.26 (m, 2H), 0.65 (m, 2H); LC-MS (Method C) 392.1 [M+H].sup.+; RT 2.09 min

Example 255-cyclopropyl-7-[2,5-difluoro-4-(hydroxymethyl)phenyl]-6-methyl-oxazolo[4,5-c]quinolin-4-one Y

(155) ##STR00112##

(156) Prepared using [2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol and 7-bromo-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 1 step (f)) and a similar procedure to that described in Example 1 step (g)

(157) .sup.1H NMR (Method B) (CDCl.sub.3): ppm 8.10 (s, 1H), 7.80 (dd, J=8.0, 0.7 Hz, 1H), 7.33 (dd, J=9.5, 5.9 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.04 (dd, J=9.6, 5.8 Hz, 1H), 4.85 (s, 2H), 3.70-3.57 (m, 1H), 1.57 (s, 3H), 1.27 (m, 2H), 0.67 (m, 2H); LC-MS (Method C) 383.1 [M+H].sup.+; RT 1.47 min

Example 264-(5-cyclopropyl)-2,6-dimethyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)benzamide Z

(158) ##STR00113##

(159) Prepared using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide and 7-bromo-5-cyclopropyl-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 4 step (c)) and a similar procedure to that described in Example 4 step (d)

(160) .sup.1H NMR (Method B) (CDCl.sub.3): ppm 7.93 (d, J=8.2 Hz, 2H), 7.74 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.1 Hz, 2H), 7.24 (d, J=8.2 Hz, 1H), 3.63 (m, 1H), 2.69 (s, 3H), 2.52 (s, 3H), 1.33-1.26 (m, 2H), 0.73-0.65 (m, 2H); LC-MS (Method C) 374.1 [M+H].sup.+; RT 1.44 min

Example 275-cyclopropyl-7-(l H-indazol-6-yl)-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one A1

(161) ##STR00114##

(162) Prepared using 6-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole and 7-bromo-5-cyclopropyl-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 4 step (c)) and a similar procedure to that described in Example 4 step (d)

(163) .sup.1H NMR (Method B) (CDCl.sub.3): ppm 8.16 (d, J=1.0 Hz, 1H), 7.84 (dd, J=8.3, 0.9 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.53 (q, J=1.1 Hz, 1H), 7.30 (d, J=7.9 Hz, 1H), 7.22 (dd, J=8.3, 1.3 Hz, 1H), 3.71-3.57 (m, 1H), 2.68 (s, 3H), 2.54 (s, 3H), 1.24 (m, 2H), 0.71 (m, 2H); LC-MS (Method C) 371.3 [M+H].sup.+; RT 1.50 min

Example 287-[4-(2-aminopropan-2-yl)phenyl]-5-cyclopropyl-2,6-dimethyloxazolo[4,5-c]quinolin-4-one B1

(164) ##STR00115##

(165) Prepared using 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan-2-amine and 7-bromo-5-cyclopropyl-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 4 step (c)) and a similar procedure to that described in Example 4 step (d)

(166) .sup.1H NMR (Method B) (D.sub.2O): ppm 7.77 (d, J=8.0 Hz, 1H), 7.70-7.55 (m, 4H), 7.35 (d, J=8.0 Hz, 1H), 3.76 (s, 3H), 3.62 (s, 1H), 2.69 (s, 3H), 2.51 (s, 3H), 1.82 (s, 3H), 1.30 (m 2H), 0.64 (m, 2H); LC-MS (Method C) 371.1 [M+H].sup.+; RT 1.26 min

Example 295-cyclopropyl-2,6-dimethyl-7-(1H-pyrazol-4-yl)oxazolo[4,5-c]quinolin-4-one C1

(167) ##STR00116##

(168) Prepared using tert butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate and 7-bromo-5-cyclopropyl-, 6-methyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 1 step (f)) and a similar procedure to that described in Example 1 step (g), followed by deprotection of the BOC group using the method described in Example 49 step (j)

(169) .sup.1H NMR (Method B) (CDCl.sub.3): ppm 7.82 (s, 2H), 7.68 (d, J=8.1 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 3.66 (m, 1H), 2.69 (d, J=7.3 Hz, 6H), 1.27 (m, 2H), 0.64 (m, 2H); LC-MS (Method C) 321.1 [M+H].sup.+; RT 1.26 min

Example 30ethyl-2-[{4-(5-cyclopropyl-6-methyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)benzoyl}amino]acetate D1

(170) ##STR00117##

(171) Prepared using ethyl N-[4-(dihydroxyboryl)benzoyl]glycinate and 7-bromo-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 1 step (f)) and a similar procedure to that described in Example 1 step (g)

(172) .sup.1H NMR (Method A) (CDCl.sub.3): ppm 8.09 (s, 1H), 7.97-7.90 (m, 2H), 7.80 (d, J=8.0 Hz, 1H), 7.52-7.44 (m, 2H), 6.72 (t, 1H), 4.34-4.25 (m, 4H), 3.64 (m, 1H), 2.53 (s, 3H), 1.57 (s, 3H), 1.31-1.28 (m, 2H), 0.70 (m, 2H); LC-MS (Method D) 446.4 [M+H].sup.+; RT 2.36 min

Example 312-[{4-(5-cyclopropyl-6-methyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)benzoyl}amino]acetic acid E1

(173) ##STR00118##

(174) To a solution of ethyl-2-[{4-(5-cyclopropyl-6-methyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)benzoyl}amino]acetate (prepared as described in Example 30) (47.2 mg, 0.10 mmol) in H.sub.2O (4.71 mL) was added Et.sub.3N (1.18 mL, 8.45 mmol) and the solution left to stir rapidly overnight. When the reaction had gone to completion the solvent was removed in vacuo to give 2-[{4-(5-cyclopropyl-6-methyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)benzoyl}amino]acetic acid E1 (29 mg, 65% yield) as the Et.sub.3N salt.

(175) .sup.1H NMR (Method A) (CDCl.sub.3): ppm 7.98-7.91 (m, 2H), 7.70 (d, J=8.0 Hz, 1H), 7.45-7.39 (m, 2H), 7.22 (d, J=8.0 Hz, 1H), 4.06 (d, J=4.2 Hz, 2H), 3.63-3.56 (m, 1H), 2.66 (s, 3H), 2.49 (s, 3H), 1.24 (m, 2H), 0.66 (m, 2H); LC-MS (Method D) 432.4 [M+H].sup.+; RT 2.03 min

Example 325-cyclopropyl-7-(2,5-difluoro-4-hydroxy-phenyl)-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one F1

(176) ##STR00119##

(177) Prepared using 2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol and 7-bromo-5-cyclopropyl-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 4 step (c)) and a similar procedure to that described in Example 4 step (d)

(178) .sup.1H NMR (Method B) (CD.sub.3OD): ppm 7.83 (d, J=8.0 Hz, 1H), 7.33-7.28 (m, 1H), 7.11 (dd, J=11.1, 6.9 Hz, 1H), 6.86-6.76 (m, 1H), 3.65 (m, 1H), 2.70 (s, 3H), 2.61-2.51 (m, 3H), 0.91 (m, 2H), 0.61 (m, 2H); LC-MS (Method C) 383.1 [M+H].sup.+; RT 1.53 min

Example 334-(5-cyclopropyl-2,6-dimethyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)-3-fluoro-benzonitrile G1

(179) ##STR00120##

(180) Prepared using 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile and 7-bromo-5-cyclopropyl-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 4 step (c)) and a similar procedure to that described in Example 4 step (d)

(181) .sup.1H NMR (Method B) (CDCl.sub.3): 7.76 (d, J=7.9 Hz, 1H), 7.60 (dd, J=7.9, 1.5 Hz, 1H), 7.55-7.43 (m, 2H), 7.17 (d, J=8.0 Hz, 1H), 3.60 (m, 1H), 2.68 (s, 3H), 2.49 (d, J=1.5 Hz, 3H), 1.26 (m, 2H), 0.64 (m, 2H); LC-MS (Method C) 374.2 [M+H].sup.+; RT 1.68 min

Example 345-cyclopropyl-7-[2,5-difluoro-4-(hydroxymethyl)phenyl]-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one H1

(182) ##STR00121##

(183) Prepared using [2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol and 7-bromo-5-cyclopropyl-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 4 step (c)) and a similar procedure to that described in Example 4 step (d)

(184) .sup.1H NMR (Method B) (CDCl.sub.3): ppm 7.73 (d, J=8.0 Hz, 1H), 7.32 (dd, J=9.5, 6.0 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.03 (dd, J=9.6, 5.8 Hz, 1H), 4.85 (s, 2H), 3.67-3.57 (m, 1H), 2.68 (s, 3H), 2.52 (d, J=1.4 Hz, 3H), 1.27 (m, 2H), 0.66 (m, 2H); LC-MS (Method C) 397.1 [M+H].sup.+; RT 1.59 min

Example 354-(5-cyclopropyl-2,6-dimethyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)-2,5-difluoro-benzamide I1 (redx05694)

(185) ##STR00122##

(186) Prepared using 2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide and 7-bromo-5-cyclopropyl-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 4 step (c)) and a similar procedure to that described in Example 4 step (d)

(187) .sup.1H NMR (Method B) (CDCl.sub.3): ppm 7.96 (dd, J=9.6, 6.3 Hz, 1H), 7.76 (dd, J=8.1, 0.7 Hz, 1H), 7.23-7.12 (m, 2H), 6.74 (m, 1H), 5.90 (m, 1H), 3.62 (m, 1H), 2.69 (s, 3H), 2.52 (d, J=1.5 Hz, 3H), 1.25 (m, 2H), 0.66 (m, 2H); LC-MS (Method C) 410.1 [M+H]*; RT 1.59 min

Example 367-[4-(aminomethyl)-3-fluoro-phenyl]-5-cyclopropyl-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one J1

(188) ##STR00123##

(189) Prepared using 4-(aminomethyl)-3-fluorophenylboronic acid and 7-bromo-5-cyclopropyl-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 4 step (c)) and a similar procedure to that described in Example 4 step (d)

(190) .sup.1H NMR (Method B) (CDCl.sub.3): ppm 7.70 (d, J=8.0 Hz, 1H), 7.47 (t, 1H), 7.24-7.03 (m, 3H), 4.03 (s, 2H), 3.67-3.56 (m, 1H), 2.68 (s, 3H), 2.52 (s, 3H), 1.31-1.24 (m, 2H), 0.67 (m, 2H); LC-MS (Method C) 378.1 [M+H].sup.+; RT 1.11 min

Example 375-cyclopropyl-7-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one K1

(191) ##STR00124##

(192) Prepared using 2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol and 7-bromo-5-cyclopropyl-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 4 step (c)) and a similar procedure to that described in Example 4 step (d)

(193) .sup.1H NMR (Method B) (CDCl.sub.3): ppm 8.81 (s, 2H), 7.80 (dd, J=7.9, 0.7 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 4.61 (s, 1H), 3.64 (m, 1H), 2.70 (s, 2H), 2.59 (s, 3H), 1.69 (s, 6H), 1.31 (m, 2H), 0.68 (m, 2H); LC-MS (Method C) 391.1 [M+H].sup.+; RT 2.92 min

Example 387-(4-amino-3-fluorophenyl)-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one L1

(194) ##STR00125##

(195) Prepared using 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and 7-bromo-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 1 step (f)) and a similar procedure to that described in Example 1 step (g)

(196) .sup.1H NMR (Method A) (CDCl.sub.3): ppm 8.06 (s, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.06 (dd, J=11.8, 1.9 Hz, 1H), 6.99 (ddd, J=8.1, 1.9, 0.7 Hz, 1H), 6.87 (dd, J=9.0, 8.2 Hz, 1H), 3.87 (s, 2H), 3.67-3.60 (m, 1H), 2.56 (s, 3H), 1.33-1.28 (m, 2H), 0.70-0.66 (m, 2H); LC-MS (Method B) 350.5 [M.sup.+ H.sup.+], RT 2.08 min

Example 395-cyclopropyl-7-(1H-indazol-5-yl)-6-methyl-oxazolo[4,5-c]quinolin-4-one M1

(197) ##STR00126##

(198) Prepared using 6-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole and 7-bromo-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 1 step (f)) and a similar procedure to that described in Example 1 step (g)

(199) .sup.1H NMR (Method A) (CDCl.sub.3): ppm 10.62 (s, 1H), 8.17 (s, 1H), 8.10 (s, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.78 (dd, J=1.6, 0.8 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.44 (dd, J=8.6, 1.5 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 3.71-3.61 (m, 1H), 2.56 (s, 3H), 1.36-1.31 (m, 2H), 0.76-0.71 (m, 2H); LC-MS (Method B) 357.4 [M.sup.+ H.sup.+], RT 1.84 min

Example 407-(4-aminophenyl)-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one N1

(200) ##STR00127##

(201) Prepared using 4-aminophenyl boronic acid pinacol ester and 7-bromo-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 1 step (f)) and a similar procedure to that described in Example 1 step (g)

(202) .sup.1H NMR (Method A) (CDCl.sub.3): ppm 8.05 (s, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 2H), 7.21 (d, J=8.5 Hz, 2H), 6.78 (d, J=8.5 Hz, 2H), 3.82 (s, 2H), 3.66-3.62 (m, 1H), 2.56 (s, 3H), 1.32-1.27 (m, 2H), 0.71-0.66 (m, 2H); LC-MS (Method B) 332.2 [M.sup.+ H.sup.+], RT 4.64 min

Example 415-cyclopropyl-7-[2-(dimethylamino)pyrimidin-5-yl]-6-methyl-oxazolo[4,5-c]quinolin-4-one O1

(203) ##STR00128##

(204) Prepared using 5-cyclopropyl-6-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 6 step (a)) and 5-bromo-2-N,N-dimethylaminopyrimidine and a similar procedure to that described in Example 1 step (g)

(205) .sup.1H NMR (Method A) (CDCl.sub.3): ppm 8.41 (s, 2H), 8.07 (s, 1H), 7.78 (d, J=7.9 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 3.66-3.61 (m, 1H), 3.27 (s, 6H), 2.60 (s, 3H), 1.31-1.26 (m, 2H), 0.72-0.63 (m, 2H); LC-MS (Method D) 362.5 [M.sup.+ H.sup.+], RT 2.19 min

Example 427-(5-acetylpyridin-2-yl)-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one P1

(206) ##STR00129##

(207) Prepared using 5-cyclopropyl-6-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 6 step (a)) and 1-(6-bromo-3-pyridyl)ethanone and a similar procedure to that described in Example 1 step (g)

(208) .sup.1H NMR (Method A) (CDCl.sub.3) ppm 9.30 (dd, J=2.3, 0.9 Hz, 1H), 8.35 (dd, J=8.2, 2.3 Hz, 1H), 8.10 (s, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.62 (dd, J=8.1, 1.0 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 3.67-3.62 (m, 1H), 2.71 (s, 3H), 2.60 (s, 3H), 1.35-1.28 (m, 2H), 0.76-0.64 (m, 2H); LC-MS (Method D) 360.5 [M.sup.+ H.sup.+], RT 1.96 min

Example 435-cyclopropyl-6-methyl-7-(1,2-oxazol-4-yl)-oxazolo[4,5-c]quinolin-4-one

(209) ##STR00130##

(210) Prepared using 5-cyclopropyl-6-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 6 step (a)) and 4-bromo-1,2-oxazole and a similar procedure to that described in Example 1 step (g)

(211) .sup.1H NMR (Method A) (CDCl.sub.3): ppm 8.63 (s, 1H), 8.50 (s, 1H), 8.09 (s, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 3.69-3.64 (m, 1H), 2.60 (s, 3H), 1.31-1.27 (m, 2H), 0.66-0.62 (m, 2H); LC-MS (Method D) 308.4 [M.sup.+ H.sup.+], RT 2.18 min.

Example 447-(1H-1,2,3-benzotriazol-5-yl)-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one R1

(212) ##STR00131##

(213) Prepared using 5-cyclopropyl-6-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 6 step (a)) and 5-bromo-1H-benzotriazole and a similar procedure to that described in Example 1 step (g)

(214) .sup.1H NMR (Method A) (DMSO-d.sub.6): ppm 8.73 (s, 1H), 8.16 (d, J=8.5 Hz, 1H), 8.05 (d, J=8.7 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.49 (d, J=7.3 Hz, 1H), 7.34 (t, J=7.4 Hz, 1H), 3.60-3.54 (m, 2H), 1.23-1.18 (m, 2H), 0.54-0.50 (m, 2H); LC-MS (Method D) 358.4 [M.sup.+ H.sup.+], RT 1.84 min.

Example 455-cyclopropyl-7-(5-hydroxypyridin-2-yl)-6-methyl-oxazolo[4,5-c]quinolin-4-one S1

(215) ##STR00132##

(216) Prepared using 5-cyclopropyl-6-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 6 step (a)) and 6-bromopyridin-3-ol and a similar procedure to that described in Example 1 step (g)

(217) .sup.1H NMR (Method A) (CDCl.sub.3): ppm 8.43-8.39 (m, 1H), 8.08 (s, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.41-7.36 (m, 1H), 7.35-7.27 (m, 2H), 3.71-3.59 (m, 1H), 2.59 (s, 3H), 1.29-1.26 (m, 2H), 0.72-0.68 (m, 2H); LC-MS (Method D) 334.4 [M.sup.+ H.sup.+], RT 1.44 min.

Example 467-(2,1,3-benzoxadiazol-5-yl)-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one T1

(218) ##STR00133##

(219) Prepared using 5-cyclopropyl-6-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 6 step (a)) and 5-bromo-2,1-3-benzoxadiazole and a similar procedure to that described in Example 1 step (g)

(220) .sup.1H NMR (Method A) (CDCl.sub.3): ppm 8.11 (s, 1H), 7.95 (dd, J=9.2, 1.1 Hz, 1H), 7.85 (d, J=5.5 Hz, 1H), 7.84 (d, J=1.1 Hz, 1H), 7.48 (dd, J=9.2, 1.4 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 3.67-3.62 (m, 1H), 2.59 (s, 4H), 1.35-1.30 (m, 2H), 0.72-0.68 (m, 2H); LC-MS (Method E) 359.4 [M.sup.+ H.sup.+], RT 7.22 min

Example 474-{5-cyclopropyl-6-methyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl}-2,5-difluorobenzoic acid U1

(221) ##STR00134##

(222) Prepared using 5-cyclopropyl-6-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 6 step (a)) and 4-bromo-2,5-difluorobenzoic acid (prepared as described in Example 58 step (a)) and a similar procedure to that described in Example 1 step (g)

(223) .sup.1H NMR (Method A) (DMSO-d.sub.6): ppm 8.84 (s, 1H), 7.82 (d, J=7.9 Hz, 1H), 7.63-7.56 (m, 2H), 7.30 (d, J=8.0 Hz, 1H), 7.22 (dd, J=10.0, 5.8 Hz, 1H), 3.62-3.54 (m, 2H), 2.45 (s, 3H), 1.20-1.14 (m, 2H), 0.51-0.45 (m, 2H); LC-MS (Method E) 397.4 [M.sup.+ H.sup.+], RT 6.52 min

Example 487-[6-(benzylamino)pyridin-3-yl]-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one V1

(224) ##STR00135##

(225) Prepared using N-benzyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinamine and and 7-bromo-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 1 step (f)) and a similar procedure to that described in Example 1 step (g)

(226) .sup.1H NMR (Method A) (CDCl.sub.3): ppm 8.18 (d, J=2.3 Hz, 1H), 8.05 (s, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.49 (dd, J=8.6, 2.4 Hz, 1H), 7.43-7.27 (m, 5H), 7.23 (d, J=8.0 Hz, 1H), 6.52 (d, J=8.5 Hz, 1H), 5.18 (t, J=5.8 Hz, 1H), 4.59 (d, J=5.6 Hz, 2H), 3.66-3.59 (m, 1H), 2.57 (s, 3H), 1.29-1.258 (m, 2H), 0.68-0.64 (m, 2H); LC-MS (Method B) 423.4 [M+H].sup.+; RT 1.69 min

Example 497-(4-amino-1-piperidyl)-5-cyclopropyl-8-fluoro-2-methyl-oxazolo[4,5-c]quinolin-4-one W1

(a) 2,4,5-trifluorobenzoyl chloride

(227) ##STR00136##

(228) A suspension of 2,4,5-trifluorobenzoic acid (5 g, 28.4 mmol) in DCM (60 mL) was cooled to 0 C. Oxalyl chloride (3.72 mL, 42.59 mmol) was added followed by 3 drops of DMF and the reaction allowed to warm to room temperature. Effervescence commenced on warming.

(229) The mixture was stirred at room temperature for 2 h then evaporated (co-evaporated from DCM3) and used without further purification

(b) ethyl 5-(2,4,5-trifluorophenyl)-oxazole-4-carboxylate

(230) ##STR00137##

(231) Ethyl isocyanoacetate (3.72 g, 31.23 mmol) in THF (30 mL) was cooled to 00 C. Et.sub.3N (11.81 mL, 85.19 mmol) was added drop wise followed by the addition of 2,4,5-trifluorobenzoyl chloride (5.52 g, 28.4 mmol) in THF (30 mL) over 5 min. The reaction was allowed to warm to room temperature and stirred overnight. The mixture was diluted with DCM (100 mL) and washed with saturated aqueous NaHCO.sub.3 (350 mL) and brine (50 mL). The organic phase was separated, dried over Na.sub.2SO.sub.4. filtered and solvent removed in vacuo to give a brown solid. Purification by flash chromatography eluting with 0-80% EtOAc in Petroleum ether (40-60) gave ethyl 5-(2,4,5-trifluorophenyl)-oxazole-4-carboxylate (3.7 g, 48% yield) as a cream solid.

(232) LC-MS (Method C) 272.0 [M+H].sup.+; RT 1.97 min

(233) ##STR00138##

(234) A solution of ethyl 5-(2,4,5-trifluorophenyl)-oxazole-4-carboxylate (2.70 g, 9.96 mmol) in 1,4-dioxane (50 mL) was treated with 1M aqueous HCl (50 mL). After stirring for 72 h at room temperature the solvent was removed in vacuo to give ethyl (Z)-2-amino-3-hydroxy-3-(2,4,5-trifluorophenyl)prop-2-enoate as a yellow oily solid (2.60 g) which was used without further purification.

(235) LC-MS (Method C) 262.0 [M+H].sup.+; RT 0.72 min

(d) ethyl 2-methyl-5-(2,4,5-trifluorophenyl)-oxazole-4-carboxylate

(236) ##STR00139##

(237) A mixture of ethyl (Z)-2-amino-3-hydroxy-3-(2,4,5-trifluorophenyl)prop-2-enoate (2.60 g, 9.95 mmol) and trimethyl orthoacetate (25. mL, 24.98 mmol) was heated under reflux at 110 C. for 2 h. After consumption of starting material (monitored by LCMS) the mixture was concentrated in vacuo to give ethyl 2-methyl-5-(2,4,5-trifluorophenyl)-oxazole-4-carboxylate (2.82 g) which was used without further purification; LC-MS (Method C) 286.1 [M+H]*; RT 1.70 min

(e) 2-methyl-5-(2,4,5-trifluorophenyl)-oxazole-4-carboxylic acid

(238) ##STR00140##

(239) A solution of ethyl 2-methyl-5-(2,4,5-trifluorophenyl)-oxazole-4-carboxylate (2.82 g, 9.9 mmol) in 1,4-dioxane (60 mL) was treated with 1M aq. LiOH (59.4 mL) and stirred at room temperature overnight. The mixture was evaporated to a minimum, partitioned with EtOAc (50 mL) and H.sub.2O (80 mL) and the aq. washed with EtOAc (250 mL). The aq. was acidified with 1M aqueous HCl (80 mL) and extracted with EtOAc (3100 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give 2-methyl-5-(2,4,5-trifluorophenyl)-oxazole-4-carboxylic acid (2.50 g, 98% yield) as a cream solid.

(240) LC-MS (Method C) 258.0 [M+H].sup.+; RT 1.41 min

(f) 2-methyl-5-(2,4,5-trifluorophenyl)-oxazole-4-carbonyl chloride

(241) ##STR00141##

(242) A suspension of 2-methyl-5-(2,4,5-trifluorophenyl)-oxazole-4-carboxylic acid (2.50 g, 9.72 mmol) in DCM (75 mL) was treated with oxalyl chloride (1.27 mL, 14.58 mmol) and cat. DMF (1 drop) and stirred at room temperature for 1 h under N.sub.2. The mixture was then evaporated and co-evaporated from DCM (3) to give a yellow powder, which was used immediately in step (g).

(g) N-cyclopropyl-2-methyl-5-(2,4,5-trifluorophenyl)-oxazole-4-carboxamide

(243) ##STR00142##

(244) A solution of 2-methyl-5-(2,4,5-trifluorophenyl)-oxazole-4-carbonyl chloride (2.68 g, 9.72 mmol) in DCM (75 mL) was treated with cyclopropylamine (1.41 mL, 20.42 mmol) and stirred at room temperature overnight. The mixture was then diluted with DCM (50 mL) and washed with saturated aqueous NaHCO.sub.3 (330 ml) and brine (30 ml). The organic phase was separated, dried over Na.sub.2SO.sub.4 filtered and solvent removed in vacuo to give N-cyclopropyl-2-methyl-5-(2,4,5-trifluorophenyl)-oxazole-4-carboxamide (2.30 g 79% yield) as a pale solid.

(245) LC-MS (Method C) 297.1 [M+H].sup.+; RT 1.62 min

(h) 5-cyclopropyl-7,8-difluoro-2-methyl-oxazolo[4,5-c]quinolin-4-one

(246) ##STR00143##

(247) A solution of N-cyclopropyl-2-methyl-5-(2,4,5-trifluorophenyl)-oxazole-4-carboxamide (500 mg, 1.69 mmol) and 18-crown-6 (446 mg, 1.69 mmol) in DMSO (10 mL) was heated at 140 C. for 50 min. On cooling the reaction was diluted with EtOAc (100 ml) and washed 5 with H.sub.2O followed by brine (30 ml). The organic phase was dried over Na.sub.2SO.sub.4, filtered and the solvent removed in vacuo. The resulting residue was purified by flash chromatography eluting with 0-100% EtOAc in heptane to give 5-cyclopropyl-7,8-difluoro-2-methyl-oxazolo[4,5-c]quinolin-4-one (300 mg, 64.% yield) as a pale brown powder.

(248) LC-MS (Method C) 277.1 [M+H].sup.+; RT 1.53 min

(i) tert-butyl N-[1-(5-cyclopropyl-8-fluoro-2-methyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)-4-piperidyl]carbamate

(249) ##STR00144##

(250) A mixture of 5-cyclopropyl-7,8-difluoro-2-methyl-oxazolo[4,5-c]quinolin-4-one (39.9 mg, 0.14 mmol), 4-Boc-aminopiperidine (37.6 mg, 0.19 mmol) and DIPEA (0.15 mL, 0.87 mmol) were heated in the microwave (Biotage Initiator) at 140 C. for 80 min. On cooling the reaction mixture was diluted with EtOAc (50 mL) and washed with water (515 mL), 0.5M aqueous HCl (230 mL), saturated aqueous NaHCO.sub.3 (50 mL) and brine (50 mL). The organic phase was dried over Na.sub.2SO.sub.4, filtered and the solvent removed in vacuo to give tert-butyl N-[1-(5-cyclopropyl-8-fluoro-2-methyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)-4-piperidyl]carbamate (60 mg, 91% yield) as a brown solid.

(251) LC-MS (Method C) 457.2 [M+H].sup.+; RT 2.14 min

(j) 7-(4-amino-1-piperidyl)-5-cyclopropyl-8-fluoro-2-methyl-oxazolo[4,5-c]quinolin-4-one W1

(252) ##STR00145##

(253) To a solution of tert-butyl N-[1-(5-cyclopropyl-8-fluoro-2-methyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)-4-piperidyl]carbamate (53.4 mg, 0.12 mmol) in DCM (3.5 mL) at room temperature was added TFA (0.11 mL, 1.4 mmol) and the mixture left stirring for 18 h. 0.5M aqueous HCl (20 mL) was added and the mixture washed with EtOAc (220 mL). The aqueous phase was basified with solid K.sub.2CO.sub.3 and extracted with DCM (330 mL). The combined organic phases were dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography eluting with 0-20% MeOH in DCM to give 7-(4-amino-1-piperidyl)-5-cyclopropyl-8-fluoro-2-methyl-oxazolo[4,5-c]quinolin-4-one W1 (11 mg, 26% yield) as an off-white solid.

(254) .sup.1H NMR (Method B) (MeOD): ppm 7.59 (d, J=7.4 Hz, 1H), 7.56 (d, J=7.83 Hz, 1H), 3.73-3.70 (m, 2H), 3.10-3.00 (m, 3H), 2.99-2.94 (m, 2H), 2.67 (s, 3H), 2.11-2.09 (m, 2H), 1.27-1.19 (m, 2H), 0.94-0.91 (m, 2H); LC-MS (Method C) 357.2 [M+H].sup.+; RT 1.11 min

Example 507-[(3R)-3-(2-aminopropan-2-yl)pyrrolidin-1-yl]-5-cyclopropyl-8-fluoro-2-methyl-oxazolo[4,5-c]quinolin-4-one X1

(255) ##STR00146##

(256) Prepared using tert-butyl N-(2-[(3R)-pyrrolidin-3-yl]propan-2-yl)carbamate and a similar procedure to that described in Example 49 steps (i) and (j)

(257) .sup.1H NMR (Method B) (MeOD): ppm 7.39 (d, J=13.04 Hz, 1H), 7.09 (d, J=12.02 Hz, 1H), 3.73-3.68 (m, 1H), 3.63-3.60 (m, 1H), 3.56-3.51 (m, 1H), 2.99-2.93 (m, 1H), 2.65 (s, 3H), 2.57-2.53 (m, 1H), 2.20-2.13 (m, 1H), 1.98-1.91 (m, 1H), 1.44-1.42 (m, 1H), 1.38 (s, 3H), 1.37 (s, 3H), 1.33-1.25 (m, 2H), 0.92-0.86 (m, 2H); LC-MS (Method C) 385.2 [M+H].sup.+; RT 1.14 min

Example 517-(3-aminopiperidin-1-yl)-5-cyclopropyl-8-fluoro-2-methyl-oxazolo[4,5-c]quinolin-4-one Y1

(258) ##STR00147##

(259) Prepared using tert-butyl N-(piperidin-3-yl)carbamate and a similar procedure to that described in Example 49 steps (i) and (j)

(260) .sup.1H NMR (Method B) (CD.sub.3OD): ppm 7.56 (d, J=7.49 Hz, 1H), 7.09 (d, J=11.88 Hz, 1H), 3.59-3.56 (m, 1H), 3.46-3.41 (m, 1H), 3.19-3.14 (m, 1H), 3.06-2.97 (m, 2H), 2.87-2.82 (m, 1H), 2.67 (s, 3H), 2.57-2.53 (m, 1H), 2.08-2.04 (m, 1H), 2.00-1.96 (m, 1H), 1.86-1.82 (m, 1H), 1.45-1.41 (m, 2H), 1.32-1.28 (m, 1H), 0.92-0.88 (m, 2H); LC-MS (Method C) 357.2 [M+H].sup.+; RT 1.03 min

Example 527-[(3R)-3-(aminomethyl)pyrrolidin-1-yl]-5-cyclopropyl-8-fluoro-2-methyl-oxazolo[4,5-c]quinolin-4-one Z1

(261) ##STR00148##

(262) Prepared using (3S) tert-butyl N-(pyrrolidin-3-ylmethyl)carbamate and a similar procedure to that described in Example 49 steps (i) and (j)

(263) .sup.1H NMR (Method B) (MeOD): ppm 7.36 (d, J=13.5 Hz, 1H), 7.06 (d, J=7.74 Hz, 1H), 3.59-3.56 (m, 1H), 3.46-3.41 (m, 1H), 3.19-3.14 (m, 1H), 2.96-2.92 (m, 2H), 2.90-2.88 (m, 1H), 2.64 (s, 3H), 2.53-2.47 (m, 1H), 2.28-2.21 (m, 1H), 1.86-1.79 (m, 1H), 1.86-1.82 (m, 1H), 1.45-1.41 (m, 2H), 0.89-0.85 (m, 2H); LC-MS (Method C) 357.2 [M+H].sup.+; RT 1.11 min

Example 535-cyclopropyl-8-fluoro-7-(3-hydroxypyrrolidin-1-yl)-2-methyl-oxazolo[4,5-c]quinolin-4-one A2

(264) ##STR00149##

(265) Prepared using pyrrolidin-3-ol and a similar procedure to that described in Example 49 step (i)

(266) .sup.1H NMR (Method B) (CDCl.sub.3): ppm 7.18 (d, J=13.0 Hz, 1H), 6.91 (d, J=7.99 Hz, 1H), 4.66 (m, 1H), 3.85-3.77 (m, 2H), 3.73-3.69 (m, 1H), 3.58-3.54 (m, 1H), 2.96-2.92 (m, 2H), 2.89-2.86 (m, 2H), 2.64 (s, 3H), 2.21-2.16 (m, 2H), 1.37-1.33 (m, 2H), 0.87-0.84 (m, 2H); LC-MS (Method C) 344.0 [M+H].sup.+; RT 1.39 min

Example 547-[3-(1-aminoethyl)pyrrolidin-1-yl]-5-cyclopropyl-8-fluoro-2-methyl-oxazolo[4,5-c]quinolin-4-one B2

(267) ##STR00150##

(268) Prepared using tert-butyl N-[1-(pyrrolidin-3-yl)ethyl]carbamate and a similar procedure to that described in Example 49 steps (i) and (j)

(269) .sup.1H NMR (Method B) (CD.sub.3OD): ppm 7.34 (d, J=12.89 Hz, 1H), 7.03 (d, J=7.93 Hz, 1H), 3.69-3.60 (m, 3H), 3.39-3.37 (m, 1H), 3.18-3.14 (m, 1H), 2.95-2.91 (m, 1H), 2.64 (s, 3H), 2.40-2.29 (m, 2H), 1.92-1.82 (m, 1H), 1.43-1.40 (m, 2H), 1.32 (d, J=6.33 Hz, 3H), 0.88-0.85 (m, 2H); LC-MS (Method C) 371.4 [M+H].sup.+; RT 1.12 min

Example 557-(4-amino-4-methylpiperidin-1-yl)-5-cyclopropyl-8-fluoro-2-methyl-oxazolo[4,5-c]quinolin-4-one C2

(270) ##STR00151##

(271) Prepared using tert-butyl N-(4-methylpiperidin-4-yl)carbamate and a similar procedure to that described in Example 49 steps (i) and (j)

(272) .sup.1H NMR (Method B) (CD.sub.3OD): ppm 7.58 (d, J=7.47 Hz, 1H), 7.51 (d, J=12.01 Hz, 1H), 3.46-3.40 (m, 2H), 3.27-3.21 (m, 2H), 3.06-3.01 (m, 1H), 2.66 (s, 3H), 1.89 (t, J=5.58 Hz, 4H), 1.46-1.41 (m, 2H), 1.37 (s, 3H), 0.93-0.88 (m, 2H); LC-MS (Method C) 357.2 [M+H]*; RT 1.05 min

Example 567-(3-aminopyrrolidin-1-yl)-5-cyclopropyl-8-fluoro-2-methyl-oxazolo[4,5-c]quinolin-4-one D2

(273) ##STR00152##

(274) Prepared using tert-butyl N-(pyrrolidin-3-yl)carbamate and a similar procedure to that described in Example 49 steps (i) and (j). Product isolated as a formate salt

(275) .sup.1H NMR (Method B) (CD.sub.3OD): ppm 8.20 (br s, 1H), 7.62 (d, J=13.4 Hz, 1H), 7.09 (d, J=8.03 Hz, 1H), 3.97 (m, 1H), 3.85 (m, 1H), 3.74 (m, 1H), 3.65 (m, 1H), 3.55 (m, 1H), 2.98 (m, 1H), 2.60 (s, 3H), 2.34 (m, 1H), 2.11 (m, 1H), 1.34 (m, 2H), 0.79 (m, 2H); LC-MS (Method C) 343.2 [M.sup.+ H.sup.+]; RT 1.81 min

Example 577-[3-(aminomethyl)pyrrolidin-1-yl]-5-cyclopropyl-8-fluoro-2-methyl-oxazolo[4,5-c]quinolin-4-one E2

(276) ##STR00153##

(277) Prepared using tert-butyl N-(pyrrolidin-3-ylmethyl)carbamate and a similar procedure to that described in Example 49 steps (i) and (j). Product isolated as a HCl salt by stirring in 1M HCl in ether followed by removal of solvent.

(278) .sup.1H NMR (Method B) (DMSO-d.sub.6): ppm 7.99 (br s, 2H), 7.58 (d, J=13.35 Hz, 1H), 7.07 (d, J=7.97 Hz, 1H), 3.72-3.51 (m, 4H), 2.97 (m, 4H), 2.59 (s, 3H), 2.19 (m, 1H), 1.82 (m, 1H), 1.36 (m, 2H) 0.78 (m, 2H); LC-MS (Method C) 357.3 [M.sup.+ H.sup.+]; RT 1.88 min

Example 584-(5-cyclopropyl-8-fluoro-4-oxo-oxazolo[4,5-c]quinolin-7-yl)benzamide F2

(279) ##STR00154##

(a) 4-bromo-2,5-difluorobenzoic acid

(280) ##STR00155##

(281) To a 78 C. solution of 1,4-dibromo-2,5-difluorobenzene (2.72 g, 9.99 mmol) in dry Et.sub.2O (30 mL) under an inert atmosphere was added 2.5 M n-butyllithium solution in hexanes (4 mL, 9.99 mmol) drop-wise and the mixture left stirring for 2 h. Crushed CO.sub.2 pellets were added slowly and the mixture was allowed to warm to ambient temperature and left stirring for 1 h.

(282) After quenching with 1M aqueous HCl (10 mL) the mixture was basified with 1M aqueous NaOH (70 mL) and then washed with Et.sub.2O (250 mL). The aqueous layer was acidified with 1M aqueous HCl (80 mL) and extracted with Et.sub.2O (3100 mL). The organic layer was washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and solvent was removed in vacuo to give 4-bromo-2,5-difluoro benzoic acid (2.3 g, 97%) as an off-white solid, which was used without further purification.

(283) .sup.1H NMR (Method B) (CDCl.sub.3): ppm 9.50 (br s, 1H), 7.78 (dd, J=8.2, 6.1 Hz, 1H), 7.46 (dd, J=9.3, 5.4 Hz, 1H); LC-MS (Method C) 234.9/236.9 [MH].sup.+; RT 3.43 min

(b) ethyl 5-(4-bromo-2,5-difluoro-phenyl)oxazole-4-carboxylate

(284) ##STR00156##

(285) To an ice cooled solution of 4-bromo-2,5-difluorobenzoic acid (6.27 g, 26.46 mmol) in DCM (80 mL) was added oxalyl chloride (3.46 mL, 39.68 mmol), followed by several drops of DMF. The mixture was then removed from the ice bath and stirred for 2 h. The solvent was removed under reduced pressure to give 4-bromo-2,5-difluorobenzoyl chloride. To an ice cooled solution of ethyl isocyanoacetate (3.18 mL, 29.1 mmol) in THF (40 mL) was added Et.sub.3N (11. mL, 79.37 mmol) followed by the slow addition of 4-bromo-2,5-difluorobenzoyl chloride in THF (40 mL). The reaction mixture was then allowed to warm to room temperature and stirred for 18 h. The reaction mixture was then diluted with DCM and washed with sat aqueous NaHCO.sub.3 followed by brine. The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give ethyl 5-(4-bromo-2,5-difluoro-phenyl)oxazole-4-carboxylate as a solid (7.78 g, 89% yield) LC-MS (Method C) 331.9/333.9 [M+H].sup.+; RT 1.77 min.

(286) ##STR00157##

(287) A solution of ethyl 5-(4-bromo-2,5-difluoro-phenyl)oxazole-4-carboxylate (7.78 g, 23.44 mmol) in 1,4-dioxane (50 mL) was treated with 2M aq. LiOH (50 mL) and stirred at room temperature overnight. The 1,4-dioxane was removed under reduced pressure and the remaining aqueous was acidified with 1M aqueous HCl, and then extracted with EtOAc.

(288) The combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and then concentrated in vacuo to give 5-(4-bromo-2,5-difluoro-phenyl)oxazole-4-carboxylic acid as an off white solid (6.05 g, 85% yield), which was used without further purification.

(289) LC-MS (Method C) 303.9/305.8 [M+H].sup.+; RT 1.46 min.

(d) 5-(4-bromo-2,5-difluoro-phenyl)-N-cyclopropyl-oxazole-4-carboxamide

(290) ##STR00158##

(291) A suspension of 5-(4-bromo-2,5-difluoro-phenyl)oxazole-4-carboxylic acid (5.5 g, 18.09 mmol) in anhydrous DCM (80 mL) was cooled in an ice bath followed by the slow addition of oxalyl chloride (2.3 mL, 27.14 mmol). Several drops of DMF were added to catalyse the reaction. The reaction mixture was allowed to warm to room temperature and stirred for 2 h, before concentrating in vacuo to give a brown liquid, which was dissolved in DCM (80 mL) and treated with cyclopropylamine (2.75 mL, 39.69 mmol). After stirring at room temperature for 2 h the reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO.sub.3 The organic phase was separated, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give 5-(4-bromo-2,5-difluoro-phenyl)-N-cyclopropyl-oxazole-4-carboxamide as a light brown solid (5.14 g, 83% yield), which was used without further purification.

(292) LC-MS (Method C) 342.8/344.7 [M+H].sup.+; RT 1.65 min

(e) 7-bromo-5-cyclopropyl-8-fluoro-oxazolo[4,5-c]quinolin-4-one

(293) ##STR00159##

(294) A mixture of 5-(4-bromo-2,5-difluoro-phenyl)-N-cyclopropyl-oxazole-4-carboxamide (1.5 g, 4.37 mmol), K.sub.2CO.sub.3 (1.81 g, 13.12 mmol) and 18-crown-6 (1.16 g, 4.37 mmol) in DMSO (20 mL) were heated in the microwave (Biotage Initiator) at 140 C. for 90 min.

(295) The reaction mixture was then diluted with EtOAc, which was washed with H.sub.2O several times followed by brine and then dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give a brown solid. The crude product was purified by flash chromatography eluting with 0-100% EtOAc in heptane to give 7-bromo-5-cyclopropyl-8-fluoro-oxazolo[4,5-c]quinolin-4-one (370 mg, 26% yield) as an off white solid.

(296) .sup.1H NMR (Method B) (CDCl.sub.3): ppm 8.22 (d, J=5.7 Hz, 1H), 8.14 (s, 1H), 7.66 (d, J=7.5 Hz, 1H), 3.04 (tt, J=6.8, 4 Hz, 1H), 1.47 (m, 2H), 0.97 (m, 2H); LC-MS (Method C) 322.9/324.8 [M+H].sup.+; RT 1.55 min

(f) 4-(5-cyclopropyl-8-fluoro-4-oxo-oxazolo[4,5-c]quinolin-7-yl)benzamide F2

(297) ##STR00160##

(298) A mixture of 7-bromo-5-cyclopropyl-8-fluoro-oxazolo[4,5-c]quinolin-4-one (40. mg, 0.12 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (10.1 mg, 0.01 mmol), Cs.sub.2CO.sub.3 (121 mg, 0.37 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzamide (30.6 mg, 0.12 mmol) in dimethoxyethane (1 mL) and H.sub.2O (0.25 mL) was heated in the microwave (Biotage Initiator) at 120 C. for 20 minute. The mixture was dry loaded onto silica and purified by flash chromatography eluting with 0-20% MeOH in DCM to give a solid, which was further purified by preparative HPLC (Method B) to give 4-(5-cyclopropyl-8-fluoro-4-oxo-oxazolo[4,5-c]quinolin-7-yl)benzamide F2 (10 mg, 22%) as a white solid

(299) .sup.1H NMR (Method B) (CD.sub.3OD): ppm 8.60 (s, 1H), 8.26 (d, J=6.5 Hz, 1H), 8.06 (m, 2H), 7.90 (d, J=9.8 Hz, 1H), 7.81 (dd, J=8.5 Hz, 2H), 3.20 (m, 1H), 1.47 (m, 2H), 1.01 (m, 2H); LC-MS (Method C) 364.1 [M+H].sup.+; RT 1.39 min

Example 597-(3-chloro-4-pyridyl)-5-cyclopropyl-8-fluoro-oxazolo[4,5-c]quinolin-4-one G2

(300) ##STR00161##

(301) Prepared using 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and 7-bromo-5-cyclopropyl-8-fluoro-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 58 step (e)) and a similar procedure to that described in Example 58 step (f)

(302) .sup.1H NMR (Method B) (DMSO-d.sub.6): ppm 8.92 (s, 1H), 8.86 (s, 1H), 8.71 (d, J=4.9 Hz, 1H), 8.07-8.03 (m, 2H), 7.66 (d, J=4.9 Hz, 1H), 3.07 (m, 1H), 1.35-1.30 (m, 2H), 0.87-0.83 (m, 2H); LC-MS (Method C) 356.2 [M+H].sup.+; RT 1.47 min

Example 605-cyclopropyl-8-fluoro-7-[6-(trifluoromethyl)-3-pyridyl]oxazolo[4,5-c]quinolin-4-one H2

(303) ##STR00162##

(304) Prepared using [6-(trifluorormethyl)-3-pyridyl]boronic acid and 7-bromo-5-cyclopropyl-8-fluoro-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 58 step (e)) and a similar procedure to that described in Example 58 step (f)

(305) .sup.1H NMR (Method B) (DMSO-d.sub.6): ppm 9.10 (s, 1H), 8.93 (s, 1H), 8.43 (d, J=8.3 Hz, 1H), 8.24 (d, J=6.5 Hz, 1H), 8.13 (d, J=7.8 Hz, 1H), 8.08 (d, J=9.9 Hz, 1H), 3.14 (m, 1H), 1.38 (m, 2H), 0.88 (m, 2H); LC-MS (Method C) 390.1 [M+H].sup.+; RT 1.69 min

Example 61ethyl 4-(5-cyclopropyl-8-fluoro-4-oxo-oxazolo[4,5-c]quinolin-7-yl)benzoate 12

(306) ##STR00163##

(307) Prepared using ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate and 7-bromo-5-cyclopropyl-8-fluoro-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 58 step (e)) and a similar procedure to that described in Example 58 step (f)

(308) .sup.1H NMR (Method B) (CDCl.sub.3): b ppm 8.21-8.16 (m, 3H), 8.07 (d, J=6.4 Hz, 1H), 7.72 (m, 3H), 4.44 (q, J=7.1 Hz, 2H), 3.10 (br s, 1H), 1.48-1.42 (m, 5H), 1.02 (m, 2H); LC-MS (Method C) 393.2 [M+H].sup.+; RT 1.80 min

Example 627-(2-aminopyrimidin-5-yl)-5-cyclopropyl-8-fluoro-oxazolo[4,5-c]quinolin-4-one J2

(309) ##STR00164##

(310) Prepared using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyrimidinamine and 7-bromo-5-cyclopropyl-8-fluoro-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 58 step (e)) and a similar procedure to that described in Example 58 step (f)

(311) .sup.1H NMR (Method B) (DMSO-d.sub.6): ppm 8.87 (s, 1H), 8.59 (d, J=1.3 Hz, 2H), 8.09 (d, J=6.7 Hz, 1H), 7.94 (d, J=9.9 Hz, 1H), 7.06 (s, 2H), 3.13 (m, 1H), 1.39 (m, 2H), 0.86 (m, 2H); LC-MS (Method C) 338.2 [M+H].sup.+; RT 1.18 min

Example 635-cyclopropyl-8-fluoro-7-(4-methoxyphenyl)oxazolo[4,5-c]quinolin-4-one

(312) ##STR00165##

(313) Prepared using 4-methoxyphenylboronic acid and 7-bromo-5-cyclopropyl-8-fluoro-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 58 step (e)) and a similar procedure to that described in Example 58 step (f)

(314) .sup.1H NMR (Method B) (DMSO-d.sub.6): ppm 8.88 (s, 1H), 8.06 (d, J=6.7 Hz, 1H), 7.92 (d, J=10 Hz, 1H), 7.64 (dd, J=6.7, 1.8 Hz, 2H), 7.14 (m, 2H), 3.85 (s, 3H), 3.15 (m, 1H), 1.36 (m, 2H), 0.87 (m, 2H); LC-MS (Method C) 351.1 [M+H].sup.+; RT 1.72 min

Example 645-cyclopropyl-8-fluoro-7-(4-hydroxyphenyl)oxazolo[4,5-c]quinolin-4-one L2

(315) ##STR00166##

(316) Prepared using 4-hydroxphenylboronic acid and 7-bromo-5-cyclopropyl-8-fluoro-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 58 step (e)) and a similar procedure to that described in Example 58 step (f)

(317) .sup.1H NMR (Method B) (DMSO-d.sub.6): ppm 9.83 (s, 1H), 8.86 (s, 1H), 8.03 (d, J=6.8 Hz, 1H), 7.89 (d, J=10.1 Hz, 1H), 7.53 (dd, J=8.5, 1.7 Hz, 2H), 6.95 (d, J=8.7 Hz, 2H), 3.14 (m, 1H), 1.36 (m, 2H), 0.86 (m, 2H); LC-MS (Method C) 337.1 [M+H].sup.+; RT 1.44 min

Example 654-(5-cyclopropyl-8-fluoro-4-oxo-oxazolo[4,5-c]quinolin-7-yl)-2,6-difluoro-benzonitrile M2

(318) ##STR00167##

(319) Prepared using 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile and 7-bromo-5-cyclopropyl-8-fluoro-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 58 step (e)) and a similar procedure to that described in Example 58 step (f)

(320) .sup.1H NMR (Method B) (CDCl.sub.3) 8.18 (s, 1H), 8.02 (d, J=6.3 Hz, 1H), 7.76 (d, J=9.6 Hz, 1H), 7.35 (d, J=9.0 Hz, 2H), 3.10 (s, 1H), 1.53-1.43 (m, 2H), 1.10-0.93 (m, 2H); LC-MS (Method C) 382.0 [M+H].sup.+; RT 1.71 min

Example 664-(5-cyclopropyl-8-fluoro-4-oxo-oxazolo[4,5-c]quinolin-7-yl)-N,N-dimethyl-benzamide N2

(321) ##STR00168##

(322) Prepared using 4-(dimethylcarbamoyl)phenylboronic acid and 7-bromo-5-cyclopropyl-8-fluoro-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 58 step (e)) and a similar procedure to that described in Example 58 step (f)

(323) .sup.1H NMR (Method B) (CDCl.sub.3) 8.14 (s, 1H), 8.04 (d, J=6.3 Hz, 1H), 7.75-7.54 (m, 5H), 3.17-3.05 (m, 7H), 1.49-1.43 (m, 2H), 1.05-0.95 (m, 2H); LC-MS (Method C) 392.0 [M+H].sup.+; RT 1.39 min

Example 674-(5-cyclopropyl-8-fluoro-4-oxo-oxazolo[4,5-c]quinolin-7-yl)-2-fluoro-N-methyl-benzamide O2

(324) ##STR00169##

(325) Prepared using [3-fluoro-4-(methylcarbamoyl)phenyl]boronic acid and 7-bromo-5-cyclopropyl-8-fluoro-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 58 step (e)) and a similar procedure to that described in Example 58 step (f)

(326) .sup.1H NMR (Method B, CDCl.sub.3) 8.27 (t, 1H), 8.15 (s, 1H), 8.06 (d, J=6.3 Hz, 1H), 7.72 (d, J=9.5 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.43 (d, J=12.9 Hz, 1H), 6.79 (s, 1H), 3.15-3.00 (m, 4H), 1.48 (d, J=6.6 Hz, 2H), 1.01 (s, 2H); LC-MS (Method C) 396.0 [M+H].sup.+; RT 1.37 min

Example 685-cyclopropyl-7-[2,5-difluoro-4-(hydroxymethyl)phenyl]-8-fluoro-oxazolo[4,5-c]quinolin-4-one P2

(327) ##STR00170##

(328) Prepared using [2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol and 7-bromo-5-cyclopropyl-8-fluoro-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 58 step (e)) and a similar procedure to that described in Example 58 step (f)

(329) .sup.1H NMR (Method B) (CDCl.sub.3) 8.08 (s, 1H), 7.96 (d, J=6.0 Hz, 1H), 7.65 (d, J=8.9 Hz, 1H), 7.31 (dd, J=9.8, 6.0 Hz, 1H), 7.13 (m, 1H), 4.79 (s, 2H), 2.99 (m, 1H), 1.37 (m, 2H), 0.93 (m, 2H); LC-MS (Method C) 387.1 [M+H].sup.+; RT 1.47 min

Example 697-(4-amino-2,5-difluoro-phenyl)-5-cyclopropyl-8-fluoro-oxazolo[4,5-c]quinolin-4-one Q2

(330) ##STR00171##

(331) Prepared using 4-amino-2,5-difluorobenzeneboronic acid pinacol ester and 7-bromo-5-cyclopropyl-8-fluoro-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 58 step (e)) and a similar procedure to that described in Example 58 step (f)

(332) .sup.1H NMR (Method B) (DMSO-d.sub.6): ppm 8.87 (s, 1H), 7.94 (dd, J=6.2, 7.8 Hz, 2H), 7.26 (dd, J=11.5, 6.8 Hz, 1H), 7.09 (s, 2H), 6.69 (dd, J=11.9, 7.4 Hz, 1H), 3.17-2.89 (m, 1H), 1.34 (t, J=6.8 Hz, 2H), 0.86 (d, J=3.7 Hz, 2H); LC-MS (Method C) 372.1 [M.sup.+ H.sup.+]; RT 1.90 min

Example 707-(6-amino-3-pyridyl)-5-cyclopropyl-8-fluoro-oxazolo[4,5-c]quinolin-4-one R2

(333) ##STR00172##

(334) Prepared using 2-aminopyridine-5-boronic acid pinacol ester and 7-bromo-5-cyclopropyl-8-fluoro-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 57 step (e)) and a similar procedure to that described in Example 57, step (f)

(335) .sup.1H NMR (Method B) (DMSO-d.sub.6): ppm 8.86 (s, 1H), 8.26 (t, J=2.0 Hz, 1H), 8.03 (d, J=6.7 Hz, 1H), 7.89 (d, J=10.1 Hz, 1H), 7.72 (dt, J=8.7, 2.2 Hz, 1H), 6.60 (d, J=8.7 Hz, 1H), 6.33 (s, 2H), 3.14 (qd, J=8.2, 7.2, 4.6 Hz, 1H), 1.43-1.29 (m, 2H), 0.92-0.78 (m, 2H); LC-MS (Method C) 337.1 [M.sup.+ H.sup.+]; RT 0.95 min.

Example 717-(4-amino-3-fluoro-phenyl)-5-cyclopropyl-8-fluoro-oxazolo[4,5-c]quinolin-4-one S2

(336) ##STR00173##

(337) Prepared using 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and 7-bromo-5-cyclopropyl-8-fluoro-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 58 step (e)) and a similar procedure to that described in Example 58 step (f)

(338) .sup.1H NMR (Method B) (CD.sub.3OD): ppm 8.56 (s, 1H), 8.16 (d, J=6.76 Hz, 1H), 7.80 (d, J=9.88 Hz, 1H), 7.36-7.28 (m, 2H), 6.99-6.95 (m, 1H), 3.20-3.16 (m, 1H), 1.50-1.45 (m, 2H), 1.00-0.96 (m, 2H); LC-MS (Method C) 354.2 [M+H].sup.+; RT 1.52 min

Example 724-(5-cyclopropyl-8-fluoro-2-methyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)benzaldehyde T2

(a) 7-bromo-5-cyclopropyl-8-fluoro-2-methyl-oxazolo[4,5-c]quinolin-4-one

(339) ##STR00174##

(340) Prepared using 4-bromo-2,5-difluorobenzoic acid (prepared as described in Example 58 step (a)) and a similar procedure to that described in Example 49 steps (a) to (h).

(341) LC-MS (Method C) 336.8/338.8 [M+H]*; RT 1.61 min

(b) 4-(5-cyclopropyl-8-fluoro-2-methyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)benzaldehyde T2

(342) ##STR00175##

(343) Prepared using 7-bromo-5-cyclopropyl-8-fluoro-2-methyl-oxazolo[4,5-c]quinolin-4-one and a similar procedure to that described in Example 58 step (f)

(344) .sup.1H NMR (Method B) (DMSO-d.sub.6): ppm 10.12 (s, 1H), 8.14 (d, J=6.7 Hz, 1H), 8.10 (d, J=8.4 Hz, 2H), 7.93 (d, J=9.9 Hz, 3H), 3.15 (m, 1H), 2.68 (s, 3H), 1.36 (m, 2H), 0.87 (m, 2H); LC-MS (Method C) 363.1 [M+H]*; RT 3.63 min

Example 735-cyclopropyl-8-fluoro-7-(1H-indazol-5-yl)-2-methyl-oxazolo[4,5-c]quinolin-4-one U2

(345) ##STR00176##

(346) Prepared using 6-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole and 7-bromo-5-cyclopropyl-8-fluoro-2-methyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 72 step (a)) and a similar procedure to that described in Example 58 step (f)

(347) .sup.1H NMR (Method B) (DMSO-d.sub.6): b ppm 13.26 (s, 1H), 8.22 (s, 1H), 8.12 (d, J=6.8 Hz, 1H), 8.09 (s, 1H), 7.87 (d, J=10 Hz, 1H), 7.72 (d, J=8.7 Hz, 1H), 7.65 (dt, J=8.6, 1.4 Hz, 1H), 3.14 (m, 1H), 2.68 (s, 3H), 1.36 (m, 2H), 0.87 (m, 2H); LC-MS (Method C) 375.0 [M+H].sup.+; RT 1.44 min

Example 745-cyclopropyl-8-fluoro-7-(3-fluoro-4-pyridyl)-2-methyl-oxazolo[4,5-c]quinolin-4-one V2

(348) ##STR00177##

(349) Prepared using 3-fluoro-4-pyridineboronic acid pinacol ester and 7-bromo-5-cyclopropyl-8-fluoro-2-methyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 72 step (a)) and a similar procedure to that described in Example 58 step (f)

(350) .sup.1H NMR (Method B) (DMSO-d.sub.6): ppm 8.80 (d, J=1.7 Hz, 1H), 8.65 (dd, J=4.9, 1 Hz, 1H), 8.13 (d, J=6.1 Hz, 1H), 7.97 (d, J=9.3 Hz, 1H), 7.73 (t, J=5.6 Hz, 1H), 3.09 (m, 1H), 2.69 (s, 3H), 1.34 (m, 2H), 0.85 (m, 2H); LC-MS (Method C) 354.2 [M+H].sup.+; RT 1.46 min

Example 755-cyclopropyl-8-fluoro-2-methyl-7-(4-pyridyl)oxazolo[4,5-c]quinolin-4-one W2

(351) ##STR00178##

(352) Prepared using 4-pyridinylboronic acid pinacol ester and 7-bromo-5-cyclopropyl-8-fluoro-2-methyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 72 step (a)) and a similar procedure to that described in Example 58 step (f)

(353) .sup.1H NMR (Method B) (CDCl.sub.3): ppm 8.80 (br s, 2H), 8.08 (d, J=4.3 Hz, 1H), 7.68 (d, J=9.7 Hz, 1H), 7.64 (br s, 2H), 3.10 (br s, 1H), 2.72 (s, 3H), 1.47 (br s, 2H), 1.00 (br s, 2H); LC-MS (Method C) 336.3 [M+H].sup.+; RT 1.16 min

Example 767-[4-(aminomethyl)-3-fluoro-phenyl]-5-cyclopropyl-8-fluoro-2-methyl-oxazolo[4,5-c]quinolin-4-one X2

(354) ##STR00179##

(355) Prepared using 4-(aminomethyl)-3-fluorophenylboronic acid and 7-bromo-5-cyclopropyl-8-fluoro-2-methyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 72 step (a)) and a similar procedure to that described in Example 58 step (f)

(356) .sup.1H NMR (Method B) (D.sub.2O): ppm 8.44 (s, 1H), 7.74 (d, J=6.5 Hz, 1H), 7.51 (t, J=7.9 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.15 (t, 2H), 4.29 (s, 2H), 2.87 (m, 1H), 2.49 (s, 3H), 1.51-1.28 (m, 2H), 0.82-0.55 (m, 2H); LC-MS (Method C) 382.3 [M+H].sup.+; RT 1.17 min

Example 777-(4-acetyl-2,5-difluoro-phenyl)-5-cyclopropyl-8-fluoro-2-methyl-oxazolo[4,5-c]quinolin-4-one Y2

(357) ##STR00180##

(358) Prepared using 1-[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanone and 7-bromo-5-cyclopropyl-8-fluoro-2-methyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 72 step (a)) and a similar procedure to that described in Example 58 step (f)

(359) .sup.1H NMR (Method B) (CD.sub.3OD): ppm 8.20 (d, J=6.0 Hz, 1H), 7.85 (d, J=9.2 Hz, 1H), 7.74 (dd, J=10.0, 5.9 Hz, 1H), 7.54 (dd, J=10.6, 5.5 Hz, 1H), 3.18-3.08 (m, 1H), 2.74-2.59 (m, 6H), 1.51-1.37 (m, 2H), 1.02-0.91 (m, 2H); LC-MS (Method C) 413.1 [M+H].sup.+; RT 1.73 min

Example 784-(5-cyclopropyl-8-fluoro-2-methyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)-2,5-difluoro-benzamide Z2

(360) ##STR00181##

(361) Prepared using 2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide and 7-bromo-5-cyclopropyl-8-fluoro-2-methyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 72 step (a)) and a similar procedure to that described in Example 58 step (f)

(362) .sup.1H NMR (Method B) (CDCl.sub.3): b ppm 8.12-7.93 (m, 2H), 7.67 (d, J=9.1 Hz, 1H), 7.33 (m, 1H), 6.75 (d, J=11.6 Hz, 1H), 5.97 (s, 1H), 3.05 (m, 1H), 2.72 (s, 3H), 1.48-1.38 (m, 2H), 1.03-0.91 (m, 2H); LC-MS (Method C) 414.1 [M+H].sup.+; RT 1.41 min

Example 797-(4-amino-2,5-difluoro-phenyl)-5-cyclopropyl-8-fluoro-2-methyl-oxazolo[4,5-c]quinolin-4-one A3

(363) ##STR00182##

(364) Prepared using 4-amino-2,5-difluorobenzeneboronic acid pinacol ester and 7-bromo-5-cyclopropyl-8-fluoro-2-methyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 72 step (a)) and a similar procedure to that described in Example 58 step (f)

(365) .sup.1H NMR (Method B) (DMSO-d.sub.6): ppm 7.97 (d, J=6.2 Hz, 1H), 7.81 (d, J=9.4 Hz, 1H), 7.25 (dd, J=11.7, 6.7 Hz, 1H), 6.69 (dd, J=11.9, 7.6 Hz, 1H), 5.83 (s, 2H), 3.15-3.00 (m, 1H), 2.67 (s, 3H), 1.33 (d, J=6.8 Hz, 2H), 0.92-0.73 (m, 2H); LC-MS (Method C) 386.2 [M.sup.+ H.sup.+]; RT 1.59 min

Example 807-(3-aminopyrrolidin-1-yl)-5-cyclopropyl-8-fluoro-oxazolo[4,5-c][1,8]naphthyridin-4-one B3

(a) 7-chloro-5-cyclopropyl-8-fluoro-oxazolo[4,5-c]1,8-naphthyridin-4-one

(366) ##STR00183##

(367) Prepared using 2,6-dichloro-5-fluoronicotinic acid and a similar procedure to that described in Example 49 steps (a) to (h)

(b) 7-(3-aminopyrrolidin-1-yl)-5-cyclopropyl-8-fluoro-oxazolo[4,5-c][1,8]napthyridin-4-one B3

(368) ##STR00184##

(369) To a stirred solution of pyrrolidin-3-amine (25 mg, 0.30 mmol) in ACN (2 mL) was added 7-chloro-5-cyclopropyl-8-fluoro-oxazolo[4,5-c][1,8]naphthyridin-4-one (33 mg, 0.12 mmol) and the reaction mixture was heated to 80 C. for 15 min under microwave irradiation (Biotage Initiator). The solvent was then removed from the crude reaction mixture. The resulting residue was purified by flash silica chromatography using 0-2.5% MeOH/NH.sub.3 in DCM to give 7-(3-aminopyrrolidin-1-yl)-5-cyclopropyl-8-fluoro-oxazolo[4,5-c][1,8]naphthyridin-4-one (6 mg, 15%) as a pale orange gum.

(370) .sup.1H NMR (Method A) (CDCl.sub.3): b ppm 7.95 (s, 1H), 7.57 (d, J=11.9 Hz, 1H), 4.05-3.93 (m, 2H), 3.93-3.82 (m, 1H), 3.82-3.73 (m, 1H), 3.62-3.51 (m, 1H), 2.96 (s, 1H), 2.30-2.14 (m, 1H), 1.90-1.78 (m, 1H), 1.56 (s, 2H), 1.37-1.27 (m, 2H), 0.94-0.87 (m, 2H); LC-MS (Method B) 330.44 [M+H].sup.+; RT 1.11 min

Example 817-[3-(aminomethyl)pyrrolidin-1-yl]-5-cyclopropyl-8-fluoro-oxazolo[4,5-c][1,8]naphthyridin-4-one C3

(371) ##STR00185##

(372) Prepared using tert-butyl N-(pyrrolidin-3-ylmethyl)carbamate and 7-chloro-5-cyclopropyl-8-fluoro-oxazolo[4,5-c][1,8]naphthyridin-4-one (prepared as described in Example 80 step (a)) and a similar procedure to that described in Example 80 step (b), followed by deprotection of the BOC group using the method described in Example 49 step (j).

(373) .sup.1H NMR (Method A) (CD.sub.3OD): ppm 8.24 (s, 1H), 7.49 (d, J=12.2 Hz, 1H), 3.92-3.83 (m, 1H), 3.83-3.73 (m, 1H), 3.66-3.57 (m, 2H), 3.38-3.29 (m, 1H), 2.80-2.72 (m, 1H), 2.70-2.67 (m, 1H), 2.39-2.26 (m, 1H), 2.14-2.03 (m, 1H), 1.66 (m, 1H), 1.23-1.17 (m, 2H), 0.76-0.69 (m, 2H); LC-MS (Method B) 344.52 [M+H].sup.+; RT 1.14 min

Example 827-(6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-5-cyclopropyl-8-fluoro-oxazolo[4,5-c][1,8]naphthyridin-4-one D3

(374) ##STR00186##

(375) Prepared using 3-azabicyclo[3.1.0]hexan-6-amine and 7-chloro-5-cyclopropyl-8-fluoro-oxazolo[4,5-c][1,8]naphthyridin-4-one (prepared as described in Example 80 step (a)) and a similar procedure to that described in Example 80 step (b),

(376) .sup.1H NMR (Method A) (CDCl.sub.3) ppm 7.95 (s, 1H), 7.57 (d, J=12.1 Hz, 1H), 4.06 (dd, J=11.5, 3.3 Hz, 2H), 3.83-3.75 (m, 2H), 2.95 (s, 1H), 2.25 (t, J=2.2 Hz, 1H), 1.76-1.69 (m, 1H), 1.62 (s, 2H), 1.37-1.28 (m, 2H), 1.27-1.25 (m, 1H), 0.93-0.86 (m, 2H); LC-MS (Method B) 342.47 [M+H].sup.+; RT 4.01 min

Example 835-cyclopropyl-7-[3-(dimethylamino)pyrrolidin-1-yl]-8-fluoro-oxazolo[4,5-c][1,8]naphthyridin-4-one E3

(377) ##STR00187##

(378) Prepared using N,N-dimethylpyrrolidin-3-amine and 7-chloro-5-cyclopropyl-8-fluoro-oxazolo[4,5-c][1,8]naphthyridin-4-one (prepared as described in Example 80 step (a)) and a similar procedure to that described in Example 80 step (b),

Example 847-(5-amino-2,4-difluorophenyl)-5-cyclopropyl-8-fluoro-oxazolo[4,5-c]1,8-naphthyridin-4-one F3

(379) ##STR00188##

(380) Prepared using 4-amino-2,5-difluorobenzeneboronic acid pinacol ester and 7-chloro-5-cyclopropyl-8-fluoro-oxazolo[4,5-c][1,8]naphthyridin-4-one (prepared as described in Example 80 step (a)) and a similar procedure to that described in Example 58 step (f)

(381) .sup.1H NMR (Method A) (DMSO-d.sub.6): ppm 8.90 (s, 1H), 8.42 (d, J=9.2 Hz, 1H), 7.39 (dd, J=11.8, 6.4 Hz, 1H), 6.66 (dd, J=12.2, 7.3 Hz, 1H), 6.01 (s, 2H), 3.05-2.99 (m, 1H), 1.29-1.17 (m, 2H), 1.01-0.78 (m, 2H); LC-MS (Method B) 373.4 [M+H].sup.+; RT 2.10 min

Example 857-(5-amino-2,4-difluorophenyl)-5-cyclopropyl-8-fluoro-oxazolo[4,5-c]1,8-naphthyridin-4-one G3

(382) ##STR00189##

(383) Prepared using 5-amino-2,4-difluorobenzeneboronic acid pinacol ester and 7-chloro-5-cyclopropyl-8-fluoro-oxazolo[4,5-c][1,8]naphthyridin-4-one (prepared as described in Example 80 step (a)) and a similar procedure to that described in Example 58 step (f)

(384) .sup.1H NMR (Method A) (DMSO-d.sub.6) ppm 8.93 (s, 1H), 8.49 (d, J=9.0 Hz, 1H), 7.24 (dd, J=11.2, 10.0 Hz, 1H), 7.14 (dd, J=9.9, 7.2 Hz, 1H), 5.29 (s, 2H), 3.09-2.91 (m, 1H), 1.35-1.16 (m, 2H), 0.92-0.71 (m, 2H); LC-MS (Method D) 373.3 [M+H].sup.+; RT 2.11 min

Example 867-(4-amino-2,5-difluorophenyl)-5-cyclopropyl-8-fluoro-2-methyl-oxazolo[4,5-c]1,8-naphthyridin-4-one H3

(a) 7-chloro-5-cyclopropyl-8-fluoro-2-methyl-oxazolo[4,5-c][1,8]naphthyridin-4-one

(385) ##STR00190##

(386) Prepared using 2,6-dichloro-5-fluoronicotinic acid and a similar procedure to that described in Example 49 steps (a) to (h)

(387) LC-MS (Method B) 294.4/295.4 [M+H].sup.+; RT 2.08 min

(b) 7-(4-amino 2,5-difluorophenyl)-5-cyclopropyl-8-fluoro-2-methyl-oxazolo[4,5c][1,8]naphthyridin-4-one H3

(388) ##STR00191##

(389) Prepared using 4-amino-2,5-difluorobenzeneboronic acid pinacol ester and 7-chloro-5-cyclopropyl-8-fluoro-2-methyl-oxazolo[4,5c][1,8]naphthyridin-4-one and a similar procedure to that described in Example 58 step (f)

(390) .sup.1H NMR (Method A) (DMSO-d.sub.6) ppm 8.17 (d, J=9.2 Hz, 1H), 7.38 (dd, J=11.8, 6.4 Hz, 1H), 6.71 (dd, J=12.1, 7.3 Hz, 1H), 5.65 (s, 2H), 3.10-3.04 (m, 1H), 2.67 (s, 3H), 1.26-1.21 (m, 2H), 0.94-0.89 (m, 2H); LC-MS (Method B) 387.4/388.4 [M+H].sup.+; RT 2.17 min

Example 875-cyclopropyl-8-fluoro-7-(1H-indazol-5-yl)-oxazolo[4,5-c]1,8-naphthyridin-4-one I3

(391) ##STR00192##

(392) Prepared using 6-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole and 7-chloro-5-cyclopropyl-8-fluoro-2-methyl-oxazolo[4,5c][1,8]naphthyridin-4-one (prepared as described in Example 86 step (a)) and a similar procedure to that described in Example 58 step (f)

(393) LC-MS (Method B) 376.4 [M+H].sup.+; RT 1.95 min

Example 88(2S)-6-[3-(aminomethyl)pyrrolidin-1-yl]-7-fluoro-2,12-dimethyl-4,11-dioxa-1,13-diazatetracyclo[7.6.1.05,16.010,14]hexadeca-5(16),6,8,10(14),12-pentaen-15-one J3

(a) 2-methyl-5-(2,3,4,5-tetrafluorophenyl)oxazole-4-carbonyl chloride

(394) ##STR00193##

(395) Prepared using 2,3,4,5-tetrafluorobenzoic acid and a similar procedure to that described in Example 49 steps (a) to (e)

(b) N-[(1S)-1-hydroxpropan-2-yl]-2-methyl-5-(2,3,4,5-tetrafluorophenyl)oxazole-4-carboxamide

(396) ##STR00194##

(397) 2-Methyl-5-(2,3,4,5-tetrafluorophenyl)oxazole-4-carbonyl chloride (1.54 g, 5.23 mmol) in DCM (75 mL) was treated with (2S)-(+)-2-aminopropan-1-ol (0.85 mL, 10.98 mmol) and stirred at room temperature overnight. The mixture was then diluted with DCM (50 mL) and washed with 0.5N aqueous HCl (250 ml) then saturated aqueous.NaHCO.sub.3. (330 mL) and brine (30 mL). The organic phase was dried over Na.sub.2SO.sub.4, filtered and evaporated to in vacuo to give N-[(1S)-1-hydroxpropan-2-yl]-2-methyl-5-(2,3,4,5-tetrafluorophenyl)oxazole-4-carboxamide (1.34 g, 77% yield) as a yellow powder.

(398) LC-MS (Method C) 333.0 [M.sup.+ H.sup.+], RT 3.42 min

(c) (2S)-6,7-difluoro-2,12-dimethyl-4,11-dioxa-1,13-diazatetracyclo[7.6.1.05,16.010,14]hexadeca-5(16),6,8,10(14),12-pentaen-15-one

(399) ##STR00195##

(400) A mixture of N-[(1S)-1-hydroxypropan-2-yl]-2-methyl-5-(2,3,4,5-tetrafluorophenyl)oxazole-4-carboxamide (1.51 g, 4.54 mmol), 18-crown-6 (1.35 g, 5.09 mmol) and K.sub.2CO.sub.3 (3.14 g, 22.72 mmol) in DMSO (30 mL) was heated at 140 C. for 40 min The mixture was diluted with EtOAc (200 mL) and washed with H.sub.2O (550 ml) then brine (100 ml). The organic extract was dried over Na.sub.2SO.sub.4 and solvent removed in vacuo to give a brown oil which was purified by flash chromatography eluting with 0-100% EtOAc in heptane to give (2S)-6,7-difluoro-2,12-dimethyl-4,11-dioxa-1,13-diazatetracyclo[7.6.1.0.sup.5,.sup.16.0.sup.10,.sup.14]hexadeca-5(16),6,8,10(14),12-pentaen-15-one (490 mg, 37% yield) as a yellow foam.

(401) LC-MS (Method C) 293.1 [M+H.sup.+], RT 3.43 min

(d) (2S)-6-[3-(aminomethyl)pyrrolidin-1-yl]-7-fluoro-2,12-dimethyl-4,11-dioxa-1,13-diazatetracyclo[7.6.1.05,16.010,14]hexadeca-5(16),6,8,10(14),12-pentaen-15-one J3

(402) ##STR00196##

(403) Prepared using tert-butyl N-(pyrrolidin-3-ylmethyl)carbamate and (2S)-6,7-difluoro-2,12-dimethyl-4,11-dioxa-1,13-diazatetracyclo[7.6.1.0.sup.5,.sup.16.0.sup.10,.sup.14]hexadeca-5(16),6,8,10(14),12-pentaen-15-one and a similar procedure to that described in Example 49 steps (i) and (j)

(404) .sup.1H NMR (Method B) (CD.sub.3OD): ppm 8.35 (brs, 1H), 7.23 (m, 1H), 5.15 (m, 1H), 4.56 (d, J=11.14 Hz, 1H), 4.13 (m, 1H), 3.76-3.48 (m, 4H), 3.25-3.05 (m, 2H), 2.67 (s, 3H), 2.61 (m, 1H), 2.28 (m, 1H), 1.80 (m, 1H), 1.38 (m, 3H); LC-MS (Method C) 373.1 [M.sup.+ H.sup.+], RT 2.27 min

Example 89(2S)-6-[(3R)-3-(aminomethyl)pyrrolidin-1-yl]-7-fluoro-2,12-dimethyl-4,11-dioxa-1,13-diazatetracyclo[7.6.1.05,16.010,14]hexadeca-5(16),6,8,10(14),12-pentaen-15-one K3

(405) ##STR00197##

(406) Prepared using (S) tert-butyl N-(pyrrolidin-3-ylmethyl)carbamate and (2S)-6,7-difluoro-2,12-dimethyl-4,11-dioxa-1,13-diazatetracyclo[7.6.1.0.sup.5,.sup.16.0.sup.10,.sup.14]hexadeca-5(16),6,8,10(14),12-pentaen-15-one (prepared as described in Example 88 step (c)) and a similar procedure to that described in Example 88 step (d)

(407) .sup.1H NMR (Method B) (CDCl.sub.3): ppm 7.16 (d, J=12.5 Hz, 1H), 5.25 (m, 1H), 4.45 (dd, J=11.1, 1.3 Hz, 1H), 4.14 (m, 1H), 3.73-3.57 (m, 3H), 3.38 (m, 1H), 2.82 (s, 2H), 2.66 (s, 3H), 2.33 (m, 1H), 2.10 (m, 1H), 1.68 (m, 1H), 1.40 (d, J=6.6 Hz, 3H); LC-MS (Method D) 373.4 [M.sup.+ H.sup.+], RT 1.70 min

Example 90(2S)-6-[(3S)-3-(aminomethyl)pyrrolidin-1-yl]-7-fluoro-2,12-dimethyl-4,11-dioxa-1,13-diazatetracyclo[7.6.1.05,16.010,14]hexadeca-5(16),6,8,10(14),12-pentaen-15-one L3

(408) ##STR00198##

(409) Prepared using (R) tert-butyl N-(pyrrolidin-3-ylmethyl)carbamate and (2S)-6,7-difluoro-2,12-dimethyl-4,11-dioxa-1,13-diazatetracyclo[7.6.1.0.sup.5,.sup.16.0.sup.10,.sup.14]hexadeca-5(16),6,8,10(14),12-pentaen-15-one (prepared as described in Example 88 step (c)) and a similar procedure to that described in Example 88 steps (d)

(410) .sup.1H NMR (Method B) (CDCl.sub.3): ppm 7.15 (d, J=12.5 Hz, 1H), 5.26 (m, 1H), 4.45 (dd, J=11.1, 1.3 Hz, 1H), 4.06 (dd, J=11.2, 2.4 Hz, 1H), 3.75 (m, 1H), 3.63 (m, 1H), 3.53 (m, 1H), 3.48 (m, 1H), 2.85 (s, 2H), 2.66 (s, 3H), 2.45 (m, 1H), 2.11 (m, 1H), 1.65 (m, 1H), 1.40 (d, J=6.7 Hz, 3H); LC-MS (Method D) 373.4 [M.sup.+ H.sup.+], RT 1.70 min

Example 912R)-7-fluoro-2,12-dimethyl-6-(4-methylpiperazin-1-yl)-4,11-dioxa-1,13-diazatetracyclo[7.6.1.05,16.010,14]hexadeca-5(16),6,8,10(14),12-pentaen-15-one M3

(411) ##STR00199##

(412) Prepared using 4-methylpiperazine and (2S)-6,7-difluoro-2,12-dimethyl-4,11-dioxa-1,13-diazatetracyclo[7.6.1.0.sup.5,.sup.16.0.sup.10,.sup.14]hexadeca-5(16),6,8,10(14),12-pentaen-15-one (prepared as described in Example 88 step (c)) and a similar procedure to that described in Example 88 step (d)

(413) .sup.1H NMR (Method B) (CD.sub.3OD): ppm 8.47 (brs, 1H), 7.37 (d, J=11.0 Hz, 1H), 5.20 (m, 1H), 4.61 (dd, J=11.44, 0.92 Hz, 1H), 4.21 (dd, J=11.46, 2.30 Hz, 1H), 3.52 (m, 4H), 3.18 (m, 4H), 2.80 (s, 3H), 2.70 (s, 3H), 1.39 (d, J=6.61 Hz, 3H); LC-MS (Method C) 373.0 [M.sup.+ H.sup.+], RT 1.00 min

Example 92(2S)-6-(4-amino-4-methylpiperidin-1-yl)-7-fluoro-2,12-dimethyl-4,11-dioxa-1,13-diazatetracyclo[7.6.1.05,16.010,14]hexadeca-5(16),6,8,10(14),12-pentaen-15-one N3

(414) ##STR00200##

(415) Prepared using t-butyl N-(4-methylpiperidin-4-yl)carbamate and (2S)-6,7-difluoro-2,12-dimethyl-4,11-dioxa-1,13-diazatetracyclo[7.6.1.0.sup.5,.sup.16.0.sup.10,.sup.14]hexadeca-5(16),6,8,10(14),12-pentaen-15-one (prepared as described in Example 88 step (c)) and a similar procedure to that described in Example 88 step (d)

(416) .sup.1H NMR (Method B) (CD.sub.3OD): ppm 8.15 (s, 2H), 7.32 (d, J=11.02 Hz, 1H), 5.21-5.16 (m, 1H), 4.61-4.58 (m, 1H), 4.21-4.18 (m, 1H), 3.44-3.37 (m, 4H), 2.69 (s, 3H), 2.06-1.99 (m, 2H), 1.92-1.87 (m, 2H), 1.51 (s, 3H), 1.39 (d, J=6.58 Hz, 3H); LC-MS (Method C) 387.1 [M+H].sup.+; RT 1.08 min

Example 93(2S)-6-(4-amino-2,5-difluorophenyl)-2-methyl-4,11-dioxa-1,13-diazatetracyclo[7.6.1.05,16.010,14]hexadeca-5(16),6,8,10(14),12-pentaen-15-one O3

(a) 5-(4-bromo-2,3-difluorophenyl)-1,3-oxazole-4-carboxylic acid

(417) ##STR00201##

(418) Prepared using 4-bromo-2,3-difluoro-benzoic acid and a similar procedure to that described in Example 58 steps (a) to (c)

(419) LC-MS (Method A) 304.2/306.3 [M+H].sup.+; RT 2.39 min

(b) 5-(4-bromo-2,3-difluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl)]oxazole-4-carboxamide

(420) ##STR00202##

(421) To a suspension of 5-(4-bromo-2,3-difluoro-phenyl)oxazole-4-carboxylic acid (1 g, 3.29 mmol) in dry DCM (15 mL) under N.sub.2 was added oxalyl chloride (0.42 mL, 4.93 mmol) drop-wise at room temperature, followed by catalytic DMF (1 drop). This was allowed to stir for 1 h. The mixture was then evaporated to dryness to give 5-(4-bromo-2,3-difluoro-phenyl)oxazole-4-carbonyl chloride (1.06 g, 3.29 mmol) as a yellow powder. This was then diluted with dry DCM (75 mL) and treated with (2S)-(+)-2-aminopropan-1-ol (0.54 mL, 6.9 mmol) under N.sub.2. This was allowed to stir at room temperature overnight. After which time the mixture was washed with saturated aqueous.NaHCO.sub.3 (330 mL) followed by brine (30 ml). The organic layer was then dried through a hydrophobic frit and evaporated to dryness to give 5-(4-bromo-2,3-difluoro-phenyl)-N-[(1S)-2-hydroxy-1-methyl-ethyl]oxazole-4-carboxamide (1 g, 84% yield) as a pale yellow solid.

(422) .sup.1H NMR (Method A)) CDCl.sub.3) 7.94 (s, 1H), 7.65 (ddd, J=8.7, 6.5, 2.1 Hz, 1H), 7.42 (ddd, J=8.6, 6.0, 2.0 Hz, 1H), 7.28-7.21 (m, 1H), 4.27-4.13 (m, 1H), 3.79-3.71 (m, 1H), 3.68-3.62 (m, 1H), 2.57 (bs, 1H), 1.29 (d, J=6.8 Hz, 3H); LC-MS (Method A) 361.2/363.2 [M+H].sup.+; RT 2.38 min

(423) ##STR00203##

(424) Prepared using 5-(4-bromo-2,3-difluoro-phenyl)-N-[(1S)-2-hydroxy-1-methyl-ethyl]oxazole-4-carboxamide and a similar procedure to that described in Example 88 step (c)

(425) .sup.1H NMR (Method A) (CDCl.sub.3) 8.16 (s, 1H), 7.53-7.43 (m, 2H), 5.38-5.28 (m, 1H), 4.58 (dd, J=11.3, 1.3 Hz, 1H), 4.22 (dd, J=11.4, 2.4 Hz, 1H), 1.45 (d, J=6.7 Hz, 3H). LC-MS (Method A) 321.3/323.3 [M+H].sup.+; RT 2.55 min.

(d) 2S)-6-(4-amino-2,5-difluorophenyl)-2-methyl-4,11-dioxa-1,13-diazatetracyclo[7.6.1.05,16.010,14]hexadeca-5(16),6,8,10(14),12-pentaen-15-one O3

(426) ##STR00204##

(427) Prepared using 4-amino-2,5-difluorobenzeneboronic acid pinacol ester and (2S)-6-bromo-2-methyl-4,11-dioxa-1,13-diazatetracyclo[7.6.1.0.sup.5,.sup.16.0.sup.10,.sup.14]hexadeca-5(16),6,8,10(14),12 pentaen-15-one and a similar procedure to that described in Example 58 step (f)

(428) .sup.1H NMR (Method A) (CDCl.sub.3): ppm 8.14 (s, 1H), 7.61 (d, J=8.2 Hz, 1H), 7.32-7.23 (m, 1H), 7.08 (dd, J=11.2, 6.4 Hz, 1H), 6.59 (dd, J=10.7, 7.5 Hz, 1H), 5.36-5.25 (m, 1H), 4.42 (dd, J=11.4, 1.3 Hz, 1H), 4.15 (dd, J=11.4, 2.4 Hz, 1H), 3.95 (s, 2H), 1.45 (d, J=6.6 Hz, 3H); LC-MS (Method A) 370.4 [M+H].sup.+; RT 2.54 min;

Example 94(2S)-6-(2-aminopyrimidin-5-yl)-2-methyl-4,11-dioxa-1,13-diazatetracyclo[7.6.1.05,16.010,14]hexadeca-5(16),6,8,10(14),12-pentaen-15-one P3

(429) ##STR00205##

(430) Prepared using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyrimidinamine and (2S)-6-bromo-2methyl-4,11-dioxa-1,13-diazatetracyclo[7.6.1.0.sup.5,.sup.16.0.sup.10,.sup.14]hexadeca-5(16),6,8,10(14),12 pentaen-15-one (prepared as described in Example 93 step (c)) and a similar procedure to that described in Example 58 step (f)

(431) .sup.1H NMR (Method A) (CDCl.sub.3): ppm 8.59 (s, 2H), 8.17 (s, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.30 (d, J=8.2 Hz, 1H), 5.43 (s, 2H), 5.41-5.28 (m, 1H), 4.46 (dd, J=11.4, 1.3 Hz, 1H), 4.20-4.12 (m, 1H), 1.48 (d, J=6.6 Hz, 3H); LC-MS (Method E) 336.4 [M+H].sup.+; RT 4.94

Example 95(-2S)-6-(6-aminopyridin-3-yl)-2-methyl-4,11-dioxa-1,13-diazatetracyclo[7.6.1.05,16.010,14]hexadeca-5(16),6,8,10(14),12-pentaen-15-one Q3

(432) ##STR00206##

(433) Prepared using 2-aminopyridine-5-boronic acid pinacol ester and (2S)-6-bromo-2methyl-4,11-dioxa-1,13-diazatetracyclo[7.6.1.0.sup.5,.sup.16.0.sup.10,.sup.14]hexadeca-5(16),6,8,10(14),12 pentaen-15-one (prepared as described in Example 93 step (c)) and a similar procedure to that described in Example 58 step (f)

(434) .sup.1H NMR (Method A) (CDCl.sub.3): ppm 8.34 (dd, J=2.4, 0.8 Hz, 1H), 8.13 (s, 1H), 7.74 (dd, J=8.5, 2.4 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.32 (d, J=8.2 Hz, 1H), 6.60 (d, J=8.5 Hz, 1H), 5.32 (qdd, J=6.7, 2.5, 1.3 Hz, 1H), 4.56 (s, 2H), 4.44 (dd, J=11.3, 1.3 Hz, 1H), 4.14 (dd, J=11.2, 2.4, 1H), 1.47 (d, J=6.7, 3H); LC-MS (Method E) 335.4 [M+H].sup.+; RT 4.59.

Example 964-[(2S)-2-methyl-15-oxo-4,11-dioxa-1,13-diazatetracyclo[7.6.1.05,16.010,14]hexadeca-5(16),6,8,10(14),12-pentaen-6-yl]benzamide R3

(435) ##STR00207##

(436) Prepared using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzamide and (2S)-6-bromo-2-methyl-4,11-dioxa-1,13-diazatetracyclo[7.6.1.0.sup.5,.sup.16.0.sup.10,.sup.14]hexadeca-5(16),6,8,10(14),12 pentaen-15-one (prepared as described in Example 93 step (c)) and a similar procedure to that described in Example 58 step (f)

(437) .sup.1H NMR (Method A) (CD.sub.3OD): ppm 7.11 (s, 1H), 6.55-6.46 (m, 2H), 6.32-6.22 (m, 3H), 6.00 (d, J=8.2 Hz, 1H), 3.56 (m, 1H), 3.04 (dd, J=11.5, 1.3 Hz, 1H), 2.78-2.70 (m, 1H), 1.88 (s, 3H), 1.19 (s, 2H); LC-MS (Method D) 362.4 [M+H].sup.+; RT 5.58 min.

Example 977-(3-aminopyrrolidin-1-yl)-5-cyclopropyl-8-fluoro-6-methoxyoxazolo[4,5-c]quinolin-4-one S3

(a) 2,4,5-trifluoro-3-methoxybenzoate

(438) ##STR00208##

(439) To 2,4,5-trifluoro-3-methoxy-benzoic acid (10 g, 48.52 mmol) in EtOH (60 mL) was added conc. sulphuric acid (2.4 mL) drop-wise. The reaction was then heated to 80 C. for 18 h. On cooling the reaction was concentrated to near dryness and DCM (200 ml) was added followed by 2M aqueous NaHCO.sub.3 (200 mL). The aqueous layer was extracted with DCM (100 mL) and the combined organic extracts were dried through a hydrophobic frit and concentrated to dryness to give ethyl 2,4,5-trifluoro-3-methoxy-benzoate (11.3 g, 99% yield) as a colourless oil, which was used without further purification.

(440) LC-MS (Method D) 235.4 [M+H].sup.+; RT 2.87

(b) Ethyl 4-(3-{[tert-butoxy)carbonyl]amino}pyrrolidin-1-yl)-2,5-difluoro-3-methoxybenzoate

(441) ##STR00209##

(442) To a solution of ethyl 2,4,5-trifluoro-3-methoxy-benzoate (11.3 g, 49. mmol) in dry ACN (150 mL) under N.sub.2 was added tert-butyl N-(pyrrolidin-3-yl)carbamate (2.35 mL, 134.23 mmol) at room temperature. The clear solution was heated at 80 C. for 4 h. On cooling the reaction mixture was partitioned between EtOAc (100 mL) and H.sub.2O (50 mL). The organic layer was then washed with brine (100 mL) and dried over Na.sub.2SO.sub.4 The solvent was removed in vacuo to give the crude product as an amber gum, which was purified by flash chromatography using an eluent system of 0-10% EtOAc in Petroleum ether (40-60) to give ethyl 4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2,5-difluoro-3-methoxy-benzoate (11 g, 56% yield) as a colourless oil.

(443) .sup.1H NMR (Method A) C(DCl.sub.3): ppm 7.31 (dd, J=14.4, 6.7 Hz, 1H), 4.73 (s, 1H), 4.37 (q, J=7.1 Hz, 2H), 4.26 (s, 1H), 3.88 (m, 1H), 3.83-3.72 (m, 4H), 3.63 (m, 1H), 3.46 (m, 1H), 2.17 (m, 1H), 1.86 (m, 1H), 1.46 (s, 9H), 1.37 (t, J=8.0 Hz, 3H); LC-MS (Method D) 401.5 [M+H].sup.+; RT 3.23

(444) ##STR00210##

(445) To a solution of ethyl 4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2,5-difluoro-3-methoxy-benzoate (2.2 g, 5.49 mmol) in dry DMSO (2 mL) under N.sub.2 was added cyclopropylamine (2.28 mL, 32.97 mmol). The mixture was heated to 110 C. in a sealed vial (10 mL capacity) for 72 h. On cooling the reaction mixture was diluted with EtOAc (20 mL) and washed with H.sub.2O (530 ml). The organic phase was dried over MgSO.sub.4 and solvent removed in vacuo. The resulting residue was purified by flash chromatography using an eluent system of 0-50% EtOAc in Petroleum ether (40-60) to give ethyl 4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-(cyclopropylamino)-5-fluoro-3-methoxy-benzoate (0.7 g, 29% yield) as a bright red oil.

(446) LC-MS (Method D) 438.5 [M+H].sup.+; RT 3.61

(d) 4-(3-{[(tert-butoxy)carbonyl]amino}pyrrolidin-1-yl)-2-(cyclopropylamino)-5-fluoro-3-methoxybenzoic acid

(447) ##STR00211##

(448) To a solution of ethyl 4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-(cyclopropylamino)-5-fluoro-3-methoxy-benzoate (3.5 g, 8 mmol) in THF (90 mL) under N.sub.2 was added 2M aq. lithium hydroxide (90 mL, 180 mmol). The reaction mixture was heated to 70 C. for 3 d. On cooling the THF was removed in vacuo and the reaction mixture was adjusted to pH 4 using 2M aqueous HCl and extracted with DCM (2100 mL). The combined DCM layers were dried through a hydrophobic frit and concentrated to dryness. The resulting residue was purified by flash chromatography using an eluent system of 0-50% EtOAc in Petroleum ether (40-60) to give 4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-(cyclopropylamino)-5-fluoro-3-methoxy-benzoic acid (0.86 g, 24%) as a beige solid.

(449) .sup.1H NMR (Method A, CDCl.sub.3): ppm 7.42 (d, J=14.9 Hz, 1H), 4.80 (s, 1H), 4.28 (s, 1H), 3.89-3.37 (m, 7H), 2.93 (m, 1H), 2.19 (m, 1H), 1.94-1.78 (m, 1H), 1.47 (s, 9H), 0.68-0.43 (m, 4H); LC-MS (Method D) 410.4 [M+H].sup.+; RT 2.89

(e) tert-butyl N-[1-(1-cyclopropyl-6-fluoro-4-hydroxy-8-methoxy-3-nitro-2-oxo-7-quinolyl)pyrrolidin-3-yl]carbamate

(450) ##STR00212##

(451) To a solution of 4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-(cyclopropylamino)-5-fluoro-3-methoxy-benzoic acid (860 mg, 2.1 mmol) in THF (15 mL) at 00 C. was added a solution of phosgene, 20% in toluene (1.11 mL, 2.1 mmol) drop-wise over 2 min giving a yellow hazy suspension/solution. The reaction was allowed to warm to room temperature and stirred for 3 h. The solution was then re-cooled to 00 C. and ethyl nitroacetate (0.35 mL, 3.15 mmol) was added drop-wise followed by NEt.sub.3 (0.44 mL, 3.15 mmol). The reaction was allowed to warm to room temperature and then heated to 70 C. for 18 h. On cooling the THF was removed in vacuo and the crude product was diluted with DCM (20 mL) followed by washing with 2 M aqueous HCl (20 mL), brine (20 ml) and H.sub.2O (20 mL). The organic extract was dried over MgSO.sub.4 and concentrated to dryness in vacuo. The crude product was purified by flash chromatography using an eluent system of 0-10% MeOH in DCM to give tert-butyl N-[1-(1-cyclopropyl-6-fluoro-4-hydroxy-8-methoxy-3-nitro-2-oxo-7-quinolyl)pyrrolidin-3-yl]carbamate (146 mg, 15% yield) as an orange solid.

(452) .sup.1H NMR (Method A) (CDCl.sub.3): ppm 7.34 (d, J=13.1 Hz, 1H), 5.08-5.01 (m, 1H), 4.36-4.22 (m, 1H), 3.96-3.66 (m, 3H), 3.57 (s, 3H), 3.54-3.43 (m, 1H), 3.31 (m, 1H), 2.24 (m, 1H), 1.97 (m, 1H), 1.46 (s, 9H), 1.16-1.04 (m, 2H), 0.78-0.63 (m, 2H); LC-MS (Method D) 479.4 [M+H].sup.+; RT 2.94

(f) tert-butyl N-[1-(3-amino-1-cyclopropyl-6-fluoro-4-hydroxy-8-methoxy-2-oxo-7-quinolyl)pyrrolidin-3-yl]carbamate

(453) ##STR00213##

(454) To a solution of tert-butyl N-[1-(1-cyclopropyl-6-fluoro-4-hydroxy-8-methoxy-3-nitro-2-oxo-7-quinolyl)pyrrolidin-3-yl]carbamate (146 mg, 0.31 mmol) in EtOH (10 mL) and H.sub.2O (1 mL) was added sodium hydrosulfite (212 mg, 1.22 mmol) in one portion The reaction was allowed to stir at 70 C. for 2 h. On cooling to room temperature a further addition of sodium hydrosulfite (212 mg, 1.22 mmol) was added and the reaction allowed to stir for 2 h. EtOH was then removed in vacuo and DCM (10 mL) and H.sub.2O (10 mL) was added. The aqueous was separated and further extracted with DCM (10 ml). The combined DCM extracts were then dried through a hydrophobic frit and concentrated to dryness to give tert-butyl N-[1-(3-amino-1-cyclopropyl-6-fluoro-4-hydroxy-8-methoxy-2-oxo-7-quinolyl)pyrrolidin-3-yl]carbamate (136 mg, 99% yield) as a brown oil, which was used without further purification

(455) LC-MS (Method D) 449.5 [M+H].sup.+; RT 2.47

(g) tert-butyl N-[1-(5-cyclopropyl-8-fluoro-6-methoxy-4-oxo-oxazolo[4,5-c]quinolin-7-yl)pyrrolidin-3-yl]carbamate

(456) ##STR00214##

(457) A solution of tert-butyl N-[1-(3-amino-1-cyclopropyl-6-fluoro-4-hydroxy-8-methoxy-2-oxo-7-quinolyl)pyrrolidin-3-yl]carbamate (100 mg, 0.22 mmol) in triethyl orthoformate (2.6 mL, 15.61 mmol) was heated to 105 C. overnight. On cooling the triethyl orthoformate was removed in vacuo to leave a dark brown solid, which was purified by flash chromatography using an eluent system of 0-100% EtOAc in Petroleum ether (40-60) to give brown solid. which on trituration with Et.sub.2O gave tert-butyl N-[1-(5-cyclopropyl-8-fluoro-6-methoxy-4-oxo-oxazolo[4,5-c]quinolin-7-yl)pyrrolidin-3-yl]carbamate (63 mg, 62% yield) as a brown solid.

(h) 7-(3-aminopyrrolidin-1-yl)-5-cyclopropyl-8-fluoro-6-methoxy-oxazolo[4,5-c]quinolin-4-one S3

(458) ##STR00215##

(459) To a solution of tert-butyl N-[1-(5-cyclopropyl-8-fluoro-6-methoxy-4-oxo-oxazolo[4,5-c]quinolin-7-yl)pyrrolidin-3-yl]carbamate (63 mg, 0.14 mmol) in DCM (10 mL) was added trifluoroacetic acid (0.09 mL, 1.18 mmol). After stirring at room temperature for 4 h the solution was filtered through a NH.sub.2 cartridge and the collected fractions evaporated to dryness. The resulting residue was purified by flash chromatography using an eluent system of 0-20% MeOH in DCM to give 7-(3-aminopyrrolidin-1-yl)-5-cyclopropyl-8-fluoro-6-methoxy-oxazolo[4,5-c]quinolin-4-one S3 (0.6 mg, 1.2% yield) as an off-white solid

(460) .sup.1H NMR (Method A) (CDCl.sub.3): ppm 7.97 (s, 1H), 7.26 (m, 1H), 3.86-3.78 (m, 2H), 3.75-3.52 (m, 2H), 3.52-3.44 (m, 4H), 3.32 (m, 1H), 2.19 (m, 1H), 1.78 (m, 1H), 1.26 (s, 2H), 1.22-1.13 (m, 2H), 0.63-0.54 (m, 2H); LC-MS (Method D) 359.4 [M+H].sup.+; RT 4.31.

Example 98[7-(4-amino-2,5-difluorophenyl)-5-cyclopropyl-6-methyl-4-oxo-4H,5H-[1,3]oxazolo[4,5-c]quinolin-2-yl]methyl acetate T3

(a) 7-bromo-2-(chloromethyl)-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one

(461) ##STR00216##

(462) To a stirred suspension of 3-amino-7-bromo-1-cyclopropyl-4-hydroxy-8-methyl-quinolin-2-one (prepared as described in Example 4 step (a)) (5.46 g, 17.66 mmol) in DCM (60 mL) under N.sub.2 at 0 C. was added 2-chloro-1,1,1-trimethoxyethane (3.33 mL, 24.73 mmol) followed by boron trifluoride diethyl etherate (2.4 mL, 19.43 mmol) drop-wise. After 35 min the reaction mixture was allowed to warm to room temperature, followed by the sequential addition of H.sub.2O (30 mL) and DCM (60 mL). After separation of the layers the aqueous was extracted with DCM (260 mL). The organic phases were combined and solvent removed in vacuo to give a residue which was purified by flash chromatography using a slow gradient of 0-50% EtOAc in DCM as eluent to give 7-bromo-2-(chloromethyl)-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one (2.84 g, 44%) as a pale pink solid.

(463) LC-MS (Method D) 367.2 [M+H].sup.+; RT 3.15 min.

(b) (7-bromo-5-cyclopropyl-6-methyl-4-oxo-oxazolo[4,5-c]quinolin-2-yl)methyl acetate

(464) ##STR00217##

(465) To a mixture of 7-bromo-2-(chloromethyl)-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one (325.0 mg, 0.88 mmol) and Cs.sub.2CO.sub.3 (432 mg, 1.33 mmol) in ACN (10 mL) was added acetic acid (0.13 mL, 2.21 mmol). The resulting mixture was stirred at 65 C. for 2.5 h. On cooling the solvent was removed under reduced pressure and the residue was partitioned between water (15 mL) and EtOAc (15 mL). The aqueous layer was extracted with EtOAc (310 mL). The combined organics were dried over MgSO.sub.4, filtered and concentrated to give the crude product (7-bromo-5-cyclopropyl-6-methyl-4-oxo-oxazolo[4,5-c]quinolin-2-yl)methyl acetate (281 mg, 81% yield) as a burgundy solid.

(466) LC-MS (Method D) 291.3/293.2 [M+H].sup.+; RT 2.86 min

(467) ##STR00218##

(468) Prepared using 4-amino-2,5-difluorobenzeneboronic acid pinacol ester and (7-bromo-5-cyclopropyl-6-methyl-4-oxo-2,3-dihydrooxazolo[4,5-c]quinolin-2-yl)methyl acetate and a similar procedure to that described in Example 58 step (f)

(469) .sup.1H NMR (Method A) (CDCl.sub.3) ppm 7.75 (d, J=8.0 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 6.95 (dd, J=11.0, 7.0 Hz, 1H), 6.61 (dd, J=10.6, 7.0 Hz, 1H), 5.35 (s, 2H), 4.01 (s, 2H), 3.66-3.59 (m, 1H), 2.53 (s, 3H), 2.20 (s, 3H), 1.33-1.28 (m, 2H), 0.69-0.61 (m, 2H); LC-MS (Method D) 440.4 [M+H].sup.+; RT 2.78 min

Example 997-(4-amino-2,5-difluorophenyl)-5-cyclopropyl-2-(hydroxymethyl)-6-methyloxazolo[4,5-c]quinolin-4-one U3

(470) ##STR00219##

(471) To a mixture of [7-(4-amino-2,5-difluoro-phenyl)-5-cyclopropyl-6-methyl-4-oxo-oxazolo[4,5-c]quinolin-2-yl]methyl acetate (prepared as described in Example 98 step (c)) (10 mg, 0.02 mmol) in H.sub.2O (2 mL) was added EtN.sub.3 (0.03 mL, 0.23 mmol) and the resulting mixture was stirred at room temperature for 1.5 h. The reaction mixture was then diluted with aqueous NH.sub.4Cl (5 mL) and extracted with EtOAc (310 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO.sub.4, filtered and concentrated to give the crude product, which was purified by flash chromatography eluting with a gradient system 25 to 100% EtOAc in Petroleum ether (40-60) to give 7-(4-amino-2,5-difluorophenyl)-5-cyclopropyl-2-(hydroxymethyl)-6-methyl-4H,5H-[1,3]oxazolo[4,5-c]quinolin-4-one U3 (5.8 mg, 4% yield) as khaki brown solid.

(472) .sup.1H NMR (Method A) (DMSO-d.sub.6) ppm 7.74 (d, J=8.0 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.07 (dd, J=11.5, 6.9 Hz, 1H), 6.67 (dd, J=11.6, 7.5 Hz, 1H), 5.99 (s, 1H), 5.70 (s, 2H), 4.71 (s, 2H), 3.60-3.56 (m, 1H), 2.47 (s, 3H), 1.20-1.16 (m, 3H), 0.52-0.48 (m, 2H); LC-MS (Method D) 398.4 [M+H].sup.+; RT 2.18 min

Example 1007-(4-amino-2,5-difluoro-phenyl)-2-(aminomethyl)-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one V3

(a) 2-(azidomethyl)-7-bromo-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one

(473) ##STR00220##

(474) To a stirred solution of 7-bromo-2-(chloromethyl)-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 98 step (a)) (600 mg, 1.63 mmol) in DMSO (15 mL) was added sodium azide (106 mg, 1.63 mmol). The reaction mixture was allowed to stir at room temperature overnight. H.sub.2O (15 mL) was added to the crude reaction mixture followed by EtOAc (50 mL) and the layers were separated. The organic layer was washed with H.sub.2O (320 mL). The solvent was then removed in vacuo and the crude residue was purified by flash chromatography using 0-60% EtOAc in Petroleum ether (40-60) as eluent to give 2-(azidomethyl)-7-bromo-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one (531 mg, 86%) as a pale brown solid.

(475) LC-MS (Method D) 374.3 [M+H].sup.+; RT 2.79 min.

(b) 7-(4-amino-2,5-difluoro-phenyl)-2-(azidomethyl)-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-on

(476) ##STR00221##

(477) Prepared using 4-amino-2,5-difluorobenzeneboronic acid pinacol ester and 2-(azidomethyl)-7-bromo-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one and a similar procedure to that described in Example 58 step (f)

(478) LC-MS (Method D) 423.4 [M+H].sup.+; RT 2.94 min.

(479) ##STR00222##

(480) To a stirred solution of 7-(4-amino-2,5-difluoro-phenyl)-2-(azidomethyl)-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one (294 mg, 0.70 mmol) in a mixture of THF (20 mL) and H.sub.2O (2 mL) was added PPh.sub.3 (274 mg, 1.04 mmol) and the reaction mixture was heated to 75 C. for 2 h. On cooling the solvent was removed and the residual water was removed by azeotroping with toluene (25 mL). The resulting residue was then purified by flash chromatography using 0-10% MeOH/NH3 (2 M) in DCM as eluent. to give 7-(4-amino-2,5-difluoro-phenyl)-2-(aminomethyl)-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one V3 (236 mg, 86%) as a pale yellow solid.

(481) .sup.1H NMR (Method A) (CDCl.sub.3): ppm 7.71 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 6.95 (dd, J=11.0, 6.6 Hz, 1H), 6.61 (dd, J=10.5, 7.5 Hz, 1H), 4.15 (s, 2H), 4.00 (s, 2H), 3.67-3.58 (m, 1H), 2.52 (d, J=1.5 Hz, 3H), 1.75 (s, 2H), 1.33-1.21 (m, 2H), 0.65 (s, 2H); LC-MS (Method B) 397.4 [M+H].sup.+; RT 5.42 min

Example 1017-(4-amino-2,5-difluoro-phenyl)-5-cyclopropyl-2-[(dimethylamino)methyl]-6-methyl-oxazolo[4,5-c]quinolin-4-one W3

(a) 7-bromo-5-cyclopropyl-2-[(dimethylamino)methyl]-6-methyl-oxazolo[4,5-c]quinolin-4-one

(482) ##STR00223##

(483) A solution of 7-bromo-2-(chloromethyl)-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one (40 mg, 0.11 mmol) (prepared as described in Example 98 step (a)) in dry dimethylamine (0.05 mL, 0.11 mmol) and DMF (5.5 mL). was treated with K.sub.2CO.sub.3 (23 mg, 0.16 mmol). The resulting reaction mixture was stirred at room temperature for 1 h. H.sub.2O (10 mL) was added to the crude reaction mixture followed by EtOAc (30 mL) and the layers were separated. The organic layer was washed with H.sub.2O (320 mL). The solvent was then removed in vacuo and the residue purified by flash chromatography using 0-5% MeOH/NH.sub.3 (1M) in DCM as eluent to give 7-bromo-5-cyclopropyl-2-[(dimethylamino)methyl]-6-methyl-oxazolo[4,5-c]quinolin-4-one (30.6 mg, 75%).

(484) LC-MS (Method B) 376.3 [M+H].sup.+; RT 2.64 min

(b) 7-(4-amino-2,5-difluoro-phenyl)-5-cyclopropyl-2-[(dimethylamino)methyl]-6-methyl-oxazolo[4,5-c]quinolin-4-one W3

(485) ##STR00224##

(486) Prepared using 4-amino-2,5-difluorobenzeneboronic acid pinacol ester and 7-bromo-5-cyclopropyl-2-[(dimethylamino)methyl]-6-methyl-oxazolo[4,5-c]quinolin-4-one and a similar procedure to that described in Example 58 step (f)

(487) .sup.1H NMR (Method A) (CDCl.sub.3): ppm 7.79 (dd, J=8.0, 0.6 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 6.95 (dd, J=11.0, 6.6 Hz, 1H), 6.61 (dd, J=10.5, 7.5 Hz, 1H), 3.99 (s, 2H), 3.85 (s, 2H), 3.62 (tt, J=6.8, 4.0 Hz, 1H), 2.52 (d, J=1.5 Hz, 3H), 2.42 (s, 6H), 1.26 (td, J=6.0, 4.9, 2.9 Hz, 2H), 0.72-0.60 (m, 2H); LC-MS (Method E) 425.4 [M+H].sup.+; RT 7.00 min

Example 1024-[2-(aminomethyl)-5-cyclopropyl-6-methyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl]benzoic acid X3

(a) 4-[2-(azidomethyl)-5-cyclopropyl-6-methyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl]benzoic acid

(488) ##STR00225##

(489) Prepared using 4-carboxybenzeneboronic acid pinacol ester and 2-(azidomethyl)-7-bromo-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 100 step (a)) and a similar procedure to that described in Example 58 step (f) LC-MS (Method B) 416.4 [M+H].sup.+; RT 2.66 min

(b) 4-[2-(aminomethyl)-5-cyclopropyl-6-methyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl]benzoic acid X3

(490) ##STR00226##

(491) Prepared using a similar procedure to that described in Example 100 step (c)

(492) LC-MS (Method B) 390.4 [M+H].sup.+; RT 4.91 min

Example 1032-(aminomethyl)-7-(2-aminopyrimidin-5-yl)-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one Y3

(a) 7-(2-aminopyrimidin-5-yl)-2-(azidomethyl)-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one

(493) ##STR00227##

(494) Prepared using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyrimidinamine and 2-(azidomethyl)-7-bromo-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 100 step (a)) and a similar procedure to that described in Example 58 step (f)

(b) 2-(aminomethyl)-7-(2-aminopyrimidin-5-yl)-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one Y3

(495) ##STR00228##

(496) Prepared using a similar procedure to that described in Example 100 step (c)

(497) .sup.1H NMR (Method A) (CDCl.sub.3): ppm 8.39 (s, 2H), 7.75 (d, J=7.9 Hz, 1H), 7.20 (d, J=7.9 Hz, 1H), 5.20 (s, 2H), 4.16 (s, 2H), 3.64 (tq, J=6.9, 4.0 Hz, 1H), 2.59 (s, 3H), 1.66 (s, 2H), 1.32-1.26 (m, 2H), 0.70-0.62 (m, 2H); LC-MS (Method B) 363.5 [M+H].sup.+; RT 3.71 min

Example 1047-(4-amino-2,5-difluoro-phenyl)-5-ethyl-8-fluoro-6-methyl-oxazolo[4,5-c]quinolin-4-one Z3

(a) 5-fluoro-7-methyl-indoline-2,3-dione

(498) ##STR00229##

(499) A mixture of 4-fluoro-2-methyl-aniline (8.88 mL, 79.91 mmol), chloral hydrate (19.62 g, 118.65 mmol), anhydrous Na.sub.2SO.sub.4 (124.86 g, 879.02 mmol) in hydrochloric acid (8.47 mL, 278.92 mmol) and H.sub.2O (450 mL) was stirred vigorously at room temperature overnight. To the resulting mixture, hydroxylamine hydrochloride (7.73 g, 111.25 mmol) was added and the mixture was heated to reflux overnight. The reaction mixture was ice cooled, and the resulting precipitate was collected by vacuum filtration and washed copiously with H.sub.2O and dried under suction. The precipitate was re-dissolved in EtOAc (500 mL) and washed with H.sub.2O (300 mL) and brine (300 mL) then dried over MgSO.sub.4. The resulting filtrate was removed in vacuo to give 5-fluoro-7-methyl-indoline-2,3-dione as a dark brown solid which was used directly in the next step without further purification.

(500) LC-MS 180.3 [M+H].sup.+; RT 1.49 min

(b) 4,6-dibromo-5-fluoro-7-methyl-indoline-2,3-dione

(501) ##STR00230##

(502) To an ice cold stirred solution of 5-fluoro-7-methyl-indoline-2,3-dione (9.9 g, 55.26 mmol) in H.sub.2SO.sub.4 (0.5 mL, 9.38 mmol) was added N-bromosuccinimide (19.67 g, 110.52 mmol) in portions over the course of 1 h. The reaction mixture was then allowed to warm to room temperature and stirred for 2 h, then re-cooled to 0-5 C. and a further portion of N-bromosuccinimide (4.92 g, 27.63 mmol) added. The reaction mixture was then allowed to warm to room temperature and stirred for a further 3 h, The reaction mixture was poured on to crushed ice with vigorous stirring forming a precipitate, which was filtered and washed with cold H.sub.2O (20 ml). The filtrate was washed with DCM (200 mL) and H.sub.2O (100 mL). The organic layer was dried over MgSO.sub.4, filtered and concentrated to dryness in vacuo before being combined with the original precipitate to give 4,6-dibromo-5-fluoro-7-methyl-indoline-2,3-dione (17.29 g, 93% yield) which was used directly in the next step.

(503) LC-MS 357.0 [M+Na].sup.+; RT 2.27 min

(504) ##STR00231##

(505) A round bottomed flask was charged with 4,6-dibromo-5-fluoro-7-methyl-indoline-2,3-dione (17.29 g, 51.31 mmol), copper (6.52 g, 102.63 mmol) and propionic acid (51.87 mL, 693.21 mmol). The resulting mixture was placed under a N.sub.2 atmosphere and heated to 130 C. for 90 min. On cooling toluene (50 ml) was added and the mixture was filtered. The collected solids were washed with toluene (550 ml) and EtOAc (550 ml). The combined organics were washed with 2M aqueous HCl until the aqueous layer was yellow in colour. The organic layer was further washed with H.sub.2O (50 mL), brine (50 mL) and dried over Na.sub.2SO.sub.4, filtered and evaporated in vacuo to give 6-bromo-5-fluoro-7-methyl-indoline-2,3-dione (11 g, 83% yield)

(506) LC-MS 286.3/288.3 [M+H].sup.+; RT 2.35 min

(d) 6-bromo-5-fluoro-7-methyl-indoline-2,3-dione

(507) ##STR00232##

(508) Iodoethane (1.25 mL, 15.5 mmol) was added drop-wise to a solution of 6-bromo-5-fluoro-7-methyl-indoline-2,3-dione (2. g, 7.75 mmol) and anhydrous K.sub.2CO.sub.3 (1.29 g, 9.3 mmol) in dry DMF (1 mL) and then heated to 100 C. for 1 h. On cooling the reaction mixture was diluted with EtOAc (100 mL) and H.sub.2O (100 mL) and the phases separated. The aqueous phase was extracted with EtOAc (270 mL) and the combined organic phases were washed with brine (200 mL), dried over MgSO.sub.4 and solvent removed in vacuo to give 6-bromo-1-ethyl-5-fluoro-7-methyl-indoline-2,3-dione (2.2 g, 99% yield) which was used directly in the next step without further purification.

(509) LC-MS (Method A) 268.3/270.3 [M+H].sup.+; RT 2.32 min

(e) 4-bromo-2-(ethylamino)-5-fluoro-3-methyl-benzoic acid

(510) ##STR00233##

(511) Drop-wise to a solution of 6-bromo-1-ethyl-5-fluoro-7-methyl-indoline-2,3-dione (2.2 g, 7.69 mmol) in 2M aq. NaOH (21 mL) was added H.sub.2O.sub.2(3.14 mL, 30.76 mmol. After 2 h stirring at room temperature the reaction mixture was diluted with DCM (150 mL) and the phases were separated. The aqueous phase was acidified to pH 3 with 2M aqueous HCl and the resulting precipitate was filtered, collected and dried overnight in a heated desiccator at 40 C. to give 4-bromo-2-(ethylamino)-5-fluoro-3-methyl-benzoic acid (1.85 g, 87% yield) as a pale yellow crystalline solid.

(512) LC-MS (Method A) 276.3/278.3 [M].sup.+; RT 1.18 min

(f) ethyl 5-[4-bromo-2-(ethylamino)-5-fluoro-3-methyl-phenyl]oxazole-4-carboxylate

(513) ##STR00234##

(514) To a solution of 4-bromo-2-(ethylamino)-5-fluoro-3-methyl-benzoic acid (1.85 g, 6.7 mmol) in dry THF (50 mL) at room temperature under N.sub.2 was added triphosgene (1.19 g, 4.02 mmol) in one portion. After stirring at room temperature for 3 h the solvent was carefully removed in vacuo. To the resulting residue under N.sub.2 was added dry THF (40 mL), followed by Et.sub.3N (7.47 mL, 53.6 mmol) drop-wise. To the resulting mixture was added ethyl isocyanoacetate (1.1 mL, 10.05 mmol) in one portion and the reaction heated to 60 C. overnight. On cooling to room temperature the solvent was removed under reduced pressure. The residue was then partitioned between EtOAc (20 mL) and brine (20 mL). 2M aqueous HCl was then added to adjust the aqueous pH to around 3. The EtOAc layer was then separated, washed 4 times with H.sub.2O, dried over MgSO.sub.4, filtered and concentrated in vacuo to afford ethyl 5-[4-bromo-2-(ethylamino)-5-fluoro-3-methyl-phenyl]oxazole-4-carboxylate (2.1 g, 84.% yield) as a yellow solid.

(515) LC-MS (Method A) 371.3/373.3 [M+H].sup.+; RT 2.79 min

(g) 7-bromo-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one

(516) ##STR00235##

(517) To a solution of ethyl 5-[4-bromo-2-(ethylamino)-5-fluoro-3-methyl-phenyl]oxazole-4-carboxylate (2.1 g, 5.66 mmol) in dry DMF (5 mL) was added NaH (60% dispersed in mineral oil) (61 mg, 1.52 mmol) in one portion. The reaction mixture was then heated to 100 C. for 1 h. On cooling to room temperature EtOAc (100 mL) and H.sub.2O (30 mL) were added and the layers separated. The aqueous layer was washed with EtOAc (50 mL) and the combined organic extracts were washed with H.sub.2O (430 mL). The organic extracts were dried over MgSO.sub.4, filtered, and concentrated in vacuo. The resulting residue was purified by flash chromatography using 50% EtOAc/Petroleum ether (40-60) as the eluent to give 7-bromo-5-ethyl-8-fluoro-6-methyl-oxazolo[4,5-c]quinolin-4-one (380 mg, 21% yield).

(518) LC-MS (Method A) 325.3/327.3 [M+H].sup.+; RT 2.31 min

(h) 7-(4-amino-2,5-difluoro-phenyl)-5-ethyl-8-fluoro-6-methyl-oxazolo[4,5-c]quinolin-4-one Z3

(519) ##STR00236##

(520) Prepared using 4-amino-2,5-difluorobenzeneboronic acid pinacol ester and 7-bromo-5-ethyl-8-fluoro-6-methyl-oxazolo[4,5-c]quinolin-4-one and a similar procedure to that described in Example 58 step (f)

(521) .sup.1H NMR (Method B) (CDCl.sub.3): b 8.11 (s, 1H), 7.57 (d, J=7.7 Hz, 1H), 6.93 (ddd, J=1.07, 6.4, 10.95 Hz, 1H), 6.62 (dd, J=7.2, 10.4 Hz, 1H), 4.62-4.52 (m, 1H), 4.48-4.38 (m, 1H), 4.00 (br. s, 2H), 2.43 (s, 3H), 1.32 (t, J=6.99 Hz, 3H); LC-MS (Method A) 374.3 [M+H].sup.+; RT 2.19 min

Example 1057-(5-amino-2,4-difluoro-phenyl)-5-ethyl-8-fluoro-6-methyl-oxazolo[4,5-c]quinolin-4-one A4

(522) ##STR00237##

(523) Prepared using 5-amino-2,4-difluorobenzeneboronic acid pinacol ester and 7-bromo-5-ethyl-8-fluoro-6-methyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 104 step (g)) and a similar procedure to that described in Example 58 step (f)

(524) .sup.1H NMR (Method A) (CDCl.sub.3): ppm 8.04 (s, 1H), 7.51 (d, J=7.7 Hz, 1H), 6.88 (dd, 6.4, 10.95 Hz, 1H), 6.62 (dd, J=7.2, 10.4 Hz, 1H), 4.62-4.52 (m, 1H), 4.55-4.45 (m, 1H), 3.62 (br. s, 2H), 2.43 (s, 3H), 1.26 (t, J=6.99 Hz, 3H); LC-MS (Method A) 374.3 [M+H].sup.+; RT 2.23 min

Example 1067-(6-amino-3-pyridyl)-5-ethyl-8-fluoro-6-methyl-oxazolo[4,5-c]quinolin-4-one B4

(525) ##STR00238##

(526) Prepared using 2-aminopyridine-5-boronic acid pinacol ester and 7-bromo-5-ethyl-8-fluoro-6-methyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 104 step (g)) and a similar procedure to that described in Example 58 step (f)

(527) .sup.1H NMR (Method A) (CDCl.sub.3): ppm 8.12 (s, 1H), 8.07 (br. s, 1H), 7.58 (d, J=7.6 Hz, 1H), 7.47-7.42 (m, 1H), 6.66 (d, J=7.6 Hz, 1H), 4.70 (br. s, 2H), 4.50 (q, J=7.0 Hz 2H), 2.45 (s, 3H), 1.35 (t, J=7.0 Hz, 3H); LC-MS (Method A) 374.3 [M+H].sup.+; RT 2.23 min

Example 1077-(4-amino-3-fluoro-phenyl)-5-ethyl-8-fluoro-6-methyl-oxazolo[4,5-c]quinolin-4-one C4

(528) ##STR00239##

(529) Prepared using 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and 7-bromo-5-ethyl-8-fluoro-6-methyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 104 step (g)) and a similar procedure to that described in Example 58 step (f)

(530) .sup.1H NMR (Method A) (CDCl.sub.3) ppm 8.11 (s, 1H), 7.55 (d, J=8.0 Hz, 1H), 6.98 (d, 8.0 Hz, 1H), 6.93-6.84 (m, 1H), 4.49 (q, J=6.8 Hz, 2H), 3.90 (br. s, 2H), 2.40 (s, 3H), 1.33 (t, J=6.8 Hz, 3H); LC-MS (Method E) 356.4 [M+H].sup.+; RT 6.17 min

Example 1087-(4-amino-2,5-difluorophenyl)-5-cyclopropyl-6-methyl-thiazolo[4,5-c]quinolin-4-one D4

(a) 5-bromo-1,3-thiazole-4-carboxylic acid

(531) ##STR00240##

(532) To a stirred solution of methyl 5-bromo-1,3-thiazole-4-carboxylate (5.00 g, 22.52 mmol) in THF (80 mL) was added an aq. solution of LiOH.H.sub.2O (2.70 g, 112.58 mmol) in H.sub.2O (20 mL). The reaction mixture was stirred at room temperature for 18 h. DCM (50 mL) and H.sub.2O (20 mL) were then added and the reaction mixture acidified to pH-2 with 2M aqueous HCl, followed by extraction with DCM (320 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO.sub.4, filtered and concentrated under reduced pressure to give 5-bromo-1,3-thiazole-4-carboxylic acid (3.09 g, 66% yield) as a yellow solid, which was used without further purification.

(533) LC-MS (Method D) 208.3/210.3 [M+H].sup.+; RT 1.36 min

(b) 5-bromo-N-cyclopropyl-1,3-thiazole-4-carboxamide

(534) ##STR00241##

(535) To a solution of 5-bromo-1,3-thiazole-4-carboxylic acid (3.09 g, 14.85 mmol) in DCM (75 mL) was added DIPEA (5.17 mL, 29.71 mmol) followed by cyclopropylamine (1.18 mL, 17.08 mmol) and HATU (6.21 g, 16.34 mmol). The reaction mixture was allowed to stir at room temperature for 6 h. The mixture was then diluted with H.sub.2O (50 mL) and the layers were separated. The aqueous layer was further extracted with DCM (325 mL) and the combined organics dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The crude reaction product was purified by flash chromatography eluting with a gradient system of 0-50% EtOAc in Petroleum ether (40-60) to give 5-bromo-N-cyclopropyl-1,3-thiazole-4-carboxamide (2.88 g, 78% yield) as a white solid.

(536) LC-MS (Method D) 247.2/249.2 [M+H].sup.+; RT 1.82 min

(537) ##STR00242##

(538) To a mixture of 4-bromo-3-fluoro-2-methylaniline (5.00 g, 24.51 mmol), potassium acetate (7.21 g, 73.52 mmol) and bis(pinacolato)diboron (7.47 g, 29.41 mmol) was added dry 1,2-dimethoxyethane (100 mL) and the mixture was flushed with N.sub.2. To this [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (2.14 g, 2.62 mmol) was added in one portion as a solid. The mixture was then heated to 90 C. for 18 h. On cooling all volatiles were removed under reduced and the crude product was purified by flash chromatography eluting with a gradient system of 0-50% EtOAc in Petroleum ether (40-60) to give 3-fluoro-2-methyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (5.05 g, 82% yield) as an amber solid.

(539) LC-MS (Method D) 252.6 [M+H].sup.+; RT 2.95 min

(d) 5-(4-amino-2-fluoro-3-methylphenyl)-N-cyclopropyl-1,3-thiazole-4-carboxamide

(540) ##STR00243##

(541) A mixture of 5-bromo-N-cyclopropyl-1,3-thiazole-4-carboxamide (2.88 g, 11.65 mmol), 3-fluoro-2-methyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.66 g, 14.57 mmol) and Cs.sub.2CO.sub.3 (5.70 g, 17.48 mmol) in 1,4-dioxane (45 mL) and H.sub.2O (5 mL) was heated to 70 C. for 10 min before addition of 1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (1.43 g, 1.75 mmol) in one portion. The reaction was further stirred at 70 C. for 45 min. On cooling all volatiles were removed under reduced pressure and the crude product was purified by flash chromatography eluting with a gradient system of 20-100% EtOAc in Petroleum ether (40-60) to give 5-(4-amino-2-fluoro-3-methylphenyl)-N-cyclopropyl-1,3-thiazole-4-carboxamide (2.78 g, 82% yield) as a redwood brown solid.

(542) LC-MS (Method D) 292.4 [M+H].sup.+; RT 2.13 min

(e) 7-amino-5-cyclopropyl-6-methyl-thiazolo[4,5-c]quinolin-4-one

(543) ##STR00244##

(544) To a mixture of 5-(4-amino-2-fluoro-3-methylphenyl)-N-cyclopropyl-1,3-thiazole-4-carboxamide (2.00 g, 6.86 mmol), K.sub.2CO.sub.3 (4.74 g, 34.32 mmol) and 18-crown-6 (1.81 g, 6.86 mmol) was added DMSO (40 mL) and the reaction mixture was heated to 160 C. for 24 h. On cooling DMSO was removed under reduced pressure and the residue partitioned between H.sub.2O (150 mL) and EtOAc (150 mL). The aq. layer was further extracted with EtOAc (2100 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO.sub.4, filtered and concentrated. The crude product was then triturated from DCM (20 mL) by drop-wise addition of petroleum ether (40-60). The solid was collected by filtration, washed with cold Et.sub.2O and air dried to give 7-amino-5-cyclopropyl-6-methyl-thiazolo[4,5-c]quinolin-4-one (1.29 g, 50% yield) as an amber solid.

(545) LC-MS (Method D) 272.4 [M+H].sup.+; RT 1.84 min

(f) 5-cyclopropyl-6-methyl-7-(tetramethyl-1,3,2-dioxaborolan-2-yl)-thiazolo[4,5-c]quinolin-4-one

(546) ##STR00245##

(547) To a cooled to 0 C. solution of 7-amino-5-cyclopropyl-6-methyl-thiazolo[4,5-c]quinolin-4-one (146 mg, 0.54 mmol) in MeOH (1 mL) and H.sub.2O (0.25 mL) was added 3M aq. HCl (0.54 mL, 1.61 mmol) and left to stir for 3 min. Sodium nitrite (37.1 mg, 0.54 mmol) was then added as a solution in H.sub.2O (0.25 mL) in one portion and the mixture was left to stir at 0 C. for 30 min. Bis(pinacolato)diboron (410 mg, 1.61 mmol) in MeOH (2 mL) was then added in one portion and the resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then extracted with DCM (310 mL) and the combined organic layers dried over MgSO.sub.4, filtered and concentrated to dryness to give 5-cyclopropyl-6-methyl-7-(tetramethyl-1,3,2-dioxaborolan-2-yl)-thiazolo[4,5-c]quinolin-4-one (120 mg, 58% yield) as a brown oil, which was used without further purification.

(548) LC-MS (Method A) 383.4 [M+H].sup.+; RT 3.16 min

(g) 7-(4-amino-2,5-difluorophenyl)-5-cyclopropyl-6-methyl-thiazolo[4,5-c]quinolin-4-one D4

(549) ##STR00246##

(550) Prepared using 5-cyclopropyl-6-methyl-7-(tetramethyl-1,3,2-dioxaborolan-2-yl)-thiazolo[4,5-c]quinolin-4-one and 4-bromo-2,5-difluoroaniline and a similar procedure to that described in Example 1 step (g)

(551) .sup.1H NMR (Method A) (CDCl.sub.3): ppm 8.88 (s, 1H), 7.54 (d, J=7.9 Hz, 1H), 7.16 (d, J=7.9 Hz, 1H), 6.95 (dd, J=11.0, 7.0 Hz, 1H), 6.61 (dd, J=10.5, 7.0 Hz, 1H), 3.98 (s, 2H), 3.68-3.63 (m, 1H), 2.53 (s, 3H), 1.34-1.17 (m, 2H), 0.77-0.59 (m, 2H); LC-MS (Method D) 384.3 [M+H].sup.+; RT 2.23 min

Example 1095-Cyclopropyl-7-(1H-indazol-5-yl)-6-methyl-thiazolo[4,5-c]quinolin-4-one E4

(552) ##STR00247##

(553) Prepared using 5-cyclopropyl-6-methyl-7-(tetramethyl-1,3,2-dioxaborolan-2-yl)-thiazolo[4,5-c]quinolin-4-one (prepared as described in Example 108 step (g)) and 5-bromoindazole and a similar procedure to that described in Example 1 step (g)

(554) .sup.1H NMR (Method A) (CDCl.sub.3): ppm 8.89 (s, 1H), 8.89 (s, 1H), 8.17 (s, 1H), 7.78-7.76 (m, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.45 (dd, J=8.5, 1.6 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 3.72-3.67 (m, 1H), 2.56 (s, 3H), 1.40-1.28 (m, 2H), 0.78-0.73 (m, 2H); LC-MS (Method D) 373.4 [M+H].sup.+; RT 2.34 min

Example 1107-[3-(aminomethyl)pyrrolidin-1-yl]-6-chloro-5-cyclopropyl-8-fluoro-2-methyl-oxazolo[4,5-c]quinolin-4-one F4

(a) tert-butyl N-[[1-(5-cyclopropyl-8-fluoro-2-methyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)pyrrolidin-3-yl]methyl]carbamate

(555) ##STR00248##

(556) Prepared using tert-butyl N-(pyrrolidin-3-ylmethyl)carbamate and 5-cyclopropyl-7,8-difluoro-2-methyl-oxazolo[4,5-c]quinolin-4-one (prepared as described in Example 49 step (h)) and a similar procedure to that described in Example 49 step (i)

(557) 1H NMR (Method A) (CDCl.sub.3): b 7.26 (d, J=13.1 Hz, 1H), 6.89 (d, J=7.8 Hz, 1H), 5.22 (s, 1H), 3.67-3.20 (m, 6H), 2.87 (m, J=6.8, 4.1, 2.8 Hz, 1H), 2.61 (s, 3H), 2.58-2.51 (m, 1H), 2.23-2.04 (m, 1H), 1.89-1.73 (m, 1H), 1.44 (s, 9H), 1.34 (m, J=8.6, 4.4, 2.9 Hz, 2H), 0.92-0.80 (m, 2H); LC-MS (Method D) 457.5 [M+H].sup.+; RT 2.91 min

(b) tert-butyl N-[[1-(6-chloro-5-cyclopropyl-8-fluoro-2-methyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)pyrrolidin-3-yl]methyl]carbamate

(558) ##STR00249##

(559) To a solution of tert-butyl N-[[1-(5-cyclopropyl-8-fluoro-2-methyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)pyrrolidin-3-yl]methyl]carbamate (71.6 mg, 0.16 mmol) in DCM (2 mL) was added 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione (46.4 mg, 0.24 mmol) in DCM (1.14 mL) and the reaction stirred at room temperature. After 1 h the reaction was quenched with aqueous sodium bisulfite (0.5 g in 5 mL) and diluted with DCM (5 mL). The layers were separated and the organic layer washed with saturated aqueous NaHCO.sub.3 and then H.sub.2O, dried over MgSO.sub.4, filtered and the solvent removed in vacuo. The resulting residue was purified by flash chromatography using 0-10% MeOH in DCM to give tert-butyl N-[[1-(6-chloro-5-cyclopropyl-8-fluoro-2-methyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)pyrrolidin-3-yl]methyl]carbamate (37.9 mg, 49% yield).

(560) LC-MS (Method D) 491.4/493.4 [M+H].sup.+; RT 3.13 min

(561) ##STR00250##

(562) Prepared using a similar procedure to that described in Example 49 step (j). Product isolated as its TFA salt

(563) .sup.1H NMR (Method A) (CDCl.sub.3): b ppm 7.57 (d, J=11.6 Hz, 1H), 3.79-3.59 (m, 4H), 3.50-3.43 (m, 1H), 3.18-3.08 (m, 2H), 2.66 (s, 4H), 2.34-2.24 (m, 1H), 1.91-1.80 (m, 1H), 1.30-1.20 (m, 2H), 0.57-0.50 (m, 2H); LC-MS (Method D) 391.4/393.4 [M+H].sup.+; RT 1.65 min

Example 111Antibacterial susceptibility testing

(564) Minimum Inhibitory Concentrations (MICs) versus planktonic bacteria are determined by the broth microdilution procedure according to the guidelines of the Clinical and Laboratory Standards Institute (Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Ninth Edition. CLSI document M07-A9, 2012) and by the agar dilution procedure according to the guidelines of the Clinical and Laboratory Standards Institute (Clinical and Laboratory Standards Institute. Susceptibility testing of Mycobacteria, Nocardiae and other aerobic Actinomycetes, Approved Standard-Second Edition. CLSI document M24-A2, 2011). The broth dilution method involves a two-fold serial dilution of compounds in 96-well microtitre plates, giving a final concentration range of 0.001-128 g/mL and a maximum final concentration of 1% DMSO. The agar dilution method involves a two-fold serial dilution of compounds in 24-well microtitre plates, giving a final concentration range of typically 0.03-32 g/mL and a maximum final concentration of 1% DMSO. The bacterial strains tested include Staphylococcus aureus ATCC 29213 and Escherichia coli ATCC 25922 (Table 1), a panel of MRSA strains, Enterococcus faecium ATCC 19434 and Streptococcus pneumoniae ATCC BAA-255 (Table 2), Haemophilus influenzae ATCC 49247, Moraxella catarrhalis ATCC 25240, Legionella pneumophila ATCC 33152, Neisseria gonorrhoeae ATCC 49226, Neisseria meningitidis ATCC 13090 and Mycobacterium smegmatis ATCC 19420 (Table 4). Strains are grown in cation-adjusted Mller-Hinton broth (supplemented with 2% w/v NaCl in the case of methicillin-resistant S. aureus strains or supplemented with 5% blood in the case of S. pneumoniae and N. meningitidis), in haemophilus test medium broth, on Mller-Hinton agar at 37 C. (in the presence of 5% CO.sub.2 in the case of N. meningitidis), or on supplemented GC agar at 37 C., 5% CO.sub.2 (in the case of N. gonorrhoeae). The MIC is determined as the lowest concentration of compound that inhibits growth following a 16-20 h incubation period for all strains with the following exceptions: 24 h incubation for Neisseria spp., 48 h incubation for L. pneumophila and 72 h incubation for M. smegmatis. The data reported correspond to the modes of three independent experiments.

(565) In Tables 1, 2 and 4 a MIC (in g/mL) of less than 1 is assigned the letter A; a MIC of from 1 to 10 is assigned the letter B; a MIC of from 10 to 100 is assigned the letter C; and a MIC of over 100 is assigned the letter D.

(566) TABLE-US-00007 TABLE 1 MIC values against wild type strains S. aureus ATCC E. coli ATCC Compound 29213 25922 1 A D 2 B D 3 B D 4 A B 5 A B 6 C D 7 B D 8 C D 9 A B 10 A D 11 B D 12 B C 13 A D 14 A C 15 A C 16 A C 17 B B 18 A D 19 A D 20 A B 21 A C 22 A B 23 A B 24 A C 25 A B 26 A D 27 A B 28 C C 29 B C 30 B D 31 D D 32 A B 33 A D 34 A B 35 A B 36 A B 37 C D 38 A B 39 A B 40 A B 41 B D 42 C D 43 B C 44 D D 45 C D 46 A B 47 C D 48 B C 49 B B 50 B B 51 B B 52 B B 53 C C 54 B B 55 B C 56 B B 57 A B 58 B C 59 B C 60 C D 61 D D 62 B C 63 D D 64 A C 65 B D 66 B D 67 B D 68 A B 69 A B 70 C D 71 B B 72 C D 73 A D 74 C C 75 B C 76 A B 77 C D 78 D D 79 A C 80 B B 81 B B 82 C B 83 C B 84 D D 85 C C 86 D D 87 D D 88 A B 89 B B 90 A B 91 C C 92 B B 93 B B 94 B C 95 B B 96 B C 97 A B 98 A B 99 A B 100 A A 101 A C 102 B D 103 B B 104 B D 105 C C 106 C D 107 C D 108 A B 109 A A 110 A A

(567) TABLE-US-00008 TABLE 2 Potency of reference compounds and test compounds against fluoroquinolone (FQ) susceptible and resistant Staphylococcus spp. and other Gram-positive bacteria S. aureus S. aureus S. aureus (MSSA) (MRSA) SACPX1-SP25 ATCC ATCC S. aureus MSSA - FQ S. aureus S. epidermidis 29213 S. aureus 43300 NRS1 resistant S. aureus VRS1 S. aureus NRS101 CLSI NRS482 Heterogeneous MRSA S. aureus S. aureus (isogenic NRS127 MRSA NRS107 MRSE control MRSA FQ MRSA AMG & TET NRS70 NRS100 mutant of MRSA LZD VAN MUP AMG, ERY E. faecium S. pneumoniae Compound strain resistant strain resistant MRSA MRSA ATCC 29213) resistant resistant resistant resistant ATCC 19434 ATCC BAA-255 Ciprofloxacin A C A C A A C D C A A B A Levofloxacin A B A C A A B D C A A B A Oxacillin A A D C D B A A A B C Vancomycin A B B B A B A B B B B A A 1 A A A A A A A A A A A D B 2 B B B D 3 B D 4 A A A B A A A D 5 A D 6 C D 7 B C 8 D D 9 A D 10 A D 11 B D 12 D D 13 A D 14 A B B B B D 15 A A A 16 B C 17 B D 18 A C 19 A D 20 A A A A A A A A B 21 A A A A A A A B 22 A C 23 A B A B B B C B D 24 A D 25 A A A A A A A C 26 A B B B B B A D 27 A A A B C C A D 28 B C 29 B D 30 B B B B B B D 31 D D 32 A C 33 A D 34 A D 35 A B A B C 36 A B A D A B B B C B C C B 37 C D 38 A B A D 39 A A A A A A A A A A A C A 40 A D 41 B D 42 C D 43 B D 44 D D 45 C D 46 A D 47 C D 48 B D 49 B C B C C D C 50 B D 51 B C 52 B B A B B B B C 53 C D 54 B B C 55 B D 56 B C 57 A B B B C 58 B D 59 B D 60 C D 61 D D 62 B D 63 D D 64 A D 65 B D 66 B D 67 B D 68 A D 69 A B A A A B D 70 C D 71 B C 72 C D 73 A D 74 C D 75 B D 76 A B A B B C C 77 C D 78 D D 79 A D 80 B C C 81 B D 82 C D 83 C D 84 D D 85 C D 86 C D 87 C D 88 A B B B B B B C 89 B B B B B C B C 90 A B A B B B C 91 C D 92 B C B C C D B D 93 B B A B B C 94 B C 95 B B B B B B B C 96 B B B B B B C 97 A C 98 A A 99 A A A B B B 100 A A A A A B B A B 101 A B 102 B D 103 B C 104 B C 105 C C 106 C D 107 C D 108 A A A A A A A A C 109 A A A A A A B D

(568) In addition to methicillin and, where present, fluoroquinolone resistance, the strains mentioned in Table 2 are also resistant to other antibiotics as indicated in Table 3

(569) TABLE-US-00009 TABLE 3 Additional resistance of tested Staphylococcus spp. Strain Also resistant to: S. aureus erythromycin NRS482 (USA300 FPR3757) S. aureus NRS1 (Mu50) aminoglycosides (AMG), vancomycin (intermediate), tetracycline (TET) S. aureus NRS70 (N315) clindamycin, erythromycin S. aureus NRS100 tetracycline S. aureus NRS127 linezolid (LZD) S. aureus VRS1 vancomycin (VAN) S. aureus NRS107 mupirocin (MUP) S. epidermidis NRS101 MRSE = methicillin-resistant S. epidermidis, aminoglycosides (AMG), erythromycin (ERY), Compound 1 has also been tested and has shown activity (MIC less than 1 g/mL) against all of the following bacterial strains: S. aureus NRS106 (fluoroquinolone susceptible MSSA); S. aureus NRS384 (MRSA - fluoroquinolone susceptible); S. aureus NRS74, S. aureus NRS108, S. aureus NRS271, S. aureus VRS8 (all strains are fluoroquinolone resistant MRSA); S. aureus SACPX1-SP28 (MSSA - fluoroquinolone resistant);

(570) Thus, certain compounds of the invention, including compound 1, exhibit excellent activity against all strains of S. aureus tested, including those which are resistant to fluoroquinolone antibiotics and other antibiotics.

(571) TABLE-US-00010 TABLE 4 Potency of reference compounds and test compounds against a panel of Gram-negative and mycobacterium strains Haemophilus Moraxella Legionella Neisseria Neisseria Mycobacterium influenzae catarrhalis pneumophila gonorrhoeae meningitidis smegmatis Compound ATCC 49247 ATCC 25240 ATCC 33152 ATCC 49226 ATCC 13090 ATCC 19420 Ciprofloxacin A A A A A A Levofloxacin A A A A A Oxacillin D Vancomycin C 1 A A A A A A 2 C 3 B 4 A 5 A 6 D 7 C 8 B 9 B 10 C 11 C 12 B 13 D 14 B 15 B 16 C 17 A 18 B 19 B 20 A 21 B 22 B 23 B B 24 B 25 A 26 B 27 B 28 B 29 B 30 B 31 D 32 B 33 C 34 B 35 B 36 B B A C A 37 C 38 A 39 A A A B 40 B 41 C 42 D 43 C 44 D 45 C 46 D 47 D 48 B 49 B 50 C 51 B 52 B 53 B 54 B 55 B 56 B 57 B B 58 B 59 B 60 B 61 D 62 B 63 D 64 A 65 C 66 C 67 C 68 A 69 A 70 D 71 A 72 B 73 B 74 B 75 B 76 B 77 D 78 C 79 A 80 C 81 B 82 C 83 C 84 D 85 B 86 C 87 C 88 B B B B B 89 B B 90 B B B 91 B 92 C 93 A B A A 94 B 95 A 96 B 97 B 98 B 99 A 100 A A A A A 101 B 102 C 103 A 104 C 105 C 106 C 107 D 108 A 109 B

(572) Thus, certain compounds of the invention have shown good activity against Gram negative bacterial strains. In particular, some compounds of the invention have shown good activity against fastidious Gram negative bacterial strains as exemplified by Neisseria spp.

(573) Certain compounds of the invention have also shown activity against M. smegmatis, a recognised fast-growing and non-pathogenic surrogate for M. tuberculosis (Tuberculosis, 2010, 90, 333). Compound 1 has also been tested and shown activity (MIC less than 8 g/mL) against the virulent tuberculosis-causative bacterial strain Mycobacterium tuberculosis H37Rv.

Example 112Human Cell Viability Assay

(574) Compounds are assessed for potential non-specific cytotoxic effects against a human hepatic cell line (HepG2 ATCC HB-8065). HepG2 cells are seeded at 20,000 cells/well in 96-well microtitre plates in minimal essential medium (MEM) supplemented with a final concentration of 10% FBS and 1 mM sodium pyruvate. After 24 h compound dilutions are prepared in Dulbecco's minimum essential media (DMEM) supplemented with final concentrations of 0.001% FBS, 0.3% bovine albumin and 0.02% HEPES and added to cells. Compounds are tested in two-fold serial dilutions over a final concentration range of 1-128 g/mL in a final DMSO concentration of 1% vol/vol. Chlorpromazine is used as a positive control. Cells are incubated with compound at 37 C. and 5% CO.sub.2 for a further 24 h, after which time the CellTiter-Glo reagent (Promega) is added. Luminescence is measured on a BMG Omega plate reader. Data are analysed using GraphPad Prism software to determine the concentration of compound that inhibits cell viability by fifty percent (IC.sub.50). The results are provided in Table 5.

(575) In Table 5, an IC.sub.50 of less than 10 is assigned the letter C; an IC.sub.50 of from 10 to 100 is assigned the letter B; and an IC.sub.50 of over 100 is assigned the letter A.

(576) TABLE-US-00011 TABLE 5 IC.sub.50 values against HepG2 Compound HepG2 Ciprofloxacin A Levofloxacin A Oxacillin B Vancomycin B 1 A 2 B 4 B 5 B 8 A 9 B 10 B 11 A 14 B 18 B 19 B 20 A 21 B 22 B 24 A 25 B 26 A 27 B 28 B 29 A 30 B 33 B 34 A 35 B 36 A 38 A 39 B 40 A 41 B 46 B 48 B 49 B 50 B 52 B 54 B 55 A 56 B 57 B 58 B 64 B 71 A 79 B 81 A 88 B 89 B 90 B 92 A 93 A 95 A 96 B 98 A 100 A 101 B 108 B

(577) Thus, the tested compounds show low toxicities against human hepatic cell lines. In particular, certain compounds of the invention showed no detectable toxicity against human hepatic cell lines.

(578) These compounds therefore show an excellent therapeutic benefit relative to their hepatic toxicity as expressed by the ratio of hepatic toxicity. All other compounds tested also demonstrate an acceptable level of hepatic toxicity relative to therapeutic activity.

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