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Title:
INHIBITORS OF PHOSPHOINOSITIDE 3-KINASE (PI3K) AND USES THEREOF
Document Type and Number:
WIPO Patent Application WO/2023/159155
Kind Code:
A1
Abstract:
Disclosed herein are compounds of Formulae 1A, 1B, 1C and 1D, (1A), (1B), (1C) and (1D) and methods of making and methods of using the same.

Inventors:
CEE VICTOR (US)
TASKER ANDREW (US)
WALTON MARY (US)
NGUYEN TOM (US)
KUBOTA MILES (US)
BUCHOWIECKI PETER (US)
TOLEDO WARSHAVIAK DORA (US)
Application Number:
PCT/US2023/062781
Publication Date:
August 24, 2023
Filing Date:
February 17, 2023
Export Citation:
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Assignee:
PIVALENT THERAPEUTICS INC (US)
International Classes:
C07D239/80; A61K31/519; A61P35/00; C07D401/04; C07D401/12; C07D401/14; C07D403/04; C07D403/12; C07D405/14; C07D413/14; C07D417/14; C07D471/04; C07D487/04; C07D495/04
Domestic Patent References:
WO2009093972A12009-07-30
WO2023060262A12023-04-13
WO2023081209A12023-05-11
Foreign References:
US20130267542A12013-10-10
Other References:
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HEPPELL JACOB T ET AL: "Synthesis, structures elucidation, DNA-PK, PI3K and antiplatelet activity of a series of novel 7- or 8-(N-substituted)-2-morpholino-quinazolines", MEDICINAL CHEMISTRY RESEARCH, BIRKHAEUSER, BOSTON, US, vol. 25, no. 8, 29 June 2016 (2016-06-29), pages 1695 - 1704, XP036013819, ISSN: 1054-2523, [retrieved on 20160629], DOI: 10.1007/S00044-016-1608-9
GAESTEL ET AL., CURRENT MEDICINAL CHEMISTRY, vol. 14, 2007, pages 2214 - 2234
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GONCALVES MDHOPKINS BDCANTIEY LC: "Phosphatidylinositol 3-Kinase, Growth Disorders, and Cancer", N ENGL J MED., vol. 379, no. 21, 22 November 2018 (2018-11-22), pages 2052 - 2062
GRAUPERA ET AL., NATURE, vol. 453, 2008, pages 662 - 6
BUSAIDY NL ET AL.: "Management of metabolic effects associated with anticancer agents targeting the PI3K-Akt-mTOR pathway", J CLIN ONCOL, vol. 30, 2012, pages 2919 - 28, XP055341230, DOI: 10.1200/JCO.2011.39.7356
BLOUIN M-J ET AL.: "Abstract 4615: the hyperinsulinemia caused by PI3K inhibitors attenuates their antineoplastic efficacy, but can be minimized by co administration of metformin", CANCER RES, vol. 73, 2013, pages 4615
OKKENHAUG KGRAUPERA MVANHAESEBROECK B: "Targeting PI3K in Cancer: Impact on Tumor Cells, Their Protective Stroma, Angiogenesis, and Immunotherapy", CANCER DSILICA GEL CHROMATOGRAPHY, vol. 6, no. 10, October 2016 (2016-10-01), pages 1090 - 1105
ARIELLA B. HANKER ET AL.: "Challenges for the clinical development of PI3K inhibitors: Strategies to improve their impact in solid tumors", CANCER DSILICA GEL CHROMATOGRAPHY, vol. 9, no. 4, April 2019 (2019-04-01), pages 482 - 491
JACQUES, J. ET AL.: "Enantiomers, Racemates and Resolutions", 1981, WILEY-INTERSCIENCE
WILEN, S. H. ET AL., TETRAHEDRON, vol. 33, 1997, pages 2725
ELIEL, E. L.: "Stereochemistry of Carbon Compounds", 1962, MCGRAW-HILL
WILEN, S. H.: "Tables of Resolving Agents and Optical Resolutions", 1972, UNIV. OF NOTRE DAME PRESS, pages: 268
BERGE ET AL.: "Pharmaceutical Salts", JOURNAL OF PHARMACEUTICAL SCIENCE, vol. 66, 1977, pages 1 - 19, XP002675560, DOI: 10.1002/jps.2600660104
LIEBERMAN, PHARMACEUTICAL DOSAGE FORMS, vol. 1-3, 1992
LLOYD, THE ART, SCIENCE AND TECHNOLOGY OF PHARMACEUTICAL COMPOUNDING, 1999
PICKAR, DOSAGE CALCULATIONS, 1999
"Remington: The Science and Practice of Pharmacy", 2003, LIPPINCOTT, WILLIAMS & WILKINS
Attorney, Agent or Firm:
DANEK, Shelley C. et al. (US)
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Claims:
WHAT IS CLAIMED IS: 1. A compound, or a pharmaceutically acceptable salt thereof, of Formula 1A, 1B, 1C or 1D: wherein: X1, X2, and X3 is each independently -CR5- or -N-; X5 is a carbon atom when a double bond is attached or is -CR5- or -N- when a single bond is attached; R is oxo or -ORx; Rx is H, C1-C6 alkyl or C1-C6 haloalkyl; or R together with R2 and the carbon and nitrogen to which they are attached forms a 5-6 membered heteroaryl ring; R1 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, C2-C6 alkenyl, C2- C6 alkynyl, C1-C6 haloalkyl, -OR1a, -SR1a, -NR1aR1a, -C(O)R1a, -C(O)OR1a, -NR1aC(O)R1a, -OC(O)R1a, - C(O)NR1bR1b, -NR1aC(O)NR1bR1b, -S(O)2NR1bR1b, NR1aS(O)2NR1bR1b, NR1aS(O)2R1a; -S(O)2R1a, aralkyl, heteroarylalkyl, heterocyclylalkyl, C3-8-cycloalkyl-alkyl, aryl, C4-8-cycloalkenyl, C3-8-cycloalkyl, 4-10 membered oxygen containing heterocyclyl; nitrogen containing heteroaryl, and nitrogen containing heterocyclyl; wherein the aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, aryl, aralkyl, C3-8-cycloalkyl and C1-C6 hydroxyalkyl; R1a and R1b are each independently selected from H, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, aryl, heteroaryl, heterocyclyl and C3-8-cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halogen, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and –(CH2)n- SO2R7 ; wherein when R1 is -C(O)NR1bR1b, -NR1aC(O)NR1bR1b, -S(O)2NR1bR1b, NR1aS(O)2NR1bR1b, two R1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, which is substituted with 0, 1, 2, or 3 substituents independently selected from halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and –(CH2)n-SO2R7; R2 is selected from H, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylsulfonyl, C1-C6 hydroxyalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, C3-8-cycloalkyl-alkyl, aryl, heteroaryl, heterocyclyl, C3-8-cycloalkyl, alkylaminoalkyl, aminoalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl and alkylaminocarbonylalkyl; or R together with R2 and the atoms to which they are attached forms a 5-6 membered ring; or when R is oxo, R1 and R2 together with the atoms to which they are attached can form a heterocyclyl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1- C2 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and -SO2R7; R3 is selected from H, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylsulfonyl, C1-C6 hydroxyalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, C3-8-cycloalkyl-alkyl, aryl, heteroaryl, heterocyclyl, C3-8-cycloalkyl, alkylaminoalkyl, aminoalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, and alkylaminocarbonylalkyl; L is a bivalent group selected from C1-C6 alkylene, -NH-C1-C6 alkylene, -C1-C6 alkylene-NH-, -N(CH3)-C1-C6 alkylene, -C1-C6 alkylene-N(CH3)-, C3-C10 cycloalkyl, 5-10 membered heteroaryl and 5-6 membered heterocyclyl, wherein the alkylene group is optionally substituted with 1-6 substituents independently selected from halo, cyano and C1-C6 alkoxy; A is selected from 5-6 membered heterocyclyl, 5-10 membered heteroaryl, C3-C10 cycloalkyl and aryl; R4 is selected from H, –(CH2)n-C(O)OR7, -(CH2)n-C(O)N(R7)2, -(CH2)n-C(O)NHR7, -(CH2)n-C(O)NHOR7, - (CH2)n-SO2R7, -SO3H, -PO2(OH)2, -SO2NH2, -SO(=NH)CH3 and heteroaryl, wherein the heteroaryl is substituted with 0, 1, 2, or 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and –(CH2)n-SO2R7; R5 is selected from H, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylsulfonyl, C1-C6 hydroxyalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaminoalkyl, aminoalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, and alkylaminocarbonylalkyl; Each R6 is independentlyselected from oxo, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C6 haloalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, -(CH2)n-OR7, -(CH2)n-N(R7)2, -(CH2)n-C(O)R7, -(CH2)n- C(O)OR7, -(CH2)n-C(O)N(R7)2, -(CH2)n-SO2R7, C3-C 10 cycloalkyl, 5-10 membered heterocyclyl, -(CH2)n- aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl is substituted with 0, 1, 2, or 3 substituents independently selected from with halo, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and–(CH2)n-SO2R7; Each R7 is independently selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, 5-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; and p is 0, 1, 2 or 3; provided that (1) when X1 and X2 are each CR5, X3 is N, and R is oxo in Formula 1A or 1B, then R1 is not morpholino; and (2) when R2 is 2-cyanobenzyl and R is oxo in Formula 1C, then R1 is not 3-aminopiperdinyl. 2. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is -SO3H, -PO2(OH)2, - SO2NH2, -SO(=NH)CH3, -C(O)OH, –(CH2)1-2-C(O)OH, -C(O)O-C1-C4 alkyl, –(CH2)1-2-C(O)O-C1-C4 alkyl, -- C(O)NH2, -(CH2)1-2-C(O)NH2, -C(O)N(C1-C4 alkyl)2, -(CH2)1-2-C(O)N(C1-C4 alkyl)2, -C(O)NHO-C1-C4 alkyl, - C(O)NH-C1-C4 alkyl, -(CH2)1-2-C(O)NH-C1-C4 alkyl, C1-C4 alkylsulfonyl, or 5-10 membered nitrogen containing heteroaryl. 3. The compound of Claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R4 is -COOH. 4. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein each R6 is independently selected from H, oxo, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -(CH2)n-OR7, -(CH2)n-N(R7)2, -(CH2)n-C(O)R7, -(CH2)n-C (O)N(R7)2, -(CH2)n-SO2R7, C3- C 10 cycloalkyl, 5-10 membered heterocyclyl, -(CH2)n-aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or –(CH2)n-SO2R7; Each R7 is independently selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, 5-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl Each n is independently 0 or 1; and p is 0 or 1. 5. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein each R6 is selected from H, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, hydroxymethyl, methoxymethyl, methylamino, dimethylamino, methylaminomethyl, dimethylaminomethyl, methylaminocarbonyl, aminocarbonyl, methylsulfonyl, methoxy and cyclopropyl, and p is 1. 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein each R2, R3 and R5 is independently selected from H, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkylsulfonyl, C1-C6 hydroxyalkyl, -(CH2)n-OR7, -(CH2)n-C(O)R7, phenyl- C1-C6 alkyl, 5-6 membered heteroaryl-C1-C6 alkyl, 5-6 membered heterocyclyl- C1-C6 alkyl, C5-C6 cycloalkyl- C1-C6 alkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl, C5-C6 cycloalkyl, C1-C6 alkylamino- C1-C6 alkyl, amino- C1-C6 alkyl, C1-C6 alkoxy- C1-C6 alkyl, carboxy C1-C6 alkyl, C1-C6 alkoxycarbonyl C1-C6 alkyl, aminocarbonylalkyl and C1-C6 alkylaminocarbonyl- C1-C6 alkyl; R7 is selected from H, C1-C3 alkyl, C3-C6 cycloalkyl, 5-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl; and n is 0, 1 or 2.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from H, cyano, fluoro, chloro, C1-C3 alkyl, C1-C2 haloalkyl, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, - (CH2)n-OR7, -(CH2)n-C(O)R7, C3-C10 cycloalkyl, phenyl and 5-6 membered heteroaryl; R7 is selected from methyl, ethyl, cyclohexyl, and phenyl; and n is 0 or 1. 8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from H, fluoro, chloro, cyano, methyl, ethyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy, benzyl, phenyl, and cyclopropyl. 9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from H, cyano, fluoro, chloro, C1-C3 alkyl, C1-C2 haloalkyl, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, - (CH2)n-OR7, -(CH2)n-C(O)R7, C3-C6 cycloalkyl, phenyl and 5-6 membered heteroaryl; R7 is selected from methyl, ethyl, cyclohexyl, and phenyl; and n is 0 or 1. 10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from H, fluoro, chloro, cyano, methylsulfonyl, hydroxymethyl, methoxy, methyl, trifluoromethyl and cyclopropyl. 11. The compound of any one of claims 1 to 10, or pharmaceutically acceptable salt thereof, wherein R5 is selected from H, cyano, halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl. 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R5 is selected from H, fluoro, chloro, cyano, methyl, trifluoromethyl, methoxy and cyclopropyl. 13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R5 is H. 14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R together with R2 and the carbon and nitrogen to which they are attached forms a triazolyl ring. 15. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R is oxo. 16. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R is selected from hydroxy, methoxy, ethoxy, -OCH2CF3, -OCH2CF2H, -OCH2CFH2 and -OCF3. 17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from 5-10 membered nitrogen containing heteroaryl, 4-10 membered nitrogen containing heterocyclyl, 4-10 membered oxygen containing heterocyclyl, 6-10 membered aryl, C4-C6 cycloalkenyl and C3-C6 cycloalkyl; wherein the nitrogen containing heteroaryl, nitrogen containing heterocyclyl, aryl, cycloalkenyl or cycloalkyl is substituted with 0, 1, 2 or 3 substituents independently selected from halo, cyano, C1-C3 alkyl, C1-C2 haloalkyl, C1- C4 alkoxy, hydroxy, phenyl, aralkyl, C3-6-cycloalkyl and C1-C3 hydroxyalkyl. 18. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from 1-piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, 2-tetrahydroisoquinolinyl, 2- tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1- imidazolidinyl, 2-tetrahydronaphthyridinyl, 2-isoindolinyl, dihydroindolyl, 2-tetrahydroisoquinolinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, oxetanyl, tetrahydrofuranyl, and 1-azetidinyl; wherein R1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, methyl,, difluoromethyl, trifluormethyl,, hydroxy, methoxy, ethoxy, , methylsulfonyl, carboxyl, amino, dimethylamino, Boc, and a ring independently selected from morpholinyl, pyrazolyl, 1-methyl-4-pyrazolyl, benzyl, phenyl, 3-pyridinyl, pyrimidinyl, 2-methoxy-4-pyrmidinyl, 5-methoxy-4- pyrmidinyl, 1,3,6-triazanaphth-5-yl, 1-thia-4,6-diazainden-7-yl and cyclopropyl, wherein the ring is unsubstituted or substituted. 19. The compound of any one of claims 1 to 16, wherein R1 is selected from pyridyl, pyrimidinyl, pyrazolyl, thienyl, oxazolyl, thiazolyl, imidazolyl, quinolinyl, 2-isoindolyl, indolyl, indazolyl, benzothiazolyl, benzofuryl, phenyl and naphthyl, cyclohexenyl, cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, and cyclohexyl; wherein the ring has one, two or three substituents independently selected from halo, cyano, C1-C3 alkyl, C1-C2 haloalkyl, C1- C4 alkoxy, hydroxy, phenyl, aralkyl, C3-6-cycloalkyl and hydroxy-C1-C3 alkyl. 20. The compound of any one of claims 1 to 16, wherein R1 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, C2- C4 alkenyl, C2-C4 alkynyl, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, C1-C3 haloalkyl, -OR1a, -SR1a, -NR1aR1a, - C(O)R1a, -C(O)OR1a, -NR1aC(O)R1a, -OC(O)R1a, -C(O)NR1bR1b, -NR1aC(O)NR1bR1b, -S(O)2NR1bR1b, NR1aS(O)2NR1bR1b, -NR1aS(O)2R1a; -S(O)2R1a, benzyl, and pyridylmethyl; each R1a is independently selected from H, C1-4-alkyl, C2-4-alkenyl, C2-4-alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C3-6- cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halogen, C1-C4 alkyl, C2-C4 alkenyl, C2- C4 alkynyl, C1-C2 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and -(CH2)n-SO2R7; each R1b is independently selected from H, C1-4-alkyl, C2-4-alkenyl, C2-4-alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C3-6- cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C2 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and -(CH2)n-SO2R7; and when R1 is - C(O)NR1bR1b, -NR1aC(O)NR1bR1b, -S(O)2NR1bR1b, or NR1aS(O)2NR1bR1b, two R1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 0, 1, 2, or 3 substituents independently selected from halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C2 haloalkyl, C1- C4 alkoxy, C1-C4 haloalkoxy, and -SO2R7. 21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein L is selected from -NH-C1-C4 alkylene, and -C1-C4 alkylene-NH-; wherein each alkylene group is optionally substituted with 1-4 substituents independently selected from halo, cyano and C1-C2 alkoxy. 22. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein L is C3- C10 cycloalkyl, 5-10 membered heteroaryl or 5-6 membered heterocyclyl.

23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein A is 5-10 membered heteroaryl, or phenyl. 24. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein A is selected from phenyl, pyridyl, benzothienyl, pyrazinyl and pyrimidinyl. 25. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein X1 and X2 are each -CR5- and X3 is N. 26. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein X1 and X2 are each -N- and X3 is N. 27. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein X1 is - CR5-, X2 is -N- and X3 is N. 28. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein X1 is -N-, X2 is -CR5- and X3 is N. 29. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein X1 and X2 are each -CR5- and X3 is -CR5-. 30. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein X1 and X2 are each -N- and X3 is -CR5-. 31. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein X1 is - CR5-, X2 is -N- and X3 is -CR5-. 32. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein X1 is -N-, X2 is -CR5- and X3 is -CR5-. 33. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from: 2-((1-(3-methyl-4-oxo-2-(piperidin-1-yl)-3,4-dihydrothieno[3,2-d]pyrimidin-7-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid; 6-chloro-3-((1-(3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinic acid; 2-((1-(3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzamide; 2-((1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 2-((1-(2-(4,4-difluoropiperidin-1-yl)-6-methoxy-3-methyl-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidin-8- yl)ethyl)amino)benzoic acid; o-(1-{12-Methyl-7-piperidino-3,4,6,8-tetraazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-10- yl}ethylamino)benzoic acid ; o-{1-[2-(4,4-Difluoro-1-piperidyl)-3-methyl-6-methyl-4-oxo-3H-1,3,5-triazanaphth-8-yl]ethylamino}benzoic acid; o-[1-(6-Methyl-7-oxo-5-piperidino-6H-1-thia-4,6-diazainden-3-yl)ethylamino]benzoic acid; o-[1-(2-Methyl-7-methyl-8-oxo-6-piperidino-7H-1,3,5,7-tetraazanaphth-4-yl)ethylamino]benzoic acid; o-[1-(6-Methyl-4-oxo-2-piperidino-3,8a-dihydro-1,4a-diaza-8-naphthyl)ethylamino]benzoic acid; 6-Chloro-3-{1-[2-(4,4-difluoro-1-piperidyl)-6-methyl-4-oxo-1,4a-diaza-8-naphthyl]ethylamino}-2- pyridinecarboxylic acid; 6-Chloro-3-{1-[2-(4,4-difluoro-1-piperidyl)-3-methyl-6-methyl-4-oxo-3H-1,3,7-triazanaphth-8-yl]ethylamino}-2- pyridinecarboxylic acid; o-{1-[2-(1-piperidyl)-3,6-dimethyl-4-oxo-3H-1,3,7-triazanaphth-8-yl]ethylamino}benzoic acid; 6-Chloro-3-{1-[2-(4,4-difluoro-1-piperidyl)-3,6-dimethyl-4-oxo-1,4a-diaza-8-naphthyl]ethylamino}-2- pyridinecarboxylic acid; o-{1-[2-(1-piperidyl)-3,6-dimethyl-4-oxo-1,4a-diaza-8-naphthyl]]ethylamino}benzoic acid; 2-((1-(3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; 3,6-dimethyl-8-(1-(phenylamino)ethyl)-2-(piperidin-1-yl)quinazolin-4(3H)-one; 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; and 2-((1-(2-(isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid. 34. The compound of claim 1 or pharmaceutically acceptable salt thereof, having a structure of Formula 2a or 2b: wherein R is oxo; wherein: R is -ORx; Rx is selected from H, methyl, ethyl, -CH2CF3, CH2CF2H, CH2CFH2 and CF3; R1 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, -OR1a, -SR1a, -NR1aR1a, -C(O)R1a, -C(O)OR1a, -NR1aC(O)R1a, -OC(O)R1a, -C(O)NR1bR1b, -NR1aC(O)NR1bR1b, -S(O)2NR1bR1b, NR1aS(O)2NR1bR1b, NR1aS(O)2R1a; -S(O)2R1a, benzyl, heteroaryl- C1-C4 alkyl, heterocyclyl- C1-C4 alkyl, C3-6-cycloalkyl-C1-C4 alkyl, phenyl, naphthyl, C5- C6 cycloalkenyl, C3-C6 -cycloalkyl, 5-10 membered nitrogen containing heteroaryl, 4-10 membered oxygen containing heterocyclyl and 4-10 membered nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C1-C6 hydroxyalkyl; R1a and R1b are each independently selected from H, C1-4-alkyl, C2-4-alkenyl, C2-4-alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C3-6- cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C2 haloalkyl, C1- C4 alkoxy, C1-C4 haloalkoxy, and -SO2R7 ; when R1 is -C(O)NR1bR1b, -NR1aC(O)NR1bR1b, -S(O)2NR1bR1b, or NR1aS(O)2NR1bR1b, two R1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, C2-C4 alkenyl, C2- C4 alkynyl, C1-C2 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and -SO2R7; R2 is selected from H, fluoro, chloro, cyano, C1-C4 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; or when R is oxo, R1 and R2 together with the nitrogen and carbon atoms to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C2 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and -SO2R7; R3 is selected from H, fluoro, chloro, cyano, C1-C4 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C3- C6 cycloalkyl; L is C1-C4 alkylene, -NH-C1-C4 alkylene, or -C1-C4 alkylene-NH-, and the alkylene group is optionally substituted with 1-4 substituents independently selected from halo, cyano and C1-C4 alkoxy; R4 is selected from H, -SO3H, -PO2(OH)2, -SO2NH2, -SO(=NH)CH3, -C(O)OH, –(CH2)1-2-C(O)OH, -C(O)O-C1- C4 alkyl, –(CH2)1-2-C(O)O-C1-C4 alkyl, --C(O)NH2, -(CH2) 1-2-C(O)NH2, -C(O)N(C1-C4 alkyl)2, -(CH2) 1-2- C(O)N(C1-C4 alkyl)2, -C(O)NHO-C1-C4 alkyl, -C(O)NH-C1-C4 alkyl, -(CH2) 1-2-C(O)NH-C1-C4 alkyl, C1- C4 alkylsulfonyl, and 5-membered nitrogen containing heteroaryl; R5 is selected from H, halo, cyano, C1-C4 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; Each R6 is independently selected from H, halo, cyano, C1-C4 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1- C2 haloalkyl, C1-C4 alkoxy, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, benzyl, heteroaryl- C1-C4 alkyl, heterocyclyl- C1-C4 alkyl, C3-C6 cycloalkyl- C1-C4 alkyl, phenyl, heteroaryl, heterocyclyl, C3-C6 cycloalkyl, C1-C4 alkylamino- C1-C4 alkyl, amino- C1-C4 alkyl, and C1-C4 alkoxy-C1-C4 alkyl; R7 is selected from H, C1-C2 alkyl, C5-C6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; and p is 0, 1, 2 or 3. 35. The compound of Claim 34 or pharmaceutically acceptable salt thereof, wherein R is oxo or methoxy; R1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2-hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl-2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1-piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, indolyl, indazolyl, benzothiazolyl, benzofuryl, dihydroindolyl, 2-tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, oxetanyl, tetrahydrofuranyl, phenyl, 2-pyridyl, 3-pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, and cyclohexyl; wherein the ring substituent in R1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, methyl, difluoromethyl, trifluormethyl, hydroxy, methoxy, ethoxy, methylsulfonyl, carboxyl, amino, dimethylamino, Boc, and a ring selected from morpholinyl, pyrazolyl, 1-methyl-4-pyrazolyl, benzyl, phenyl, 3-pyridinyl, pyrimidinyl, 2- methoxy-4-pyrmidinyl, 5-methoxy-4-pyrmidinyl, 1,3,6-triazanaphth-5-yl, 1-thia-4,6-diazainden-7-yl and cyclopropyl, wherein the ring is unsubstituted or substituted; R2 is selected from H, fluoro, chloro, cyano, methyl, ethyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R3 is selected from H, fluoro, chloro, cyano, methyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is selected from phenyl, 2-pyridyl, 3-pyridyl, and 1-benzimidazolyl; L is selected from ethylenyl, 1-methylethylenyl, -NH-CH2- and -NHCH(CH3)- , and wherein the ethylenyl, or -NHCH2- group is optionally substituted with 1-4 substituents independently selected from fluoro, cyano and methoxy; R5 is selected from H, fluoro, chloro, cyano, C1-C4 alkyl, trifluoromethyl, methoxy and cyclopropyl; R4 is selected from methylsulfonyl, -SO3H, -PO2(OH)2, -SO2NH2, - SO(=NH)CH3, -C(O)OH, -C(O)O-C1-C4 alkyl, -C(O)NHO-C1-C4 alkyl, -C(O)NH2, -C(O)NH-ethyl, -C(O)NH- isopropyl,triazolyl and tetrazolyl; R6 is selected from H, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and methoxy; and p is 0 or 1. 36, The compound of Claim 34 or pharmaceutically acceptable salt thereof, wherein R is oxo; A is benzotriazolyl and R4 is H. 36. The compound of any of Claims 34-35 or pharmaceutically acceptable salt thereof, wherein R4 is -COOH. 37. The compound of Claim 34 or pharmaceutically acceptable salt thereof, wherein R is oxo.

37. The compound of claim 1 or pharmaceutically acceptable salt thereof, having a structure of Formula 3a or 3b: Wherein R is oxo wherein: R is -ORx; Rx is selected from H, methyl, ethyl, -CH2CF3, CH2CF2H, CH2CFH2 and CF3; R1 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, -OR1a, -SR1a, -NR1aR1a, -C(O)R1a, -C(O)OR1a, -NR1aC(O)R1a, -OC(O)R1a, -C(O)NR1bR1b, -NR1aC(O)NR1bR1b, -S(O)2NR1bR1b, NR1aS(O)2NR1bR1b, NR1aS(O)2R1a; -S(O)2R1a, benzyl, heteroaryl- C1-C4 alkyl, heterocyclyl- C1-C4 alkyl, C3-6-cycloalkyl-C1-C4 alkyl, phenyl, naphthyl, C5- C6 cycloalkenyl, C3-C6 cycloalkyl, 5-10 membered nitrogen containing heteroaryl, 4-10 membered oxygen containing heterocyclyl and 4-10 membered nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C1-C6 hydroxyalkyl; R1a and R1b are each independently selected from H, C1-4-alkyl, C2-4-alkenyl, C2-4-alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C3-6- cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C2 haloalkyl, C1- C4 alkoxy, C1-C4 haloalkoxy, and -SO2R7; when R1 is -C(O)NR1bR1b, -NR1aC(O)NR1bR1b, -S(O)2NR1bR1b, or NR1aS(O)2NR1bR1b, two R1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, C2-C4 alkenyl, C2- C4 alkynyl, C1-C2 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and -SO2R7; R2 is selected from H, fluoro, chloro, cyano, C1-C4 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; or when R is oxo, R1 and R2 together with the nitrogen and carbon atoms to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C2 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and -SO2R7; R3 is selected from H, fluoro, chloro, cyano, C1-C4 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C3- C6 cycloalkyl; L is C1-C4 alkylene, -NH-C1-C4 alkylene, or -C1-C4 alkylene-NH-, and the alkylene group is optionally substituted with 1-4 substituents independently selected from halo, cyano and C1-C4 alkoxy; R4 is selected from -H, SO3H, -PO2(OH)2, -SO2NH2, -SO(=NH)CH3, -C(O)OH, –(CH2)1-2-C(O)OH, -C(O)O-C1- C4 alkyl, –(CH2)1-2-C(O)O-C1-C4 alkyl, --C(O)NH2, -(CH2) 1-2-C(O)NH2, -C(O)N(C1-C4 alkyl)2, -(CH2) 1-2- C(O)N(C1-C4 alkyl)2, -C(O)NHO-C1-C4 alkyl, -C(O)NH-C1-C4 alkyl, -(CH2)1-2-C(O)NH-C1-C4 alkyl, C1- C4 alkylsulfonyl, and 5-membered nitrogen containing heteroaryl; R5 is selected from H, halo, cyano, C1-C4 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; Each R6 is independently selected from H, halo, cyano, C1-C4 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1- C2 haloalkyl, C1-C4 alkoxy, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, benzyl, heteroaryl- C1-C4 alkyl, heterocyclyl- C1-C4 alkyl, C3-C6 cycloalkyl- C1-C4 alkyl, phenyl, heteroaryl, heterocyclyl, C3-C6 cycloalkyl, C1-C4 alkylamino- C1-C4 alkyl, amino- C1-C4 alkyl, and C1-C4 alkoxy-C1-C4 alkyl; R7 is selected from H, C1-C2 alkyl, C5-C6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; and p is 0, 1, 2 or 3. 38. The compound of Claim 37 or pharmaceutically acceptable salt thereof, wherein R is oxo or methoxy; R1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2-hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl-2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1-piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, indolyl, indazolyl, benzothiazolyl, benzofuryl, dihydroindolyl, 2-tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, oxetanyl, tetrahydrofuranyl, phenyl, 2-pyridyl, 3-pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, and cyclohexyl; wherein the ring substituent in R1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, methyl, difluoromethyl, trifluormethyl, hydroxy, methoxy, ethoxy, methylsulfonyl, carboxyl, amino, dimethylamino, Boc, and a ring selected from morpholinyl, pyrazolyl, 1-methyl-4-pyrazolyl, benzyl, phenyl, 3-pyridinyl, pyrimidinyl, 2- methoxy-4-pyrmidinyl, 5-methoxy-4-pyrmidinyl, 1,3,6-triazanaphth-5-yl, 1-thia-4,6-diazainden-7-yl and cyclopropyl, wherein the ring is unsubstituted or substituted; R2 is selected from H, fluoro, chloro, cyano, methyl, ethyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R3 is selected from H, fluoro, chloro, cyano, methyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is selected from phenyl, 2-pyridyl, 3-pyridyl, and 1-benzimidazolyl; L is selected from ethylenyl, 1-methylethylenyl, -NH-CH2- and -NHCH(CH3)- , and wherein the ethylenyl, or -NHCH2- group is optionally substituted with 1-4 substituents independently selected from fluoro, cyano and methoxy; R5 is selected from H, fluoro, chloro, cyano, C1-C4 alkyl, trifluoromethyl, methoxy and cyclopropyl; R4 is selected from methylsulfonyl, -SO3H, -PO2(OH)2, -SO2NH2, - SO(=NH)CH3, -C(O)OH, -C(O)O-C1-C4 alkyl, -C(O)NHO-C1-C4 alkyl, -C(O)NH2, -C(O)NH-ethyl, -C(O)NH- isopropyl,triazolyl and tetrazolyl; R6 is selected from H, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and methoxy; and p is 0 or 1. 39. The compound of any of Claims 38-39 or pharmaceutically acceptable salt thereof, wherein R4 is -COOH. 40. The compound of claim 1 or pharmaceutically acceptable salt thereof, having a structure of Formula 4a or 4b: Wherein R is oxo wherein: R is -ORx; Rx is selected from H, methyl, ethyl, -CH2CF3, CH2CF2H, CH2CFH2 and CF3; R1 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, C2-C4 alkenyl, C2- C4 alkynyl, C1-C4 haloalkyl, -OR1a, -SR1a, -NR1aR1a, -C(O)R1a, -C(O)OR1a, -NR1aC(O)R1a, -OC(O)R1a, - C(O)NR1bR1b, -NR1aC(O)NR1bR1b, -S(O)2NR1bR1b, NR1aS(O)2NR1bR1b, NR1aS(O)2R1a; -S(O)2R1a, benzyl, heteroaryl- C1-C4 alkyl, heterocyclyl- C1-C4 alkyl, C3-6-cycloalkyl-C1-C4 alkyl, phenyl, naphthyl, C5- C6 cycloalkenyl, C3-C6 cycloalkyl, 5-10 membered nitrogen containing heteroaryl, 4-10 membered oxygen containing heterocyclyl; and 4-10 membered nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C1-C6 hydroxyalkyl; R1a and R1b are each independently selected from H, C1-4-alkyl, C2-4-alkenyl, C2-4-alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C3-6- cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C2 haloalkyl, C1- C4 alkoxy, C1-C4 haloalkoxy, and -SO2R7 ; when R1 is -C(O)NR1bR1b, -NR1aC(O)NR1bR1b, -S(O)2NR1bR1b, or NR1aS(O)2NR1bR1b, two R1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, C2-C4 alkenyl, C2- C4 alkynyl, C1-C2 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and -SO2R7; R2 is selected from H, fluoro, chloro, cyano, C1-C4 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; or when R is oxo, R1 and R2 together with the nitrogen and carbon atoms to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C2 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and -SO2R7; R3 is selected from H, fluoro, chloro, cyano, C1-C4 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C3- C6 cycloalkyl; L is C1-C4 alkylene, -NH-C1-C4 alkylene, or -C1-C4 alkylene-NH-, and the alkylene group is optionally substituted with 1-4 substituents independently selected from halo, cyano and C1-C4 alkoxy; R4 is selected from H, -SO3H, -PO2(OH)2, -SO2NH2, -SO(=NH)CH3, -C(O)OH, –(CH2)1-2-C(O)OH, -C(O)O-C1- C4 alkyl, –(CH2)1-2-C(O)O-C1-C4 alkyl, --C(O)NH2, -(CH2) 1-2-C(O)NH2, -C(O)N(C1-C4 alkyl)2, -(CH2) 1-2- C(O)N(C1-C4 alkyl)2, -C(O)NHO-C1-C4 alkyl, -C(O)NH-C1-C4 alkyl, -(CH2) 1-2-C(O)NH-C1-C4 alkyl, C1- C4 alkylsulfonyl, and 5-membered nitrogen containing heteroaryl; Each R6 is independently selected from H, halo, cyano, C1-C4 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1- C2 haloalkyl, C1-C4 alkoxy, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, benzyl, heteroaryl- C1-C4 alkyl, heterocyclyl- C1-C4 alkyl, C3-C6 cycloalkyl- C1-C4 alkyl, phenyl, heteroaryl, heterocyclyl, C3-C6 cycloalkyl, C1-C4 alkylamino- C1-C4 alkyl, amino- C1-C4 alkyl, and C1-C4 alkoxy-C1-C4 alkyl; R7 is selected from H, C1-C2 alkyl, C5-C6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; and p is 0, 1, 2 or 3. 41. The compound of Claim 40 or pharmaceutically acceptable salt thereof, wherein R is oxo or methoxy; R1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2-hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl-2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1-piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, indolyl, indazolyl, benzothiazolyl, benzofuryl, dihydroindolyl, 2-tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, oxetanyl, tetrahydrofuranyl, phenyl, 2-pyridyl, 3-pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, and cyclohexyl; wherein the ring substituent in R1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, methyl, difluoromethyl, trifluormethyl, hydroxy, methoxy, ethoxy, methylsulfonyl, carboxyl, amino, dimethylamino, Boc, and a ring selected from morpholinyl, pyrazolyl, 1-methyl-4-pyrazolyl, benzyl, phenyl, 3-pyridinyl, pyrimidinyl, 2- methoxy-4-pyrmidinyl, 5-methoxy-4-pyrmidinyl, 1,3,6-triazanaphth-5-yl, 1-thia-4,6-diazainden-7-yl and cyclopropyl, wherein the ring is unsubstituted or substituted; R2 is selected from H, fluoro, chloro, cyano, methyl, ethyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R3 is selected from H, fluoro, chloro, cyano, methyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is selected from phenyl, 2-pyridyl, 3-pyridyl, and 1-benzimidazolyl; L is selected from ethylenyl, 1-methylethylenyl, -NH-CH2- and -NHCH(CH3)- , and wherein the ethylenyl, or -NHCH2- group is optionally substituted with 1-4 substituents independently selected from fluoro, cyano and methoxy; R5 is selected from H, fluoro, chloro, cyano, C1-C4 alkyl, trifluoromethyl, methoxy and cyclopropyl; R4 is selected from methylsulfonyl, -SO3H, -PO2(OH)2, -SO2NH2, - SO(=NH)CH3, -C(O)OH, -C(O)O-C1-C4 alkyl, -C(O)NHO-C1-C4 alkyl, -C(O)NH2, -C(O)NH-ethyl, -C(O)NH- isopropyl,triazolyl and tetrazolyl; R6 is selected from H, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and methoxy; and p is 0 or 1. 42. The compound of either Claim 40 or 41 or pharmaceutically acceptable salt thereof, wherein R4 is -COOH. 43. The compound of claim 1 or pharmaceutically acceptable salt thereof, having a structure of Formula 5a or 5b: Wherein R is oxo; wherein: R is -ORx; Rx is selected from H, methyl, ethyl, -CH2CF3, CH2CF2H, CH2CFH2 and CF3; R1 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, C2-C4 alkenyl, C2- C4 alkynyl, C1-C4 haloalkyl, -OR1a, -SR1a, -NR1aR1a, -C(O)R1a, -C(O)OR1a, -NR1aC(O)R1a, -OC(O)R1a, - C(O)NR1bR1b, -NR1aC(O)NR1bR1b, -S(O)2NR1bR1b, NR1aS(O)2NR1bR1b, NR1aS(O)2R1a; -S(O)2R1a, benzyl, heteroaryl- C1-C4 alkyl, heterocyclyl- C1-C4 alkyl, C3-8-cycloalkyl-C1-C4 alkyl, phenyl, naphthyl, C5- C6 cycloalkenyl, C3-C6 cycloalkyl, 5-10 membered nitrogen containing heteroaryl, 4-10 membered oxygen containing heterocyclyl; and 4-10 membered nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C1-C6 hydroxyalkyl; R1a and R1b are each independently selected from H, C1-4-alkyl, C2-4-alkenyl, C2-4-alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C3-6- cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C2 haloalkyl, C1- C4 alkoxy, C1-C4 haloalkoxy, and -SO2R7 ; when R1 is -C(O)NR1bR1b, -NR1aC(O)NR1bR1b, -S(O)2NR1bR1b, or NR1aS(O)2NR1bR1b, two R1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, C2-C4 alkenyl, C2- C4 alkynyl, C1-C2 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and -SO2R7; R2 is selected from H, fluoro, chloro, cyano, C1-C4 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; or when R is oxo, R1 and R2 together with the nitrogen and carbon atoms to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C2 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and -SO2R7; R3 is selected from H, fluoro, chloro, cyano, C1-C4 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C3- C6 cycloalkyl; L is C1-C4 alkylene, -NH-C1-C4 alkylene, or -C1-C4 alkylene-NH-, and the alkylene group is optionally substituted with 1-4 substituents independently selected from halo, cyano and C1-C4 alkoxy; R4 is selected from H, -SO3H, -PO2(OH)2, -SO2NH2, -SO(=NH)CH3, -C(O)OH, –(CH2)1-2-C(O)OH, -C(O)O-C1- C4 alkyl, –(CH2)1-2-C(O)O-C1-C4 alkyl, --C(O)NH2, -(CH2) 1-2-C(O)NH2, -C(O)N(C1-C4 alkyl)2, -(CH2) 1-2- C(O)N(C1-C4 alkyl)2, -C(O)NHO-C1-C4 alkyl, -C(O)NH-C1-C4 alkyl, -(CH2) 1-2-C(O)NH-C1-C4 alkyl, C1- C4 alkylsulfonyl, and 5-membered nitrogen containing heteroaryl; Each R6 is independently selected from H, halo, cyano, C1-C4 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1- C2 haloalkyl, C1-C4 alkoxy, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, benzyl, heteroaryl- C1-C4 alkyl, heterocyclyl- C1-C4 alkyl, C3-C6 cycloalkyl- C1-C4 alkyl, phenyl, heteroaryl, heterocyclyl, C3-C6 cycloalkyl, C1-C4 alkylamino- C1-C4 alkyl, amino- C1-C4 alkyl, and C1-C4 alkoxy-C1-C4 alkyl; R7 is selected from H, C1-C2 alkyl, C5-C6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; and p is 0, 1, 2 or 3. 44. The compound of Claim 43 or pharmaceutically acceptable salt thereof, wherein R is oxo or methoxy; R1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2-hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl-2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1-piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, indolyl, indazolyl, benzothiazolyl, benzofuryl, dihydroindolyl, 2-tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, oxetanyl, tetrahydrofuranyl, phenyl, 2-pyridyl, 3-pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, and cyclohexyl; wherein the ring substituent in R1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, methyl, difluoromethyl, trifluormethyl, hydroxy, methoxy, ethoxy, methylsulfonyl, carboxyl, amino, dimethylamino, Boc, and a ring selected from morpholinyl, pyrazolyl, 1-methyl-4-pyrazolyl, benzyl, phenyl, 3-pyridinyl, pyrimidinyl, 2- methoxy-4-pyrmidinyl, 5-methoxy-4-pyrmidinyl, 1,3,6-triazanaphth-5-yl, 1-thia-4,6-diazainden-7-yl and cyclopropyl, wherein the ring is unsubstituted or substituted; R2 is selected from H, fluoro, chloro, cyano, methyl, ethyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R3 is selected from H, fluoro, chloro, cyano, methyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is selected from phenyl, 2-pyridyl, 3-pyridyl, and 1-benzimidazolyl; L is selected from ethylenyl, 1-methylethylenyl, -NH-CH2- and -NHCH(CH3)- , and wherein the ethylenyl, or -NHCH2- group is optionally substituted with 1-4 substituents independently selected from fluoro, cyano and methoxy; R5 is selected from H, fluoro, chloro, cyano, C1-C4 alkyl, trifluoromethyl, methoxy and cyclopropyl; R4 is selected from methylsulfonyl, -SO3H, -PO2(OH)2, -SO2NH2, - SO(=NH)CH3, -C(O)OH, -C(O)O-C1-C4 alkyl, -C(O)NHO-C1-C4 alkyl, -C(O)NH2, -C(O)NH-ethyl, -C(O)NH- isopropyl,triazolyl and tetrazolyl; R6 is selected from H, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and methoxy; and p is 0 or 1. 45. The compound of either Claim 43 or 44 or pharmaceutically acceptable salt thereof, wherein R4 is -COOH. 46. The compound of claim 1 or pharmaceutically acceptable salt thereof, having a structure of Formula 6a, 6b or 6c: wherein: X1, X2, X3 and X4 is each independently -CR5- or -N-; R1 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, C2-C4 alkenyl, C2- C4 alkynyl, C1-C4 haloalkyl, -OR1a, -SR1a, -NR1aR1a, -C(O)R1a, -C(O)OR1a, -NR1aC(O)R1a, -OC(O)R1a, - C(O)NR1bR1b, -NR1aC(O)NR1bR1b, -S(O)2NR1bR1b, NR1aS(O)2NR1bR1b, NR1aS(O)2R1a; -S(O)2R1a, benzyl, heteroaryl- C1-C4 alkyl, heterocyclyl- C1-C4 alkyl, C3-8-cycloalkyl-C1-C4 alkyl, phenyl, naphthyl, C5- C6 cycloalkenyl, C3-C6 cycloalkyl, 5-10 membered nitrogen containing heteroaryl, 4-10 membered oxygen containing heterocyclyl and 4-10 membered nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C1-C6 hydroxyalkyl; R1a and R1b are each independently selected from H, C1-4-alkyl, C2-4-alkenyl, C2-4-alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C3-6- cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C2 haloalkyl, C1- C4 alkoxy, C1-C4 haloalkoxy, and -SO2R7 ; when R1 is -C(O)NR1bR1b, -NR1aC(O)NR1bR1b, -S(O)2NR1bR1b, or NR1aS(O)2NR1bR1b, two R1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, C2-C4 alkenyl, C2- C4 alkynyl, C1-C2 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and -SO2R7; R3 is selected from H, fluoro, chloro, cyano, C1-C4 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C3- C6 cycloalkyl; L is C1-C4 alkylene, -NH-C1-C4 alkylene, or -C1-C4 alkylene-NH-, and the alkylene group is optionally substituted with 1-4 substituents independently selected from halo, cyano and C1-C4 alkoxy; R4 is selected from H, -SO3H, -PO2(OH)2, -SO2NH2, -SO(=NH)CH3, -C(O)OH, –(CH2)1-2-C(O)OH, -C(O)O-C1- C4 alkyl, –(CH2)1-2-C(O)O-C1-C4 alkyl, --C(O)NH2, -(CH2) 1-2-C(O)NH2, -C(O)N(C1-C4 alkyl)2, -(CH2) 1-2- C(O)N(C1-C4 alkyl)2, -C(O)NHO-C1-C4 alkyl, -C(O)NH-C1-C4 alkyl, -(CH2) 1-2-C(O)NH-C1-C4 alkyl, C1- C4 alkylsulfonyl, and 5-membered nitrogen containing heteroaryl; R5 is selected from H, halo, cyano, C1-C4 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; Each R6 is independently selected from H, halo, cyano, C1-C4 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1- C2 haloalkyl, C1-C4 alkoxy, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, benzyl, heteroaryl- C1-C4 alkyl, heterocyclyl- C1-C4 alkyl, C3-C6 cycloalkyl- C1-C4 alkyl, phenyl, heteroaryl, heterocyclyl, C3-C6 cycloalkyl, C1-C4 alkylamino- C1-C4 alkyl, amino- C1-C4 alkyl, and C1-C4 alkoxy-C1-C4 alkyl; R7 is selected from H, C1-C2 alkyl, C5-C6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; R10 is selected from H, halo, cyano, C1-C4 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, benzyl, phenyl, substituted or unsubstituted 5-6 membered heteroaryl, and cyclopropyl; and p is 0, 1, 2 or 3. 47. The compound of Claim 46 or pharmaceutically acceptable salt thereof, wherein R1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2-hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl-2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1-piperidinyl, 1-piperazinyl, 2-isoindolyl, 2- isoindolinyl, indolyl, indazolyl, benzothiazolyl, benzofuryl, dihydroindolyl, 2-tetrahydroisoquinolinyl, 2- tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1- imidazolidinyl, 1-azetidinyl, oxetanyl, tetrahydrofuranyl, phenyl, 2-pyridyl, 3-pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, and cyclohexyl; wherein the ring substituent in R1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, methyl, difluoromethyl, trifluormethyl, hydroxy, methoxy, ethoxy, methylsulfonyl, carboxyl, amino, dimethylamino, Boc, and a ring selected from morpholinyl, pyrazolyl, 1- methyl-4-pyrazolyl, benzyl, phenyl, 3-pyridinyl, pyrimidinyl, 2-methoxy-4-pyrmidinyl, 5-methoxy-4-pyrmidinyl, 1,3,6-triazanaphth-5-yl, 1-thia-4,6-diazainden-7-yl and cyclopropyl, wherein the ring is unsubstituted or substituted; R2 is selected from H, fluoro, chloro, cyano, methyl, ethyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R3 is selected from H, fluoro, chloro, cyano, methyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is selected from phenyl, 2- pyridyl, 3-pyridyl, and 1-benzimidazolyl; L is selected from ethylenyl, 1-methylethylenyl, -NH-CH2- and - NHCH(CH3)- , and wherein the ethylenyl, or -NHCH2- group is optionally substituted with 1-4 substituents independently selected from fluoro, cyano and methoxy; R5 is selected from H, fluoro, chloro, cyano, C1-C4 alkyl, trifluoromethyl, methoxy and cyclopropyl; R4 is selected from methylsulfonyl, -SO3H, -PO2(OH)2, - SO2NH2, -SO(=NH)CH3, -C(O)OH, -C(O)O-C1-C4 alkyl, -C(O)NHO-C1-C4 alkyl, -C(O)NH2, -C(O)NH-ethyl, - C(O)NH-isopropyl,triazolyl and tetrazolyl; R6 is selected from H, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and methoxy; R10 is selected from H, fluoro, chloro, cyano, C1-C4 alkyl, trifluoromethyl, ethenyl, propynyl, methoxy, 1-methyl-3-pyrazolyl, 1-methyl-4-pyrazolyl, and cyclopropyl; X1 and X2 are each -CH-; X3 is -N-; X4 is -CR5- or -N- ; and p is 0 or 1. 48. The compound of either Claim 46 or 47 or pharmaceutically acceptable salt thereof, wherein R4 is -COOH. 49. The compound of claim 1 or pharmaceutically acceptable salt thereof, having a structure of Formula 7: wherein: X1 and X2 is each independently -CR5- or -N-; R1 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, C2-C4 alkenyl, C2- C4 alkynyl, C1-C4 haloalkyl, -OR1a, -SR1a, -NR1aR1a, -C(O)R1a, -C(O)OR1a, -NR1aC(O)R1a, -OC(O)R1a, - C(O)NR1bR1b, -NR1aC(O)NR1bR1b, -S(O)2NR1bR1b, NR1aS(O)2NR1bR1b, NR1aS(O)2R1a; -S(O)2R1a, benzyl, heteroaryl- C1-C4 alkyl, heterocyclyl- C1-C4 alkyl, C3-8-cycloalkyl-C1-C4 alkyl, phenyl, naphthyl, C5- C6 cycloalkenyl, C3-C6 cycloalkyl, 5-10 membered nitrogen containing heteroaryl, 4-10 membered oxygen containing heterocyclyl; and 4-10 membered nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C1-C6 hydroxyalkyl; R1a and R1b are each independently selected from H, C1-4-alkyl, C2-4-alkenyl, C2-4-alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C3-6- cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C2 haloalkyl, C1- C4 alkoxy, C1-C4 haloalkoxy, and -SO2R7 ; when R1 is -C(O)NR1bR1b, -NR1aC(O)NR1bR1b, -S(O)2NR1bR1b, or NR1aS(O)2NR1bR1b, two R1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, C2-C4 alkenyl, C2- C4 alkynyl, C1-C2 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and -SO2R7; R2 is selected from H, fluoro, chloro, cyano, C1-C4 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; or R1 and R2 together with the nitrogen and carbon atoms to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C2 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and -SO2R7; R3 is selected from H, fluoro, chloro, cyano, C1-C4 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C3- C6 cycloalkyl; L is C1-C4 alkylene, -NH-C1-C4 alkylene, or -C1-C4 alkylene-NH-, and the alkylene group is optionally substituted with 1-4 substituents independently selected from halo, cyano and C1-C4 alkoxy; R4 is selected from H, -SO3H, -PO2(OH)2, -SO2NH2, -SO(=NH)CH3, -C(O)OH, –(CH2)1-2-C(O)OH, -C(O)O-C1- C4 alkyl, –(CH2)1-2-C(O)O-C1-C4 alkyl, --C(O)NH2, -(CH2)1-2-C(O)NH2, -C(O)N(C1-C4 alkyl)2, -(CH2)1-2- C(O)N(C1-C4 alkyl)2, -C(O)NHO-C1-C4 alkyl, -C(O)NH-C1-C4 alkyl, -(CH2) 1-2-C(O)NH-C1-C4 alkyl, C1- C4 alkylsulfonyl, and 5-membered nitrogen containing heteroaryl; R5 is selected from H, halo, cyano, C1-C4 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; Each R6 is independently selected from H, halo, cyano, C1-C4 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1- C2 haloalkyl, C1-C4 alkoxy, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, benzyl, heteroaryl- C1-C4 alkyl, heterocyclyl- C1-C4 alkyl, C3-C6 cycloalkyl- C1-C4 alkyl, phenyl, heteroaryl, heterocyclyl, C3-C6 cycloalkyl, C1-C4 alkylamino- C1-C4 alkyl, amino- C1-C4 alkyl, and C1-C4 alkoxy-C1-C4 alkyl; R7 is selected from H, C1-C2 alkyl, C5-C6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; and p is 0, 1, 2 or 3.

50. The compound of Claim 49 or pharmaceutically acceptable salt thereof, wherein R1 is selected methyl, ethyl, isopropyl, 1,1-dimethyl-2-hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl-2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1-piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, indolyl, indazolyl, benzothiazolyl, benzofuryl, dihydroindolyl, 2-tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2- pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, oxetanyl, tetrahydrofuranyl, phenyl, 2- pyridyl, 3-pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, and cyclohexyl; wherein the ring substituent in R1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, methyl, difluoromethyl, trifluormethyl, hydroxy, methoxy, ethoxy, methylsulfonyl, carboxyl, amino, dimethylamino, Boc, and a ring selected from morpholinyl, pyrazolyl, 1-methyl-4-pyrazolyl, benzyl, phenyl, 3-pyridinyl, pyrimidinyl, 2-methoxy-4-pyrmidinyl, 5- methoxy-4-pyrmidinyl, 1,3,6-triazanaphth-5-yl, 1-thia-4,6-diazainden-7-yl and cyclopropyl, wherein the ring is unsubstituted or substituted; R2 is selected from H, fluoro, chloro, cyano, methyl, ethyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R3 is selected from H, fluoro, chloro, cyano, methyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is selected from phenyl, 2-pyridyl, 3- pyridyl, and 1-benzimidazolyl; L is selected from ethylenyl, 1-methylethylenyl, -NH-CH2- and -NHCH(CH3)- , and wherein the ethylenyl, or -NHCH2- group is optionally substituted with 1-4 substituents independently selected from fluoro, cyano and methoxy; R5 is selected from H, fluoro, chloro, cyano, C1-C4 alkyl, trifluoromethyl, methoxy and cyclopropyl; R4 is selected from methylsulfonyl, -SO3H, -PO2(OH)2, -SO2NH2, -SO(=NH)CH3, - C(O)OH, -C(O)O-C1-C4 alkyl, -C(O)NHO-C1-C4 alkyl, -C(O)NH2, -C(O)NH-ethyl, -C(O)NH-isopropyl,triazolyl and tetrazolyl; R6 is selected from H, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and methoxy; X1 and X2 are each -CH-; and p is 0 or 1. 51. The compound of either Claim 49 or 50 or pharmaceutically acceptable salt thereof, wherein R4 is -COOH. 52. The compound of Claim 1 or pharmaceutically acceptable salt thereof, having a structure of of Formula 8a or 8b, or a pharmaceutically acceptable salt thereof: wherein R is oxo;

wherein: R is -ORx; Rx is selected from H, methyl, ethyl, -CH2CF3, CH2CF2H, CH2CFH2 and CF3; R1 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, C2-C4 alkenyl, C2- C4 alkynyl, C1-C4 haloalkyl, -OR1a, -SR1a, -NR1aR1a, -C(O)R1a, -C(O)OR1a, -NR1aC(O)R1a, -OC(O)R1a, - C(O)NR1bR1b, -NR1aC(O)NR1bR1b, -S(O)2NR1bR1b, NR1aS(O)2NR1bR1b, NR1aS(O)2R1a; -S(O)2R1a, benzyl, heteroaryl- C1-C4 alkyl, heterocyclyl- C1-C4 alkyl, C3-8-cycloalkyl-C1-C4 alkyl, phenyl, naphthyl, C5- C6 cycloalkenyl, C3-C6 cycloalkyl, 5-10 membered nitrogen containing heteroaryl, 4-10 membered oxygen containing heterocyclyl; and 4-10 membered nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C1-C6 hydroxyalkyl; R1a and R1b are each independently selected from H, C1-4-alkyl, C2-4-alkenyl, C2-4-alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C3-6- cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C2 haloalkyl, C1-C4 alkoxy, C1- C4 haloalkoxy, and -SO2R7; when R1 is -C(O)NR1bR1b, -NR1aC(O)NR1bR1b, -S(O)2NR1bR1b, or NR1aS(O)2NR1bR1b, two R1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, C2-C4 alkenyl, C2- C4 alkynyl, C1-C2 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and -SO2R7; R2 is selected from H, fluoro, chloro, cyano, C1-C4 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; or when R is oxo, R1 and R2 together with the nitrogen and carbon atoms to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C2 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and -SO2R7; R3 is selected from H, fluoro, chloro, cyano, C1-C4 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C3- C6 cycloalkyl; L is C1-C4 alkylene, -NH-C1-C4 alkylene, or -C1-C4 alkylene-NH-, and the alkylene group is optionally substituted with 1-4 substituents independently selected from halo, cyano and C1-C4 alkoxy; R4 is selected from H, -SO3H, -PO2(OH)2, -SO2NH2, -SO(=NH)CH3, -C(O)OH, –(CH2)1-2-C(O)OH, -C(O)O-C1- C4 alkyl, –(CH2)1-2-C(O)O-C1-C4 alkyl, --C(O)NH2, -(CH2)1-2-C(O)NH2, -C(O)N(C1-C4 alkyl)2, -(CH2)1-2- C(O)N(C1-C4 alkyl)2, -C(O)NHO-C1-C4 alkyl, -C(O)NH-C1-C4 alkyl, -(CH2)1-2-C(O)NH-C1-C4 alkyl, C1- C4 alkylsulfonyl, and 5-membered nitrogen containing heteroaryl; R5 is selected from H, halo, cyano, C1-C4 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; Each R6 is independently selected from H, halo, cyano, C1-C4 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1- C2 haloalkyl, C1-C4 alkoxy, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, benzyl, heteroaryl- C1-C4 alkyl, heterocyclyl- C1-C4 alkyl, C3-C6 cycloalkyl- C1-C4 alkyl, phenyl, heteroaryl, heterocyclyl, C3-C6 cycloalkyl, C1-C4 alkylamino- C1-C4 alkyl, amino- C1-C4 alkyl, and C1-C4 alkoxy-C1-C4 alkyl; R7 is selected from H, C1-C2 alkyl, C5-C6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; and p is 0, 1, 2 or 3. 53. The compound of Claim 52 or pharmaceutically acceptable salt thereof, wherein R is oxo or methoxy; R1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2-hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl-2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1-piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, indolyl, indazolyl, benzothiazolyl, benzofuryl, dihydroindolyl, 2-tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, oxetanyl, tetrahydrofuranyl, phenyl, 2-pyridyl, 3-pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, and cyclohexyl; wherein the ring substituent in R1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, methyl, difluoromethyl, trifluormethyl, hydroxy, methoxy, ethoxy, methylsulfonyl, carboxyl, amino, dimethylamino, Boc, and a ring selected from morpholinyl, pyrazolyl, 1-methyl-4-pyrazolyl, benzyl, phenyl, 3-pyridinyl, pyrimidinyl, 2- methoxy-4-pyrmidinyl, 5-methoxy-4-pyrmidinyl, 1,3,6-triazanaphth-5-yl, 1-thia-4,6-diazainden-7-yl and cyclopropyl, wherein the ring is unsubstituted or substituted; R2 is selected from H, fluoro, chloro, cyano, methyl, ethyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R3 is selected from H, fluoro, chloro, cyano, methyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is selected from phenyl, 2-pyridyl, 3-pyridyl, and 1-benzimidazolyl; L is selected from ethylenyl, 1-methylethylenyl, -NH-CH2- and -NHCH(CH3)- , and wherein the ethylenyl, or -NHCH2- group is optionally substituted with 1-4 substituents independently selected from fluoro, cyano and methoxy; R5 is selected from H, fluoro, chloro, cyano, C1-C4 alkyl, trifluoromethyl, methoxy and cyclopropyl; R4 is selected from methylsulfonyl, -SO3H, -PO2(OH)2, -SO2NH2, - SO(=NH)CH3, -C(O)OH, -C(O)O-C1-C4 alkyl, -C(O)NHO-C1-C4 alkyl, -C(O)NH2, -C(O)NH-ethyl, -C(O)NH- isopropyl,triazolyl and tetrazolyl; R6 is selected from H, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and methoxy; and p is 0 or 1. 54. The compound of either Claim 52 or 53 or pharmaceutically acceptable salt thereof, wherein R4 is -COOH. 55. The compound of claim 1 or pharmaceutically acceptable salt thereof, having a structure of Formula 9: wherein: R is oxo or -ORx; Rx is selected from H, methyl, ethyl, -CH2CF3, CH2CF2H, CH2CFH2 and CF3; R1 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, C2-C4 alkenyl, C2- C4 alkynyl, C1-C4 haloalkyl, -OR1a, -SR1a, -NR1aR1a, -C(O)R1a, -C(O)OR1a, -NR1aC(O)R1a, -OC(O)R1a, - C(O)NR1bR1b, -NR1aC(O)NR1bR1b, -S(O)2NR1bR1b, NR1aS(O)2NR1bR1b, NR1aS(O)2R1a; -S(O)2R1a, benzyl, heteroaryl- C1-C4 alkyl, heterocyclyl- C1-C4 alkyl, C3-8-cycloalkyl-C1-C4 alkyl, phenyl, naphthyl, C5- C6 cycloalkenyl, C3-C6 cycloalkyl, 5-10 membered nitrogen containing heteroaryl, 4-10 membered oxygen containing heterocyclyl; and 4-10 membered nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C1-C6 hydroxyalkyl; R1a and R1b are each independently selected from H, C1-4-alkyl, C2-4-alkenyl, C2-4-alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C3-6- cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C2 haloalkyl, C1- C4 alkoxy, C1-C4 haloalkoxy, and -SO2R7; when R1 is -C(O)NR1bR1b, -NR1aC(O)NR1bR1b, -S(O)2NR1bR1b, or NR1aS(O)2NR1bR1b, two R1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, C2-C4 alkenyl, C2- C4 alkynyl, C1-C2 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and -SO2R7; R2 is selected from H, fluoro, chloro, cyano, C1-C4 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; or when R is oxo, R1 and R2 together with the nitrogen and carbon atoms to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C2 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and -SO2R7; R3 is selected from H, fluoro, chloro, cyano, C1-C4 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C3- C6 cycloalkyl; L is C1-C4 alkylene, -NH-C1-C4 alkylene, or -C1-C4 alkylene-NH-, and the alkylene group is optionally substituted with 1-4 substituents independently selected from halo, cyano and C1-C4 alkoxy; R4 is selected from H, -SO3H, -PO2(OH)2, -SO2NH2, -SO(=NH)CH3, -C(O)OH, –(CH2)1-2-C(O)OH, -C(O)O-C1- C4 alkyl, –(CH2)1-2-C(O)O-C1-C4 alkyl, --C(O)NH2, -(CH2)1-2-C(O)NH2, -C(O)N(C1-C4 alkyl)2, -(CH2)1-2- C(O)N(C1-C4 alkyl)2, -C(O)NHO-C1-C4 alkyl, -C(O)NH-C1-C4 alkyl, -(CH2)1-2-C(O)NH-C1-C4 alkyl, C1- C4 alkylsulfonyl, and 5-membered nitrogen containing heteroaryl; Each R6 is independently selected from H, halo, cyano, C1-C4 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1- C2 haloalkyl, C1-C4 alkoxy, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, benzyl, heteroaryl- C1-C4 alkyl, heterocyclyl- C1-C4 alkyl, C3-C6 cycloalkyl- C1-C4 alkyl, phenyl, heteroaryl, heterocyclyl, C3-C6 cycloalkyl, C1-C4 alkylamino- C1-C4 alkyl, amino- C1-C4 alkyl, and C1-C4 alkoxy-C1-C4 alkyl; R7 is selected from H, C1-C2 alkyl, C5-C6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; and p is 0, 1, 2 or 3. 56. The compound of Claim 55 or pharmaceutically acceptable salt thereof, wherein R is oxo or methoxy; R1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2-hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl-2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1-piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, indolyl, indazolyl, benzothiazolyl, benzofuryl, dihydroindolyl, 2-tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, oxetanyl, tetrahydrofuranyl, phenyl, 2-pyridyl, 3-pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, and cyclohexyl; wherein the ring substituent in R1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, methyl, difluoromethyl, trifluormethyl, hydroxy, methoxy, ethoxy, methylsulfonyl, carboxyl, amino, dimethylamino, Boc, and a ring selected from morpholinyl, pyrazolyl, 1-methyl-4-pyrazolyl, benzyl, phenyl, 3-pyridinyl, pyrimidinyl, 2- methoxy-4-pyrmidinyl, 5-methoxy-4-pyrmidinyl, 1,3,6-triazanaphth-5-yl, 1-thia-4,6-diazainden-7-yl and cyclopropyl, wherein the ring is unsubstituted or substituted; R2 is selected from H, fluoro, chloro, cyano, methyl, ethyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R3 is selected from H, fluoro, chloro, cyano, methyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is selected from phenyl, 2-pyridyl, 3-pyridyl, and 1-benzimidazolyl; L is selected from ethylenyl, 1-methylethylenyl, -NH-CH2- and -NHCH(CH3)- , and wherein the ethylenyl, or -NHCH2- group is optionally substituted with 1-4 substituents independently selected from fluoro, cyano and methoxy; R5 is selected from H, fluoro, chloro, cyano, C1-C4 alkyl, trifluoromethyl, methoxy and cyclopropyl; R4 is selected from methylsulfonyl, -SO3H, -PO2(OH)2, -SO2NH2, - SO(=NH)CH3, -C(O)OH, -C(O)O-C1-C4 alkyl, -C(O)NHO-C1-C4 alkyl, -C(O)NH2, -C(O)NH-ethyl, -C(O)NH- isopropyl,triazolyl and tetrazolyl; R6 is selected from H, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and methoxy; and p is 0 or 1. 57. The compound of either Claim 55 or 56 or pharmaceutically acceptable salt thereof, wherein R4 is -COOH. 58. The compound of claim 1 or pharmaceutically acceptable salt thereof, having a structure of Formula 10a, 10b or 10c: wherein: X1, X2, X3, and X6 is each independently -CR5- or -N-; R1 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, C2-C4 alkenyl, C2- C4 alkynyl, C1-C4 haloalkyl, -OR1a, -SR1a, -NR1aR1a, -C(O)R1a, -C(O)OR1a, -NR1aC(O)R1a, -OC(O)R1a, - C(O)NR1bR1b, -NR1aC(O)NR1bR1b, -S(O)2NR1bR1b, NR1aS(O)2NR1bR1b, NR1aS(O)2R1a; -S(O)2R1a, benzyl, heteroaryl- C1-C4 alkyl, heterocyclyl- C1-C4 alkyl, C3-8-cycloalkyl-C1-C4 alkyl, phenyl, naphthyl, C5- C6 cycloalkenyl, C3-C8 cycloalkyl, 5-10 membered nitrogen containing heteroaryl, 4-10 membered oxygen containing heterocyclyl and 4-10 membered nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C1-C6 hydroxyalkyl; R1a and R1b are each independently selected from H, C1-4-alkyl, C2-4-alkenyl, C2-4-alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C3-6- cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C2 haloalkyl, C1- C4 alkoxy, C1-C4 haloalkoxy, and -SO2R7 ; when R1 is -C(O)NR1bR1b, -NR1aC(O)NR1bR1b, -S(O)2NR1bR1b, or NR1aS(O)2NR1bR1b, two R1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkyl, C2-C4 alkenyl, C2- C4 alkynyl, C1-C2 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and -SO2R7; R3 is selected from H, fluoro, chloro, cyano, C1-C4 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C3- C6 cycloalkyl; L is C1-C4 alkylene, -NH-C1-C4 alkylene, or -C1-C4 alkylene-NH-, and the alkylene group is optionally substituted with 1-4 substituents independently selected from halo, cyano and C1-C4 alkoxy; R4 is selected from H, -SO3H, -PO2(OH)2, -SO2NH2, -SO(=NH)CH3, -C(O)OH, –(CH2)1-2-C(O)OH, -C(O)O-C1- C4 alkyl, –(CH2)1-2-C(O)O-C1-C4 alkyl, --C(O)NH2, -(CH2)1-2-C(O)NH2, -C(O)N(C1-C4 alkyl)2, -(CH2)1-2- C(O)N(C1-C4 alkyl)2, -C(O)NHO-C1-C4 alkyl, -C(O)NH-C1-C4 alkyl, -(CH2)1-2-C(O)NH-C1-C4 alkyl, C1- C4 alkylsulfonyl, and 5-membered nitrogen containing heteroaryl; R5 is selected from H, halo, cyano, C1-C4 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; Each R6 is independently selected from H, halo, cyano, C1-C4 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1- C2 haloalkyl, C1-C4 alkoxy, C1-C4 alkylsulfonyl, C1-C4 hydroxyalkyl, benzyl, heteroaryl- C1-C4 alkyl, heterocyclyl- C1-C4 alkyl, C3-C6 cycloalkyl- C1-C4 alkyl, phenyl, heteroaryl, heterocyclyl, C3-C6 cycloalkyl, C1-C4 alkylamino- C1-C4 alkyl, amino- C1-C4 alkyl, and C1-C4 alkoxy-C1-C4 alkyl; R7 is selected from H, C1-C2 alkyl, C5-C6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; R10 is selected from H, halo, cyano, C1-C4 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, benzyl, phenyl, substituted or unsubstituted 5-6 membered heteroaryl, and cyclopropyl; and p is 0, 1, 2 or 3. 47. The compound of Claim 46 or pharmaceutically acceptable salt thereof, wherein R1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2-hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl-2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1-piperidinyl, 1-piperazinyl, 2-isoindolyl, 2- isoindolinyl, indolyl, indazolyl, benzothiazolyl, benzofuryl, dihydroindolyl, 2-tetrahydroisoquinolinyl, 2- tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1- imidazolidinyl, 1-azetidinyl, oxetanyl, tetrahydrofuranyl, phenyl, 2-pyridyl, 3-pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, and cyclohexyl; wherein the ring substituent in R1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, methyl, difluoromethyl, trifluormethyl, hydroxy, methoxy, ethoxy, methylsulfonyl, carboxyl, amino, dimethylamino, Boc, and a ring selected from morpholinyl, pyrazolyl, 1- methyl-4-pyrazolyl, benzyl, phenyl, 3-pyridinyl, pyrimidinyl, 2-methoxy-4-pyrmidinyl, 5-methoxy-4-pyrmidinyl, 1,3,6-triazanaphth-5-yl, 1-thia-4,6-diazainden-7-yl and cyclopropyl, wherein the ring is unsubstituted or substituted; R2 is selected from H, fluoro, chloro, cyano, methyl, ethyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R3 is selected from H, fluoro, chloro, cyano, methyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is selected from phenyl, 2- pyridyl, 3-pyridyl, and 1-benzimidazolyl; L is selected from ethylenyl, 1-methylethylenyl, -NH-CH2- and - NHCH(CH3)- , and wherein the ethylenyl, or -NHCH2- group is optionally substituted with 1-4 substituents independently selected from fluoro, cyano and methoxy; R5 is selected from H, fluoro, chloro, cyano, C1-C4 alkyl, trifluoromethyl, methoxy and cyclopropyl; R4 is selected from methylsulfonyl, -SO3H, -PO2(OH)2, - SO2NH2, -SO(=NH)CH3, -C(O)OH, -C(O)O-C1-C4 alkyl, -C(O)NHO-C1-C4 alkyl, -C(O)NH2, -C(O)NH-ethyl, - C(O)NH-isopropyl,triazolyl and tetrazolyl; R6 is selected from H, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and methoxy; each R10 is independently selected from H, fluoro, chloro, cyano, C1-C4 alkyl, trifluoromethyl, methoxy, ethoxy and cyclopropyl; X1 and X2 are -CH-; X3 is -N-; X6 is -CR10- or -N- ; and p is 0 or 1. 48. The compound of either Claim 46 or 47 or pharmaceutically acceptable salt thereof, wherein R4 is -COOH. 58. The compound of any one of claims 1, 34, 37, 40, 43, 46, 49, 52 and 55 or pharmaceutically acceptable salt thereof, wherein R4-A- is selected from wherein R6 is halo, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C3-C5 cycloalkyl; and p is 0, 1, or 2. 59. The compound of claim 58 or pharmaceutically acceptable salt thereof, wherein R4-A- is wherein R6 is fluoro, chloro, bromo or trifluoromethyl; and p is 0 or 1. 60. The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein R1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2-hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl-2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, and dimethylaminocarbonyl. 61. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein A is selected from phenyl, benzothienyl, pyrazinyl, pyrimidinyl, 2-pyridyl, 3-pyridyl, and 1-benzimidazolyl. 62. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein L is selected from ethylenyl, 1-methylethylenyl, -NH-CH2- and -NHCH(CH3)-, wherein the ethylenyl, or -NHCH2- group is optionally substituted with 1-4 substituents independently selected from fluoro, cyano and methoxy. 63. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is - selected from methylsulfonyl, -SO3H, -PO2(OH)2, -SO2NH2, -SO(=NH)CH3, -C(O)OH, -C(O)O-C1-C4 alkyl, -C(O)NHO-C1- C4 alkyl, -C(O)NH2, -C(O)NH-ethyl, -C(O)NH-isopropyl, triazolyl and tetrazolyl. 64. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from Examples 1-218. 65. A pharmaceutical composition comprising, a compound of any one of claims 1 to 64, and a pharmaceutically acceptable carrier. 66. A method of treating a disease or disorder associated with modulation of phosphoinositide 3 -kinase alpha (PI3K ^), comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 64 or a pharmaceutical composition of claim 65. 67. The method of claim 66, wherein the compound has greater selectivity for mutant PI3K ^ over wild-type PI3K ^. 68. The method of claim 66 or claim 67, wherein the PI3K associated with the disease or disorder has a H1047R mutation. 69. The method of any one of claims 66-68, wherein the disease or disorder is a cancer.

70. The method of claim 69, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer. 71. The method of any one of claims 66-68, wherein the disease or disorder is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome), or PIK3CA-related overgrowth syndrome (PROS). 72. A method of inhibiting phosphoinositide 3-kinase (PI3K), comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 64 or a pharmaceutical composition of claim 65. 73. A method of treating cancer or a disorder, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 64 or a pharmaceutical composition of claim 65. 74. The method of claim 73, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer. 75 The method of claim 73, wherein the disorder is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) or PIK3CA-related overgrowth syndrome (PROS). 76. A compound of any one of claims 1 to 64 or a pharmaceutical composition of claim 65, for use in treating a disease or disorder associated with modulating PI3K. 77. The compound for use of claim 76, wherein the disease associated with modulating PI3K is a cancer. 78. The compound for use of claim 77, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer. 79. The compound for use of claim 71, wherein the disorder is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) or PIK3CA-related overgrowth syndromes (PROS). 80. Use of a compound of any one of claims 1 to 64 or a pharmaceutical composition of claim 65, in the manufacture of a medicament for the treatment of a disease associated with modulating PI3K. 81. The use of a compound of claim 80, wherein the disease associated with modulating PI3K is a cancer. 82. The use of a compound of claim 80, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.

83. The use of a compound of claim 80 wherein the disease is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) or PIK3CA-related overgrowth syndromes (PROS).
Description:
INHIBITORS OF PHOSPHOINOSITIDE 3-KINASE (PI3K) AND USES THEREOF INCORPORATION BY REFERENCE OF MATERIAL SUBMITTED ELECTRONICALLY [001] The Sequence Listing, which is a part of the present disclosure, is submitted concurrently with the specification as a xml file. The name of the file containing the Sequence Listing is “54045_Seqlisting.XML", which was created on February 9, 2023, and is 5,456 bytes in size. The subject matter of the Sequence Listing is incorporated herein in its entirety by reference. In the event that seqeunce information in the specification conflicts with information in the electronic sequence listing, the specification is controlling. FIELD [002] The present invention relates to compounds and compositions capable of acting as inhibitors of phosphoinositide 3-kinase (PI3K). More specifically, invention relates to compounds and compositions capable of acting as inhibitors of PI3K mutants, such as H1047R. The compounds and compositions may be used in the treatment of cancer. BACKGROUND [003] The present disclosure is directed to allosteric inhibitors of phosphoinositide 3-kinase (PI3K) useful in the treatment of diseases or disorders associated with PI3K modulation. The disclosure is directed toward compounds and compositions which inhibit PI3K, methods of treating a disease or disorder associated with PI3K (e.g., CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome), PIK3CA-related overgrowth syndrome (PROS), breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer), and methods of using PI3K inhibitors in combination with one or more additional disorder or cancer therapy. [004] The activity of cells can be regulated by external signals that stimulate or inhibit intracellular events. The process by which stimulatory or inhibitory signals are transmitted into and within a cell to elicit an intracellular response is referred to as signal transduction. Over the past decades, cascades of signal transduction events have been elucidated and found to play a central role in a variety of biological responses. Defects in various components of signal transduction pathways have been found to account for a vast number of diseases, including numerous forms of cancer, inflammatory disorders, metabolic disorders, vascular and neuronal diseases (Gaestel et al. Current Medicinal Chemistry (2007) 14:2214-2234). [005] PI3Ks are members of a unique and conserved family of intracellular lipid kinases that phosphorylate the 3’-OH group on phosphatidylinositols or phosphoinositides. The PI3K family comprises 15 kinases with distinct substrate specificities, expression patterns, and modes of regulation (Katso et al., 2001). The class I PI3Ks (p110 ^, p110 ^, p110 ^, and p110 ^) are typically activated by tyrosine kinases or G-protein coupled receptors to generate PIP3, which engages downstream effectors such as those in the pathways of Akt/PDKl, mTOR, the Tec family kinases, and the Rho family GTPases. The class II and III PI3-Ks play a key role in intracellular trafficking through the synthesis of PI(3)P and PI(3,4)P 2. [006] The PI3K isoforms have been implicated, for example, in a variety of human cancers and disorders. Mutations in the gene coding for PI3K isoforms or mutations which lead to upregulation of a PI3K isoform are believed to occur in many human cancers. Mutations in the gene coding for a PI3K isoform are point mutations clustered within several hotspots in helical and kinase domains. [007] Currently PI3K ^ inhibitors are nearly equipotent to wild-type and mutant PI3K ^. Mutant selective inhibitors have been elusive due to the PI3K ^ mutations’ location far from the active site. As such, inhibitors which target a second, peripheral binding pocket near a known mutation (e.g., H1047R) may provide a route to selective PI3K ^ inhibition. Thus, targeting a mutated, peripheral binding pocket of PI3K ^, may in turn provide a valuable therapeutic target for drug development. DETAILED DESCRIPTION [008] One embodiment relates to compounds of Formula 1A, 1B, 1C or 1D, or a pharmaceutically acceptable salt thereof: wherein: X 1 , X 2 , and X 3 is each independently -CR 5 - or -N-; X 5 is a carbon atom when a double bond is attached or is -CR 5 - or -N- when a single bond is attached; R is oxo or -OR x ; R x is H, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; or R together with R 2 and the carbon and nitrogen to which they are attached forms a 5-6 membered heteroaryl ring; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , - C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , NR 1a S(O) 2 R 1a ; -S(O) 2 R 1a , aralkyl, heteroarylalkyl, heterocyclylalkyl, C 3-8 -cycloalkyl-alkyl, aryl, C 4 - 8 -cycloalkenyl, C 3-8 -cycloalkyl, 4-10 membered oxygen containing heterocyclyl; nitrogen containing heteroaryl, and nitrogen containing heterocyclyl; wherein the aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, aryl, aralkyl, C 3-8 -cycloalkyl and C 1 - C 6 hydroxyalkyl; R 1a and R 1b are each independently selected from H, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, aryl, heteroaryl, heterocyclyl and C 3-8 -cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, or –(CH 2 ) n -SO 2 R 7 ; wherein when R 1 is -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , two R 1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, which is substituted with 0, 1, 2, or 3 substituents independently selected from halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and –(CH 2 ) n -SO 2 R 7 ; R 2 is selected from H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 - C 6 alkoxy, C 1 -C 6 alkylsulfonyl, C 1 -C 6 hydroxyalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, C 3-8 -cycloalkyl-alkyl, aryl, heteroaryl, heterocyclyl, C 3-8 -cycloalkyl, alkylaminoalkyl, aminoalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl and alkylaminocarbonylalkyl; or R together with R 2 and the atoms to which they are attached forms a 5-6 membered ring; or when R is oxo, R 1 and R 2 together with the atoms to which they are attached can form a heterocyclyl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1- C 4 haloalkoxy, and -SO 2 R 7 ; R 3 is selected from H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 - C 6 alkoxy, C 1 -C 6 alkylsulfonyl, C 1 -C 6 hydroxyalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, C 3 - 8 -cycloalkyl-alkyl, aryl, heteroaryl, heterocyclyl, C 3 - 8 -cycloalkyl, alkylaminoalkyl, aminoalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, and alkylaminocarbonylalkyl; L is a bivalent group selected from C 1 -C 6 alkylene, -NH-C 1 -C 6 alkylene, -C 1 -C 6 alkylene-NH-, -N(CH 3 )- C 1 -C 6 alkylene, -C 1 -C 6 alkylene-N(CH 3 )-,C 3 -C 10 cycloalkyl, 5-10 membered heteroaryl and 5-6 membered heterocyclyl, wherein the alkylene group is optionally substituted with 1-6 substituents independently selected from halo, cyano and C 1 -C 6 alkoxy; A is selected from 5-6 membered heterocyclyl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl and aryl; R 4 is selected from H, –(CH 2 ) n -C(O)OR 7 , -(CH 2 ) n -C(O)N(R 7 ) 2 , -(CH 2 ) n -C(O)NHR 7 , -(CH 2 ) n -C(O)NHOR 7 , -(CH 2 ) n -SO 2 R 7 , -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 and heteroaryl, wherein the heteroaryl is substituted with 0, 1, 2, or 3 substituents independently selected from halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 - C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and –(CH 2 ) n -SO 2 R 7 ; R 5 is selected from H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 - C 6 alkoxy, C 1 -C 6 alkylsulfonyl, C 1 -C 6 hydroxyalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaminoalkyl, aminoalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, and alkylaminocarbonylalkyl; Each R 6 is independentlyselected from oxo, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 - C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, -(CH 2 ) n -OR 7 , -(CH 2 ) n -N(R 7 ) 2 , -(CH 2 ) n -C(O)R 7 , -(CH 2 ) n -C(O)OR 7 , - (CH 2 ) n -C(O)N(R 7 ) 2 , -(CH 2 ) n -SO 2 R 7 , C 3 -C 10 cycloalkyl, 5-10 membered heterocyclyl, -(CH 2 ) n -aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl is substituted with 0, 1, 2, or 3 substituents independently selected from with halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 - C 6 alkoxy, C 1 -C 6 haloalkoxy, and–(CH 2 ) n -SO 2 R 7 ; Each R 7 is independently selected from H, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 5-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; and p is 0, 1, 2 or 3; provided that (1) when X 1 and X 2 are each CR 5 , X 3 is N, and R is oxo in Formula 1A or 1B, then R 1 is not morpholino; and (2) when R 2 is 2-cyanobenzyl and R is oxo in Formula 1C, then R 1 is not 3-aminopiperdinyl. [009] One embodiment relates to compounds of Formula 1A, 1B or 1C, or a pharmaceutically acceptable salt thereof: wherein: X 1 , X 2 and X 3 is each independently -CR 5 - or -N-; R is oxo or -OR x ; R x is H, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; or R together with R 2 and the carbon and nitrogen to which they are attached forms a 5-membered heteroaryl ring; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, -OR 1a , - SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , - S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , NR 1a S(O) 2 R 1a ; -S(O) 2 R 1a , aralkyl, heteroarylalkyl, heterocyclylalkyl, C 3-8 - cycloalkyl-alkyl, aryl, C 4 - 8 -cycloalkenyl, C 3-8 -cycloalkyl, nitrogen containing heteroaryl, and nitrogen containing heterocyclyl; wherein the aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, aryl, aralkyl, C 3-8 - cycloalkyl and C 1 -C 6 hydroxyalkyl; R 1a and R 1b are each independently selected from H, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, aryl, heteroaryl, heterocyclyl and C 3 - 8 -cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and –(CH 2 ) n -SO 2 R 7 ; wherein when R 1 is -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , two R 1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, which is substituted with 0, 1, 2, or 3 substituents independently selected from halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and –(CH 2 ) n -SO 2 R 7 ; R 2 is selected from H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylsulfonyl, C 1 -C 6 hydroxyalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, C 3-8 -cycloalkyl-alkyl, aryl, heteroaryl, heterocyclyl, C 3-8 -cycloalkyl, alkylaminoalkyl, aminoalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl and alkylaminocarbonylalkyl; R 3 is selected from H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylsulfonyl, C 1 -C 6 hydroxyalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, C 3 - 8 -cycloalkyl-alkyl, aryl, heteroaryl, heterocyclyl, C 3 - 8 -cycloalkyl, alkylaminoalkyl, aminoalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, and alkylaminocarbonylalkyl; L is a bivalent group selected from C 1 -C 6 alkylene, -NH-C 1 -C 6 alkylene, -C 1 -C 6 alkylene-NH-, -N(CH 3 )-C 1 - C 6 alkylene, -C 1 -C 6 alkylene-N(CH 3 )-,C 3 -C 10 cycloalkyl, 5-10 membered heteroaryl and 5-6 membered heterocyclyl, wherein the alkylene group is substituted with 0-6 substituents independently selected from halo, cyano and C 1 -C 6 alkoxy; A is selected from 5-6 membered heterocyclyl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl and aryl; R 4 is selected from –(CH 2 ) n -C(O)OR 7 , -(CH 2 ) n -C(O)N(R 7 ) 2 , -(CH 2 ) n -C(O)NHOR 7 , -(CH 2 ) n -SO 2 R 7 , -SO 3 H, - PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 and heteroaryl, wherein the heteroaryl is substituted with 0, 1, 2, or 3 substituents independently selected from halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 - C 6 alkoxy, C 1 -C 6 haloalkoxy, and –(CH 2 ) n -SO 2 R 7 ; R 5 is selected from H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylsulfonyl, C 1 -C 6 hydroxyalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaminoalkyl, aminoalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, and alkylaminocarbonylalkyl; Each R 6 is independentlyselected from oxo, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 - C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, -(CH 2 ) n -OR 7 , -(CH 2 ) n -N(R 7 ) 2 , -(CH 2 ) n -C(O)R 7 , -(CH 2 ) n -C(O)OR 7 , - (CH 2 ) n -C(O)N(R 7 ) 2 , -(CH 2 ) n -SO 2 R 7 , C 3 -C 10 cycloalkyl, 5-10 membered heterocyclyl, -(CH 2 ) n -aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl is substituted with 0, 1, 2, or 3 substituents independently selected from with halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 - C 6 alkoxy, C 1 -C 6 haloalkoxy, and–(CH 2 ) n -SO 2 R 7 ; Each R 7 is independently selected from H, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 5-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; and p is 0, 1, 2 or 3; provided that (1) when X 1 and X 2 are each CR 5 , X 3 is N, and R is oxo in Formula 1A or 1B, then R 1 is not morpholino; and (2) when R 2 is 2-cyanobenzyl and R is oxo in Formula 1C, then R 1 is not 3-aminopiperdinyl. [010] In one embodiment, R 4 is -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, –(CH 2 ) 1-2 -C(O)OH, - C(O)O-C 1 -C 4 alkyl, –(CH 2 ) 1-2 -C(O)O-C 1 -C 4 alkyl, --C(O)NH 2 , -(CH 2 ) 1-2 -C(O)NH 2 , -C(O)N(C 1 -C 4 alkyl) 2 , -(CH 2 ) 1-2 - C(O)N(C 1 -C 4 alkyl) 2 , -C(O)NHO-C 1 -C 4 alkyl, -C(O)NH-C 1 -C 4 alkyl, -(CH 2 ) 1-2 -C(O)NH-C 1 -C 4 alkyl, C 1 - C 4 alkylsulfonyl, and 5-10 membered nitrogen containing heteroaryl. [011] In one embodiment, R 4 is -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, –(CH 2 ) 1-2 -C(O)OH, - C(O)O-C 1 -C 4 alkyl, –(CH 2 ) 1-2 -C(O)O-C 1 -C 4 alkyl, --C(O)NH 2 , -(CH 2 ) 1-2 -C(O)NH 2 , -C(O)N(C 1 -C 4 alkyl) 2 , -(CH 2 ) 1-2 - C(O)N(C 1 -C 4 alkyl) 2 , -C(O)NHO-C 1 -C 4 alkyl, and tetrazolyl. [012] In one embodiment, R 4 is -COOH. [013] In one embodiment, R 4 is selected from methylsulfonyl, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , - C(O)O CH 3 , -C(O)NHOCH 3 , -C(O)NH 2 , -C(O)NH-ethyl, -C(O)NH-isopropyl, triazolyl and tetrazolyl. [014] In one embodiment, R 6 is independently selected from H, oxo, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, -(CH 2 ) n -OR 7 , -(CH 2 ) n -N(R 7 ) 2 , -(CH 2 ) n -C(O)R 7 , -(CH 2 ) n -C (O)N(R 7 ) 2 , -(CH 2 ) n -SO 2 R 7 , C 3 - C 10 cycloalkyl, 5-10 membered heterocyclyl, -(CH 2 ) n -aryl, or 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with halogen, C 1 - C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, or –(CH 2 ) n -SO 2 R 7 ; Each R 7 is independently selected from H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 5-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl; each n is independently 0 or 1; and p is 0 or 1. [015] In one embodiment, R 6 is independently selected from oxo, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, -(CH 2 ) n -OR 7 , -(CH 2 ) n -N(R 7 ) 2 , -(CH 2 ) n -C(O)R 7 , -(CH 2 ) n -C (O)N(R 7 ) 2 , -(CH 2 ) n -SO 2 R 7 , C 3 - C 10 cycloalkyl, 5-10 membered heterocyclyl, -(CH 2 ) n -aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with halogen, C 1 - C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, or –(CH 2 ) n -SO 2 R 7 ; Each R 7 is independently selected from H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 5-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl; each n is independently 0 or 1; and p is 0 or 1. [016] In one embodiment, R 6 is selected from H, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, hydroxymethyl, methoxymethyl, methylamino, dimethylamino, methylaminomethyl, dimethylaminomethyl, methylaminocarbonyl, aminocarbonyl, methylsulfonyl, methoxy and cyclopropyl, and p is 1. [017] In one embodiment, R 6 is selected from fluoro, chloro, cyano, methyl, trifluoromethyl, hydroxymethyl, methoxymethyl, methylamino, dimethylamino, methylaminomethyl, dimethylaminomethyl, methylaminocarbonyl, aminocarbonyl, methylsulfonyl, and cyclopropyl; and p is 1. [018] In one embodiment, each R 2 , R 3 and R 5 is independently selected from H, halo, cyano, C 1 -C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 hydroxyalkyl, -(CH 2 ) n -OR 7 , -(CH 2 ) n -C(O)R 7 , phenyl- C 1 -C 6 alkyl, 5-6 membered heteroaryl-C 1 -C 6 alkyl, 5-6 membered heterocyclyl- C 1 -C 6 alkyl, C 5 -C 6 cycloalkyl- C 1 -C 6 alkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl, C 5 -C 6 cycloalkyl, C 1 -C 6 alkylamino- C 1 -C 6 alkyl, amino- C 1 -C 6 alkyl, C 1 -C 6 alkoxy- C 1 -C 6 alkyl, carboxy C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonyl C 1 -C 6 alkyl, aminocarbonylalkyl and C 1 -C 6 alkylaminocarbonyl- C 1 -C 6 alkyl; R 7 is selected from H, C 1 -C 3 alkyl, C 3 - C 6 cycloalkyl, 5-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl; and n is 0, 1 or 2. [019] In one embodiment, R 2 is selected from H, cyano, fluoro, chloro, C 1 -C 3 alkyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, -(CH 2 ) n -OR 7 , -(CH 2 ) n -C(O)R 7 , C 3 -C 10 cycloalkyl, phenyl and 5-6 membered heteroaryl; R 7 is selected from methyl, ethyl, cyclohexyl, and phenyl; and n is 0 or 1. [020] In one embodiment, R 2 is selected from H, fluoro, chloro, cyano, methyl, ethyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy, benzyl, phenyl, and cyclopropyl. [021] In one embodiment, R 2 is H, fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, benzyl, phenyl, or cyclopropyl. [022] In one embodiment, R 3 is H, cyano, fluoro, chloro, C 1 -C 3 alkyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, -(CH 2 ) n -OR 7 , -(CH 2 ) n -C(O)R 7 , C 3 -C 6 cycloalkyl, phenyl and 5-6 membered heteroaryl; R 7 is selected from methyl, ethyl, cyclohexyl, and phenyl; and n is 0 or 1. [023] In one embodiment, R 3 is selected from H, fluoro, chloro, cyano, methylsulfonyl, hydroxymethyl, methoxy, methyl, trifluoromethyl and cyclopropyl. [024] In one embodiment, R 3 is H, fluoro, chloro, methyl or trifluoromethyl. [025] In one embodiment, R 5 is H, cyano, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl. [026] In one embodiment, R 5 is selected from H, fluoro, chloro, cyano, methyl, trifluoromethyl, methoxy and cyclopropyl. [027] In one embodiment, R 5 is H, fluoro, chloro, methyl or trifluoromethyl. [028] In one embodiment, R 5 is H. [029] In one embodiment, R together with R 2 and the carbon and nitrogen to which they are attached forms a triazolyl ring. [030] In one embodiment, R is oxo. [031] In one embodiment, R is selected from hydroxy, methoxy, ethoxy, -OCH 2 CF 3 , OCH 2 CF 2 H, OCH 2 CFH 2 and OCF 3 . [032] In one embodiment, R 1 is selected from 5-10 membered nitrogen containing heteroaryl, 4-10 membered nitrogen containing heterocyclyl, 4-10 membered oxygen containing heterocyclyl, 6-10 membered aryl, C 4 -C 6 cycloalkenyl and C 3 -C 6 cycloalkyl; wherein the nitrogen containing heteroaryl, nitrogen containing heterocyclyl, aryl, cycloalkenyl or cycloalkyl is substituted with 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 -C 3 alkyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, hydroxy, phenyl, aralkyl, C 3-6 -cycloalkyl and C 1 -C 3 hydroxyalkyl. [033] In one embodiment, R 1 is selected from 5-10 membered nitrogen containing heteroaryl, 5-10 membered nitrogen containing heterocyclyl, 6-10 membered aryl, C 4 -C 6 cycloalkenyl and C 3 -C 6 cycloalkyl; wherein the nitrogen containing heteroaryl, nitrogen containing heterocyclyl, aryl, cycloalkenyl or cycloalkyl is substituted with 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 -C 3 alkyl, C 1 -C 2 haloalkyl, C 1 - C 4 alkoxy, hydroxy, phenyl, aralkyl, C 3 - 6 -cycloalkyl and C 1 -C 3 hydroxyalkyl. [034] In one embodiment, R 1 is selected from 1-piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, 2- tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1- imidazolinyl, 1-imidazolidinyl, 2-tetrahydronaphthyridinyl, 2-isoindolinyl, dihydroindolyl, 2-tetrahydroisoquinolinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, oxetanyl, tetrahydrofuranyl, and 1-azetidinyl; wherein R 1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, methyl,, difluoromethyl, trifluormethyl, hydroxy, methoxy, ethoxy, , methylsulfonyl, carboxyl, amino, dimethylamino, Boc, and a ring independently selected from morpholinyl, pyrazolyl, 1-methyl-4-pyrazolyl, benzyl, phenyl, 3-pyridinyl, pyrimidinyl, 2-methoxy-4-pyrmidinyl, 5-methoxy-4- pyrmidinyl, 1,3,6-triazanaphth-5-yl, 1-thia-4,6-diazainden-7-yl and cyclopropyl, wherein the ring is unsubstituted or substituted. [035] In one embodiment, R 1 is selected from 1-piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, 2- tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1- imidazolinyl, 1-imidazolidinyl, and 1-azetidinyl; wherein R 1 is substituted with 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, benzyl, phenyl, and cyclopropyl. [036] In one embodiment, R 1 is selected from pyridyl, pyrimidinyl, pyrazolyl, thienyl, oxazolyl, thiazolyl, imidazolyl, quinolinyl, 2-isoindolyl, indolyl, indazolyl, benzothiazolyl, benzofuryl, phenyl and naphthyl, cyclohexenyl, cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, and cyclohexyl; wherein the ring has one, two or three substituents independently selected from halo, cyano, C 1 -C 3 alkyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, hydroxy, phenyl, aralkyl, C 3-6 -cycloalkyl and hydroxy-C 1 -C 3 alkyl. [037] In one embodiment, R 1 is selected from pyridyl, pyrimidinyl, pyrazolyl, thienyl, oxazolyl, imidazolyl, quinolinyl, phenyl and naphthyl, cyclohexenyl and cyclohexyl; wherein the ring has one, two or three substituents independently selected from halo, cyano, C 1 -C 3 alkyl, C 1 -C 2 haloalkyl, C 1 - C 4 alkoxy, hydroxy, phenyl, aralkyl, C 3 - 6 -cycloalkyl and hydroxy-C 1 -C 3 alkyl. [038] In one embodiment, R 1 is selected from C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 - C 2 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , -C(O)NR 1b R 1b , - NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , -NR 1a S(O) 2 R 1a ; -S(O) 2 R 1a , benzyl, and pyridylmethyl; each R 1a is independently selected from H, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C 3-6 - cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -(CH 2 ) n -SO 2 R 7 ; each R 1b is independently selected from H, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C 3 - 6 - cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -(CH 2 ) n -SO 2 R 7 ; and when R 1 is -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , or NR 1a S(O) 2 NR 1b R 1b , two R 1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 0, 1, 2, or 3 substituents independently selected from halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 . [039] In one embodiment, R 1 is selected from C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, and C 1 -C 3 haloalkyl. [040] In one embodiment, R 7 is selected from H, C 1 -C 2 alkyl, C 5 -C 6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl. [041] In one embodiment, R 7 is selected from methyl, ethyl and phenyl. [042] In one embodiment, L is -NH-C 1 -C 4 alkylene, or -C 1 -C 4 alkylene-NH-; wherein each alkylene group is substituted with 0-4 substituents independently selected from halo, cyano and C 1 -C 2 alkoxy. [043] In one embodiment, L is selected from ethylenyl, 1-methylethylenyl, -NH-CH 2 - and -NHCH(CH 3 )- , and wherein the ethylenyl, or -NHCH 2 - group is optionally substituted with 1-4 substituents independently selected from fluoro, cyano and methoxy. [044] In one embodiment, L is C 3 -C 10 cycloalkyl, 5-10 membered heteroaryl or 5-6 membered heterocyclyl. [045] In one embodiment, A is a ring selected from 5-6 membered heterocyclyl and C 3 -C 6 cycloalkyl. [046] In one embodiment, A is 5-10 membered heteroaryl or phenyl. [047] In one embodiment, A is selected from phenyl, pyridyl, benzimidazolyl, benzothienyl, pyrazinyl and pyrimidinyl. [048] In one embodiment, A is selected from phenyl, pyridyl, benzothienyl, pyrazinyl and pyrimidinyl. [049] In one embodiment, A is selected from phenyl, 3-pyridyl and 2-pyridyl. [050] In one embodiment, X 1 and X 2 are each -CR 5 - and X 3 is N. [051] In one embodiment, X 1 and X 2 are each -N- and X 3 is N. [052] In one embodiment, X 1 is -CR 5 - , X 2 is -N- and X 3 is N. [053] In one embodiment, X 1 is -N-, X 2 is -CR 5 - and X 3 is N. [054] In one embodiment, X 1 and X 2 are each -CR 5 - and X 3 is -CR 5 - . [055] In one embodiment, X 1 and X 2 are each -N- and X 3 is -CR 5 -. [056] In one embodiment, X 1 is -CR 5 -, X 2 is -N- and X 3 is -CR 5 -. [057] In one embodiment, X 1 is -N-, X 2 is -CR 5 - and X 3 is -CR 5 -. [058] One aspect of the invention relates to compounds having a structure of Formula 2a or 2b, or a pharmaceutically acceptable salt thereof: Wherein R is oxo; wherein: R is -OR x ; R x is selected from H, methyl, ethyl, -CH 2 CF 3 , CH 2 CF 2 H, CH 2 CFH 2 and CF 3 ; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 2 -C 4 alkenyl, C 2 - C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , - C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , NR 1a S(O) 2 R 1a ; -S(O) 2 R 1a , benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3-6 -cycloalkyl-C 1 -C 4 alkyl, phenyl, naphthyl, C 5 - C 6 cycloalkenyl, C 3 -C 6 -cycloalkyl, 5-10 membered nitrogen containing heteroaryl, 4-10 membered oxygen containing heterocyclyl and 4-10 membered nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C 1 -C 6 hydroxyalkyl; R 1a and R 1b are each independently selected from H, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C 3 - 6 - cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 - C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; when R 1 is -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , or NR 1a S(O) 2 NR 1b R 1b , two R 1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 - C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 2 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; or when R is oxo, R 1 and R 2 together with the nitrogen and carbon atoms to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 3 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 3 - C 6 cycloalkyl; L is C 1 -C 4 alkylene, -NH-C 1 -C 4 alkylene, or -C 1 -C 4 alkylene-NH- , and the alkylene group is optionally substituted with 1-4 substituents independently selected from halo, cyano and C 1 -C 4 alkoxy; R 4 is selected from H, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, –(CH 2 ) 1-2 -C(O)OH, -C(O)O-C 1 - C 4 alkyl, –(CH 2 ) 1-2 -C(O)O-C 1 -C 4 alkyl, --C(O)NH 2 , -(CH 2 ) 1-2 -C(O)NH 2 , -C(O)N(C 1 -C 4 alkyl) 2 , -(CH 2 ) 1-2 - C(O)N(C 1 -C 4 alkyl) 2 , -C(O)NHO-C 1 -C 4 alkyl, -C(O)NH-C 1 -C 4 alkyl, -(CH 2 ) 1-2 -C(O)NH-C 1 -C 4 alkyl, C 1 - C 4 alkylsulfonyl, and 5-membered nitrogen containing heteroaryl; R 5 is selected from H, halo, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; Each R 6 is independently selected from H, halo, cyano, C 1 -C 4 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl- C 1 -C 4 alkyl, phenyl, heteroaryl, heterocyclyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkylamino- C 1 -C 4 alkyl, amino- C 1 -C 4 alkyl, and C 1 -C 4 alkoxy-C 1 -C 4 alkyl; R 7 is selected from H, C 1 -C 2 alkyl, C 5 -C 6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; and p is 0, 1, 2 or 3 [059] In one embodiment, R is -OR x ; R x is selected from H, methyl, ethyl, -CH 2 CF 3 , CH 2 CF 2 H, CH 2 CFH 2 and CF 3 ; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , - SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , - S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , NR 1a S(O) 2 R 1a ; -S(O) 2 R 1a , benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 - C 4 alkyl, C 3 - 8 cycloalkyl-C 1 -C 4 alkyl, phenyl, naphthyl, C 5 -C 6 cycloalkenyl, C 5 -C 6 cycloalkyl, nitrogen containing heteroaryl, and nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C 1 -C 6 hydroxyalkyl; R 1a and R 1b are each independently selected from H, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C 3-6 - cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; when R 1 is -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , or NR 1a S(O) 2 NR 1b R 1b , two R 1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 2 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; R 3 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 3 - C 6 cycloalkyl; L is C 1 -C 4 alkylene, -NH-C 1 -C 4 alkylene, or -C 1 -C 4 alkylene-NH- , and the alkylene group is substituted with 0-4 substituents independently selected from halo, cyano and C 1 -C 4 alkoxy; R 4 is selected from -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, –(CH 2 ) 1-2 -C(O)OH, -C(O)O- C 1 -C 4 alkyl, –(CH 2 ) 1-2 -C(O)O-C 1 -C 4 alkyl, --C(O)NH 2 , -(CH 2 ) 1-2 -C(O)NH 2 , -C(O)N(C 1 -C 4 alkyl) 2 , -(CH 2 ) 1-2 - C(O)N(C 1 -C 4 alkyl) 2 , -C(O)NHO-C 1 -C 4 alkyl, and tetrazolyl; R 5 is selected from H, halo, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; Each R 6 is independently selected from H, halo, cyano, C 1 -C 4 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl- C 1 -C 4 alkyl, phenyl, heteroaryl, heterocyclyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkylamino- C 1 - C 4 alkyl, amino- C 1 -C 4 alkyl, and C 1 -C 4 alkoxy-C 1 -C 4 alkyl; R 7 is selected from H, C 1 -C 2 alkyl, C 5 -C 6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; and p is 0, 1, 2 or 3. [060] In one embodiment, R is oxo or methoxy; R 1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2- hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl- 2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1- piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, indolyl, indazolyl, benzothiazolyl, benzofuryl, dihydroindolyl, 2-tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1- imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, oxetanyl, tetrahydrofuranyl, phenyl, 2-pyridyl, 3-pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, and cyclohexyl; wherein the ring substituent in R 1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, methyl, difluoromethyl, trifluormethyl, hydroxy, methoxy, ethoxy, methylsulfonyl, carboxyl, amino, dimethylamino, Boc, and a ring selected from morpholinyl, pyrazolyl, 1-methyl-4- pyrazolyl, benzyl, phenyl, 3-pyridinyl, pyrimidinyl, 2-methoxy-4-pyrmidinyl, 5-methoxy-4-pyrmidinyl, 1,3,6- triazanaphth-5-yl, 1-thia-4,6-diazainden-7-yl and cyclopropyl, wherein the ring is unsubstituted or substituted; R 2 is selected from H, fluoro, chloro, cyano, methyl, ethyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R 3 is selected from H, fluoro, chloro, cyano, methyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is selected from phenyl, 2-pyridyl, 3-pyridyl, and 1-benzimidazolyl; L is selected from ethylenyl, 1-methylethylenyl, -NH-CH 2 - and -NHCH(CH 3 )- , and wherein the ethylenyl, or - NHCH 2 - group is optionally substituted with 1-4 substituents independently selected from fluoro, cyano and methoxy; R 5 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methoxy and cyclopropyl; R 4 is selected from methylsulfonyl, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, -C(O)O-C 1 -C 4 alkyl, - C(O)NHO-C 1 -C 4 alkyl, -C(O)NH 2 , -C(O)NH-ethyl, -C(O)NH-isopropyl,triazolyl and tetrazolyl; R 6 is selected from H, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and methoxy; and p is 0 or 1. [061] In one embodiment, R is oxo or methoxy; R 1 is selected from methyl, ethyl, butyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1- piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, 2-tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1- pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, phenyl, pyridyl, pyrimidinyl and cyclohexyl; wherein the ring substituent in R 1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, benzyl, phenyl, and cyclopropyl; R 2 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R 3 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is phenyl or pyridyl; L is selected from ethylenyl, 1-methylethylenyl, -NH-CH 2 - and -NHCH(CH 3 )- , and wherein the ethylenyl, or -NHCH 2 - group is substituted with 0-4 substituents independently selected from fluoro, cyano and methoxy; R 5 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methoxy and cyclopropyl; R 4 is selected from -SO 3 H, - PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, -C(O)O-C 1 -C 4 alkyl, -C(O)NHO-C 1 -C 4 alkyl and tetrazolyl; R 6 is selected from H, fluoro, chloro, bromo, cyano, C 1 -C 4 alkyl, trifluoromethyl, and methoxy; and p is 0 or 1. [062] In one embodiment, R 4 is -COOH. [063] In one embodiment, R is oxo; A is benzotriazolyl and R 4 is H. [064] One aspect of the invention relates to compounds having a structure of Formula 3a or 3b, or a pharmaceutically acceptable salt thereof: Wherein R is oxo wherein: R is -OR x ; R x is selected from H, methyl, ethyl, -CH 2 CF 3 , CH 2 CF 2 H, CH 2 CFH 2 and CF 3 ; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 2 -C 4 alkenyl, C 2 - C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , - C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , NR 1a S(O) 2 R 1a ; -S(O) 2 R 1a , benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3-6 -cycloalkyl-C 1 -C 4 alkyl, phenyl, naphthyl, C 5 - C 6 cycloalkenyl, C 3 -C 6 cycloalkyl, 5-10 membered nitrogen containing heteroaryl, 4-10 membered oxygen containing heterocyclyl and 4-10 membered nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C 1 -C 6 hydroxyalkyl; R 1a and R 1b are each independently selected from H, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C 3 - 6 - cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 - C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; when R 1 is -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , or NR 1a S(O) 2 NR 1b R 1b , two R 1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 - C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 2 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; or when R is oxo, R 1 and R 2 together with the nitrogen and carbon atoms to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 3 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 3 - C 6 cycloalkyl; L is C 1 -C 4 alkylene, -NH-C 1 -C 4 alkylene, or -C 1 -C 4 alkylene-NH- , and the alkylene group is optionally substituted with 1-4 substituents independently selected from halo, cyano and C 1 -C 4 alkoxy; R 4 is selected from -H, SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, –(CH 2 ) 1-2 -C(O)OH, -C(O)O-C 1 - C 4 alkyl, –(CH 2 ) 1-2 -C(O)O-C 1 -C 4 alkyl, --C(O)NH 2 , -(CH 2 ) 1-2 -C(O)NH 2 , -C(O)N(C 1 -C 4 alkyl) 2 , -(CH 2 ) 1-2 - C(O)N(C 1 -C 4 alkyl) 2 , -C(O)NHO-C 1 -C 4 alkyl, -C(O)NH-C 1 -C 4 alkyl, -(CH 2 ) 1-2 -C(O)NH-C 1 -C 4 alkyl, C 1 - C 4 alkylsulfonyl, and 5-membered nitrogen containing heteroaryl; R 5 is selected from H, halo, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; Each R 6 is independently selected from H, halo, cyano, C 1 -C 4 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl- C 1 -C 4 alkyl, phenyl, heteroaryl, heterocyclyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkylamino- C 1 -C 4 alkyl, amino- C 1 -C 4 alkyl, and C 1 -C 4 alkoxy-C 1 -C 4 alkyl; R 7 is selected from H, C 1 -C 2 alkyl, C 5 -C 6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; and p is 0, 1, 2 or 3. [065] In one embodiment, R is -OR x ; R x is selected from H, methyl, ethyl, -CH 2 CF 3 , CH 2 CF 2 H, CH 2 CFH 2 and CF 3 ; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , - SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , - S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , NR 1a S(O) 2 R 1a ; -S(O) 2 R 1a , benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 - C 4 alkyl, C 3-8 cycloalkyl-C 1 -C 4 alkyl, phenyl, naphthyl, C 5 -C 6 cycloalkenyl, C 5 -C 6 cycloalkyl, nitrogen containing heteroaryl, and nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C 1 -C 6 hydroxyalkyl; R 1a and R 1b are each independently selected from H, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C 3-6 - cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; when R 1 is -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , or NR 1a S(O) 2 NR 1b R 1b , two R 1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 2 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; R 3 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 3 - C 6 cycloalkyl; L is C 1 -C 4 alkylene, -NH-C 1 -C 4 alkylene, or -C 1 -C 4 alkylene-NH- , and the alkylene group is substituted with 0-4 substituents independently selected from halo, cyano and C 1 -C 4 alkoxy; R 4 is selected from -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, –(CH 2 ) 1-2 -C(O)OH, -C(O)O- C 1 -C 4 alkyl, –(CH 2 ) 1-2 -C(O)O-C 1 -C 4 alkyl, --C(O)NH 2 , -(CH 2 ) 1-2 -C(O)NH 2 , -C(O)N(C 1 -C 4 alkyl) 2 , -(CH 2 ) 1-2 - C(O)N(C 1 -C 4 alkyl) 2 , -C(O)NHO-C 1 -C 4 alkyl, and tetrazolyl; R 5 is selected from H, halo, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; Each R 6 is independently selected from H, halo, cyano, C 1 -C 4 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl- C 1 -C 4 alkyl, phenyl, heteroaryl, heterocyclyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkylamino- C 1 - C 4 alkyl, amino- C 1 -C 4 alkyl, and C 1 -C 4 alkoxy-C 1 -C 4 alkyl; R 7 is selected from H, C 1 -C 2 alkyl, C 5 -C 6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; and p is 0, 1, 2 or 3. [066] In one embodiment, R is oxo or methoxy; R 1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2- hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl- 2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1- piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, indolyl, indazolyl, benzothiazolyl, benzofuryl, dihydroindolyl, 2-tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1- imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, oxetanyl, tetrahydrofuranyl, phenyl, 2-pyridyl, 3-pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, and cyclohexyl; wherein the ring substituent in R 1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, methyl, difluoromethyl, trifluormethyl, hydroxy, methoxy, ethoxy, methylsulfonyl, carboxyl, amino, dimethylamino, Boc, and a ring selected from morpholinyl, pyrazolyl, 1-methyl-4- pyrazolyl, benzyl, phenyl, 3-pyridinyl, pyrimidinyl, 2-methoxy-4-pyrmidinyl, 5-methoxy-4-pyrmidinyl, 1,3,6- triazanaphth-5-yl, 1-thia-4,6-diazainden-7-yl and cyclopropyl, wherein the ring is unsubstituted or substituted; R 2 is selected from H, fluoro, chloro, cyano, methyl, ethyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R 3 is selected from H, fluoro, chloro, cyano, methyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is selected from phenyl, 2-pyridyl, 3-pyridyl, and 1-benzimidazolyl; L is selected from ethylenyl, 1-methylethylenyl, -NH-CH 2 - and -NHCH(CH 3 )- , and wherein the ethylenyl, or - NHCH 2 - group is optionally substituted with 1-4 substituents independently selected from fluoro, cyano and methoxy; R 5 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methoxy and cyclopropyl; R 4 is selected from methylsulfonyl, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, -C(O)O-C 1 -C 4 alkyl, - C(O)NHO-C 1 -C 4 alkyl, -C(O)NH 2 , -C(O)NH-ethyl, -C(O)NH-isopropyl,triazolyl and tetrazolyl; R 6 is selected from H, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and methoxy; and p is 0 or 1 [067] In one embodiment, R is oxo or methoxy; R 1 is selected from methyl, ethyl, butyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1- piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, 2-tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1- pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, phenyl, pyridyl, pyrimidinyl and cyclohexyl; wherein the ring substituent in R 1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, benzyl, phenyl, and cyclopropyl; R 2 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R 3 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is phenyl or pyridyl; L is selected from ethylenyl, 1-methylethylenyl, -NH-CH 2 - and -NHCH(CH 3 )- , and wherein the ethylenyl or -NHCH 2 - group is substituted with 0-4 substituents independently selected from fluoro, cyano and methoxy; R 5 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methoxy and cyclopropyl; R 4 is selected from -SO 3 H, - PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, -C(O)O-C 1 -C 4 alkyl, -C(O)NHO-C 1 -C 4 alkyl and tetrazolyl; R 6 is selected from H, fluoro, chloro, bromo, cyano, C 1 -C 4 alkyl, trifluoromethyl, and methoxy; and p is 0 or 1. [068] In one embodiment, R 4 is -COOH. [069] One aspect of the invention relates to compounds having a structure of Formula 4a or 4b, or a pharmaceutically acceptable salt thereof: Wherein R is oxo wherein: R is -OR x ; R x is selected from H, methyl, ethyl, -CH 2 CF 3 , CH 2 CF 2 H, CH 2 CFH 2 and CF 3 ; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , - C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , NR 1a S(O) 2 R 1a ; -S(O) 2 R 1a , benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3 - 6 -cycloalkyl-C 1 -C 4 alkyl, phenyl, naphthyl, C 5 - C 6 cycloalkenyl, C 3 -C 6 cycloalkyl, 5-10 membered nitrogen containing heteroaryl, 4-10 membered oxygen containing heterocyclyl; and 4-10 membered nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C 1 -C 6 hydroxyalkyl; R 1a and R 1b are each independently selected from H, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C 3-6 - cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; when R 1 is -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , or NR 1a S(O) 2 NR 1b R 1b , two R 1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 2 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; or when R is oxo, R 1 and R 2 together with the nitrogen and carbon atoms to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 - C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 3 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 3 - C 6 cycloalkyl; L is C 1 -C 4 alkylene, -NH-C 1 -C 4 alkylene, or -C 1 -C 4 alkylene-NH- , and the alkylene group is optionally substituted with 1-4 substituents independently selected from halo, cyano and C 1 -C 4 alkoxy; R 4 is selected from H, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, –(CH 2 ) 1-2 -C(O)OH, - C(O)O-C 1 -C 4 alkyl, –(CH 2 ) 1-2 -C(O)O-C 1 -C 4 alkyl, --C(O)NH 2 , -(CH 2 ) 1-2 -C(O)NH 2 , -C(O)N(C 1 -C 4 alkyl) 2 , -(CH 2 ) 1-2 - C(O)N(C 1 -C 4 alkyl) 2 , -C(O)NHO-C 1 -C 4 alkyl, -C(O)NH-C 1 -C 4 alkyl, -(CH 2 ) 1-2 -C(O)NH-C 1 -C 4 alkyl, C 1 - C 4 alkylsulfonyl, and 5-membered nitrogen containing heteroaryl; Each R 6 is independently selected from H, halo, cyano, C 1 -C 4 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl- C 1 -C 4 alkyl, phenyl, heteroaryl, heterocyclyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkylamino- C 1 - C 4 alkyl, amino- C 1 -C 4 alkyl, and C 1 -C 4 alkoxy-C 1 -C 4 alkyl; R 7 is selected from H, C 1 -C 2 alkyl, C 5 -C 6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; and p is 0, 1, 2 or 3. [070] In one embodiment, R is -OR x ; R x is selected from H, methyl, ethyl, CH 2 CF 3 , CH 2 CF 2 H, CH 2 CFH 2 and CF 3 ; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , - S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , NR 1a S(O) 2 R 1a ; -S(O) 2 R 1a , benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 - C 4 alkyl, C 3 - 8 cycloalkyl-C 1 -C 4 alkyl, phenyl, naphthyl, C 5 -C 6 cycloalkenyl, C 5 -C 6 cycloalkyl, nitrogen containing heteroaryl, and nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C 1 -C 6 hydroxyalkyl; R 1a and R 1b are each independently selected from H, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C 3-6 - cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; when R 1 is -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , or NR 1a S(O) 2 NR 1b R 1b , two R 1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 2 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; R 3 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 3 - C 6 cycloalkyl, L is C 1 -C 4 alkylene, -NH-C 1 -C 4 alkylene, or -C 1 -C 4 alkylene-NH-, and the alkylene group is substituted with 0-4 substituents independently selected from halo, cyano and C 1 -C 4 alkoxy; R 4 is selected from -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, –(CH 2 ) 1-2 -C(O)OH, -C(O)O- C 1 -C 4 alkyl, –(CH 2 ) 1-2 -C(O)O-C 1 -C 4 alkyl, --C(O)NH 2 , -(CH 2 ) 1-2 -C(O)NH 2 , -C(O)N(C 1 -C 4 alkyl) 2 , -(CH 2 ) 1-2 - C(O)N(C 1 -C 4 alkyl) 2 , -C(O)NHO-C 1 -C 4 alkyl, and tetrazolyl; Each R 6 is independently selected from H, halo, cyano, C 1 -C 4 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl- C 1 -C 4 alkyl, phenyl, heteroaryl, heterocyclyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkylamino- C 1 - C 4 alkyl, amino- C 1 -C 4 alkyl, and C 1 -C 4 alkoxy-C 1 -C 4 alkyl; R 7 is selected from H, C 1 -C 2 alkyl, C 5 -C 6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; and p is 0, 1, 2 or 3. [071] In one embodiment, R is oxo or methoxy; R 1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2- hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl- 2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1- piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, indolyl, indazolyl, benzothiazolyl, benzofuryl, dihydroindolyl, 2-tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1- imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, oxetanyl, tetrahydrofuranyl, phenyl, 2-pyridyl, 3-pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, and cyclohexyl; wherein the ring substituent in R 1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, methyl, difluoromethyl, trifluormethyl, hydroxy, methoxy, ethoxy, methylsulfonyl, carboxyl, amino, dimethylamino, Boc, and a ring selected from morpholinyl, pyrazolyl, 1-methyl-4- pyrazolyl, benzyl, phenyl, 3-pyridinyl, pyrimidinyl, 2-methoxy-4-pyrmidinyl, 5-methoxy-4-pyrmidinyl, 1,3,6- triazanaphth-5-yl, 1-thia-4,6-diazainden-7-yl and cyclopropyl, wherein the ring is unsubstituted or substituted; R 2 is selected from H, fluoro, chloro, cyano, methyl, ethyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R 3 is selected from H, fluoro, chloro, cyano, methyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is selected from phenyl, 2-pyridyl, 3-pyridyl, and 1-benzimidazolyl; L is selected from ethylenyl, 1-methylethylenyl, -NH-CH 2 - and -NHCH(CH 3 )- , and wherein the ethylenyl, or - NHCH 2 - group is optionally substituted with 1-4 substituents independently selected from fluoro, cyano and methoxy; R 5 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methoxy and cyclopropyl; R 4 is selected from methylsulfonyl, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, -C(O)O-C 1 -C 4 alkyl, - C(O)NHO-C 1 -C 4 alkyl, -C(O)NH 2 , -C(O)NH-ethyl, -C(O)NH-isopropyl,triazolyl and tetrazolyl; R 6 is selected from H, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and methoxy; and p is 0 or 1. [072] In one embodiment, R is oxo or methoxy; R 1 is selected from methyl, ethyl, butyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1- piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, 2-tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1- pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, phenyl, pyridyl, pyrimidinyl and cyclohexyl; wherein the ring substituent in R 1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, benzyl, phenyl, and cyclopropyl; R 2 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R 3 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is phenyl or pyridyl; L is selected from ethylenyl, 1-methylethylenyl, -NH-CH 2 - and -NHCH(CH 3 )- , and wherein the ethylenyl or -NHCH 2 - group is substituted with 0-4 substituents independently selected from fluoro, cyano and methoxy; R 4 is selected from - SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, -C(O)O-C 1 -C 4 alkyl, -C(O)NHO-C 1 -C 4 alkyl, and tetrazolyl; R 6 is selected from H, fluoro, chloro, bromo, cyano, C 1 -C 4 alkyl, trifluoromethyl, and methoxy; and p is 0 or 1 [073] In one embodiment, R 4 is -COOH. [074] One aspect of the invention relates to compounds having a structure of Formula 5a or 5b, or a pharmaceutically acceptable salt thereof: Wherein R is oxo;

wherein: R is -OR x ; R x is selected from H, methyl, ethyl, -CH 2 CF 3 , CH 2 CF 2 H, CH 2 CFH 2 and CF 3 ; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , - C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , NR 1a S(O) 2 R 1a ; -S(O) 2 R 1a , benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3-8 -cycloalkyl-C 1 -C 4 alkyl, phenyl, naphthyl, C 5 - C 6 cycloalkenyl, C 3 -C 6 cycloalkyl, 5-10 membered nitrogen containing heteroaryl, 4-10 membered oxygen containing heterocyclyl; and 4-10 membered nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C 1 -C 6 hydroxyalkyl; R 1a and R 1b are each independently selected from H, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C 3-6 - cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; when R 1 is -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , or NR 1a S(O) 2 NR 1b R 1b , two R 1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 2 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; or when R is oxo, R 1 and R 2 together with the nitrogen and carbon atoms to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 - C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 3 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 3 - C 6 cycloalkyl; L is C 1 -C 4 alkylene, -NH-C 1 -C 4 alkylene, or -C 1 -C 4 alkylene-NH- , and the alkylene group is optionally substituted with 1-4 substituents independently selected from halo, cyano and C 1 -C 4 alkoxy; R 4 is selected from H, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, –(CH 2 ) 1-2 -C(O)OH, - C(O)O-C 1 -C 4 alkyl, –(CH 2 ) 1-2 -C(O)O-C 1 -C 4 alkyl, --C(O)NH 2 , -(CH 2 ) 1-2 -C(O)NH 2 , -C(O)N(C 1 -C 4 alkyl) 2 , -(CH 2 ) 1-2 - C(O)N(C 1 -C 4 alkyl) 2 , -C(O)NHO-C 1 -C 4 alkyl, -C(O)NH-C 1 -C 4 alkyl, -(CH 2 ) 1-2 -C(O)NH-C 1 -C 4 alkyl, C 1 - C 4 alkylsulfonyl, and 5-membered nitrogen containing heteroaryl; Each R 6 is independently selected from H, halo, cyano, C 1 -C 4 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl- C 1 -C 4 alkyl, phenyl, heteroaryl, heterocyclyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkylamino- C 1 - C 4 alkyl, amino- C 1 -C 4 alkyl, and C 1 -C 4 alkoxy-C 1 -C 4 alkyl; R 7 is selected from H, C 1 -C 2 alkyl, C 5 -C 6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; and p is 0, 1, 2 or 3. [075] In one embodiment, R is -OR x ; R x is selected from H, methyl, ethyl, CH 2 CF 3 , CH 2 CF 2 H, CH 2 CFH 2 and CF 3 ; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , - S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , NR 1a S(O) 2 R 1a ; -S(O) 2 R 1a , benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 - C 4 alkyl, C 3-8 cycloalkyl-C 1 -C 4 alkyl, phenyl, naphthyl, C 5 -C 6 cycloalkenyl, C 5 -C 6 cycloalkyl, nitrogen containing heteroaryl, and nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C 1 -C 6 hydroxyalkyl; R 1a and R 1b are each independently selected from H, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C 3-6 - cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -(CH 2 ) n - SO 2 R 7 ; when R 1 is -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , or NR 1a S(O) 2 NR 1b R 1b , two R 1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 2 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; R 3 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 3 - C 6 cycloalkyl, L is C 1 -C 4 alkylene, -NH-C 1 -C 4 alkylene, or -C 1 -C 4 alkylene-NH-, and wherein the alkylene group is substituted with 0-4 substituents selected from halo, cyano and C 1 -C 4 alkoxy; R 4 is selected from -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , , -C(O)OH, –(CH 2 ) 1-2 -C(O)OH, -C(O)O- C 1 -C 4 alkyl, –(CH 2 ) 1-2 -C(O)O-C 1 -C 4 alkyl, --C(O)NH 2 , -(CH 2 ) 1-2 -C(O)NH 2 , -C(O)N(C 1 -C 4 alkyl) 2 , -(CH 2 ) 1-2 - C(O)N(C 1 -C 4 alkyl) 2 , -C(O)NHO-C 1 -C 4 alkyl, and tetrazolyl; Each R 6 is independently selected from H, halo, cyano, C 1 -C 4 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl- C 1 -C 4 alkyl, phenyl, heteroaryl, heterocyclyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkylamino- C 1 - C 4 alkyl, amino- C 1 -C 4 alkyl, and C 1 -C 4 alkoxy-C 1 -C 4 alkyl; R 7 is selected from H, C 1 -C 2 alkyl, C 5 -C 6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; and p is 0, 1, 2 or 3. [076] In one embodiment, R is oxo or methoxy; R 1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2- hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl- 2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1- piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, indolyl, indazolyl, benzothiazolyl, benzofuryl, dihydroindolyl, 2-tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1- imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, oxetanyl, tetrahydrofuranyl, phenyl, 2-pyridyl, 3-pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, and cyclohexyl; wherein the ring substituent in R 1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, methyl, difluoromethyl, trifluormethyl, hydroxy, methoxy, ethoxy, methylsulfonyl, carboxyl, amino, dimethylamino, Boc, and a ring selected from morpholinyl, pyrazolyl, 1-methyl-4- pyrazolyl, benzyl, phenyl, 3-pyridinyl, pyrimidinyl, 2-methoxy-4-pyrmidinyl, 5-methoxy-4-pyrmidinyl, 1,3,6- triazanaphth-5-yl, 1-thia-4,6-diazainden-7-yl and cyclopropyl, wherein the ring is unsubstituted or substituted; R 2 is selected from H, fluoro, chloro, cyano, methyl, ethyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R 3 is selected from H, fluoro, chloro, cyano, methyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is selected from phenyl, 2-pyridyl, 3-pyridyl, and 1-benzimidazolyl; L is selected from ethylenyl, 1-methylethylenyl, -NH-CH 2 - and -NHCH(CH 3 )- , and wherein the ethylenyl, or - NHCH 2 - group is optionally substituted with 1-4 substituents independently selected from fluoro, cyano and methoxy; R 5 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methoxy and cyclopropyl; R 4 is selected from methylsulfonyl, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, -C(O)O-C 1 -C 4 alkyl, - C(O)NHO-C 1 -C 4 alkyl, -C(O)NH 2 , -C(O)NH-ethyl, -C(O)NH-isopropyl,triazolyl and tetrazolyl; R 6 is selected from H, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and methoxy; and p is 0 or 1. [077] In one embodiment, R is oxo or methoxy; methyl, ethyl, butyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1-piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, 2-tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2- pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, phenyl, pyridyl, pyrimidinyl and cyclohexyl; wherein the ring substituent in R 1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, benzyl, phenyl, and cyclopropyl; R 2 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R 3 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is phenyl or pyridyl; L is selected from ethylenyl, 1-methylethylenyl, - NH-CH 2 - and -NHCH(CH 3 )- , and wherein the ethylenyl or -NHCH 2 - group is substituted with 0-4 substituents independently selected from fluoro, cyano and methoxy; R 4 is selected from -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , - SO(=NH)CH 3 , -C(O)OH, -C(O)O-C 1 -C 4 alkyl, -C(O)NHO-C 1 -C 4 alkyl and tetrazolyl; R 6 is selected from H, fluoro, chloro, bromo, cyano, C 1 -C 4 alkyl, trifluoromethyl, and methoxy; and p is 0 or 1 [078] In one embodiment, R 4 is -COOH. [079] One aspect of the invention relates to compounds having a structure of Formula 6a, 6b or 6c, or a pharmaceutically acceptable salt thereof: wherein: X 1 , X 2 , X 3 and X 4 is each independently -CR 5 - or -N-; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , - C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , NR 1a S(O) 2 R 1a ; -S(O) 2 R 1a , benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3-8 -cycloalkyl-C 1 -C 4 alkyl, phenyl, naphthyl, C 5 - C 6 cycloalkenyl, C 3 -C 6 cycloalkyl, 5-10 membered nitrogen containing heteroaryl, 4-10 membered oxygen containing heterocyclyl and 4-10 membered nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C 1 -C 6 hydroxyalkyl; R 1a and R 1b are each independently selected from H, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C 3 - 6 - cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; when R 1 is -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , or NR 1a S(O) 2 NR 1b R 1b , two R 1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 3 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 3 - C 6 cycloalkyl; L is C 1 -C 4 alkylene, -NH-C 1 -C 4 alkylene, or -C 1 -C 4 alkylene-NH- , and the alkylene group is optionally substituted with 1-4 substituents independently selected from halo, cyano and C 1 -C 4 alkoxy; R 4 is selected from H, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, –(CH 2 ) 1-2 -C(O)OH, - C(O)O-C 1 -C 4 alkyl, –(CH 2 ) 1-2 -C(O)O-C 1 -C 4 alkyl, --C(O)NH 2 , -(CH 2 ) 1-2 -C(O)NH 2 , -C(O)N(C 1 -C 4 alkyl) 2 , -(CH 2 ) 1-2 - C(O)N(C 1 -C 4 alkyl) 2 , -C(O)NHO-C 1 -C 4 alkyl, -C(O)NH-C 1 -C 4 alkyl, -(CH 2 ) 1-2 -C(O)NH-C 1 -C 4 alkyl, C 1 - C 4 alkylsulfonyl, and 5-membered nitrogen containing heteroaryl; R 5 is selected from H, halo, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; Each R 6 is independently selected from H, halo, cyano, C 1 -C 4 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl- C 1 -C 4 alkyl, phenyl, heteroaryl, heterocyclyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkylamino- C 1 - C 4 alkyl, amino- C 1 -C 4 alkyl, and C 1 -C 4 alkoxy-C 1 -C 4 alkyl; R 7 is selected from H, C 1 -C 2 alkyl, C 5 -C 6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; R 10 is selected from H, halo, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, benzyl, phenyl, substituted or unsubstituted 5-6 membered heteroaryl, and cyclopropyl; and p is 0, 1, 2 or 3. [080] One aspect of the invention relates to compounds having a structure of Formula 6a or 6b, or a pharmaceutically acceptable salt thereof: wherein: X 1 , X 2 , X 3 and X 4 is each independently -CR 5 - or -N-; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , - S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , NR 1a S(O) 2 R 1a ; -S(O) 2 R 1a , benzyl, heteroaryl- C 1 -C 6 alkyl, heterocyclyl- C 1 - C 6 alkyl, cycloalkyl- C 1 -C 6 alkyl, phenyl, naphthyl, C 5 -C 6 cycloalkenyl, C 5 -C 6 cycloalkyl, 5-10 membered nitrogen containing heteroaryl, and 5-10 membered nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C 1 -C 6 hydroxyalkyl; R 1a and R 1b are each independently selected from H, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C 3 - 6 - cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; when R 1 is -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , or NR 1a S(O) 2 NR 1b R 1b , two R 1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, and C 3 - C 6 cycloalkyl, L is C 1 -C 4 alkylene, -NH-C 1 -C 4 alkylene, or -C 1 -C 4 alkylene-NH-, and wherein the alkylene group is substituted with 0-4 substituents selected from halo, cyano and C 1 -C 4 alkoxy; R 3 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; R 4 is selected from -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , , -C(O)OH, –(CH 2 ) 1-2 -C(O)OH, -C(O)O- C 1 -C 4 alkyl, –(CH 2 ) 1-2 -C(O)O-C 1 -C 4 alkyl, --C(O)NH 2 , -(CH 2 ) 1-2 -C(O)NH 2 , -C(O)N(C 1 -C 4 alkyl) 2 , -(CH 2 ) 1-2 - C(O)N(C 1 -C 4 alkyl) 2 , -C(O)NHO-C 1 -C 4 alkyl, and tetrazolyl; R 5 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; Each R 6 is independently selected from H, halo, cyano, C 1 -C 4 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl- C 1 -C 4 alkyl, phenyl, heteroaryl, heterocyclyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkylamino- C 1 - C 4 alkyl, amino- C 1 -C 4 alkyl, and C 1 -C 4 alkoxy-C 1 -C 4 alkyl; R 7 is selected from H, C 1 -C 2 alkyl, C 5 -C 6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; R 10 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; Each n is independently 0, 1 or 2; and p is 0, 1, 2 or 3. [081] In one embodiment, R 1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2-hydroxyethyl, 1,1- dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl-2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1-piperidinyl, 1- piperazinyl, 2-isoindolyl, 2-isoindolinyl, indolyl, indazolyl, benzothiazolyl, benzofuryl, dihydroindolyl, 2- tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1- imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, oxetanyl, tetrahydrofuranyl, phenyl, 2-pyridyl, 3-pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, and cyclohexyl; wherein the ring substituent in R 1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, methyl, difluoromethyl, trifluormethyl, hydroxy, methoxy, ethoxy, methylsulfonyl, carboxyl, amino, dimethylamino, Boc, and a ring selected from morpholinyl, pyrazolyl, 1-methyl-4- pyrazolyl, benzyl, phenyl, 3-pyridinyl, pyrimidinyl, 2-methoxy-4-pyrmidinyl, 5-methoxy-4-pyrmidinyl, 1,3,6- triazanaphth-5-yl, 1-thia-4,6-diazainden-7-yl and cyclopropyl, wherein the ring is unsubstituted or substituted; R 2 is selected from H, fluoro, chloro, cyano, methyl, ethyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R 3 is selected from H, fluoro, chloro, cyano, methyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is selected from phenyl, 2-pyridyl, 3-pyridyl, and 1-benzimidazolyl; L is selected from ethylenyl, 1-methylethylenyl, -NH-CH 2 - and -NHCH(CH 3 )- , and wherein the ethylenyl, or - NHCH 2 - group is optionally substituted with 1-4 substituents independently selected from fluoro, cyano and methoxy; R 5 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methoxy and cyclopropyl; R 4 is selected from methylsulfonyl, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, -C(O)O-C 1 -C 4 alkyl, - C(O)NHO-C 1 -C 4 alkyl, -C(O)NH 2 , -C(O)NH-ethyl, -C(O)NH-isopropyl,triazolyl and tetrazolyl; R 6 is selected from H, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and methoxy; R 10 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, ethenyl, propynyl, methoxy, 1-methyl-3-pyrazolyl, 1-methyl-4-pyrazolyl, and cyclopropyl; X 1 and X 2 are -CH-; X 3 is -N-; X 4 is -CR 5 - or -N- ; and p is 0 or 1. [082] In one embodiment, R 1 is selected from methyl, ethyl, butyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1-piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, 2-tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2- pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, phenyl, pyridyl, pyrimidinyl and cyclohexyl; wherein the ring substituent in R 1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, benzyl, phenyl, and cyclopropyl; R 3 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is phenyl or pyridyl; L is selected from ethylenyl, 1-methylethylenyl, -NH-CH 2 - and -NHCH(CH 3 )- , and wherein the ethylenyl or -NHCH 2 - group is substituted with 0-4 substituents independently selected from fluoro, cyano and methoxy; R 5 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methoxy and cyclopropyl; R 4 is selected from -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, -C(O)O-C 1 -C 4 alkyl, - C(O)NHO-C 1 -C 4 alkyl and tetrazolyl; R 6 is selected from H, fluoro, chloro, bromo, cyano, C 1 -C 4 alkyl, trifluoromethyl, and methoxy; R 10 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methoxy and cyclopropyl; and p is 0 or 1. [083] In one embodiment, R 4 is -COOH. [084] One aspect of the invention relates to compounds having a structure of Formula 7, or a pharmaceutically acceptable salt thereof: wherein: X 1 and X 2 is each independently -CR 5 - or -N-; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , - C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , NR 1a S(O) 2 R 1a ; -S(O) 2 R 1a , benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3 - 8 -cycloalkyl-C 1 -C 4 alkyl, phenyl, naphthyl, C 5 - C 6 cycloalkenyl, C 3 -C 6 cycloalkyl, 5-10 membered nitrogen containing heteroaryl, 4-10 membered oxygen containing heterocyclyl; and 4-10 membered nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C 1 -C 6 hydroxyalkyl; R 1a and R 1b are each independently selected from H, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C 3-6 - cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; when R 1 is -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , or NR 1a S(O) 2 NR 1b R 1b , two R 1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 2 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; or R 1 and R 2 together with the nitrogen and carbon atoms to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 3 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 3 - C 6 cycloalkyl; L is C 1 -C 4 alkylene, -NH-C 1 -C 4 alkylene, or -C 1 -C 4 alkylene-NH- , and the alkylene group is optionally substituted with 1-4 substituents independently selected from halo, cyano and C 1 -C 4 alkoxy; R 4 is selected from H, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, –(CH 2 ) 1-2 -C(O)OH, - C(O)O-C 1 -C 4 alkyl, –(CH 2 ) 1-2 -C(O)O-C 1 -C 4 alkyl, --C(O)NH 2 , -(CH 2 ) 1-2 -C(O)NH 2 , -C(O)N(C 1 -C 4 alkyl) 2 , -(CH 2 ) 1-2 - C(O)N(C 1 -C 4 alkyl) 2 , -C(O)NHO-C 1 -C 4 alkyl, -C(O)NH-C 1 -C 4 alkyl, -(CH 2 ) 1-2 -C(O)NH-C 1 -C 4 alkyl, C 1 - C 4 alkylsulfonyl, and 5-membered nitrogen containing heteroaryl; R 5 is selected from H, halo, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; Each R 6 is independently selected from H, halo, cyano, C 1 -C 4 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl- C 1 -C 4 alkyl, phenyl, heteroaryl, heterocyclyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkylamino- C 1 - C 4 alkyl, amino- C 1 -C 4 alkyl, and C 1 -C 4 alkoxy-C 1 -C 4 alkyl; R 7 is selected from H, C 1 -C 2 alkyl, C 5 -C 6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; and p is 0, 1, 2 or 3. [085] In one embodiment, X 1 and X 2 is each independently -CR 5 - or -N-; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , - S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , NR 1a S(O) 2 R 1a ; -S(O) 2 R 1a , benzyl, heteroaryl- C 1 -C 6 alkyl, heterocyclyl- C 1 - C 6 alkyl, cycloalkyl- C 1 -C 6 alkyl, phenyl, naphthyl, C 5 -C 6 cycloalkenyl, C 5 -C 6 cycloalkyl, nitrogen containing heteroaryl, and nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C 1 -C 6 hydroxyalkyl; R 1a and R 1b are each independently selected from H, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C 3-6 - cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; when R 1 is -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , or NR 1a S(O) 2 NR 1b R 1b , two R 1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 2 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; R 3 is selected from H, , fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 3 - C 6 cycloalkyl, L is C 1 -C 4 alkylene, -NH-C 1 -C 4 alkylene, or -C 1 -C 4 alkylene-NH-, and wherein the alkylene group is substituted with 0-4 substituents selected from halo, cyano and C 1 -C 4 alkoxy; R 4 is selected from -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, –(CH 2 ) 1-2 -C(O)OH, -C(O)O- C 1 -C 4 alkyl, –(CH 2 ) 1-2 -C(O)O-C 1 -C 4 alkyl, -C(O)NH 2 , -(CH 2 ) 1-2 -C(O)NH 2 , -C(O)N(C 1 -C 4 alkyl) 2 , -(CH 2 ) 1-2 - C(O)N(C 1 -C 4 alkyl) 2 , -C(O)NHO-C 1 -C 4 alkyl, and tetrazolyl; R 5 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; Each R 6 is independently selected from H, halo, cyano, C 1 -C 4 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl- C 1 -C 4 alkyl, phenyl, heteroaryl, heterocyclyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkylamino- C 1 - C 4 alkyl, amino- C 1 -C 4 alkyl, and C 1 -C 4 alkoxy-C 1 -C 4 alkyl; R 7 is selected from H, C 1 -C 2 alkyl, C 5 -C 6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; and p is 0, 1, 2 or 3. [086] In one embodiment, R is oxo or methoxy; R 1 is selected methyl, ethyl, isopropyl, 1,1-dimethyl-2- hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl- 2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1- piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, indolyl, indazolyl, benzothiazolyl, benzofuryl, dihydroindolyl, 2-tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1- imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, oxetanyl, tetrahydrofuranyl, phenyl, 2-pyridyl, 3-pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, and cyclohexyl; wherein the ring substituent in R 1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, methyl, difluoromethyl, trifluormethyl, hydroxy, methoxy, ethoxy, methylsulfonyl, carboxyl, amino, dimethylamino, Boc, and a ring selected from morpholinyl, pyrazolyl, 1-methyl-4- pyrazolyl, benzyl, phenyl, 3-pyridinyl, pyrimidinyl, 2-methoxy-4-pyrmidinyl, 5-methoxy-4-pyrmidinyl, 1,3,6- triazanaphth-5-yl, 1-thia-4,6-diazainden-7-yl and cyclopropyl, wherein the ring is unsubstituted or substituted; R 2 is selected from H, fluoro, chloro, cyano, methyl, ethyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R 3 is selected from H, fluoro, chloro, cyano, methyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is selected from phenyl, 2-pyridyl, 3-pyridyl, and 1-benzimidazolyl; L is selected from ethylenyl, 1-methylethylenyl, -NH-CH 2 - and -NHCH(CH 3 )- , and wherein the ethylenyl, or - NHCH 2 - group is optionally substituted with 1-4 substituents independently selected from fluoro, cyano and methoxy; R 5 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methoxy and cyclopropyl; R 4 is selected from methylsulfonyl, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, -C(O)O-C 1 -C 4 alkyl, - C(O)NHO-C 1 -C 4 alkyl, -C(O)NH 2 , -C(O)NH-ethyl, -C(O)NH-isopropyl,triazolyl and tetrazolyl; R 6 is selected from H, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and methoxy; X 1 and X 2 are -CH-; and p is 0 or 1. [087] In one embodimwent, R 1 is selected from methyl, ethyl, butyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1-piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, 2-tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2- pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, phenyl, pyridyl, pyrimidinyl and cyclohexyl; wherein the ring substituent in R 1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, benzyl, phenyl, and cyclopropyl; R 2 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R 3 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is phenyl or pyridyl; L is selected from ethylenyl, 1-methylethylenyl, - NH-CH 2 - and -NHCH(CH 3 )- , and wherein the ethylenyl or -NHCH 2 - group is substituted with 0-4 substituents independently selected from fluoro, cyano and methoxy; R 5 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methoxy and cyclopropyl; R 4 is selected from -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , - C(O)OH, -C(O)O-C 1 -C 4 alkyl, -C(O)NHO-C 1 -C 4 alkyl and tetrazolyl; R 6 is selected from H, fluoro, chloro, bromo, cyano, C 1 -C 4 alkyl, trifluoromethyl, and methoxy; and p is 0 or 1. [088] In one embodiment, R 4 is -COOH. [089] One aspect of the invention relates to compounds having structures of Formula 8a or 8b, or a pharmaceutically acceptable salt thereof: Wherein R is oxo; wherein: R is -OR x ; R x is selected from H, methyl, ethyl, -CH 2 CF 3 , CH 2 CF 2 H, CH 2 CFH 2 and CF 3 ; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , - C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , NR 1a S(O) 2 R 1a ; -S(O) 2 R 1a , benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3-8 -cycloalkyl-C 1 -C 4 alkyl, phenyl, naphthyl, C 5 - C 6 cycloalkenyl, C 3 -C 6 cycloalkyl, 5-10 membered nitrogen containing heteroaryl, 4-10 membered oxygen containing heterocyclyl; and 4-10 membered nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C 1 -C 6 hydroxyalkyl; R 1a and R 1b are each independently selected from H, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C 3-6 - cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; when R 1 is -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , or NR 1a S(O) 2 NR 1b R 1b , two R 1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 2 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; or when R is oxo, R 1 and R 2 together with the nitrogen and carbon atoms to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 - C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 3 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 3 - C 6 cycloalkyl; L is C 1 -C 4 alkylene, -NH-C 1 -C 4 alkylene, or -C 1 -C 4 alkylene-NH- , and the alkylene group is optionally substituted with 1-4 substituents independently selected from halo, cyano and C 1 -C 4 alkoxy; R 4 is selected from H, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, –(CH 2 ) 1-2 -C(O)OH, - C(O)O-C 1 -C 4 alkyl, –(CH 2 ) 1-2 -C(O)O-C 1 -C 4 alkyl, --C(O)NH 2 , -(CH 2 ) 1-2 -C(O)NH 2 , -C(O)N(C 1 -C 4 alkyl) 2 , -(CH 2 ) 1-2 - C(O)N(C 1 -C 4 alkyl) 2 , -C(O)NHO-C 1 -C 4 alkyl, -C(O)NH-C 1 -C 4 alkyl, -(CH 2 ) 1-2 -C(O)NH-C 1 -C 4 alkyl, C 1 - C 4 alkylsulfonyl, and 5-membered nitrogen containing heteroaryl; R 5 is selected from H, halo, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; Each R 6 is independently selected from H, halo, cyano, C 1 -C 4 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl- C 1 -C 4 alkyl, phenyl, heteroaryl, heterocyclyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkylamino- C 1 - C 4 alkyl, amino- C 1 -C 4 alkyl, and C 1 -C 4 alkoxy-C 1 -C 4 alkyl; R 7 is selected from H, C 1 -C 2 alkyl, C 5 -C 6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; and p is 0, 1, 2 or 3. [090] In one embodiment, R is -OR x ; R x is selected from H, methyl, ethyl, CH 2 CF 3 , CH 2 CF 2 H, CH 2 CFH 2 and CF 3; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , - SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , -C(O)NR 1a R 1a , -NR 1a C(O)NR 1a R 1a , - S(O) 2 NR 1a R 1a , NR 1a S(O) 2 NR 1a R 1a , NR 1a S(O) 2 R 1a ; -S(O) 2 R 1a , benzyl, heteroaryl- C 1 -C 6 alkyl, heterocyclyl- C 1 - C 6 alkyl, cycloalkyl- C 1 -C 6 alkyl, phenyl, naphthyl, C 5 -C 6 cycloalkenyl, C 5 -C 6 cycloalkyl, nitrogen containing heteroaryl, and nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C 1 -C 6 hydroxyalkyl; R 1a and R 1b are each independently selected from H, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C 3 - 6 - cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; when R 1 is -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , or NR 1a S(O) 2 NR 1b R 1b , two R 1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 2 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; R 3 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 3 - C 6 cycloalkyl; L is C 1 -C 4 alkylene, -NH-C 1 -C 4 alkylene, or -C 1 -C 4 alkylene-NH-, and wherein the alkylene group is substituted with 0-4 substituents selected from halo, cyano and C 1 -C 4 alkoxy; R 4 is selected from -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , , -C(O)OH, –(CH 2 ) 1-2 -C(O)OH, -C(O)O- C 1 -C 4 alkyl, –(CH 2 ) 1-2 -C(O)O-C 1 -C 4 alkyl, --C(O)NH 2 , -(CH 2 ) 1-2 -C(O)NH 2 , -C(O)N(C 1 -C 4 alkyl) 2 , -(CH 2 ) 1-2 - C(O)N(C 1 -C 4 alkyl) 2 , -C(O)NHO-C 1 -C 4 alkyl, and tetrazolyl; R 5 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; Each R 6 is independently selected from H, halo, cyano, C 1 -C 4 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl- C 1 -C 4 alkyl, phenyl, heteroaryl, heterocyclyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkylamino- C 1 - C 4 alkyl, amino- C 1 -C 4 alkyl, and C 1 -C 4 alkoxy-C 1 -C 4 alkyl; R 7 is selected from H, C 1 -C 2 alkyl, C 5 -C 6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; and p is 0, 1, 2 or 3. [091] In one embodiment, R is oxo or methoxy; R 1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2- hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl- 2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1- piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, indolyl, indazolyl, benzothiazolyl, benzofuryl, dihydroindolyl, 2-tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1- imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, oxetanyl, tetrahydrofuranyl, phenyl, 2-pyridyl, 3-pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, and cyclohexyl; wherein the ring substituent in R 1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, methyl, difluoromethyl, trifluormethyl, hydroxy, methoxy, ethoxy, methylsulfonyl, carboxyl, amino, dimethylamino, Boc, and a ring selected from morpholinyl, pyrazolyl, 1-methyl-4- pyrazolyl, benzyl, phenyl, 3-pyridinyl, pyrimidinyl, 2-methoxy-4-pyrmidinyl, 5-methoxy-4-pyrmidinyl, 1,3,6- triazanaphth-5-yl, 1-thia-4,6-diazainden-7-yl and cyclopropyl, wherein the ring is unsubstituted or substituted; R 2 is selected from H, fluoro, chloro, cyano, methyl, ethyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R 3 is selected from H, fluoro, chloro, cyano, methyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is selected from phenyl, 2-pyridyl, 3-pyridyl, and 1-benzimidazolyl; L is selected from ethylenyl, 1-methylethylenyl, -NH-CH 2 - and -NHCH(CH 3 )- , and wherein the ethylenyl, or - NHCH 2 - group is optionally substituted with 1-4 substituents independently selected from fluoro, cyano and methoxy; R 5 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methoxy and cyclopropyl; R 4 is selected from methylsulfonyl, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, -C(O)O-C 1 -C 4 alkyl, - C(O)NHO-C 1 -C 4 alkyl, -C(O)NH 2 , -C(O)NH-ethyl, -C(O)NH-isopropyl,triazolyl and tetrazolyl; R 6 is selected from H, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and methoxy; and p is 0 or 1. [092] In one embodiment, R is oxo or methoxy; R 1 is selected from methyl, ethyl, butyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1- piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, 2-tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1- pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, phenyl, pyridyl, pyrimidinyl and cyclohexyl; wherein the ring substituent in R 1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, benzyl, phenyl, and cyclopropyl; R 2 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R 3 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is phenyl or pyridyl; L is selected from ethylenyl, 1-methylethylenyl, -NH-CH 2 - and -NHCH(CH 3 )- , and wherein the ethylenyl or -NHCH 2 - group is substituted with 0-4 substituents independently selected from fluoro, cyano and methoxy; R 5 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methoxy and cyclopropyl; R 4 is selected from -SO 3 H, - PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, -C(O)O-C 1 -C 4 alkyl, -C(O)NHO-C 1 -C 4 alkyl and tetrazolyl; R 6 is selected from H, fluoro, chloro, bromo, cyano, C 1 -C 4 alkyl, trifluoromethyl, and methoxy; and p is 0 or 1. [093] In one embodiment, R 4 is carboxy. [094] One aspect of the invention relates to compounds of Formula 9, or a pharmaceutically acceptable salt thereof: wherein: R is oxo or -OR x ; R x is selected from H, methyl, ethyl, -CH 2 CF 3 , CH 2 CF 2 H, CH 2 CFH 2 and CF 3 ; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , - C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , NR 1a S(O) 2 R 1a ; -S(O) 2 R 1a , benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3-8 -cycloalkyl-C 1 -C 4 alkyl, phenyl, naphthyl, C 5 - C 6 cycloalkenyl, C 3 -C 6 cycloalkyl, 5-10 membered nitrogen containing heteroaryl, 4-10 membered oxygen containing heterocyclyl; and 4-10 membered nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C 1 -C 6 hydroxyalkyl; R 1a and R 1b are each independently selected from H, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C 3-6 - cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; when R 1 is -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , or NR 1a S(O) 2 NR 1b R 1b , two R 1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 2 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; or when R is oxo, R 1 and R 2 together with the nitrogen and carbon atoms to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 - C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 3 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 3 - C 6 cycloalkyl; L is C 1 -C 4 alkylene, -NH-C 1 -C 4 alkylene, or -C 1 -C 4 alkylene-NH-, and the alkylene group is optionally substituted with 1-4 substituents independently selected from halo, cyano and C 1 -C 4 alkoxy; R 4 is selected from H, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, –(CH 2 ) 1-2 -C(O)OH, - C(O)O-C 1 -C 4 alkyl, –(CH 2 ) 1-2 -C(O)O-C 1 -C 4 alkyl, --C(O)NH 2 , -(CH 2 ) 1-2 -C(O)NH 2 , -C(O)N(C 1 -C 4 alkyl) 2 , -(CH 2 ) 1-2 - C(O)N(C 1 -C 4 alkyl) 2 , -C(O)NHO-C 1 -C 4 alkyl, -C(O)NH-C 1 -C 4 alkyl, -(CH 2 ) 1-2 -C(O)NH-C 1 -C 4 alkyl, C 1 - C 4 alkylsulfonyl, and 5-membered nitrogen containing heteroaryl; Each R 6 is independently selected from H, halo, cyano, C 1 -C 4 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl- C 1 -C 4 alkyl, phenyl, heteroaryl, heterocyclyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkylamino- C 1 - C 4 alkyl, amino- C 1 -C 4 alkyl, and C 1 -C 4 alkoxy-C 1 -C 4 alkyl; R 7 is selected from H, C 1 -C 2 alkyl, C 5 -C 6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; and p is 0, 1, 2 or 3. [095] In one embodiment, R is oxo or -OR x ; R x is selected from H, methylr ethyl, CH 2 CF 3 , CH 2 CF 2 H, CH 2 CFH 2 and CF 3; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , --C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , - S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b ,NR 1a S(O) 2 R 1a ; -S(O) 2 R 1a , benzyl, heteroaryl- C 1 -C 6 alkyl, heterocyclyl- C 1 - C 6 alkyl, cycloalkyl- C 1 -C 6 alkyl, phenyl, naphthyl, C 5 -C 6 cycloalkenyl, C 5 -C 6 cycloalkyl, nitrogen containing heteroaryl, and nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C 1 -C 6 hydroxyalkyl; R 1a and R 1b are each independently selected from H, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C 3-6 - cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; when R 1 is -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , or NR 1a S(O) 2 NR 1b R 1b , two R 1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 2 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; R 3 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 3 - C 6 cycloalkyl, L is C 1 -C 4 alkylene, -NH-C 1 -C 4 alkylene, or -C 1 -C 4 alkylene-NH-, and wherein the alkylene group is substituted with 0-4 substituents selected from halo, cyano and C 1 -C 4 alkoxy; R 4 is selected from -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , , -C(O)OH, –(CH 2 ) 1-2 -C(O)OH, -C(O)O- C 1 -C 4 alkyl, –(CH 2 ) 1-2 -C(O)O-C 1 -C 4 alkyl, --C(O)NH 2 , -(CH 2 ) 1-2 -C(O)NH 2 , -C(O)N(C 1 -C 4 alkyl) 2 , -(CH 2 ) 1-2 - C(O)N(C 1 -C 4 alkyl) 2 , -C(O)NHO-C 1 -C 4 alkyl, and tetrazolyl; Each R 6 is independently selected from H, halo, cyano, C 1 -C 4 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl- C 1 -C 4 alkyl, phenyl, heteroaryl, heterocyclyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkylamino- C 1 - C 4 alkyl, amino- C 1 -C 4 alkyl, and C 1 -C 4 alkoxy-C 1 -C 4 alkyl; R 7 is selected from H, C 1 -C 2 alkyl, C 5 -C 6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; and p is 0, 1, 2 or 3. [096] In one embodiment, R is oxo or methoxy; R 1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2- hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl- 2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1- piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, indolyl, indazolyl, benzothiazolyl, benzofuryl, dihydroindolyl, 2-tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1- imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, oxetanyl, tetrahydrofuranyl, phenyl, 2-pyridyl, 3-pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, and cyclohexyl; wherein the ring substituent in R 1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, methyl, difluoromethyl, trifluormethyl, hydroxy, methoxy, ethoxy, methylsulfonyl, carboxyl, amino, dimethylamino, Boc, and a ring selected from morpholinyl, pyrazolyl, 1-methyl-4- pyrazolyl, benzyl, phenyl, 3-pyridinyl, pyrimidinyl, 2-methoxy-4-pyrmidinyl, 5-methoxy-4-pyrmidinyl, 1,3,6- triazanaphth-5-yl, 1-thia-4,6-diazainden-7-yl and cyclopropyl, wherein the ring is unsubstituted or substituted; R 2 is selected from H, fluoro, chloro, cyano, methyl, ethyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R 3 is selected from H, fluoro, chloro, cyano, methyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is selected from phenyl, 2-pyridyl, 3-pyridyl, and 1-benzimidazolyl; L is selected from ethylenyl, 1-methylethylenyl, -NH-CH 2 - and -NHCH(CH 3 )- , and wherein the ethylenyl, or - NHCH 2 - group is optionally substituted with 1-4 substituents independently selected from fluoro, cyano and methoxy; R 5 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methoxy and cyclopropyl; R 4 is selected from methylsulfonyl, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, -C(O)O-C 1 -C 4 alkyl, - C(O)NHO-C 1 -C 4 alkyl, -C(O)NH 2 , -C(O)NH-ethyl, -C(O)NH-isopropyl,triazolyl and tetrazolyl; R 6 is selected from H, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and methoxy; and p is 0 or 1. [097] In one embodiment, R is oxo or methoxy; R 1 is selected from methyl, ethyl, butyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1- piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, 2-tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1- pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, phenyl, pyridyl, pyrimidinyl and cyclohexyl; wherein the ring substituent in R 1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, benzyl, phenyl, and cyclopropyl; R 2 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R 3 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is phenyl or pyridyl; L is selected from ethylenyl, 1-methylethylenyl, -NH-CH 2 - and -NHCH(CH 3 )- , and wherein the ethylenyl or -NHCH 2 - group is substituted with 0-4 substituents independently selected from fluoro, cyano and methoxy; R 4 is selected from - SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, -C(O)O-C 1 -C 4 alkyl, -C(O)NHO-C 1 -C 4 alkyl and tetrazolyl; R 6 is selected from H, fluoro, chloro, bromo, cyano, C 1 -C 4 alkyl, trifluoromethyl, and methoxy; and p is 0 or 1. [098] In one embodiment, R 4 is carboxy. [099] One aspect of the invention relates to compounds of Formula 10a, 10b, and 10c, or a pharmaceutically acceptable salt thereof: wherein: X 1 , X 2 , X 3 , and X 6 is each independently -CR 5 - or -N-; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , - C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , NR 1a S(O) 2 R 1a ; -S(O) 2 R 1a , benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3-8 -cycloalkyl-C 1 -C 4 alkyl, phenyl, naphthyl, C 5 - C 6 cycloalkenyl, C 3 -C 8 cycloalkyl, 5-10 membered nitrogen containing heteroaryl, 4-10 membered oxygen containing heterocyclyl and 4-10 membered nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C 1 -C 6 hydroxyalkyl; R 1a and R 1b are each independently selected from H, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C 3-6 - cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; when R 1 is -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , or NR 1a S(O) 2 NR 1b R 1b , two R 1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 3 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 3 - C 6 cycloalkyl; L is C 1 -C 4 alkylene, -NH-C 1 -C 4 alkylene, or -C 1 -C 4 alkylene-NH- , and the alkylene group is optionally substituted with 1-4 substituents independently selected from halo, cyano and C 1 -C 4 alkoxy; R 4 is selected from H, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, –(CH 2 ) 1-2 -C(O)OH, - C(O)O-C 1 -C 4 alkyl, –(CH 2 ) 1-2 -C(O)O-C 1 -C 4 alkyl, --C(O)NH 2 , -(CH 2 ) 1-2 -C(O)NH 2 , -C(O)N(C 1 -C 4 alkyl) 2 , -(CH 2 ) 1-2 - C(O)N(C 1 -C 4 alkyl) 2 , -C(O)NHO-C 1 -C 4 alkyl, -C(O)NH-C 1 -C 4 alkyl, -(CH 2 ) 1-2 -C(O)NH-C 1 -C 4 alkyl, C 1 - C 4 alkylsulfonyl, and 5-membered nitrogen containing heteroaryl; R 5 is selected from H, halo, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; Each R 6 is independently selected from H, halo, cyano, C 1 -C 4 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl- C 1 -C 4 alkyl, phenyl, heteroaryl, heterocyclyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkylamino- C 1 - C 4 alkyl, amino- C 1 -C 4 alkyl, and C 1 -C 4 alkoxy-C 1 -C 4 alkyl; R 7 is selected from H, C 1 -C 2 alkyl, C 5 -C 6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; R 10 is selected from H, halo, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, benzyl, phenyl, substituted or unsubstituted 5-6 membered heteroaryl, and cyclopropyl; and p is 0, 1, 2 or 3. [0100] In one embodiment, R 1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2-hydroxyethyl, 1,1- dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl-2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1-piperidinyl, 1- piperazinyl, 2-isoindolyl, 2-isoindolinyl, indolyl, indazolyl, benzothiazolyl, benzofuryl, dihydroindolyl, 2- tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1- imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, oxetanyl, tetrahydrofuranyl, phenyl, 2-pyridyl, 3-pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, and cyclohexyl; wherein the ring substituent in R 1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, methyl, difluoromethyl, trifluormethyl, hydroxy, methoxy, ethoxy, methylsulfonyl, carboxyl, amino, dimethylamino, Boc, and a ring selected from morpholinyl, pyrazolyl, 1-methyl-4- pyrazolyl, benzyl, phenyl, 3-pyridinyl, pyrimidinyl, 2-methoxy-4-pyrmidinyl, 5-methoxy-4-pyrmidinyl, 1,3,6- triazanaphth-5-yl, 1-thia-4,6-diazainden-7-yl and cyclopropyl, wherein the ring is unsubstituted or substituted; R 2 is selected from H, fluoro, chloro, cyano, methyl, ethyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R 3 is selected from H, fluoro, chloro, cyano, methyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is selected from phenyl, 2-pyridyl, 3-pyridyl, and 1-benzimidazolyl; L is selected from ethylenyl, 1-methylethylenyl, -NH-CH 2 - and -NHCH(CH 3 )- , and wherein the ethylenyl, or - NHCH 2 - group is optionally substituted with 1-4 substituents independently selected from fluoro, cyano and methoxy; R 5 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methoxy and cyclopropyl; R 4 is selected from methylsulfonyl, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, -C(O)O-C 1 -C 4 alkyl, - C(O)NHO-C 1 -C 4 alkyl, -C(O)NH 2 , -C(O)NH-ethyl, -C(O)NH-isopropyl,triazolyl and tetrazolyl; R 6 is selected from H, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and methoxy; each R 10 is independently selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methoxy, ethoxy and cyclopropyl; X 1 and X 2 are -CH-; X 3 is - N-; X 6 is -CR 10 - or -N-; and p is 0 or 1. [0101] In one embodiment, R 4 is -COOH. [0102] In one embodiment, R 4 -A- is selected from wherein R 6 is selected from halo, C 1 -C 3 alkyl, C 1 - C 3 haloalkyl, C 1 -C 3 alkoxy, and C 3 -C 5 cycloalkyl; wherein R 6 is a substituent on either or both rings; and p is 0, 1, or 2. [0103] In one embodiment, R 4 -A- is ; wherein 6 R is fluoro, chloro, bromo or trifluoromethyl; and p is 0 or 1. [0104] In one embodiment, R 1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2-hydroxyethyl, 1,1- dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl-2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, and dimethylaminocarbonyl. [0105] In one embodiment, A is selected from phenyl, benzothienyl, pyrazinyl, pyrimidinyl, 2-pyridyl, 3-pyridyl, and 1-benzimidazolyl. [0106] In one embodiment, L is selected from ethylenyl, 1-methylethylenyl, -NH-CH 2 - and -NHCH(CH 3 )- , wherein the ethylenyl, or -NHCH 2 - group is optionally substituted with 1-4 substituents independently selected from fluoro, cyano and methoxy. [0107] In one embodiment, R 4 is selected from methylsulfonyl, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , - C(O)OH, -C(O)O-C 1 -C 4 alkyl, -C(O)NHO-C 1 -C 4 alkyl, -C(O)NH 2 , -C(O)NH-ethyl, -C(O)NH-isopropyl, triazolyl and tetrazolyl. [0108] In one embodiment, the compound is selected from 2-((1-(3-methyl-4-oxo-2-(piperidin-1-yl)-3,4-dihydrothieno[3 ,2-d]pyrimidin-7-yl)ethyl)amino)benzoic acid ; 2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyr imidin-9-yl)ethyl)amino)benzoic acid ; 2-((1-(2-(4,4-difluoropiperidin-1-yl)-6-methoxy-3-methyl-4-o xo-3,4-dihydropyrido[3,2-d]pyrimidin-8- yl)ethyl)amino)benzoic acid ; 6-chloro-3-((1-(3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4-di hydroquinazolin-8-yl)ethyl)amino)picolinic acid ; 2-((1-(3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4-dihydroquin azolin-8-yl)ethyl)amino)benzamide; 2-((1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydroquinazolin-8-y l)ethyl)amino)benzoic acid; o-(1-{12-Methyl-7-piperidino-3,4,6,8-tetraazatricyclo[7.4.0. 0 2,6 ]trideca-1(9),2,4,7,10,12-hexaen-10- yl}ethylamino)benzoic acid ; o-{1-[2-(4,4-Difluoro-1-piperidyl)-3-methyl-6-methyl-4-oxo-3 H-1,3,5-triazanaphth-8-yl]ethylamino}benzoic acid; o-[1-(6-Methyl-7-oxo-5-piperidino-6H-1-thia-4,6-diazainden-3 -yl)ethylamino]benzoic acid; o-[1-(2-Methyl-7-methyl-8-oxo-6-piperidino-7H-1,3,5,7-tetraa zanaphth-4-yl)ethylamino]benzoic acid; o-[1-(6-Methyl-4-oxo-2-piperidino-3,8a-dihydro-1,4a-diaza-8- naphthyl)ethylamino]benzoic acid; 6-Chloro-3-{1-[2-(4,4-difluoro-1-piperidyl)-6-methyl-4-oxo-1 ,4a-diaza-8-naphthyl]ethylamino}-2- pyridinecarboxylic acid; 6-Chloro-3-{1-[2-(4,4-difluoro-1-piperidyl)-3-methyl-6-methy l-4-oxo-3H-1,3,7-triazanaphth-8-yl]ethylamino}-2- pyridinecarboxylic acid; o-{1-[2-(1-piperidyl)-3,6-dimethyl-4-oxo-3H-1,3,7-triazanaph th-8-yl]ethylamino}benzoic acid; 6-Chloro-3-{1-[2-(4,4-difluoro-1-piperidyl)-3,6-dimethyl-4-o xo-1,4a-diaza-8-naphthyl]ethylamino}-2- pyridinecarboxylic acid; o-{1-[2-(1-piperidyl)-3,6-dimethyl-4-oxo-1,4a-diaza-8-naphth yl]]ethylamino}benzoic acid; 2-((1-(3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4-dihydroquin azolin-8-yl)ethyl)amino)benzoic acid; 3,6-dimethyl-8-(1-(phenylamino)ethyl)-2-(piperidin-1-yl)quin azolin-4(3H)-one; 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4 -dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; and 2-((1-(2-(isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroqui nazolin-8-yl)ethyl)amino)benzoic acid. METHOD OF INHIBITION AND TREATMENT [ 0109] In another aspect, the present disclosure generally relates to methods for treating cancer. These methods comprise administering to a subject in need thereof, a therapeutically effective amount of a PI3K inhibitor (e.g., PI3Kα inhibitor or PI3Kα H1047R mutant inhibitor). In some embodiments, the PI3K inhibitor (e.g., PI3Kα inhibitor or PI3Kα H1047R mutant inhibitor) is a compound of any one of Formulas 1-10, or a pharmaceutically acceptable salt thereof. [0110] In another aspect, the present disclosure provides a compound obtainable by, or obtained by, a method for preparing a compound as described herein (e.g., a method comprising one or more steps described in the Schemes). [0111] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of any one of Formulas 1-10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. [0112] In another aspect, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g., the intermediate is selected from the intermediates described in the Examples). [0113] In another aspect, the present disclosure provides a method of modulating PI3K (e.g., PI3Kα) activity (e.g., in vitro or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound of any one of Formulas 1-10, or a pharmaceutically acceptable salt thereof. [0114] In some embodiments, the PI3Kα sequence correlates with NCBI Reference Sequence: NP 006209.2. In some embodiments, the PI3Kα sequence correlates with NCBI Reference Sequence: NP_006210.1. In some embodiments, an amino acid sequence encoding PI3Kα comprises or consists of an amino acid sequence: [0115] In some aspects, an amino acid sequence encoding PI3Kα with a H1047R mutation comprises or consists of an amino acid sequence: [0116] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Formulas 1-10, or a pharmaceutically acceptable salt thereof. [0117] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of a compound of any one of Formulas 1-10, or a pharmaceutically acceptable salt thereof. [0118] In another aspect, the present disclosure provides a compound of any one of Formulas 1-10, or a pharmaceutically acceptable salt thereof, for use in modulating PI3Kα) activity (e.g., in vitro or in vivo). [0119] In another aspect, the present disclosure provides a compound of any one of Formulas 1-10, or a pharmaceutically acceptable salt thereof, for use in greater inhibition for mutant PI3K ^ over wild-type PI3K ^. [0120] In another aspect, the present disclosure provides a compound of any one of Formulas 1-10, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder disclosed herein. [0121] In another aspect, the present disclosure provides use of a compound of Formulas 1-10, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for modulating P13K (e.g., PI3Kα) activity (e.g., in vitro or in vivo). [0122] In another aspect, the present disclosure provides use of a compound of any one of Formulas 1-10, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder disclosed herein. [0123] In another aspect, the present disclosure provides a method of preparing a compound of any one of Formulas 1-10, or a pharmaceutically acceptable salt thereof. [0124] In another aspect, the present disclosure provides a method of preparing a compound of any one of Formulas 1-10, comprising one or more steps described herein. [0125] In another aspect, disclosed is a method of impacting the phosphoinositide 3 -kinases (PI3Ks) signaling pathway, such as in treating allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel diseases, chronic obstructive pulmonary disorder, psoriasis, multiple sclerosis, asthma, disorders related to diabetic complications, and inflammatory complications of the cardiovascular system such as acute coronary syndrome. [0126] Genetic alterations in genes in PI3K signaling are believed to be involved in a range of cancers such as endometrial cancer, breast cancer, esophageal squamous-cell cancer, cervical squamous-cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small-cell lung cancer, esophagogastric cancer, nerve-sheath tumor, head and neck squamous-cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft-tissue sarcoma, prostate cancer, fibrolamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, cholangiocarcinoma, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, renal non- clear-cell carcinoma, renal clear-cell carcinoma, germ-cell carcinoma, thymic tumor, pheochromocytoma, miscellaneous neuroepithelial tumor, thyroid cancer, leukemia, and encapsulated glioma (Goncalves MD, Hopkins BD, Cantiey LC. Phosphatidylinositol 3- Kinase, Growth Disorders, and Cancer. N Engl J Med.2018 Nov 22;379(21):2052-2062). [0127] The alpha (a) isoform of PI3K has been implicated, for example, in a variety of human cancers. Angiogenesis has been shown to selectively require the α isoform of PI3K in the control of endothelial cell migration. (Graupera et al, Nature 2008; 453; 662-6). Mutations in the gene coding for PI3Kα or mutations which lead to upregulation of PI3Kα are believed to occur in many human cancers such as lung, stomach, endometrial, ovarian, bladder, breast, colon, brain, prostate, and skin cancers. Mutations in the gene coding for PI3Kα are point mutations clustered within several hotspots in helical and kinase domains, such as E542K, E545K, N345K, H1047L and H1047R. Many of these mutations have been shown to be oncogenic gain-of-function mutations. Because of the high rate of PI3Kα mutations, targeting of this pathway may provide valuable therapeutic opportunities. While other PI3K isoforms such as PI3Kδ or PI3Kγ are expressed primarily in hematopoietic cells, PI3Kα, along with PI3Kβ, is expressed constitutively. Due to the central role of PI3Kα in regulating organismal glucose homeostasis, PI3K inhibition in patients often gives rise to hyperglycemia and/or hyperinsulinemia (Busaidy NL, et al., Management of metabolic effects associated with anticancer agents targeting the PI3K-Akt- mTOR pathway. J Clin Oncol 2012;30:2919-28). High levels of circulating insulin could potentially be mitogenic and/or antiapoptotic for cancer cells and thus negate the antiproliferative effects of PI3K inhibitors (Blouin M-J, et al., Abstract 4615: the hyperinsulinemia caused by PI3K inhibitors attenuates their antineoplastic efficacy, but can be minimized by co administration of metformin. Cancer Res 2013;73:4615). [0128] In the setting of cancer with mutated PI3Kα, one way to overcome the problem of compensatory production of insulin and/or glucose upon systemic PI3Kα inhibition is with inhibitors with enhanced selectivity for mutant PI3K ^ over wild-type PI3Kα. This would create an increased window for drug dosing to selectively inhibit the pathologic signaling of mutant PI3Kα in the cancer cells without affecting the wild-type PI3K ^ in the host tissues that control systemic metabolism (Okkenhaug K, Graupera M, Vanhaesebroeck B. Targeting PI3K in Cancer: Impact on Tumor Cells, Their Protective Stroma, Angiogenesis, and Immunotherapy. Cancer Dsilica gel chromatography.2016 Oct;6(10): 1090-1105), thus limiting toxicities and permitting higher doses and more complete inhibition of the drug target (Ariella B. Hanker, et al, Challenges for the clinical development of PI3K inhibitors: Strategies to improve their impact in solid tumors. Cancer Dsilica gel chromatography.2019 Apr; 9(4): 482-491). [0129] The present disclosure provides methods of treating, preventing, or ameliorating a disease or disorder in which PI3K plays a role by administering to a patient in need thereof a therapeutically effective amount of a PI3K inhibitor. The methods of the present disclosure can be used in the treatment of a variety of PI3K- dependent diseases and disorders. [0130] In some embodiments, the disease of disorder is a cancer (e.g., breast cancer, brain cancers, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, and head and neck cancer). In some embodiments, the disease or disorder associated with PI3K includes, but is not limited to, CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome), PIK3CA-related overgrowth syndrome (PROS), endometrial cancer, breast cancer, esophageal squamous-cell cancer, cervical squamous- cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small-cell lung cancer, esophagogastric cancer, nerve-sheath tumor, head and neck squamous-cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft-tissue sarcoma, prostate cancer, fibrolamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, cholangiocarcinoma, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, renal non-clear-cell carcinoma, renal clear-cell carcinoma, germ-cell carcinoma, thymic tumor, pheochromocytoma, miscellaneous neuroepithelial tumor, thyroid cancer, leukemia, and encapsulated glioma. [0131] In some embodiments, the cancer is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer, astrocytoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, osteosarcoma, malignant fibrous histiocytoma, brain tumors, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor, cancer of unknown primary, cardiac (heart) tumors, atypical teratoid/rhabdoid tumor, primary CNS lymphoma, cervical cancer, cholangiocarcinoma, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, mycosis fungoides, Sezary syndrome, ductal carcinoma in situ (DCIS), embryonal tumors, medulloblastoma, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, malignant gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic disease, hairy cell leukemia, head and neck cancer, hepatocellular cancer, Langerhans cell histiocytosis, Hodgkin lymphoma, islet cell tumors, pancreatic neuroendocrine tumors, Kaposi sarcoma, kidney cancer, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, male breast cancer, intraocular melanoma, Merkel cell carcinoma, malignant mesothelioma, metastatic cancer, metastatic squamous neck cancer, midline tract carcinoma with nut gene changes, mouth cancer, multiple endocrine neoplasia syndromes, multiple myeloma/plasma cell neoplasms, myelodysplastic syndromes, myelodysplastic neoplasms, myeloproliferative neoplasms, chronic myeloproliferative neoplasm, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, lip and oral cavity cancer, oropharyngeal cancer, malignant fibrous histiocytoma of bone, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors (islet cell tumors), papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, plasma cell neoplasm, multiple myeloma, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, recurrent cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, childhood vascular tumors, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma of the skin, testicular cancer, oropharyngeal cancer, hypopharyngeal cancer, thymoma, thymic carcinoma, thyroid cancer, tracheobronchial tumors, transitional cell cancer of the renal pelvis and ureter, urethral cancer, uterine sarcoma, vaginal cancer, vascular tumors, vulvar cancer, and Wilms tumor. [0132] In some embodiments, the cancer is endometrial cancer, breast cancer, esophageal squamous-cell cancer, cervical squamous-cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small cell lung cancer, esophagogastric cancer, nerve- sheath tumor, head and neck squamous-cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft- tissue sarcoma, prostate cancer, fibrolamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, cholangiocarcinoma, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, renal non-clear-cell carcinoma, renal clear-cell carcinoma, germ-cell carcinoma, thymic tumor, pheochromocytoma, miscellaneous neuroepithelial tumor, thyroid cancer, leukemia, or encapsulated glioma. [0133] In some embodiments, the cancer is a breast cancer, a prostate cancer, or a brain cancer. [0134] In some embodiments, the cancer is a breast cancer. In some embodiments, the cancer is a prostate cancer. In some embodiments, the cancer is a brain cancer. [0135] In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is ductal carcinoma in situ (DCIS). In some embodiments, the breast cancer is invasive ductal carcinoma. In some embodiments, the breast cancer is triple negative breast cancer. In some embodiments, the breast cancer is medullary carcinoma. In some embodiments, the breast cancer is tubular carcinoma. In some embodiments, the breast cancer is mucinous carcinoma. In some embodiments, the breast cancer is Paget disease of the breast or nipple. In some embodiments, the breast cancer is inflammatory breast cancer (IBC). [0136] In some embodiments, the prostate cancer is an adenocarcinoma. In some embodiments, the prostate cancer is a small cell carcinoma. In some embodiments, the prostate cancer is a neuroendocrine tumor. In some embodiments, the prostate cancer is a transitional cell carcinoma. In some embodiments, the prostate cancer is a sarcoma. [0137] In some embodiments, the brain cancer is an acoustic neuroma. In some embodiments, the brain cancer is an astrocytoma. In some embodiments, the brain cancer is a brain metastasis. In some embodiments, the brain cancer is choroid plexus carcinoma. In some embodiments, the brain cancer is craniopharyngioma. In some embodiments, the brain cancer is an embryonal tumor. In some embodiments, the brain cancer is an ependymoma. In some embodiments, the brain cancer is a glioblastoma. In some embodiments, the brain cancer is a glioma. In some embodiments, the brain cancer is a medulloblastoma. In some embodiments, the brain cancer is a meningioma. In some embodiments, the brain cancer is an oligodendroglioma. In some embodiments, the brain cancer is a pediatric brain tumor. In some embodiments, the brain cancer is a pineoblastoma. In some embodiments, the brain cancer is a pituitary tumor. [0138] In some embodiments, the disease or disorder associated with PI3K includes, but is not limited to, CLOVES syndrome (congenial lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome), PIK3CA-related overgrowth syndrome (PROS), breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer. [0139] In some embodiments, the diseases or disorder associated with PI3K is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome). [0140] In some embodiments, the disease or disorder associated with PI3K is PIK3CA-related overgrowth syndrome (PROS). [0141] In some embodiments, the disease or disorder associated with PI3K is breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer. [0142] In some embodiments, the disease or disorder associated with PI3K is breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer. In some embodiments, the disease or disorder associated with PI3K is leukemia, lymphoma, or sarcoma. [0143] In some embodiments, the cancer is endometrial cancer, head and neck cancer, or a sarcoma. [0144] In some embodiments, the cancer is endometrial cancer. In some embodiments the cancer is head and neck cancer. In some embodiments, the cancer is a sarcoma. [0145] In some embodiments, the sarcoma is soft tissue sarcoma, osteosarcoma, chondrosarcoma, Ewing sarcoma, hemangioendothelioma, angiosarcoma, fibrosarcoma, myofibrosarcoma, chordoma, adamantinoma, liposarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, synovial sarcoma, or malignant solitary fibrous tumor. [0146] In some embodiments, the sarcoma is soft tissue sarcoma. In some embodiments the soft tissue sarcoma is liposarcoma, atypical lipomatous tumor, dermatofibrosarcoma protuberans, malignant solitary fibrous tumor, inflammatory myofibroblastic tumor, low-grade myofibroblastic sarcoma, fibrosarcoma, myxofibrosarcoma, low-grade fibromyxoid sarcoma, giant cell tumor of soft tissues, leiomyosarcoma, malignant glomus tumor, rhabdomyosarcoma, hemangioendothelioma, angiosarcoma of soft tissue, extraskeletal osteosarcoma, gastrointestinal stromal tumor, malignant gastrointestinal stromal tumor (GIST), malignant peripheral nerve sheath tumor, malignant Triton tumor, malignant granular cell tumor, malignant ossifying fibromyxoid tumor, stromal sarcoma, myoepithelial carcinoma, malignant phosphaturic mesenchymal tumor, synovial sarcoma, epithelioid sarcoma, alveolar soft part sarcoma, clear cell sarcoma of soft tissue, extraskeletal myxoid chondrosarcoma, extraskeletal Ewing sarcoma, desmoplastic small round cell tumor, extrarenal rhabdoid tumor, perivascular epithelioid cell tumor, intimal sarcoma, undifferentiated spindle cell sarcoma, undifferentiated pleomorphic sarcoma, undifferentiated round cell sarcoma, undifferentiated epithelioid sarcoma, or undifferentiated sarcoma, not otherwise specified. [0147] In some aspects, the present disclosure provides a method of treating or preventing a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [0148] In some aspects, the present disclosure provides a method of treating a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [0149] In some aspects, the present disclosure provides a method of treating or preventing a breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [0150] In some aspects, the present disclosure provides a method of treating a breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [0151] In some aspects, the present disclosure provides a method of treating or preventing a prostate cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [0152] In some aspects, the present disclosure provides a method of treating a prostate cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [0153] In some aspects, the present disclosure provides a method of treating or preventing a brain cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [0154] In some aspects, the present disclosure provides a method of treating a brain cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [0155] In some aspects, the present disclosure provides a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof for use in modulating PI3K (e.g., PI3K ^) activity (e.g., in vitro or in vivo). [0156] In some aspects, the present disclosure provides a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein. [0157] In some aspects, the present disclosure provides a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein. [0158] In some aspects, the present disclosure provides a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof for use in treating or preventing a cancer in a subject in need thereof. [0159] In some aspects, the present disclosure provides a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof for use in treating a cancer in a subject in need thereof. [0160] In some aspects, the present disclosure provides a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof for use in treating or preventing a breast cancer in a subject in need thereof. [0161] In some aspects, the present disclosure provides a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof for use in treating a breast cancer in a subject in need thereof. [0162] In some aspects, the present disclosure provides a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof for use in treating or preventing a prostate cancer in a subject in need thereof. [0163] In some aspects, the present disclosure provides a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof for use in treating a prostate cancer in a subject in need thereof. [0164] In some aspects, the present disclosure provides a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof for use in treating or preventing a brain cancer in a subject in need thereof. [0165] In some aspects, the present disclosure provides a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof for use in treating a brain cancer in a subject in need thereof. [0166] In some aspects, the present disclosure provides use of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulating PI3K (e.g., PI3K ^) activity (e.g., in vitro or in vivo). [0167] In some aspects, the present disclosure provides use of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein. [0168] In some aspects, the present disclosure provides use of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein. [0169] In some aspects, the present disclosure provides use of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a cancer in a subject in need thereof. [0170] In some aspects, the present disclosure provides use of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a cancer in a subject in need thereof. [0171] In some aspects, the present disclosure provides use of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a breast cancer in a subject in need thereof. [0172] In some aspects, the present disclosure provides use of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a breast cancer in a subject in need thereof. [0173] In some aspects, the present disclosure provides use of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a prostate cancer in a subject in need thereof. [0174] In some aspects, the present disclosure provides use of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a prostate cancer in a subject in need thereof. [0175] In some aspects, the present disclosure provides use of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a brain cancer in a subject in need thereof. [0176] In some aspects, the present disclosure provides use of a compound of any one of Formulas 1-10 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a brain cancer in a subject in need thereof. [0177] The present disclosure provides compounds that function as modulators of PI3K activity. The present disclosure therefore provides a method of modulating PI3K activity in vitro or in vivo, said method comprising contacting a cell with a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, as defined herein. [0178] In some embodiments, PI3K modulation is inhibition of PI3K. [0179] In some embodiments, the PI3K inhibitor is a compound of any one of Formulas 1-10, or a pharmaceutically acceptable salt thereof. In some embodiments, the PI3K inhibitor is a PI3K ^ inhibitor. In some embodiments, the PI3K inhibitor is a PI3Kα H1047R mutant inhibitor. In some embodiments, the PI3K inhibitor is ^ ^ ^ non-selective. In some embodiments, the PI3K inhibitor is alpha selective. In some embodiments, the PI3K inhibitor is beta selective. [0180] Effectiveness of compounds of the disclosure can be determined by industry-accepted assays/disease models according to standard practices of elucidating the same as described in the art and are found in the current general knowledge. [0181] The present disclosure also provides a method of treating a disease or disorder in which PI3K activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein. [0182] The disclosure provides a method of modulating the activity of the PI3Kα allosteric active site, wherein the modulation is induced through peripheral site targeting. In some embodiments, the peripheral site is targeted with an agent selected from a small molecule, a peptide, a peptidomimetic, a protein, a protein mimetic, a nucleic acid, an antibody, an antibody- drug conjugate, a nucleoprotein complex, an immunotherapy, or a combination thereof. Routes of Administration [0183] The compounds of Formulas 1-10 or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action). Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrastemal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly. DEFINITIONS [0184] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts. [0185] The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di- and multivalent radicals, having the number of carbon atoms designated (i.e., C 1 -C 10 means one to ten carbons). Alkyl is an uncyclized chain. Preferred alkyl substituents are C 1 -C 6 alkyl. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. The term “alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, -CH 2 CH 2 CH 2 CH 2 -. [0186] An unsaturated alkyl group is one having one or more double bonds or triple bonds referred to as “alkenyl” or “alkynyl” groups, respectively. Preferred alkenyl substituents are C 2 -C 6 alkenyl and preferred alkynyl substituents are C 2 -C 6 alkynyl. Examples of alkenyl or alkynyl groups include, but are not limited to, ethenyl, vinyl, 2-propenyl, butenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- propynyl, 3-propynyl, and 3-butynyl. [0187] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, S, B, As, or Si), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) (e.g., O, N, P, S, B, As, or Si) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is an uncyclized chain. Examples include, but are not limited to: -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N(CH 3 )-CH 3 , -CH 2 -S-CH 2 -CH 3 , -CH 2 -CH 2 , -S(O)-CH 3 , - CH 2 -CH 2 -S(O) 2 -CH 3 , -CH=CH-O-CH 3 , -Si(CH 3 ) 3 , -CH 2 -CH=N-OCH 3 , -CH=CH-N(CH 3 )-CH 3 , -O-CH 3 , -O-CH 2 -CH 3 , and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 3 and -CH 2 - O-Si(CH 3 ) 3 . Heteroalkyl also includes terms such as alkoxy, and alkylamino. [0188] An “alkoxy” is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-). Preferred alkoxy substituents include C 1-4 alkoxy. Examples of alkoxy groups include, but are not limited to methoxy, ethoxy, and propoxy. Preferred alkylamino substituents include mono substituted C 1-4 alkylamino and disubstituted alkylamino. Examples of alkylamino groups include, but are not limited to methylamino, dimethylamino, and diethylamino. [0189] Anther subgroup of heteroalkyl includes “alkoxyalkyl” where an alkyl group is substituted with an alkoxy group, as defined above. Preferred alkoxyalkyl substituents include C 1-4 alkoxy- C 1-4 alkyl. Examples of alkoxyalkyl groups include, but are not limited to methoxymethyl, ethoxymethyl, and methoxyethyl. [0190] As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as , alkyl-NR'R'', alkyl-OR', alkyl-SR', and/or alkyl-SO 2 R'. [0191] An “aralkyl” is an alkyl substituent substituted with an aryl moiety. Preferred aralkyl substituents include unsubstituted or substituted phenyl-C 1-4 alkyl. Examples of aralkyl groups include benzyl or phenethyl. [0192] Similarly, “heteroarylalkyl”, “heterocyclylalkyl”, and “cycloalkylalkyl” are alkyl groups substituted with heteroaryl, heterocyclyl and cycloalkyl moieties, respectively. [0193] The term “cycloalkyl” by itself or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl”. Cycloalkyl are not fully aromatic rings. Preferred cycloalkyl substituents include C 3 -C 6 cycloalkyl. A “cycloalkylene” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl. For example, a cycloalkyl group having 3 to 8 ring members may be referred to as a (C 3 - C 8 )cycloalkyl, a cycloalkyl group having 3 to 7 ring members may be referred to as a (C 3 -C 7 )cycloalkyl and a cycloalkyl group having 4 to 7 ring members may be referred to as a (C 4 -C 7 )cycloalkyl. In certain embodiments, the cycloalkyl group can be a (C 3 -C 10 )cycloalkyl, a (C 3 -C 8 )cycloalkyl, a (C 3 -C 7 )cycloalkyl, a (C 3 -C 6 )cycloalkyl, or a (C 4 -C 7 )cycloalkyl group and these may be referred to as C 3 -C 10 cycloalkyl, C 3 -C 8 cycloalkyl, C 3 -C 7 cycloalkyl, C 3 - C 6 cycloalkyl, or C 4 -C 7 cycloalkyl groups. [0194] The term “cycloalkenyl” by itself or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkenyl”. Cycloalkenyl are not fully aromatic rings. Preferred cycloalkenyl substituents include C 4 -C 6 cycloalkenyl. For example, a cycloalkenyl group having 4 to 8 ring members may be referred to as a (C 4 - C 8 )cycloalkenyl, a cycloalkenyl group having 3 to 7 ring members may be referred to as a (C 3 -C 7 )cycloalkenyl and a cycloalkenyl group having 4 to 6 ring members may be referred to as a (C 4 -C 6 )cycloalkenyl. [0195] The term “heterocycloalkyl” by itself or in combination with other terms, mean, unless otherwise stated, cyclic versions of “heteroalkyl”. Heterocycloalkyl rings are not fully aromatic. Heterocycloalkyl is also referred by the term heterocyclyl. Preferred heterocyclyl substituents include C 3 -C 7 oxygen or nitrogen containing rings, or both nitrogen and oxygen atoms. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. A “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from heterocycloalkyl. [0196] “Heterocyclyl” refers to a cyclic group that includes at least one saturated, partially unsaturated, but non- aromatic, cyclic ring. Heterocyclyl groups include at least one heteroatom as a ring member. Typical heteroatoms include O, S, and N and are independently chosen. Heterocyclyl groups include monocyclic ring systems and bicyclic ring systems. Bicyclic heterocyclyl groups include at least one non-aromatic ring with at least one heteroatom ring member that may be fused to a cycloalkyl ring or may be fused to an aromatic ring where the aromatic ring may be carbocyclic or may include one or more heteroatoms. The point of attachment of a bicyclic heterocyclyl group may be at the non-aromatic cyclic ring that includes at least one heteroatom or at another ring of the heterocyclyl group. For example, a heterocyclyl group derived by removal of a hydrogen atom from one of the 9-membered heterocyclic compounds shown below may be attached to the rest of the molecule at the 5- membered ring or at the 6-membered ring. In some embodiments, a heterocyclyl group includes 5 to 10 ring members of which 1, 2, 3 or 4 or 1, 2, or 3 are heteroatoms independently selected from O, S, or N. In other embodiments, a heterocyclyl group includes 3 to 7 ring members of which 1, 2, or 3 heteroatom are independently selected from O, S, or N. In such 3-7 membered heterocyclyl groups, only 1 of the ring atoms is a heteroatom when the ring includes only 3 members and includes 1 or 2 heteroatoms when the ring includes 4 members. In some embodiments, a heterocyclyl group includes 3 or 4 ring members of which 1 is a heteroatom selected from O, S, or N. In other embodiments, a heterocyclyl group includes 5 to 7 ring members of which 1, 2, or 3 are heteroatoms independently selected from O, S, or N. Typical heterocyclyl groups include, but are not limited to, groups derived from epoxides, aziridine, azetidine, imidazolidine, morpholine, piperazine, piperidine, hexahydropyrimidine, 1,4,5,6-tetrahydropyrimidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran, tetrahydropyran, benzimidazolone, pyridinone, and the like. Heterocyclyl groups may be fully saturated, but may also include one or more double bonds. Examples of such heterocyclyl groups include, but are not limited to, 1,2,3,6-tetrahydropyridinyl, 3,6-dihydro-2H-pyranyl, 3,4-dihydro-2H-pyranyl, 2,5-dihydro-1H-pyrolyl, 2,3-dihydro- 1H-pyrolyl, 1H-azirinyl, 1,2-dihydroazetenyl, and the like. Substituted heterocyclyl also includes ring systems substituted with one or more oxo (=O) or oxide (-O-) substituents, such as piperidinyl N-oxide, morpholinyl-N- oxide, 1-oxo-1-thiomorpholinyl, pyridinonyl, benzimidazolonyl, benzo[d]oxazol-2(3H)-only, 3,4-dihydroisoquinolin- 1(2H)-only, indolin-only, 1H-imidazo[4,5-c]pyridin-2(3H)-only, 7H-purin-8(9H)-only, imidazolidin-2-only, 1H- imidazol-2(3H)-only, 1,1-dioxo-1-thiomorpholinyl, and the like. The term heterocyclyl also includes spiro rings and bridged rings. [0197] The terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. [0198] The terms “hydrido”, or “H” is a hydrogen radical. [0199] The term “haloalkyl” is meant to include monohaloalkyl and polyhaloalkyl. For example, the term “C 1 -C 3 - haloalkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 3- bromopropyl, and the like. [0200] The term “acyl” means, unless otherwise stated, -C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0201] The term “aryl” means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. [0202] The term “heteroaryl” refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Thus, the term “heteroaryl” includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. “Heteroaryl” refers to a monovalent heteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system. Heteroaryl groups typically include 5- to 14-membered, but more typically include 5- to 10-membered aromatic, monocyclic, bicyclic, and tricyclic rings containing one or more, for example, 1, 2, 3, or 4, or in certain embodiments, 1, 2, or 3, heteroatoms chosen from O, S, or N, with the remaining ring atoms being carbon. In monocyclic heteroaryl groups, the single ring is aromatic and includes at least one heteroatom. In some embodiments, a monocyclic heteroaryl group may include 5 or 6 ring members and may include 1, 2, 3, or 4 heteroatoms, 1, 2, or 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom where the heteroatom(s) are independently selected from O, S, or N. In bicyclic aromatic rings, both rings are aromatic. In bicyclic heteroaryl groups, at least one of the rings must include a heteroatom, but it is not necessary that both rings include a heteroatom although it is permitted for them to do so. For example, the term “heteroaryl” includes a 5- to 7- membered heteroaromatic ring fused to a carbocyclic aromatic ring or fused to another heteroaromatic ring. In tricyclic aromatic rings, all three of the rings are aromatic and at least one of the rings includes at least one heteroatom. For fused, bicyclic and tricyclic heteroaryl ring systems where only one of the rings contains one or more heteroatoms, the point of attachment may be at the ring including at least one heteroatom or at a carbocyclic ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In certain embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In certain embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1. Heteroaryl does not encompass or overlap with aryl as defined above. Examples of heteroaryl groups include, but are not limited to, groups derived from acridine, carbazole, cinnoline, furan, imidazole, indazole, indole, indolizine, isobenzofuran, isochromene, isoindole, isoquinoline, isothiazole, 2H- benzo[d][1,2,3]triazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, and the like. In certain embodiments, the heteroaryl group can be between 5 to 20 membered heteroaryl, such as, for example, a 5 to 14 membered or 5 to 10 membered heteroaryl. In certain embodiments, heteroaryl groups can be those derived from thiophene, pyrrole, benzothiophene, 2H-benzo[d][1,2,3]triazole benzofuran, indole, pyridine, quinoline, imidazole, benzimidazole, oxazole, tetrazole, and pyrazine. [0203] An “arylene” and a “heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. [0204] The term “carbonyl” refers to the radical–C(O) which may also be referred to as –C(=O) group. [0205] The term “carboxy” refers to the radical -CO 2 H, -C(O)OH which may also be referred to as–C(=O)OH. [0206] The term “cyano” refers to the radical -CN. [0207] The term “amino” refers to the radical -NH 2 . [0208] The term “aminocarbonyl” refers to the radical -CO-NH 2 . Aminocarbonyl radicals may be substituted with one or two alkyl groups to form “alkylaminocarbonyl” groups. [0209] The term “alkylcarbonyl” refers to the radical alkyl-CO-. [0210] The terms “hydroxyl” and “hydroxy” refers to the radical -OH. [0211] The term “oxo,” as used herein, means an oxygen that is double bonded to a carbon atom. [0212] A “lower substituent” or “ lower substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -C 10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. [0213] In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group. [0214] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted C 1 -C 20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -C 10 aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C 1 -C 20 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C 3 -C 8 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C 6 -C 10 arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene. [0215] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -C 10 aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C 1 -C 8 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C 3 -C 7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C 6 -C 10 arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene. In some embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below. [0216] In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., is an unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, and/or unsubstituted heteroarylene, respectively). In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is substituted (e.g., is a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene, respectively). [0217] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, wherein if the substituted moiety is substituted with a plurality of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of substituent groups, each substituent group is different. [0218] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one size-limited substituent group, wherein if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of size- limited substituent groups, each size-limited substituent group is different. [0219] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one lower substituent group, wherein if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group is different. [0220] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size- limited substituent group, and/or lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group is different. [0221] Certain compounds of the present invention possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present invention. The compounds of the present invention do not include those that are known in art to be too unstable to synthesize and/or isolate. The present invention is meant to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. [0222] As used herein, the term “isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms. [0223] The term “tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another. [0224] It will be apparent to one skilled in the art that certain compounds of this invention may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the invention. [0225] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the (R)- and (S)- configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. As used herein and unless otherwise indicated, the term “stereoisomer” or “stereomerically pure” means one stereoisomer of a compound that is substantially free of other stereoisomers of that compound. For example, a stereomerically pure compound having one chiral center will be substantially free of the mirror image enantiomer of the compound. A stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more preferably greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, even more preferably greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and most preferably greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. If the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. A bond drawn with a wavy line indicates that both stereoisomers are encompassed. This is not to be confused with a wavy line drawn perpendicular to a bond which indicates the point of attachment of a group to the rest of the molecule. As described above, this invention encompasses the use of stereomerically pure forms of such compounds, as well as the use of mixtures of those forms. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular compound of the invention may be used in methods and compositions of the invention. These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al. (1997) Tetrahedron 33:2725; Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972). [0226] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium [D] or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of this is selected from invention. [0227] It should be noted that throughout the application that alternatives are written in Markush groups, for example, each amino acid position that contains more than one possible amino acid. It is specifically contemplated that each member of the Markush group should be considered separately, thereby comprising another embodiment, and the Markush group is not to be read as a single unit. [0228] The terms “a” or “an,” as used in herein means one or more. In addition, the phrase “substituted with a[n],” as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is “substituted with an unsubstituted C 1 -C 20 alkyl, or unsubstituted 2 to 20 membered heteroalkyl,” the group may contain one or more unsubstituted C 1 -C 20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls. [0229] Moreover, where a moiety is substituted with an R substituent, the group may be referred to as “R- substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. [0230] Reference to the formulas expressly depicts all divisions thereof, e.g. formula 1 in the description expressly includes formulas 1A, 1B, 1C and 1D. [0231] The term “pharmaceutically acceptable salts” is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g. methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. [0232] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents. [0233] In addition to salt forms, the present invention provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Prodrugs of the compounds described herein may be converted in vivo after administration. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent. [0234] Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention. [0235] “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention. [0236] The term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration. [0237] “Contacting” is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g. chemical compounds including biomolecules or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated; however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents that can be produced in the reaction mixture. The term “contacting” may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a protein or enzyme. In some embodiments contacting includes allowing a compound described herein to interact with a protein or enzyme that is involved in a signaling pathway. [0238] The terms “disease” or “condition” refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein. The disease may be a cancer. In some further instances, “cancer” refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc., including solid and lymphoid cancers, kidney, breast, lung, bladder, colon, ovarian, prostate, pancreas, stomach, brain, head and neck, skin, uterine, testicular, glioma, esophagus, and liver cancer, including hepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma, non-Hodgkin’s lymphomas (e.g., Burkitt’s, Small Cell, and Large Cell lymphomas), Hodgkin’s lymphoma, leukemia (including AML, ALL, and CML), or multiple myeloma. As used herein, the term “cancer” refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g. humans), including leukemia, carcinomas, and sarcomas. [0239] The term "leukemia" refers broadly to progressive, malignant diseases of the blood-forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. [0240] The term "sarcoma" generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance. [0241] The term "melanoma" is taken to mean a tumor arising from the melanocytic system of the skin and other organs. [0242] The term "carcinoma" refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated with a compound or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, or carcinoma villosum. [0243] The terms “treating”, or “treatment” refers to any indicia of success in the therapy or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation. The term "treating" and conjugations thereof, may include prevention of an injury, pathology, condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing. [0244] “Patient” or “subject in need thereof” refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In some embodiments, a patient is human. [0245] An “effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g. achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, or reduce one or more symptoms of a disease or condition). An example of an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount.” A “reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist. A “function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols.1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). [0246] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art. [0247] As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan. [0248] Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present invention should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state. [0249] As used herein, the term "administering" means oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal) compatible with the preparation. Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. [0250] "Co-administer" it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies. The compounds of the invention can be administered alone or can be coadministered to the patient. Coadministration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). Thus, the preparations can also be combined, when desired, with other active substances (e.g. to reduce metabolic degradation). The compositions of the present invention can be delivered transdermally, by a topical route, or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols. [0251] A “cell” as used herein, refers to a cell carrying out metabolic or other function sufficient to preserve or replicate its genomic DNA. A cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring. Cells may include prokaryotic and eukaroytic cells. [0252] “Control” or “control experiment” is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison in evaluating experimental effects. In some embodiments, a control is the measurement of the activity of a protein in the absence of a compound as described herein (including embodiments and examples). [0253] The term “modulator” refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of the target of the molecule. [0254] The term “modulate” is used in accordance with its plain ordinary meaning and refers to the act of changing or varying one or more properties. “Modulation” refers to the process of changing or varying one or more properties. For example, as applied to the effects of a modulator on a target protein, to modulate means to change by increasing or decreasing a property or function of the target molecule or the amount of the target molecule. [0255] The term “associated” or “associated with” in the context of a substance or substance activity or function associated with a disease (e.g. a protein associated disease) means that the disease (e.g. cancer) is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function. [0256] The term “signaling pathway” as used herein refers to a series of interactions between cellular and optionally extra-cellular components (e.g. proteins, nucleic acids, small molecules, ions, lipids) that conveys a change in one component to one or more other components, which in turn may convey a change to additional components, which is optionally propogated to other signaling pathway components. GENERAL SYNTHETIC SCHEMES [0257] The compounds of this invention can be synthesized according to the following procedure of Schemes I- VIII, wherein the substituents are as defined for Formulas 1-10, above, except where further noted. [0258] The following abbreviations are used: RT, rt room temperature, ambient temperature DCM, CH 2 C1 2 dichloromethane DIEA, DIPEA, EtNiPr 2 diisopropylethylamine, Hünig's base TEA, Et 3 N triethylamine H 2 O water DMF dimethylformamide DMSO dimethylsulfoxide DMSO -d6 deuterated dimethylsulfoxide K 2 CO 3 potassium carbonate AcCN, MeCN, ACN acetonitrile TFA trifluoroacetic acid HCl hydrochloric acid HOAc, AcOH acetic acid THF tetrahydrofuran CHCl 3 chloroform CDCl 3 Deuterated chloroform EtOAc, EA ethyl acetate Na 2 SO 4 sodium sulfate mg milligram g gram ml, mL milliliter h, hr hour min minutes MgSO 4 magnesium sulfate NH 4 C1 ammonium chloride NH 4 OH ammonium hydroxide H 2 O water NaHCO 3 sodium bicarbonate MeOH methanol NaOH sodium hydroxide EtOH ethanol Cs 2 CO 3 cesium carbonate iPrOH, IPA isopropanol Pd(PPh 3 ) 2 Cl 2 bis(triphenylphosphine) palladium dichloride Ar argon N 2 nitrogen CO 2 carbon dioxide Pd(dppf)Cl 2 PdCl 2 (dppf) 1,1′-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II ) Pd(OAc) 2 Palladium(II) acetate Pd(dba) 2 Bis(dibenzylideneacetone)palladium(0) BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl PE petroleum ether NaBH 4 sodium borohydride NaBH 3 CN sodium cyano borohydride HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate NBS N-bromosuccinimide MsCl Mesyl chloride, methanesulfonyl chloride NaSMe Sodium thiomethoxide CSCl 2 Thiophosgene KF Potassium fluoride POCl 3 phosphorous oxychloride DCE dichloroethane LiCl lithium chloride LiOH lithium hydroxide NaH sodium hydride n-BuLi butyllithium MeNH 2 methyl amine PBr 3 phophorous tribromide MeI, CH 3 I methyl iodide MTBE methyl tertbutyl ether SOCl 2 thionyl chloride CDI carbonyldiimidazole NH 4 CO 3 ammonium carbonate Ph 3 P triphenyl phosphine FA formic acid SiO 2 silica EDC 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide Eq., equiv. equivalents SCHEME I [0259] The 3,4,6,8-tetraazatricyclo[7.4.0.0 2,6 ]trideca-1(13),2,4,7,9,11-hexaene compounds of the invention can be synthesized according to Scheme I. The tricyclic compounds are prepared from corresponding amino benzoic acids, amino pyridyl carboxylic acids and amino pyrimidinyl carboxylic acids. The aryl acids are converted to amides, such as by coupling ammonium chloride and HATU and DIPEA. Cyclization of the amides, such as with CSCl 2 , yields the 2-chloro bicyclic pyrimidinones. Chlorination, such as with POCl 3 , yields the 4- chloro bicyclic dihydro-pyrimidines. Conversion of the chloro derivatives to the hydrazines and the resulting cyclization yields the bromo tricyclic compounds. Preparation of the desired compounds of Formula 6 where L is alkyl, involves conversion of the bromo compounds to the corresponding ketones/aldehydes, alcohols, alkyl halides. SCHEME II [0260] The 1,3,5-triazanaphthalen-4-ones of the invention can be synthesized according to Scheme II from corresponding amino pyridyl carboxylic acids. The aryl acids are converted to amides, such as by coupling substituted amines and HATU. Bromination of the amides, such as with NBS, yields the corresponding 4-bromo pyridines. Cyclization of the bromo amides, such as with triphosgene, yields the 4-bromo bicyclic diones. Chlorination, such as with POCl 3 , yields 4-bromo-6-chloro bicyclic 1,3,5-triazanaphthalen-4-ones. Conversion of the chloro compounds, such as with substitution with amines (where R 1 is an amine or nitrogen containing heterocyclyl or heteroaryl ring). Substitution at the 6-chloro substituent, such as with methylboronic ester in the presence of PdCl 2 dppf and base, yields the R 3 substituted compounds (where R 3 is methyl). Preparation of the desired benzoic acid substituted aminoalkyl compounds of Formula 3 (where R is oxo), involves conversion of the bromo compounds to the corresponding protected amine, coupling with the 2-bromobenzoic ester, and deprotection/hydrolysis. SCHEME III [0261] The 1-thia-4,6-diazainden-7-ones of the invention can be synthesized according to Scheme III. 5,7- Dichloro 1-thia-4,6-diazaindenes are oxidized, such as with NaOH in THF, to yield the 5-chloro-1-thia-4,6- diazainden-7-ones. The 5-chloro-1-thia-4,6-diazainden-7-ones are converted to the R 2 substituted compounds, such as with treatment with sodium hydride and the iodo reagents. Bromination of the R 2 substituted compounds, such as with NBS, yields the corresponding 3-bromo-5-chloro-1-thia-4,6-diazainden-7-ones. The 3- bromo-5-chloro-1-thia-4,6-diazainden-7-ones are converted to the disubstituted compounds (where R 1 is an amine or nitrogen-containing heterocyclyl or heteroaryl ring), such as by coupling with substituted amines and base. Alkylation of the bromo compounds, such as with Pd(OAc) 2 and butyl vinyl ether, yields the 3-ketones. Reduction of the ketone, such as with NaBH 4 , yields the alcohols. Preparation of the desired benzoic acid substituted aminoalkyl compounds of Formula 8 (where R is oxo), involves treatment with MsCl, coupling with the 2-aminobenzoic ester, and deprotection/hydrolysis. SCHEME IV [0262] The 1,3,5,7-tetraazanaphthalen-4-ones of the invention can be synthesized according to Scheme IV from corresponding 5-amino-2,4-dichloropyrimidin-4-yl alkoxycarbonyls. The 6-chloro substituent is selectively converted to the methylthio compounds, such as by coupling NaSMe. Treatment of the 2-chloro substituent, such as with MeB(OH) 2 [where R 3 is methyl], yields the tetrasubstituted pyrimidines. Conversion of the ester, such as with base and addition of an amine in the presence of HATU, provides the corresponding amide. Cyclization of the amide, such as with triphosgene provides the dihydro 1,3,5,7-tetraazanaphthalen-2,4-diones. Treatment with POCl 3 yields the 2-chloro-1,3,5,7-tetraazanaphthalen-4-ones. Conversion of the chloro derivatives, such as with a primary or secondary amines in the presence of DIEA, provides the R 1 substituted compounds. Conversion of the methylthio group, such as with SO 2 Cl 2 , provides the 8-chloro compounds. Preparation of the desired compounds of Formula 5 where L is alkyl, involves conversion of the bromo compounds to the corresponding ketones/aldehydes, alcohols, alkyl halides. SCHEME V [0263] The 1,4a-diaza-4-naphthalenones of the invention can be synthesized according to Scheme V from corresponding 5-amino-pyridines. The 2-hydroxy 1,4a-diaza-4-naphthalenones are formed by addition of a dione to the pyridines. Treatment of the 2-hydroxy substituent, such as with MsCl and a primary or secondary amine yields the yields the R 1 substituted pyrimidines converted to the disubstituted compounds [where R 1 is an amine or nitrogen containing heterocyclyl or heteroaryl ring]. Alkylation of the bromo substituent, such as with Pd(OAc) 2 and butyl vinyl ether, and treatment with acid yields the 8-ketones. Reduction of the ketone, such as with NaBH 4 , yields the alcohols. Preparation of the desired compounds of Formula 7 (where -L-A-R 4 is benzoic acid substituted aminoalkyl), involves treatment with PBr 3 or MsCl, coupling with the 2-aminobenzoic ester, and deprotection/hydrolysis.

SCHEME VI [0264] Similarly, 1,4a-diaza-4-naphthalenones of the invention (where -L-A-R 4 is carboxypyridyl substituted aminoalkyl), can be synthesized according to Scheme VI from corresponding 8-methylketones in Scheme V. Treatment of the of the ketone with tertbutyl-sulfinylamine yields the protected amino alkyl compounds. Deprotection and coupling with the 3-fluoro-pyridyl ester, and ester hydrolysis yields the desired compounds. SCHEME VII [0265] Methods of preparing 1,3,7-triazanaphthalen-4-one intermediates (where R 2 and R 3 are methyl), can be synthesized according to Scheme VII from corresponding 3-pyridines. Bromination of the pyridine such as with NBS provides the 6-bromo pyridyl amines. Alkylation of the bromo group, such as with the methyl boronic ester, yields the 6-methyl compounds. Hydrolysis of the ester, such as with base, and treatment with CH 3 -NCS, yields the 2-thio-1,3,7-triazanapthalen-4-one. Treatment of the thio compounds with SO 2 Cl 2 yields the 2-chloro intermediates. Alternatively, the 3-amino-4-carboxylic acids can be treated with methylamine to form the corresponding amide. Cyclization with CDI or triphosgene then chlorination with POCl 3 yields the 2-chloro-1,3,7- triazanapthalen-4-ones intermediates. SCHEME VIII [0266] Methods of preparing 1,4a-diaza-4-naphthalenone intermediates (where R 2 and R 3 are methyl), can be synthesized according to Scheme VIII from corresponding 2,4,6-trichlorphenol. Treatment of the phenols with the diacid provides the diester. Treatment of a 2-aminopyridine with the diester yields the 2-hydroxy-11,4a- diaza-4-naphthalenone intermediates. SCHEME IX [0267] Methods of preparing 4-oxo-3,4-dihydroquinazolines (where R 2 and R 3 are methyl), can be synthesized according to Scheme IX from corresponding bromoanilines. Anilines 1 are substituted with R 1 substituted carboxylic acids and treated with T3P in PhMe and heated at reflux to form the 8-bromo-4-oxo-3,4- dihydroquinazolines 3. 8-Acetyl-4-oxo-3,4-dihydroquinazolines 5 are formed from the 8-bromo-4-oxo-3,4- dihydroquinazolines 2 such as with treatment with tributyl(1-ethoxyvinyl)tin. Conversion of the acetyl compound to the corresponding ethylidene sulfinamides 7, results from treatment with (R)-2-methylpropane-2-sulfinamide and Ti(O-iPr) 4 . Reduction of ethylidene sulfinamides 7, such as with NaBH 3 CN, provides the ethylsulfinamides 8. Removal of the sulfinamide group, such as with treatment with acid, more particularly 1M HCl, provides the primary amines 9, which can be coupled with substituted rings A, such as fluoropyridines, to provide the compounds of Formula 2a-2b. SCHEME X [0268] Methods of preparing benzo[c]2,7-naphthyridines (where X 5 is C and R and R 2 form pyrdine), can be synthesized according to Scheme X from corresponding anilines and pyridines. Reaction of (phenylboronic esters with substituted pyridines, such as in the presence of Pd(dppf)Cl 2 gives the benzo[c]2,7-naphthyridin-7-yl sulfinamides. The amines are prepared by removal of the sulfinamide, such as by treatment with acid, for example HCl. Couplng with halo substituted rings, such as fluoropyridines, provides the substituted amines of Formula 10 A-C. SCHEME XI [0269] Methods of preparing 4-oxo-3,4-dihydroquinazolines (where R is phenyl, R 2 and R 3 are methyl), can be synthesized according to Scheme XI from corresponding anilines. Treatment of the anilines with triethylorothoformate in ther prescence of acid, such as TFA, provdes the 8-bromo-4-oxo-3,4-dihydroquinazolines (where R 1 is H). Treatment of the bromo compounds with Pd(PPh 3 ) 2 Cl 2 and tributyl (1-ethoxyvinyl)tin provides the 8-acetyl compounds. Conversion of the acetyl compound to the corresponding ethylidene sulfinamides results from treatment with (R)-2-methylpropane-2-sulfinamide and Ti(O-iPr) 4 . Reduction of ethylidene sulfinamides 7, such as with NaBH 3 CN, provides the ethylsulfinamides. Removal of the sulfinamide group, such as with treatment with acid, more particularly 1M HCl, provides the primary amines, which can be coupled with substituted rings A, such as fluoropyridines, to provide the compounds 11 (where R 1 is H). Providing 4-oxo-3,4- dihydroquinazolines (where R 1 is not H) is accomplished by Pd/Cu arylation, such as by treatment of the compounds 11 with Pd(OAc) 2 , CuI, 4,4'-dimethoxy-2,2'-bipyridine, and LiOtBu-. SCHEME XII [0270] Methods of preparing 4-oxo-3,4-dihydroquinazolines (where R is phenyl, R 2 and R 3 are methyl), can be synthesized according to Scheme XII from corresponding primary amines using nucleophilic aromatic substitution [SnAr] . Treatment of the 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-phenyl-3,4-dihydroquina zolin-4-ones with fluoro substituted pyridines and ethylbis(propan-2-yl)amine provides methyl 3-{[(1R)-1-(3,6-dimethyl-4-oxo- 2-phenyl-3,4-dihydroquinazolin-8-yl)ethyl]amino}-6-methylpyr idine-2-carboxylate. Conversion to the free acid can be achieved such as by treatment with LiOH. SCHEME XIII [0271] Methods of preparing 4-oxo-3,4-dihydroquinazolines (where R is phenyl, R 2 and R 3 are methyl), can be synthesized according to Scheme XIII from corresponding primary amines using Buchwald coupling. Primary amines can be coupled with iodosubstituted compounds such as with standard Buchwald coupling conditions, for example tris(dibenzylideneacetone)dipalladium(0), XantPhos and cesium carbonate to the desired substituted amines. Conversion to the free acid can be achieved such as by treatment with LiOH. SCHEME XIV [ 0272] Methods of preparing 4-oxo-3,4-dihydroquinazolines (where R 4 are amides), can be synthesized according to Scheme XIV from corresponding acids. The acids can be converted to the amides by standard amidation chemistry, such as coupling with primary amines with HATU. SCHEME XV [0273] Methods of preparing BOC-protected 4-oxo-3,4-dihydroquinazolines (where R 1 is substituted aryl or heteraryl substituentsamides), can be synthesized according to Scheme XV from corresponding halo substituted compounds 11 using Suzuki coupling chemistry. The halo substituted compounds 11, made by methods similar to that described previously, can be converted to the substituted ring compounds by standard Suzuki coupling chemistry, such as coupling with Pd(dppf)Cl 2 and K 2 CO 3 . Conversion to the free acid can be achieved such as by treatment with TFA. SCHEME XVI [0274] Methods of preparing 4-oxo-3,4-dihydroquinazoline acids, can be synthesized according to Scheme XVI from corresponding esters using ether cleavage chemistry. The esters, made by methods similar to that described previously, can be converted to the acids with treatment with BBr 3 . At a temperature between about 0 °C and RT. SCHEME XVII [0275] Methods of preparing 4-oxo-3,4-dihydroquinazoline acids, can be synthesized according to Scheme XVII from corresponding BOC-protected acids using SnAR chemistry. The acids are first Boc protected, such as with BOC anhydride and DMAP, then coupled to primary amines substituted 4-oxo-3,4-dihydroquinazoline, prepared as described elsewhere, using DIPEA. The compounds are deprotected, such as with TFA, to provide the acids of the invention. [0276] The following examples contain detailed descriptions of the methods of preparation of compounds of Formulas 1-10. These detailed descriptions fall within the scope, and serve to exemplify, the above described General Synthetic Procedure which form part of the invention. These detailed descriptions are presented for illustrative purposes only and are not intended as a restriction on the scope of the invention. All parts are by weight and temperatures are in Degrees centigrade unless otherwise indicated. General Methods 1 HNMR experiment was run on Bruker Avance III 400 MHz, at 25 °C. Preparative methods: CP Preparative Pre-HPLC Method A: Mobile Phase: A: Water (10mM NH 4 HCO 3 ) B:ACN Gradient: 25% - 55% B within 9 min, stop at 17min Flow Rate: 30 ml/min Column: Xtimate Prep C1810µm 21.2×250mm Column Temperature: 40C Detection: UV (214 nm, 254 nm) Method B: Mobile Phase: A: Water (0.2% FA ) B:ACN Gradient: 25% - 55% B within 9 min, stop at 17min Flow Rate: 30 ml/min Column: Boston Prep C1810µm 21.2×250mm Column Temperature: 40 °C Detection: UV (214 nm, 254 nm) LCMS experiments: [0277] All CP LCMS experiments were run on Agilent 1200, with a column temperature of 40 °C, monitoring UV absorption at 214 nm and scanning a mass range from 100-1000. Individual conditions vary slightly as described in the methods below: [0278] LCMS CP Method A (014): Column: Xbridge SB-C184.6*50MM, 3.5um; Mobile Phase: A: Water (0.1%TFA), B: ACN (0.1%TFA); Gradient: 5% B increase to 95% B over 1.8 min, stop at 3 min. Flow Rate: 1.8 mL/min [0279] LCMS CP Method B (026): Column: XBridge C18, 4.6*50mm, 3.5um; Mobile Phase: A: Water (0.05%TFA), B: ACN (0.05%TFA); Gradient: 5% B increase to 95% B over 1.7min, stop at 3 min. Flow Rate: 2.0 mL/min [0280] LCMS CP Method C (025): Column: XBridge C1850*4.6mm, 3.5um; Mobile Phase: A: H 2 O (10mM NH 4 HCO 3 ), B: MeCN; Gradient: 5%-95% B in 1.3min, 95%B for 2.95min, back to 5%B within 0.05 min; Flow Rate: 2.0 mL/min [0281] LCMS CP Method D (028): Column: X-Bridge C18, 4.6*50mm, 3.5um; Mobile phase: A 10mM NH 4 HCO 3 in water B ACN; Gradient: 5% increase to 95%B within 1.4min, 95%B for 1.6min; Flow Rate: 2.0 ml/min [0282] LCMS CP Method E (008): Column: XBridge SB-C18, 4.6*50mm, 3.5um; Mobile Phase: A: Water (10mM NH 4 HCO 3 ), B: ACN; Gradient: 5% increase to 95%B within 1.4min, 95%B for 2.9min, back to 5%B within 0.05min; Flow Rate: 2.0 ml/min [0283] LCMS CP Method F (051): Column: XBridge C18, 4.6*150mm, 3.5um; Mobile Phase: A: Water (10mM NH 4 HCO 3 ) B: ACN; Gradient: 5% increase to 95%B within 9.5min, 95%B for 5min; Flow Rate: 1.0 ml/min [0284] LCMS CP Method G (054): Column: XBridge C18, 4.6*50mm, 3.5um; Mobile Phase: A: Water (10mM NH 4 HCO 3 ) B: ACN; Gradient: 5% increase to 95%B within 1.4min, 95%B for 1.7min; Flow Rate: 2.0 ml/min [0285] LCMS CP Method H (032): Column: Poroshell 120 EC C182.7 um 3.0* 30 mm; Mobile Phase: A: water (0.01%TFA) B: ACN (0.01% TFA); Gradient: 5%- 95% B in 1.5 min; Flow Rate: 1.6 ml/min [0286] LCMS CP Method I (015): Column: SunFire C183.5 um 4.6* 50 mm; Mobile Phase: A: Water (0.01%TFA) B: ACN (0.01%TFA ); Gradient: 5% increase to 95%B within 1.4 min, 95%B for 2.95 min, back to 5%B within 0.05 min; Flow Rate: 2.0 ml/min [0287] LCMS CP Method J (009): Column: XBrige C18, 4.6* 50 mm, 3.5 um; Mobile phase: A: Water (10mM NH 4 HCO 3 ) B: ACN; Gradient from 10 to 95% of B in 1.5 min at 1.8 ml/min [0288] LCMS CP Method K (038): Column: SunFire C18 (4.6x 50 mm, 3.5 um); Mobile phase: H 2 O (0.01%TFA) (A) / ACN (0.01%TFA) (B); Elution program: Gradient from 10 to 95% of B in 1.4 min at 2 ml/min [0289] LCMS CP Method L (039): Column: XBridge C18, 4.6* 50 mm, 3.5 um; Mobile Phase: A: Water (10mM NH 4 HCO 3 ) B: ACN; Gradient: 5% increase to 95%B within 1.4 min, 95%B for 1.6 min; Flow Rate: 1.8 ml/min [0290] LCMS CP Method M (052): Column Agilent InfinityLab Poroshell 120EC-C184.6* 50 mm 4micron; Mobile Phase: A: Water (0.01%tfa) B: ACN (0.01%tfa); Gradient: 10% increase to 95%B within 1.5 min 95%B for 1.5 min; Flow Rate: 1.8 ml/min [0291] LCMS CP Method N (053): Column: Kinetex 2.6 um EVO C18100A, 4.6* 50 mm; Mobile Phase: A: Water (10mM NH 4 HCO 3 ) B: ACN; Gradient: 10% increase to 95%B within 1.3 min, 95%B for 1.5 min; Flow Rate: 2.2 ml/min [0292] LCMS CP Method O (044): Column: Proshell 120 EC-C1830* 3 mm, 2.7 um; Mobile Phase: A: water (0.01%TFA) B: ACN (0.01%TFA); Gradient: 5%-95% B in 1.05 min; Flow Rate: 1.6 ml/min [0293] LCMS CP Method P (022): Column: Xbridge C18, 3.5 um, 4.6 mm* 50 mm; Mobile Phase: A:water(0.01%TFA) B:ACN(0.01%TFA); Gradient: 5%B increase to 95%B within 1.3 min, 95%B for 1.6 min; Flow Rate 2.0 ml/min [0294] LCMS CP Method Q (033): Column: Xbridge C18, 3.5 um, 4.6* 50 mm; Mobile Phase: A: Water (10mM NH 4 HCO 3 ) B: ACN; Gradient: 5%B increase to 95%B within 1.3 min, 95%B for 1.7 min; Flow Rate: 1.8 ml/min [0295] LCMS CP Method R (056): Column: Xbridge C18, 3.5 um, 4.6* 50 mm; Mobile Phase: A: Water (10mM NH 4 HCO 3 ) B: ACN; Gradient: 5% increase to 95%B within 1.3 min, 95%B for 1.7 min; Flow Rate: 1.8 ml/min [0296] LCMS CP Method S (020): Column: Sunfire C18, 4.6* 50 mm, 3.5 um; Mobile Phase: A: water (0.01%TFA) B: ACN (0.01%TFA); Gradient: 5%B increase to 95%B within 1.3 min, 95%B for 1.7 min. Flow Rate: 2.0 ml/min [0297] LCMS CP Method T (024): Column: Agilent Poroshell, 30* 3.0 mm, 2.7 um; Mobile Phase: A: water (0.01%TFA) B: ACN (0.01%TFA); Gradient: 5% increase to 95%B within 1.0 min, 95%B for 1.0 min; Flow Rate: 1.6 ml/min [0298] Preparation 1: THF (50 mL) was cooled to -78°C. LDA (2.0 M in THF/heptane/ethylbenzene) (6 mL, 1.2 eq., 12 mmol) was added, and then 2-chloropyrazine (893 µL, 10 mmol) was added dropwise. The solution was stirred at -78°C for 1 hour, then a solution of N,N-dimethylbenzamide (1.79 g, 1.2 eq., 12 mmol) in THF (4 mL) was added dropwise and the solution was stirred at -78°C for 30 minutes before quenching with saturated aqueous NH 4 Cl (50 mL). After warming, the mixture was extracted with EtOAc, washed with brine and dried over Na 2 SO 4 . Volatiles were removed in vacuo, and the crude residue was purified by silica gel flash chromatography (15% EtOAc/hexanes isocratic). Fractions containing the compound were collected and concentrated to give 2- benzoyl-3-chloropyrazine (899 mg, 41%) as a yellow oil. LCMS: 219.9 [M+H] + . [0299] Preparation 2: n-BuLi (190 mg, 1.1 eq., 2.97 mmol) was added to a solution of 5-bromo-4-chloro-2- methoxypyridine (0.6 g, 2.7 mmol) in THF (27 mL, 331 mmol) at -78 °C slowly and stirred for 30 min. N-methoxy- N-methylpropanamide (395 µL, 1.2 eq., 3.24 mmol) was added to the mixture and stirred at -78 °C for 30 min. The mixture was warmed to r.t. for 1 h. The reaction was quenched with sat. aqueous NH 4 Cl solution (20 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 X 10 mL). The organic layers were combined, dried over MgSO 4 , filtered, and concentrated in vacuo. The crude was purified by ISCO silica column chromatography (0-100% EtOAc/Hex). Fractions containing the product were collected and concentrated in vacuo to give 1-(4-chloro-6-methoxypyridin-3-yl)propan-1-one (157 mg, 786 µmol) as a clear oil. LCMS: 200.0 [M+H] + . [0300] Preparation 3: 2,6-Dibromo-4-methylaniline (5 g, 18.9 mmol), tributyl(1-ethoxyethenyl)stannane (6.38 mL, 18.9 mmol), and Pd(PPh 3 ) 2 Cl 2 (662 mg, 0.05 eq., 944 µmol) were suspended in 1,4-dioxane (189 mL, 2.21 mol), purged with Ar, and heated to 90 °C. The mixture was stirred for 2 h , then cooled to 50 °C.2 N HCl (5 mL) was added and the mixture was stirred for 30 min. The mixture was cooled to r.t. and stirred with sat. KF solution (5 mL) for 10 min. The mixture was diluted with EtOAc (40 mL) and washed with Brine (50 mL). The organic layer was separated, dried over MgSO 4 , filtered over Celite, and concentrated in vacuo. The crude product was purified by ISCO silica flash column chromatography (0-100% EtOAc/Hex). Fractions containing the compound were collected and concentrated in vacuo to give 1-(2-amino-3-bromo-5-methylphenyl)ethan-1-one (1.72 g, 7.54 mmol) as a yellow solid. LCMS: 228.0 [M+H] + . [0301] Preparation 4: 1-(2-Amino-3-bromo-5-methylphenyl)ethan-1-one (0.5 g, 2.19 mmol), (R)-2- methylpropane-2-sulfinamide (531 mg, 2 eq., 4.38 mmol), and titanium(4+) tetraethanolate (1.38 mL, 3 eq., 6.58 mmol) were heated at reflux in THF (21.9 mL, 269 mmol) for 16 h. The mixture was cooled to r.t. then diluted with brine (10 mL). The mixture was filtered over Celite and washed with EtOAc (100 mL). The precipitate was separated from the aqueous, dried over MgSO 4 , filtered, and concentrated in vacuo. The crude was purified by ISCO silica column chromatography (0-100% EtOAc/Hex). Fractions containing the compound were collected and concentrated in vacuo to give (R)-N-[(1Z)-1-(2-amino-3-bromo-5-methylphenyl)ethylidene]-2- methylpropane- 2-sulfinamide (0.6 g, 1.81 mmol) as a yellow oil. LCMS: 331.0 [M+H] + . [0302] Preparation 5: DIBAL (767 mg, 3 eq., 5.43 mmol) was slowly added to a solution of (R)-N-[(1Z)-1-(2- amino-3-bromo-5-methylphenyl)ethylidene]-2-methylpropane-2-s ulfinamide (0.6 g, 1.81 mmol) in THF (18.1 mL, 223 mmol) at -78 °C and stirred for 3 h. The mixture was quenched with brine (10 mL), extracted with EtOAc (3 X 10 mL). The organic layers were combined, dried over MgSO 4 , filtered, and concentrated in vacuo. The crude was purified by ISCO silica column chromatography (25-100% EtOAc/Hex). Fractions containing the compound were collected and concentrated in vacuo to give (R)-N-[(1R)-1-(2-amino-3-bromo-5-methylphenyl)ethyl]-2- methylpropane-2-sulfinamide (487 mg, 1.46 mmol) as a yellow solid. LCMS: 333.0 [M+H] + ; 96% ee. [0303] Preparation 6: (R)-N-[(1R)-1-(2-Amino-3-bromo-5-methylphenyl)ethyl]-2-methy lpropane-2-sulfinamide (1.65 g, 4.95 mmol), B 2 Pin 2 (1.89 g, 1.5 eq., 7.43 mmol), KOAc (1.46 g, 3 eq., 14.9 mmol), and Pd(dppf)Cl 2 (362 mg, 0.1 eq., 495 µmol) were suspended in 1,4-dioxane (49.5 mL, 580 mmol). The mixture was purged with Ar and heated to 80 °C. After 16 h, the mixture was cooled to r.t. and filtered over Celite. The filtrated was concentrated in vacuo. The crude was purified with ISCO silica column chromatography (20-100% EtOAc/Hex). Fractions containing the compound were collected and concentrated in vacuo to give (R)-N-[(1R)-1-[2-amino-5- methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl ]ethyl]-2-methylpropane-2-sulfinamide (2.11 g, 5.55 mmol) as a yellow oil. LCMS: 381.2 [M+H] + . Example 1 2-((1-(3,6-Dimethyl-4-oxo-2-(piperidin-1-yl)-3,4-dihydroquin azolin-8-yl)ethyl)amino)benzoic acid [0304] Step 1: A mixture of 2-amino-3-bromo-5-methylbenzoic acid (2.29 g, 10 mmol), methanamine hydrochloride (1.0 g, 15 mmol), HATU (5.15 g, 15 mmol) and DIPEA (3.87 g, 30 mmol) in DCM (50 ml) was stirred at RT overnight. Water (50 ml) was added and the mixture was extracted with DCM (50 ml*3). The combined organic phases were washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by chromatography (PE: EA = 3:1) to afford 2-amino-3-bromo-5-methylbenzamide (2.2 g, 91%) as a white solid. [0305] Step 2: To a solution of 2-amino-3-bromo-5-methylbenzamide (2.2 g, 9.09 mmol) in dioxane (40 ml) was added thiophosgene (2.07 g, 18.18 mmol) dropwise. The mixture was stirred at RT for 1 h and then stirred at 105 °C for 1 h. The mixture was concentrated to afford crude 8-bromo-2-chloro-3,6-dimethylquinazolin-4(3H)-one (2.59 g, purity: 70% (254 nm)) as a yellow solid which was used directly in the next step without further purification. LCMS: (M + H) + =287.0; Retention time = 1.23 min. LCMS CP Method B [0306] Step 3: To a solution of 8-bromo-2-chloro-3,6-dimethylquinazolin-4(3H)-one (2.59 g, 9.06 mmol) in DCM (50 ml) was added piperidine (1.5 g, 18.12 mmol) and the mixture was stirred at 40 °C overnight. Water (50 ml) was added and the mixture was extracted with DCM (50 ml*3). The combined organic phases were washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 5:1) to afford 8-bromo-3,6-dimethyl-2-(piperidin-1-yl)quinazolin-4(3H)-one (2.1 g, 67%) as a yellow solid. LCMS: (M + H) + =336.1; Retention time = 1.45 min. LCMS CP Method B [0307] Step 4: A mixture of 8-bromo-3,6-dimethyl-2-(piperidin-1-yl)quinazolin-4(3H)-one (1.0 g, 3.0 mmol), Pd(PPh 3 ) 2 Cl 2 (210 mg, 0.3 mmol) and tributyl(1-ethoxyvinyl)stannane (1.31 g, 3.6 mmol) in dioxane (25 ml) was stirred at 95 °C under N 2 overnight. HCl (1.5 ml, 2 M) was added and the mixture was stirred at 50 °C for 0.5 h, 50 ml of saturated KF solution was added and the mixture was stirred at RT for 0.5 h. Filtered and the filter cake was washed with EtOAc (10 ml*3). The aqueous phase was extracted with EtOAc (50 ml*3). The combined organic phases were washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 5:1) to afford 8-acetyl-3,6-dimethyl-2-(piperidin-1-yl)quinazolin-4(3H)-one (500 mg, 56%) as a yellow solid. LCMS: (M + H) + =300.3; Retention time = 1.02 min. LCMS CP Method B [0308] Step 5: A solution of 8-acetyl-3,6-dimethyl-2-(piperidin-1-yl)quinazolin-4(3H)-one (500 mg, 1.67 mmol) in MeOH (20 ml) was added NaBH 4 (127 mg, 3.34 mmol) in portions at 0 °C and the mixture was stirred at RT for 1 h. The mixture was diluted with water (20 ml) and extracted with DCM (30 ml*3). The combined organic phases were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to afford crude 8-(1-hydroxyethyl)-3,6- dimethyl-2-(piperidin-1-yl)quinazolin-4(3H)-one (500 mg, 99%) as a yellow oil for the next step without further purification. LCMS: (M + H) + =302.2; Retention time = 1.09 min. LCMS CP Method B [0309] Step 6: To a solution of 8-(1-hydroxyethyl)-3,6-dimethyl-2-(piperidin-1-yl)quinazolin -4(3H)-one (500 mg, 1.66 mmol) in DCM (30 ml) was added PBr 3 (900 mg, 3.32 mmol) dropwise at 0 °C and the mixture was stirred at RT for 1 h. The mixture was cooled to 0 °C and the pH was adjusted to 8 with saturated aqueous NaHCO 3 solution. The mixture was extracted with DCM (40 ml*3). The combined organic phases were washed with brine, dried over Na 2 SO 4 and concentrated to afford crude 8-(1-bromoethyl)-3,6-dimethyl-2-(piperidin-1-yl)quinazolin- 4(3H)-one (450 mg, 75%) as a yellow oil which was used directly in the next step without further purification. LCMS: (M–Br+OMe) + =316.3; Retention time = 1.24 min. LCMS CP Method B [0310] Step 7: A mixture of 8-(1-bromoethyl)-3,6-dimethyl-2-(piperidin-1-yl)quinazolin-4 (3H)-one (450 mg, 1.24 mmol) and methyl 2-aminobenzoate (280 mg, 1.86 mmol) in DMF (10 ml) was stirred at 80 °C overnight. After cooled to RT, water (50 ml) was added and the mixture was extracted with EtOAc (40 ml*3). The combined organic phases were washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by chromatography (PE: EA = 5:1) to afford methyl 2-((1-(3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate (170 mg, 32%) as a yellow solid. LCMS: (M + H) + =435.0; Retention time = 2.06 min. LCMS CP Method D [0311] Step 8: A mixture of methyl 2-((1-(3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4-dihydroquin azolin-8- yl)ethyl)amino)benzoate (170 mg, 0.39 mmol) and LiOH (46 mg, 1.95 mmol) in MeOH (5 ml) and H 2 O (1 ml) was stirred at 50 °C for 8 h. The mixture was concentrated and the pH was adjusted to 4-5 with 1 N HCl. The mixture was concentrated and the residue was purified by Prep-HPLC (Method A) to afford 2-((1-(3,6-dimethyl-4-oxo-2- (piperidin-1-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benz oic acid (109.6 mg, 69%) as a white solid. LCMS: (M + H) + =421.0; Retention time = 1.33 min. LCMS CP Method D. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 8.51 (s, 1 H), 7.78 (dd, J = 1.6, 8.4 Hz, 1 H), 7.70 (s, 1 H), 7.46 (s, 1 H), 7.18-7.14 (m, 1 H), 6.47 (t, J = 8.0 Hz, 2 H), 5.42-5.39 (m, 1 H), 3.48 (s, 3 H), 3.41-3.19 (m, 4 H), 2.32 (s, 3 H), 1.70-1.61 (m, 6 H), 1.56 (d, J = 6.4 Hz, 3 H). Example 2 3,6-Dimethyl-8-(1-(phenylamino)ethyl)-2-(piperidin-1-yl)quin azolin-4(3H)-one [0312] A mixture of 8-acetyl-3,6-dimethyl-2-(piperidin-1-yl)quinazolin-4(3H)-one (180 mg, 0.6 mmol), aniline (111.6 mg, 1.2 mmol) and HOAc (72 mg, 1.2 mmol) in MeOH (5 mL) was stirred at RT for 6 h, then NaBH 3 CN (75.6 mg, 1.2 mmol) was added and the mixture was stirred at RT overnight. Water (20 mL) was added and the mixture was extracted with DCM (20 mL*3). The combined organic phases were washed with brine, dried over Na 2 SO 4, filtered and concentrated. The residue was purified by Prep-HPLC (method A) to afford 3,6-dimethyl-8-(1- (phenylamino)ethyl)-2-(piperidin-1-yl)quinazolin-4(3H)-one (107.5 mg, 48%) as a brown solid. LCMS: (M + H) + =377.0; Retention time = 1.89 min. LCMS CP Method D. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 7.67 (s, 1 H), 7.53 (s, 1 H), 6.95 (t, J = 8.0 Hz, 2 H), 6.48-6.41 (m, 3 H), 6.19 (d, J = 7.2 Hz, 1 H), 5.31 (t, J = 6.8 Hz, 1 H), 3.48 (s, 3 H), 3.20 (s, 4 H), 2.31 (s, 3 H), 1.70-1.62 (m, 6 H), 1.44 (d, J = 6.8 Hz, 3 H). Example 3 2-((1-(2-(4,4-Dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4 -dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [0313] Step 1: A mixture of 2-amino-3-bromo-5-methylbenzoic acid (2.00 g, 8.67 mmol), methanamine hydrochloride (0.874 mg, 13.0 mmol), HATU (4.95 g, 13.0 mmol) and DIPEA (2.24 g, 17.4 mmol) in DCM (50 mL) was stirred at RT overnight. Water (50 mL) was added and the separated aqueous layer was extracted with DCM (50 mL*3). The combined organic phases were washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 3:1) to afford 2-amino-3-bromo-5- methylbenzamide (2.1 g, 99.7%) as a white solid. LCMS: (M + H) + =242.9; Retention time = 1.37 min. LCMS CP Method D. [0314] Step 2: To a solution of 2-amino-3-bromo-5-methylbenzamide (2.2 g, 9.09 mmol) in dioxane (40 mL) was added thiophosgene (2.07 g, 18.18 mmol) dropwise. The mixture was stirred at RT for 1 h and at 105 °C for additional 1 h. The mixture was concentrated to afford the crude 8-bromo-2-chloro-3,6-dimethylquinazolin-4(3H)- one (2.59 g, purity: 70% (254 nm)) as a yellow solid which was used directly in the next step reaction without further purification. LCMS: (M + H) + =287.0; Retention time = 1.23 min. LCMS CP Method B [0315] Step 3: To a solution of 8-bromo-2-chloro-3,6-dimethylquinazolin-4(3H)-one (1.00 g, mmol) in DCM (50 mL) were added 4,4-dimethylpiperidine hydrogen chloride (0.593 mg, 5.24 mmol) and DIPEA (0.902 mg, 6.99 mmol). The resulting mixture was stirred at 40 °C overnight. Water (50 mL) was added and the mixture was extracted with DCM (50 mL*3). The combined organic phases were washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 5:1) to afford 8-bromo-2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethylquinazoli n-4(3H)-one (1.00 g, 78.7%) as a yellow solid. LCMS: (M + H) + =364.2; Retention time = 2.21 min. LCMS CP Method G. [0316] Step 4: A mixture of 8-bromo-2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethylquinazoli n-4(3H)-one (1.0 g, 2.754 mmol), Pd(PPh 3 ) 2 Cl 2 (0.996 mg, 1.378 mmol) and tributyl(1-ethoxyvinyl)stannane (1.31 g, 3.6 mmol) in dioxane (25 mL) was heated to 95 °C and stirred at the same temperature overnight under N 2 . HCl aqueous solution (1.5 mL, 2 M) was added into the mixture and the mixture stirred at 50 °C for 0.5 h. Then saturated aqueous KF solution (50 mL) was added and the mixture was stirred at RT for additional 0.5 h. The mixture was filtered and the filter cake was washed with ethyl acetate (10 mL*3). The filtrate was extracted with ethyl acetate (50 mL*3). The combined organic phases were washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 5:1) to afford 8-acetyl-2-(4,4- dimethylpiperidin-1-yl)-3,6-dimethylquinazolin-4(3H)-one (800 mg, 88.9%) as a yellow solid. LCMS: (M + H) + =328.1; Retention time = 2.04 min. LCMS CP Method G. [0317] Step 5: To a solution of 8-acetyl-2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethylquinazol in-4(3H)-one (200 mg, 0.612 mmol) in MeOH (20 mL) was added NaBH 4 (46.48 mg, 1.223 mmol) in portions at 0 °C and the resulting mixture was stirred at RT for 1 h. The mixture was diluted with water (20 mL) and extracted with DCM (30 mL*3). The combined organic phases were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to afford the crude 2-(4,4-dimethylpiperidin-1-yl)-8-(1-hydroxyethyl)-3,6-dimeth ylquinazolin-4(3H)-one (210 mg, 99%) as a yellow oil which was used directly in the next step reaction without further purification. LCMS: (M + H) + =330.3; Retention time = 1.96 min. LCMS CP Method G. [0318] Step 6: To a solution of 2-(4,4-dimethylpiperidin-1-yl)-8-(1-hydroxyethyl)-3,6-dimeth ylquinazolin-4(3H)- one (210 mg, 0.638 mmol) in DCM (30 mL) was added PBr 3 (346 mg, 1.276 mmol) dropwise at 0 °C and the resulting mixture was stirred at RT for 1 h. The mixture was cooled 0 °C and the pH value was adjusted to 8 with saturated aqueous solution of NaHCO 3 . The mixture was extracted with DCM (40 ml*3). The combined organic phases were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to afford the crude 8-(1- bromoethyl)-2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethylquina zolin-4(3H)-one (200 mg, 80.1%) as a yellow oil which was used directly in the next step reaction without further purification. LCMS: (M –Br +OMe) + =344.4; Retention time = 1.92 min. LCMS CP Method G. [0319] Step 7: A solution of 8-(1-bromoethyl)-2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl quinazolin-4(3H)-one (200 mg, 0.512 mmol) and methyl 2-aminobenzoate (154.5 mg, 1.023 mmol) in DMF (10 mL) was stirred at 80 °C for 3 hours. After cooled to RT, water (50 ml) was added and the mixture was extracted with ethyl acetate (40 ml*3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 5:1) to afford methyl 2-((1- (2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihyd roquinazolin-8-yl)ethyl)amino)benzoate (150 mg, 63.4%) as a yellow solid. LCMS: (M + H) + =463.3; Retention time = 1.63 min. LCMS CP Method B. [0320] Step 8: A mixture of methyl 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4 - dihydroquinazolin-8-yl)ethyl)amino)benzoate (150 mg, 0.325 mmol), LiOH (68.1mg, 1.623 mmol), MeOH (5 mL) and H 2 O (1 mL) was stirred at 50 °C for 16 h. Then the mixture was concentrated and the pH value was adjusted to 4-5 with 1 N HCl aqueous solution. The mixture was concentrated and the residue was purified by Prep-HPLC (Method B) to afford 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4 -dihydroquinazolin-8- yl)ethyl)amino)benzoic acid (77.5 mg, 53.3%) as a white solid. LCMS: (M + H) + =449.4; Retention time = 1.63 min. LCMS CP Method G. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 8.42 (s, 1 H), 7.78 - 7.70 (m, 2 H), 7.45 (s, 1 H), 7.19 -7.16 (m, 1 H), 6.50-6.46 (m, 2 H), 5.41 (s, 1 H), 3.46 (s, 3 H), 3.23- 3.21 (m, 4 H), 2.31 (s, 3 H), 1.57 - 1.47 (m, 7 H), 1.00 (s, 6 H). Example 4 2-((1-(2-(Isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroqui nazolin-8-yl)ethyl)amino)benzoic acid [0321] Step 1: To a solution of 8-bromo-2-chloro-3,6-dimethylquinazolin-4(3H)-one (600 mg, 2.10 mmol) in DCM (50 ml) was added isoindoline (499.3 mg, 4.195 mmol) and the mixture was stirred at 40 °C overnight. Water (50 mL) was added and the mixture was extracted with DCM (50 mL*3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 5:1) to afford 8-bromo-2-(isoindolin-2-yl)-3,6-dimethylquinazolin-4(3H)-one (500 mg, 64.5%) as a yellow solid. LCMS: (M + H) + =370.1; Retention time = 2.07 min. LCMS CP Method G. [0322] Step 2: A mixture of 8-bromo-2-(isoindolin-2-yl)-3,6-dimethylquinazolin-4(3H)-one (500 mg, 1.35 mmol), Pd(PPh 3 ) 2 Cl 2 (285 mg, 0.406 mmol) and tributyl(1-ethoxyvinyl)stannane (1.36 g, 3.78 mmol) and dioxane (25 mL) was stirred at 95 °C overnight under N 2 . After cooled to RT, HCl (1.5 mL, 2 M) was added into the mixture and stirred at 50 °C for 0.5 h. The saturated aqueous KF solution (50 mL) was added and the mixture was stirred at RT for additional 0.5 h. The mixture was filtered and the filter cake was washed with ethyl acetate (10 mL*3). The filtrate was extracted with ethyl acetate (50 mL*3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 5:1) to afford 8-acetyl-2-(isoindolin-2-yl)-3,6-dimethylquinazolin-4(3H)-on e (350 mg, 77.6%) as a yellow solid. LCMS: (M + H) + =334.2; Retention time = 1.90 min. LCMS CP Method G [0323] Step 3: To a solution of 8-acetyl-2-(isoindolin-2-yl)-3,6-dimethylquinazolin-4(3H)-on e (350 mg, 1.05 mmol) in MeOH (20 mL) was added NaBH 4 (79.8 mg, 2.10 mmol) in portions at 0 °C and the mixture was stirred at RT for 1 h. Then the mixture was diluted with water (20 mL) and extracted with DCM (30 mL*3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated to afford the crude 8-(1-hydroxyethyl)-2-(isoindolin-2-yl)-3,6-dimethylquinazoli n-4(3H)-one (300 mg, 85.2%) as a yellow oil which was used directly in the next step reaction without further purification. LCMS: (M + H) + =336.3; Retention time = 1.81 min. LCMS CP Method G. [0324] Step 4: To a solution of 8-(1-hydroxyethyl)-2-(isoindolin-2-yl)-3,6-dimethylquinazoli n-4(3H)-one (300 mg, 0.896 mmol) in DCM (30 mL) was added PBr 3 (432 mg, 1.79 mmol) dropwise at 0 °C and the mixture was stirred at RT for 1 h. Then the mixture was cooled 0 °C and the pH value was adjusted to 8 with saturated aqueous solution of NaHCO 3 . The mixture was extracted with DCM (40 ml*3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated to afford the crude 8-(1-bromoethyl)-2- (isoindolin-2-yl)-3,6-dimethylquinazolin-4(3H)-one (280 mg, 78.7%) as a yellow oil which was used directly in the next step reaction without further purification. LCMS: (M–Br+OMe) + =350.3; Retention time = 1.27 min. LCMS CP Method B [0325] Step 5: A solution of 8-(1-bromoethyl)-2-(isoindolin-2-yl)-3,6-dimethylquinazolin- 4(3H)-one (280 mg, 0.705 mmol) and methyl 2-aminobenzoate (213 mg, 1.41 mmol) in DMF (10 mL) was stirred at 80 °C overnight. After cooled to RT, water (50 mL) was added and the mixture was extracted with ethyl acetate (40 mL*3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 5:1) to afford methyl 2-((1-(2-(isoindolin-2-yl)- 3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)be nzoate (100 mg, 30.3%) as a yellow solid. LCMS: (M + H) + =469.2; Retention time = 1.51 min. LCMS CP Method B. [0326] Step 6: A mixture of methyl 2-((1-(2-(isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroqui nazolin-8- yl)ethyl)amino)benzoate (100 mg, 0.39 mmol) and LiOH (44.8 mg, 1.068 mmol), MeOH (5 mL) and H 2 O (1 mL) was stirred at 50 °C for 8 h. Then the mixture was concentrated and the pH value was adjusted to 5 with 1 N HCl aqueous solution. The mixture was concentrated and the residue was purified by Prep-HPLC (Method B) to afford 2-((1-(2-(isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroqui nazolin-8-yl)ethyl)amino)benzoic acid (33.2 mg, 34.2%) as a white solid. LCMS: (M + H) + =455.2; Retention time = 1.64 min. LCMS CP Method G. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 8.41 (s, 1 H), 7.78 -7.69 (m, 2 H), 7.42 -7.30 (m, 5 H), 7.17- 7.13 (m, 1 H), 6.49-6.45 (m, 2 H), 5.42 (s, 1 H), 5.11-5.00 (m, 4H), 3.61 (s, 3 H), 2.33-2.30 (m, 3 H), 1.57 (d, J = 6.8 Hz, 3 H). Example 5 2-((1-(3,6-Dimethyl-4-oxo-2-phenyl-3,4-dihydroquinazolin-8-y l)ethyl)amino)benzoic acid [0327] .Step 1: A mixture of 2-amino-3-bromo-5-methylbenzoic acid (2.29 g, 10 mmol), methanamine hydrochloride (1.0 g, 15 mmol), HATU (5.15 g, 15 mmol) and DIPEA (3.87 g, 30 mmol) in DCM (50 ml) was stirred at RT overnight. Water (50 ml) was added and the separated aqueous layer was extracted with DCM (50 ml*3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE: EA = 3:1) to afford 2- amino-3-bromo-5-methylbenzamide (2.2 g, 91%) as a white solid. LCMS: (M + H) + =242.9; Retention time = 1.37 min. LCMS CP Method D [0328] Step 2: To a solution of 2-amino-3-bromo-5-methylbenzamide (726 mg, 3.0 mmol) in DMSO (15 ml) was added phenylmethanol (648 mg, 6.0 mmol) and the mixture was stirred at 120 °C overnight under O 2 . After cooling to RT, water (80 ml) was added and the mixture was extracted with ethyl acetate (60 ml*3). The combined organic phases were washed with brine, dried over sodium sulfate filtered and concentrated. The residue was purified by column chromatography on silica gel (PE: EA = 10:1) to afford 8-bromo-3,6-dimethyl-2- phenylquinazolin-4(3H)-one (500 mg, 51%) as a colorless oil. LCMS: (M + H) + = 329.1; Retention time = 1.30 min. LCMS CP Method B. [0329] Step 3: To a solution of 8-bromo-3,6-dimethyl-2-phenylquinazolin-4(3H)-one (500 mg, 1.52 mmol, Step 2) in dioxane (25 ml) were added ethyl tributylstannane carboxylate (1.1 g, 3.04 mmol) and Pd(PPh 3 ) 2 Cl 2 (213 mg, 0.304 mmol) and the resulting mixture was stirred overnight at 95 °C under N 2 . HCl (1.5 ml, 2 M) was added into the mixture and stirred at 50 °C for 0.5 h. Sat KF (50 ml) was added and the mixture was stirred at RT for 0.5 h. The mixture was filtered and the filter cake was washed with EtOAc (10 ml*3). The aqueous phase was extracted with EtOAc (50 ml*3) and the combined organic phases were washed with brine, dried over sodium sulfate filtered and concentrated. The residue was purified by column chromatography on silica gel (PE: EA = 5:1) to afford 8-acetyl-3,6-dimethyl-2-phenylquinazolin-4(3H)-one (230 mg, 52%) as a yellow solid. LCMS: (M + H) + = 293.2; Retention time = 1.79 min. LCMS CP Method G. [0330] Step 4: To a solution of 8-acetyl-3,6-dimethyl-2-phenylquinazolin-4(3H)-one (230 mg, 0.79 mmol, Step 3) in MeOH (20 ml) was added NaBH 4 (60 mg, 1.58 mmol) in portions at 0 °C. The mixture was stirred at RT for 1 h. The mixture was diluted with water (20 ml) and extracted with DCM (30 ml*3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated to afford the crude 8-(1- hydroxyethyl)-3,6-dimethyl-2-phenylquinazolin-4(3H)-one (230 mg, 99%) as a yellow oil which was used directly in the next step without further purification. LCMS: (M + H) + = 295.3; Retention time = 1.15 min. LCMS CP Method B. [0331] Step 5: To a solution of 8-(1-hydroxyethyl)-3,6-dimethyl-2-phenylquinazolin-4(3H)-one (230 mg, 0.78 mmol, Step 4) in DCM (20 ml) was added PBr 3 (422 mg, 1.56 mmol) dropwise at 0 °C. The mixture was stirred at RT for 1 h. The mixture was cooled 0 °C and the pH was adjusted to 8 with saturated aqueous solution of NaHCO 3 . The mixture was extracted with DCM (40 ml*3) and the combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated to afford the crude 8-(1-bromoethyl)-3,6-dimethyl-2- phenylquinazolin-4(3H)-one (200 mg, 72%) as a yellow oil which was used directly in the next step without further purification. LCMS: (M +H) + =357.0; Retention time = 1.39 min. LCMS CP Method B. [0332] Step 6: To a solution of 8-(1-bromoethyl)-3,6-dimethyl-2-phenylquinazolin-4(3H)-one (200 mg, 0.56 mmol, Step 5) in DMF (10 ml) was added methyl 2-aminobenzoate (169 mmol, 1.12 mmol) and the mixture was heated to 80 °C and stirred overnight. After cooling to RT, water (50 ml) was added and the mixture was extracted with EtOAc (40 ml*3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE: EA = 5:1) to afford methyl 2-((1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydroquinazolin-8-y l)ethyl)amino)benzoate (110 mg, 46%) as a yellow solid. LCMS: (M + H) + = 428.3; Retention time = 1.48 min. LCMS CP Method B [0333] Step 7: To a solution of methyl 2-((1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoate (110 mg, 0.26 mmol, Step 6) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (31 mg, 1.3 mmol) and the mixture was stirred at 50 °C overnight. The mixture was concentrated to remove MeOH and the pH was adjusted to 4-5 with 1 N HCl. The mixture was concentrated and the residue was purified by Prep- HPLC (Method A) to afford 2-((1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydroquinazolin-8-y l)ethyl)amino)benzoic acid (66.5 mg, 63%) as a white solid. LCMS: (M + H) + =414.2; Retention time = 2.01 min. LCMS CP Method G . 1 H NMR (400 MHz, DMSO-d 6 ) δ:12.67 (s, 1 H), 8.40 (d, J = 5.2 Hz, 1 H), 7.88 (s, 1 H), 7.79-7.76 (m, 3 H), 7.58- 7.57 (m, 4 H), 7.18-7.14 (m, 1 H), 6.51-6.40 (m, 2 H), 5.50-5.47 (m1 H), 3.41 (s, 3 H), 2.38 (s, 3 H), 1.53 (d, J = 6.4 Hz, 3 H). Example 6 2-((1-(3,6-Dimethyl-4-oxo-2-(piperidin-1-yl)-3,4-dihydroquin azolin-8-yl)ethyl)amino)benzamide [0334] To a solution of 2-((1-(3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4-dihydroquin azolin-8- yl)ethyl)amino)benzoic acid (90 mg, 0.21 mmol, Ex.1) in DMF (5 ml) were added NH 4 Cl (22 mg, 0.42 mmol), EDCI (48 mg, 0.25 mmol) and DMAP (13 mg, 0.11 mmol). The mixture was stirred at RT overnight. Water (30 ml) was added and the mixture was extracted with ethyl acetate (20 ml*3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by Prep-HPLC (method A) to afford 2-((1-(3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4-dihydroquin azolin-8- yl)ethyl)amino)benzamide (57.6 mg, 65%) as a white solid LCMS: (M + H) + =420.0; Retention time = 1.68 min. LCMS CP Method D 1 H NMR (400 MHz, DMSO-d 6 ) δ: 8.72 (d, J = 6.8 Hz, 1 H), 7.86 (s, 1 H), 7.69 (d, J = 1.2 Hz, 1 H), 7.59-7.57 (m, 1 H), 7.44 (d, J = 1.6 Hz, 1 H), 7.19 (s, 1 H), 7.09-7.05 (m, 1 H), 6.47-6.38 (m, 2 H), 5.39- 5.33 (m, 1 H), 3.48 (s, 3 H), 3.20-3.18 (m, 4 H), 2.31 (s, 3 H), 1.70-1.61 (m, 6 H), 1.51 (d, J = 6.4 Hz, 3 H). Example 7 6-chloro-3-((1-(3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4-di hydroquinazolin-8-yl)ethyl)amino)picolinic acid [0335] Step 1: To a solution of 8-(1-bromoethyl)-3,6-dimethyl-2-(piperidin-1-yl)quinazolin-4 (3H)-one (300 mg, 0.83 mmol) in DMF (10 ml) was methyl 3-amino-6-chloropicolinate (308 mg, 1.66 mmol) and the mixture was heated to 80 °C and stirred overnight. Cooling to RT, water (50 ml) was added and the mixture was extracted with EtOAc (40 ml*3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE: EA = 5:1) to afford methyl 6-chloro-3-((1-(3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4-di hydroquinazolin-8-yl)ethyl)amino)picolinate (150 mg, 38.6%) as a yellow solid. LCMS: (M + H) + =470.1; Retention time = 1.49 min. LCMS CP Method B [0336] Step 2: To a solution of methyl 6-chloro-3-((1-(3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (150 mg, 0.32 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (38 mg, 1.6 mmol) and the mixture was stirred at 50 °C overnight. The mixture was concentrated to remove MeOH and the pH value was adjusted to 4-5 with 1 N HCl. The mixture was concentrated and the residue was purified by Prep-HPLC (Method A) to afford 6-chloro-3-((1-(3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinic acid (110 mg, 75%) as a white solid. LCMS: (M + H) + =456.2; Retention time = 2.23 min. LCMS CP Method G 1 H NMR (400 MHz, DMSO-d 6 ) δ:8.47 (d, J = 7.2 Hz, 1 H), 7.73 (s, 1 H), 7.50 (s, 1 H), 7.34 (d, J = 8.8 Hz, 1 H), 7.10 (d, J= 8.8 Hz, 1 H), 5.37-5.34 (m, 1 H), 3.47 (s, 3 H), 3.25- 3.13 (m, 4 H), 2.33 (s, 3 H), 1.76-1.68 (m, 6 H), 1.61 (d, J = 6.8 Hz, 3 H).

Example 8 2-((1-(3-methyl-4-oxo-2-(piperidin-1-yl)-3,4-dihydrothieno[3 ,2-d]pyrimidin-7-yl)ethyl)amino)benzoic acid [0337] Step 1: 2-chlorothieno[3,2-d]pyrimidin-4(3H)-one. A mixture of 2,4-dichlorothieno[3,2-d]pyrimidine (5 g, 24.38 mmol, 1 eq) and 5N NaOH (10 mL, 2 eq) in THF (30 mL) was heated at 80 °C for 16 h. The mixture was cooled to RT, concentrated, cooled in an ice bath, and acidified with 6N HCl until pH=4-5. The precipitated solid was collected, rinsed with water, dried to give 2-chlorothieno[3,2-d]pyrimidin-4(3H)-one (3.78 g, 83%). MS (m/z): 187.0 (M+H). [0338] Step 2: 2-chloro-3-methylthieno[3,2-d]pyrimidin-4(3H)-one. To a suspension of NaH (60% in mineral oil, 0.56 g, 13.92 mmol, 1.3 eq) in THF (30 mL) was added 2-chlorothieno[3,2-d]pyrimidin-4(3H)-one (2.0 g, 10.72 mmol, 1 eq) in several portions. After the addition was completed, the mixture was stirred for another 30 minutes, then MeI (2.3 g, 16.08 mmol, 1.5 eq) was added, then stirred at RT for 16 h. Saturated aqueous NH 4 Cl was added, followed by water, and the mixture was extracted with EtOAc (3x). The combined organic extracts were dried over MgSO 4 , concentrated, and purified by silica gel chromatography (0-30 % EtOAc/Hexanes) to give 2-chloro-3-methylthieno[3,2-d]pyrimidin-4(3H)-one (0.22 g, 10%). MS (m/z): 201.1 (M+H). [0339] Step 3: 7-bromo-2-chloro-3-methylthieno[3,2-d]pyrimidin-4(3H)-one. A mixture of 2-chloro-3- methylthieno[3,2-d]pyrimidin-4(3H)-one (1.25 g, 6.23 mmol, 1 eq) and NBS (1.33 g, 7.48 mmol, 1.2 eq) in DMF (10 mL) was heated to 70 °C for 24 h. The reaction was cooled to RT, water was added, and the precipitated solid was collected by filtration. The solid was rinsed with water, dried to give 7-bromo-2-chloro-3- methylthieno[3,2-d]pyrimidin-4(3H)-one (0.85 g, 49%). MS (m/z): 280.9 (M+H). [0340] Step 4: 7-bromo-3-methyl-2-(piperidin-1-yl)thieno[3,2-d]pyrimidin-4( 3H)-one. A mixture of 7- bromo-2-chloro-3-methylthieno[3,2-d]pyrimidin-4(3H)-one (0.85 g, 3.05 mmol, 1 eq), DIEA (1.6 mL, 9.16 mmol, 3 eq), and piperidine (0.39 g, 4.58 mmol, 1.5 eq) in DMSO (10 mL) was heated at 80 °C for 16 h. water was added, and the mixture was extracted with EtOAc (3x). The combined organic extracts were dried over MgSO 4 , filtered, concentrated, and purified by silica gel chromatography (0-50 % EtOAc/Hexanes) to give 7-bromo-3- methyl-2-(piperidin-1-yl)thieno[3,2-d]pyrimidin-4(3H)-one (0.96 g, 92.6%). MS (m/z): 328.1 (M+H). [0341] Step 5: 7-acetyl-3-methyl-2-(piperidin-1-yl)thieno[3,2-d]pyrimidin-4 (3H)-one. A mixture of 7-bromo-3- methyl-2-(piperidin-1-yl)thieno[3,2-d]pyrimidin-4(3H)-one (0.54 g, 1.64 mmol, 1 eq), n-butylvinyl ether (0.82 g, 8.22 mmol, 5 eq), Ph 3 P (0.065 g, 0.025 mmol, 0.15 eq), Et 3 N (0.25 g, 2.47 mmol, 1.5 eq), and Pd(OAc) 2 (0.056 g, 0.025 mmol, 0.15 eq) in MeCN (5 mL) was heated to 90 ° C in 16h. water was added, extracted with EtOAc (3x). The combined organic extracts were dried over MgSO 4 , concentrated, and purified by silica gel chromatography (0-40% EtOAc/Hexanes) to give 7-(1-butoxyvinyl)-3-methyl-2-(piperidin-1-yl)thieno[3,2- d]pyrimidin-4(3H)-one (0.125 g, 22%). To a stirred solution of 7-(1-butoxyvinyl)-3-methyl-2-(piperidin-1- yl)thieno[3,2-d]pyrimidin-4(3H)-one (0.125 g, 0.36 mmol, 1 equiv) in MeOH (2 mL) was added 6N HCl (0.3 mL, 5 equiv). The stirring was continued for 1 h. The mixture was concentrated to dryness to give 7-acetyl-3-methyl-2- (piperidin-1-yl)thieno[3,2-d]pyrimidin-4(3H)-one (0.12 g, 90%). MS (m/z): 292.1 (M+H). [0342] Step 6: 7-(1-hydroxyethyl)-3-methyl-2-(piperidin-1-yl)thieno[3,2-d]p yrimidin-4(3H)-one. To a stirred solution of 7-acetyl-3-methyl-2-(piperidin-1-yl)thieno[3,2-d]pyrimidin-4 (3H)-one (128.8 mg, 0.44 mmol, 1 eq) in MeOH (5 mL) at 0 °C was added NaBH 4 (26 mg, 0.66 mmol, 1.5 eq). The stirring was continued for 1 h. Saturated aq. NH 4 Cl was added, diluted further with water, extracted with DCM (3x). The combined organic extracts were dried over MgSO 4 , concentrated and purified by silica gel chromatography (0-50% EtOAc/Hexanes) to give 7-(1-hydroxyethyl)-3-methyl-2-(piperidin-1-yl)thieno[3,2-d]p yrimidin-4(3H)-one (111.2 mg, 85.4%). MS (m/z): 294.1 (M+H). [0343] Step 7: Methyl 2-((1-(3-methyl-4-oxo-2-(piperidin-1-yl)-3,4-dihydrothieno[3 ,2-d]pyrimidin-7- yl)ethyl)amino)benzoate. To a stirred mixture of 7-(1-hydroxyethyl)-3-methyl-2-(piperidin-1-yl)thieno[3,2- d]pyrimidin-4(3H)-one (115.5 mg, 0.379 mmol, 1 eq) and DIEA (50 mg, 0.46 mmol, 1.2 eq) in DCM (3 mL) was added MsCl (52.1 mg, 0.46 mmol, 1.2 eq) .The stirring was continued for 2 h. The mixture was concentrated, water was added, extracted with EtOAc (3x). The combined organic extracts were dried over MgSO 4 , concentrated, and purified by silica gel chromatography (0-40% EtOAc/Hexanes) to give 1-(3-methyl-4-oxo-2- (piperidin-1-yl)-3,4-dihydrothieno[3,2-d]pyrimidin-7-yl)ethy l methanesulfonate (33.4 mg, 23.8%). MS (m/z): 372.1 (M+H). A mixture of 1-(3-methyl-4-oxo-2-(piperidin-1-yl)-3,4-dihydrothieno[3,2-d ]pyrimidin-7-yl)ethyl methanesulfonate (33.4 mg, 0.09 mmol, 1 eq) and methyl 2-aminobenzoate (20.4 mg, 0.14 mmol, 1.5 eq) in DMF (2 mL) was heated to 80 °C in 16 h. The mixture was cooled to RT, water was added, extracted with EtOAc (3x). The combined organic extracts were dried over MgSO 4 , concentrated, and purified by silica gel chromatography (0-60% EtOAc/Hexanes) to give methyl 2-((1-(3-methyl-4-oxo-2-(piperidin-1-yl)-3,4- dihydrothieno[3,2-d]pyrimidin-7-yl)ethyl)amino)benzoate (16.5 mg, 43%). MS (m/z): 427.2 (M+H). [0344] Step 8: 2-((1-(3-methyl-4-oxo-2-(piperidin-1-yl)-3,4-dihydrothieno[3 ,2-d]pyrimidin-7- yl)ethyl)amino)benzoic acid. To a stirred solution of methyl 2-((1-(3-methyl-4-oxo-2-(piperidin-1-yl)-3,4- dihydrothieno[3,2-d]pyrimidin-7-yl)ethyl)amino)benzoate ( 16.5 mg, 0.0387 mmol, 1equiv) in MeOH (1 mL) was added 2N LiOH (0.2 mL, 0.194 mmol, 5 equiv). The mixture was stirred at 50 °C for 16 h. The mixture was cooled to RT, concentrated to dryness, diluted with water, extracted with MTBE (3x, discarded). The basic aqueous layer was acidified until pH = 4-5 with 6N HCl, extracted with DCM (3x). The organic extracts were dried over MgSO 4 , concentrated to dryness to give 2-((1-(3-methyl-4-oxo-2-(piperidin-1-yl)-3,4-dihydrothieno[3 ,2- d]pyrimidin-7-yl)ethyl)amino)benzoic acid (6.3 mg, 39.6%). 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 7.6 Hz, 1H), 7.86 (s, 1H), 7.77 (dd, J = 7.9, 1.8 Hz, 1H), 7.26 (ddd, J = 8.7, 7.1, 1.8 Hz, 1H), 6.71 (d, J = 8.5 Hz, 1H), 6.52 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 4.96 (d, J = 5.2 Hz, 1H), 3.46 (s, 4H), 3.16 (d, J = 5.7 Hz, 4H), 1.64 (q, J = 9.3 Hz, 8H). MS (m/z): 413.1 (M+H). Example 9 2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyr imidin-9-yl)ethyl)amino)benzoic acid [0345] Step 1: A solution of 3-bromo-5-methylpyridin-2-amine (2.00 g, 10.6 mmol, 1.00 eq) in acetone (14 mL) was heated at 56 °C, then bis(2,4,6-trichlorophenyl) malonate (5.00 g, 10.8 mmol, 1.02 eq) was added portionwise. After stirring at reflux for 2 h, the mixture was concentrated in vacuo to ~5 mL in volume. The resulting solids were collected by filtration to afford 9-bromo-2-hydroxy-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (2.1 g, 78% yield) as a light-yellow solid. LCMS m/z [M+H] + 255.0 obs. [0346] Step 2: A 0 °C solution of 9-bromo-2-hydroxy-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (2.1 g, 8.2 mmol, 1.0 eq) and Et3N (2.3 mL, 17 mmol, 2.0 equiv) in DCE (27 mL) was treated dropwise with methanesulfonyl chloride (890 µL, 12 mmol, 1.4 equiv). After the addition was completed, the resulting mixture warmed to RTand stirred vigorously for 30 min. Piperidine (2.4 mL, 25 mmol, 3.0 equiv) was added and the resulting mixture stirred vigorously at 70 °C for 18 h. The mixture was concentrated in vacuo and then treated with H 2 O (50 mL). The resulting suspension stirred vigorously at RTfor 1 h. A sticky beige solid was collected by filtration and then further purified by SiO 2 chromatography (10–30% (10% MeOH in EtOAc) in hexanes) to give 9-bromo-7-methyl- 2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (2.0 g, 76% yield) as a light-yellow solid. LCMS m/z [M+H] + 322.0 obs. [0347] Step 3: A mixture of 9-bromo-7-methyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidi n-4-one (2.0 g, 6.2 mmol, 1.0 equiv), butyl vinyl ether (970 µL, 7.5 mmol, 1.2 equiv) and BINAP (390 mg, 0.62 mmol, 0.10 equiv) in DMF (52 mL) was deoxygenated with bubbling argon gas for 10 min, then Pd(OAc) 2 (70 mg, 0.31 mmol, 0.050 equiv) was added. The resulting mixture stirred vigorously at 120 °C for 18 h. The mixture was concentrated in vacuo, then dissolved in EtOAc (300 mL) and washed with LiCl solution (3 × 200 mL). The combined aqueous washes were extracted with DCM (3 × 50 mL). The combined organic extracts were dried over anhydrous MgSO 4 , filtered, and concentrated in vacuo. The crude material was purified twice by SiO 2 column chromatography (0–20% EtOAc in DCM, then 10–30% (10% MeOH in EtOAc) in hexanes) to give 9-(1- butoxyvinyl)-7-methyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyr imidin-4-one (250 mg, 12% yield) as a yellow oil. LCMS m/z [M+H] + 342.2 obs. [0348] Step 4: 4 N HCl (13 mL) was added to a stirring solution of 9-(1-butoxyvinyl)-7-methyl-2-(piperidin-1-yl)- 4H-pyrido[1,2-a]pyrimidin-4-one (250 mg, 0.74 mmol) in AcOH (3.7 mL). After stirring for 1 h at room temp, the mixture was neutralized to pH 7~8 with 10 N NaOH. The resulting precipitates were collected by filtrated to afford 9-acetyl-7-methyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimid in-4-one (160 mg, 78% yield) as a tan solid. LCMS m/z [M+H] + 286.1 obs. [0349] Steps 5 and 6: A 0 °C solution of 9-acetyl-7-methyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimid in-4-one (160 mg, 0.56 mmol, 1.0 equiv) in MeOH (6.7 mL) was treated portionwise with NaBH 4 (42 mg, 1.1 mmol, 2.0 equiv). After the addition was completed, the mixture was warmed to RT and stirred for 2.5 h. The reaction was quenched at 0 °C with water (10 mL) and extracted with DCM (3 × 10 mL). The combined organic extracts were dried over anhydrous MgSO 4 , filtered, and concentrated in vacuo to give crude 9-(1-hydroxyethyl)-7-methyl-2- (piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (LCMS m/z [M+H] + 288.2 obs.), which was dissolved in DCM (10 mL) and then cooled to 0 °C. Phosphorus tribromide (110 µL, 1.1 mmol, 2.0 equiv) was slowly added. After the addition was completed, the mixture was warmed to RTand stirred for 1.6 h. The reaction was quenched at 0 °C with sat. aq. NaHCO 3 (15 mL) and then extracted with DCM (3 × 10 mL). The combined organic extracts were dried over anhydrous MgSO 4 , filtered, and concentrated in vacuo to give crude 9-(1-bromoethyl)-7-methyl-2- (piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one as a yellow wax which was carried into the next step without purification. LCMS m/z [M–Br+OMe+H] + 302.2 obs. [0350] Step 7: A mixture of 9-(1-bromoethyl)-7-methyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a ]pyrimidin-4-one (150 mg, 0.44 mmol, 1.0 equiv) and methyl 2-aminobenzoate (99 mg, 0.65 mmol, 1.5 equiv) in DMF (3.5 mL) was heated at 80 °C for 18 h. The reaction was diluted with EtOAc (30 mL) and sequentially washed with LiCl solution (3 × 30 mL) and brine (1 × 30 mL). The organic phase was dried over anhydrous MgSO 4 , filtered, and concentrated in vacuo. The resulting yellow oil was purified by SiO 2 chromatography (0–40% (10% MeOH in EtOAc) in hexanes) to give methyl 2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyr imidin-9- yl)ethyl)amino)benzoate (37 mg, 20% yield) as a yellow oil. LCMS m/z [M+H] + 421.2 obs.9-(1-Hydroxyethyl)-7- methyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (98 mg) was isolated as a side product. LCMS m/z [M+H] + 288.2 obs. [0351] Step 8: A 0 °C solution of 9-(1-hydroxyethyl)-7-methyl-2-(piperidin-1-yl)-4H-pyrido[1,2 -a]pyrimidin-4-one (96 mg, 0.33 mmol, 1.0 equiv) and DIPEA (120 µL, 0.67 mmol, 2.0 equiv) in DCM (1.5 mL) was treated dropwise with methanesulfonyl chloride (36 µL, 0.47 mmol, 1.4 equiv). After the addition was completed, the mixture was warmed to RTand stirred for 18 h. The mixture was concentrated in vacuo to afford crude 9-(1-chloroethyl)-7- methyl-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, which was used in the next step without purification, assuming theoretical yield. LCMS m/z [M+H] + 306.1 obs. [0352] Step 9: A solution of 9-(1-chloroethyl)-7-methyl-2-(piperidin-1-yl)-4H-pyrido[1,2- a]pyrimidin-4-one (100 mg, 0.33 mmol, 1.0 equiv) in DMF (1.6 mL) was treated with methyl 2-aminobenzoate (76 mg, 0.50 mmol, 1.5 equiv) and heated at 80 °C for 18 h. Additional 2-aminobenzoate (76 mg, 0.50 mmol, 1.5 equiv) was added, then the mixture heated at 120 °C for 5.5 h. The reaction was diluted with EtOAc (30 mL) and sequentially washed with LiCl solution (3 × 30 mL) and brine (1 × 30 mL). The organic phase was dried over anhydrous MgSO 4 , filtered, and concentrated in vacuo. The resulting yellow oil was purified by SiO 2 chromatography (0–40% (10% MeOH in EtOAc) in hexanes) to give methyl 2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyr imidin-9- yl)ethyl)amino)benzoate (81 mg, 58% yield) as an orange oil. LCMS m/z [M+H] + 421.2 obs. [0353] Step 10: A solution of methyl 2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyr imidin-9- yl)ethyl)amino)benzoate (120 mg, 0.28 mmol, 1.0 equiv) in MeOH (3.5 mL) was treated with an aqueous solution of LiOH (2 N, 700 µL, 5.0 equiv). The resulting mixture stirred at 50 °C for 18 h. The mixture was concentrated in vacuo, then dissolved in H 2 O (30 mL) and extracted with MTBE (3 × 30 mL). The aqueous phase was acidified to pH 3, then extracted with DCM (3 × 30 mL). The combined organic extracts were dried over anhydrous MgSO 4 , filtered, and concentrated in vacuo. Approximately half of the crude material was purified by prep-TLC (64% hexanes, 32% EtOAc, 3% MeOH, 1% AcOH) to give 2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (12 mg, 9% yield, 1:1 acetate complex) as an off-white solid after lyophilization. LCMS m/z [M+H] + 407.2 obs. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.05 (d, J = 6.6 Hz, 1H), 8.49–8.47 (m, 1H), 7.79 (dd, J = 7.6, 2.2 Hz, 1H), 7.51 (d, J = 2.2 Hz, 1H), 6.92–6.84 (m, 1H), 6.39–6.32 (m, 1H), 6.03 (br d, J = 8.1 Hz, 1H), 5.62 (s, 1H), 5.15–5.07 (m, 1H), 3.1–3.62 (m, 4H), 2.20 (d, J = 1.2 Hz, 3H), 1.79 (s, 5H), 1.69– 1.61 (m, 2H), 1.61–1.52 (m, 4H), 1.49 (d, J = 6.6 Hz, 3H).

Example 10 2-((1-(2-(4,4-difluoropiperidin-1-yl)-6-methoxy-3-methyl-4-o xo-3,4-dihydropyrido[3,2-d]pyrimidin-8- yl)ethyl)amino)benzoic acid [0354] Step 1: 3-amino-6-chloro-N-methylpicolinamide. To a stirred mixture of 3-amino-6-chloropicolinic acid (0.2 g, 1.16 mmol, 1 equiv), MeNH 2 (2M in THF, 0.7 mL, 1.39 mmol, 1.2 equiv), and DIEA (0.51 mL, 2.89 mmole, 2.5 equiv) in DCM (4 mL) was added HATU (0.53 g, 1.39 mmol, 1.2 equiv). The stirring was continued for 2h. H 2 O was added and extracted with DCM (3x). The combined extracts were dried over MgSO 4 , filtered, concentrated, and purified by silica gel chromatography (30% EtOAc/Hexanes) to give 3-amino-6-chloro-N- methylpicolinamide (0.19 g, 87.6%). MS (m/z): 186.0 (M+H). [0355] Step 2: 3-amino-4-bromo-6-chloro-N-methylpicolinamide. A mixture of 3-amino-6-chloro-N- methylpicolinamide (0.84 g, 4.51 mmol, 1 equiv) and NBS (0.96 g, 5.41 mmol, 1.2 equiv) in DMF (10 mL) was stirred at 80 °C in 1h. The mixture was cooled to RT, H 2 O was added, and the precipitated solid was collected, rinsed with H 2 O, dried, and purified by silica gel chromatography (0-40% EtOAc/Hexanes) to give 3-amino-4- bromo-6-chloro-N-methylpicolinamide (0.75 g, 63%). MS (m/z): 265.1 (M+H). [0356] Step 3: 8-bromo-6-chloro-3-methylpyrido[3,2-d]pyrimidine-2,4(1H,3H)- dione. To a stirred mixture of 3-amino-4-bromo-6-chloro-N-methylpicolinamide (0.75 g, 2.83 mmol, 1 equiv) and DIEA (1.5 mL, 8.51 mmol, 3 equiv) in DCM (15 mL) at 0 °C was added triphosgene (1.4 g, 4.54 mmol, 1.5 equiv). The mixture was stirred at RT for 2h, then heated to 45 °C in 2h. The mixture was cooled to RT, concentrated to dryness, added H 2 O. The precipitated solid was collected by filtration, rinsed with H 2 O, dried to give 8-bromo-6-chloro-3-methylpyrido[3,2- d]pyrimidine-2,4(1H,3H)-dione (0.76 g, 93.4%). MS (m/z): 291.9 (M+H). [0357] Step 4: 8-bromo-2,6-dichloro-3-methylpyrido[3,2-d]pyrimidin-4(3H)-on e. To a stirred mixture of 8- bromo-6-chloro-3-methylpyrido[3,2-d]pyrimidine-2,4(1H,3H)-di one (0.76 g, 2.62 mmol, 1 equiv) and DIEA (1.4 mL, 7.85 mmol, 3 equiv) in toluene (5 mL) was added POCl 3 (4.9 mL, 52.32 mmol, 20 equiv). The mixture was stirred at 80 °C in 24h. The mixture was cooled to RT, concentrated to dryness, added ice water, basified with saturated NaHCO 3 , extracted with DCM (3x). The combined organic extracts were dried over MgSO 4 , concentrated to give 8-bromo-2,6-dichloro-3-methylpyrido[3,2-d]pyrimidin-4(3H)-on e (0.88 g, 100%). MS (m/z): [0358] Step 5: 8-bromo-6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methylpyri do[3,2-d]pyrimidin-4(3H)-one. To a stirred suspension of 8-bromo-2,6-dichloro-3-methylpyrido[3,2-d]pyrimidin-4(3H)-on e (0.88 g, 2.85 mmol, 1 equiv) in i-PrOH (15 mL) was added DIEA (1.1 g, 8.55 mmol, 3 equiv), and 4,4-difluoropiperidine HCl (0.54 g, 3.7 mmol, 1.3 equiv) was heated at 80 °C in 16h. The mixture was cooled to RT, concentrated to dryness, H 2 O was added, extracted with EtOAc (3x). The combined organic extracts were dried over MgSO 4 , concentrated, and purified by silica gel chromatography (40% EtOAc/Hexanes) to give 8-bromo-6-chloro-2-(4,4-difluoropiperidin-1- yl)-3-methylpyrido[3,2-d]pyrimidin-4(3H)-one (0.89 g, 87%). MS (m/z): 393.0 (M+H). [0359] Step 6: 8-acetyl-6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methylpyr ido[3,2-d]pyrimidin-4(3H)-one. A mixture of 8-bromo-6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methylpyri do[3,2-d]pyrimidin-4(3H)-one (0.575 g, 1.46 mmol, 1 equiv), tributyl(1-ethoxyvinyl)stannane (0.63 g, 1.76 mmol, 1.2 equiv), and PdCl 2 dppf (0.1 g, 0.15 mmol, 0.1 equiv) in p-dioxane (7 mL) was heated at 95 °C in 4h. The mixture was cooled to RT and added 3mL of 6N HCl. The mixture was stirred at RT for 1h. The mixture was diluted with EtOAc, then washed with saturated NaHCO 3 . The organic layer was dried over MgSO 4 , concentrated, and purified by silica gel chromatography (20% EtOAc/DCM) to give 8-acetyl-6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methylpyr ido[3,2-d]pyrimidin-4(3H)- one (0.35 g, 67%). MS (m/z): 357.1 (M+H). [0360] Step 7: 6-chloro-2-(4,4-difluoropiperidin-1-yl)-8-(1-hydroxyethyl)-3 -methylpyrido[3,2-d]pyrimidin- 4(3H)-one. To a stirred suspension of 8-acetyl-6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methylpyr ido[3,2- d]pyrimidin-4(3H)-one (0.35 g, 0.98 mmol, 1 equiv) in MeOH (10 mL) at 0 °C was added NaBH 4 (0.06 g, 1.46 mmol, 1.5 equiv). The mixture was stirred at 0 °C for 1h, slowly quenched by saturated NH 4 Cl, then diluted further with H 2 O, The precipitated solid was collected by filtration, rinsed with H 2 O, dried to give 6-chloro-2-(4,4- difluoropiperidin-1-yl)-8-(1-hydroxyethyl)-3-methylpyrido[3, 2-d]pyrimidin-4(3H)-one (0.297 g, 86%). MS (m/z): 359.1 (M+H). [0361] Step 8: 8-(1-bromoethyl)-6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-m ethylpyrido[3,2-d]pyrimidin- 4(3H)-one. To a stirred solution of 6-chloro-2-(4,4-difluoropiperidin-1-yl)-8-(1-hydroxyethyl)-3 -methylpyrido[3,2- d]pyrimidin-4(3H)-one (0.1 g, 0.3 mmol, 1 equiv) in DCM (4 mL) at 0 °C was added PBr 3 (0.3 mL, 1.1 mmol, 4 equiv). The mixture was stirred at RT for 2h, cooled to 0 °C, basified with saturated NaHCO 3 until pH=7-8, extracted with DCM (3x). The combined organic extracts were dried over MgSO 4 , filtered, concentrated to give 8- (1-bromoethyl)-6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-met hylpyrido[3,2-d]pyrimidin-4(3H)-one (0.082 g, 69.4%). MS (m/z): 421.0 (M+H). [0362] Step 9: methyl 2-((1-(6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methyl-4-ox o-3,4-dihydropyrido[3,2- d]pyrimidin-8-yl)ethyl)amino)benzoate. A mixture of 8-(1-bromoethyl)-6-chloro-2-(4,4-difluoropiperidin-1-yl)-3- methylpyrido[3,2-d]pyrimidin-4(3H)-one (82 mg, 0.194 mmol, 1 equiv) and methyl 2-aminobenzoate (62 mg, 0.41 mmol, 2.1 equiv) in DMF (2 mL) was heated at 80 °C in 16h. H 2 O was added, to give methyl 2-((1-(6-chloro-2- (4,4-difluoropiperidin-1-yl)-3-methyl-4-oxo-3,4-dihydropyrid o[3,2-d]pyrimidin-8-yl)ethyl)amino)benzoate (0.054 g, 54%). MS (m/z): 492.1 (M+H). [0363] Step 10: 2-((1-(2-(4,4-difluoropiperidin-1-yl)-6-methoxy-3-methyl-4-o xo-3,4-dihydropyrido[3,2- d]pyrimidin-8-yl)ethyl)amino)benzoic acid. To a stirred solution of methyl 2-((1-(6-chloro-2-(4,4- difluoropiperidin-1-yl)-3-methyl-4-oxo-3,4-dihydropyrido[3,2 -d]pyrimidin-8-yl)ethyl)amino)benzoate (54 mg, 0.11 mmol, 1 equiv) in MeOH (2 mL) was added 2N LiOH (0.3 mL, 0.55 mmol, 5 equiv). The reaction mixture was stirred at 50 °C in 16h, cooled to RT, concentrated to remove the excess of MeOH, diluted with H 2 O, extracted with MTBE, 3x, discarded). The basic aqueous layer was acidified with 6N HCl until pH= 4-5, extracted with DCM (3x). The combined extracts were dried over MgSO 4 , concentrated, and purified prep. TLC plate to give 2-((1-(2- (4,4-difluoropiperidin-1-yl)-6-methoxy-3-methyl-4-oxo-3,4-di hydropyrido[3,2-d]pyrimidin-8-yl)ethyl)amino)benzoic acid (5 mg, 8%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.18 (s, 1H), 8.04 (ddd, J = 12.3, 8.0, 1.7 Hz, 1H), 7.22 (ddd, J = 8.8, 7.1, 1.7 Hz, 1H), 7.10 (s, 1H), 6.73 – 6.59 (m, 1H), 6.34 – 6.22 (m, 1H), 5.35 (d, J = 6.7 Hz, 1H), 4.04 (s, 2H), 3.68 (s, 3H), 3.56 – 3.36 (m, 4H), 2.26 (d, J = 14.3 Hz, 4H), 1.75 – 1.62 (m, 4H). MS (m/z): 474.1 (M+H). [0364] Other compounds were made via methods similar to that described in the examples and the Generic Synthetic Schemes: o-(1-{12-Methyl-7-piperidino-3,4,6,8-tetraazatricyclo[7.4.0. 0 2,6 ]trideca-1(9),2,4,7,10,12-hexaen-10- yl}ethylamino)benzoic acid [Example 11]; o-[1-(2-Methyl-7-methyl-8-oxo-6-piperidino-7H-1,3,5,7-tetraa zanaphth-4-yl)ethylamino]benzoic acid [Example 12]; 6-Chloro-3-{1-[2-(4,4-difluoro-1-piperidyl)-6-methyl-4-oxo-1 ,4a-diaza-8-naphthyl]ethylamino}-2- pyridinecarboxylic acid [Example 13]; 6-Chloro-3-{1-[2-(4,4-difluoro-1-piperidyl)-3-methyl-6-methy l-4-oxo-3H-1,3,7-triazanaphth-8- yl]ethylamino}-2-pyridinecarboxylic acid [Example 14]; o-{1-[2-(1-piperidyl)-3,6-dimethyl-4-oxo-3H-1,3,7-triazanaph th-8-yl]ethylamino}benzoic acid [Example 15]; 6-Chloro-3-{1-[2-(4,4-difluoro-1-piperidyl)-3,6-dimethyl-4-o xo-1,4a-diaza-8-naphthyl]ethylamino}-2- pyridinecarboxylic acid [Example 16]; and o-{1-[2-(1-piperidyl)-3,6-dimethyl-4-oxo-1,4a-diaza-8-naphth yl]]ethylamino}benzoic acid [Example 17]. Example 18 (R)-6-chloro-3-((1-(2-(1-methoxycyclopropyl)-3,6-dimethyl-4- oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0365] Step 1: T3P 50% in PhMe (0.75 g, 2.37 mmol) was added to 1-methoxycyclopropane-1-carboxylic acid (0.25 g, 2.15 mmol) and 2-amino-3-bromo-N,5-dimethylbenzamide (0.58 g, 2.37 mmol) suspended in PhMe (20 mL) and heated to reflux for 16 h. The mixture was cooled to r.t., diluted with EtOAc (20 mL), washed with sat. aq. NaHCO 3 (30 mL), separated, dried over MgSO 4 , filtered, and concentrated in vacuo. The crude product was purified by ISCO silica column chromatography (0-100% EtOAc/Hex). Fractions containing the product containing the product were collected and concentrated in vacuo to give 8-bromo-2-(1-methoxycyclopropyl)-3,6- dimethylquinazolin-4(3H)-one (0.52 g, 75%) as a white solid. LCMS: 324.8 [M+H] + . [0366] Step 2: 8-Bromo-2-(1-methoxycyclopropyl)-3,6-dimethylquinazolin-4(3H )-one (0.52 g, 1.62 mmol), Pd(PPh 3 ) 2 Cl 2 (114 mg, 1.62 mmol), and tributyl(1-ethoxyvinyl)tin (0.66 mL, 1.95 mmol) were suspended in dioxane (16 mL), purged with Ar, and stirred at 100 °C for 3 h.2 N HCl (5 mL) was added to the mixture and stirred at 50 °C for 20 min. The mixture was dried over MgSO 4 , filtered over Celite, and concentrated in vacuo. The crude product was purified by ISCO silica column chromatography (0-100% EtOAc/Hex). Fractions containing the product containing the product were collected and concentrated in vacuo to give 8-acetyl-2-(1- methoxycyclopropyl)-3,6-dimethylquinazolin-4(3H)-one (0.44 g, 94%) as a light yellow solid. LCMS: 287.0 [M+H] + . [0367] Step 3: 8-Acetyl-2-(1-methoxycyclopropyl)-3,6-dimethylquinazolin-4(3 H)-one (0.44 g, 1.52 mmol), (R)-2- methylpropane-2-sulfinamide (0.32 g, 3.05 mmol), Ti(O-iPr) 4 (1.35 mL, 4.57 mmol), was heated to reflux in THF (15 mL) for 36 h. The mixture was cooled to r.t., filtered, and concentrated in vacuo. The crude product was purified by ISCO silica column chromatography (0-100% EtOAc/Hex). Fractions containing the product containing the product were collected and concentrated in vacuo to give (R,Z)-N-(1-(2-(1-methoxycyclopropyl)- 3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethylidene)-2- methylpropane-2-sulfinamide (173 mg g, 29%) as a yellow oil. LCMS: 390.0 [M+H] + . [0368] Step 4: NaBH 3 CN (84.0 mg, 0.13 mmol) was added to a mixture of (R,Z)-N-(1-(2-(1- methoxycyclopropyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin -8-yl)ethylidene)-2-methylpropane-2-sulfinamide (173 mg, 0.44 mmol), AcOH (0.20 mL, 3.55 mmol), DCM:MeOH (1:1, 4 mL) at 0 °C and stirred for 30 min. The mixture was diluted with DCM (10 mL) washed with sat. aq. NaHCO 3 solution (10 mL), separated, dried over MgSO 4 , filtered, and concentrated in vacuo. The crude product was purified by ISCO silica column chromatography (0-100% EtOAc/Hex). Fractions containing the product containing the product were collected and concentrated in vacuo to give (R)-N-((R)-1-(2-(1-methoxycyclopropyl)-3,6-dimethyl-4-oxo-3, 4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (160 mg g, 92%) as a yellow oil. LCMS: 392.0 [M+H] + . [0369] Step 5: 1 M HCl in MeOH (1.2 mL) was added to a mixture of (R)-N-((R)-1-(2-(1-methoxycyclopropyl)- 3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methy lpropane-2-sulfinamide (160 mg, 0.41 mmol) in MeOH (1 mL) at r.t. and stirred for 20 min. The mixture was concentrated in vacuo to give (R)-8-(1-aminoethyl)-2- (1-methoxycyclopropyl)-3,6-dimethylquinazolin-4(3H)-one hydrochloride (0.04 g, 30%) as a yellow oil. LCMS: 288.0 [M+H] + . [0370] Step 6: (R)-8-(1-aminoethyl)-2-(1-methoxycyclopropyl)-3,6-dimethylqu inazolin-4(3H)-one hydrochloride (0.04 g, 0.124 mmol), methyl 6-chloro-3-fluoropicolinate (35.0 mg, 0.15 mmol), DIPEA (0.06 mL, 0.37 mmol) was dissolved in DMF (1 mL) and heated to 100 °C for 16 h. The mixture was cooled to r.t., diluted with EtOAc (5 mL), washed with sat. aq. NH 4 Cl solution (5 mL), separated, washed with aq. LiCl solution (3 X 5 mL), separated, dried over MgSO 4 , filtered, and concentrated in vacuo. The crude product was used in the next reaction without any further purification.1 M LiOH solution (1 mL) was added to a mixture of the product in THF (1 mL). The mixture was stirred for 2 h at r.t.2 N HCl (1 mL) was added to the mixture and the mixture was concentrated in vacuo. The crude product was purified by prep HPLC C18 (20-95% MeCN/H 2 O + 0.1% FA). Fractions containing the product were collected and concentrated in vacuo to give (R)-6-chloro-3-((1-(2-(1-methoxycyclopropyl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picoli nic acid (21.4 mg, 41%, over 2 steps) as a white solid. LCMS: 442.9 [M+H] + . Example 19 (R)-6-chloro-3-((1-(2-(3-hydroxybicyclo[1.1.1]pentan-1-yl)-3 ,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0371] A solution of methyl (R)-6-chloro-3-((1-(2-(3-methoxybicyclo[1.1.1]pentan-1-yl)-3 ,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (28 mg, 0.05 mmol, 1 eq.) in DCM (1 mL) was cooled to 0°C and treated with dropwise with boron tribromide (1M in DCM, 300 µl, 6 eq.) and warmed to RT. The mixture was poured into water, extracted 3x with DCM, dried over MgSO 4 , filtered, and concentrated in vacuo. The residue was purified by reverse phase prep-HPLC (10-50% MeCN/water with 0.1% FA gradient). Combined fractions containing the product, froze, and lyophilized overnight. (R)-6-chloro-3-((1-(2-(3-hydroxybicyclo[1.1.1]pentan-1- yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amin o)picolinic acid (15 mg, 64%) was recovered as a white solid. LCMS: 455.1 [M+H] + . Example 20 -chloro-3-{[(1R)-1-{5-ethyl-2-methoxy-9-methylbenzo[c]2,7-na phthyridin-7-yl}ethyl]amino}pyridine-2-carboxylic acid [0372] Step 1: (R)-2-Methyl-N-[(1R)-1-[3-methyl-5-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2- yl)phenyl]ethyl]propane-2-sulfinamide; methanamine (312 mg, 786 µmol), 1-(4-chloro-6-methoxypyridin-3- yl)propan-1-one (157 mg, 786 µmol), Pd(dppf)Cl 2 (57.5 mg, 0.1 eq., 78.6 µmol), water (70.8 µL, 5 eq., 3.93 mmol), and K 2 CO 3 (326 mg, 3 eq., 2.36 mmol) were suspended in 1,4-dioxane (7.86 mL, 92.2 mmol) and heated to 80 °C for 16 h. The mixture was cooled to r.t. and brine (5 mL) was added to the mixture. The organic layer was separated, dried over MgSO 4 , filtered over Celite, and concentrated in vacuo. The crude was purified by ISCO silica column chromatography (0-100% EtOAc/Hex to 0-10% MeOH/EtOAc). Fractions containing the compound were collected and concentrated in vacuo to give (R)-N-[(1R)-1-{5-ethyl-2-methoxy-9- methylbenzo[c]2,7-naphthyridin-7-yl}ethyl]-2-methylpropane-2 -sulfinamide (298 mg, 746 µmol) as a yellow oil. LCMS: 400.2 [M+H] + . [0373] Step 2: HCl (245 mg, 9 eq., 6.71 mmol), was added to a solution of (R)-N-[(1R)-1-{5-ethyl-2-methoxy-9- methylbenzo[c]2,7-naphthyridin-7-yl}ethyl]-2-methylpropane-2 -sulfinamide (298 mg, 746 µmol) in MeOH (3 mL) and stirred at r.t. for 2 h. The mixture was concentrated in vacuo and used in the next reaction without further purification. [0374] Step 3: Methyl 6-chloro-3-fluoropyridine-2-carboxylate (170 mg, 1.2 eq., 895 µmol), ethylbis(propan-2- yl)amine (531 µL, 4 eq., 2.98 mmol), 1,4-dioxane (7.46 mL, 87.4 mmol) were added to the vial and heated to 110 °C and stirred for 16 h. The mixture was cooled to r.t., diluted with EtOAc (10 mL), then washed with sat. aqueous NH 4 Cl solution (10 mL), then washed with aqueous LiCl solution (3 X 20 mL), dried over MgSO 4 , filtered, and concentrated in vacuo. The crude was purified by ISCO silica column chromatography (20-100% EtOAc/Hex). Fractions containing the compound were collected ad concentrated in vacuo to give methyl 6- chloro-3-{[(1R)-1-{5-ethyl-2-methoxy-9-methylbenzo[c]2,7-nap hthyridin-7-yl}ethyl]amino}pyridine-2-carboxylate (197 mg, 424 µmol) as a yellow oil. LCMS: 465.1 [M+H] + . [0375] Step 4: LiOH (20.9 mg, 5 eq., 871 µmol) was added to a solution of methyl 6-chloro-3-{[(1R)-1-{5-ethyl- 2-methoxy-9-methylbenzo[c]2,7-naphthyridin-7-yl}ethyl]amino} pyridine-2-carboxylate (81 mg, 174 µmol) in THF (1.74 mL, 21.4 mmol) and stirred at r.t. for 5 h.2 N HCl (2 mL) was added the mixture. The mixture was extracted with DCM (3 X 5 mL) and separated. The organic layers were combined, dried over MgSO 4 , filtered, and dried in vacuo. The crude product was purified by prep HPLC (25-95% MeCN/H 2 O + 0.1% FA). Fractions containing the product were collected and dried in vacuo to give 6-chloro-3-{[(1R)-1-{5-ethyl-2-methoxy-9-methylbenzo[c]2,7- naphthyridin-7-yl}ethyl]amino}pyridine-2-carboxylic acid (30.3 mg, 67.2 µmol) as a off-white solid. LCMS: 451.1 [M+H] + Example 21 (R)-6-chloro-3-((1-(2-(3-(difluoromethyl)phenyl)-3,6-dimethy l-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0376] Step 1. TFA (0.1 mL, 1.03 mmol) was added to a solution of 2-amino-3-bromo-N,5-dimethylbenzamide (3.0 g, 12.3 mmol) in triethylorothoformate (60 mL) and stirred at r.t. for 3 d. The mixture was concentrated in vacuo and used in the next reaction without further purification. Pd(PPh 3 ) 2 Cl 2 (0.43 g, 0.62 mmol), [0377] Step 2. Tributyl(1-ethoxyvinyl)tin (5.00 mL, 14.9 mmol), and dioxane 62 mL was added to a flask containing the crude compound from the previous reaction, purged with Ar, and heated at reflux for 16 h.2 N HCl (5 mL) was added to the mixture and stirred at 50 °C for 1 h. The mixture was cooled and dried over MgSO 4 . The slurry was filtered over Celite and the filter cake was washed with EtOAc (50 mL). The filtrate was concentrated in vacuo and purified by ISCO silica column chromatography (0-100% EtOAc/Hex). Fractions containing the compound were collected and concentrated in vacuo to give 8-acetyl-3,6-dimethylquinazolin-4(3H)-one (1.98 g, 74%) as a yellow solid. LCMS: 217.1 [M+H] + . [0378] Step 3. 8-Acetyl-3,6-dimethylquinazolin-4(3H)-one (1.98 g, 9.16 mmol), (R)-2-methylpropane-2- sulfinamide (2.22 g, 18.31 mmol), Ti(OEt) 4 (5.76 mL, 27.5 mmol), was heated at reflux in THF for 16 h. The mixture was cooled to r.t. and concentrated in vacuo. The crude was purified by ISCO silica column chromatography (0-10% MeOH/DCM). Fractions containing the compound were collected and concentrated in vacuo. The compound was used immediately in the next reaction. [0379] Step 4. The compound was dissolved in DCM:MeOH (1:1, 90 mL) and cooled to 0 °C. AcOH (4.07 mL, 73.3 mmol) and NaBH 3 CN (1.73 g, 27.5 mmol) was added to the mixture and stirred for 30 min. The reaction was quenched with sat. aq. NaHCO 3 solution (50 mL) and the organic layer was separated. The aqueous layer was extracted with DCM (3 X 50 mL), the organic layers were combined, dried over MgSO 4 , filtered, and concentrated in vacuo. The crude was purified by ISCO silica column chromatography (50-100% EtOAc/Hex to 0-10% MeOH/EtOAc) Fractions containing the compound as a racemic mixture were collected and concentrated in vacuo. The mixture was separated by ISCO Gold C18 chromatography (20-100% MeCN/H 2 O +0.1% FA). Fractions containing the single desired diasteriomer were collected and concentrated in vacuo to give (R)-N-((R)- 1-(3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-me thylpropane-2-sulfinamide (0.97 g, 33% yield) as a yellow solid. LCMS: 322.1 [M+H]+. [0380] Step 5. 3 M HCl in MeOH (6 mL) was added to a solution of (R)-N-((R)-1-(3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (0.50 g, 1.56 mmol in MeOH (6 mL) and stirred at r.t. for 1 h. The mixture was concentrated in vacuo and used in the next reaction without further purification. [0381] Step 6. Methyl 6-chloro-3-fluoropicolinate (0.32 g, 1.71 mmol), DIPEA (1.1 mL, 6.22 mmol), and DMF (6 mL) were added to the vial and the mixture was heated to 100 °C for 6 h. The mixture was cooled to r.t., diluted with EtOAc (10 mL) washed with sat. aq. NH 4 Cl solution (10 mL) and separated. The organic layer was washed with aq. LiCl solution (3 X 10 mL), separated, dried over MgSO 4 , filtered, and concentrated in vacuo. The crude was purified by ISCO column chromatography (0-100% EtOAc/Hex). Fractions containing the compound were collected and concentrated in vacuo to give methyl (R)-6-chloro-3-((1-(3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (445 mg, 74%) as a yellow oil. LCMS: 387.1[M+H]+. [0382] Step 7. A mixture of methyl (R)-6-chloro-3-((1-(3,6-dimethyl-4-oxo-3,4-dihydroquinazolin -8- yl)ethyl)amino)picolinate (40.0 mg, 103 umol), Pd(OAc) 2 (2.30 mg, 10.3 umol), CuI (3.90 mg, 20.7 umol), 4,4'- dimethoxy-2,2'-bipyridine (4.50 mg, 20.7 umol), 2.2 M LiOt-Bu in THF (0.12 mL, 0.26 mmol) suspended in DMF (1.0 mL) at 120 °C for 5 min. The mixture was cooled to r.t. and 1-(difluoromethyl)-3-iodobenzene (105 mg, 414 umol) was added then heated to 120 °C for 1 h. The mixture was cooled to r.t., diluted with DCM (5 mL) and washed with 2 N citric acid solution (5 mL). The organic layer was separated, and the aqueous solution was extracted with DCM (3 X 5 mL). The organic layers were combined, dried over MgSO 4 , filtered, and concentrated in vacuo. The crude was purified by C18 prep HPLC (20-95% MeCN/H 2 O + 0.1% FA) to give (R)-6-chloro-3-((1- (2-(3-(difluoromethyl)phenyl)-3,6-dimethyl-4-oxo-3,4-dihydro quinazolin-8-yl)ethyl)amino)picolinic acid (6.9 mg , 13%) as a white solid. LCMS: 499.1[M+H]+. Example 22 3-{[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydroquinazoli n-8-yl)ethyl]amino}-6-methylpyridine-2- carboxylic acid [0383] Step 1. 8-[(1R)-1-Aminoethyl]-3,6-dimethyl-2-phenyl-3,4-dihydroquina zolin-4-one (0.1 g, 341 µmol), methyl 3-fluoro-6-methylpyridine-2-carboxylate (57.7 mg, 341 µmol), and ethylbis(propan-2-yl)amine (178 µL, 3 eq., 1.02 mmol) were dissolved in DMF (1.36 mL, 17.6 mmol) and stirred at 100 °C for 4 days. The mixture was cooled to r.t., diluted with EtOAc (10 mL), washed with sat. aq. NH 4 Cl solution (10 mL), washed with aq. LiCl solution (3 X 10 mL), dried over MgSO 4 , filtered, and concentrated in vacuo. The crude was purified by ISCO silica flash column chromatography (0-100% EtOAc/Hex). Fractions containing the compound were collected and concentrated in vacuo to give methyl 3-{[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydroquinazoli n-8- yl)ethyl]amino}-6-methylpyridine-2-carboxylate (20.4 mg, 46.1 µmol) as a yellow oil. LCMS: 443.2 [M+H]+. [0384] Step 2. LiOH (3.31 mg, 3 eq., 138 µmol) was added to a solution of methyl 3-{[(1R)-1-(3,6-dimethyl-4- oxo-2-phenyl-3,4-dihydroquinazolin-8-yl)ethyl]amino}-6-methy lpyridine-2-carboxylate (20.4 mg, 46.1 µmol) in THF (461 µL, 5.66 mmol) and stirred at r.t. for 16 h. The mixture was diluted with DCM (5 mL), acidified with 2 N HCl (2 mL), and separated. The aqueous layer was extracted with DCM (3 X 5 mL). Organic layers were combined, dried over MgSO 4 , filtered, and concentrated in vacuo. The crude was purified by C18 prep HPLC (20 - 95% MeCN/H 2 O + 0.1% FA). Fractions containing the compound were collected and concentrated in vacuo to give 3-{[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydroquinazoli n-8-yl)ethyl]amino}-6-methylpyridine-2- carboxylic acid (6 mg, 14 µmol) as an off-white solid. LCMS: 429.2 [M+H]+. Example 23 (R)-2-((1-(2-(4,4-difluoropiperidin-1-yl)-3,6-dimethyl-4-oxo -3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [0385] Step 1. (R)-8-(1-Aminoethyl)-2-(4,4-difluoropiperidin-1-yl)-3,6-dime thylquinazolin-4(3H)-one (67 mg, 0.17 mmol), methyl 2-iodobenzoate (29.3 µl, 0.20 mmol, 1.2 eq.), tris(dibenzylideneacetone)dipalladium(0) (15.2 mg, 0.017 mmol, 0.1 eq.), XantPhos (19.3 mg, 0.033 mmol, 0.2 eq.), and cesium carbonate (163 mg, 0.50 mmol, 3 eq.) were degassed 3x with argon.1,4-dioxane (1 mL) was added, degassed briefly with argon, and heated to 95°C overnight. The mixture was cooled, and the mixture was filtered through Celite, washed with EtOAc, concentrated, and purified crude residue by silica gel flash chromatography (0-15% EtOAc/hexanes gradient). Fractions containing the product were collected and concentrated to give methyl (R)-2-((1-(2-(4,4- difluoropiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinaz olin-8-yl)ethyl)amino)benzoate (43 mg, 55%) as a light orange foam. LCMS: 471.0 [M+H]+. [0386] Step 2. A suspension of methyl (R)-2-((1-(2-(4,4-difluoropiperidin-1-yl)-3,6-dimethyl-4-oxo -3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate (43 mg, 0.09 mmol, 1 eq.) in MeOH (1 mL) and THF (0.5 mL) was treated with LiOH (1N aq., 457 µl, 0.46 mmol, 5 eq.) and heated to 50°C overnight. The mixture was cooled, concentrated in vacuo, and acidified to pH 4-5. The mixture was extracted 3x with DCM, dried over MgSO 4 , and filtered. The filtrate was concentrated in vacuo and (R)-2-((1-(2-(4,4-difluoropiperidin-1-yl)-3,6-dimethyl-4-oxo - 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (37 mg, 89%) was recovered as an off-white solid. The product could be purified by reverse phase prep-HPLC or reverse phase flash chromatography if necessary. LCMS: 457.3 [M+H]+. Example 24 (R)-6-chloro-3-((1-(2-(4,4-difluoropiperidin-1-yl)-3,6-dimet hyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)-N-methylpicolinamide [0387] HATU (29.0 mg, 76.0 umol) was added to a mixture of (R)-6-chloro-3-((1-(2-(4,4-difluoropiperidin-1-yl)- 3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)-p icolinic acid (25.0 mg, 51.0 umol), DIPEA 26.0 uL, 2 M MeNH 2 in THF (30 uL, 60 umol), in DCM (0.5 mL) and stirred at r.t. for 16 h. The mixture was diluted with DCM (5 mL), washed with sat. aq. NH 4 Cl (5 mL), separated, dried over MgSO 4 , filtered and concentrated in vacuo. The crude was purified by Prep TLC (40% EtOAc/Hex). The product was scrapped from the plate, eluted with DCM and concentrated in vacuo to give (R)-6-chloro-3-((1-(2-(4,4-difluoropiperidin-1-yl)-3,6-dimet hyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)-N-methylpicolinamide (13.0 mg, 50%) as a green solid. LCMS: 505.2 [M+H]+. Example 25 (R)-6-chloro-3-((1-(3,6-dimethyl-2-(6-(1-methyl-1H-pyrazol-4 -yl)pyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0388] Step 1, 2-Amino-3-bromo-N,5-dimethylbenzamide (1.00 g, 4.11 mmol), Pd(PPh 3 ) 2 Cl 2 (0.29 g, 0.41 mmol), and tributyl(1-ethoxyvinyl)stannane (1.67 mL, 4.94 mmol) were suspended in dioxane (17 mL), purged with Ar, and heated to 100 °C for 5 h.2 N HCl (1 mL) was added to the mixture and heated to 50 °C for 10 min. The mixture was cooled to r.t., diluted with EtOAc (20 mL), and washed with sat. aq. KF solution (20 mL). The organic layer was separated, dried over MgSO 4 , filtered over Celite, and concentrated in vacuo. The crude was purified by ISCO silica column chromatography (40-100% EtOAc/Hex). Fractions containing the compound were collected and concentrated in vacuo to give 3-acetyl-2-amino-N,5-dimethylbenzamide (0.65 g, 77%) as a yellow solid. LCMS: 207.1 M+H]+. [0389] Step 2. 3-Acetyl-2-amino-N,5-dimethylbenzamide (0.57 g, 2.76 mmol), 6-iodonicotinic acid (0.83 g, 3.32 mmol), 50% w/w T3P in PhMe (1.06 g, 3.32 mmol) were heated at reflux in PhMe (28 mL) for 4 h. The mixture was cooled to r.t., diluted with EtOAc (30 mL), and washed with sat. aq. NaHCO 3 (40 mL). The organic layer was separated, dried over MgSO 4 , filtered, and concentrated in vacuo. The crude was purified by ISCO silica column chromatography (0-100% EtOAc/Hex). Fractions containing the compound were collected and concentrated in vacuo to give 8-acetyl-2-(6-iodopyridin-3-yl)-3,6-dimethylquinazolin-4(3H) -one (0.24 g, 21%) as a yellow solid. LCMS: 420.0 [M+H] + . [0390] Step 3. 8-Acetyl-2-(6-iodopyridin-3-yl)-3,6-dimethylquinazolin-4(3H) -one (0.24 g, 0.57 mmol), (R)-2- methylpropane-2-sulfinamide (0.14 g, 1.14 mmol), and Ti(OEt) 4 (0.36 mL, 1.72 mmol) were heated to reflux in THF (6 mL) for 16 h. The mixture was cooled to r.t. and concentrated in vacuo. The crude was purified by a silica plug with 10% MeOH/DCM to elute. The crude was concentrated in vacuo and used in the next reaction without further purification. [0391] Step 4. NaBH 3 CN (0.11 g, 1.72 mmol) was added to a vial containing the crude from step 3 with AcOH (0.13 mL, 2.29 mmol) in DCM:MeOH (1:1, 5 mL) at 0 °C and stirred for 1 h. The mixture was diluted with DCM (10 mL) and washed with sat. aq. NaHCO 3 (10 mL). The organic layer was separated, dried over MgSO 4 , filtered, and concentrated in vacuo. The crude was purified by ISCO silica column chromatography (0-100% EtOAc/Hex – 0-10% MeOH/EtOAc). Fractions containing the compound were collected and concentrated in vacuo to give (R)-N-((R)-1-(2-(6-iodopyridin-3-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2- sulfinamide (0.18 g, 60%) as a yellow oil. LCMS: 525.0 [M+H] + . [0392] Step 5.3 M HCl in MeOH (2 mL) was added to a mixture of (R)-N-((R)-1-(2-(6-iodopyridin-3-yl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpro pane-2-sulfinamide (0.18 g, 0.34 mmol) in MeOH (3 mL) and stirred at r.t. for 3 h. The mixture was concentrated in vacuo and used in the next reaction without further purification. [0393] Step 6. tert-butyl 6-chloro-3-fluoropicolinate (0.12 g, 0.52 mmol) and DIPEA (0.25 mL, 1.37 mmol) were added to the crude product from step 6 and dissolved in DMF (3 mL). The mixture was heated to 100 °C and stirred for 24 h. The mixture was cooled to r.t., diluted with EtOAc (5 mL), and washed with sat. aq. NH 4 Cl solution (5 mL). The organic layer was separated, washed with aq. LiCl solution (3 X 5 mL), separated, dried over MgSO 4 , filtered, and concentrated in vacuo. The crude was purified by ISCO silica column chromatography (0-100% EtOAc/Hex). Fractions containing the compound were collected and concentrated in vacuo to give tert- butyl (R)-6-chloro-3-((1-(2-(6-iodopyridin-3-yl)-3,6-dimethyl-4-ox o-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinate (69.4 mg, 32%, over 2 steps) as a yellow solid. LCMS: 654.0 [M+H] + . [0394] Step 7. tert-Butyl (R)-6-chloro-3-((1-(2-(6-iodopyridin-3-yl)-3,6-dimethyl-4-ox o-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinate (36.0 mg, 57.2 umol), Pd(dppf)Cl 2 (4.2 mg, 5.70 umol), K 2 CO 3 (23.8 mg, 0.17 mmol), (1- Methyl-1H-pyrazol-4-yl)boronic acid (7.90 mg, 62.9 umol) were suspended in dioxane:H 2 O (4:1, 0.5 mL), purged with Ar, and heated to 90 °C for 16 h. The mixture was cooled to r.t., diluted with EtOAc (2 mL), dried with MgSO 4 , filtered over Celite, and concentrated in vacuo. The crude product as purified by ISCO silica column chromatography (0-100% EtOAc/Hex – 0-10% MeOH/EtOAc). Fractions containing the compound were collected and concentrated in vacuo to give tert-butyl (R)-6-chloro-3-((1-(3,6-dimethyl-2-(6-(1-methyl-1H-pyrazol-4 - yl)pyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amin o)picolinate (22.8 mg, 68%) as a yellow oil. LCMS: 586.2 [M+H] + . [0395] Step 8. tert-Butyl (R)-6-chloro-3-((1-(3,6-dimethyl-2-(6-(1-methyl-1H-pyrazol-4 -yl)pyridin-3-yl)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (23.0 mg, 39.2 umol) was stirred in TFA:DCM (1:1, 2 mL), at r.t. for 2 h. The mixture was concentrated in vacuo. The crude product was purified C18 prep HPLC (20-95% MeCN/H 2 O +0.1% FA). Fractions containing the product were collected and concentrated in vacuo to (R)-6- chloro-3-((1-(3,6-dimethyl-2-(6-(1-methyl-1H-pyrazol-4-yl)py ridin-3-yl)-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid (12.1 mg, 58%) as a white solid. LCMS: 530.2 [M+H] + . Example 26 (R)-6-chloro-3-((1-(3,6-dimethyl-4-oxo-2-(trifluoromethyl)-3 ,4-dihydroquinazolin-8-yl)ethyl)amino)picolinic acid [0396] A solution of methyl (R)-6-chloro-3-((1-(3,6-dimethyl-4-oxo-2-(trifluoromethyl)-3 ,4-dihydroquinazolin-8- yl)ethyl)amino)picolinate (32 mg, 0.070 mmol) in DCM (800 µL) 0 °C was treated dropwise with BBr 3 (1.0 M solution in DCM, 210 µL, 0.21 mmol). After the addition was completed, the mixture was warmed to room temp. After 3 d, the reaction was quenched by adding sat. aq. NaHCO 3 (5 mL) and diluted with DCM (5 mL). The layers were partitioned and the aqueous phase was extracted with DCM (2 × 5 mL). The combined organic phases were dried over anhydrous MgSO 4 , filtered, and concentrated in vacuo. The resulting crude yellow oil was purified by RP-HPLC (25–50–95% (MeCN in H 2 O)+0.1% FA) to afford (R)-6-chloro-3-((1-(3,6-dimethyl-4-oxo-2- (trifluoromethyl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)pic olinic acid (14 mg, 45% yield) as a gray-white solid . Example 27 (R)-6-chloro-3-((1-(2-(difluoromethyl)-3,6-dimethyl-4-oxo-3, 4-dihydroquinazolin-8-yl)ethyl)amino)picolinic acid [0397] Step 1: A heterogeneous mixture of 6-chloro-3-fluoropicolinic acid (3.3 g, 19 mmol) and DMAP (2.7 g, 22 mmol) in DCM (30 mL) was treated dropwise with Boc 2 O (5.1 mL, 22 mmol) at room temp. After 16 h, the mixture was concentrated in vacuo. The resulting crude material was purified by SiO 2 chromatography (0–40% EtOAc/hexanes) to give tert-butyl 6-chloro-3-fluoropicolinate (3.8 g, 89% yield) as a clear oil that solidified upon standing. [0398] Step 2: A solution of crude (R)-8-(1-aminoethyl)-2-(difluoromethyl)-3,6-dimethylquinazol in-4(3H)-one (1.5 mmol), in DMF (7 mL) was treated with tert-butyl 6-chloro-3-fluoropicolinate (690 mg, 3.0 mmol) and DIPEA (1.3 mL, 7.4 mmol). The resulting solution heated at 120 °C for 16 h. After cooling to room temp, the reaction was diluted with EtOAc (150 mL) and sequentially washed with sat. aq. LiCl solution (3 × 100 mL) and brine (1 × 100 mL). The organic phase was dried over anhydrous MgSO 4 , filtered, and concentrated in vacuo. The resulting crude was purified by SiO 2 chromatography (0–33% EtOAc/hexanes) to give tert-butyl (R)-6-chloro-3-((1-(2- (difluoromethyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinate in low purity, which was carried to the next step without additional purification. [0399] Step 3: A solution of tert-butyl (R)-6-chloro-3-((1-(2-(difluoromethyl)-3,6-dimethyl-4-oxo-3, 4- dihydroquinazolin-8-yl)ethyl)amino)picolinate in DCM (6 mL) at RT was treated with TFA (4 mL). After 2 h, the mixture was concentrated in vacuo and then purified by C18 chromatography (10–100% (MeCN in H 2 O)+0.1% FA) to give (R)-6-chloro-3-((1-(2-(difluoromethyl)-3,6-dimethyl-4-oxo-3, 4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid ( 32% yield over 3 steps) as a fluffy white solid. Example 28 (R)-6-chloro-3-((1-(2-(4,4-difluoropiperidin-1-yl)-6-fluoro- 3-methyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0400] Step 1. HATU (6.49 g, 17.1 mmol) was added to a mixture of 2-amino-3-bromo-5-fluorobenzoic acid (2.00 g, 8.54 mmol), methylamine hydrochloride (1.07 g, 17.1 mmol), DIPEA (5.95 mL, 34.2 mmol), in DCM (85 mL) and stirred at r.t. for 3 h. The mixture was washed with sat. aq. NH 4 Cl (80 mL), separated, dried over MgSO 4 , filtered, and concentrated in vacuo. The crude was purified by ISCO silica column chromatography (0- 100% EtOAc/Hex). Fractions containing the compound were collected and concentrated in vacuo to give 2- amino-3-bromo-5-fluoro-N-methylbenzamide (2.08 g, 99%) as a white solid. LCMS: 248.9 [M+H] + . [0401] Step 2.2-amino-3-bromo-5-fluoro-N-methylbenzamide (2.08 g, 8.42 mmol), CDI (2.73 g, 16.8 mmol), and DBU (3.47 mL, 25.3 mmol), were heated to reflux in DCM (80 mL) for 1 h. The mixture was cooled to r.t., washed with 2 N HCl (40 mL), and separated. The aqueous layer was extracted with DCM (3 X 25 mL). The organic layers were combined, dried over MgSO 4 , filtered, and concentrated in vacuo. The solid was washed with EtOAc and filtered. The precipitate was dried and gave 8-bromo-6-fluoro-3-methylquinazoline-2,4(1H,3H)- dione (1.31, 57%) as a white solid. LCMS: 274.1 [M+H] + . [0402] Step 3. DIPEA (2.5 mL, 14.4 mmol) was added to a mixture of 8-bromo-6-fluoro-3-methylquinazoline- 2,4(1H,3H)-dione (1.31 g, 4.79 mmol) in POCl 3 (25 mL) and heated at reflux for 24 h. The mixture was cooled to r.t., concentrated in vacuo, and the crude was purified by ISCO silica column chromatography (0-100% EtOAc/Hex). Fractions containing the compound were collected and concentrated in vacuo to give 8-bromo-2- chloro-6-fluoro-3-methylquinazolin-4(3H)-one (1.26 g, 90%) as a white solid. LCMS: 292.9 [M+H] + . [0403] Step 4. 8-Bromo-2-chloro-6-fluoro-3-methylquinazolin-4(3H)-one (1.26 g, 4.32 mmol), 4,4- difluoropiperidine hydrochloride (1.36 g, 8.64 mmol), and DIPEA (3.0 mL, 17.3 mmol) were heated to reflux in THF (45 mL) for 16 h. The mixture was cooled to r.t., diluted with EtOAc (20 mL), washed with sat. aq. NH 4 Cl (40 mL), separated, washed with H 2 O (40 mL), separated, dried over MgSO 4 , filtered, and concentrated in vacuo to give 8-bromo-2-(4,4-difluoropiperidin-1-yl)-6-fluoro-3-methylquin azolin-4(3H)-one (1.47 g, 90%) as a brown solid. LCMS: 375.9 [M+H] + . [0404] Step 5. 8-Bromo-2-(4,4-difluoropiperidin-1-yl)-6-fluoro-3-methylquin azolin-4(3H)-one (0.97 g, 2.58 mmol), Pd(PPh 3 ) 2 Cl 2 (180 mg, 0.26 mmol), and tributyl(1-ethoxyvinyl)stannane (1.05 mL, 3.09 mmol) were dissolved in dioxane (25 mL), purged with Ar, and heated to 100 °C for 2 h.2 N HCl (5 mL) was added to the mixture and stirred for 20 min at 50 °C. The mixture was cooled to r.t. and washed with aq. KF solution (10 mL). The mixture was extracted with EtOAc (30 mL), separated, dried over MgSO 4 , filtered over Celite, and concentrated in vacuo. The crude was purified by ISCO silica column chromatography (0-100% EtOAc/Hex). Fractions containing the compound were collected and concentrated in vacuo to give 8-acetyl-2-(4,4- difluoropiperidin-1-yl)-6-fluoro-3-methylquinazolin-4(3H)-on e (0.61 g, 70%) as a brown solid. LCMS: 340.1 [M+H] + . [0405] Step 6. 8-Acetyl-2-(4,4-difluoropiperidin-1-yl)-6-fluoro-3-methylqui nazolin-4(3H)-one (813 mg, 2.39 mmol), (R)-2-methylpropane-2-sulfinamide (581 mg, 4.79 mmol), and Ti(O-iPr) 4 (2.90 mL, 9.58 mmol) were heated to reflux in THF (20 mL) for 6 h. The mixture was cooled to r.t., filtered over Celite, and concentrated in vacuo. The crude was purified by ISCO silica column chromatography (0-100% EtOAc/Hex). Fractions containing the compound were collected and concentrated in vacuo to give (R,Z)-N-(1-(2-(4,4-difluoropiperidin-1-yl)-6- fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethylidene) -2-methylpropane-2-sulfinamide (0.48 g, 45%) as a dark yellow solid. LCMS: 443.1 [M+H] + . [0406] Step 7. NaBH 3 CN (204 mg, 3.25 mmol) was added to a mixture of (R,Z)-N-(1-(2-(4,4-difluoropiperidin- 1-yl)-6-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)eth ylidene)-2-methylpropane-2-sulfinamide (0.48 g, 1.08 mmol), AcOH (0.50 mL, 8.68 mmol), in DCM:MeOH (1:1, 10 mL) at 0 °C. The mixture was stirred for 20 min then quenched with sat. aq. NaHCO 3 (10 mL). The mixture was diluted with DCM (10 mL) and separated. The organic layer was dried over MgSO 4 , filtered, and concentrated in vacuo. The crude was purified by ISCO silica column chromatography (0-100% EtOAc/Hex). Fractions containing the compound were collected and concentrated in vacuo to give (R)-N-((R)-1-(2-(4,4-difluoropiperidin-1-yl)-6-fluoro-3-meth yl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)-2-methylpropane-2-sulfinamide (0.28 g, 59%) as a white foam. LCMS: 445.1 [M+H] + . [0407] Step 8. 1 M HCl in EtOAc (6.4 mL, 6.37 mmol) was added to (R)-N-((R)-1-(2-(4,4-difluoropiperidin-1-yl)- 6-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2- methylpropane-2-sulfinamide (283 mg, 0.64 mmol) dissolved in EtOAc (6 mL) and stirred for 2 h at r.t. The mixture was concentrated in vacuo and used in the next reaction without further purification. [0408] Step 9. The amine from Step 8 (50 mg, 0.15 mmol), methyl 6-chloro-3-fluoropicolinate (33 mg, 0.18 mmol), DIPEA (0.10 mL, 0.59 mmol) was dissolved in DMF (1.5 mL) and heated to 100 °C for 24 h. The mixture was cooled to r.t., diluted with EtOAc (5 mL), washed with sat. aq. NH 4 Cl solution (5 mL), separated, washed with aq. LiCl solution (3 X 5 mL), separated, dried over MgSO 4 , filtered, and concentrated in vacuo. The crude material was used in the next reaction without any further purification. [0409] Step 10. LiOH solution (1M , 1 mL) was added to a mixture of the material from Step 9 in THF (1 mL). The mixture was stirred for 2 h at r.t.2 N HCl (1 mL) was added to the mixture and the mixture was concentrated in vacuo. The crude product was purified by prep HPLC C18 (20-95% MeCN/H 2 O + 0.1% FA). Fractions containing the product were collected and concentrated in vacuo to give (R)-6-chloro-3-((1-(2-(4,4- difluoropiperidin-1-yl)-6-fluoro-3-methyl-4-oxo-3,4-dihydroq uinazolin-8-yl)ethyl)amino)picolinic acid (12.3 mg, 17%, over 3 steps) as a white solid. LCMS: 495.1 [M+H] + . Example 29 6-chloro-3-((1-(2-(4,4-difluoropiperidin-1-yl)-3,6,7-trimeth yl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0410] Step 1. 2-Amino-4,5-dimethylbenzoic acid (1.00 g, 6.05 mmol) and NBS (1.19 g, 6.66 mmol) was stirred in DMF (20 mL) at r.t. for 16 h. Additional NBS (0.60 g) was added to the mixture and stirred for 1 h at r.t. H 2 O (20 mL was added to the mixture and filtered. The precipitate was washed with H 2 O (40 mL). The precipitate was dissolved in DCM/MeOH (10:1) (20 mL), dried over MgSO 4 , filtered, and concentrated in vacuo. The compound was used in the next reaction without further purification. [0411] Step 2. The compound from Step 1 was added to a flask containing methylamine hydrochloride (0.76 g, 12.1 mmol), HATU (4.60 g, 12.1 mmol), DIPEA (4.2 mL, 24.2 mmol) and DCM (61 mL). The mixture was stirred at r.t. for 2 h. The mixture was washed with sat. NH 4 Cl (50 mL), separated, washed with sat. aq. NaHCO 3 solution (50 mL), separated, dried over MgSO 4 , filtered, and concentrated in vacuo. The crude product was purified by ISCO silica column chromatography (0-100% EtOAc/Hex). Fractions containing the compound were collected and concentrated in vacuo to give 2-amino-3-bromo-N,4,5-trimethylbenzamide (0.83 g, 53%) as an off- white solid. LCMS: 257.0 [M+H] + . [0412] Step 3. 2-Amino-3-bromo-N,4,5-trimethylbenzamide (0.83 g, 3.23 mmol), CDI (1.05 g, 6.46 mmol), DBU (1.33 mL, 9.68 mmol), was heated to reflux for 1 h in DCM (32 mL). The mixture was cooled to r.t., washed with 2 N HCl, separated, dried over MgSO 4 , filtered, and concentrated in vacuo to give 8-bromo-3,6,7- trimethylquinazoline-2,4(1H,3H)-dione (0.89 g, 97%) as a cream solid. LCMS: 283.0 [M+H] + . [0413] Step 4. 8-Bromo-3,6,7-trimethylquinazoline-2,4(1H,3H)-dione (0.89 g, 3.14 mmol) and DIPEA (1.1 mL, 6.28 mmol) was heated to reflux in POCl 3 (30 mL) for 24 h. The mixture was cooled to r.t. and concentrated in vacuo. The crude was purified by ISCO silica column chromatography (0-100% EtOAc/Hex). Fractions containing the compound were collected and concentrated in vacuo to give 8-bromo-2-chloro-3,6,7-trimethylquinazolin- 4(3H)-one (0.53 g, 56%) as a white solid. LCMS: 302.9 [M+H] + . [0414] Step 5. 8-Bromo-2-chloro-3,6,7-trimethylquinazolin-4(3H)-one (0.53 g, 1.76 mmol), 4,4- difluoropiperidine hydrochloride (0.55 g, 3.51 mmol), and DIPEA (1.22 mL, 7.03 mmol), were heated to reflux in THF (17 mL) for 15 h. The mixture was cooled to r.t., diluted with DCM (40 mL), washed with sat. aq. NH 4 Cl solution (40 mL), separated, dried over MgSO 4 , filtered, and concentrated in vacuo. The crude was purified by ISCO silica column chromatography (0-100% EtOAc/Hex). Fractions containing the compound were collected and concentrated in vacuo to give 8-bromo-2-(4,4-difluoropiperidin-1-yl)-3,6,7-trimethylquinaz olin-4(3H)-one (0.41 g, 60%) as a white solid. LCMS: 387.9 [M+H] + . [0415] Step 6. 8-Bromo-2-(4,4-difluoropiperidin-1-yl)-3,6,7-trimethylquinaz olin-4(3H)-one (0.41 g, 1.06 mmol), Pd(PPh 3 ) 2 Cl 2 (74.0 mg, 0.11 mmol), and tributyl(1-ethoxyvinyl)stannane (0.43 mL, 1.27 mmol) were suspended in dioxane (11 mL). The mixture was purged with Ar and heated to 100 °C for 2 h.2 N HCl (2 mL) was added to the mixture and heated to 50 °C for 20 min. The mixture was cooled to r.t., dried over MgSO 4 , filtered over Celite, and concentrated in vacuo. The crude was purified by ISCO silica column chromatography (0-100% EtOAc/Hex). Fractions containing the compound were collected and concentrated in vacuo to give 8-acetyl-2-(4,4- difluoropiperidin-1-yl)-3,6,7-trimethylquinazolin-4(3H)-one (0.40 g, 60%) as an white solid. LCMS: 350.0 [M+H] + . [0416] Step 7. NaBH 4 (0.19 g, 5.15 mmol) was added to a solution of 8-acetyl-2-(4,4-difluoropiperidin-1-yl)- 3,6,7-trimethylquinazolin-4(3H)-one (0.36 g, 1.03 mmol) in MeOH (10 mL) and stirred at r.t. for 5 d. The mixture was diluted with DCM (20 mL), filtered over Celite, and concentrated in vacuo. The crude was purified by ISCO silica column chromatography (20-100% EtOAc/Hex). Fractions containing the compound and starting material were collected and concentrated in vacuo. The mixture was carried into the next reaction without further purification. [0417] Step 8. The mixture from Step 7 was added to a vial containing PBr 3 (0.1 mL, 1.03 mmol) in DCM (10 mL) and stirred at r.t. for 1 h. The mixture was concentrated in vacuo. The crude was purified by ISCO silica column chromatography (0-100% EtOAc/Hex). Fractions containing the compound were collected and concentrated in vacuo to give 8-(1-bromoethyl)-2-(4,4-difluoropiperidin-1-yl)-3,6,7-trimet hylquinazolin-4(3H)-one (70.0 mg, 16% over 2 steps) as a colorless oil. [0418] Step 9. 8-(1-Bromoethyl)-2-(4,4-difluoropiperidin-1-yl)-3,6,7-trimet hylquinazolin-4(3H)-one (70.0 mg, 0.17 mmol), methyl 3-amino-6-chloropicolinate (37.8 mg, 0.20 mmol), K 2 CO 3 (28.0 mg, 0.20 mmol) was stirred in MeCN (2 mL) at 50 °C for 16 h. The mixture was cooled to r.t., filtered over Celite, and concentrated in vacuo. The crude was purified by ISCO silica column chromatography (0-100% EtOAc/Hex). Fractions containing the compound were collected and concentrated in vacuo to give methyl 6-chloro-3-((1-(2-(4,4-difluoropiperidin-1-yl)- 3,6,7-trimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino )picolinate (0.17 g, 43%) as a light yellow solid. LCMS: 328.0 [M+H] + . [0419] Step 10. Methyl 6-chloro-3-((1-(2-(4,4-difluoropiperidin-1-yl)-3,6,7-trimeth yl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (0.17 g, 0.17 mmol) was stirred in an 1 M aq LiOH:THF (1:1, 2 mL) at r.t. for 16 h. The mixture was acidified with 4 N HCl to pH 1 and concentrated in vacuo. The crude was purified by ISCO silica column chromatography (0-100% EtOAc/Hex). Fractions containing the product were collected and concentrated in vacuo. The product was further purified by C18 prep HPLC (20-95% MeCN/H 2 O +0.1% FA). Fractions containing the product were collected and concentrated in vacuo to give 6-chloro-3-((1-(2-(4,4- difluoropiperidin-1-yl)-3,6,7-trimethyl-4-oxo-3,4-dihydroqui nazolin-8-yl)ethyl)amino)picolinic acid (6.90 mg, 8%) as a white solid. LCMS: 506.1 [M+H] + . Example 30 6-chloro-3-{[(1R)-1-{2,6,6-trimethyl-11-oxo-6H,7H,8H,9H,11H- pyrido[2,1-b]quinazolin-4- yl}ethyl]amino}pyridine-2-carboxylic acid [0420] Step 1. A solution of 2-amino-3-bromo-5-methylbenzoic acid (1 g, 1.1 eq., 4.35 mmol) and sulfuryl dichloride (10 mL, 35 eq., 138 mmol) in toluene (10 mL, 84.5 mmol) was stirred at 105 °C for 16 h. The reaction was quenched with ice cold water (30 mL) and extracted with EtOAc (2* 30 mL). The organic layer was collected and dried over Na 2 SO 4 , filtered and dried under reduced pressure. The crude compound obtained was further purified by combi flash chromatography (20 % EtOAc in Hexane ) to furnish the desired 4-bromo-2,6,6-trimethyl- 6H,7H,8H,9H,11H-pyrido[2,1-b]quinazolin-11-one (0.50 g, 39.39% yield) as a pale yellow solid. LCMS: 322.9 [M+H] + . [0421] Step 2. To a stirred solution of 4-bromo-2,6,6-trimethyl-6H,7H,8H,9H,11H-pyrido[2,1-b]quinazo lin-11- one (0.2 g, 0.623 mmol) and tributyl(1-ethoxyethenyl)stannane (0.318 mL, 1.5 eq., 0.934 mmol) in 1,4-dioxane (2 mL) was added Pd(PPh 3 ) 2 Cl 2 (43.7 mg, 0.1 eq., 0.062 mmol) at RT and resulting mixture was stirred at 100 °C for 16 h. After completion, 2N HCl was added and was stirred at 50 °C for 2h. After 2 h, reaction was neutralized by sat. NaHCO 3 solution (10 mL) and diluted with water (15 mL) and extracted with EtOAc (2* 20 mL). The combined organic layer was dried over Na 2 SO 4 , filtered and dried under reduced pressure to afford the crude material. The crude was purified by combi flash chromatography (40 % EtOAc in Hexane) to furnish the desired 4-acetyl-2,6,6-trimethyl-6H,7H,8H,9H,11H-pyrido[2,1-b]quinaz olin-11-one (150 mg, 84.72%) as a brown solid. [0422] Step 3. To a stirred solution of 4-acetyl-2,6,6-trimethyl-6H,7H,8H,9H,11H-pyrido[2,1-b]quinaz olin-11- one (0.5 g, 1.76 mmol) and (R)-2-methylpropane-2-sulfinamide (213 mg, 1.76 mmol) in THF (10 mL) was added titanium(4+) tetrakis(propan-2-olate) (3.76 mL, 7 eq., 12.3 mmol) at RT. The resulting mixture was stirred at 70 °C for 16 h. After completion, the reaction was quenched with water (10 mL), filtered through Celite and the filtrate was concentrated under reduced pressure to afford the crude compound. The crude was purified by Combi flash chromatography (50% EtOAc in Hexane) to afford (R)-2-methyl-N-[(1E)-1-{2,6,6-trimethyl-11-oxo- 6H,7H,8H,9H,11H-pyrido[2,1-b]quinazolin-4-yl}ethylidene]prop ane-2-sulfinamide (250 mg, 36.69% yield) as a pale yellow solid. LCMS: 285.1 [M+H] + . [0423] Step 4. To a stirred solution of (R)-2-methyl-N-[(1E)-1-{2,6,6-trimethyl-11-oxo-6H,7H,8H,9H,1 1H- pyrido[2,1-b]quinazolin-4-yl}ethylidene]propane-2-sulfinamid e (0.4 g, 1.03 mmol) in THF (5 mL, 61.4 mmol) was added boron(3+) oxolane trihydride (177 mg, 2 eq., 2.06 mmol) at -78 °C. The resulting mixture was stirred at - 78 °C for 1 h. After completion, the reaction was quenched with MeOH (1 mL), diluted with water and extracted with EtOAc (2* 20 mL). The combined organic layer was dried over Na 2 SO 4 , filtered and dried under reduced pressure. The crude was purified by column chromatography (40% EtOAc in Hex) to furnish the desired (R)-2- methyl-N-[(1R)-1-{2,6,6-trimethyl-11-oxo-6H,7H,8H,9H,11H-pyr ido[2,1-b]quinazolin-4-yl}ethyl]propane-2- sulfinamide (150 mg, 37.31%) as a pale yellow gum. LCMS: 390.1 [M+H] + . [0424] Step 5. To a stirred solution of (R)-2-methyl-N-[(1R)-1-{2,6,6-trimethyl-11-oxo-6H,7H,8H,9H,1 1H- pyrido[2,1-b]quinazolin-4-yl}ethyl]propane-2-sulfinamide (150 mg, 0.385 mmol) in DCM (1 mL, 15.6 mmol) was added 4M HCl in dioxane (2 mL) at 0 °C. The resulting mixture was stirred at RT for 1 h. After completion, the mixture was concentrated under reduced pressure to afford crude which was washed with diethyl ether (10 mL) and dried to afford 4-[(1R)-1-aminoethyl]-2,6,6-trimethyl-6H,7H,8H,9H,11H-pyrido [2,1-b]quinazolin-11-one (90 mg, 81.9%) as a brown solid. LCMS: 286.1 [M+H] + . [0425] Step 6. To a stirred solution of 4-[(1R)-1-aminoethyl]-2,6,6-trimethyl-6H,7H,8H,9H,11H-pyrido [2,1- b]quinazolin-11-one (80 mg, 0.280 mmol) and methyl 6-chloro-3-fluoropyridine-2-carboxylate (69.1 mg, 1.3 eq., 0.364 mmol) in DMF (1.6 mL, 20.7 mmol) was added DIPEA (0.244 mL, 5 eq., 1.4 mmol) at RT. The resulting mixture was stirred at 100 °C for 4 h. The reaction was quenched with ice cold water (20 mL) and the resulting solid precipitate was filtered and washed water (10 mL). The precipitate was dried under reduced pressure to afford methyl 6-chloro-3-{[(1R)-1-{2,6,6-trimethyl-11-oxo-6H,7H,8H,9H,11H- pyrido[2,1-b]quinazolin-4- yl}ethyl]amino}pyridine-2-carboxylate (60 mg, 47.05% yield) as an off white solid. LCMS: 455.0 [M+H] + . [0426] Step 7. To a stirred solution of methyl 6-chloro-3-{[(1R)-1-{2,6,6-trimethyl-11-oxo-6H,7H,8H,9H,11H- pyrido[2,1-b]quinazolin-4-yl}ethyl]amino}pyridine-2-carboxyl ate (50 mg, 0.110 mmol) in MeOH (2 mL, 49.4 mmol) and water (0.5 mL, 27.8 mmol), was added LiOH (23.1 mg, 5 eq., 0.549 mmol) at 0 °C and resulting mixture was stirred at RT for 1 h. After completion, the mixture was concentrated under reduced pressure and resulting crude was acidified with 6N HCl at 0 °C. The solid precipitate obtained was filtered off and washed with water (10 ml) followed by diethyl ether (5 mL). The crude compound was dried under reduced pressure to afford 6-chloro-3- {[(1R)-1-{2,6,6-trimethyl-11-oxo-6H,7H,8H,9H,11H-pyrido[2,1- b]quinazolin-4-yl}ethyl]amino}pyridine-2-carboxylic acid (6 mg, 12.38%) as an off white solid. LCMS: 441.3 [M+H] + . Examples 31 and 32 6-chloro-3-{[(1R)-1-{9-methyl-5-phenyl-[1,2,4]triazolo[1,5-c ]quinazolin-7-yl}ethyl]amino}pyridine-2- carboxylic acid 6-chloro-3-{[(1R)-1-{9-methyl-5-phenyl-[1,2,4]triazolo[4,3-c ]quinazolin-7-yl}ethyl]amino}pyridine-2- carboxylic acid [0427] Step 1. To a stirred solution of 2-amino-3-bromo-5-methylbenzoic acid (1 g, 4.35 mmol) in pyridine (5 mL) at 0 °C under N 2 atmosphere was added with benzoyl chloride (1.01 mL, 8.69 mmol) at 0°C and resulting mixture was stirred at RT for 1 h. After completion the reaction was quenched with water (100 mL) and resulting residue was filtered and dried under reduced pressure to result in crude 8-bromo-6-methyl-2-phenyl-4H-3,1- benzoxazin-4-one (1.3 g, 96.78%) as pale yellow solid which taken for next step without further purification. LCMS: 318.0 [M+H] + .. [0428] Step 2. To a stirred solution of 8-bromo-6-methyl-2-phenyl-4H-3,1-benzoxazin-4-one (1.7 g, 5.38 mmol) in Aq. ammonia (40 mL) at RT under N 2 atmosphere, resulting mixture was stirred at 100 °C for 1 hours. After completion the reaction was quenched with water (30 mL) and resulting residue was filtered. The obtained solid was dried under reduced vacuum to afford crude 8-bromo-6-methyl-2-phenyl-3,4-dihydroquinazolin-4-one (1.4 g, 82%) as white solid, which was as such taken for next step. LCMS: 316.9 [M+H] + . [0429] Step 3. To a solution of 8-bromo-6-methyl-2-phenyl-3,4-dihydroquinazolin-4-one (1.4 g, 4.44 mmol) dissolved in POCl 3 (3.74 mL, 40 mmol) under N 2 . The resulting mixture was stirred at reflux (105 °C) for 4 hours. After completion of the reaction, the reaction was quenched with ice water and obtained solid was filtered, dried under reduced pressure to result in crude 8-bromo-4-chloro-6-methyl-2-phenylquinazoline (1.46 g, 98%) as off white solid, which was as such taken for next step. LCMS: 333.0 (M+H) + . [0430] Step 4. To a solution of 8-bromo-4-chloro-6-methyl-2-phenylquinazoline (1.46 g, 4.38 mmol) dissolved in ethanol (14.6 mL, 250 mmol) was added hydrazine hydrate (2.92 mL, 48.2 mmol) under argon. The temperature was maintained at 0 °C during addition. The resulting mixture was stirred at RT for 10 minutes. After completion of the reaction, the reaction was quenched with water and the obtained solid was filtered, dried under reduced pressure to result in crude compound 8-bromo-4-hydrazinyl-6-methyl-2-phenylquinazoline (1.3 g, 90.23%) as off white solid, which was as such taken for next step. LCMS: 330.9 (M+H) + . [0431] Step 5. To a solution of 8-bromo-4-hydrazinyl-6-methyl-2-phenylquinazoline (1.3 g, 3.95 mmol) dissolved in (diethoxymethoxy)ethane (3.27 mL, 19.7 mmol) under argon. The resulting mixture was stirred at 130 °C for 16 hours. After completion of the reaction, the reaction was quenched with water and resulting residue was filtered, dried under reduced pressure to result in crude 7-bromo-9-methyl-5-phenyl-[1,2,4]triazolo[4,3- c]quinazoline (1.32 g, 98%) which was as such taken for next step. LCMS: 340.8 (M+H) + . [0432] Step 6. To a solution of 7-bromo-9-methyl-5-phenyl-[1,2,4]triazolo[4,3-c]quinazoline (0.6 g, 1.77 mmol) and tributyl(1-ethoxyethenyl)stannane (0.904 mL, 2.65 mmol) dissolved in 1,4-dioxane (6 mL) was added Pd(PPh 3 ) 2 Cl 2 (0.124 g, 0.177 mmol) under N 2 . The resulting mixture was stirred at 100 °C for 16 hours. After complete consuming of the starting material, the reaction was quenched with 4 M HCl (0.1 mL) in dioxane, stirred at 0 °C for 10 minutes and resulting reaction was quenched with water and resulting residue was extracted into EtOAc (30 mL x 2 times). The combined organic layer was washed with sat. NaHCO 3 (10 mL x 3 times), brine (10 mL x 2 times), dried over Na 2 SO 4 and evaporated under reduced pressure to result in crude compound which was purified by Combi flash chromatography using EtOAc-hexane gradient over a period of 45 minutes. The product eluted at around 100% EtOAc-hexane. Pure fractions were collected and concentrated to afford 1-{9- methyl-5-phenyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl}ethan- 1-one (0.99 g, 85%) as off-white solid. LCMS: 303.2 (M+H) + . [0433] Step 7. To a solution of 1-{9-methyl-5-phenyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl}e than-1-one (0.45 g, 1.49 mmol) and (R)-2-methylpropane-2-sulfinamide (0.361 g, 2.98 mmol) dissolved in THF (2.25 mL) was added titanium(4+) tetrakis(propan-2-olate) (6.82 mL, 22.3 mmol) under argon. The resulting mixture was stirred at 80 °C for 16 hours. After completion of the reaction, the reaction was quenched with water and resulting residue was filtered. The filtrate was dried under reduced pressure to result in crude compound which was purified by Combi flash chromatography using 60% EtOAc: Hexane as eluent. The pure fractions were collected and concentrated to afford (R)-2-methyl-N-[(1Z)-1-{9-methyl-5-phenyl-[1,2,4]triazolo[4, 3-c]quinazolin-7- yl}ethylidene]propane-2-sulfinamide (260 mg, 43.08%) as off-white solid. LCMS: 406.2 (M+H) + . [0434] Step 8. To a solution of (R)-2-methyl-N-[(1Z)-1-{9-methyl-5-phenyl-[1,2,4]triazolo[4, 3-c]quinazolin-7- yl}ethylidene]propane-2-sulfinamide (0.23 g, 0.567 mmol) dissolved in THF (2.3 mL) was added boron(3+) oxolane trihydride (0.073 g, 0.85 mmol) under N 2 . The temperature was maintained at -78 °C during addition. The resulting mixture was stirred at -78 °C for 1 hours. After completion of the reaction, the reaction was quenched with MeOH, stirred for 15 minutes at RT, evaporated under reduced pressure to result in crude (R)-2- methyl-N-(1-{9-methyl-5-phenyl-[1,2,4]triazolo[4,3-c]quinazo lin-7-yl}ethyl)propane-2-sulfinamide (0.23 g, 99% yield) as complex which was as such taken for next step. LCMS: 408.0 (M+H) + . [0435] Step 9. To a solution of (R)-2-methyl-N-(1-{9-methyl-5-phenyl-[1,2,4]triazolo[4,3-c]q uinazolin-7- yl}ethyl)propane-2-sulfinamide (0.23 g, 0.564 mmol) dissolved in 1,4-dioxane (2.3 mL) and MeOH (0.23 mL) was added 4 M HCl (1.15 mL) in dioxane under N 2 . The temperature was maintained at 0 °C during addition. The resulting mixture was stirred at RT for 1 hour. After completion of the reaction, the mixture was evaporated to minimum amount and quenched with ice cooled water and resulting residue was extracted into EtOAc (10 mL). The aqueous layer was evaporated to remove excess of EtOAc left, basified with saturated NaHCO 3 (5 mL) (made pH=8) extracted with EtOAc (20 mL). The combined organic layer was washed with brine (5 mL x 2 times), dried over Na 2 SO 4 and evaporated under reduced pressure to result in crude (1R)-1-{9-methyl-5-phenyl- [1,2,4]triazolo[4,3-c]quinazolin-7-yl}ethan-1-amine (0.12 g, 73%) as pale yellow solid which was as such taken for next step. LCMS: 304.0 (M+H) + . [0436] Step 10. To a solution of (1R)-1-{9-methyl-5-phenyl-[1,2,4]triazolo[4,3-c]quinazolin-7 -yl}ethan-1-amine (0.1 g, 0.33 mmol) and methyl 6-chloro-3-fluoropyridine-2-carboxylate (0.093 g, 0.49 mmol) dissolved in DMF (1 mL) was added DIPEA (0.115 mL, 0.65 mmol) under argon. The resulting mixture was stirred at 100 °C for 4 hours. After completion of the reaction, the reaction was quenched with ice cooled water and resulting residue was filtered, dried under reduced pressure to result in crude compound which was purified by Combi flash chromatography using EtOAc-hexane gradient over a period of 30 minutes (Column size 14 g). The product elutes at around 42.3 % EtOAc-hexane. Pure fractions were collected and concentrated to afford methyl 6- chloro-3-{[(1R)-1-{9-methyl-5-phenyl-[1,2,4]triazolo[4,3-c]q uinazolin-7-yl}ethyl]amino}pyridine-2-carboxylate (0.085 g, 54%) as off-white solid. LCMS: 473.0 (M+H) + . [0437] Step 11. To a solution of methyl 6-chloro-3-{[(1R)-1-{9-methyl-5-phenyl-[1,2,4]triazolo[4,3-c ]quinazolin- 7-yl}ethyl]amino}pyridine-2-carboxylate (0.08 g, 0.16 mmol) dissolved in MeOH (0.5 mL) and THF (0.5 mL) was added LiOH hydrate (0.014 g, 0.338 mmol) in water (1 mL) under N 2 . The resulting mixture was stirred at RT for 2 hours. After completion of the reaction (two spots were formed; the desired product and the rearranged side product), the mixture was evaporated completely and quenched with ice cooled water. The combined layer was acidified with 1N HCl, solid thrown out was filtered and dried under reduced pressure to result in crude compound which was purified by reverse phase prep-HPLC. The two spots were separated by prep-HPLC using Column: X-Select CSH C18 (19 mm X 250 mm X 5 mic); Mobile phase (A): 0.1% ammonia in water; Mobile phase (B): Acetonitrile; Flow rate: 18.0 mL/min; Rt of Product: 14.787 and 10.983). The pure fractions obtained for both the products were collected and concentrated separately to afford the desired product 6-chloro-3-{[(1R)- 1-{9-methyl-5-phenyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl}e thyl]amino}pyridine-2-carboxylic acid (0.005 g, 6.4%) as white solid. LCMS: 457.3 (M-H) + . The rearranged side product 6-chloro-3-{[(1R)-1-{9-methyl-5-phenyl- [1,2,4]triazolo[1,5-c]quinazolin-7-yl}ethyl]amino}pyridine-2 -carboxylic acid (0.025 g, 32.2%) was also obtained as white solid. LCMS: 457.3 (M-H) + . Example 33 (R)-6-chloro-3-((1-(5-ethyl-2,9-dimethylimidazo[1,2-c]quinaz olin-7-yl)ethyl)amino)picolinic acid [0438] Step 1. To a solution of 2-amino-3-bromo-5-methylbenzoic acid (3 g, 13 mmol) was added propionic anhydride (4.2 mL, 32.6 mmol) under N 2 atmosphere at RT. The resulting mixture was stirred at 130 °C in microwave for 10 min. After completion, the reaction was quenched with water (50 mL) and resulting residue was filtered, dried under reduced pressure to get crude 8-bromo-2-ethyl-6-methyl-4H-benzo[d] [1,3] oxazin-4-one (3.4 g, yield: 97.25%) as off-white solid. LCMS: 270.1 (M +2H) + . [0439] Step 2. To 8-bromo-2-ethyl-6-methyl-4H-benzo[d] [1,3] oxazin-4-one (12.5 g, 44 mmol) was added Aq. ammonia (25%) (50 mL) in a 250 mL sealed tube and stirred at 100 °C for 1 h. After 1 h, the mixture was cooled to RT, precipitation observed which was filtered and dried on vacuum to afford crude 8-bromo-2-ethyl-6- methylquinazolin-4(3H)-one (12 g, crude) as off-white solid confirmed by analysis. LCMS: 268.1 (M+H)+. [0440] Step 3. To 8-bromo-2-ethyl-6-methylquinazolin-4(3H)-one (3 g, 11.2 mmol) in toluene (24 mL, 203 mmol) was added phosphoryl trichloride (2.4 mL, 25.7 mmol) and stirred at 120 °C for 3 h under N 2 atmosphere. After 3 h the mixture was concentrated to afford 8-bromo-4-chloro-2-ethyl-6-methylquinazoline (2.0 g, yield: 62.36%) as brown gum. LCMS: 283.9 (M-H) + . [0441] Step 4. To a stirred solution of 8-bromo-4-chloro-2-ethyl-6-methylquinazoline (1 g, 3.5 mmol) in THF (10 mL, 123 mmol) was added NH 4 OH (10 mL) and stirred at 80°C for 16 h. After 16 h, the mixture was cooled, quenched with water (50 mL) and conc. HCl until pH~4 and extracted with EtOAc (50 mL), the obtained aq. layer was again basified with NaHCO 3 Aq. solution (50 mL) until pH~8 and extracted with EtOAc (3*50 mL). The combined organic layer was dried over sodium sulphate, filtered, and concentrated to afford 8-bromo-2-ethyl-6- methylquinazolin-4-amine (0.6 g, yield: 64%) as yellow solid confirmed by analysis. LCMS: 267.1 (M+H)+. [0442] Step 5. To a stirred solution of 8-bromo-2-ethyl-6-methylquinazolin-4-amine (1.2 g, 4.51 mmol) in DMF (12 mL) was added 1-chloropropan-2-one (626 mg, 6.76 mmol) and stirred at 130 °C for 1 h in microwave. After 1 h, the reaction was quenched with water (50 mL) and extracted with EtOAc (3* 45mL). The combined organic layer was dried over sodium sulphate, filtered and concentrated to afford crude 7-bromo-5-ethyl-2,9- dimethylimidazo[1,2-c] quinazoline (1 g, yield: 72.91%) as brown solid. LCMS: 306.1 (M +2H)+. [0443] Step 6. To a stirred solution of 7-bromo-5-ethyl-2,9-dimethylimidazo[1,2-c]quinazoline (1.0 g, 3.29 mmol) in 1,4-dioxane (15 mL) was added Pd(PPh 3 ) 2 Cl 2 (231 mg, 0.329 mmol). Dibutyl(1- ethoxyethenyl)propylstannane (3.42 g, 9.86 mmol) was added and the mixture was stirred at 100 °C for 3 h in sealed tube. After 3 h to this solution was added 4M HCl in dioxane (15 mL) at RT and stirred at same temperature for 1 h. After 1 h, the reaction was quenched with water (50 mL) and neutralized with aq. solution of NaHCO 3 (15 mL) (pH~8) then extracted with EtOAc (3*50 mL). The combined organic layer was dried over sodium sulphate filtered and concentrated to afford crude. Crude was purified by Combi flash column chromatography using EtOAc in hexane as mobile phase. Desired product eluted in 25% EtOAc in hexane to afford 1-{5-ethyl-2,9-dimethylimidazo[1,2-c] quinazolin-7-yl}ethan-1-one (0.8 g, 91.03% yield) as off-white solid. LCMS: 268.2 (M+H)+. [0444] Step 7. To a stirred solution of 1-{5-ethyl-2,9-dimethylimidazo[1,2-c] quinazolin-7-yl} ethan-1-one (1.2 g, 4.49 mmol) in THF (7.5 mL, 92.2 mmol) was added (R)-2-methylpropane-2-sulfinamide (1.36 g, 11.2 mmol) followed by addition of titanium(IV) isopropoxide (13.3 mL, 44.9 mmol) and stirred at 100 °C for 1 h in microwave. After 1 h the reaction was quenched with water (50 mL) and extracted with EtOAc (3*50 mL) combined organic layer was dried over sodium sulphate, filtered and concentrated to afford crude material. Crude was loaded in automated column chromatography using EtOAc in hexane as mobile phase desired spot eluded in 15% EtOAc in hexane to afford (R,Z)-N-(1-(5-ethyl-2,9-dimethylimidazo[1,2-c]quinazolin-7- yl)ethylidene)-2-methylpropane-2-sulfinamide (0.8 g, 48.1%) as off-white solid confirmed by analysis. LCMS: 371.2 (M+H)+. [0445] Step 8. To a stirred solution of (R)-N-[(1Z)-1-{5-ethyl-2,9-dimethylimidazo[1,2-c]quinazolin- 7- yl}ethylidene]-2-methylpropane-2-sulfinamide (0.4 g, 1.08 mmol) in THF (2 mL, 24.6 mmol) was added borane THF (464 mg, 5.4 mmol) at -78°C and stirred at same temperature for 1 h. After 1 h reaction was quenched with water (25 mL) and extracted with EtOAc (3*50 mL) then organic layer was dried over sodium sulphate, filtered and concentrated to afford crude. Crude was purified by combi flash column chromatography using EtOAc in hexane as mobile phase. The desired spot eluded in 25% EtOAc in hexane to afford (R)-N-((R)-1-(5-ethyl-2,9- dimethylimidazo[1,2-c]quinazolin-7-yl)ethyl)-2-methylpropane -2-sulfinamide (0.4 g, 96%) as brown solid. LCMS: 373.2 (M+H)+. [0446] Step 9. To a stirred solution of (R)-N-((R)-1-(5-ethyl-2,9-dimethylimidazo[1,2-c]quinazolin-7 -yl)ethyl)-2- methylpropane-2-sulfinamide (0.4 g, 1.07 mmol) in DCM:MeOH (2:1) (1.78 mL) was added 4M HCl in dioxane (5 mL, 20 mmol) and stirred at RT for 1 h. After 1 h mixture was concentrated and triturated with n-pentane (15 mL) and Diethyl ether (15mL) to afford (R)-1-(5-ethyl-2,9-dimethylimidazo[1,2-c]quinazolin-7-yl)eth an-1-amine (0.180 g, 62.47%) as yellow solid. LCMS: 269.0 (M+H)+ . [0447] Step 10. To a stirred solution of (R)-1-(5-ethyl-2,9-dimethylimidazo[1,2-c]quinazolin-7-yl)eth an-1-amine (0.1 g, 0.373 mmol) in DMF (3 mL, 38.7 mmol) was added ethylbis(propan-2-yl)amine (0.198 mL, 1.12 mmol) followed by addition of methyl 6-chloro-3-fluoropyridine-2-carboxylate (0.091 g, 0.484 mmol) and the mixture was stirred at 100 °C for 4 h. After 4 h the reaction was cooled and quenched with water (15 mL) and extracted with EtOAc (3*25 mL). The combined organic layer was dried over sodium sulphate, filtered and concentrated to afford crude. Crude material was loaded in automated column chromatography using EtOAc in hexane as mobile phase desired spot eluded in 45% EtOAc in hexane to afford methyl (R)-6-chloro-3-((1-(5-ethyl-2,9- dimethylimidazo[1,2-c]quinazolin-7-yl)ethyl)amino)picolinate (15 mg, 9.19%) as off-white solid. LCMS: 438.0 (M +H)+ . [0448] Step 11. To a stirred solution of methyl 6-chloro-3-{[(1R)-1-{5-ethyl-2,9-dimethylimidazo[1,2- c]quinazolin-7-yl}ethyl]amino}pyridine-2-carboxylate (15 mg, 0.034 mmol) in THF:MeOH:Water(1:1:1) (1.5 mL) was added LiOH (0.004 g, 0.171 mmol) and the mixture was stirred at 0 °C to RT for 2 h. After 2 h, the mixture was neutralized by 6N HCl Aq. solution up to pH~5 and then the mixture was concentrated to afford crude material. The crude was submitted for Prep. HPLC which was performed in method mentioned below to afford (R)-6-chloro-3-((1-(5-ethyl-2,9-dimethylimidazo[1,2-c]quinaz olin-7-yl)ethyl)amino)picolinic acid (1.2 mg, 8.26% yield) as white solid. LCMS: 424.3 (M+H)+. Example 34 6-chloro-3-{[(1R)-1-{5-ethyl-9-methyl-[1,2,4]triazolo[4,3-c] quinazolin-7-yl}ethyl]amino}pyridine-2- carboxylic acid [0449] Step 1. 2-Amino-3-bromo-5-methylbenzoic acid (3.0 g, 13 mmol) was dissolved in propanoyl propanoate (4.2 mL, 32.6 mmol) under N 2 at RT. The resulting mixture was stirred at 130 °C in microwave for 10 minutes. After completion, the reaction was quenched with water (100 mL) and the resulting residue was filtered and dried under reduced pressure to afford 8-bromo-2-ethyl-6-methyl-4H-3,1-benzoxazin-4-one 6.2 g (combined from other batches) as off-white solid. [0450] Step 2. 8-Bromo-2-ethyl-6-methyl-4H-3,1-benzoxazin-4-one (6.2 g, 23.1 mmol) in Aq. ammonia (30 mL) was stirred at RT under N 2 atmosphere. The resulting mixture was stirred at 100 °C for 1 h. After completion, the reaction was quenched with water (50 mL) and resulting residue was filtered off. The obtained solid was dried under vacuum to afford the pure 8-bromo-2-ethyl-6-methyl-3,4-dihydroquinazolin-4-one (5.3 g, 85.8%) as white solid. LCMS: 269.1(M+2H)+. [0451] Step 3. To a stirred solution of 8-bromo-2-ethyl-6-methyl-3,4-dihydroquinazolin-4-one (3 g, 11.2 mmol) in toluene (15 mL) at 0 °C under N 2 atmosphere was added phosphoroyl trichloride (8.5 mL, 89.8 mmol). The reaction was heated to reflux at 120 °C for 1 hour. After completion the resulting mixture was evaporated to dryness under reduced pressure to afford crude (3 g) and was immediately taken forward to next step. LCMS: 286.0 [M+H]+. [0452] Step 4. To a stirred solution of 8-bromo-4-chloro-2-ethyl-6-methylquinazoline (3 g, 10.5 mmol) in hydrazine hydrate (7 mL, 116 mmol) at 0 °C under N 2 atmosphere, was added ethanol (3 mL). The resulting mixture was stirred at RT for 16 hours. After completion the reaction was quenched with water (200 mL) and resulting residue was filtered, dried under reduced pressure to result in crude 8-bromo-2-ethyl-4-hydrazinyl-6- methylquinazoline (5.88 g, 47% purity) as orange coloured solid, which was as such taken for next step. LCMS: 282.9 (M+H)+. Step 5. To solid 8-bromo-2-ethyl-4-hydrazinyl-6-methylquinazoline (4.0 g, 14.2 mmol) was added with (diethoxymethoxy)ethane (11.8 mL, 71.1 mmol) and the mixture was stirred at 130 °C for 1 hour in microwave. After completion, the reaction was quenched with water and resulting residue was extracted into EtOAc (50 mL x 2 times). The combined organic layer was washed with brine (20mL x 2 times), dried over Na 2 SO 4 and evaporated under reduced pressure to result in crude compound which was purified by Combi flash chromatography using EtOAc-hexane gradient over a period of 45 minutes (Column size 40 g). The product eluted at around 70% EtOAc-hexane. Pure fractions were collected and concentrated to afford 7-bromo-5-ethyl- 9-methyl-[1,2,4]triazolo[4,3-c]quinazoline (0.73 g, 17.6%) as pale yellow solid. LCMS: 293.0 (M+H)+. [0453] Step 5. To a solution of 7-bromo-5-ethyl-9-methyl-[1,2,4]triazolo[4,3-c]quinazoline (0.72 g, 2.47 mmol) and tributyl(1-ethoxyethenyl)stannane (1.26 mL, 3.71 mmol) dissolved in 1,4-dioxane (7.2 mL) was added Pd(PPh 3 ) 2 Cl 2 (0.17 g, 0.247 mmol) under N 2 . The resulting mixture was stirred at 100 °C for 3 hours. After complete consuming of the starting material, the reaction was quenched with 4 M HCl (0.7 mL) in dioxane, stirred at 0 °C for 30 minutes and resulting reaction was quenched with water and resulting residue was extracted into EtOAc (50 mL x 2 times). The combined organic layer was washed with sat. NaHCO 3 (10 mL x 3 times), brine (10 mL x 2 times), dried over Na 2 SO 4 and evaporated under reduced pressure to result in crude compound. The crude was purified by Combi flash chromatography using EtOAc-hexane gradient over a period of 30 min (Column size 12 g). Required product elutes at around 35.5 % EtOAc-hexane. Pure fractions were collected and concentrated to afford 1-{5-ethyl-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl}et han-1-one (0.4 g, 63.61%) as pale yellow solid. LCMS: 255.1 (M+H)+. [0454] Step 6. To a solution of 1-{5-ethyl-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl}et han-1-one (0.4 g, 1.57 mmol) and (R)-2-methylpropane-2-sulfinamide (736 mg, 6.29 mmol) dissolved in THF (0.4 mL) was added titanium(4+) tetrakis(propan-2-olate) (9.6 mL, 31.5 mmol) under argon. The resulting mixture was stirred at 80°C for 16 hours. After completion, the reaction was quenched with water and resulting residue was filtered, filtrate was extracted into EtOAc (20 mL x 2 times). The combined organic layer was washed with water (10mL x 2 times), brine (10mL x 2 times), dried over Na 2 SO 4 and evaporated under reduced pressure to result in crude compound. The crude was purified by Combi flash chromatography using EtOAc-hexane gradient over a period of 30 minutes (Column size 12 g). Required product elutes at around 65% EtOAc-hexane. Pure fractions were collected and concentrated to afford (R)-N-[(1Z)-1-{5-ethyl-9-methyl-[1,2,4]triazolo[4,3-c]quinaz olin-7- yl}ethylidene]-2-methylpropane-2-sulfinamide (0.290 g, 51.57 %) as pale yellow liquid. LCMS: 358.2 (M+H)+. [0455] Step 7. To a solution of (R)-N-[(1Z)-1-{5-ethyl-9-methyl-[1,2,4]triazolo[4,3-c]quinaz olin-7-yl}ethylidene]- 2-methylpropane-2-sulfinamide (0.290 g, 0.811 mmol) dissolved in THF (1.2 mL) was added boron(3+) oxolane trihydride (105 mg, 1.22 mmol) under N 2 . The temperature was maintained at -78 °C during addition. The resulting mixture was stirred at -78 °C for 1 hour. After completion, the reaction was quenched with MeOH, stirred for 15 minutes at RT and evaporated under reduced pressure to result in crude (R)-N-(1-{5-ethyl-9-methyl- [1,2,4]triazolo[4,3-c]quinazolin-7-yl}ethyl)-2-methylpropane -2-sulfinamide (0.290 g, 99.44%) as complex, which was as such taken for next step. LCMS: 360.1(M+H)+. [0456] Step 8. To a solution of (R)-N-(1-{5-ethyl-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin- 7-yl}ethyl)-2- methylpropane-2-sulfinamide (0.4 g, 1.11 mmol) dissolved in 1,4-dioxane (4.53 mL, 53.2 mmol) and MeOH (0.4 mL) was added 4 M HCl (4.5 mL) in dioxane under N 2 . The temperature was maintained at 0 °C during addition. The resulting mixture was stirred at RT for 1 hours. After completion of the reaction, the mixture was evaporated to minimum amount and quenched with ice cooled water. The resulting residue was extracted into EtOAc (10 mL). The Aqueous layer was evaporated to remove excess of EtOAc left, basified with sat. NaHCO 3 (5 mL) (made pH~8) and extracted with EtOAc (20 mL). The combined organic layer was washed with brine (5 mL x 2 times), dried over Na 2 SO 4 and evaporated under reduced pressure to result in crude (1R)-1-{5-ethyl-9-methyl- [1,2,4]triazolo[4,3-c]quinazolin-7-yl}ethan-1-amine (0.340 g crude) as pale yellow solid which was as such taken for next step withput further purification. LCMS: 256.2(M+H)+ . [0457] Step 9. To a solution of (1R)-1-{5-ethyl-9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7- yl}ethan-1-amine (0.320 g, 1.25 mmol) and methyl 6-chloro-3-fluoropyridine-2-carboxylate (0.356 g, 1.88 mmol) dissolved in dimethyl sulfoxide (3.2 mL) was added DIPEA (0.437 mL, 2.51 mmol) under N 2 . The resulting mixture was stirred at 100°C for 4 hours. After completion of the reaction, the mixture was quenched with water (10 mL) and the resulting residue was extracted into EtOAc (10 mL x 2 times). The combined organic layer was washed with water (10 mL x 2 times), brine (10 mL x 2 times), dried over Na 2 SO 4 and evaporated under reduced pressure to result in crude compound which was purified by Combi flash chromatography using EtOAc-hexane gradient over a period of 30 minutes (Column size 12 g). The product eluted at around 40% EtOAc-hexane. Pure fractions were collected and concentrated to afford methyl 6-chloro-3-{[(1R)-1-{5-ethyl-9-methyl-[1,2,4]triazolo[4,3- c]quinazolin-7-yl}ethyl]amino}pyridine-2-carboxylate (210 mg, 39.44%) as white solid. LCMS: 425.1 (M+H)+ . [0458] Step 10. To a solution of methyl 6-chloro-3-{[(1R)-1-{5-ethyl-9-methyl-[1,2,4]triazolo[4,3-c] quinazolin-7- yl}ethyl]amino}pyridine-2-carboxylate (0.2 g, 0.471 mmol) dissolved in MeOH (1 mL) and THF (1 mL) was added LiOH hydrate (0.039 g, 0.941 mmol) in water (2 mL) under N 2 . The temperature was maintained at 0 °C during addition. The resulting mixture was stirred at RT for 2 hours. After completion, the mixture was evaporated to a minimum amount and quenched with ice cooled water. The pH of the mixture was made pH 5 with 1N HCl, the solid throw-out was filtered and concentrated to afford 6-chloro-3-{[(1R)-1-{5-ethyl-9-methyl-[1,2,4]triazolo[4,3- c]quinazolin-7-yl}ethyl]amino}pyridine-2-carboxylic acid ( 0.165 g, 85%) as off white solid. LCMS: 411.3 (M+H)+. Example 35 6-chloro-3-{[(1R)-1-{5-ethyl-9-methylimidazo[1,2-c]quinazoli n-7-yl}ethyl]amino}pyridine-2-carboxylic acid [0459] Step 1. 2-Amino-3-bromo-5-methylbenzoic acid (3 g g, 13 mmol) was dissolved in propanoyl propanoate (4.2 mL, 32.6 mmol) under N 2 at RT. The resulting mixture was stirred at 130 °C in microwave for 10 minutes. After completion, the reaction was quenched with water (100 mL) and resulting residue was filtered and dried under reduced pressure to afford the crude 8-bromo-2-ethyl-6-methyl-4H-3,1-benzoxazin-4-one as off-white solid. The crude compound was used in the next step without any purification. [0460] Step 2. To a stirred solution 8-bromo-2-ethyl-6-methyl-4H-3,1-benzoxazin-4-one (6.2 g, 23.1 mmol) in Aq. ammonia (30 mL) at RT under a N 2 atmosphere. The resulting mixture was stirred at 100 °C for 1 h. After completion, the mixture was quenched with water (50 mL) and resulting residue was filtered off. The obtained solid was dried under vacuum to afford the pure 8-bromo-2-ethyl-6-methyl-3,4-dihydroquinazolin-4-one (5.3 g, 85.8%) as white solid. LCMS: 269.1(M+2H) + . [0461] Step 3. To a solution of 8-bromo-2-ethyl-6-methyl-3,4-dihydroquinazolin-4-one (1.5 g, 5.62 mmol) and (1H-1,2,3-benzotriazol-1-yloxy)tris(dimethylamino)phosphaniu m; was added hexafluoro-λ⁵-phosphanuide (3.23 g, 7.3 mmol), 2H,3H,4H,6H,7H,8H,9H,10H-pyrimido[1,2-a]azepine (1.7 mL, 11.2 mmol) dissolved in DMF (15 mL). After the mixture was stirred for 10 minutes, 2-aminoethan-1-ol (1.03 mL, 16.8 mmol) was added at RT under argon. The resulting mixture was stirred at RT for 10 hours. After the starting materials were completely consumed, the reaction was quenched with water (50 mL) and resulting residue was extracted with EtOAc (30 mL x 2 times). The combined organic layers were washed with water (30 mL x 2 times), brine (10 mL x 2 times), dried over Na 2 SO 4 and evaporated under reduced pressure to furnish the crude compound which was purified by Combi flash chromatography using EtOAc-hexane gradient (50% EtOAc: Hexane) over a period of 30 minutes (Column size 24 g). The pure fractions were collected and concentrated to afford pure compound 2-[(8-bromo-2- ethyl-6-methylquinazolin-4-yl)amino]ethan-1-ol (2.6 g, crude) as off-white solid. LCMS: 312.1 [M+2H] + . [0462] Step 4. To a stirred solution of 2-[(8-bromo-2-ethyl-6-methylquinazolin-4-yl)amino]ethan-1-ol (4.6 g, 14.8 mmol) in THF (46 mL) were added triethylamine (8.27 mL, 59.3 mmol) and mesyl chloride (2.3 mL, 29.7 mmol) at 0 °C. The resulting mixture was stirred at 70 °C for 16 hours. The reaction was cooled down, and diluted with water (5 mL). The solid product was filtered off and washed with MeOH (5 mL) and water (5 mL). The solid obtained was dried under reduced pressure to afford 7-bromo-5-ethyl-9-methyl-2H,3H-imidazo[1,2-c]quinazoline (3.6 g, 83.09%) as yellow solid. LCMS: 294.0 [M+2H]+. [0463] Step 5. To a stirred solution of 7-bromo-5-ethyl-9-methyl-2H,3H-imidazo[1,2-c]quinazoline (3.6 g, 12.3 mmol) in toluene (30 mL) was added MnO 2 (5.36 g, 61.6 mmol) at RT and resulting mixture was stirred at 110 °C for 36 hours. After the starting materials were fully consumed, the mixture was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to afford crude of 7-bromo-5-ethyl-9-methylimidazo[1,2- c]quinazoline (0.75 g, 20.98%) as yellow liquid. LCMS: 292.0 [M+2H] + . [0464] Step 6. To a solution of 7-bromo-5-ethyl-9-methylimidazo[1,2-c]quinazoline (0.4 g, 1.38 mmol) and tributyl(1-ethoxyethenyl)stannane (0.705 mL, 2.07 mmol) dissolved in 1,4-dioxane (4.01 mL) was added Pd(PPh 3 ) 2 Cl 2 (96.8 mg, 0.138 mmol) under N 2 . The resulting mixture was stirred at 100 °C for 3 hours. After complete consuming of the starting material, the reaction was quenched with 4 M HCl (0.4 mL) in dioxane and stirred at 0 °C for 30 minutes. The resulting mixture was quenched with water (10 mL) and resulting residue was extracted with EtOAc (50 mL x 2 times). The combined organic layer was washed with sat. NaHCO 3 (10 mL x 3 times), brine (10 mL x 2 times), dried over Na 2 SO 4 and evaporated under reduced pressure to afford the crude compound which was purified by Combi flash chromatography using EtOAc-hexane gradient (30% EtOAc: Hexane) over a period of 30 min (Column size 12 g). The pure fractions were collected and concentrated to afford 1-{5-ethyl-9-methylimidazo[1,2-c]quinazolin-7-yl}ethan-1-one (0.2 g, 57.28%) as pale yellow liquid. LCMS: 254.2 (M+2H) + . [0465] Step 7. To a solution of 1-{5-ethyl-9-methylimidazo[1,2-c]quinazolin-7-yl}ethan-1-one (0.2 g, 0.790 mmol) and (R)-2-methylpropane-2-sulfinamide (0.38 g, 3.16 mmol) dissolved in THF (2 mL, 24.6 mmol) was added titanium(4+) tetrakis(propan-2-olate) (4.83 mL, 15.8 mmol) under argon. The resulting mixture was stirred at 80 °C for 16 hours. After completion of the reaction, it was quenched with water (20 mL) and the resulting residue was filtered off. The filtrate was extracted into EtOAc (10 mL x 2 times). The combined organic layer was washed with water (10mL x 2 times), brine (10mL x 2 times), dried over Na 2 SO 4 and evaporated under reduced pressure to result in crude compound which was purified by Combi flash chromatography using EtOAc-hexane gradient (70% EtOAc: Hexane) over a period of 30 minutes (Column size 12 g). The pure fractions were collected and concentrated to afford (R)-N-[(1Z)-1-{5-ethyl-9-methylimidazo[1,2-c]quinazolin-7-yl }ethylidene]-2- methylpropane-2-sulfinamide (98 mg, 34.8%) as pale yellow liquid. LCMS: 357.2 (M+H) + [0466] Step 8. To a solution of (R)-N-[(1Z)-1-{5-ethyl-9-methylimidazo[1,2-c]quinazolin-7-yl }ethylidene]-2- methylpropane-2-sulfinamide (80 mg, 0.224 mmol) dissolved in THF (1 mL, 12.3 mmol) was added boron(3+) oxolane trihydride (57.9 mg, 0.673 mmol) under N 2 . The temperature was maintained at -78 °C during addition. The resulting mixture was stirred at -78 °C for 1 hour. After complete consumption of the starting materials, the reaction was quenched with MeOH (5 mL), stirred for 15 minutes at RT, evaporated under reduced pressure to furnish the crude compound of (R)-N-(1-{5-ethyl-9-methylimidazo[1,2-c]quinazolin-7-yl}ethy l)-2-methylpropane-2- sulfinamide (80 mg, 99%) as complex which was taken for next step without further purification. LCMS: 359.2(M+H) + . [0467] Step 9. To a solution of (R)-N-(1-{5-ethyl-9-methylimidazo[1,2-c]quinazolin-7-yl}ethy l)-2-methylpropane- 2-sulfinamide (80 mg, 0.223 mmol) dissolved in 1,4-dioxane (0.909 mL, 10.7 mmol) and MeOH (0.091 mL, 2.25 mmol) was added 4 M HCl (0.115 mL, 2 eq., 0.446 mmol) in dioxane under N 2 . The temperature was maintained at 0 °C during addition. The resulting mixture was stirred at RT for 1 h. After the starting materials were completely consumed, the mixture was evaporated to minimum amount, quenched with ice cooled water (5 mL) and the resulting residue was extracted into EtOAc (10 mL). The Aqueous layer was evaporated to remove excess of EtOAc left, basified with saturated NaHCO 3 (5 mL) (made Ph~8) extracted with EtOAc (20 mL). The combined organic layer was washed with brine (5 mL x 2 times), dried over Na 2 SO 4 and evaporated under reduced pressure to result in crude (1R)-1-{5-ethyl-9-methylimidazo[1,2-c]quinazolin-7-yl}ethan- 1-amine (0.06 g, crude) as pale yellow solid which was taken for next step without further purification. LCMS: 255.1 (M+H) + . [0468] Step 10. To a solution of (1R)-1-{5-ethyl-9-methylimidazo[1,2-c]quinazolin-7-yl}ethan- 1-amine (0.055 g, 0.216 mmol) and methyl 6-chloro-3-fluoropyridine-2-carboxylate (0.06 g, 0.236 mmol) dissolved in dimethyl sulfoxide (0.602 mL) was added DIPEA (0.082 mL, 0.472 mmol) under N 2 . The resulting mixture was stirred at 80 °C for 4 hours. After completion of the reaction, the reaction was quenched with ice cooled water (10 mL) and resulting residue was extracted into EtOAc (10 mL x 2 times). The combined organic layer was washed with water (10 mL x 2 times), brine (10 mL x 2 times), dried over Na 2 SO 4 and evaporated under reduced pressure to result in crude compound which was purified by Combi flash chromatography using EtOAc-hexane gradient ( over a period of 30 min (Column size 4 g). Required product elutes at around 39% EtOAc-hexane. Pure fractions were collected and concentrated to afford methyl 6-chloro-3-{[(1R)-1-{5-ethyl-9-methylimidazo[1,2- c]quinazolin-7-yl}ethyl]amino}pyridine-2-carboxylate (0.021 g, 21%) as off-white solid. LCMS: 424.2 (M+H) + . [0469] Step 11. To a solution of methyl 6-chloro-3-{[(1R)-1-{5-ethyl-9-methylimidazo[1,2-c]quinazoli n-7- yl}ethyl]amino}pyridine-2-carboxylate (0.021 g, 0.050 mmol) dissolved in MeOH (0.5 mL) and THF (0.3 mL) was added LiOH hydrate (0.004g, 0.099 mmol) in water (0.5 mL) under N 2 . The temperature was maintained at 0 °C during addition. The resulting mixture was stirred at RT for 2 hours. Progress of the reaction was monitored by TLC (5% MeOH: DCM). After the starting material was fully consumed, the reaction was quenched with ice cooled water (5 mL). The solvents were evaporated in vacuum followed by addition of 1N HCl to the mixture, solid throw-out was filtered off and dried to give the crude compound. The crude product was purified by reverse phase prep-HPLC (Column: Sunfire C18 OBD (250 mm X 19 mm X 5 mic); Mobile phase (A): 0.1% Formic acid in Water; Mobile phase (B): Acetonitrile; Flow rate: 19.0 mL/min; Rt of Product: 15.669). Pure fractions were collected and concentrated to afford pure 6-chloro-3-{[(1R)-1-{5-ethyl-9-methylimidazo[1,2-c]quinazoli n-7- yl}ethyl]amino}pyridine-2-carboxylic acid (0.008 g, 39.4%) as white solid. LCMS: 408.3 (M-H) + EXAMPLE 36 (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl- [1,2,4]triazolo[4,3-c]quinazolin-7- yl)ethyl)amino)picolinic acid [0470] Step 1: To a mixture of 2-amino-3-bromo-5-methylbenzoic acid (4.6 g, 20 mmol), NH 4 Cl (3.18 g, 60 mmol) and HATU (11.4 g, 30 mmol) in DCM (80 ml) was added DIPEA (7.74 g, 60 mmol), the mixture was stirred at RT overnight. Water (100 ml) was added, the separated aqueous layer was extracted with DCM (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated, the residue was purified by chromatography (DCM: MeOH = 30:1) to afford 2-amino-3-bromo-5-methylbenzamide (2.0 g, 44%) as a white solid. LCMS: (M + H) + =229.0 [0471] Step 2: To a solution of 2-amino-3-bromo-5-methylbenzamide (2.0 g, 8.8 mmol) in dioxane (40 ml) was added thiophosgene (2.02 g, 17.6 mmol) dropwise. The mixture was stirred at RT for 2 hours. then the mixture was stirred at 105 °C for 2 hours. the mixture was concentrated to afford crude 8-bromo-2-chloro-6- methylquinazolin-4(3H)-one (2.39 g) as a yellow solid for the next step without further purification. LCMS: (M + H) + =273.0 [0472] Step 3: To a solution of crude 8-bromo-2-chloro-6-methylquinazolin-4(3H)-one (2.39 g, 8.8 mmol) in DCM (50 ml) was added piperidine (3.19 g, 26.4 mmol), the mixture was stirred at 40 °C for 5 days. Water (50 ml) was added and the mixture was extracted with DCM (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 3:1) to afford 8-bromo-2-(4,4-difluoropiperidin-1-yl)-6-methylquinazolin-4( 3H)-one (1.85 g, 59%) as a white solid. LCMS: (M + H) + =358.0 [0473] Step 4: A mixture of 8-bromo-2-(4,4-difluoropiperidin-1-yl)-6-methylquinazolin-4( 3H)-one (1.0 g, 2.8 mmol) in POCl 3 (15 ml) was stirred at 100 °C for 30 min. Cooling to RT, the mixture was poured into ice-water and adjusted pH = 8-9 with a saturated solution of NaHCO 3 , the resulting mixture was extracted with DCM (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE:EA = 20:1) to afford 8-bromo-4-chloro-2-(4,4-difluoropiperidin-1-yl)-6- methylquinazoline (940 mg, 90%) as a yellow solid. LCMS: (M + H) + =376.0 [0474] Step 5: To a solution of 8-bromo-4-chloro-2-(4,4-difluoropiperidin-1-yl)-6-methylquin azoline (940 mg, 2.5 mmol) in EtOH (20 ml) at RT was added N 2 H 4 .H 2 O (625 mg, 12.5 mmol). The mixture was stirred at RT overnight. The mixture was filtrated and the cake was dried under reduce pressure to afford 8-bromo-2-(4,4- difluoropiperidin-1-yl)-4-hydrazineyl-6-methylquinazoline (850 mg, 91%) as a yellow solid. LCMS: (M + H) + =372.1 [0475] Step 6: A mixture of 8-bromo-2-(4,4-difluoropiperidin-1-yl)-4-hydrazineyl-6-methy lquinazoline (850 mg, 2.29 mmol) in triethoxymethane (10 ml) was heated to 150 °C and stirred for 30 min. Cooling to RT, the mixture was filtrated, the cake was washed with PE and dried under reduce pressure to afford 7-bromo-5-(4,4- difluoropiperidin-1-yl)-9-methyl-[1,2,4]triazolo[4,3-c]quina zoline (700 mg, 80%) as a yellow solid. LCMS: (M + H) + =382.1 [0476] Step 7: To a mixture of 7-bromo-5-(4,4-difluoropiperidin-1-yl)-9-methyl-[1,2,4]triaz olo[4,3-c]quinazoline (700 mg, 1.84 mmol) and ethyl tributylstannanecarboxylate (1.33 g, 3.68 mmol) in dioxane (15 ml) was added Pd(PPh 3 ) 2 Cl 2 (129 mg, 0.184 mmol). The mixture was stirred at 95 °C under N 2 for 16 hours. HCl (2.0 ml, 1 M) was added into the mixture and stirred at 50 °C for 0.5 hour, then 50 ml sat KF was added and the mixture was stirred at RT for 0.5 hour. the gray was filtered, the filter cake was washed with EtOAc (30 ml*3), the separated aqueous phase was extracted with EtOAc (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 1:1) to afford 1-(5-(4,4- difluoropiperidin-1-yl)-9-methyl-[1,2,4]triazolo[4,3-c]quina zolin-7-yl)ethan-1-one (300 mg, 46%) as a brown oil. LCMS: (M + H) + =346.2 [0477] Step 8: To a mixture of 1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-[1,2,4]triazolo[4 ,3-c]quinazolin-7- yl)ethan-1-one (300 mg, 0.87 mmol) and (R)-2-methylpropane-2-sulfinamide (210 mg, 1.74 mmol) in THF (20 ml) at RT was added Ti(i-PrO) 4 (1.24 g, 4.35 mmol). The mixture was stirred at 75 °C for 48 hours. Cooling to RT, brine (50 ml) was added and the mixture was stirred for 0.5 hour. the resulting mixture was filtrated and the cake was washed with EtOAc (40 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)-N-(1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-[1,2,4]t riazolo[4,3-c]quinazolin-7- yl)ethylidene)-2-methylpropane-2-sulfinamide (390 mg) as a yellow oil for the next step without further purification. LCMS: (M + H) + = 449.0 [0478] Step 9: To a mixture of crude (R,Z)-N-(1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-[1,2,4]t riazolo[4,3- c]quinazolin-7-yl)ethylidene)-2-methylpropane-2-sulfinamide (390 mg, 0.87 mmol) and HOAc (164 mg, 6.96 mmol) in DCM (10 ml) and MeOH (10 ml) was added NaBH 3 CN (127 mg, 2.61 mmol) in portions at 0 °C, the mixture was stirred for 1 hour. The reaction was quenched with a saturated solution of NH 4 Cl (20 ml) and extracted with DCM (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (method A) to afford (R)-N-(1-(5-(4,4-difluoropiperidin-1-yl)- 9-methyl-[1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)-2-meth ylpropane-2-sulfinamide (150 mg, 38%) as a colorless oil. LCMS: (M + H) + = 451.0 [0479] Step 10: A mixture of (R)-N-(1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-[1,2,4]tri azolo[4,3-c]quinazolin-7- yl)ethyl)-2-methylpropane-2-sulfinamide (150 mg, 0.33mmol) in a solution of HCl in MeOH (3 ml, 4 M) was stirred at RT for 10 min. The mixture was poured into ice-water and adjusted PH=8 with a saturated solution of NaHCO 3 , The mixture was extracted with DCM/MeOH (20 ml*3, 10/1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford (R)-1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl- [1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethan-1-amine (100 mg, 87%) as a colorless oil. LCMS: (M + H) + =347.2 [0480] Step 11: To a mixture of (R)-1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl-[1,2,4]triazo lo[4,3-c]quinazolin-7- yl)ethan-1-amine (100 mg, 0.29 mmol) and methyl 6-chloro-3-fluoropicolinate (82 mg, 0.435 mmol) in DMSO (5 ml) was added DIPEA (112 mg, 0.87 mmol), the mixture was heated to 95 °C and stirred for 16 hours. Cooling to RT, H 2 O (25 ml) was added and the mixture was extracted with EtOAc (20 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-TLC (PE: EA = 2:1) to afford methyl (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl- [1,2,4]triazolo[4,3-c]quinazolin-7- yl)ethyl)amino)picolinate (120 mg, 81%) as a white solid. LCMS: (M + H) + =516.2 [0481] Step 12: To a mixture of methyl (R)-6-chloro-3-((1-(5-(4,4-difluoropiperidin-1-yl)-9-methyl- [1,2,4]triazolo[4,3-c]quinazolin-7-yl)ethyl)amino)picolinate (120 mg, 0.23 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (55 mg, 2.3 mmol). The mixture was stirred at 50 °C for 1 hour. the mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM (20 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to afford (R)-6-chloro-3-((1-(5- (4,4-difluoropiperidin-1-yl)-9-methyl-[1,2,4]triazolo[4,3-c] quinazolin-7-yl)ethyl)amino)picolinic acid (70 mg, 60%) as a white solid. LCMS: (M + H) + =502.1 EXAMPLE 37 (R)-6-chloro-3-((1-(2,5-diethyl-9-methylimidazo[1,2-c]quinaz olin-7-yl)ethyl)amino)picolinic acid [0482] Step 1: To a mixture of methyl (R)-3-((1-(2-bromo-5-ethyl-9-methylimidazo[1,2-c]quinazolin- 7- yl)ethyl)amino)-6-chloropicolinate (110 mg, 0.219 mmol), tripropyl(vinyl)stannane (72.7 mg, 0.263 mmol), CuCl (4.35 mg, 0.0439 mmol) and LiCl (1.84 mg, 0.0439 mmol) in DMF (5 mL) was added Pd(PPh 3 ) 4 (50.72 mg, 0.0439 mmol). The mixture was stirred at 110 °C for 40 min. Water (50 mL) was added and the mixture was extracted with EtOAc (50 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated, The residue was purified by chromatography (PE: EA = 5:1) to afford methyl (R)-6-chloro-3-((1-(5- ethyl-9-methyl-2-vinylimidazo[1,2-c]quinazolin-7-yl)ethyl)am ino)picolinate (24 mg, 24.3%) as a yellow solid. LCMS: (M + H) + =450.3 [0483] Step 2: To a mixture of methyl (R)-6-chloro-3-((1-(5-ethyl-9-methyl-2-vinylimidazo[1,2-c]qu inazolin-7- yl)ethyl)amino)picolinate (24 mg, 0.0534 mmol) in THF (5 mL) was added PtO 2 (20%, 4.8 mg) at RT. The mixture was stirred at RT for 2 hours. The mixture was filtered and the filter was concentrated under vacuum to afford crude methyl (R)-6-chloro-3-((1-(2,5-diethyl-9-methylimidazo[1,2-c]quinaz olin-7-yl)ethyl)amino)picolinate (20 mg, crude) as a yellow solid for the next step without further purification. LCMS: (M + H) + = 452.4 [0484] Step3: To a solution of methyl (R)-6-chloro-3-((1-(2,5-diethyl-9-methylimidazo[1,2-c]quinaz olin-7- yl)ethyl)amino)picolinate (20 mg, 0.0443 mmol) in THF (5 mL) and H 2 O (1 mL) was added LiOH (9.31 mg, 0.222 mmol). The mixture was stirred at 50 °C for 3 hours. The mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM: MeOH (10:1, 50 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to afford (R)-6-chloro-3-((1-(2,5- diethyl-9-methyl-imidazo[1,2-c]quinazolin-7-yl)ethyl)amino)p icolinic acid (6.0 mg, 30.9%) as a white solid. LCMS: (M + H) + = 438.1 EXAMPLE 38 (R)-6-chloro-3-(1-(5-ethyl-9-methyl-2-(1-methyl-1H-pyrazol-3 -yl)imidazo[1,2-c]quinazolin-7- yl)ethylamino)picolinic acid [0485] Step 1: To a mixture of (R)-methyl 3-(1-(2-bromo-5-ethyl-9-methylimidazo[1,2-c]quinazolin-7- yl)ethylamino)-6-chloropicolinate (200 mg, 0.4 mmol) and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-pyrazole (42 mg, 0.2 mmol) in THF (4 ml) and H 2 O (1 ml) were added K3PO 4 (170 mg, 0.8 mmol) and RuPhos Pd G4 (68 mg, 0.08 mmol). The mixture was stirred at 80 °C for 1 hour in a microwave. The mixture was concentrated and purified by silica gel column chromatography (PE: EA= 2: 1) to afford (R)-methyl 6-chloro-3-(1- (5-ethyl-9-methyl-2-(1-methyl-1H-pyrazol-3-yl)imidazo[1,2-c] quinazolin-7-yl)ethylamino)picolinate (90 mg, 45 %) as a white solid. LCMS: (M + H) + = 504.3 [0486] Step 2: To a solution of (R)-methyl 6-chloro-3-(1-(5-ethyl-9-methyl-2-(1-methyl-1H-pyrazol-3- yl)imidazo[1,2-c]quinazolin-7-yl)ethylamino)picolinate (90 mg, 0.18 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (21.6 mg, 0.90 mmol). The mixture was stirred at 50 °C for 1 hour. The mixture was adjusted to pH = 5 - 6 with HCl (1 M) and concentrated, the mixture was purified by Pre-HPLC (Method B) to afford (R)-6-chloro-3- (1-(5-ethyl-9-methyl-2-(1-methyl-1H-pyrazol-3-yl)imidazo[1,2 -c]quinazolin-7-yl)ethylamino)picolinic acid (24.3 mg, 28%) as a white solid. LCMS: (M + H) + = 490.1 EXAMPLE 39 (R)-6-chloro-3-(1-(5-ethyl-9-methyl-2-(prop-1-ynyl)imidazo[1 ,2-c]quinazolin-7-yl)ethylamino)picolinic acid [0487] Step 1: To a mixture of (R)-methyl 3-(1-(2-bromo-5-ethyl-9-methylimidazo[1,2-c]quinazolin-7- yl)ethylamino)-6-chloropicolinate (160 mg, 0.32 mmol), propyne (1mol/L in DMF) (3.2 ml, 3.2 mmol), CuI (12 mg, 0.064 mmol) and TEA (97 mg, 0.96 mmol) in 1.4-dioxane (3 ml) was added Pd(PPh 3 ) 2 Cl 2 (45 mg, 0.064 mmol). The mixture was stirred at 90 °C for 16 hours. The mixture was filtered and the filter was concentrated. The residue was purified by silica gel column chromatography (DCM: EA= 20: 1) to afford (R)-methyl 6-chloro-3-(1-(5- ethyl-9-methyl-2-(prop-1-ynyl)imidazo[1,2-c]quinazolin-7-yl) ethylamino)picolinate (60 mg, 40%) as a yellow solid. LCMS: (M + H) + = 462.3 [0488] Step 2: To a solution of (R)-methyl 6-chloro-3-(1-(5-ethyl-9-methyl-2-(prop-1-ynyl)imidazo[1,2- c]quinazolin-7-yl)ethylamino)picolinate (60 mg, 0.13 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (16 mg, 0.65 mmol). The mixture was stirred at 50 °C for 1 hour. The mixture was adjusted to pH = 5 - 6 with HCl (1 M) and concentrated, the residue was purified by Pre-HPLC (Method B) to afford (R)-6-chloro-3-(1-(5-ethyl-9- methyl-2-(prop-1-ynyl)imidazo[1,2-c]quinazolin-7-yl)ethylami no)picolinic acid (15.7 mg, 27%) as a yellow solid. LCMS: (M + H) + = 448.0 [0489] The following compounds were prepared by methods similar to the procedures described above:

3-[(R)-1-{2-[1-(5-methoxy-4-pyrimidinyl)-4-piperidyl]-3-meth yl-6-methyl-4-oxo-8-quinazolinyl}ethylamino]- 6-chloro-2-pyridinecarboxylic acid [0490] Step 1: tert-butyl 4-(8-bromo-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)pip eridine-1-carboxylate. A mixture of 2-amino-3-bromo-N,5-dimethylbenzamide (3.4 g, 14 mmol), tert-butyl 4-formylpiperidine-1-carboxylate (4.47 g, 1.5 eq., 21 mmol), MgSO 4 (8.42 g, 5 eq., 69.9 mmol), and 4-methylbenzene-1-sulfonic acid hydrate (798 mg, 0.3 eq., 4.2 mmol) in DCM (60 mL, 937 mmol) was stirred at RT for 2h. The solid was filtered off, washed with DCM. The filtrate was washed with saturated NaHCO 3 , dried over MgSO 4 , concentrated, and purified by ISCO (50% EtOAc/Hexanes) to give tert-butyl 4-(8-bromo-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2- yl)piperidine-1-carboxylate (4.39 g, 72%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.00 (dd, J = 2.0, 1.0 Hz, 1H), 7.84 (d, J = 1.9 Hz, 1H), 4.28 (d, J = 13.4 Hz, 2H), 3.68 (s, 3H), 3.03 – 2.87 (m, 3H), 2.46 (s, 3H), 2.10 – 1.87 (m, 4H), 1.51 (s, 9H). [0491] Step 2: tert-butyl 4-(8-acetyl-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)pi peridine-1-carboxylate. A mixture of tert-butyl 4-(8-bromo-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)pip eridine-1-carboxylate (4.3 g, 9.85 mmol), tributyl(1-ethoxyethenyl)stannane (4.27 g, 1.2 eq., 11.8 mmol), and Pd(PPh 3 ) 2 Cl 2 (484 mg, 0.07 eq., 690 µmol) in 1,4-dioxane (50 mL, 586 mmol) was heated at 100°C over the weekend. The mixture was cooled to RT and added 10 mL of 1N HCl and stirred for 30 minutes. The mixture was diluted with EtOAc, washed with H 2 O, brine. dried over MgSO 4 , concentrated, and purified by ISCO (50% EtOAc/Hexanes) to give tert-butyl 4-(8- acetyl-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)piperid ine-1-carboxylate (3.62 g, 91%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.22 (dd, J = 2.2, 0.9 Hz, 1H), 7.87 (d, J = 2.2 Hz, 1H), 4.32 (s, 2H), 3.71 (s, 3H), 3.01 (tt, J = 9.8, 4.4 Hz, 1H), 2.87 (s, 5H), 2.50 (s, 3H), 1.93 (tt, J = 11.1, 6.4 Hz, 4H), 1.51 (s, 9H). MS (m/z): 400.2 (M+H). [0492] Step 3: tert-butyl 4-{3,6-dimethyl-8-[(1E)-1-{[(R)-2-methylpropane-2-sulfinyl]i mino}ethyl]-4-oxo-3,4- dihydroquinazolin-2-yl}piperidine-1-carboxylate. A mixture of tert-butyl 4-(8-acetyl-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-2-yl)piperidine-1-carboxylate (3.6 g, 9.01 mmol), titanium(IV) ethoxide (5.67 mL, 3 eq., 27 mmol), and (R)-2-methylpropane-2-sulfinamide (2.18 g, 2 eq., 18 mmol) in THF (30 mL, 369 mmol) was heated to reflux in 24h. The mixture was cooled to RT, concentrated to dryness, and purified by ISCO 50-100% EtOAc/Hexanes) to give tert-butyl 4-{3,6-dimethyl-8-[(1E)-1-{[(R)-2-methylpropane-2-sulfinyl]i mino}ethyl]-4-oxo- 3,4-dihydroquinazolin-2-yl}piperidine-1-carboxylate (3.79 g, 83%). MS (m/z): 503.2 (M+H). Step 4: tert-butyl 4- {3,6-dimethyl-8-[(1R)-1-{[(R)-2-methylpropane-2-sulfinyl]ami no}ethyl]-4-oxo-3,4-dihydroquinazolin-2-yl}piperidine- 1-carboxylate. To a stirred solution of tert-butyl 4-{3,6-dimethyl-8-[(1E)-1-{[(R)-2-methylpropane-2- sulfinyl]imino}ethyl]-4-oxo-3,4-dihydroquinazolin-2-yl}piper idine-1-carboxylate (2.79 g, 5.55 mmol) in MeOH (14 mL, 344 mmol) and DCM (40 mL, 625 mmol) at 0°C was added acetic acid (2.54 mL, 8 eq., 44.4 mmol), followed by NaBH 3 CN (523 mg, 1.5 eq., 8.33 mmol). The mixture was stirred at 0°C for 1h.6N NH 4 Cl was added, and stirred for 10 minutes, extracted with DCM (3x). The combined extracts were dried over MgSO 4 , concentrated, an d purified first by ISCO (5% MeOH/DCM) to give tert-butyl 4-{3,6-dimethyl-8-[(1R)-1-{[(R)-2-methylpropane-2- sulfinyl]amino}ethyl]-4-oxo-3,4-dihydroquinazolin-2-yl}piper idine-1-carboxylate (2.36 g, 83%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.97 (dd, J = 2.2, 1.0 Hz, 1H), 7.45 (d, J = 2.1 Hz, 1H), 5.16 (s, 1H), 4.82 (t, J = 7.4 Hz, 1H), 4.31 (s, 2H), 3.67 (s, 3H), 2.99 (tt, J = 11.0, 3.7 Hz, 1H), 2.49 (d, J = 9.6 Hz, 2H), 2.46 (s, 3H), 2.02 – 1.82 (m, 4H), 1.63 (d, J = 6.9 Hz, 3H), 1.51 (s, 9H), 1.22 (s, 9H). [0493] Step 5: tert-butyl 4-{8-[(1R)-1-aminoethyl]-3,6-dimethyl-4-oxo-3,4-dihydroquina zolin-2-yl}piperidine-1- carboxylate. To a stirred solution of tert-butyl 4-{3,6-dimethyl-8-[(1R)-1-{[(R)-2-methylpropane-2- sulfinyl]amino}ethyl]-4-oxo-3,4-dihydroquinazolin-2-yl}piper idine-1-carboxylate (2.36 g, 4.68 mmol) in MeOH (20 mL) at 0°C was added HCl (170 mg, 4.68 mmol). The stirring was continued at 0oC for 3h, then concentrated to dryness, diluted with H 2 O, neutralized with saturated NaHCO 3 , extracted with DCM (4x). The combined extracts were dried over MgSO 4 , concentrated, and purified by ISCO (0-20% MeOH/DCM in 1% NH 4 OH) to give tert-butyl 4-{8-[(1R)-1-aminoethyl]-3,6-dimethyl-4-oxo-3,4-dihydroquina zolin-2-yl}piperidine-1-carboxylate (1.15 g, 56%). MS (m/z): 401.3 (M+H). [0494] Step 6: methyl 3-{[(1R)-1-(2-{1-[(tert-butoxy)carbonyl]piperidin-4-yl}-3,6- dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl]amino}-6-chloropyridine-2-carbo xylate. A mixture of tert-butyl 4-{8-[(1R)-1- aminoethyl]-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl}pi peridine-1-carboxylate (1.15 g, 2.87 mmol), methyl 6-chloro-3-fluoropyridine-2-carboxylate (653 mg, 1.2 eq., 3.45 mmol), and ethylbis(propan-2-yl)amine (1.53 mL, 3 eq., 8.61 mmol) in (dimethyl sulfoxide (10 mL, 140 mmol) was heated to 100°C in 16h. The mixture was cooled to RT, H 2 O was added, extracted with EtOAc (3x). The combined extracts were dried over MgSO 4 , concentrated, and purified by ISCO (50-100% EtOAc/Hexanes) to give methyl 3-{[(1R)-1-(2-{1-[(tert-butoxy)carbonyl]piperidin- 4-yl}-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl]am ino}-6-chloropyridine-2-carboxylate (1.52 g, 93%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.98 (dd, J = 2.1, 1.0 Hz, 1H), 7.48 (d, J = 2.1 Hz, 1H), 7.06 (d, J = 8.9 Hz, 1H), 6.85 (d, J = 9.0 Hz, 1H), 5.56 (q, J = 6.6 Hz, 1H), 4.32 (d, J = 13.5 Hz, 2H), 4.02 (s, 3H), 3.72 (s, 3H), 3.04 (q, J = 6.7 Hz, 1H), 2.92 (td, J = 11.8, 6.9 Hz, 2H), 2.41 (s, 3H), 2.02 – 1.96 (m, 3H), 1.66 (d, J = 6.7 Hz, 3H), 1.50 (s, 9H). MS (m/z): 570.2 (M+H). [0495] Step 7: methyl 6-chloro-3-{[(1R)-1-[3,6-dimethyl-4-oxo-2-(piperidin-4-yl)-3 ,4-dihydroquinazolin-8- yl]ethyl]amino}pyridine-2-carboxylate. To a stirred solution of methyl 3-{[(1R)-1-(2-{1-[(tert- butoxy)carbonyl]piperidin-4-yl}-3,6-dimethyl-4-oxo-3,4-dihyd roquinazolin-8-yl)ethyl]amino}-6-chloropyridine-2- carboxylate (1.5 g, 2.63 mmol) in MeOH (15 mL, 370 mmol) at RT was added HCl (767 mg, 8 eq., 21 mmol). The stirring was continued overnight. The mixture was concentrated to dryness to give methyl 6-chloro-3-{[(1R)-1- [3,6-dimethyl-4-oxo-2-(piperidin-4-yl)-3,4-dihydroquinazolin -8-yl]ethyl]amino}pyridine-2-carboxylate hydrochloride (1.5 g, 2.96 mmol). The crude was dissolved in H 2 O, cooled in an ice bath, basified with sat. NaHCO 3 until pH=7-8, extracted with DCM (3x). The extracts were dried over MgSO 4 , concentrated to give methyl 6-chloro-3- {[(1R)-1-[3,6-dimethyl-4-oxo-2-(piperidin-4-yl)-3,4-dihydroq uinazolin-8-yl]ethyl]amino}pyridine-2-carboxylate (1.5 g, 100%). MS (m/z): 470.2 (M+H). [0496] Step 8: methyl 3-[(R)-1-{2-[1-(5-methoxy-4-pyrimidinyl)-4-piperidyl]-3-meth yl-6-methyl-4-oxo-8- quinazolinyl}ethylamino]-6-chloro-2-pyridinecarboxylate. A mixture of methyl 3-{(R)-1-[3-methyl-6-methyl-4-oxo-2- (4-piperidyl)-8-quinazolinyl]ethylamino}-6-chloro-2-pyridine carboxylate (40 mg, 85.1 µmol), 4-chloro-5- methoxypyrimidine (14.8 mg, 1.2 eq., 102 µmol) and ethylbis(propan-2-yl)amine (75.3 µL, 5 eq., 426 µmol) in DMF (2 mL) was stirred at RT in 16h, then heated to 50°C in The mixture was cooled to RT, H 2 O was added, the solid was filtered, washed with H 2 O, dried to give methyl 3-[(R)-1-{2-[1-(5-methoxy-4-pyrimidinyl)-4-piperidyl]-3- methyl-6-methyl-4-oxo-8-quinazolinyl}ethylamino]-6-chloro-2- pyridinecarboxylate (49 mg, 84.8 µmol). MS (m/z): 578.2 (M+H). [0497] Step 9: 3-[(R)-1-{2-[1-(5-methoxy-4-pyrimidinyl)-4-piperidyl]-3-meth yl-6-methyl-4-oxo-8- quinazolinyl}ethylamino]-6-chloro-2-pyridinecarboxylic acid. To a stirred solution of methyl 3-[(R)-1-{2-[1-(5- methoxy-4-pyrimidinyl)-4-piperidyl]-3-methyl-6-methyl-4-oxo- 8-quinazolinyl}ethylamino]-6-chloro-2- pyridinecarboxylate (49 mg, 84.8 µmol) in MeOH (1.99 mL, 49.2 mmol) at RT was added LiOH hydrate (28.5 mg, 8 eq., 678 µmol). The stirring was continued at RT in 16h. The mixture was concentrated to dryness, diluted with H 2 O, acidified with 3N HCl, extracted with DCM (3x). The combined extracts were dried over MgSO 4 , concentrated, and purified by reverse prep. hplc to give 3-[(R)-1-{2-[1-(5-methoxy-4-pyrimidinyl)-4-piperidyl]-3- methyl-6-methyl-4-oxo-8-quinazolinyl}ethylamino]-6-chloro-2- pyridinecarboxylic acid (29 mg, 61%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.55 (s, 1H), 8.18 (s, 1H), 7.96 (s, 1H), 7.74 (dd, J = 2.1, 1.0 Hz, 1H), 7.49 (d, J = 2.1 Hz, 1H), 7.09 (d, J = 8.9 Hz, 1H), 6.89 (d, J = 9.0 Hz, 1H), 5.39 (t, J = 6.5 Hz, 1H), 4.53 (d, J = 13.4 Hz, 2H), 3.78 (s, 3H), 3.59 (s, 3H), 3.04 (t, J = 12.9 Hz, 2H), 2.29 (s, 3H), 2.00 (d, J = 13.1 Hz, 2H), 1.91 – 1.74 (m, 2H), 1.48 (d, J = 6.7 Hz, 3H). MS (m/z): 564.2 (M+H). Example 41 3-[(R)-1-{2-[1-(2-methoxy-4-pyrimidinyl)-4-piperidyl]-3-meth yl-6-methyl-4-oxo-8-quinazolinyl}ethylamino]- 6-chloro-2-pyridinecarboxylic acid. [0498] The title compound (36 mg, 75%) was prepared in the same method as described in Example 40. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.46 (s, 1H), 7.93 (d, J = 6.1 Hz, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.49 (d, J = 2.1 Hz, 1H), 7.12 (d, J = 8.9 Hz, 4H), 6.91 (d, J = 9.0 Hz, 1H), 6.48 (d, J = 6.2 Hz,1H), 5.44 – 5.32 (m, 1H), 4.44 (s, 2H), 3.72 (s, 3H), 3.59 (s, 3H), 3.03 (t, J = 12.7 Hz, 2H), 2.29 (s, 3H), 2.03 (d, J = 13.2 Hz, 2H), 1.76 (d, J = 12.7 Hz, 2H), 1.49 (d, J = 6.7 Hz, 3H). MS (m/z): 564.2 (M+H). . Example 42 3-[(R)-1-{2-[1-(6-chloro-2-cyano-3-pyridyl)-4-piperidyl]-3-m ethyl-6-methyl-4-oxo-8- quinazolinyl}ethylamino]-6-chloro-2-pyridinecarboxylic acid. [0499] The title compound (23 mg, 46%) was prepared in the same method as described in Example 40. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.67 (s, 1H), 7.83 (dd, J = 2.1, 1.0 Hz, 1H), 7.80 (d, J = 9.0 Hz, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.58 (d, J = 2.1 Hz, 1H), 7.22 (d, J = 8.9 Hz, 1H), 7.00 (d, J = 8.9 Hz, 1H), 5.51 (t, J = 6.6 Hz, 1H), 3.78 (d, J = 12.1 Hz, 2H), 3.66 (s, 3H), 3.19 (t, J = 12.2 Hz, 2H), 2.38 (s, 3H), 2.20 – 1.97 (m, 4H), 1.59 (d, J = 6.6 Hz, 3H). MS (m/z): 592.2 (M+H).

Example 43 6-chloro-3-{[(1R)-1-{3,6-dimethyl-4-oxo-2-[1-(pyridin-3-yl)p iperidin-4-yl]-3,4-dihydroquinazolin-8- yl}ethyl]amino}pyridine-2-carboxylic acid [0500] Step 1. methyl 6-chloro-3-{[(1R)-1-{3,6-dimethyl-4-oxo-2-[1-(pyridin-3-yl)p iperidin-4-yl]-3,4- dihydroquinazolin-8-yl}ethyl]amino}pyridine-2-carboxylate. A mixture of methyl 6-chloro-3-{[(1R)-1-[3,6- dimethyl-4-oxo-2-(piperidin-4-yl)-3,4-dihydroquinazolin-8-yl ]ethyl]amino}pyridine-2-carboxylate (51 mg, 109 µmol), 3-iodopyridine (28.9 mg, 1.3 eq., 141 µmol), cesium carbonate (53 mg, 1.5 eq., 163 µmol), [5- (diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylph osphane (6.28 mg, 0.1 eq., 10.9 µmol), and tris(1,5-diphenylpenta-1,4-dien-3-one) dipalladium (4.97 mg, 0.05 eq., 5.43 µmol) in 1,4-dioxane (2 mL, 23.4 mmol) was heated to 100°C in 16h. The mixture was cooled to RT, H 2 O was added, extracted with EtOAc (3x). The combined extracts were dried over MgSO 4 , concentrated, and purified by ISCO (0-10% MeOH/DCM) to give methyl 6-chloro-3-{[(1R)-1-{3,6-dimethyl-4-oxo-2-[1-(pyridin-3-yl)p iperidin-4-yl]-3,4-dihydroquinazolin-8- yl}ethyl]amino}pyridine-2-carboxylate (20.1 mg, 34%). MS (m/z): 547.2 (M+H). [0501] Step 2: 6-chloro-3-{[(1R)-1-{3,6-dimethyl-4-oxo-2-[1-(pyridin-3-yl)p iperidin-4-yl]-3,4- dihydroquinazolin-8-yl}ethyl]amino}pyridine-2-carboxylic acid. To a stirred solution of methyl 6-chloro-3- {[(1R)-1-{3,6-dimethyl-4-oxo-2-[1-(pyridin-3-yl)piperidin-4- yl]-3,4-dihydroquinazolin-8-yl}ethyl]amino}pyridine-2- carboxylate (20 mg, 36.6 µmol) in MeOH (2 mL, 49.4 mmol) at RT was added LiOH hydrate (12.3 mg, 8 eq., 292 µmol). The mixture was stirred at rt overnight. The mixture was concentrated to dryness, diluted with H 2 O, acidified with 3N HCl until pH=4-5, extracted with DCM (3x). The combined extracts were dried over MgSO 4 , concentrated, and purified by reverse prep. hplc to give 6-chloro-3-{[(1R)-1-{3,6-dimethyl-4-oxo-2-[1-(pyridin-3- yl)piperidin-4-yl]-3,4-dihydroquinazolin-8-yl}ethyl]amino}py ridine-2-carboxylic acid (7.6 mg, 39%) as formic salt. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.28 (s, 1H), 8.37 (d, J = 3.0 Hz, 1H), 8.20 (s, 1H), 7.99 (dd, J = 4.6, 1.3 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 2.1 Hz, 1H), 7.39 (ddd, J = 8.6, 3.1, 1.4 Hz, 1H), 7.22 (dd, J = 8.4, 4.5 Hz, 1H), 7.04 (d, J = 8.7 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 3.91 (d, J = 12.2 Hz, 2H), 3.66 (s, 3H), 3.22 (s, 1H), 2.91 (t, J = 11.8 Hz, 2H), 2.59 – 2.53 (m, 1H), 2.49 – 2.39 (m, 1H), 2.36 (s, 3H), 2.17 – 1.96 (m, 4H), 1.54 (d, J = 6.6 Hz, 2H), 1.25 (s, 1H), 0.85 (dt, J = 10.9, 6.7 Hz, 1H). MS (m/z): 533.2 (M+H). Example 44 methyl (R)-6-chloro-3-((1-(6-chloro-2-(4,4-difluoropiperidin-1-yl)- 3-methyl-4-oxo-3,4-dihydropyrido[3,2- d]pyrimidin-8-yl)ethyl)amino)picolinate [0502] Step 1: 3-amino-6-chloro-N-methylpicolinamide. To a stirred mixture of 3-amino-6-chloropicolinic acid (4.0 g, 23.18 mmol, 1 eq.), methylamine HCl (1.9 g, 28 mmol, 1.2 eq.), and DIEA (9 g, 69.53 mmol, 3 eq.) in DMF ( 40 mL) at RT was added HATU (10.6 g, 28 mmol, 1,2 eq.). The stirring was continued for 16h. H 2 O was added, extracted with EtOAc (3x). The combined extracts were dried over MgSO 4 , concentrated, and purified by ISCO (30% EtOAc/Hexanes) to give 3-amino-6-chloro-N-methylpicolinamide (3.74 g, 87%). MS (m/z): 186.1 (M+H). [0503] Step 2: 3-amino-4-bromo-6-chloro-N-methylpicolinamide. To a stirred solution of 3-amino-6-chloro- N-methylpicolinamide (3.7 g, 19.93 mmol, 1 eq.) in DMF (30 mL)at RT was added NBS (4.3 g, 24.18 mmol, 1.2 eq.). The stirring was continued for 16h. Saturated NaHCO 3 was added. The precipitated solid was collected, washed with H 2 O, dried, and purified by ISCO (30% EtOAc/Hexanes) to give 3-amino-4-bromo-6-chloro-N- methylpicolinamide (4.2 g, 78.9%). MS (m/z): 263.9 (M+H). [0504] Step 3: 8-bromo-6-chloro-3-methylpyrido[3,2-d]pyrimidine-2,4(1H,3H)- dione. To a stirred mixture of 3-amino-4-bromo-6-chloro-N-methylpicolinamide (4.2 g, 15.88 mmol, 1 eq.) and Et3N (4.82 g, 47.64 mmol, 3 eq.) in DCM (50 mL) at 0 °C was added triphosgene (7.1 g, 23.82 mol, 1.5 eq.) in dropwise. After the addition was completed, the mixture was heated to 45°C in 16h. The raction mixture was cooled to RT, concentrated to dryness, H 2 O was added, and the precipitated solid was collected. The solid was washed with H 2 O, dried to give 8-bromo-6-chloro-3-methylpyrido[3,2-d]pyrimidine-2,4(1H,3H)- dione (4.42 g, 95.8%). MS (m/z): 291.9 (M+H). [0505] Step 4: 8-bromo-2,6-dichloro-3-methylpyrido[3,2-d]pyrimidin-4(3H)-on e. To a stirred mixture of 8- bromo-6-chloro-3-methylpyrido[3,2-d]pyrimidine-2,4(1H,3H)-di one (4.42 g, 15.22 mmol, 1eq.) and DIEA (8 mL, 45.64 mmol, 8 eq.) in toluene (50 mL) was added POCl 3 (28.3 mL, 46.65 mmol, 20 eq.). The mixture was heated to 100°C in 16h. The mixture was cooled to RT, concentrated to dryness, crushed ice was added to the crude, then basified with saturated NaHCO 3 until pH=7-8, extracted with DCM (3x). The combined extracts were dried over MgSO 4 , concentrated, and purified by ISCO (30% EtOAc/Hexanes) to give 8-bromo-2,6-dichloro-3- methylpyrido[3,2-d]pyrimidin-4(3H)-one ( 1.82 g, 37%). MS (m/z): 309.9 (M+H). [0506] Step 5: 8-bromo-6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methylpyri do[3,2-d]pyrimidin-4(3H)-one. A mixture of 8-bromo-2,6-dichloro-3-methylpyrido[3,2-d]pyrimidin-4(3H)-on e (1.82 g, 5.89 mmol, 1 eq.), 4,4- difluoropiperidine hydrochloride (1.02 g, 6.48 mmol, 1.1 eq.), and DIEA (2.3 g, 17.67 mmol, 3 eq.) in IPA (50 mL) was heated to 80°C in 16h. The mixture was cooled to RT, concentrated to dryness, and purified by ISCO (40% EtOAc/Hexane) to give 8-bromo-6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methylpyri do[3,2-d]pyrimidin-4(3H)-one (1.95 g, 84.4%). MS (m/z): 393.0 (M+H). [0507] Step 6: 8-acetyl-6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methylpyr ido[3,2-d]pyrimidin-4(3H)-one. A mixture of 8-bromo-6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methylpyri do[3,2-d]pyrimidin-4(3H)-one (1.95 g, 4.95 mmol, 1eq.), tributyl(1-ethoxyvinyl)tin (2.2 g, 5.45 mmol, 1.2 eq.), and PdCl 2 (PPh 3 ) 2 (0.35 g, 0.49 mmol, 0.1 eq.) in toluene (30 mL) was heated to 100°C in 16h. The mixture was cooled to RT, added 6N HCl (20 mL), and heated to 50°C in 30 min., then, 10 ml of saturated KF was added, stirred for 30 min., extracted with EtOAc (3x). The combined extracts were dried over MgSO 4 , concentrated, and purified by ISCO (0-50% EtOAc/Hexanes) to give 8-acetyl-6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methylpyr ido[3,2-d]pyrimidin-4(3H)-one (1.23 g, 70%). MS (m/z): 357.1 (M+H). [0508] Step 7: (R,E)-N-(1-(6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methyl -4-oxo-3,4-dihydropyrido[3,2- d]pyrimidin-8-yl)ethylidene)-2-methylpropane-2-sulfinamide. A mixture of 8-acetyl-6-chloro-2-(4,4- difluoropiperidin-1-yl)-3-methylpyrido[3,2-d]pyrimidin-4(3H) -one (1.1 g, 3.08 mmol, 1 eq.), (R)-2-methylpropane- 2-sulfinamide (0.45 g, 3.70 mmol, 1.2 eq.), and titanium(IV) isopropoxide (1.1 g, 3.70 mmol, 1.2 eq) in THF (20 mL) was heated tyo 70°C in 24h. The mixture was cooled to RT, H 2 O was added, stirred in EtOAc, filtered off the solid, washed with EtOAc. The layers were separated. The organic layer was dried over MgSO 4 , concentrated, and purified by ISCO (50% EtOAc/Hexanes) to give (R,E)-N-(1-(6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methyl -4- oxo-3,4-dihydropyrido[3,2-d]pyrimidin-8-yl)ethylidene)-2-met hylpropane-2-sulfinamide ( 1.12 g, 79.4%). MS (m/z): 460.2 (M+H). [0509] Step 8: (R)-N-((R)-1-(6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-meth yl-4-oxo-3,4-dihydropyrido[3,2- d]pyrimidin-8-yl)ethyl)-2-methylpropane-2-sulfinamide. To a stirred mixture of (R,E)-N-(1-(6-chloro-2-(4,4- difluoropiperidin-1-yl)-3-methyl-4-oxo-3,4-dihydropyrido[3,2 -d]pyrimidin-8-yl)ethylidene)-2-methylpropane-2- sulfinamide (1.1 g, 3.06 mmole, 1 eq.) and AcOH (1.1 mL, 11.74 mmol, 8 eq.) at 0°C was added NaCNBH 3 (410 mg, 6.5 mmol, 3 eq.) The resulting mixture was stirred at RT for 1h, quenched with 6N NH 4 OH, extracted with DCM (3x). The combined extracts were dried over MgSO 4 , concentrated to give (R)-N-((R)-1-(6-chloro-2-(4,4- difluoropiperidin-1-yl)-3-methyl-4-oxo-3,4-dihydropyrido[3,2 -d]pyrimidin-8-yl)ethyl)-2-methylpropane-2- sulfinamide (1.11 g, 99%). MS (m/z): 462.1 (M+H). [0510] Step 9: (R)-8-(1-aminoethyl)-6-chloro-2-(4,4-difluoropiperidin-1-yl) -3-methylpyrido[3,2- d]pyrimidin-4(3H)-one hydrochloride. To a stirred solution of (R)-N-((R)-1-(6-chloro-2-(4,4-difluoropiperidin-1- yl)-3-methyl-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidin-8-yl)et hyl)-2-methylpropane-2-sulfinamide (0.4 g, 0.00087 mmol, 1 eq.) in MeOH (5 mL) was added 4M HCl in p-dioxane (0.9 mL, 3.46 mmol), 5 eq.). The mixture was stirred at RT for 1h, concentrated to dryness to give (R)-8-(1-aminoethyl)-6-chloro-2-(4,4-difluoropiperidin-1-yl) -3- methylpyrido[3,2-d]pyrimidin-4(3H)-one hydrochloride (341 mg, 100%). MS (m/z): 358.1 (M+H). [0511] Step 10: methyl (R)-6-chloro-3-((1-(6-chloro-2-(4,4-difluoropiperidin-1-yl)- 3-methyl-4-oxo-3,4- dihydropyrido[3,2-d]pyrimidin-8-yl)ethyl)amino)picolinate. A mixture of (R)-8-(1-aminoethyl)-6-chloro-2-(4,4- difluoropiperidin-1-yl)-3-methylpyrido[3,2-d]pyrimidin-4(3H) -one (162 mg, 0.00045 mmol), methyl 6-chloro-3- fluoropicolinate (100.8 mg, 0.00054 mmol, 1.2 eq.), and K 2 CO 3 (312 mg, 0.0023 mmol, 5 eq.) in DMSO (5 mL) was stirred at RT for 48h. H 2 O was added and the precipitated solid was collected. The crude solid was washed with H 2 O, dried, and purified by ISCO (0-5% MeOH/DCM) to give methyl (R)-6-chloro-3-((1-(6-chloro-2-(4,4- difluoropiperidin-1-yl)-3-methyl-4-oxo-3,4-dihydropyrido[3,2 -d]pyrimidin-8-yl)ethyl)amino)picolinate (85.1 mg, 35.6%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.37 (d, J = 7.6 Hz, 1H), 7.78 (s, 1H), 7.38 (d, J = 9.0 Hz, 1H), 7.14 (d, J = 9.1 Hz, 1H), 5.35 – 5.25 (m, 1H), 3.86 (s, 3H), 3.51 (s, 7H), 2.22 (s, 4H), 1.66 (d, J = 6.7 Hz, 3H). MS (m/z): 526.6 (M+H). Example 45 (R)-6-chloro-3-((1-(6-chloro-3-methyl-4-oxo-2-phenyl-3,4-dih ydropyrido[3,4-d]pyrimidin-8- yl)ethyl)amino)picolinic acid [0512] Step 1: 5-amino-2-chloro-N-methylisonicotinamide. The title compound (4.7 g, 88%) was prepared in the same method as described in Example 44. (MS (m/z): 185.2 (M+H). ). [0513] Step 2: 3-amino-2-bromo-6-chloro-N-methylisonicotinamide. The title compound (6.69 g, 100%) was prepared in the same method as described in Example 44. MS (m/z): 265.0 (M+H). [0514] Step 3: 8-bromo-6-chloro-3-methyl-2-phenylpyrido[3,4-d]pyrimidin-4(3 H)-one. A mixture of 3- amino-2-bromo-6-chloro-N-methylisonicotinamide (1.5 g, 5.67 mmol, 1 eq.), benzaldehyde (0.72 g, 6.81 mmol, 1.2 eq), and iodine (1.44 g, 5.95 mmol, 1.05 eq.) in EtOH (20 mL) was heated to 80°C in 16h. The mixture was cooled to RT, quenched with saturated Na 2 S 2 O 3 , diluted with H 2 O, extracted with DCM (3x). The combine extracts were dried over MgSO 4 , concentrated, and purified by ISCO (30% EtOAc/Hexanes) to give 8-bromo-6- chloro-3-methyl-2-phenyl-2,3-dihydropyrido[3,4-d]pyrimidin-4 (1H)-one (1.5 g, 4.25 mmol) which was dissolved in CHCl 3 (20 mL) and added DDQ (1.02 g, 4.47 mmol, 1.05 eq.). The mixture was stirred at RT in 16h. The precipitated solid was filtered off, washed with DCM. The filtrate was concentrated and purified by ISCO (30% EtOAc/Hexanes) to give 8-bromo-6-chloro-3-methyl-2-phenylpyrido[3,4-d]pyrimidin-4(3 H)-one (1.15 g, 58%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.99 (s, 1H), 7.61 – 7.52 (m, 2H), 7.48 (td, J = 5.2, 2.4 Hz, 3H), 3.46 (d, J = 3.3 Hz, 3H). [0515] Step 4: 8-acetyl-6-chloro-3-methyl-2-phenylpyrido[3,4-d]pyrimidin-4( 3H)-one. A mixture of 8- bromo-6-chloro-3-methyl-2-phenylpyrido[3,4-d]pyrimidin-4(3H) -one (1.38 g, 3.94 mmol, 1eq.), Ac-TMS (0.91 g, 7.87 mmol, 2 eq.), Pd(Ph 3 P) 4 (0.45 g, 0.1 eq.) in DCE (20 mL) was heated to 80°C in 48h. The mixture was cooled to RT, H 2 O was added, extracted with DCM (3x). The combined extracts were dried over MgSO 4 , concentrated, and purified by ISCO (30% EtOAc/Hexanes) to give 8-acetyl-6-chloro-3-methyl-2-phenylpyrido[3,4- d]pyrimidin-4(3H)-one (0.495 g, 40%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.15 (s, 1H), 7.56 – 7.49 (m, 2H), 7.45 (q, J = 6.5 Hz, 3H), 3.47 (s, 3H), 2.66 (s, 3H). [0516] Step 5: (R,E)-N-(1-(6-chloro-3-methyl-4-oxo-2-phenyl-3,4-dihydropyri do[3,4-d]pyrimidin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide. The title compound (290 mg, 63%) was prepared in the same method as described in Example 40. MS (m/z): 417.1 (M+H). [0517] Step 6: (R)-N-((R)-1-(6-chloro-3-methyl-4-oxo-2-phenyl-3,4-dihydropy rido[3,4-d]pyrimidin-8- yl)ethyl)-2-methylpropane-2-sulfinamide. The title compound (87 mg, 31%) was prepared in the same method as described in Example 40. MS (m/z): 419.1 (M+H). [0518] Step 7: (R)-8-(1-aminoethyl)-6-chloro-3-methyl-2-phenylpyrido[3,4-d] pyrimidin-4(3H)-one hydrochloride. The title compound (80.3 mg, 100%) was prepared in the same method as described in Example 40. MS (m/z): 315.1 (M+H). [0519] Step 8: tert-butyl (R)-6-chloro-3-((1-(6-chloro-3-methyl-4-oxo-2-phenyl-3,4-dih ydropyrido[3,4- d]pyrimidin-8-yl)ethyl)amino)picolinate. The title compound (41.6 mg, 38%) was prepared in the same method as described in Example 40 (tert butyl ester was used instead of methyl ester). MS (m/z): 526 (M+H). [0520] Step 9: (R)-6-chloro-3-((1-(6-chloro-3-methyl-4-oxo-2-phenyl-3,4-dih ydropyrido[3,4-d]pyrimidin-8- yl)ethyl)amino)picolinic acid (ONCV-000118). To a stirred solution of tert-butyl (R)-6-chloro-3-((1-(6-chloro-3- methyl-4-oxo-2-phenyl-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl )ethyl)amino)picolinate (41 mg, 0.00008 mmol, 1 eq.) in DCM (1 mL) was added TFA (0.5 mL) at RT for 1h. The mixture was concentrated to dryness, diluted with H 2 O was added, neutralized with saturated NaHCO 3 , extracted with DCM (3x). The combined extracts were dried over MgSO 4 , concentrated to dryness to give (R)-6-chloro-3-((1-(6-chloro-3-methyl-4-oxo-2-phenyl-3,4- dihydropyrido[3,4-d]pyrimidin-8-yl)ethyl)amino)picolinic acid (10.3 mg, 28%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.02 (s, 1H), 8.73 (d, J = 8.2 Hz, 1H), 8.01 (s, 1H), 7.81 – 7.74 (m, 2H), 7.65 – 7.54 (m, 3H), 7.43 – 7.27 (m, 3H), 5.70 – 5.60 (m, 1H), 3.40 (s, 3H), 1.55 (d, J = 6.6 Hz, 3H). MS (m/z): 470.1 (M+H).

Example 46 (R)-6-chloro-3-((1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydrop yrido[3,4-d]pyrimidin-8- yl)ethyl)amino)picolinic acid [0521] Step 1: (R)-N-((R)-1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydropyrido[ 3,4-d]pyrimidin-8-yl)ethyl)-2- methylpropane-2-sulfinamide. A mixture of (R)-N-((R)-1-(6-chloro-3-methyl-4-oxo-2-phenyl-3,4- dihydropyrido[3,4-d]pyrimidin-8-yl)ethyl)-2-methylpropane-2- sulfinamide (27.8 mg, 0.00007 mmol, 1eq), trimethylboroxine (13 mg, 0.00010 mmol, 1.5 eq.), K 2 CO 3 (28 mg, 0.0002 mmol, 3 eq.), and PdCl 2 (amphos) 2 (5 mg, 0.000007 mmol, 0.1 eq.) in p-dioxane/H 2 O (2 mL/0.4 mL) was heated at 99°C in 48h. The mixture was cooled to RT, filtered through Celite, washed with EtOAc. The layers were separated. The organic layer was dried over MgSO 4 , concentrated to give (R)-N-((R)-1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydropyrido[ 3,4- d]pyrimidin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (26.4 mg, 100%). MS (m/z): 399.1 (M+H). [0522] Step 2: (R)-8-(1-aminoethyl)-3,6-dimethyl-2-phenylpyrido[3,4-d]pyrim idin-4(3H)-one hydrochloride. The title compound (31.5 mg, 100%) was prepared in the same methods as described in Example 40. MS (m/z): 295.1 (M+H). [0523] Step 3: methyl (R)-6-chloro-3-((1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydrop yrido[3,4-d]pyrimidin- 8-yl)ethyl)amino)picolinate. The title compound (31.8 mg, 65%) was prepared in the same method as described in Example 40. MS (m/z): 464.1 (M+H). [0524] Step 4: (R)-6-chloro-3-((1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydrop yrido[3,4-d]pyrimidin-8- yl)ethyl)amino)picolinic acid. The title compound 12.6 mg, 42%) was prepared in the same method as described in Example 40 Step 10. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.92 (s, 1H), 8.99 (d, J = 7.9 Hz, 1H), 7.86 (d, J = 0.7 Hz, 1H), 7.81 – 7.71 (m, 2H), 7.65 – 7.54 (m, 2H), 7.42 (d, J = 9.1 Hz, 1H), 7.36 (d, J = 8.9 Hz, 1H), 5.64 (p, J = 6.7 Hz, 1H), 3.39 (s, 3H), 2.66 (s, 3H), 1.53 (d, J = 6.5 Hz, 3H). MS (m/z): 450.1 (M+H). Example 47 (R)-6-Chloro-3-((1-(2-(3-cyanophenyl)-3,6-dimethyl-4-oxo-3,4 -dihydroquinazolin-8-yl)ethyl)amino)picolinic acid. [0525] The title compound 16.8 mg, 39%) was prepared in the same method as described in Example 48. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.00 (s, 1H), 8.42 (d, J = 7.0 Hz, 1H), 8.29 (t, J = 1.7 Hz, 1H), 8.12 (dt, J = 7.9, 1.4 Hz, 1H), 8.07 (dt, J = 7.8, 1.4 Hz, 1H), 7.92 (dd, J = 2.1, 1.0 Hz, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.29 (d, J = 8.9 Hz, 1H), 7.00 (d, J = 9.1 Hz, 1H), 5.46 (q, J = 6.7 Hz, 1H), 3.40 (s, 3H), 2.42 (s, 2H), 1.58 (d, J = 6.6 Hz, 3H). MS (m/z: 473.0 (M+H). Example 48 (R)-6-Chloro-3-((1-(2-(5-cyanopyridin-3-yl)-3,6-dimethyl-4-o xo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid. [0526] The title compound (20.4 mg, 51%) was prepared in the same method as described in Example 48. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.99 (s, 1H), 9.27 (d, J = 2.1 Hz, 1H), 9.23 (d, J = 2.0 Hz, 1H), 8.79 (t, J = 2.1 Hz, 1H), 8.50 (s, 1H), 7.93 (dd, J = 2.1, 1.0 Hz, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.27 (d, J = 8.9 Hz, 1H), 7.01 (d, J = 9.0 Hz, 1H), 5.44 (d, J = 6.8 Hz, 1H), 3.45 (s, 3H), 2.42 (s, 3H), 1.58 (d, J = 6.6 Hz, 3H). MS (m/z): 475.1 (M+H).

Example 49 (R)-6-chloro-3-((1-(2-(3-cyano-5-fluorophenyl)-3,6-dimethyl- 4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid. [0527] The title compound (10.6 mg, 34%) was prepared in the same method as described in Example 48. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.87 (s, 1H), 8.14 (t, J = 1.4 Hz, 1H), 8.09 – 8.01 (m, 2H), 7.87 (dd, J = 2.0, 1.0 Hz, 1H), 7.58 (d, J = 2.1 Hz, 1H), 7.12 (d, J = 8.9 Hz, 1H), 6.83 (d, J = 8.9 Hz, 1H), 5.36 (t, J = 6.6 Hz, 1H), 3.36 (s, 3H), 2.37 (s, 3H), 1.51 (d, J = 6.7 Hz, 3H). MS (m/z): 492.1 (M+H). Example 50 (R)-6-chloro-3-((1-(2-(2,6-difluorophenyl)-3,6-dimethyl-4-ox o-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid. [0528] The title compound (54.5 mg, 85%) was prepared in the same method as described in Example 48. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.48 (s, 1H), 7.94 – 7.87 (m, 1H), 7.76 (tt, J = 8.5, 6.6 Hz, 1H), 7.42 (td, J = 8.8, 4.9 Hz, 2H), 7.05 (d, J = 8.7 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 5.35 (t, J = 6.5 Hz, 1H), 3.39 (s, 3H), 2.41 (s, 3H), 1.51 (d, J = 6.7 Hz, 3H). MS (m/z): 485.1 (M+H).

Example 51 6-chloro-3-(((R)-1-(2-((1s,3S)-3-hydroxycyclobutyl)-3,6-dime thyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid. [0529] The title compound was prepared in the same method as described in Example 14. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.62 (s, 1H), 7.73 (dd, J = 2.1, 1.0 Hz, 1H), 7.53 (d, J = 2.1 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 7.00 (d, J = 9.0 Hz, 1H), 5.38 (s, 1H), 4.06 (p, J = 7.6 Hz, 1H), 3.40 (s, 3H), 3.22 – 3.11 (m, 2H), 2.67 – 2.50 (m, 2H), 2.36 (d, J = 10.3 Hz, 1H), 2.30 (s, 3H), 2.27 – 2.18 (m, 1H), 1.59 (d, J = 6.7 Hz, 3H). MS (m/z): 443.1 (M+H). Example 52 3-{(R)-1-[3-methyl-6-methyl-2-(2-methyl-5-pyrimidinyl)-4-oxo -8-quinazolinyl]ethylamino}-6-chloro-2- pyridinecarboxylic acid [0530] Step 1: 8-bromo-3-methyl-6-methyl-2-(2-methyl-5-pyrimidinyl)-1,2,3,4 -tetrahydro-4-quinazolinone. A mixture of N-methyl-4-amino-5-bromo-3-toluamide (1 g, 4.11 mmol) and 2-methyl-5-pyrimidinecarbaldehyde (603 mg, 1.2 eq., 4.94 mmol) in acetic acid (8 mL, 140 mmol) was heated at 60°C for 48h. The mixture was cooled to RT, concentrated to dryness, added H 2 O, extracted with EtOAc (3x). The combined extracts were dried over MgSO 4 , concentrated to give 8-bromo-3-methyl-6-methyl-2-(2-methyl-5-pyrimidinyl)-1,2,3,4 -tetrahydro-4- quinazolinone (1.43 g, 4.12 mmol). MS (m/z): 347.1 (M+H). [0531] Step 2: 8-bromo-3-methyl-6-methyl-2-(2-methyl-5-pyrimidinyl)-3,4-dih ydro-4-quinazolinone. To a stirred solution of 8-bromo-3-methyl-6-methyl-2-(2-methyl-5-pyrimidinyl)-1,2,3,4 -tetrahydro-4-quinazolinone (1.43 g, 4.12 mmol) in chloroform (14.3 mL, 179 mmol) at RT was added 4,5-dichloro-3,6-dioxo-1,4-cyclohexadiene- 1,2-dicarbonitrile (935 mg, 4.12 mmol). The mixture was stirred at RT in 16h, concentrated to dryness, triturated in EtOAc. The solid was collected by filtration, washed with EtOAc, dried to give 8-bromo-3-methyl-6-methyl-2-(2- methyl-5-pyrimidinyl)-3,4-dihydro-4-quinazolinone (1.27 g, 3.68 mmol). MS (m/z): 345.1 (M+H). [0532] Step 3: 8-acetyl-3-methyl-6-methyl-2-(2-methyl-5-pyrimidinyl)-4(3H)- quinazolinone. A mixture of 8- bromo-3-methyl-6-methyl-2-(2-methyl-5-pyrimidinyl)-3,4-dihyd ro-4-quinazolinone (1.2 g, 3.48 mmol), tributyl(1- ethoxyethenyl)stannane (1.51 g, 1.2 eq., 4.17 mmol), and dichloro-palladamethane—triphenylphosphine (1/2) (244 mg, 0.1 eq., 348 µmol) in 1,4-dioxane (7 mL, 82.1 mmol) and DMF (7 mL, 90.4 mmol) was heated to 100°C in 16h. The mixture was cooled to RT and added 6N HCl (5 mL) and stirred at 50°C for 30 minutes, then added saturated KF (5 mL) and stirred for another 30 minutes, diluted with H 2 O, extracted with EtOAc (3x). The combined extracts were dried over MgSO 4 , concentrated, and purified by ISCO (50%EtOAc/Hexanes) to give 8- acetyl-3-methyl-6-methyl-2-(2-methyl-5-pyrimidinyl)-4(3H)-qu inazolinone (0.4 g, 37%). MS (m/z): 309.1 (M+H). [0533] Step 4: 8-[1-(tert-butylsulfinylimino)ethyl]-3-methyl-6-methyl-2-(2- methyl-5-pyrimidinyl)-4(3H)- quinazolinone. A mixture of 8-acetyl-3-methyl-6-methyl-2-(2-methyl-5-pyrimidinyl)-4(3H)- quinazolinone (470 mg, 1.52 mmol), (R)-(+)-2-Methyl-2-propanesulfinamide (259 mg, 1.4 eq., 2.13 mmol), and Titanium(IV) isopropoxide (910 mg, 2.1 eq., 3.2 mmol) in THF (6 mL, 73.7 mmol) was heated at 75°C in 24h. The mixture was cooled to RT, added H 2 O, filtered off the solid, washed with EtOAc. The layers were separated. The organic layer was dried over MgSO 4 , concentrated, and purified by ISCO (50% EtOAc/hexanes) to give 8-[1-(tert- butylsulfinylimino)ethyl]-3-methyl-6-methyl-2-(2-methyl-5-py rimidinyl)-4(3H)-quinazolinone (376 mg, 60%). MS (m/z): 412.1 (M+H). [0534] Step 5: 8-[(R)-1-(tert-butylsulfinylamino)ethyl]-3-methyl-6-methyl-2 -(2-methyl-5-pyrimidinyl)- 4(3H)-quinazolinone. To a stirred solution of 8-[1-(tert-butylsulfinylimino)ethyl]-3-methyl-6-methyl-2-(2- methyl-5- pyrimidinyl)-4(3H)-quinazolinone (506 mg, 1.23 mmol) in MeOH (5 mL, 123 mmol) and DCM (5 mL, 78.1 mmol) at 0oC was added acetic acid (591 mg, 8 eq., 9.84 mmol), followed by NaCNBH 3 (232 mg, 3 eq., 3.69 mmol). The mixture was stirred at RT for 1h, quenched with 6N NH 4 OH, stirred for 5 minutes, extracted with DCM (3x). The combined extracts were dried over MgSO 4 , concentrated, and purified by ISCO (0-5% MeOH/DCM) to give 8-[(R)-1-(tert-butylsulfinylamino)ethyl]-3-methyl-6-methyl-2 -(2-methyl-5-pyrimidinyl)-4(3H)-quinazolinone (40 mg, 96.7 µmol). MS (m/z): 414.2 (M+H). [0535] Step 6: 8-[(R)-1-aminoethyl]-3-methyl-6-methyl-2-(2-methyl-5-pyrimid inyl)-4(3H)-quinazolinone— hydrogen chloride (1/1). To a stirred solution of 8-[(R)-1-(tert-butylsulfinylamino)ethyl]-3-methyl-6-methyl-2 -(2- methyl-5-pyrimidinyl)-4(3H)-quinazolinone (40 mg, 96.7 µmol) in MeOH (3 mL, 74.1 mmol) at RT was added HCl (10.6 mg, 3 eq., 290 µmol). The stirring was continued at RT for 1h. The mixture was concentrated to dryness to give 8-[(R)-1-aminoethyl]-3-methyl-6-methyl-2-(2-methyl-5-pyrimid inyl)-4(3H)-quinazolinone-hydrogen chloride (1/1) (30 mg, 86.7 µmol). MS (m/z): 310.1 (M+H). To a stirred solution of 8-[(R)-1-(tert-butylsulfinylamino)ethyl]- 3-methyl-6-methyl-2-(2-methyl-5-pyrimidinyl)-4(3H)-quinazoli none (40 mg, 96.7 µmol) in MeOH (3 mL, 74.1 mmol) at RT was added HCl (10.6 mg, 3 eq., 290 µmol). The stirring was continued at RT for 1h. The mixture was concentrated to dryness to give 8-[(R)-1-aminoethyl]-3-methyl-6-methyl-2-(2-methyl-5-pyrimid inyl)-4(3H)- quinazolinone-hydrogen chloride (1/1) (30 mg, 86.7 µmol). MS (m/z): 310.1 (M+H). [0536] Step 7: methyl 3-{(R)-1-[3-methyl-6-methyl-2-(2-methyl-5-pyrimidinyl)-4-oxo -8- quinazolinyl]ethylamino}-6-chloro-2-pyridinecarboxylate. A mixture of 8-[(R)-1-aminoethyl]-3-methyl-6- methyl-2-(2-methyl-5-pyrimidinyl)-4(3H)-quinazolinone-hydrog en chloride (1/1) (30 mg, 86.7 µmol), methyl 6- chloro-3-fluoro-2-pyridinecarboxylate (19.7 mg, 1.2 eq., 104 µmol), and N-ethylbis(isopropyl)amine (76.8 µL, 5 eq., 434 µmol) in DMSO (2 mL, 27.9 mmol) was heated to 100°C in 16h. The mixture was cooled to RT, added H 2 O, extracted with EtOAc (3x). The combined extracts were dried over MgSO 4 , concentrated and purified by ISCO (50% EtOAc/Hexanes) to give methyl 3-{(R)-1-[3-methyl-6-methyl-2-(2-methyl-5-pyrimidinyl)-4-oxo -8- quinazolinyl]ethylamino}-6-chloro-2-pyridinecarboxylate (15 mg, 31.3 µmol). MS (m/z): 479.1 (M+H). [0537] Step 8: 3-{(R)-1-[3-methyl-6-methyl-2-(2-methyl-5-pyrimidinyl)-4-oxo -8-quinazolinyl]ethylamino}- 6-chloro-2-pyridinecarboxylic acid. To a stirred solution of methyl 3-{(R)-1-[3-methyl-6-methyl-2-(2-methyl-5- pyrimidinyl)-4-oxo-8-quinazolinyl]ethylamino}-6-chloro-2-pyr idinecarboxylate (15 mg, 31.3 µmol) in MeOH (1 mL, 24.7 mmol) at RT was added LiOH (6.57 mg, 5 eq., 157 µmol). The stirring was continued at RT in 16 h. The mixture was concentrated to dryness, then purified by reverse prep. HPLC to give 3-{(R)-1-[3-methyl-6-methyl-2- (2-methyl-5-pyrimidinyl)-4-oxo-8-quinazolinyl]ethylamino}-6- chloro-2-pyridinecarboxylic acid (4.5 mg, 9.68 µmol). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.15 (s, 2H), 8.61 (s, 1H), 7.91 (dd, J = 2.0, 1.0 Hz, 1H), 7.65 (d, J = 2.1 Hz, 1H), 7.26 (d, J = 8.9 Hz, 1H), 7.02 (d, J = 9.0 Hz, 1H), 5.48 – 5.37 (m, 1H), 3.49 (s, 3H), 2.75 (s, 3H), 2.42 (s, 3H), 1.59 (d, J = 6.7 Hz, 3H). MS (m/z): 465.1 (M+H). Example 53 3-{(R)-1-[3-methyl-6-methyl-2-(5-methyl-2-pyrimidinyl)-4-oxo -8-quinazolinyl]ethylamino}-6-chloro-2- pyridinecarboxylic acid [0538] Step 1: 8-bromo-3-methyl-6-methyl-2-(5-methyl-2-pyrimidinyl)-1,2,3,4 -tetrahydro-4-quinazolinone. A mixture of N-methyl-4-amino-5-bromo-3-toluamide (1.2 g, 4.94 mmol), 5-methyl-2-pyrimidinecarboxylic acid (818 mg, 1.2 eq., 5.92 mmol), 2-chloro-1-methyl-1-pyridylium iodide (1.89 g, 1.5 eq., 7.4 mmol), and N- ethylbis(isopropyl)amine (2.62 mL, 3 eq., 14.8 mmol) in Dichloroethane (20 mL) was heated at 75°C for 48h. The mixture was cooled to RT, concentrated to dryness, added H 2 O, extracted with EtOAc (3x). The combined extracts were dried over MgSO 4 , concentrated to give 8-bromo-3-methyl-6-methyl-2-(5-methyl-2-pyrimidinyl)- 1,2,3,4-tetrahydro-4-quinazolinone (1.7 g, 4.9 mmol). MS (m/z): 347.1 (M+H). [0539] Step 2: 8-bromo-3-methyl-6-methyl-2-(5-methyl-2-pyrimidinyl)-3,4-dih ydro-4-quinazolinone. To a stirred 8-bromo-3-methyl-6-methyl-2-(5-methyl-2-pyrimidinyl)-1,2,3,4 -tetrahydro-4-quinazolinone (1.7 g, 4.9 mmol) in chloroform (20 mL, 251 mmol) was added HMDS (3.16 g, 4 eq., 19.6 mmol), and Iodine (1.24 g, 4.9 mmol). The mixture was stirred at RT for 2h, quenched with saturated Na 2 S 2 O 3 , stirred for 10 minutes. The layers were separated. The aqueous was extracted with EtOAc (2x). The combined organic layers were dried over MgSO 4 , concentrated, and purified by ISCO (20-100% EtOAc/Hexanes) to give 8-bromo-3-methyl-6-methyl-2-(5- methyl-2-pyrimidinyl)-3,4-dihydro-4-quinazolinone (910 mg, 2.64 mmol). MS (m/z): 345.1 (M+H). [0540] Step 3: 8-acetyl-3-methyl-6-methyl-2-(5-methyl-2-pyrimidinyl)-4(3H)- quinazolinone. A mixture of 8- bromo-3-methyl-6-methyl-2-(5-methyl-2-pyrimidinyl)-3,4-dihyd ro-4-quinazolinone (0.9 g, 2.61 mmol), tributyl(1- ethoxyethenyl)stannane (1.13 g, 1.2 eq., 3.13 mmol), and dichloro-palladamethane—triphenylphosphine (1/2) (183 mg, 0.1 eq., 261 µmol) in 1,4-dioxane (5.25 mL, 61.6 mmol) and DMF (5.25 mL, 67.8 mmol) was heated to 100°C in 16h. The mixture was cooled to RT and added 6N HCl (5 mL) and stirred at 50°C for 30 minutes, then added saturated KF (5 mL) and stirred for another 30 minutes, diluted with H 2 O, extracted with EtOAc (3x). The combined extracts were dried over MgSO 4 , concentrated, and purified by ISCO (50%EtOAc/Hexanes) to give 8- acetyl-3-methyl-6-methyl-2-(5-methyl-2-pyrimidinyl)-4(3H)-qu inazolinone (0.6 g, 75%). MS (m/z): 309.1 (M+H). [0541] Step 4: (R,E)-N-(1-(3,6-dimethyl-2-(5-methylpyrimidin-2-yl)-4-oxo-3, 4-dihydroquinazolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide. A mixture of 8-acetyl-3-methyl-6-methyl-2-(5-methyl-2- pyrimidinyl)-4(3H)-quinazolinone (0.6 g, 1.95 mmol), (R)-(+)-2-Methyl-2-propanesulfinamide (330 mg, 1.4 eq., 2.72 mmol), and Titanium(IV) isopropoxide (1.16 g, 2.1 eq., 4.09 mmol) in THF (7.66 mL, 94.1 mmol) was heated at 75°C in 24h. The mixture was cooled to RT, added H 2 O, filtered off the solid, washed with EtOAc. The layers were separated. The organic layer was dried over MgSO 4 , concentrated, and purified by ISCO (50% EtOAc/hexanes) to give 8-[1-(tert-butylsulfinylimino)ethyl]-3-methyl-6-methyl-2-(5- methyl-2-pyrimidinyl)-4(3H)- quinazolinone (45.5 mg, 6%). MS (m/z): 412.1 (M+H). [0542] Step 5: (R)-N-((R)-1-(3,6-dimethyl-2-(5-methylpyrimidin-2-yl)-4-oxo- 3,4-dihydroquinazolin-8- yl)ethyl)-2-methylpropane-2-sulfinamide. To a stirred solution of 8-[1-(tert-butylsulfinylimino)ethyl]-3-methyl-6- methyl-2-(5-methyl-2-pyrimidinyl)-4(3H)-quinazolinone (45.5 mg, 111 µmol) in MeOH (450 µL, 11.1 mmol) and DCM (450 µL, 7.02 mmol) at 0°C was added acetic acid (53.1 mg, 8 eq., 885 µmol), followed by NaCNBH 3 (20.8 mg, 3 eq., 332 µmol). The mixture was stirred at RT for 1h, quenched with 6N NH 4 OH, stirred for 5 minutes, extracted with DCM (3x). The combined extracts were dried over MgSO 4 , concentrated, and purified by ISCO (0- 5% MeOH/DCM) to give 8-[(R)-1-(tert-butylsulfinylamino)ethyl]-3-methyl-6-methyl-2 -(5-methyl-2-pyrimidinyl)- 4(3H)-quinazolinone (39 mg, 85%). MS (m/z): 414.2 (M+H). [0543] Step 6: 8-[(R)-1-aminoethyl]-3-methyl-6-methyl-2-(5-methyl-2-pyrimid inyl)-4(3H)-quinazolinone hydrogen chloride. To a stirred solution of 8-[(R)-1-(tert-butylsulfinylamino)ethyl]-3-methyl-6-methyl-2 -(5-methyl- 2-pyrimidinyl)-4(3H)-quinazolinone (40 mg, 96.7 µmol) in MeOH (3 mL, 74.1 mmol) at RT was added HCl (10.6 mg, 3 eq., 290 µmol). The stirring was continued at RT for 1h. The mixture was concentrated to dryness to give 8-[(R)-1-aminoethyl]-3-methyl-6-methyl-2-(5-methyl-2-pyrimid inyl)-4(3H)-quinazolinone hydrogen chloride (33 mg, 99%). MS (m/z): 310.1 (M+H). [0544] Step 7: methyl 3-{(R)-1-[3-methyl-6-methyl-2-(5-methyl-2-pyrimidinyl)-4-oxo -8- quinazolinyl]ethylamino}-6-chloro-2-pyridinecarboxylate. A mixture of 8-[(R)-1-aminoethyl]-3-methyl-6- methyl-2-(5-methyl-2-pyrimidinyl)-4(3H)-quinazolinone-hydrog en chloride (1/1) (33 mg, 95.4 µmol), methyl 6- chloro-3-fluoro-2-pyridinecarboxylate (21.7 mg, 1.2 eq., 115 µmol), and N-ethylbis(isopropyl)amine (84.5 µL, 5 eq., 477 µmol) in dimethyl sulfoxide (2 mL, 27.9 mmol) was heated to 100°C in 16h. The mixture was cooled to RT, added H 2 O, extracted with EtOAc (3x). The combined extracts were dried over MgSO 4 , concentrated and purified by ISCO (50% EtOAc/Hexanes) to give methyl 3-{(R)-1-[3-methyl-6-methyl-2-(5-methyl-2-pyrimidinyl)-4- oxo-8-quinazolinyl]ethylamino}-6-chloro-2-pyridinecarboxylat e (45 mg, 94 µmol). MS (m/z): 479.1 (M+H). [0545] Step 8: 3-{(R)-1-[3-methyl-6-methyl-2-(5-methyl-2-pyrimidinyl)-4-oxo -8-quinazolinyl]ethylamino}- 6-chloro-2-pyridinecarboxylic acid. To a stirred solution of methyl 3-{(R)-1-[3-methyl-6-methyl-2-(5-methyl-2- pyrimidinyl)-4-oxo-8-quinazolinyl]ethylamino}-6-chloro-2-pyr idinecarboxylate (45 mg, 94 µmol) in MeOH (3 mL, 74.1 mmol) at RT was added LiOH monohydrate (19.7 mg, 5 eq., 470 µmol). The stirring was continued at RT in 16h. The mixture was concentrated to dryness, then purified by reverse prep. HPLC to give 3-{(R)-1-[3-methyl-6- methyl-2-(5-methyl-2-pyrimidinyl)-4-oxo-8-quinazolinyl]ethyl amino}-6-chloro-2-pyridinecarboxylic acid (8.9 mg, 19.1 µmol). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.93 (s, 2H), 8.62 (s, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.63 (d, J = 2.1 Hz, 1H), 7.21 (d, J = 8.9 Hz, 1H), 6.90 (d, J = 8.9 Hz, 1H), 5.41 (t, J = 6.5 Hz, 1H), 3.36 (s, 3H), 2.70 (s, 3H), 2.43 (s, 3H), 1.54 (d, J = 6.7 Hz, 3H). MS (m/z): 465.1 (M+H). Example 54 6-chloro-3-{[(1S)-1-(2-ethyl-3,6-dimethyl-4-oxo-3,4-dihydroq uinazolin-8-yl)-2- hydroxyethyl]amino}pyridine-2-carboxylic acid [0546] Step 1: 8-bromo-2-ethyl-3,6-dimethylquinazolin-4(3H)-one. To a stirred mixture of 2-amino-3-bromo- N,5-dimethylbenzamide (5 g, 20.57 mmo, 1eq.l) and triethylortho propionate (5.5 g, 30.85 mmol, 1.5 eq.) in DCE (30 mL) at RT was added TFA (0.24 g, 2.06 mmol, 0.1 eq.). The mixture was stirred at RT for 16h. The mixture was concentrated to dryness to give 8-bromo-2-ethyl-3,6-dimethylquinazolin-4(3H)-one (5.9 g, 100%). MS (m/z): 281.1 (M+H). [0547] Step 2: 2-ethyl-3,6-dimethyl-8-vinylquinazolin-4(3H)-one. A mixture of 8-bromo-2-ethyl-3,6- dimethylquinazolin-4(3H)-one (2.2 g, 7.82 mmol, 1eq.), tributyl(vinyl)tin (3.23 g, 10.17 mmol, 1.3eq.), and Pd(PPh 3 ) 2 Cl 2 (0.55 g, 0.78 mmol, 0.1 eq.) in p-dioxane (30 mL) was heated at 100°C in 24h. The mixture was cooled to RT, added saturated KF (3 mL), stirred for 30 minutes, extracted with EtOAc (3x). The combined extracts were dried over MgSO 4 , concentrated, and purified by ISCO (40% EtOAc/Hexanes) to give 2-ethyl-3,6- dimethyl-8-vinylquinazolin-4(3H)-one (1.9 g, 100%). MS (m/z): 229.2 (M+H). [0548] Step 3: 8-(1,2-dihydroxyethyl)-2-ethyl-3,6-dimethylquinazolin-4(3H)- one. To a stirred solution of 2- ethyl-3,6-dimethyl-8-vinylquinazolin-4(3H)-one (1.9 g, 8.32 mmol, 1 eq.) in MeCN/H 2 O (1:1, 20 mL) was added mCPBA (1.72 g, 9.99 mmol, 1.2 eq.). The mixture was stirred at RT for 24h, then heated to reflux for 3h, cooled to RT, added, saturated NaHCO 3 , stirred for 30 minutes, extracted with DCM (3x). The combined extracts were dried over MgSO 4 , concentrated to give 8-(1,2-dihydroxyethyl)-2-ethyl-3,6-dimethylquinazolin-4(3H)- one (1.9 g, 87%). MS (m/z): 263.1 (M+H). [0549] Step 4: 8-(2-((tert-butyldimethylsilyl)oxy)-1-hydroxyethyl)-2-ethyl- 3,6-dimethylquinazolin-4(3H)- one. To a stirred mixture of give 8-(1,2-dihydroxyethyl)-2-ethyl-3,6-dimethylquinazolin-4(3H)- one (1.9 g, 7.24 mmol, 1eq.) and imidazole (0.6 g, 8.69 mmol, 1.2 eq.) in DCM (40 mL) at RT was added TBS-Cl (1.1 g, 7.97 mmol, 1 eq.). The mixture was stirred at RT for 48h, added H 2 O, the layers were separated. The aqueous was extracted with DCM (2x). The combined organic extracts were dried over MgSO 4 , concentrated, and purified by ISCO 90-30% EtOAc/Hexanes) to give 8-(2-((tert-butyldimethylsilyl)oxy)-1-hydroxyethyl)-2-ethyl- 3,6- dimethylquinazolin-4(3H)-one (0.83 g, 31%). MS (m/z): 377.2 (M+H). [0550] Step 5: 8-(2-((tert-butyldimethylsilyl)oxy)acetyl)-2-ethyl-3,6-dimet hylquinazolin-4(3H)-one. To a stirred solution of 8-(2-((tert-butyldimethylsilyl)oxy)-1-hydroxyethyl)-2-ethyl- 3,6-dimethylquinazolin-4(3H)-one (0.83 g, 2.21 mmol, 1 eq.) in DCM (15 mL) at RT was added Dess-Martin periodinane (1.3 g, 3.08 mmol, 2.2 eq.). The mixture was stirred at RT for 2h, quenched with saturated NaHCO 3 , stirred for 10 minutes, extracted with DCM (3x). The combined extracts were dried over MgSO 4 , concentrated to give 8-(2-((tert- butyldimethylsilyl)oxy)acetyl)-2-ethyl-3,6-dimethylquinazoli n-4(3H)-one (0.8 g, 97%). MS (m/z): 375.1 (M+H). [0551] Step 6: (R,Z)-N-(2-((tert-butyldimethylsilyl)oxy)-1-(2-ethyl-3,6-dim ethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide. A mixture of 8-(2-((tert- butyldimethylsilyl)oxy)acetyl)-2-ethyl-3,6-dimethylquinazoli n-4(3H)-one (0.83 g, 2.21 mmol, 1 eq.), (R)-2- methylpropane-2-sulfinamide (0.54 g, 4.43 mmol, 2 eq.), and titanium(IV) isopropoxide (1 g, 4.43 mmol, 2 eq.) in THF 10 mL) was heated at 70°C in 16h. The mixture was cooled to RT, added H 2 O, filtered off the solid through Celite, washed with EtOAc. The layers were separated. The aqueous layer was extracted with EtOAc (3x). The combined organic extracts were dried over MgSO 4 , concentrated, and purified by ISCO (50% EtOAc/Hexanes) to give (R,Z)-N-(2-((tert-butyldimethylsilyl)oxy)-1-(2-ethyl-3,6-dim ethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethylidene)- 2-methylpropane-2-sulfinamide (250 mg, 24%). MS (m/z): 478.1 (M+H). [0552] Step 7: (R)-N-[(1R)-2-[(tert-butyldimethylsilyl)oxy]-1-(2-ethyl-3,6- dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl]-2-methylpropane-2-sulfinamide. To a stirred solution of (R)-N-[(1Z)-2-[(tert- butyldimethylsilyl)oxy]-1-(2-ethyl-3,6-dimethyl-4-oxo-3,4-di hydroquinazolin-8-yl)ethylidene]-2-methylpropane-2- sulfinamide (250 mg, 523 µmol) in MeOH (8 mL) at 0°C was added NaBH 4 (99 mg, 5 eq., 2.62 mmol). The mixture was stirred at the same temperature for 1h. Saturated aq. NH 4 Cl was added, stirred for 5 minutes, then extracted with DCM (3x). The combined extracts were dried over MgSO 4 , concentrated, and purified by ISCO (0- 50% EtOAc/DCM) to give (R)-N-[(1R)-2-[(tert-butyldimethylsilyl)oxy]-1-(2-ethyl-3,6- dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl]-2-methylpropane-2-sulfinamide (116 mg, 46%). MS (m/z): 480.1 (M+H). [0553] Step 8: 8-[(1S)-1-amino-2-hydroxyethyl]-2-ethyl-3,6-dimethyl-3,4-dih ydroquinazolin-4-one hydrochloride. To a stirred solution of (R)-N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-(2-ethyl-3,6- dimethyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl]-2-methylpropane-2-sulfinam ide (118 mg, 246 µmol) in MeOH (4 mL) at RT was added HCl (0.6 mL, 10 eq., 2.46 mmol). The mixture was stirred at RT for 2h, then concentrated to dryness to give 8-[(1S)-1-amino-2-hydroxyethyl]-2-ethyl-3,6-dimethyl-3,4-dih ydroquinazolin-4-one hydrochloride (73.2 mg, 100%). MS (m/z): 262.1 (M+H). [0554] Step 9: methyl 6-chloro-3-{[(1S)-1-(2-ethyl-3,6-dimethyl-4-oxo-3,4-dihydroq uinazolin-8-yl)-2- hydroxyethyl]amino}pyridine-2-carboxylate. A mixture of methyl 6-chloro-3-fluoropyridine-2-carboxylate (60.6 mg, 1.3 eq., 320 µmol), 8-[(1S)-1-amino-2-hydroxyethyl]-2-ethyl-3,6-dimethyl-3,4-dih ydroquinazolin-4-one hydrochloride (73.2 mg, 246 µmol), and DIEA (218 µL, 5 eq., 1.23 mmol) in DMSO (2 mL) was heated at 100°C in 16h. The mixture was cooled to RT, H 2 O was added, extracted with EtOAc (3x). The combined extracts were dried over MgSO 4 , concentrated, and purified by ISCO (50% EtOAc/Hexanes) to give methyl 6-chloro-3-{[(1S)-1- (2-ethyl-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)-2-hy droxyethyl]amino}pyridine-2-carboxylate (54.7 mg, 52%). MS (m/z): 430.1 (M+H). [0555] Step 10: 6-chloro-3-{[(1S)-1-(2-ethyl-3,6-dimethyl-4-oxo-3,4-dihydroq uinazolin-8-yl)-2- hydroxyethyl]amino}pyridine-2-carboxylic acid. To a stirred solution of methyl 6-chloro-3-{[(1S)-1-(2-ethyl- 3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)-2-hydroxyethy l]amino}pyridine-2-carboxylate (54.7 mg, 127 µmol) in MeOH (4 mL) at RT was added 2N lithium(1+) hydroxide (0.6 mL, 10 eq., 1.27 mmol). The stirred was continued at RT for 3h. The mixture was concentrated to dryness, diluted with H 2 O, and acidified with 6N HCl until pH= 4-5. The precipitated solid was collected, washed with H 2 O, dried to give 6-chloro-3-{[(1S)-1-(2-ethyl- 3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)-2-hydroxyethy l]amino}pyridine-2-carboxylic acid (32.4 mg, 61%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.89 (s, 1H), 8.66 (d, J = 7.0 Hz, 1H), 7.76 (dd, J = 2.1, 1.0 Hz, 1H), 7.45 (d, J = 2.1 Hz, 1H), 7.24 (d, J = 8.9 Hz, 1H), 6.93 (d, J = 9.1 Hz, 1H), 5.40 (q, J = 5.9 Hz, 1H), 5.13 (t, J = 5.2 Hz, 1H), 3.83 (dt, J = 9.5, 4.5 Hz, 1H), 3.70 (dt, J = 11.0, 5.7 Hz, 1H), 3.48 (s, 3H), 2.86 (q, J = 7.2 Hz, 2H), 2.29 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H). MS (m/z): 417.1 (M+H). Example 55 8-[(1R)-1-{[6-chloro-2-(4H-1,2,4-triazol-3-yl)pyridin-3-yl]a mino}ethyl]-3,6-dimethyl-2-phenyl-3,4- dihydroquinazolin-4-one [0556] Step 1: 3-bromo-6-chloropyridine-2-carboxamide. To a stirred mixture of 3-bromo-6-chloropyridine- 2-carboxylic acid (1 g, 4.23 mmol), NH 4 Cl (452 mg, 2 eq., 8.46 mmol), and ethylbis(propan-2-yl)amine (1.87 mL, 2.5 eq., 10.6 mmol) in DMF (8 mL) was added [(dimethylamino)({3H-[1,2,3]triazolo[4,5-b]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-λ⁵-phosphanuide (1.93 g, 1.2 eq., 5.08 mmol). The stirring was continued for 3h. H 2 O was added, extracted with EtOAc (3x). The combined extracts were dried over MgSO 4 , concentrated, and purified by ISCO (50% EtOAc/Hexanes) to give 3-bromo-6-chloropyridine-2-carboxamide (585 mg, 59%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.22 (d, J = 8.5 Hz, 1H), 8.15 – 8.01 (m, 1H), 7.85 (s, 1H), 7.57 (d, J = 8.5 Hz, 1H). [0557] Step 2: 3-bromo-6-chloro-2-(4H-1,2,4-triazol-3-yl)pyridine. A mixture of 3-bromo-6-chloropyridine-2- carboxamide (585 mg, 2.48 mmol) and 1,1-dimethoxymethanamine (2.4 mL, 10 eq., 24.8 mmol) was heated at 120°C for 4h. The mixture was cooled to RT, concentrated to dryness. The oil residue was dissolved in acetic acid (5 mL, 87.3 mmol) and added hydrazine hydrate (1 mL, 5 eq., 12.4 mmol) and 1 mL H 2 O. The mixture was heated to 90°C in 1h. LCMS showed the desired mass. The mixture was cooled to RT, H 2 O was added. The precipitated solid was collected, washed with H 2 O, dried to give 3-bromo-6-chloro-2-(4H-1,2,4-triazol-3- yl)pyridine (496 mg, 77%). MS (m/z): 259.1 (M+H). [0558] Step 3: 3-bromo-6-chloro-2-[4-(oxan-2-yl)-4H-1,2,4-triazol-3-yl]pyri dine. A mixture of 3-bromo-6- chloro-2-(4H-1,2,4-triazol-3-yl)pyridine (338 mg, 1.3 mmol), 3,4-dihydro-2H-pyran (594 µL, 5 eq., 6.51 mmol), and 4-methylbenzene-1-sulfonic acid hydrate (24.8 mg, 0.1 eq., 130 µmol) in THF (5 mL, 61.4 mmol) was heated to 80°C for 16h. The mixture was cooled to rt, diluted with EtOAc, washed with saturated NaHCO 3 . The organic layer was dried over MgSO 4 , concentrated, and purified by ISCO (0-50% EtOAc/Hexanes) to give 3-bromo-6- chloro-2-[4-(oxan-2-yl)-4H-1,2,4-triazol-3-yl]pyridine (439 mg, 98%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.90 (s, 1H), 8.30 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 5.68 (dd, J = 9.5, 2.7 Hz, 1H), 3.97 (d, J = 11.8 Hz, 1H), 3.76 – 3.59 (m, 1H), 2.22 – 2.08 (m, 1H), 2.00 (m, 2H), 1.71 (s, 1H), 1.58 (p, J = 4.4 Hz, 2H). [0559] Step 4: 8-[(1R)-1-({6-chloro-2-[4-(oxan-2-yl)-4H-1,2,4-triazol-3-yl] pyridin-3-yl}amino)ethyl]-3,6- dimethyl-2-phenyl-3,4-dihydroquinazolin-4-one. A mixture of 3-bromo-6-chloro-2-[4-(oxan-2-yl)-4H-1,2,4- triazol-3-yl]pyridine (141 mg, 1.2 eq., 409 µmol), 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-phenyl-3,4- dihydroquinazolin-4-one (0.1 g, 341 µmol), dicaesium(1+) carbonate (333 mg, 3 eq., 1.02 mmol), [5- (diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylph osphane (39.4 mg, 0.2 eq., 68.2 µmol), and tris(1,5-diphenylpenta-1,4-dien-3-one) dipalladium (31.2 mg, 0.1 eq., 34.1 µmol) in 1,4-dioxane (2 mL, 23.4 mmol) was heated to 100°C in 24h. Saturated NH 4 Cl was added, extracted with EtOAc (3x). The combined extracts were dried over MgSO 4 , concentrated, and purified by ISCO (50% EtOAc/Hexanes) to give 8-[(1R)-1- ({6-chloro-2-[4-(oxan-2-yl)-4H-1,2,4-triazol-3-yl]pyridin-3- yl}amino)ethyl]-3,6-dimethyl-2-phenyl-3,4- dihydroquinazolin-4-one (28.2 mg, 15%). MS (m/z): 556.2 (M+H). [0560] Step 5: 8-[(1R)-1-{[6-chloro-2-(4H-1,2,4-triazol-3-yl)pyridin-3-yl]a mino}ethyl]-3,6-dimethyl-2- phenyl-3,4-dihydroquinazolin-4-one. To a stirred solution of 8-[(1R)-1-({6-chloro-2-[4-(oxan-2-yl)-4H-1,2,4- triazol-3-yl]pyridin-3-yl}amino)ethyl]-3,6-dimethyl-2-phenyl -3,4-dihydroquinazolin-4-one (28.2 mg, 50.7 µmol) in MeOH (3 mL) at RT was added HCl (0.2 mL, 10 eq., 507 µmol). The stirring was continued for 1h at 50°C. The mixture was concentrated to dry and purified by reverse prep. HPLC. The pure fractions were concentrated to dryness to give 8-[(1R)-1-{[6-chloro-2-(4H-1,2,4-triazol-3-yl)pyridin-3-yl]a mino}ethyl]-3,6-dimethyl-2-phenyl-3,4- dihydroquinazolin-4-one (5.4 mg, 23%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.71 (d, J = 6.8 Hz, 1H), 8.37 (s, 1H), 8.20 (s, 1H), 7.87 – 7.79 (m, 1H), 7.74 – 7.64 (m, 2H), 7.57 – 7.43 (m, 4H), 7.13 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 9.0 Hz, 1H), 5.43 (t, J = 6.7 Hz, 1H), 3.29 (s, 3H), 2.30 (s, 3H), 1.56 (d, J = 6.7 Hz, 3H). MS (m/z): 472.2 (M+H). Example 56 6-chloro-3-{[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydro quinazolin-8-yl)ethyl]amino}pyridine-2- carbonitrile. [0561] A mixture of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-phenyl-3,4-dihydroquina zolin-4-one (145 mg, 493 µmol), 6-chloro-3-fluoropyridine-2-carbonitrile (92.5 mg, 1.2 eq., 591 µmol), and ethylbis(propan-2-yl)amine (262 µL, 3 eq., 1.48 mmol) in DMF (3 mL, 38.7 mmol) was heated to 90°C in 2h. LCMS showed the major desired mass, the mixture was cooled to RT, H 2 O was added, extracted with EtOAc (3x). The extracts were dried over MgSO 4 , concentrated and purified by ISCO (0-30% EtOAc/Hexanes) to give 6-chloro-3-{[(1R)-1-(3,6-dimethyl-4- oxo-2-phenyl-3,4-dihydroquinazolin-8-yl)ethyl]amino}pyridine -2-carbonitrile (183 mg, 86%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.91 (dd, J = 2.1, 1.0 Hz, 1H), 7.80 (d, J = 2.1 Hz, 1H), 7.77 – 7.69 (m, 2H), 7.61 – 7.54 (m, 3H), 7.38 (d, J = 9.1 Hz, 1H), 7.12 (dd, J = 9.9, 8.4 Hz, 2H), 5.47 (p, J = 6.8 Hz, 1H), 3.41 (s, 3H), 2.45 – 2.38 (m, 3H), 1.58 (d, J = 6.7 Hz, 3H). MS (m/z): 430.1 (M+H). Example 57 3-{[(1R)-1-(2-{1-[(tert-butoxy)carbonyl]piperidin-4-yl}-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl]amino}-6-chloropyridine-2-carboxylic acid. [0562] To a stirred solution of methyl 3-{[(1R)-1-(2-{1-[(tert-butoxy)carbonyl]piperidin-4-yl}-3,6- dimethyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl]amino}-6-chloropyridine-2-c arboxylate (48 mg, 84.2 µmol) in MeOH (3 mL) at RT was added LiOH hydrate (17.7 mg, 5 eq., 421 µmol). The mixture was stirred at 50°C for 2h. The mixture was concentrated to dryness, diluted with H 2 O, cooled in an ice bath, acidified with 6N HCl. The precipitated solid was collected, washed with H 2 O, dried to give 3-{[(1R)-1-(2-{1-[(tert-butoxy)carbonyl]piperidin-4-yl}-3,6- dimethyl-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl]amino}-6-chloropyridine -2-carboxylic acid (46 mg, 98%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.42 (d, J = 7.0 Hz, 1H), 7.82 (dd, J = 2.1, 0.9 Hz, 1H), 7.58 (d, J = 2.1 Hz, 1H), 7.29 (d, J = 9.0 Hz, 1H), 7.05 (d, J = 9.1 Hz, 1H), 5.50 (p, J = 6.7 Hz, 1H), 4.07 (d, J = 12.9 Hz, 2H), 3.63 (s, 3H), 3.28 – 3.18 (m, 1H), 2.93 (s, 2H), 2.37 (s, 3H), 1.98 (d, J = 13.2 Hz, 2H), 1.74 (t, J = 12.7 Hz, 2H), 1.60 (d, J = 6.7 Hz, 3H), 1.40 (s, 9H). MS (m/z): 556.2 (M+H). Example 58 3-[(R)-1-{3-methyl-6-methyl-4-oxo-2-[1-(1,3,6-triaza-5-napht hyl)-4-piperidyl]-8-quinazolinyl}ethylamino]-6- chloro-2-pyridinecarboxylic acid. [0563] The title compound (23 mg, 46%) was prepared in the same method as described in Example 40. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.60 (s, 1H), 9.32 (s, 1H), 8.44 (d, J = 5.8 Hz, 1H), 7.84 – 7.75 (m, 1H), 7.60 (d, J = 2.1 Hz, 1H), 7.27 – 7.16 (m, 2H), 7.04 (d, J = 9.0 Hz, 1H), 5.52 (s, 1H), 4.25 (d, J = 13.0 Hz, 2H), 3.68 (s, 3H), 2.38 (s, 2H), 2.26 – 2.06 (m, 4H), 1.60 (d, J = 6.7 Hz, 2H). MS (m/z): 585.2 (M+H). Example 59 3-[(R)-1-{2-[1-(5-chloro-1-thia-4,6-diaza-7-indenyl)-4-piper idyl]-3-methyl-6-methyl-4-oxo-8- quinazolinyl}ethylamino]-6-chloro-2-pyridinecarboxylic acid. [0564] The title compound (23 mg, 44%) was prepared in the same method as described in Example 40. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.94 (s, 1H), 8.47 (s, 1H), 8.29 (d, J = 5.5 Hz, 1H), 7.83 (dd, J = 2.1, 1.0 Hz, 1H), 7.57 (d, J = 2.1 Hz, 1H), 7.40 (d, J = 5.5 Hz, 1H), 7.18 (d, J = 8.9 Hz, 1H), 7.00 (d, J = 9.1 Hz, 1H), 5.47 (t, J = 6.7 Hz, 1H), 4.83 – 4.70 (m, 2H), 3.68 (s, 3H), 3.57 – 3.43 (m, 3H), 2.37 (s, 3H), 2.21 (s, 2H), 1.97 (p, J = 11.3 Hz, 2H), 1.55 (d, J = 6.7 Hz, 3H). MS (m/z): 624.1 (M+H). Example 60 (R)-6-chloro-3-((1-(2-(4,4-difluoropiperidin-1-yl)-3,6-dimet hyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8- yl)ethyl)amino)picolinic acid [0565] Step 1: To a stirred solution of methyl 5-amino-2-methylisonicotinate (100 mg, 0.60 mmol) in MeCN (2 mL) at Rtwas added NBS (130 mg, 0.72 mmol) in a single portion. The stirring was continued for 2 h. Sat. aq. NaHCO 3 was added and stirred for 5 min, then the mixture was extracted with EtOAc (3×). The combined organic extracts were dried over anhydrous MgSO 4 and then concentrated to give crude methyl 3-amino-2- bromo-6-methylisonicotinate. [0566] Step 2: To a stirred solution of crude methyl 3-amino-2-bromo-6-methylisonicotinate in MeOH (20 mL) as added 5 N NaOH (3 equiv) and the mixture stirred at Rtovernight. The mixture was concentrated to dryness, cooled to 0 °C in an ice-water bath, then acidified with 6 N HCl to pH 5-6. The resulting precipitate was collected by filtration to give 3-amino-2-bromo-6-methylisonicotinic acid (600 mg, 30% yield over 2 steps). [0567] Step 3: From 3-amino-2-bromo-6-methylisonicotinic acid, (R)-6-chloro-3-((1-(2-(4,4-difluoropiperidin-1- yl)-3,6-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-y l)ethyl)amino)picolinic acid was synthesized in a method analogous to the synthesis of (R)-6-chloro-3-((1-(2-(4,4-difluoropiperidin-1-yl)-6-fluoro- 3-methyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinic acid as an off-white solid, LCMS [M+H] + 493.1 obs. EXAMPLE 61 (R)-6-chloro-3-((1-(6-chloro-3-methyl-2-(1-methylcyclopropyl )-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8- yl)ethyl)amino)picolinic acid [0568] Step 1: NIS (3.6 g, 16 mmol) was added to a 0 °C solution of 5-amino-2-chloroisonicotinic acid (1.7 g, 10 mmol) in DMF (13 mL). After the addition was completed, the mixture stirred at room temp, then stirred at 80 °C for 16 h. The reaction was quenched with sat. aq. Na 2 S 2 O 3 (20 mL) and diluted with EtOAc (110 mL). The mixture was sequentially washed with LiCl solution (3×100 mL) and brine (1×100 mL). The organic phase was dried over anhydrous MgSO 4 , filtered, and concentrated in vacuo to give crude 3-amino-6-chloro-2- iodoisonicotinic acid as a dark red solid which was carried to the next step without purification. [0569] Step 2: A mixture of crude 3-amino-6-chloro-2-iodoisonicotinic acid (2.5 g, 8.3 mmol), DIPEA (4.3 mL, 25 mmol), HATU (4.7 g, 12 mmol), and methylamine hydrochloride (840 mg, 12 mmol) in DCM (20 mL) stirred at Rtfor 16 h. The mixture was diluted with DCM (100 mL) and sequentially washed with sat. aq. NH 4 Cl (100 mL), water (100 mL), and brine (100 mL); then dried over anhydrous MgSO 4 , filtered, and concentrated in vacuo. The crude material was purified by SiO 2 chromatography (0–50% (10% MeOH in EtOAc) in hexanes to give 3-amino- 6-chloro-2-iodo-N-methylisonicotinamide (2.4 g, 93% yield) as a light-yellow solid. [0570] Step 3: From 3-amino-6-chloro-2-iodo-N-methylisonicotinamide, (R)-6-chloro-3-((1-(6-chloro-3-methyl- 2-(1-methylcyclopropyl)-4-oxo-3,4-dihydropyrido[3,4-d]pyrimi din-8-yl)ethyl)amino)picolinic acid was synthesized analogously to Example 45. EXAMPLE 62 (R)-6-chloro-3-((1-(3,6-dimethyl-2-(1-methylcyclopropyl)-4-o xo-3,4-dihydropyrido[3,4-d]pyrimidin-8- yl)ethyl)amino)picolinic acid [0571] From (R)-N-((R)-1-(6-chloro-3-methyl-2-(1-methylcyclopropyl)-4-ox o-3,4-dihydropyrido[3,4-d]pyrimidin- 8-yl)ethyl)-2-methylpropane-2-sulfinamide, (R)-6-chloro-3-((1-(3,6-dimethyl-2-(1-methylcyclopropyl)-4-o xo-3,4- dihydropyrido[3,4-d]pyrimidin-8-yl)ethyl)amino)picolinic acid was synthesized in a method analogous to the synthesis of (R)-6-chloro-3-((1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydrop yrido[3,4-d]pyrimidin-8- yl)ethyl)amino)picolinic acid (Example 46) . EXAMPLE 63 (R)-6-chloro-3-((1-(2-(4,4-difluoropiperidin-1-yl)-7-methyl- 4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)picolinic acid [0572] From 3-bromo-5-methylpyridin-2-amine and 4,4-difluoropiperidine hydrochloride, 9-acetyl-2-(4,4- difluoropiperidin-1-yl)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4 -one analogously to 9-acetyl-7-methyl-2-(piperidine-1- yl)-4H-pyrido[1,2-a]pyrimidin-4-one (Example 9, Steps 1–4). From 9-acetyl-2-(4,4-difluoropiperidin-1-yl)-7-methyl- 4H-pyrido[1,2-a]pyrimidin-4-one, (R)-6-chloro-3-((1-(2-(4,4-difluoropiperidin-1-yl)-7-methyl- 4-oxo-4H-pyrido[1,2- a]pyrimidi–9-yl)ethyl)amino)picolinic acid was synthesized analogously to Example 18. EXAMPLE 64 (R)-6-chloro-3-((1-(2-(4,4-difluoropiperidin-1-yl)-3-ethyl-6 -methyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0573] Step 1: A solution of 2-amino-3-bromo-5-methylbenzoic acid (2.0 g, 8.7 mmol), ethyl isothiocyanate (1.6 mL, 18 mmol), and DIPEA (6.0 mL, 35 mmol) in dioxane (20 mL) heated at 90 °C for 3 d. The mixture cooled to Rtand was diluted with DCM (100 mL) and sat. aq. NH 4 Cl (100 mL). The layers were partitioned and the aqueous layer was extracted with DCM (2 × 100 mL). The combined organic extracts were dried over anhydrous MgSO 4 , filtered, and concentrated in vacuo. The resulting beige solid was purified by SiO 2 chromatography (0–10% MeOH in DCM) to give 8-bromo-3-ethyl-6-methyl-2-thioxo-2,3-dihydroquinazolin-4(1H )-one (2.6 g, >99% yield) as a light-brown solid. [0574] Step 2: A solution of 8-bromo-3-ethyl-6-methyl-2-thioxo-2,3-dihydroquinazolin-4(1H )-one (2.6 g, 8.7 mmol) in chloroform (45 mL) was treated with sulfuryl chloride (700 µL, 8.7 mmol). The resulting solution heated at reflux for 5 h. After cooling to room temp, the mixture was diluted with DCM (200 mL) and sequentially washed with sat. aq. NaHCO 3 (2 × 200 mL) and brine (1 × 150 mL). The organic phase was dried over anhydrous MgSO 4 , filtered, and concentrated in vacuo to give crude 8-bromo-2-chloro-3-ethyl-6-methylquinazolin-4(3H)-one as a yellow solid which was carried to the next step without purification, assuming theoretical yield. [0575] Step 3: A mixture of crude 8-bromo-2-chloro-3-ethyl-6-methylquinazolin-4(3H)-one (2.6 g, 8.7 mmol), 4,4-difluoropiperidine hydrochloride (1.4 g, 8.7 mmol), and DIPEA (3.8 mL, 22 mmol) in DCM (25 mL) were heated at 45 °C overnight. After cooling to room temp, the mixture was diluted with DCM (100 mL) and sequentially washed with sat. aq. NaHCO 3 (2 × 100 mL) and brine (1 × 100 mL). The organic phase was dried over anhydrous MgSO 4 , filtered, and concentrated in vacuo. The resulting crude material was purified by SiO 2 chromatography (5–45% EtOAc/hexanes) to afford 8-bromo-2-(4,4-difluoropiperidin-1-yl)-3-ethyl-6- methylquinazolin-4(3H)-one (770 mg, 23% yield) as a yellow solid. [0576] Step 4: A mixture of 8-bromo-2-(4,4-difluoropiperidin-1-yl)-3-ethyl-6-methylquina zolin-4(3H)-one (240 mg, 0.63 mmol), cesium fluoride (380 mg, 2.5 mmol), and TMS-acetal (180 µL, 1.3 mmol) in DCE (3.0 mL) was deoxygenated with bubbling argon gas for 10 min, then tetrakis(triphenylphosphine)palladium(0) (73 mg, 0.063 mmol) was added. The resulting heterogeneous mixture stirred vigorously at 75 °C overnight. After cooling to room temp, the mixture was filtered through Celite® and then concentrated in vacuo. The crude material was purified by SiO 2 chromatography (5–45% EtOAc/hexanes) to give 8-acetyl-2-(4,4-difluoropiperidin-1-yl)-3-ethyl-6- methylquinazolin-4(3H)-one (140 mg, 65% yield) as a light-yellow solid. [0577] Step 5: From 8-acetyl-2-(4,4-difluoropiperidin-1-yl)-3-ethyl-6-methylquin azolin-4(3H)-one, (R)-6-chloro- 3-((1-(2-(4,4-difluoropiperidin-1-yl)-3-ethyl-6-methyl-4-oxo -3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinic acid was synthesized analogously to Example 18. EXAMPLE 65 (R)-6-chloro-3-(1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydrois oquinolin-5-yl)ethylamino)picolinic acid [0578] Step 1: To a mixture of 2-amino-3-bromo-5-methylbenzoic acid (4 g, 17.5 mmol) and H 2 SO 4 (31.2 g, 175 mmol) in H 2 O (60 ml) was added a solution of NaNO 2 (1.2 g, 17.5 mmol) in H 2 O (16 ml) dropwise at 0 °C. The mixture was stirred at 0 °C for 0.5 hour. Then a solution of KI (5.8 g, 35 mmol) in H 2 O (16 ml) was added dropwise and the mixture was stirred at 60 °C for 2.5 h. The reaction was quenched with sat sodium thiosulfate and the mixture was extracted with EtOAc (150 ml * 3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by flash (PE: EA = 4: 1) to afford 3-bromo-2-iodo- 5-methylbenzoic acid (3 g, 50 %) as a white solid. LCMS: (M + H) + = 341.0 [0579] Step 2: To a mixture of 3-bromo-2-iodo-5-methylbenzoic acid (3 g, 8.82 mmol) and methylamine hydrochloride (900 mg, 13.23 mmol) in DMF (50 ml) were added DIPEA (2.28 g, 17.64 mmol) and HATU (4.02 g, 10.58 mmol). The mixture was stirred at RT for 2 h. Water (250 ml) was added and the mixture was extracted with EtOAc (100 ml * 3). The combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by flash (DCM: EA = 5: 1) to afford 3-bromo-2-iodo-N,5- dimethylbenzamide (2.5 g, 80%) as a yellow solid. [0580] Step 3: To a mixture of 3-bromo-2-iodo-N,5-dimethylbenzamide (1.6 g, 4.53 mmol) and acetophenone (1.1 g, 9.06 mmol) in DMSO (15 ml) were added Cs 2 CO 3 (3.0 g, 9.06 mmol) and CuBr (65 mg, 0.45 mmol). The mixture was stirred 80 °C for 16 h. Water (100 ml) was added and the mixture was extracted with EtOAc (60 ml * 3). The combined organic phase was dried over Na 2 SO 4 and concentrated. The residue was purified by flash (PE: EA = 5: 1) to afford 5-bromo-2,7-dimethyl-3-phenylisoquinolin-1(2H)-one (450 mg, 30%) as a yellow solid. LCMS: (M+ H) + = 328.1 [0581] Step 4: To a mixture of 5-bromo-2,7-dimethyl-3-phenylisoquinolin-1(2H)-one (750 mg, 2.29 mmol) and tributyl(1-ethoxyvinyl)stannane (1.66 g, 4.58 mmol) in 1.4-dioxane (15 ml) was added Pd(PPh 3 ) 2 Cl 2 (161 mg, 0.229 mmol). The mixture was stirred at 100 °C under N 2 for 16 h. HCl (3 ml, 1 M) was added and the mixture was stirred at 50 °C for 0.5 hour, then 40 ml sat KF was added and the mixture was stirred at RT for 0.5 hour. The gray suspension was filtered and the filter cake was washed with DCM (50 ml*3), the separated aqueous phase was extracted with DCM (30 ml * 3), the combined organic phase was brine, dried over Na 2 SO 4 and concentrated. The residue was purified by flash (PE: EA = 2: 1) to afford 5-acetyl-2,7-dimethyl-3- phenylisoquinolin-1(2H)-one (540 mg, 81%) as a yellow solid. LCMS: (M+ H) + = 292.0 [0582] Step 5: To a mixture of 5-acetyl-2,7-dimethyl-3-phenylisoquinolin-1(2H)-one (540 mg, 1.86 mmol) and (R)-2-methylpropane-2-sulfinamide (450 mg, 3.72 mmol) and THF (15 ml) was added Ti(Oi-Pr) 4 (15 ml). The mixture was stirred at 75 °C under N 2 for 16 h. The mixture was diluted with EtOAc (30ml) and 30 ml brine was added, the mixture was stirred at RT for 0.5 hour. The resulting mixture was filtrated and the cake was washed with EtOAc (40 mL*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)-N-(1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoquinol in-5-yl)ethylidene)-2-methylpropane- 2-sulfinamide (700 mg, 95%) as a yellow oil. LCMS: (M+ H) + = 395.1 [0583] Step 6: To a mixture of crude (R,Z)-N-(1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoquinol in-5- yl)ethylidene)-2-methylpropane-2-sulfinamide (620 mg, 1.57 mmol) and AcOH (754 mg, 12.56 mmol) in DCM/MeOH (1: 1) (15 ml) was added NaBH 3 CN (297 mg, 4.71 mmol) 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction was quenched with sat NH 4 Cl and extracted with DCM (40 ml * 3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method A) to afford (R)-N-((R)-1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoquin olin-5-yl)ethyl)-2-methylpropane-2- sulfinamide (210 mg, 34 %) as a white solid. LCMS: (M+ H) + = 397.2 [0584] Step 7: A mixture of (R)-N-((R)-1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoquin olin-5-yl)ethyl)-2- methylpropane-2-sulfinamide (210 mg, 0.53 mmol) in HCl (3 M in MeOH) (5 ml) was stirred at RT for 0.5 hour. The mixture was poured into ice-water and adjusted PH=8 with a saturated solution of NaHCO 3 , the mixture was extracted with DCM/MeOH (30 mL*3, 10/1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford (R)-5-(1-aminoethyl)-2,7-dimethyl-3-phenylisoquinolin-1(2H)- one (150 mg, 97%) as a yellow solid. LCMS: (M+ H) + = 293.1 [0585] Step 8: To a mixture of (R)-5-(1-aminoethyl)-2,7-dimethyl-3-phenylisoquinolin-1(2H)- one (90 mg, 0.31 mmol) and methyl 6-chloro-3-fluoropicolinate (88 mg, 0.47 mmol) in DMSO (5 ml) was added DIPEA (120 mg, 0.93 mmol). The mixture was stirred at 100 °C for 16 h. Water (30 ml) was added and the mixture was extracted with EtOAc (30 ml*3), the combined organic phase was dried over with anhydrous Na 2 SO 4 and concentrated to afford (R)-methyl 6-chloro-3-(1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoqui nolin-5-yl)ethylamino)picolinate (90 mg, 63%) as a yellow solid. LCMS: (M+ H) + = 462.1 [0586] Step 9: To a solution of (R)-methyl 6-chloro-3-(1-(2,7-dimethyl-1-oxo-3-phenyl-1,2-dihydroisoqui nolin-5- yl)ethylamino)picolinate (90 mg, 0.2 mmol) in MeOH/H 2 O (5: 1) (5 ml) was added LiOH (24 mg, 1.0 mmol). The mixture was stirred at 50 °C for 1 hour. The mixture was adjusted to pH = 5 – 6 with HCl (1 M) and concentrated, the residue was purified by Pre-HPLC (Method B) to afford (R)-6-chloro-3-(1-(2,7-dimethyl-1-oxo-3-phenyl-1,2- dihydroisoquinolin-5-yl)ethylamino)picolinic acid (38.9 mg, 44%) as a white solid. LCMS: (M + H) + = 448.2. EXAMPLE 66 (R)-6-chloro-3-((1-(2-(4,4-difluoropiperidin-1-yl)-3,7-dimet hyl-4-oxo-4H-pyrido [1,2-a]pyrimidin-9- yl)ethyl)amino)picolinic acid [0587] Step 1: To a solution of 2,4,6-trichlorophenol (10 g, 50.6 mmol) in POCl 3 (200 mL) was added 2- methylmalonic acid (7.18 g, 60.8 mmol). The mixture was stirred at 110 °C for 5 h. Cooling to RT, the mixture was poured into ice-water and adjusted pH 8-9 with a saturated solution of NaHCO 3 , the resulting mixture was extracted with DCM (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 2:1) to give bis(2,4,6-trichlorophenyl) 2- methylmalonate (22 g, 91.1 %) as a white solid. LCMS: (M + Na) =496.8 [0588] Step 2: To a solution of bis(2,4,6-trichlorophenyl) 2-methylmalonate (15.3 g, 0.192 mmol,) in acetone (500 mL) was added 3-bromo-5-methylpyridin-2-amine (5 g, 26.7 mmol). The mixture was stirred at 60 °C for 12 h. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL×3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (PE: EA=4：1) to give 9-bromo-2-hydroxy-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-o ne (5.5 g, 57.9 %) as a yellow solid. LCMS: (M + H) + =269.0 [0589] Step 3: To a solution of 9-bromo-2-hydroxy-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-o ne (3.5 g, 13.3 mmol) in POCl 3 (50 mL) was added PCl 5 (276.9 mg, 1.33 mmol). The mixture was stirred at 100 °C for 5 h. Cooling to RT, the mixture was poured into ice-water and adjusted pH = 8-9 with a saturated solution of NaHCO 3 , the resulting mixture was extracted with DCM (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE : EA = 20:1) to give 9- bromo-2-chloro-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (2.2 g, 57.5 %) as a yellow solid. LCMS: (M + H) + =287.1 [0590] Step 4: To a solution of 9-bromo-2-chloro-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-on e (2.2 g, 7.65 mmol) in DCM(20 mL) were added 4,4-difluoropiperidine (1.85 g, 15.3 mmol) and DIEA (2.97 g, 22.95 mmol). The mixture was stirred at 40 °C for 2 h. Water (50 ml) was added and the mixture was extracted with DCM (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 3:1) to give the target 9-bromo-2-(4,4-difluoropiperidin-1-yl)-3,7- dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (2.2 g, 77.3 %) as a white solid. LCMS: (M + H) + =372.0 [0591] Step 5: To a mixture of 9-bromo-2-(4,4-difluoropiperidin-1-yl)-3,7-dimethyl-4H-pyrid o[1,2-a]pyrimidin-4- one (2.2 g, 5.91 mmol) and tributyl(1-ethoxyvinyl)stannane (2.56 g, 0.709 mmol) in dioxane (25 ml) was added Pd(PPh 3 ) 2 Cl 2 (414 mg, 0.591 mmol,). The mixture was stirred at 95 °C under N 2 for 16 h. HCl (6.0 ml, 1 M) was added into the mixture and stirred at 50 °C for 0.5 hour, then 50 ml sat KF was added and the mixture was stirred at RT for 0.5 hour. The gray was filtered, the filter cake was washed with EtOAc (30 ml*3), the separated aqueous phase was extracted with EtOAc (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 1:1) to give the target 9- acetyl-2-(4,4-difluoropiperidin-1-yl)-3,7-dimethyl-4H-pyrido [1,2-a]pyrimidin-4-one (1.8 g, 90.7%) as a yellow solid. LCMS: (M + H) + =336.2 [0592] Step 6: To a mixture of 9-acetyl-2-(4,4-difluoropiperidin-1-yl)-3,7-dimethyl-4H-pyri do[1,2-a]pyrimidin-4- one (1.8 g, 5.36 mmol) and (R)-2-methylpropane-2-sulfinamide (1.3 g, 10.72 mmol) in THF (20 ml) at RT was added Ti(i-PrO) 4 (20 ml). The mixture was stirred at 75 °C for 12 h. Cooling to RT, brine (50 ml) was added and the mixture was stirred for 0.5 hour. The resulting mixture was filtrated and the cake was washed with EtOAc (50 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)-N-(1-(2-(4,4-difluoropiperidin-1-yl)-3,7-dimethyl-4-ox o-4H-pyrido[1,2-a]pyrimidin-9-yl)ethylidene)-2- methylpropane-2-sulfinamide (1.5 g) as a yellow oil for the next step without further purification. LCMS: (M + H) + = 439.3 [0593] Step 7: To a solution of (R,Z)-N-(1-(2-(4,4-difluoropiperidin-1-yl)-3,7-dimethyl-4-ox o-4H-pyrido[1,2- a]pyrimidin-9-yl)ethylidene)-2-methylpropane-2-sulfinamide (1.5 g, 3.42 mmol) in DCM (20 mL) and MeOH(20 mL) were added NaBH 3 CN (322 mg,5.13 mmol) and HOAc (0.2 mL) at 0 °C. The mixture was stirred for 1 hour. The reaction was quenched with saturated NH 4 Cl solution (20 ml) and extracted with DCM (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (method A) to afford (R)-N-(1-(2-(4,4-difluoropiperidin-1-yl)-3,7-dimethyl-4-oxo- 4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)-2-methylpropane-2-sulfinamide (1.0 g, 66.4 %) as a white solid. LCMS: (M + H) + = 441.3 [0594] Step 8: To a solution of (R)-N-(1-(2-(4,4-difluoropiperidin-1-yl)-3,7-dimethyl-4-oxo- 4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)-2-methylpropane-2-sulfinamide (1.0 g, 2.27 mmol) in MeOH (4 mL) was added a solution of HCl in MeOH (10 ml, 4 M).The mixture was stirred at RT for 5 min. The mixture was poured into ice-water and adjusted PH=8 with a saturated solution of NaHCO 3 , the mixture was extracted with DCM/MeOH (20 ml*3, 10/1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (DCM: MeOH=10:1) to give (R)-9-(1-aminoethyl)-2-(4,4- difluoropiperidin-1-yl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimid in-4-one (400 mg, 52.4 %) as a yellow solid. LCMS: (M + H) + =337.3 [0595] Step 9: To a solution of (R)-9-(1-aminoethyl)-2-(4,4-difluoropiperidin-1-yl)-3,7-dime thyl-4H-pyrido[1,2- a]pyrimidin-4-one (100 mg, 0.297 mmol) in DMSO (5 mL) were added 6-chloro-3-fluoropicolinic acid (78 mg, 0.446 mmol) and DIEA (115 mg, 0.891 mmol). The mixture was stirred at 100 °C for 5 h. Water (30 ml) was added, the mixture was adjusted to pH=1 with HCl (1 M) and extracted with EtOAc (50 mL×3). The separated organic layer was washed with brine (30 mL). The combined organics were dried over Na 2 SO 4 and concentrated, the residue was purified by Pre-HPLC (Method B) to give (R)-6-chloro-3-((1-(2-(4,4-difluoropiperidin-1-yl)-3,7- dimethyl-4-oxo-4H-pyrido [1,2-a]pyrimidin-9-yl)ethyl)amino)picolinic acid (20.9 mg, 14.1 %) as a white solid. LCMS: (M + H) + =492.0 EXAMPLE 67 (R)-2-((1-(2-(4,4-difluoropiperidin-1-yl)-3,7-dimethyl-4-oxo -4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid [0596] Step 1: To a solution of (R)-9-(1-aminoethyl)-2-(4,4-difluoropiperidin-1-yl)-3,7-dime thyl-4H-pyrido[1,2- a]pyrimidin-4-one (150 mg, 0.446 mmol) in dioxane (10 mL) were added methyl 2-iodobenzoate (175 mg, 0.669 mmol), Pd2(dba) 3 (41 mg, 0.045 mmol), Xant-Phos (155 mg, 0.268 mmol) and Cs 2 CO 3 (436 mg, 1.338 mmol). The mixture was stirred at 100 °C for 12 h. Cooling to RT, the mixture was diluted with water (40 mL) and extracted with EtOAc (40 mL×3). The combined organics was dried over Na 2 SO 4 and concentrated, the residue was purified by silica gel column chromatography (PE: EA=3:1) to give methyl (R)-2-((1-(2-(4,4-difluoropiperidin- 1-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethy l) amino)benzoate (90 mg, 42.8 %) as a yellow solid. LCMS: (M + H) + =471.3 [0597] Step 2: To a solution of methyl (R)-2-((1-(2-(4,4-difluoropiperidin-1-yl)-3,7-dimethyl-4-oxo -4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl) amino)benzoate (90 mg, 0.191 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (46 mg, 1.91 mmol). The mixture was stirred at 50 °C for 1 hour. The mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM (20 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to afford (R)-2-((1-(2-(4,4-difluoropiperidin-1-yl)- 3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amin o)benzoic acid (53.4 mg, 61.2 %) as a white solid. LCMS: (M + H) + =457.1 EXAMPLE 68 3,6-dimethyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl)-2- (piperidine-1-yl)quinazolin-4(3H)-one [0598] To a solution of 8-(1-bromoethyl)-3,6-dimethyl-2-(piperidine-1-yl)quinazolin- 4(3H)-one (70 mg, 0.19 mmol) in DMF (2 ml) was added 2-(methylsulfonyl)aniline (49 mg, 0.29 mmol), the mixture was stirred at 80 °C for 2 h. The mixture was purified by Pre-HPLC (Method B) to afford 3,6-dimethyl-8-(1-((2- (methylsulfonyl)phenyl)amino)ethyl)-2-(piperidine-1-yl)quina zolin-4(3H)-one (8.6 mg, 9.9 %) as a white solid. LCMS: (M + H) + =455.0 EXAMPLE 69 2-((1-(2-cyclohexyl-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin -8-yl)ethyl)amino)benzoic acid [0599] Step 1: To a solution of 2-amino-3-bromo-N,5-dimethylbenzamide (1.0 g, 4.114 mmol,) in DMSO (20 mL) was added cyclohexanecarbaldehyde (0.93 g, 8.227 mmol,). The mixture was stirred under O 2 at 120 °C for 2 h. The mixture was diluted with water (100 mL) and extracted with EtOAc (40 mL×3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (PE: EA=4：1) to afford 8-bromo-2-cyclohexyl-3,6-dimethylquinazolin-4(3H)-one (230 mg, 16.6%) as a yellow solid. LCMS: (M + H) + =335.1 [0600] Step 2: To a mixture of 8-bromo-2-cyclohexyl-3,6-dimethylquinazolin-4(3H)-one (230 mg, 0.686 mmol) and tributyl(1-ethoxyvinyl)stannane (294 g, 0.823 mmol) in dioxane (15 ml) was added Pd(PPh 3 ) 2 Cl 2 (48 mg, 0.069 mmol). The mixture was stirred at 95 °C under N 2 for 16 h. HCl (2.0 ml, 1 M) was added into the mixture and stirred at 50 °C for 0.5 hour, then 50 ml sat KF was added and the mixture was stirred at RT for 0.5 hour. The gray was filterted, the filter cake was washed with EtOAc (30 ml*3), the separated aqueous phase was extracted with EtOAc (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 1:1) to afford 8-acetyl-2-cyclohexyl-3,6- dimethylquinazolin-4(3H)-one (200 mg, 97.6%) as a yellow solid. LCMS: (M + H) + =299.1 [0601] Step 3: To a solution of 8-acetyl-2-cyclohexyl-3,6-dimethylquinazolin-4(3H)-one (200 mg, 0.67 mmol) in MeOH (15 mL) was added NaBH 4 (50.7 mg, 1.34 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction was quenched with Ammonium chloride solution (40 mL) and extracted with EtOAc (40 mL×3). The combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (DCM: MeOH=10:1) to afford 2-cyclohexyl-8-(1-hydroxyethyl)-3,6- dimethylquinazolin-4(3H)-one (200 mg, 98.5 %). LCMS: (M + H) + = 301.2 [0602] Step 4: To a solution of 2-cyclohexyl-8-(1-hydroxyethyl)-3,6-dimethylquinazolin-4(3H) -one (200 mg, 0.66 mmol) in DCM (5 mL) was added PBr 3 (10 mL). The mixture was stirred at RT for 2 h. The reaction was quenched with ice water (40 mL) and extracted with DCM (40 mL×3). The combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford 8-(1-bromoethyl)-2-cyclohexyl-3,6-dimethylquinazolin- 4(3H)-one (220 mg, 92.4 %) as a yellow oil for the next step without further purification. LCMS: (M + H) + = 363.1 Step 5: To a solution of 8-(1-bromoethyl)-2-cyclohexyl-3,6-dimethylquinazolin-4(3H)-o ne (200 mg, 0.551 mmol) in DMF (15 mL) were added methyl 2-aminobenzoate (100 mg, 0.66 mmol). The mixture was stirred at 80 °C for 4 h. The mixture was diluted with water (60 mL) and extracted with EtOAc (40 mL×3). The combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (PE: EA=1:1) to give methyl 2-((1-(2-cyclohexyl-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino) benzoate (85 mg, 35.5 %). LCMS: (M + H) + =434.2 [0603] Step 6: To a solution of methyl 2-((1-(2-cyclohexyl-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin -8- yl)ethyl)amino)benzoate (85 mg, 0.196 mmol) in MeOH (5 mL) were added THF (5 mL), LiOH (47 mg, 1.96 mmol) and H 2 O (5 mL). The mixture was stirred at 40 °C for 1 hour. The mixture was adjusted to pH = 5 with HCl (1 M). The mixture was diluted with water (20 mL) and extracted with DCM (30 mL×3). The combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre- HPLC (Method B) to afford 2-((1-(2-cyclohexyl-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin -8- yl)ethyl)amino)benzoic acid (23.9 mg, 29.06 %) as a white solid. LCMS: (M + H) + =420.2 EXAMPLE 70 2-((1-(3,6-dimethyl-4-oxo-2-(piperidine-1-yl)-3,4-dihydroqui nazolin-8-yl)ethyl)amino)-N-methoxybenzamide [0604] To a mixture of 2-((1-(3,6-dimethyl-4-oxo-2-(piperidine-1-yl)-3,4-dihydroqui nazolin-8- yl)ethyl)amino)benzoic acid (50 mg, 0.12 mmol) and O-methylhydroxylamine (15 mg, 0.18 mmol) in DMF (4 mL) were added EDCI (34 mg, 0.18 mmol) and DMAP (44 mg, 0.36 mmol) at RT. The resulting mixture was stirred at RT for 2 h. The mixture was diluted with water (25 mL) and extracted with EtOAc (30 mL×3), the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by Prep-HPLC (Method A) to afford 2-((1-(3,6-dimethyl-4-oxo-2-(piperidine-1-yl)-3,4-dihydroqui nazolin-8- yl)ethyl)amino)-N-methoxybenzamide (29.2 mg, 54.2%) as a white solid. LCMS (ESI) m/z: [M+H] + = 450.3 EXAMPLE 71 1-(1-(3,6-dimethyl-4-oxo-2-(piperidine-1-yl)-3,4-dihydroquin azolin-8-yl)ethyl)-1H-benzo[d]imidazole-4- carboxylic acid [0605] To a mixture of 8-(1-bromoethyl)-3,6-dimethyl-2-(piperidine-1-yl)quinazolin- 4(3H)-one (200 mg, 0.55 mmol) in DMF (5 ml) was added methyl 1H-benzo[d]imidazole-4-carboxylate (116 mg, 0.66 mmol) and NaH (44 mg, 1.1 mmol) at 0 °C, the mixture was stirred at 0 °C for 4 h. Water (50 ml) was added and the mixture was extracted with EtOAc (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to afford 1-(1-(3,6-dimethyl-4-oxo-2- (piperidine-1-yl)-3,4-dihydroquinazolin-8-yl)ethyl)-1H-benzo [d]imidazole-4-carboxylic acid (39.8 mg, 16 %) as a white solid. LCMS: (M + H) + =446.2 EXAMPLE 72 8-(1-((2-(2H-tetrazol-5-yl)phenyl)amino)ethyl)-3,6-dimethyl- 2-(piperidine-1-yl)quinazolin-4(3H)-one [0606] Step 1: To a solution of 88-(1-bromoethyl)-3,6-dimethyl-2-(piperidine-1-yl)quinazolin -4(3H)-one (150 mg, 0.413 mmol) in DMF (15 mL) was added 2-aminobenzonitrile (73 mg, 0.619 mmol). The mixture was stirred at 80 °C for 4 h. The mixture was diluted with water (60 mL) and extracted with EA (40 mL×3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (PE: EA=1:1) to afford 2-((1-(3,6-dimethyl-4-oxo-2-(piperidine-1-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzonitrile (75 mg, 45.04 %) as a white solid. LCMS: (M + H) + =402.1 [0607] Step 2: To a solution of 2-((1-(3,6-dimethyl-4-oxo-2-(piperidine-1-yl)-3,4-dihydroqui nazolin-8- yl)ethyl)amino)benzonitrile (75 mg, 0.186 mmol) in toluene (10 mL) were added TMSCN (28 mg, 0.28 mmol) and DBTO (45 mg, 0.224 mmol). The mixture was stirred under N 2 at 105 °C for 2 h. Cooling to RT, the mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL×3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method A) to afford 8-(1-((2- (2H-tetrazol-5-yl)phenyl)amino)ethyl)-3,6-dimethyl-2-(piperi dine-1-yl)quinazolin-4(3H)-one (23.9 mg, 29.06 %). LCMS: (M + H) + =445.0 EXAMPLE 73 (R)-2-((1-(6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methyl- 4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid [0608] Step 1: To a solution of (R)-8-(1-aminoethyl)-6-chloro-2-(4,4-difluoropiperidin-1-yl) -3-methylquinazolin- 4(3H)-one (120 mg, 0.34 mmol) and methyl 2-iodobenzoate (178 mg, 0.68 mmol) in dioxane (5 mL) were added Pd2(dba)3 (32 mg, 0.03 mmol) and Xant-Phos (99 mg, 0.17 mmol) and Cs 2 CO 3 (439 mg, 1.35 mmol) at RT. The resulting mixture was heated to 100 °C and stirred for 16 h under N 2 . Cooling to RT, the mixture was diluted with water (30 mL) and extracted with EtOAc (40 mL×3), the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by silica gel column chromatography (PE: EA=5:1) to give methyl (R)-2-((1-(6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methyl- 4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoate (150 mg, 91%) as a white solid. LCMS (ESI) m/z: [M+H] + = 490.9 [0609] Step 2: To a solution of methyl (R)-2-((1-(6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methyl- 4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate (150 mg, 0.31 mmol) in THF (3mL) and MeOH (3 mL) were added LiOH (30 mg, 1.22 mmol) and H 2 O (3 mL) at RT, The resulting mixture was stirred at RT for 1 hour. The reaction was adjusted to pH = 5 with 1M HCl and extracted with DCM (30 mL x 3), the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by Prep-HPLC (Method B) to give (R)-2-((1-(6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methyl- 4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid (67.9 mg, 46%) as a white solid. LCMS (ESI) m/z: [M+H] + = 477.1 EXAMPLES 74 AND 75 methyl (R)-6-chloro-3-((1-(6-chloro-2-(4,4-difluoropiperidin-1-yl)- 3-methyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinate (R)-6-chloro-3-((1-(6-chloro-2-(4,4-difluoropiperidin-1-yl)- 3-methyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0610] Step 1: To a solution of 2-amino-3-bromo-5-chloro-N-methylbenzamide (2.5 g, 9.48 mmol) in dioxane (40 ml) was added thiophosgene (2.18 g, 18.96 mmol) dropwise. The mixture was stirred at RT for 1 hour. Then the mixture was stirred at 105 °C for 1 hour. The mixture was concentrated to afford crude 8-bromo-2,6-dichloro- 3-methylquinazolin-4(3H)-one (2.9 g) as a yellow solid for the next step without further purification. LCMS: (M + H) + =306.9 [0611] Step 2: To a solution of 8-bromo-2-chloro-3,6-dimethylquinazolin-4(3H)-one (2.9 g, 4.41mmol) in DCM (50 ml) were added DIPEA (3.64 g, 28.23 mmol) and 4,4-difluoropiperidine (2.28 g, 8.82 mmol), the mixture was stirred at 40 °C for 16 h. Water (50 ml) was added and the mixture was extracted with DCM (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 5:1) to afford 8-bromo-6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methylquin azolin- 4(3H)-one (3.4 g, 92.1%) as a yellow solid. LCMS: (M + H) + =392.0 [0612] Step 3: To a mixture of 8-bromo-6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methylquin azolin-4(3H)-one (3.4 g, 8.67 mmol) and tributyl(1-ethoxyvinyl)stannane (6.26 g, 17.34 mmol) in dioxane (25 ml) was added Pd(PPh 3 ) 2 Cl 2 (609 mg, 0.867 mmol,). The mixture was stirred at 95 °C under N 2 for 16 h. HCl (9.0 ml, 1 M) was added into the mixture and stirred at 50 °C for 0.5 hour, then 50 ml sat KF was added and the mixture was stirred at RT for 0.5 hour. The gray was filtered, the filter cake was washed with EtOAc (30 ml*3), the separated aqueous phase was extracted with EtOAc (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 1:1) to give 8-acetyl-6- chloro-2-(4,4-difluoropiperidin-1-yl)-3-methylquinazolin-4(3 H)-one (2.1 g, 68.1%) as a yellow solid. LCMS: (M + H) + =356.1 [0613] Step 4: To a mixture of 8-acetyl-6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methylqui nazolin-4(3H)-one (2.1 g, 5.90 mmol) and (R)-2-methylpropane-2-sulfinamide (1.43 g, 11.80 mmol) in THF (20 ml) at RT was added Ti(i- PrO) 4 (20 ml). The mixture was stirred at 75 °C for 12 h. Cooling to RT, brine (50 ml) was added and the mixture was stirred for 0.5 hour. The resulting mixture was filtrated and the cake was washed with EtOAc (40 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)-N-(1- (6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2- sulfinamide (2.0 g) as a yellow oil for the next step without further purification. LCMS: (M + H) + = 459.1 [0614] Step 5: To a solution of (R,Z)-N-(1-(6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methyl -4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (2.0 g, 4.36 mmol) in DCM (20 mL) and MeOH(20 mL) were added NaBH 3 CN (548 mg, 8.72 mmol) and HOAc (0.2 mL) at 0 °C. The mixture was stirred at 0 °C for 2 h. The mixture was diluted with saturated NH 4 Cl solution (20 ml) and extracted with DCM (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (method A) to give (R)-N-(1-(6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methyl-4 -oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (1.8 g, 89.4%) as a white solid. LCMS: (M + H) + = 461.2 [0615] Step 6: To a solution of (R)-N-(1-(6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methyl-4 -oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (1.8 g, 3.90 mmol) in MeOH (4 mL) was added a solution of HCl in MeOH (10 ml, 4 M).The mixture was stirred at RT for 5 min. The mixture was poured into ice- water and adjusted PH=8 with a saturated solution of NaHCO 3 , the mixture was extracted with DCM/MeOH (20 ml*3, 10/1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (DCM: MeOH=10:1) to give (R)-8-(1-aminoethyl)-6- chloro-2-(4,4-difluoropiperidin-1-yl)-3-methylquinazolin-4(3 H)-one (1.2 g, 3.36 mmol, yields=86.1 %) LCMS: (M + H) + =357.1 [0616] Step 7: To a solution of (R)-8-(1-aminoethyl)-6-chloro-2-(4,4-difluoropiperidin-1-yl) -3-methylquinazolin- 4(3H)-one (250 mg, 0.70 mmol) in DMSO (5 mL) were added methyl methyl 6-chloro-3-fluoropicolinate (200 mg, 1.05 mmol) and DIEA (271 mg, 2.10 mmol). The mixture was stirred at 100 °C for 2 h. The mixture was diluted with water (30 ml) and extracted with DCM (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The cured was purified by silica gel column chromatography (PE: EA=3:1) to give methyl (R)-6-chloro-3-((1-(6-chloro-2-(4,4-difluoropiperidin-1-yl)- 3-methyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinate (200 mg, 54 %) as a white solid. LCMS: (M + H) + =526.1 [0617] Step 8: To a solution of methyl (R)-6-chloro-3-((1-(6-chloro-2-(4,4-difluoropiperidin-1-yl)- 3-methyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinate (160 mg, 0.30 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (73 mg, 3.04 mmol). The mixture was stirred at 50 °C for 3 h. The mixture was adjusted to pH 4-5 with 1 M HCl and extracted with DCM (20 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to give (R)-6-chloro-3-((1-(6- chloro-2-(4,4-difluoropiperidin-1-yl)-3-methyl-4-oxo-3,4-dih ydroquinazolin-8-yl)ethyl)amino)picolinic acid (107.4 mg, 70.0%) as a white solid. LCMS: (M + H) + =512.1 EXAMPLE 76 (R)-6-chloro-3-((1-(6-methyl-4-oxo-2-(3,3-difluoroazetidin-1 -yl)-4H-chromen-8-yl)ethyl)amino)picolinic acid [0618] Step 1: To a solution of 2-amino-3-bromo-5-methylbenzamide (1 g, 4.10 mmol) in dioxane (40 ml) was added thiophosgene (946 mg, 8.23 mmol) dropwise. The mixture was stirred at RT for 1 hour. Then the mixture was stirred at 105 °C for 1 hour. The mixture was concentrated to afford crude 8-bromo-2-chloro-3,6- dimethylquinazolin-4(3H)-one (1.0 g, purify: 50% (254 nm)) as a yellow solid for the next step without further purification. LCMS: (M + H) + =287.0 [0619] Step 2: To a solution of 8-bromo-2-chloro-3,6-dimethylquinazolin-4(3H)-one (1.0 g, 3.48 mmol) in DCM (50 ml) were added DIPEA (1.35 g, 10.44 mmol) and 3,3-difluoroazetidine (647 mg, 6.96 mmol), the mixture was stirred at 40 °C overnight. Water (50 ml) was added and the mixture was extracted with DCM (60 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 5:1) to afford 8-bromo-2-(3,3-difluoroazetidin-1-yl)-3,6-dimethylquinazolin -4(3H)- one (1.1 g, 92.0%) as a yellow solid. LCMS: (M + H) + =344.0 [0620] Step 3: To a mixture of 8-bromo-2-(3,3-difluoroazetidin-1-yl)-3,6-dimethylquinazolin -4(3H)-one (1.1 g, 3.2 mmol) and tributyl(1-ethoxyvinyl)stannane (2.31 g, 6.4 mmol) in dioxane (25 ml) was added Pd(PPh 3 ) 2 Cl 2 (225 mg, 0.32 mmol,). The mixture was stirred at 95 °C under N 2 for 16 h. HCl (4.0 ml, 1 M) was added into the mixture and the mixture was stirred at 50 °C for 0.5 hour, then 50 ml sat KF was added and the mixture was stirred at RT for 0.5 hour. The gray was filtered, the filter cake was washed with EtOAc (100 ml*3), the separated aqueous phase was extracted with EtOAc (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 1:1) to give 8-acetyl-2- (3,3-difluoroazetidin-1-yl)-3,6-dimethylquinazolin-4(3H)-one (800 mg, 81.3%) as a yellow solid. LCMS: (M + H) + =308.1 [0621] Step 4: To a mixture of 8-acetyl-2-(3,3-difluoroazetidin-1-yl)-3,6-dimethylquinazoli n-4(3H)-one (800 mg, 2.6 mmol) and (R)-2-methylpropane-2-sulfinamide (629 mg, 5.2 mmol) in THF (20 ml) at RT was added Ti(i- PrO) 4 (20 ml). The mixture was stirred at 75 °C for 12 h. Cooling to RT, brine (50 ml) was added and the mixture was stirred for 0.5 hour. The resulting mixture was filtrated and the cake was washed with EtOAc (40 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)-N-(1- (2-(3,3-difluoroazetidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydr oquinazolin-8-yl)ethylidene)-2-methylpropane-2- sulfinamide (900 mg) as a yellow oil for the next step without further purification. LCMS: (M + H) + = 411.1 [0622] Step 5: To a solution of (R,Z)-N-(1-(2-(3,3-difluoroazetidin-1-yl)-3,6-dimethyl-4-oxo -3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (900 mg, 2.17 mmol) in DCM (20 mL) and MeOH(20 mL) were added NaBH 3 CN (273 mg, 4.34 mmol) and HOAc (0.2 mL) at 0 °C. The mixture was stirred at 0 °C for 2 h. The mixture was diluted with saturated NH 4 Cl solution (50 ml) and extracted with DCM (100 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (method A) to give (R)-N-(1-(2-(3,3-difluoroazetidin-1-yl)-3,6-dimethyl-4-oxo-3 ,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (750 mg, 83.9 %) as a white solid. LCMS: (M + H) + = 413.2 [0623] Step 6: To a solution of (R)-N-(1-(2-(3,3-difluoroazetidin-1-yl)-3,6-dimethyl-4-oxo-3 ,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (750 mg, 1.82 mmol) in MeOH (4 mL) was added a solution of HCl in MeOH (10 ml, 4 M).The mixture was stirred at RT for 5 min. The mixture was poured into ice- water and adjusted PH=8 with a saturated solution of NaHCO 3 , the mixture was extracted with DCM/MeOH (50 ml*3, 10/1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (DCM: MeOH=10:1) to give (R)-8-(1-aminoethyl)-2- (3,3-difluoroazetidin-1-yl)-3,6-dimethylquinazolin-4(3H)-one (500 mg, 89.0 %) as a white solid. LCMS: (M + H) + =309.1 [0624] Step 7: To a solution of (R)-8-(1-aminoethyl)-2-(3,3-difluoroazetidin-1-yl)-3,6-dimet hylquinazolin-4(3H)- one (100 mg, 0.32 mmol) in DMSO (5 mL) were added methyl 6-chloro-3-fluoropicolinate (91 mg, 0.48 mmol) and DIEA (124 mg, 0.96 mmol). The mixture was stirred at 100 °C for 2 h. The mixture was diluted with water (30 ml) and extracted with EtOAc (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (PE: EA=3:1) to give methyl (R)-6-chloro-3-((1-(2-(3,3-difluoroazetidin-1-yl)-3,6-dimeth yl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinate (75 mg, 46.9 %) as a yellow solid. LCMS: (M + H) + =478.1 [0625] Step 8: To a solution of methyl (R)-6-chloro-3-((1-(2-(3,3-difluoroazetidin-1-yl)-3,6-dimeth yl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (75 mg, 0.15 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (36 mg, 1.5 mmol). The mixture was stirred at 50 °C for 1 hour. The mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to give (R)-6-chloro-3-((1-(6- methyl-4-oxo-2-(3,3-difluoroazetidin-1-yl)-4H-chromen-8-yl)e thyl)amino)picolinic acid (40.7 mg, 60.0 %) as a white solid. LCMS: (M + H) + =464.1 EXAMPLE 77 (R)-6-chloro-3-((1-(2-(3,3-difluoropyrrolidin-1-yl)-3,6-dime thyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0626] Step 1: To a solution of 2-amino-3-bromo-5-methylbenzamide (1.5 g, 6.17 mmol) in dioxane (40 ml) was added thiophosgene (946 mg, 8.23 mmol) dropwise. The mixture was stirred at RT for 1 hour. Then the mixture was stirred at 105 °C for 1 hour. The mixture was concentrated to afford crude 8-bromo-2-chloro-3,6- dimethylquinazolin-4(3H)-one (1.3 g, purify: 68% (254 nm)) as a yellow solid for the next step without further purification. LCMS: (M + H) + =287.0 [0627] Step 2: To a solution of 8-bromo-2-chloro-3,6-dimethylquinazolin-4(3H)-one (1.3 g, 4.53 mmol) in DCM (50 ml) were added DIPEA (1.75 g, 13.59 mmol) and 3,3-difluoropyrrolidine (969 mg, 9.06 mmol), the mixture was stirred at 40 °C overnight. Water (100 ml) was added and the mixture was extracted with DCM (80 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 5:1) to afford 8-bromo-2-(3,3-difluoropyrrolidin-1-yl)-3,6-dimethylquinazol in-4(3H)- one (1.1 g, 67.8%) as a yellow solid. LCMS: (M + H) + =358.0 [0628] Step 3: To a mixture of 8-bromo-2-(3,3-difluoropyrrolidin-1-yl)-3,6-dimethylquinazol in-4(3H)-one (1.1 g, 3.07 mmol) and tributyl(1-ethoxyvinyl)stannane (2.22 g, 6.14 mmol) in dioxane (25 ml) was added Pd(PPh 3 ) 2 Cl 2 (215 mg, 0.307 mmol,). The mixture was stirred at 95 °C under N 2 for 16 h. HCl (3.0 ml, 1 M) was added into the mixture and stirred at 50 °C for 0.5 hour, then 50 ml sat KF was added and the mixture was stirred at RT for 0.5 hour. The gray was filtered, the filter cake was washed with EtOAc (100 ml*3), the separated aqueous phase was extracted with EtOAc (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 1:1) to give 8-acetyl-2-(3,3- difluoropyrrolidin-1-yl)-3,6-dimethylquinazolin-4(3H)-one (700 mg, 71.0%) as a yellow solid. LCMS: (M + H) + =322.1 [0629] Step 4: To a mixture of 8-acetyl-2-(3,3-difluoropyrrolidin-1-yl)-3,6-dimethylquinazo lin-4(3H)-one (700 mg, 2.18 mmol) and (R)-2-methylpropane-2-sulfinamide (649 mg, 5.36 mmol) in THF (20 ml) at RT was added Ti(i-PrO) 4 (20 ml). The mixture was stirred at 75 °C for 12 h. Cooling to RT, brine (50 ml) was added and the mixture was stirred for 0.5 hour. The resulting mixture was filtrated and the cake was washed with EA (80 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)- N-(1-(2-(3,3-difluoropyrrolidin-1-yl)-3,6-dimethyl-4-oxo-3,4 -dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2- sulfinamide (850 mg) as a yellow oil for the next step without further purification. LCMS: (M + H) + = 425.0 [0630] Step 5: To a solution of (R,Z)-N-(1-(2-(3,3-difluoropyrrolidin-1-yl)-3,6-dimethyl-4-o xo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (850 mg, 2.00mmol) in DCM (20 mL) and MeOH (20 mL) were added NaBH 3 CN (251 mg, 4.00 mmol) and HOAc (0.2 mL) at 0 °C. The mixture was stirred at 0 °C for 2 h. The mixture was diluted with saturated NH 4 Cl solution (50 ml) and extracted with DCM (80 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (method A) to give (R)-N-(1-(2-(3,3-difluoropyrrolidin-1-yl)-3,6-dimethyl-4-oxo -3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (700 mg, 82%) as a white solid. LCMS: (M + H) + = 427.3 [0631] Step 6: To a solution of (R)-N-(1-(2-(3,3-difluoropyrrolidin-1-yl)-3,6-dimethyl-4-oxo -3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (700 mg, 1.64 mmol) in MeOH (4 mL) was added a solution of HCl in MeOH (10 ml, 4 M).The mixture was stirred at RT for 10 min. The mixture was poured into ice- water and adjusted PH=8 with a saturated solution of NaHCO 3 , the mixture was extracted with DCM/MeOH (80 ml*3, 10/1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (DCM: MeOH=10:1) to give (R)-8-(1-aminoethyl)-2- (3,3-difluoropyrrolidin-1-yl)-3,6-dimethylquinazolin-4(3H)-o ne (400 mg, 73.2 %) as a yellow solid. LCMS: (M + H) + =323.1 [0632] Step 7: To a solution of (R)-8-(1-aminoethyl)-2-(3,3-difluoropyrrolidin-1-yl)-3,6-dim ethylquinazolin-4(3H)- one (80 mg, 0.248 mmol) in DMSO (5 mL) were added methyl methyl 6-chloro-3-fluoropicolinate (71 mg, 0.372 mmol) and DIEA (96 mg, 0.744 mmol). The mixture was stirred at 100 °C for 2 h. The mixture was diluted with water (30 ml) and extracted with EtOAc (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (PE: EA=3:1) to give methyl (R)-6-chloro-3-((1-(2-(3,3-difluoropyrrolidin-1-yl)-3,6-dime thyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinate (70 mg, 56.5 %) as a yellw oil. LCMS: (M + H) + =493.1 [0633] Step 8: To a solution of methyl (R)-6-chloro-3-((1-(2-(3,3-difluoropyrrolidin-1-yl)-3,6-dime thyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (70 mg, 0.14 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (34 mg, 1.4 mmol). The mixture was stirred at 50 °C for 1 hour. The mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM (20 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to give (R)-6-chloro-3-((1-(2-(3,3- difluoropyrrolidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquina zolin-8-yl)ethyl)amino)picolinic acid (48.2 mg, 71.4 %) as a white solid. LCMS: (M + H) + =478.1 EXAMPLE 78 (R)-2-((1-(2-(3,3-difluoroazetidin-1-yl)-3,6-dimethyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid [0634] Step 1: To a solution (R)-8-(1-aminoethyl)-2-(3,3-difluoroazetidin-1-yl)-3,6-dimet hylquinazolin-4(3H)-one (150 mg, 0.49 mmol) in dioxane (10 mL) were added methyl 2-iodobenzoate (193 mg, 0.735 mmol), Pd2(dba) 3 (45 mg, 0.049 mmol), Xant-Phos (141 mg, 0.25 mmol) and Cs 2 CO 3 (479 mg, 1.47 mmol). The mixture was stirred at 100 °C for 12 h. Water (40 mL) was added and the mixture was extracted with EtOAc (40 mL×3). The organic layer was washed with brine (30 mL), dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (PE: EA=3:1) to give methyl (R)-2-((1-(2-(3,3-difluoroazetidin-1-yl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoa te (100 mg, 46.9 %) as a yellow solid. LCMS: (M + H) + =443.2 [0635] Step 2: To a solution of methyl (R)-2-((1-(2-(3,3-difluoroazetidin-1-yl)-3,6-dimethyl-4-oxo- 3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate (100 mg, 0.23 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (55 mg, 2.3 mmol). The mixture was stirred at 50 °C for 1 hour. The mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM (40 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to give (R)-2-((1-(2-(3,3- difluoroazetidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazo lin-8-yl)ethyl)amino)benzoic acid (57.5mg, 56.5 %) as a white solid. LCMS: (M + H) + =429.1 EXAMPLE 79 (R)-2-((1-(2-(3,3-difluoropyrrolidin-1-yl)-3,6-dimethyl-4-ox o-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid [0636] Step 1: To a solution of (R)-8-(1-aminoethyl)-2-(3,3-difluoropyrrolidin-1-yl)-3,6-dim ethylquinazolin-4(3H)- one (120 mg, 0.372 mmol) in dioxane (10 mL) were added methyl 2-iodobenzoate (146 mg, 0.558 mmo), Pd 2 (dba) 3 (34 mg, 0.037 mmol), Xant-Phos (129 mg, 0.223 mmol) and Cs 2 CO 3 (364 mg, 1.166 mmol). The mixture was stirred at 100 °C for 12 h. The mixture was diluted with water (50 mL) and the mixture was extracted with EtOAc (50 mL×3), the combined organics were dried over Na 2 SO 4 and concentrated and the residue was purified by silica gel column chromatography (PE: EA=5:2) to give methyl (R)-2-((1-(2-(3,3-difluoropyrrolidin-1-yl)- 3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)be nzoate (80 mg, 47.0 %) as a yellow solid. LCMS: (M + H) + =457.1 [0637] Step 2: To a solution of methyl (R)-2-((1-(2-(3,3-difluoropyrrolidin-1-yl)-3,6-dimethyl-4-ox o-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate (80 mg, 0.175 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (42 mg, 1.75 mmol). The mixture was stirred at 50 °C for 1 hour. The mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM (20 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to give (R)-2-((1-(2-(3,3- difluoropyrrolidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquina zolin-8-yl)ethyl)amino)benzoic acid (33.1 mg, 42.9 %) as a white solid. LCMS: (M + H) + =443.1 EXAMPLE 80 (R)-6-chloro-3-((1-(2-(4,4-difluoropiperidin-1-yl)-3-methyl- 4-oxo-6-(trifluoromethyl)-3,4-dihydroquinazolin- 8-yl)ethyl)amino)picolinic acid [0638] Step 1: To a mixture of (R)-8-(1-aminoethyl)-2-(4,4-difluoropiperidin-1-yl)-3-methyl -6- (trifluoromethyl)quinazolin-4(3H)-one (80 mg, 0.21 mmol) and methyl 6-chloro-3-fluoropicolinate (60 mg, 0.32 mmol) in DMSO (3 ml) was added DIPEA (54 mg, 0.42 mmol), the mixture was heated to 90 °C overnight. Cooling to RT, water (20 ml) was added and the mixture was extracted with EtOAc (20 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre- TLC (PE: EA = 3:1) to afford methyl (R)-6-chloro-3-((1-(2-(4,4-difluoropiperidin-1-yl)-3-methyl- 4-oxo-6- (trifluoromethyl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)pic olinate (80 mg, 68%) as a yellow oil. LCMS: (M + H) + =560.2 [0639] Step 2: To a mixture of methyl (R)-6-chloro-3-((1-(2-(4,4-difluoropiperidin-1-yl)-3-methyl- 4-oxo-6- (trifluoromethyl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)pic olinate (80 mg, 0.14 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (17 mg, 0.7 mmol). The mixture was stirred at 50 °C for 3 h. Cooling to RT, the mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM (20 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to afford (R)-6-chloro-3-((1-(2-(4,4-difluoropiperidin-1-yl)-3-methyl- 4-oxo-6-(trifluoromethyl)-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid (43.8 mg, 56%) as a white solid. LCMS: (M + H) + =546.0 EXAMPLE 81 (R)-2-(1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydroquinazolin- 8-yl)ethylamino)benzoic acid [0640] Step 1: To a mixture of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-phenylquinazolin-4(3H)-o ne (200 mg, 0.68 mmol), methyl 2-iodobenzoate (267 mg, 1.02 mmol), Cs 2 CO 3 (443 mg, 1.36 mmol) in 1.4-dioxane (5 ml) were added Xant-Phos (157 mg, 0.272 mmol) and Pd 2 (dba) 3 (125 mg, 0.136 mmol). The mixture was stirred at 100 °C for 16 h under N 2 . Water (30 ml) was added and the mixture was extracted with DCM (20 ml*), the combined organic phase was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by flash (PE: EA= 3: 1) to afford (R)-methyl 2-(1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydroquinazolin-8- yl)ethylamino)benzoate (190 mg, 66%) as a yellow solid. LCMS: (M + H) + = 482.3 [0641] Step 2: To a solution of (R)-methyl 2-(1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydroquinazolin-8- yl)ethylamino)benzoate (190 mg, 0.4 mmol) in MeOH/H 2 O (5: 1) (5 ml) was added LiOH (48 mg, 2.0 mmol). The mixture was stirred at 50 °C for 16 h. The mixture was adjusted to pH = 5 – 6 with HCl (1 M) and concentrated, the residue was purified by Pre-HPLC (Method B) to afford (R)-2-(1-(3,6-dimethyl-4-oxo-2-phenyl-3,4- dihydroquinazolin-8-yl)ethylamino)benzoic acid (112.5 mg, 68%) as a white solid. LCMS: (M + H) + = 414.3 EXAMPLE 82 (R)-2-((1-(2-(4,4-difluoropiperidin-1-yl)-3-methyl-4-oxo-6-( trifluoromethyl)-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid [0642] Step 1: To a mixture of 2-amino-3-bromo-5-(trifluoromethyl)benzoic acid (5.0 g, 17.7 mmol), methylamine hydrochloride (1.81 g, 26.6 mmol) and HATU (7.4 g, 19.5 mmol) in DCM (80 ml) was added DIPEA (6.85 g, 53.1 mmol), the mixture was stirred at room temoerature for 3 h. Water (100 ml) was added and the mixture was extracted with DCM (100 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (DCM: EA = 20:1) to afford 2-amino-3-bromo-N-methyl-5-(trifluoromethyl)benzamide (4.0 g, 76%) as a white solid. LCMS: (M + H) + =297.1 [0643] Step 2: To a solution of 2-amino-3-bromo-N-methyl-5-(trifluoromethyl)benzamide (2.0 g, 6.8 mmol) in dioxane (30 ml) was added Thiophosgene (1.56 g, 13.6 mmol), the mixture was stirred at RT for 1 hour, then heated to 105 °C and stirred for 1 hour. The resulting mixture was concentrated, the residue was dissolved with DCM (30 ml), 4,4-difluoropiperidine (1.65 g, 13.6 mmol) and DIPEA (1.75 g, 13.6 mmol) were added, the mixture was stirred at 50 °C overnight. Cooling to RT, water (50 ml) was added and the mixture was extracted with DCM (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (PE: EA = 6:1) to afford 8-bromo-2-(4,4- difluoropiperidin-1-yl)-3-methyl-6-(trifluoromethyl)quinazol in-4(3H)-one (910 mg, 31%) as a yellow solid. LCMS: (M + H) + =426.0 [0644] Step 3: To a mixture of 8-bromo-2-(4,4-difluoropiperidin-1-yl)-3-methyl-6-(trifluoro methyl)quinazolin- 4(3H)-one (910 mg, 2.14 mmol) and ethyl tributylstannanecarboxylate (1.55 g, 4.28 mmol) in dioxane (20 ml) was added Pd(PPh 3 ) 2 Cl 2 (300 mg, 0.43 mmol). The mixture was stirred at 95 °C under N 2 for 16 h. HCl (3 ml, 1 M) was added into the mixture and stirred at 50 °C for 0.5 hour, then a saturated solution of KF (50 ml) was added and the mixture was stirred at rt for 0.5 hour. The gray was filtered, the filter cake was washed with EA (50 ml*3), the separated aqueous phase was extracted with EA (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 5:1) to afford 8-acetyl-2-(4,4-difluoropiperidin-1-yl)-3-methyl-6-(trifluor omethyl)quinazolin-4(3H)-one (800 mg, 96%) as a yellow solid. LCMS: (M + H) + =390.0 [0645] Step 4: To a mixture of 8-acetyl-2-(4,4-difluoropiperidin-1-yl)-3-methyl-6-(trifluor omethyl)quinazolin- 4(3H)-one (800 mg 2.06 mmol) and (R)-2-methylpropane-2-sulfinamide (499 mg, 4.12 mmol) in THF (30 ml) at RT was added Ti(i-PrO) 4 (2.93 g, 10.3 mmol). The mixture was stirred at 75 °C for 24 h. Cooling to RT, the mixture was diluted with EtOAc (50 ml) and brine (50 ml) was added, the mixture was stirred at rt for 0.5 hour. The resulting mixture was filtrated and the cake was washed with EA (80 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)-N-(1-(2-(4,4-difluoropiperidin-1-yl)- 3-methyl-4-oxo-6-(trifluoromethyl)-3,4-dihydroquinazolin-8-y l)ethylidene)-2-methylpropane-2-sulfinamide (1.0 g, 100%) as a yellow oil for the next step without further purification. LCMS: (M + H) + = 493.1 [0646] Step 5: To a mixture To a mixture (R,Z)-N-(1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydroquinazoli n-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (1.0 g, 2 mmol) and HOAc (960 mg, 16 mmol) in DCM (10 ml) and MeOH (10 ml) at 0 °C was added NaBH 3 CN (186 mg, 6 mmol) slowly, the mixture was stirred for 1 hour. A saturated solution of NH 4 Cl (100 ml) and the mixture was extracted with DCM (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified Pre-HPLC (method A) to afford (R)-N-(1-(2-(4,4-difluoropiperidin-1-yl)-3-methyl-4-oxo-6-(t rifluoromethyl)-3,4-dihydroquinazolin-8- yl)ethyl)-2-methylpropane-2-sulfinamide (400 mg, 40% (two steps)) as a white solid. LCMS: (M + H) + = 495.0 [0647] Step 6: A mixture of (R)-N-(1-(2-(4,4-difluoropiperidin-1-yl)-3-methyl-4-oxo-6-(t rifluoromethyl)-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (400 mg, 0.81 mmol) in a solution of HCl in MeOH (15 ml, 4 M) was stirred at RT for 0.5 hour. The mixture was poured into ice-water and adjusted PH=8 with a saturated solution of NaHCO 3 , The mixture was extracted with DCM/MeOH (30 ml*3, 10/1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford (R)-8-(1-aminoethyl)-2-(4,4- difluoropiperidin-1-yl)-3-methyl-6-(trifluoromethyl)quinazol in-4(3H)-one (200 mg, 63%) as a yellow solid. LCMS: (M + H) + =391.1 [0648] Step 7: To a mixture of (R)-8-(1-aminoethyl)-2-(4,4-difluoropiperidin-1-yl)-3-methyl -6- (trifluoromethyl)quinazolin-4(3H)-one (120 mg, 0.31 mmol), methyl 2-iodobenzoate (162 mg, 0.62 mmol), Pd2(dba)3 (53 mg, 0.062 mmol)and xantphos (71 mg, 0.124 mmol) in dioxane (5 ml) was added Cs 2 CO 3 (202 mg, 0.62 mmol), the mixture was stirred at 100 °C for 24 h. Cooling to RT, water (30 ml) was added and the mixture was extracted with DCM (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-TLC (PE: EA = 3:1) to afford methyl (R)-2-((1-(2-(4,4- difluoropiperidin-1-yl)-3-methyl-4-oxo-6-(trifluoromethyl)-3 ,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (120 mg, 74%) as a yellow solid. LCMS: (M + H) + =525.0 [0649] Step 8: To a mixture of methyl (R)-2-((1-(2-(4,4-difluoropiperidin-1-yl)-3-methyl-4-oxo-6-( trifluoromethyl)- 3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (120 mg, 0.23 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (28 mg, 1.15 mmol). The mixture was stirred at 50 °C for 3 h. Cooling to RT, the mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM (20 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to afford (R)-2-((1-(2- (4,4-difluoropiperidin-1-yl)-3-methyl-4-oxo-6-(trifluorometh yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (48.3 mg, 41%) as a white solid. LCMS: (M + H) + =511.0 EXAMPLE 83 (R)-6-chloro-3-((1-(2-(3-fluorophenyl)-3,6-dimethyl-4-oxo-3, 4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0650] Step 1: To a mixture of 2-amino-3-bromo-N,5-dimethylbenzamide (1.4 g, 5.8 mmol) in DMSO (30 ml) was added 3-fluorobenzaldehyde (1.08 g, 8.7 mmol). The mixture was stirred at 135 °C under O 2 for 16 h. The mixture was poured into water (150 ml) and stirred for 0.5 hour, the mixture was filtered and the cake was washed with water (20 ml*3), the cake was dried under reduce pressure to afford 8-bromo-2-(3-fluorophenyl)-3,6- dimethylquinazolin-4(3H)-one (800 mg, 40%) as a white solid. LCMS: (M+H) + = 347.1 [0651] Step 2: To a mixture of 8-bromo-2-(3-fluorophenyl)-3,6-dimethylquinazolin-4(3H)-one (800 mg, 2.3 mmol) and tributyl(1-ethoxyvinyl)stannane (1.67 g, 4.6 mmol) in 1.4-dioxane (30 ml) was added Pd(PPh 3 ) 2 Cl 2 (161 mg, 0.23 mmol). The mixture was heated to 100 °C and stirred under N 2 for 6 h. HCl (3 ml, 1 M) was added into the mixture and stirred at 50 °C for 0.5 hour, then a saturated solution of KF (40 ml) and stirred at RT for 0.5 hour. The gray suspension was filtered. The filter cake was washed with EtOAc (50 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (PE: EA= 4: 1) to afford 8-acetyl-2-(3-fluorophenyl)-3,6-dimethylquinazolin-4(3H)-one (650 mg, 90%) as a yellow solid. LCMS: (M + H) + = 311.2 [0652] Step 3: To a mixture of 8-acetyl-2-(3-fluorophenyl)-3,6-dimethylquinazolin-4(3H)-one (650 mg, 2.1 mmol) and (R)-2-methylpropane-2-sulfinamide (508 mg, 4.2 mmol) in THF (15 ml) was added Ti(i-PrO) 4 (15 ml). the mixture was stirred at 75 °C under N 2 for 16 h. The mixture was diluted with EtOAc (50 ml) and a saturated solution of NaCl (50 ml) was added, the mixture was stirred at RT for 0.5 hour. The resulting mixture was filtered and the filter cake was washed with EtOAc (30 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)-N-(1-(2-(3-fluorophenyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (867 mg, 100% yield) as a yellow oil for the next step without further purification. LCMS: (M + H) + = 414.0 [0653] Step 4: To a mixture of crude (R,Z)-N-(1-(2-(3-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydr oquinazolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (867 mg, 2.1 mmol) and HOAc (1.01 g, 16.8 mmol) in DCM (10 ml) and MeOH (10 ml) at 0°C was added NaBH 3 CN (397 mg, 6.3 mmol) slowly. The mixture was stirred at RT for 1 hour. A saturated solution of NH 4 Cl (40 ml) was added and the mixture was extracted with DCM (40 ml * 3), the combined organic phase was washed with brine, dried with Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (method A) to afford (R)-N-((R)-1-(2-(3-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihy droquinazolin-8- yl)ethyl)-2-methylpropane-2-sulfinamide (280 mg, 32% yield) as a yellow solid. LCMS: (M + H) + = 416.0 [0654] Step 5: A mixture of (R)-N-((R)-1-(2-(3-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihy droquinazolin-8- yl)ethyl)-2-methylpropane-2-sulfinamide (200 mg, 0.48 mmol) in a solution of HCl in MeOH (5 ml, 4 M) was stirred at RT for 10 min. the mixture was poured into ice-water and adjusted pH = 8-9 with a saturated solution of NaHCO 3 , the mixture was extracted with DCM/MeOH (20 ml*5, 10/1), the combined organic phase was dried over Na 2 SO 4 and concentrated to afford (R)-8-(1-aminoethyl)-2-(3-fluorophenyl)-3,6-dimethylquinazol in-4(3H)- one (140 mg, 93%) as a yellow solid. LCMS: (M + H) + = 312.1 [0655] Step 6: To a mixture of (R)-8-(1-aminoethyl)-2-(3-fluorophenyl)-3,6-dimethylquinazol in-4(3H)-one (80 mg, 0.26 mmol) and methyl 6-chloro-3-fluoropicolinate (74 mg, 0.39 mmol) in DMSO (4 ml) was added DIPEA (101 mg, 0.78 mmol), the mixture was heated to 90 °C overnight. Cooling to RT, water (20 ml) was added and the mixture was extracted with EtOAc (20 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-TLC (DCM: MeOH = 30:1) to afford methyl (R)-6- chloro-3-((1-(2-(3-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihy droquinazolin-8-yl)ethyl)amino)picolinate (80 mg, 64%) as a yellow solid. LCMS: (M + H) + =481.1 [0656] Step 7: To a mixture of methyl (R)-6-chloro-3-((1-(2-(3-fluorophenyl)-3,6-dimethyl-4-oxo-3, 4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (85 mg, 0.18 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (22 mg, 0.9 mmol). The mixture was stirred at 50 °C for 16 h. Cooling to RT, the mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM (20 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to afford (R)-6-chloro-3- ((1-(2-(3-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinaz olin-8-yl)ethyl)amino)picolinic acid (48.5 mg, 58%) as a white solid. LCMS: (M + H) + =467.0 EXAMPLE 84 (R)-3-((1-(2-(4,4-difluoropiperidin-1-yl)-3,6-dimethyl-4-oxo -3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0657] Step 1: To a mixture of (R)-8-(1-aminoethyl)-2-(4,4-difluoropiperidin-1-yl)-3,6-dime thylquinazolin-4(3H)- one (100 mg, 0.3 mmol) and methyl 6-chloro-3-fluoropicolinate (85 mg, 0.45 mmol) in DMSO (5 ml) was added DIPEA (77 mg, 0.6 mmol), the mixture was heated to 90 °C overnight. Cooling to RT, water (30 ml) was added and the mixture was extracted with EtOAc (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-TLC (PE:EA = 3:1) to afford methyl (R)-6- chloro-3-((1-(2-(4,4-difluoropiperidin-1-yl)-3,6-dimethyl-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinate (70 mg, 46%) as a yellow solid. LCMS: (M + H) + =506.0 [0658] Step 2: To a solution of methyl (R)-6-chloro-3-((1-(2-(4,4-difluoropiperidin-1-yl)-3,6-dimet hyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (70 mg, 0.14 mmol) in MeOH (5 ml) was added Pd (15 mg, 20%). The mixture was stirred at RT under H 2 balloon overnight. The mixture was filtered and the filtrates were concentrated to afford methyl (R)-3-((1-(2-(4,4-difluoropiperidin-1-yl)-3,6-dimethyl-4-oxo -3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinate (60 mg, 90%) as a yellow oil. LCMS: (M + H) + =472.3 [0659] Step 3: To a mixture of methyl (R)-3-((1-(2-(4,4-difluoropiperidin-1-yl)-3,6-dimethyl-4-oxo -3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (60 mg, 0.13 mmol) in MeOH (4 ml) and H 2 O (1 ml) was added LiOH (16 mg, 0.65 mmol). The mixture was stirred at 50 °C for 4 h. The mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM (20 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to afford (R)-3-((1-(2-(4,4- difluoropiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinaz olin-8-yl)ethyl)amino)picolinic acid (26.8 mg, 45%) as a white solid. LCMS: (M + H) + =458.3 EXAMPLE 85 (R)-6-chloro-3-((1-(2-(4-fluorophenyl)-3,6-dimethyl-4-oxo-3, 4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0660] Step 1: To a solution of 2-amino-3-bromo-N,5-dimethylbenzamide (2.5 g, 10.29 mmol,) in DMSO (50 mL) was added (4-fluorophenyl)methanol (2.59 g, 20.58 mmol,). The mixture was stirred under O 2 at 120 °C for 12 h. The mixture was diluted with water (200 mL) and extracted with EtOAc (100 mL×3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (PE: EA=4：1) to give 8-bromo-2-(4-fluorophenyl)-3,6-dimethylquinazolin-4(3H)-one (2.3 g, 64.4 %) as a yellow solid. LCMS: (M + H) + =346.9 [0661] Step 2: To a mixture of 8-bromo-2-(4-fluorophenyl)-3,6-dimethylquinazolin-4(3H)-one (2.3 g, 6.63 mmol mmol) and tributyl(1-ethoxyvinyl)stannane (4.79 g, 13.26 mmol) in dioxane (25 ml) was added Pd(PPh 3 ) 2 Cl 2 (465 mg, 0.66 mmol,). The mixture was stirred at 95 °C under N 2 for 16 h. HCl (7.0 ml, 1 M) was added into the mixture and the mixture was stirred at 50 °C for 0.5 hour, then 50 ml sat KF was added and the mixture was stirred at RT for 0.5 hour. The gray was filtered, the filter cake was washed with EtOAc (30 ml*3), the separated aqueous phase was extracted with EtOAc (100 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 1:1) to give 8-acetyl-2- (4-fluorophenyl)-3,6-dimethylquinazolin-4(3H)-one (1.8 g, 87.6%) as a yellow solid. LCMS: (M + H) + =311.0 [0662] Step 3: To a mixture of 8-acetyl-2-(4-fluorophenyl)-3,6-dimethylquinazolin-4(3H)-one (1.8 g, 5.81 mmol) and (R)-2-methylpropane-2-sulfinamide (1.41 g, 11.62 mmol) in THF (20 ml) at RT was added Ti(i-PrO) 4 (20 ml). The mixture was stirred at 75 °C for 12 h. Cooling to RT, brine (50 ml) was added and the mixture was stirred for 0.5 hour. The resulting mixture was filtrated and the cake was washed with EtOAc (200 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)-N-(1-(2-(4- fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl) ethylidene)-2-methylpropane-2-sulfinamide (2.0 g) as a yellow oil for the next step without further purification. LCMS: (M + H) + = 414.0 [0663] Step 4: To a solution of (R,Z)-N-(1-(2-(4-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydr oquinazolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (2.0 g, 4.84 mmol) in EtOH (20 mL) was added a solution of LiBH 4 (4.84 ml, 4.84 mmol, 1 M) at -20 °C. The mixture was stirred at RT for 2 h. The reaction was quenched with saturated NH 4 Cl solution (200 ml) and extracted with DCM (100 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (method A) to give (R)- N-((R)-1-(2-(4-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroq uinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (330 mg, 16.3%) as a white solid. LCMS: (M + H) + = 416.2 [0664] Step 5: To a solution of (R)-N-((R)-1-(2-(4-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihy droquinazolin-8- yl)ethyl)-2-methylpropane-2-sulfinamide (330 mg, 0.79 mmol) in MeOH (4 mL) was added a solution of HCl in MeOH (10 ml, 4 M).The mixture was stirred at RT for 5 min. The mixture was poured into ice-water and adjusted PH=8 with a saturated solution of NaHCO 3 , the mixture was extracted with DCM/MeOH (20 ml*3, 10/1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (DCM: MeOH=10:1) to give (R)-8-(1-aminoethyl)-2-(4-fluorophenyl)-3,6- dimethylquinazolin-4(3H)-one (220 mg, 89.9 %) as a white solid. LCMS: (M + H) + =312.0 [0665] Step 6: To a solution of methyl (R)-8-(1-aminoethyl)-2-(4-fluorophenyl)-3,6-dimethylquinazol in-4(3H)- one (110 mg, 0.36 mmol) in DMSO (5 mL) were added methyl 6-chloro-3-fluoropicolinate (137 mg, 0.72 mmol) and DIEA (139 mg, 1.08 mmol). The mixture was stirred at 100 °C for 2 h. The mixture was diluted with water (30 ml) and extracted with EtOAc (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The cured was purified by silica gel column chromatography (PE: EA=3:1) to give methyl (R)- 6-chloro-3-((1-(2-(4-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-di hydroquinazolin-8-yl)ethyl)amino) picolinate (130 mg, 75.0 %) as a yellow oil. LCMS: (M + H) + =481.2 [0666] Step 7: To a solution of methyl (R)-6-chloro-3-((1-(2-(4-fluorophenyl)-3,6-dimethyl-4-oxo-3, 4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (130 mg, 0.27 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (65 mg, 2.70 mmol). The mixture was stirred at 50 °C for 1 hour. The mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM (20 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to give (R)-6-chloro-3-((1-(2-(4- fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl) ethyl)amino)picolinic acid (83.4 mg, 66.3%) as a white solid. LCMS: (M + H) + =467.1 EXAMPLE 86 (R)-6-chloro-3-((1-(2-(2-fluorophenyl)-3,6-dimethyl-4-oxo-3, 4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0667] Step 1: To a mixture of 2-amino-3-bromo-N,5-dimethylbenzamide (1.5 g, 6.2 mmol) in DMSO (30 ml) was added 2-fluorobenzaldehyde (1.15 g, 9.3 mmol). The mixture was stirred at 120 °C under O 2 for 16 h. The mixture was poured into water (150 ml) and stirred for 0.5 hour, the mixture was filtered and the cake was washed with water (20 ml*3), the cake was dried under reduce pressure to afford 8-bromo-2-(2-fluorophenyl)-3,6- dimethylquinazolin-4(3H)-one (1.0 g, 48%) as a yellow solid. LCMS: (M+H) + = 347.0 [0668] Step 2: To a mixture of 8-bromo-2-(2-fluorophenyl)-3,6-dimethylquinazolin-4(3H)-one (1.0 g, 2.9 mmol) and tributyl(1-ethoxyvinyl)stannane (2.1 g, 5.8 mmol) in 1.4-dioxane (30 ml) was added Pd(PPh 3 ) 2 Cl 2 (204 mg, 0.29 mmol). The mixture was heated to 100 °C and stirred under N 2 for 6 h. HCl (6 ml, 1 M) was added into the mixture and stirred at 50 °C for 0.5 hour, then a saturated solution of KF (40 ml) and stirred at rt for 0.5 hour. The gray suspension was filtered. The filter cake was washed with EtOAc (50 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (PE: EA= 4: 1) to afford 8-acetyl-2-(2-fluorophenyl)-3,6-dimethylquinazolin-4(3H)-one (800 mg, 89%) as a yellow solid. LCMS: (M + H) + = 311.1 [0669] Step 3: To a mixture of 8-acetyl-2-(2-fluorophenyl)-3,6-dimethylquinazolin-4(3H)-one (800 mg, 2.58 mmol) and (R)-2-methylpropane-2-sulfinamide (624 mg, 5.16 mmol) in THF (15 ml) was added Ti(i-PrO) 4 (15 ml). the mixture was stirred at 75 °C under N 2 for 16 h. The mixture was diluted with EtOAc (50 ml) and a saturated solution of NaCl (50 ml) was added, the mixture was stirred at RT for 0.5 hour. The resulting mixture was filtered and the filter cake was washed with EtOAc (30 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)-N-(1-(2-(2-fluorophenyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (900 mg, 90% yield) as a yellow oil for the next step without further purification. LCMS: (M + H) + = 414.0 [0670] Step 4: To a solution of (R,Z)-N-(1-(2-(2-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydr oquinazolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (900 mg, 2.18 mmol) in THF (20 ml) at 0°C was added a solution of LiBH 4 in THF (2.18 ml, 2.18 mmol, 1 M) slowly. The mixture was stirred at 0°C for 0.5 hour. A saturated solution of NH 4 Cl (40 ml) was added and the mixture was extracted with EtOAc (30 ml * 3), the combined organic phase was washed with brine, dried with Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (method A) to afford (R)-N-((R)-1-(2-(2-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihy droquinazolin-8-yl)ethyl)-2- methylpropane-2-sulfinamide (250 mg, 28% yield) as a white solid. LCMS: (M + H) + = 416.0 [0671] Step 5: A mixture of (R)-N-((R)-1-(2-(2-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihy droquinazolin-8- yl)ethyl)-2-methylpropane-2-sulfinamide (250 mg, 0.6 mmol) in a solution of HCl in MeOH (5 ml, 4 M) was stirred at RT for 10 min. the mixture was poured into ice-water and adjusted pH = 8-9 with a saturated solution of NaHCO 3 , the mixture was extracted with DCM/MeOH (20 ml*5, 10/1), the combined organic phase was dried over Na 2 SO 4 and concentrated to afford (R)-8-(1-aminoethyl)-2-(2-fluorophenyl)-3,6-dimethylquinazol in-4(3H)- one (170 mg, 91%) as a yellow solid.LCMS: (M + H) + = 312.1 [0672] Step 6: To a mixture of (R)-8-(1-aminoethyl)-2-(2-fluorophenyl)-3,6-dimethylquinazol in-4(3H)-one (100 mg, 0.32 mmol) and methyl 6-chloro-3-fluoropicolinate (91 mg, 0.48 mmol) in DMSO (5 ml) was added DIPEA (83 mg, 0.64 mmol), the mixture was heated to 90 °C overnight. Cooling to RT, water (30 ml) was added and the mixture was extracted with EtOAc (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-TLC (PE:EA = 4:1) to afford methyl (R)-6-chloro-3- ((1-(2-(2-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinaz olin-8-yl)ethyl)amino)picolinate (70 mg, 45%) as a yellow solid.LCMS: (M + H) + =481.1 [0673] Step 7: To a mixture of methyl (R)-6-chloro-3-((1-(2-(2-fluorophenyl)-3,6-dimethyl-4-oxo-3, 4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (70 mg, 0.15 mmol) in THF (1 ml), MeOH (1 ml) and H 2 O (1 ml) was added LiOH (18 mg, 0.75 mmol). The mixture was stirred at RT for 3 h. The mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM (20 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to afford (R)-6-chloro-3-((1-(2- (2-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid (25.8 mg, 38%) as a white solid. LCMS: (M + H) + =467.1 EXAMPLE 87 (R)-6-chloro-3-((1-(2-(3-pyridyl)-3,6-dimethyl-4-oxo-3,4-dih ydroquinazolin-8-yl)ethyl)amino)picolinic acid [0674] Step 1: To a mixture of 2-amino-3-bromo-N,5-dimethylbenzamide (2.42 g, 10 mmol), nicotinic acid (1.85 g, 15 mmol) and a solution of T 3 P in EtOAc (19 g, 30 mmol, 50% in EtOAc) was added DIPEA (3.87 g, 30 mmol), the mixture was heated to 120 °C and stirred for 10 min, then P 2 O 5 (4.26 g, 30 mmol) was added and the mixture was stirred for 20 min. the mixture was poured into ice-water and stirred at RT for 1 hour. The gray was filtrated and the cake was washed with water (30 ml*3), the collected solid was dried under reduced pressure to afford – bromo-3,6-dimethyl-2-(pyridin-3-yl)quinazolin-4(3H)-one (1.5 g, 46%) as a yellow solid. LCMS: (M + H) + =330.0 [0675] Step 2: To a mixture of 8-bromo-3,6-dimethyl-2-(pyridin-3-yl)quinazolin-4(3H)-one (1.5 g, 4.56 mmol), and tributyl(1-ethoxyvinyl)stannane (3.31 g, 9.12 mmol) in 1.4-dioxane (100 ml) was added Bis(tri-tert- butylphosphine)palladium(0) (234 mg, 0.456 mmol). The mixture was heated to 100 °C and stirred under N 2 for 4 h. HCl (5 ml, 1 M) was added into the mixture and stirred at 50 °C for 0.5 hour, then a saturated solution of KF (40 ml) and stirred at RT for 0.5 hour. The gray suspension was filtered. The filter cake was washed with EtOAc (50 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (PE: EA= 3: 1) to afford 8-acetyl-3,6-dimethyl-2- (pyridin-3-yl)quinazolin-4(3H)-one (1.0 g, 75%) as a white solid. LCMS: (M + H) + = 294.0 [0676] Step 3: To a mixture of 8-acetyl-3,6-dimethyl-2-(pyridin-3-yl)quinazolin-4(3H)-one (900 mg, 3.07 mmol) and (R)-2-methylpropane-2-sulfinamide (743 mg, 6.14 mmol) in THF (20 ml) was added Ti(i-PrO) 4 (30 ml). the mixture was stirred at 75 °C under N 2 for 16 h. The mixture was diluted with EtOAc (50 ml) and a saturated solution of NaCl (50 ml) was added, the mixture was stirred at RT for 0.5 hour. The resulting mixture was filtered and the filter cake was washed with EtOAc (30 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)-N-(1-(3,6-dimethyl-4-oxo-2-(pyridin-3-yl)-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (1.22 g, 100% yield) as a yellow oil for the next step without further purification. LCMS: (M + H) + = 397.0 [0677] Step 4: To a solution of crude (R,Z)-N-(1-(3,6-dimethyl-4-oxo-2-(pyridin-3-yl)-3,4-dihydroq uinazolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (987 mg, 2.49 mmol) in THF (20 ml) at 0°C was added a solution of LiBH 4 in THF (2.5 ml, 2.5 mmol, 1 M) slowly. The mixture was stirred at 0°C for 1 hour. A saturated solution of NH 4 Cl (40 ml) was added and the mixture was extracted with EtOAc (30 ml * 3), the combined organic phase was washed with brine, dried with Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (method A) to afford (R)-N-((R)-1-(3,6-dimethyl-4-oxo-2-(pyridin-3-yl)-3,4-dihydr oquinazolin-8-yl)ethyl)-2-methylpropane-2- sulfinamide (140 mg, 14% yield) as a white solid. LCMS: (M + H) + = 399.0 [0678] Step 5: A mixture of (R)-N-((R)-1-(3,6-dimethyl-4-oxo-2-(pyridin-3-yl)-3,4-dihydr oquinazolin-8-yl)ethyl)- 2-methylpropane-2-sulfinamide (140 mg, 0.35 mmol) in a solution of HCl in MeOH (5 ml, 4 M) was stirred at RT for 10 min. the mixture was poured into ice-water and adjusted pH = 8-9 with a saturated solution of NaHCO 3 , the mixture was extracted with DCM/MeOH (20 ml*5, 10/1), the combined organic phase was dried over Na 2 SO 4 and concentrated to afford (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(pyridin-3-yl)quinazolin -4(3H)-one (100 mg, 97%) as a yellow solid. LCMS: (M + H) + = 295.0 [0679] Step 6: To a mixture of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(pyridin-3-yl)quinazolin -4(3H)-one (100 mg, 0.34 mmol) and methyl 6-chloro-3-fluoropicolinate (96 mg, 0.51 mmol) in DMSO (5 ml) was added DIPEA (88 mg, 0.68 mmol), the mixture was heated to 90 °C overnight. Cooling to RT, water (30 ml) was added and the mixture was extracted with EtOAc (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-TLC (PE:EA = 1:1) to afford methyl (R)-6-chloro-3- ((1-(3,6-dimethyl-4-oxo-2-(pyridin-3-yl)-3,4-dihydroquinazol in-8-yl)ethyl)amino)picolinate (100 mg, 64%) as a yellow solid. LCMS: (M + H) + =464.1 [0680] Step 7: To a mixture of methyl (R)-6-chloro-3-((1-(3,6-dimethyl-4-oxo-2-(pyridin-3-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (100 mg, 0.22 mmol) in THF (2 ml), MeOH (2 ml) and H 2 O (2 ml) was added LiOH (26 mg, 1.1 mmol). The mixture was stirred at RT for 3 h. The mixture was adjusted to pH = 4- 5 with 1 M HCl and extracted with DCM (20 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to afford (R)-6-chloro-3-((1-(2- (pyridine-3-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-y l)ethyl)amino)picolinic acid (59.3 mg, 60%) as a white solid. LCMS: (M + H) + =450.1 EXAMPLE 88 (R)-6-chloro-3-((1-(6-cyano-2-(4,4-difluoropiperidin-1-yl)-3 -methyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0681] Step 1: To a solution of (R)-8-(1-aminoethyl)-6-chloro-2-(4,4-difluoropiperidin-1-yl) -3-methylquinazolin- 4(3H)-one (300 mg, 0.841 mmol,) in DCM (5 mL) was added di-tert-butyl piperidine (275 mg, 1.262 mmol) and TEA (255 mg, 2.523 mmol) at 0 °C. The mixture was stirred at RT for 1 hour. The mixture was diluted with water (40 mL) and extracted with DCM (50 mL×3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The cured was purified by silica gel column chromatography (PE: EA=6：1) to give tert-butyl (R)-(1-(6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methyl-4-o xo-3,4-dihydroquinazolin-8-yl)ethyl)carbamate (300 mg, 78.1 %) as a yellow solid. LCMS: (M + H) + =457.1 [0682] Step 2: To a solution of tert-butyl (R)-(1-(6-chloro-2-(4,4-difluoropiperidin-1-yl)-3-methyl-4-o xo-3,4- dihydroquinazolin-8-yl)ethyl)carbamate (300 mg, 0.657 mmol) in DMF (5 mL) were added Ruphos G4 (56 mg, 0.066 mmol) and Zn(CN) 2 (154 mg, 1.314 mmol). The mixture was stirred in a microwave under N 2 at 100 °C for 1 hour. Cooling to RT, water (40 mL) was added and the mixture was with EtOAc (40 mL×3). The combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated, the residue was purified by silica gel column chromatography (PE: EA=3：1) to give tert-butyl (R)-(1-(6-cyano-2-(4,4-difluoropiperidin-1-yl)-3-methyl- 4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)carbamate (280 mg, 95.2 %) as a yellow solid. LCMS: (M + H) + =448.0 [0683] Step 3: A mixture of tert-butyl (R)-(1-(6-cyano-2-(4,4-difluoropiperidin-1-yl)-3-methyl-4-ox o-3,4- dihydroquinazolin-8-yl)ethyl)carbamate (280 mg, 0.626 mmol) and TFA (3 ml) was stirred at RT for 1 hour. The mixture was poured into ice-water and adjusted PH=8 with a saturated solution of NaHCO 3 , the mixture was extracted with DCM/MeOH (50 ml*3, 10/1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (DCM: MeOH=10:1) to give (R)-8-(1-aminoethyl)-2-(4,4-difluoropiperidin-1-yl)-3-methyl -4-oxo-3,4-dihydroquinazoline-6-carbonitrile(200 mg, 92.0 %) as a white solid. LCMS: (M + H) + = 348.0 [0684] Step 4: To a solution of methyl (R)-8-(1-aminoethyl)-2-(4,4-difluoropiperidin-1-yl)-3-methyl -4-oxo-3,4- dihydroquinazoline-6-carbonitrile (100 mg, 0.288 mmol) in DMSO (5 mL) were added methyl methyl 6-chloro-3- fluoropicolinate (82 mg, 0.432 mmol) and DIEA (111 mg, 0.864 mmol). The mixture was stirred at 100 °C for 2 h. The mixture was diluted with water (30 ml) and extracted with EtOAc (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (PE: EA=4:1) to give the target methyl (R)-6-chloro-3-((1-(6-cyano-2-(4,4-difluoropiperidin-1-yl)- 3-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picoli nate (60 mg, 40.2 %) as a yellow solid. LCMS: (M + H) + =517.1 [0685] Step 5: To a solution of methyl (R)-6-chloro-3-((1-(6-cyano-2-(4,4-difluoropiperidin-1-yl)-3 -methyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino) picolinate (60 mg, 0.116 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (28 mg, 1.16 mmol). The mixture was stirred at 50 °C for 1 hour. The mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM (20 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to give (R)-6-chloro-3-((1-(6- cyano-2-(4,4-difluoropiperidin-1-yl)-3-methyl-4-oxo-3,4-dihy droquinazolin-8-yl)ethyl)amino)picolinic acid (20.1 mg, 34.5 %) as a white solid. LCMS: (M + H) + =503.1 EXAMPLE 89 (R)-6-chloro-3-((1-(3,6-dimethyl-4-oxo-2-(pyridin-2-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinic acid [0686] Step 1: To a mixture of 2-amino-3-bromo-N,5-dimethylbenzamide (2.42 g, 10 mmol), picolinic acid (1.85 g, 15 mmol) and a solution of T 3 P in EtOAc (19 g, 30 mmol, 50% in EtOAc) was added DIPEA (3.87 g, 30 mmol), the mixture was heated to 120 °C and stirred for 10 min, then P 2 O 5 (4.26 g, 30 mmol) was added and the mixture was stirred for 20 min. the mixture was poured into ice-water and stirred at RT for 1 hour. The gray was filtrated and the cake was washed with water (30 ml*3), the collected solid was dried under reduced pressure to afford 8- bromo-3,6-dimethyl-2-(pyridin-2-yl)quinazolin-4(3H)-one (1.6 g, 49%) as a yellow solid. LCMS: (M + H) + =330.0 [0687] Step 2: To a mixture of 8-bromo-3,6-dimethyl-2-(pyridin-2-yl)quinazolin-4(3H)-one (1.6 g, 4.9 mmol), and tributyl(1-ethoxyvinyl)stannane (3.47 g, 9.6 mmol) in 1.4-dioxane (50 ml) was added Bis(tri-tert- butylphosphine)palladium(0) (251 mg, 0.49 mmol). The mixture was heated to 100 °C and stirred under N 2 for 4 h. HCl (5 ml, 1 M) was added into the mixture and stirred at 50 °C for 0.5 hour, then a saturated solution of KF (40 ml) and stirred at RT for 0.5 hour. The gray suspension was filtered, the filter cake was washed with EtOAc (50 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (PE: EA= 3: 1) to afford 8-acetyl-3,6-dimethyl-2- (pyridin-2-yl)quinazolin-4(3H)-one (980 mg, 68%) as a white solid. LCMS: (M + H) + = 294.1 [0688] Step 3: To a mixture of 8-acetyl-3,6-dimethyl-2-(pyridin-2-yl)quinazolin-4(3H)-one (980 mg, 3.34 mmol) and (R)-2-methylpropane-2-sulfinamide (808 mg, 6.68 mmol) in THF (20 ml) was added Ti(i-PrO) 4 (20 ml). the mixture was stirred at 75 °C under N 2 for 16 h. The mixture was diluted with EtOAc (50 ml) and a saturated solution of NaCl (50 ml) was added, the mixture was stirred at RT for 0.5 hour. The resulting mixture was filtered and the filter cake was washed with EtOAc (30 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)-N-(1-(3,6-dimethyl-4-oxo-2-(pyridin-2-yl)-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (1.32 g, 100% yield) as a yellow oil for the next step without further purification. LCMS: (M + H) + = 397.0 [0689] Step 4: To a solution of crude (R,Z)-N-(1-(3,6-dimethyl-4-oxo-2-(pyridin-2-yl)-3,4-dihydroq uinazolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (1.32 g, 3.34 mmol) in EtOH (20 ml) at 0°C was added a solution of LiBH 4 in THF (6.68 ml, 6.68 mmol, 1 M) dropwise. The mixture was stirred at 0°C for 1 hour. A saturated solution of NH 4 Cl (40 ml) was added and the mixture was extracted with EtOAc (50 ml * 3), the combined organic phase was washed with brine, dried with Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (method A) to afford (R)-N-((R)-1-(3,6-dimethyl-4-oxo-2-(pyridin-2-yl)-3,4-dihydr oquinazolin-8-yl)ethyl)-2-methylpropane-2- sulfinamide (200 mg, 16% yield) as a white solid. LCMS: (M + H) + = 399.0 [0690] Step 5: A mixture of (R)-N-((R)-1-(3,6-dimethyl-4-oxo-2-(pyridin-2-yl)-3,4-dihydr oquinazolin-8-yl)ethyl)- 2-methylpropane-2-sulfinamide (200 mg, 0.5 mmol) in a solution of HCl in MeOH (3 ml, 4 M) was stirred at RT for 10 min. the mixture was poured into ice-water and adjusted pH = 8-9 with a saturated solution of NaHCO 3 , the mixture was extracted with DCM/MeOH (20 ml*5, 10/1), the combined organic phase was dried over Na 2 SO 4 and concentrated to afford (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(pyridin-2-yl)quinazolin -4(3H)-one (140 mg, 95%) as a yellow oil. LCMS: (M + H) + = 295.0 [0691] Step 6: To a mixture of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(pyridin-2-yl)quinazolin -4(3H)-one (140 mg, 0.48 mmol) and methyl 6-chloro-3-fluoropicolinate (136 mg, 0.72 mmol) in DMSO (5 ml) was added DIPEA (186 mg, 1.44 mmol), the mixture was heated to 90 °C overnight. Cooling to RT, water (30 ml) was added and the mixture was extracted with EtOAc (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-TLC (PE : EA = 1:1) to afford methyl (R)-6-chloro-3- ((1-(3,6-dimethyl-4-oxo-2-(pyridin-2-yl)-3,4-dihydroquinazol in-8-yl)ethyl)amino)picolinate (126 mg, 57%) as a yellow solid. LCMS: (M + H) + =464.1 [0692] Step 7: To a mixture of methyl (R)-6-chloro-3-((1-(3,6-dimethyl-4-oxo-2-(pyridin-2-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (126 mg, 0.27 mmol) in THF (2 ml), MeOH (2 ml) and H 2 O (2 ml) was added LiOH (26 mg, 1.08 mmol). The mixture was stirred at RT for 3 h. The mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM (20 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to afford (R)-6-chloro-3-((1- (3,6-dimethyl-4-oxo-2-(pyridin-2-yl)-3,4-dihydroquinazolin-8 -yl)ethyl)amino)picolinic acid (100 mg, 83%) as a white solid. LCMS: (M + H) + =450.1 EXAMPLE 90 (R)-6-chloro-3-((1-(2-(4,4-difluoropiperidin-1-yl)-6-ethynyl -3-methyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0693] Step 1: To a solution of 2-amino-3-bromobenzoic acid (4.3 g, 19.90 mmol) in DCM (50 mL) was added N-(l2-iodaneylidene)thiohydroxylamine (4.9 g, 21.89 mmol). The mixture was stirred at 100 °C for 2 h. The mixture was diluted with water (100 ml) and extracted with DCM (100 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The cured was purified by silica gel column chromatography (DCM: MeOH=10:1) to give 2-amino-3-bromo-5-iodobenzoic acid (6.0 g, 88.2 %) as a red solid. LCMS: (M + H) + =342.0 [0694] Step 2: To a solution of 2-amino-3-bromo-5-iodobenzoic acid (6 g, 17.55 mmol) in DCM (500 mL) were added MeNH 2 .HCl (1.42 g, 21.06 mmol), HATU (6.41 g, 16.85 mmol) and DIPEA (5.44 g, 42.11 mmol). The mixture was stirred at RT for 3 h. The mixture was diluted with water (200 ml) and extracted with DCM (300 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The cured was purified by silica gel column chromatography (PE: EA=4:1) to give 2-amino-3-bromo-5-iodo-N-methylbenzamide (4.0 g, 64.2 %) as a yellow solid. LCMS: (M + H) + =355.0 [0695] Step 3. To a solution of 2-amino-3-bromo-5-iodo-N-methylbenzamide (3.54 g, 9.97 mmol) in dioxane (50 mL) was added thiophosgene (2.29 g, 19.95 mmol). The mixture was stirred at RT for 1 hour. Then the mixture was stirred at 105 °C for 1 hour. The mixture was concentrated. The residue was dissolved in DCM (50 ml) and then 4,4-difluoropiperidine (2.42 g, 19.95 mmol) and DIEA (3.87 g, 29.92 mmol) were added. The mixture was stirred at 40 °C overnight. Water (50 ml) was added and the mixture was extracted with DCM (100 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (PE: EA = 5:1) to give 8-bromo-2-(4,4-difluoropiperidin-1-yl)-6- iodo-3-methylquinazolin-4(3H)-one (4.0 g, 82.8 %) as a yellow solid. LCMS: (M + H) + =484.0 [0696] Step 4: To a solution of 8-bromo-2-(4,4-difluoropiperidin-1-yl)-6-iodo-3-methylquinaz olin-4(3H)-one (4.0 g, 8.26 mmol) in DMF (100 mL) were added ethynyltrimethylsilane (1.22 g, 12.40 mmol), Pd(PPh 3 ) 2 Cl 2 (579 mg, 0.83 mmo), CuI (157 mg, 0.83 mmol) and TEA (2.51 g, 24.789 mmol). The mixture was stirred at 100 °C under N 2 for 16 h. The mixture was diluted with water (500 ml) and extracted with EtOAc (100 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The cured was purified by silica gel column chromatography (PE: EA=4:1) to give 8-bromo-2-(4,4-difluoropiperidin-1-yl)-3-methyl-6- ((trimethylsilyl)ethynyl)quinazolin-4(3H)-one (3.5 g, 6.60 mmol, yields=79.9 %). LCMS: (M + H) + =454.0 [0697] Step 5: To a mixture of 8-bromo-2-(4,4-difluoropiperidin-1-yl)-3-methyl-6- ((trimethylsilyl)ethynyl)quinazolin-4(3H)-one (3.5 g, 6.60 mmol) and tributyl(1-ethoxyvinyl)stannane (2.86 g, 7.99 mmol) in dioxane (30 ml) was added Pd(PPh 3 ) 2 Cl 2 (463 mg, 0.66 mmol,). The mixture was stirred at 95 °C under N 2 for 16 h. HCl (7.0 ml, 1 M) was added into the mixture and the mixture was stirred at 50 °C for 0.5 hour, then 50 ml sat KF was added and the mixture was stirred at RT for 0.5 hour. The gray was filtered, the filter cake was washed with EtOAc (100 ml*3), the separated aqueous phase was extracted with EtOAc (100 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 3:1) to give the target 8-acetyl-2-(4,4-difluoropiperidin-1-yl)-3-methyl-6- ((trimethylsilyl)ethynyl) quinazolin-4(3H)-one (1.9 g, 68.9%) as a yellow solid.LCMS: (M + H) + =418.1 [0698] Step 6: To a mixture of 8-acetyl-2-(4,4-difluoropiperidin-1-yl)-3-methyl-6- ((trimethylsilyl)ethynyl)quinazolin-4(3H)-one (1.9 g, 4.55 mmol) and (R)-2-methylpropane-2-sulfinamide (1.10 g, 9.10 mmol) in THF (20 ml) at RT was added Ti(i-PrO) 4 (20 ml). The mixture was stirred at 75 °C for 12 h. Cooling to RT, brine (50 ml) was added and the mixture was stirred for 0.5 hour. The resulting mixture was filtrated and the cake was washed with EtOAc (40 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)-N-(1-(2-(4,4-difluoropiperidin-1-yl)-3-methyl-4-oxo-6- ((trimethylsilyl)ethynyl)-3,4-dihydroquinazolin-8-yl)ethylid ene)-2-methylpropane-2-sulfinamide (2.0 g) as a yellow oil for the next step without further purification. LCMS: (M + H) + = 521.0 [0699] Step 7: To a solution of (R,Z)-N-(1-(2-(4,4-difluoropiperidin-1-yl)-3-methyl-4-oxo-6- ((trimethylsilyl)ethynyl)-3,4-dihydroquinazolin-8-yl)ethylid ene)-2-methylpropane-2-sulfinamide (2.0 g, 3.84 mmol) in DCM (20 mL) and MeOH(20 mL) were added NaBH 3 CN (484 mg, 7.68 mmol) and HOAc (0.2 mL) at 0 °C. The mixture was stirred at RT for 2 h. The mixture was diluted with saturated NH 4 Cl solution (20 ml) and extracted with DCM (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (method A) to give (R)-N-((R)-1-(2-(4,4-difluoropiperidin-1-yl)-3-methyl-4- oxo-6-((trimethylsilyl)ethynyl)-3,4-dihydroquinazolin-8-yl)e thyl)-2-methylpropane-2-sulfinamide (1.8 g, 89.5%) as a white solid. LCMS: (M + H) + = 523.0 [0700] Step 8: To a solution of (R)-N-((R)-1-(2-(4,4-difluoropiperidin-1-yl)-3-methyl-4-oxo- 6- ((trimethylsilyl)ethynyl)-3,4-dihydroquinazolin-8-yl)ethyl)- 2-methylpropane-2-sulfinamide (1.8 g, 3.44 mmol) in MeOH (4 mL) was added a solution of HCl in MeOH (20 ml, 4 M).The mixture was stirred at RT for 30 min. The mixture was poured into ice-water and adjusted PH=8 with a saturated solution of NaHCO 3 , the mixture was extracted with DCM/MeOH (100 ml*3, 10/1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (DCM: MeOH=10:1) to afford (R)-8-(1-aminoethyl)-2-(4,4-difluoropiperidin-1-yl)-3-methyl -6-((trimethylsilyl)ethynyl)quinazolin-4(3H)-one (1.2 g, 83.4 %) as a white solid.LCMS: (M + H) + =419.1 [0701] Step 9: To a solution of (R)-8-(1-aminoethyl)-2-(4,4-difluoropiperidin-1-yl)-3-methyl -6- ((trimethylsilyl)ethynyl)quinazolin-4(3H)-one (150 mg, 0.36 mmol) in DMSO (5 mL) were added methyl methyl 6- chloro-3-fluoropicolinate (137 mg, 0.72 mmol) and DIEA (139 mg, 1.08 mmol). The mixture was stirred at 100 °C for 2 h. The mixture was diluted with water (30 ml) and extracted with EtOAc (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (PE: EA=4:1) to give methyl (R)-6-chloro-3-((1-(2-(4,4-difluoropiperidin-1-yl)-3-methyl- 4- oxo-6-((trimethylsilyl)ethynyl)-3,4-dihydroquinazolin-8-yl)e thyl)amino)picolinate (80 mg, 10.1 %) as a yellow oil.LCMS: (M + H) + =516.2 [0702] Step 10: To a solution of methyl (R)-6-chloro-3-((1-(2-(4,4-difluoropiperidin-1-yl)-3-methyl- 4-oxo-6- ((trimethylsilyl)ethynyl)-3,4-dihydroquinazolin-8-yl)ethyl)a mino) picolinate (80 mg, 0.14 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (34 mg, 1.40 mmol). The mixture was stirred at RT for 3 h. The mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM (20 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to give (R)-6- chloro-3-((1-(2-(4,4-difluoropiperidin-1-yl)-6-ethynyl-3-met hyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid (33.7 mg, 47.9 %) as a white solid.LCMS: (M + H) + =502.1 EXAMPLE 91 (R)-6-chloro-3-((1-(2-(2-cyanopropan-2-yl)-3,6-dimethyl-4-ox o-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0703] Step 1: To a solution of 2-amino-3-bromo-N,5-dimethylbenzamide (1.76 g, 7.24 mmol) in THF (100 mL) were added DIEA (5 mL), 2-cyano-2-methylpropanoic acid (930 mg, 8.22 mmol) and CMPI (4.79 g, 18.75 mmol) at RT. The mixture was stirred at 70 °C for 18 h. The mixture was concentrated to remove THF, water (150 mL) was added and the mixture was extracted with EtOAc (150 mL×2). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was washed with cool EtOAc (15 mL×2) and filtered to give 3-bromo-2-(2-cyano-2-methylpropanamido)-N,5-dimethylbenzamid e (1500 mg, 61.2 %) as a white solid. LCMS: (M + H) + =338.1 [0704] Step 2: To a solution of 3-bromo-2-(2-cyano-2-methylpropanamido)-N,5-dimethylbenzamid e (1.4 mg, 4.139 mmol) in DCM (60 mL) were added HMDS (2.0 g, 12.392 mmol) and I2 (1.1 g, 4.334 mmol) at RT. The mixture was stirred at 50 °C for 96 h. After cooling with ice bath, the mixture was added saturated aqueous Na 2 S 2 O 3 solution (80 mL×2), the organic layer war washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by silica gel column chromatography (DCM: EA=10:1) to give 2-(8-bromo-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-2- methylpropanenitrile (960 mg, 72.4 %) as a white solid. LCMS: (M + H) + =319.9 [0705] Step 3: To a solution of 2-(8-bromo-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-2- methylpropanenitrile (960 mg, 2.998 mmol) in dioxane (35 mL) were added tributyl(1-ethoxyvinyl)stannane (2.2 g, 6.091 mmol) and Pd(PPh 3 ) 2 Cl 2 (230 mg, 0.328 mmol) at RT. The mixture was stirred at 100 °C for 16 h under N 2 . The mixture was added HCl (3 mL, 1M) and stirred at 50 °C for 0.5 hour. The mixture was added saturated aqueous KF solution (15 mL) and stirred at RT for 0.5 hour. The gray suspension was filtered. The filter cake was washed with H 2 O (10 mL×2) and EtOAc (20 mL×2). The aqueous phase was extracted with EA (120 ml). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by silica gel column chromatography (DCM: EA=10:1) to give 2-(8-acetyl-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylpropaneni trile (810 mg, 95.4 %) as a white solid. LCMS: (M + H) + =284.0 [0706] Step 4: To a solution of 2-(8-acetyl-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-2 - methylpropanenitrile (810 mg, 2.859 mmol) in THF (10 mL) were added (R)-2-methylpropane-2-sulfinamide (700 mg, 5.775 mmol) and Ti(Oi-Pr) 4 (10 mL) at RT. The mixture was stirred at 75 °C for 16 h under N 2 . After cooling with ice bath, the mixture was added saturated aqueous NaCl solution (16 mL) and stirred at RT for 5 mins. The suspension was filtered. The filter cake was washed with H 2 O (10 mL×2) and EtOAc (20 mL×2). The aqueous phase was extracted with EtOAc (100 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give crude (R,Z)-N-(1-(2-(2-cyanopropan-2-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (1.1 g, 99.5 %) as a red solid. LCMS: (M + H) + =387.0 [0707] Step 5: To a solution of crude (R,Z)-N-(1-(2-(2-cyanopropan-2-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (1.1 g, 2.846 mmol) in MeOH (12 mL) were added DCM (12 mL), AcOH (1.4 mL) and NaBH 3 CN (530 mg, 8.434 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour. The mixture was added with aqueous NH 4 Cl solution (12 mL) and extracted with DCM (100 mL×2), the combined organic layers were washed with H 2 O (80 mL) and then brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by Prep-HPLC (method A) to give (R)-N-((R)-1-(2-(2- cyanopropan-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8 -yl)ethyl)-2-methylpropane-2-sulfinamide (700 mg, 63.3 %) as a white solid. LCMS: (M + H) + =389.0 [0708] Step 6: To a solution of (R)-N-((R)-1-(2-(2-cyanopropan-2-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin- 8-yl)ethyl)-2-methylpropane-2-sulfinamide (700 mg, 1.802 mmol) in MeOH (10 mL) was added HCl (4 mL, 3M in MeOH) at RT. The mixture was stirred at RT for 1 hour. The mixture was neutralized with aqueous NaHCO 3 solution to pH = 8 and extracted with DCM (100 mL×2), the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give (R)-2-(8-(1-aminoethyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-2-yl)-2-methylpropanenitrile (500 mg, 97.5 %) as a yellow solid. LCMS: (M + H) + =285.0 [0709] Step 7: To a solution of (R)-2-(8-(1-aminoethyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinaz olin-2-yl)-2- methylpropanenitrile (150 mg, 0.528 mmol) in DMSO (4 mL) were added methyl 6-chloro-3-fluoropicolinate (140 mg, 0.739 mmol) and DIEA (0.4 mL). The mixture was stirred at 100 °C for 4 h. After cooling to RT, water (40 mL) was added and the mixture was extracted with EtOAc (40 mL×2). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by silica gel column chromatography (PE: EA=1:1) to give methyl (R)-6-chloro-3-((1-(2-(2-cyanopropan-2-yl)-3,6-dimethyl- 4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinate (200 mg, 83.5 %) as a colorless oil. LCMS: (M + H) + = 454.0 [0710] Step 8: To a solution of methyl (R)-6-chloro-3-((1-(2-(2-cyanopropan-2-yl)-3,6-dimethyl-4-ox o-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (200 mg, 0.441 mmol) in THF (4 mL) were added H 2 O (4 mL) and LiOH•H 2 O (50 mg, 1.192 mmol) at RT. The mixture was stirred at RT for 0.5 hour. The mixture was neutralized with HCl (1M) to pH = 6. The mixture was purified by Prep-HPLC (method B) to give (R)-6-chloro-3-((1-(2-(2- cyanopropan-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8 -yl)ethyl)amino)picolinic acid (95 mg, 49.0 %) as a white solid. LCMS: (M + H) + = 440.1 EXAMPLE 92 (R)-2-((1-(2-cyclopentyl-3,6-dimethyl-4-oxo-3,4-dihydroquina zolin-8-yl)ethyl)amino)benzoic acid [0711] Step1: To a mixture of (R)-8-(1-aminoethyl)-2-cyclopentyl-3,6-dimethylquinazolin-4( 3H)-one (200 mg, 0.7 mmol), methyl 2-iodobenzoate (367 mg, 1.4 mmol) and Cs 2 CO 3 (456 mg, 1.4 mmol) in dioxane (10 ml) were added Pd 2 (dba) 3 (128 mg, 0.14 mmol) and XantPhos (161 mg, 0.28 mmol). The mixture was stirred at 100 °C under N 2 for 24 h. Cooling to RT, water (20 ml) was added and the mixture was extracted with DCM (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-TLC (PE:EA = 4:1) to afford methyl (R)-2-((1-(2-cyclopentyl-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate (140 mg, 48%) as a yellow oil. LCMS: (M + H) + =420.3 [0712] Step2: To a mixture of methyl (R)-2-((1-(2-cyclopentyl-3,6-dimethyl-4-oxo-3,4-dihydroquina zolin-8- yl)ethyl)amino)benzoate (140 mg, 0.33 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (79 mg, 3.3 mmol), the mixture was stirred at 50 °C for 4 h. Cooling to RT, the mixture was adjusted to pH = 5-6 with 1 M HCl and extracted with DCM (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (method B) to afford (R)-2-((1-(2-cyclopentyl-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoi c acid (85.4 mg, 64%) as a white solid. LCMS: (M + H)+ =406.2 EXAMPLE 93 (R)-6-chloro-3-((1-(2-cyclobutyl-3,6-dimethyl-4-oxo-3,4-dihy droquinazolin-8-yl)ethyl)amino)picolinic acid [0713] Step 1: To a mixture of 2-amino-3-bromo-N,5-dimethylbenzamide (2.42 g, 10 mmol) and TEA (2.02 g, 15 mmol) in DCM (50 ml) was added cyclobutanecarbonyl chloride (1.77 g, 15 mmol) dropwise. The mixture was stirred at RT overnight. Water (50 ml) was added and the separated aqueous was extracted with DCM (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (DCM: MeOH = 50:1) to afford 3-bromo-2-(cyclobutanecarboxamido)-N,5- dimethylbenzamide (2.5 g, 77%) as a yellow solid. LCMS: (M + H) + =324.9 [0714] Step 2: To a mixture of 3-bromo-2-(cyclobutanecarboxamido)-N,5-dimethylbenzamide (2.5 g, 7.72 mmol) and I 2 (1.96 g, 7.72 mmol) in DCM (50 ml) was added HMDS (3.73 g, 23.16 mmol). The mixture was stirred at 50 °C overnight. Cooling to room tempersature, the mixture was washed with a saturated solution of Na 2 S 2 SO 3 (50 ml*2) and washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE:EA = 5:1) to afford 8-bromo-2-cyclobutyl-3,6-dimethylquinazolin-4(3H)-one (2.1 g, 89%) as a white solid. LCMS: (M + H)+ =307.0 [0715] Step 3: To a mixture of 8-bromo-2-cyclobutyl-3,6-dimethylquinazolin-4(3H)-one (2.1 g, 6.86 mmol) and tributyl(1-ethoxyvinyl)stannane (4.97 g, 13.72 mmol) in dioxane (50 ml) was added Pd(PPh 3 ) 2 Cl 2 (482 mg, 0.686 mmol). The mixture was stirred at 100 °C under N 2 overnight. HCl (7 ml, 1 M) was added into the mixture and stirred at 50 °C for 0.5 hour, then a saturated solution of KF (40 ml) and stirred at RT for 0.5 hour. The gray suspension was filtered. The filter cake was washed with EtOAc (50 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE:EA = 10:1-5:1) to afford 8-acetyl-2-cyclobutyl-3,6-dimethylquinazolin-4(3H)-one (1.7 g, 91%) as a white solid. LCMS: (M + H) + =271.2 [0716] Step 4: To a mixture of 8-acetyl-2-cyclobutyl-3,6-dimethylquinazolin-4(3H)-one (1.7 g, 6.3 mmol) and (R)-2-methylpropane-2-sulfinamide (1.52 g, 12.6 mmol) in THF (50 ml) was added Ti(O-iPr) 4 (17.89 g, 63 mmol), the mixture was stirred at 75 °C for 48 h. Cooling to RT, Brine (100 ml) was added and stirred at RT for 0.5 hour, the mixture was filtrated and the cake was washed with EA (50 ml*3), the separated aqueous was extracted with ethyl acatate (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,E)-N-(1-(2-cyclobutyl-3,6-dimethyl-4-oxo-3,4-dihydroquina zolin-8-yl)ethylidene)- 2-methylpropane-2-sulfinamide (2.35 g, 100%) as a yellow oil for the next step without further purification. LCMS: (M + H)+ =374.0 [0717] Step 5: To a mixture of crude (R,E)-N-(1-(2-cyclobutyl-3,6-dimethyl-4-oxo-3,4-dihydroquina zolin-8- yl)ethylidene)-2-methylpropane-2-sulfin (2.35 g, 6.3 mmol) and HOAc (3.02 g, 50.4 mmol) in DCM (30 ml) and MeOH (30 ml) was added NaBH 3 CN (1.19 g, 18.9 mmol) slowly at 0 °C. the mixture was stirred for 2 h. A saturate solution of NH 4 Cl (100 ml) was added and stirred for 0.5 hour, the separated aqueous was extracted with DCM (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (method A) to afford (R)-N-((R)-1-(2-cyclobutyl-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (800 mg, 34%) as a yellow solid. LCMS: (M + H)+ =376.0 [0718] Step 6: A mixture of (R)-N-((R)-1-(2-cyclobutyl-3,6-dimethyl-4-oxo-3,4-dihydroqui nazolin-8-yl)ethyl)-2- methylpropane-2-sulfinamide (800 mg, 2.13 mmol) in a solution of HCl in MeOH (15 ml, 4 M) was stirred at RT for 10 min. The mixture was poured into ice-water and adjusted PH= 8-9 with a saturate solution of NaHCO 3 , the mixture was extracted with DCM/MeOH (50 ml*3, 10/1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford (R)-8-(1-aminoethyl)-2-cyclobutyl-3,6-dimethylquinazolin-4(3 H)- one (500 mg, 87%) as a yellow solid. LCMS: (M + H)+ =272.0 [0719] Step 7: To a mixture of (R)-8-(1-aminoethyl)-2-cyclobutyl-3,6-dimethylquinazolin-4(3 H)-one (100 mg, 0.37 mmol) and methyl 6-chloro-3-fluoropicolinate (106 mg, 0.56 mmol) in DMSO (5 ml) was added DIPEA (95 mg, 0.74 mmol), the mixture was heated to 90 °C for 3 h. Cooling to RT, water (30 ml) was added and the mixture was extracted with EtOAc (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-TLC (PE:EA = 5:1) to afford methyl (R)-6-chloro-3- ((1-(2-cyclobutyl-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8 -yl)ethyl)amino)picolinate (120 mg, 74%) as a yellow solid. LCMS: (M + H) + =441.1 [0720] Step 8: To a mixture of methyl (R)-6-chloro-3-((1-(2-cyclobutyl-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (120 mg, 0.27 mmol) in MeOH (10 ml) and H 2 O (2 ml) was added LiOH (32 mg, 1.35 mmol). The mixture was stirred at 50 °C for 4 h. The mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to afford (R)-6-chloro-3-((1-(2- cyclobutyl-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)eth yl)amino)picolinic acid (87.3 mg, 76%) as a white solid. LCMS: (M + H) + =427.1 EXAMPLE 94 (R)-6-chloro-3-((1-(3,6-dimethyl-2-(1-methylcyclobutyl)-4-ox o-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0721] Step 1: To a mixture of 2-amino-3-bromo-N,5-dimethylbenzamide (1.7 g, 7 mmol), 1-methylcyclobutane- 1-carboxylic acid (1.2 g, 10.5 mmol) and CMPI (2.68 g, 10.5 mmol) in THF (50 ml) was added DIPEA (1.81 g, 14 mmol). The mixture was stirred at 75 °C overnight. Water (50 ml) was added and the mixture was extracted with EtOAc (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (DCM: MeOH = 50:1) to afford 3-bromo-N,5-dimethyl-2-(1- methylcyclobutane-1-carboxamido)benzamide (2.0 g, 84%) as a yellow solid. LCMS: (M + H) + =339.0 [0722] Step 2: To a mixture of 3-bromo-N,5-dimethyl-2-(1-methylcyclobutane-1-carboxamido)be nzamide (2.0 g, 5.92 mmol) and I 2 (1.50 g, 5.92 mmol) in DCM (50 ml) was added HMDS (2.86 g, 17.76 mmol). The mixture was stirred at 50 °C for 3 h. Cooling to RT, the mixture was washed with a saturated solution of Na 2 S 2 SO 3 (50 ml*2) and washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE:EA = 5:1) to afford 8-bromo-3,6-dimethyl-2-(1-methylcyclobutyl)quinazolin-4(3H)- one (1.8 g, 95%) as a white solid. LCMS: (M + H)+ =321.1 [0723] Step 3: To a mixture of 8-bromo-3,6-dimethyl-2-(1-methylcyclobutyl)quinazolin-4(3H)- one (1.8 g, 5.6 mmol) and tributyl(1-ethoxyvinyl)stannane (4.05 g, 11.2 mmol) in dioxane (30 ml) was added Pd(PPh 3 ) 2 Cl 2 (393 mg, 0.56 mmol). The mixture was stirred at 100 °C under N 2 overnight. HCl (6 ml, 1 M) was added into the mixture and stirred at 50 °C for 0.5 hour, then a saturated solution of KF (40 ml) and stirred at RT for 0.5 hour. The gray suspension was filtered. The filter cake was washed with EtOAc (50 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE:EA = 5:1) to afford 8-acetyl-3,6-dimethyl-2-(1-methylcyclobutyl)quinazolin-4(3H) -one (1.4 g, 88%) as a yellow solid. LCMS: (M + H) + =285.2 [0724] Step 4: To a mixture of 8-acetyl-3,6-dimethyl-2-(1-methylcyclobutyl)quinazolin-4(3H) -one (1.4 g, 4.93 mmol) and (R)-2-methylpropane-2-sulfinamide (1.19 g, 9.86 mmol) in THF (50 ml) was added Ti(O-iPr) 4 (20 ml), the mixture was stirred at 75 °C for 24 h. Cooling to RT, Brine (100 ml) was added and stirred at RT for 0.5 hour, the mixture was filtrated and the cake was washed with EtOAc (50 ml*3), the separated aqueous was extracted with EtOAc (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,E)-N-(1-(3,6-dimethyl-2-(1-methylcyclobutyl)-4-oxo-3,4-di hydroquinazolin-8-yl)ethylidene)-2- methylpropane-2-sulfinamide (1.9 g, 100%) as a yellow oil for the next step without further purification. LCMS: (M + H)+ =388.0 [0725] Step 5: To a mixture of crude (R,E)-N-(1-(3,6-dimethyl-2-(1-methylcyclobutyl)-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (1.9 g, 4.9 mmol) and HOAc (2.35 g, 39.2 mmol) in DCM (30 ml) and MeOH (30 ml) was added NaBH 3 CN (0.926 g, 14.7 mmol) slowly at 0 °C. the mixture was stirred for 4 h. A saturate solution of NH 4 Cl (100 ml) was added and stirred for 0.5 hour, the mixture was extracted with DCM (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (method A) to afford (R)-N-((R)-1-(3,6-dimethyl-2-(1- methylcyclobutyl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2- methylpropane-2-sulfinamide (800 mg, 41%) as a yellow solid. LCMS: (M + H)+ =390.0 [0726] Step 6: A mixture of (R)-N-((R)-1-(3,6-dimethyl-2-(1-methylcyclobutyl)-4-oxo-3,4- dihydroquinazolin-8- yl)ethyl)-2-methylpropane-2-sulfinamide (800 mg, 2.06 mmol) in a solution of HCl in MeOH (20 ml, 4 M) was stirred at RT for 10 min. The mixture was poured into ice-water and adjusted PH= 8-9 with a saturate solution of NaHCO 3 , the mixture was extracted with DCM/MeOH (50 ml*3, 10/1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(1- methylcyclobutyl)quinazolin-4(3H)-one (550 mg, 94%) as a yellow solid. LCMS: (M + H)+ =286.2 [0727] Step 7: To a mixture of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(1-methylcyclobutyl)quin azolin-4(3H)-one (100 mg, 0.35 mmol) and methyl 6-chloro-3-fluoropicolinate (99 mg, 0.53 mmol) in DMSO (5 ml) was added DIPEA (135 mg, 1.05 mmol), the mixture was heated to 90 °C for 5 h. Cooling to RT, water (30 ml) was added and the mixture was extracted with EtOAc (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-TLC (PE:EA = 5:1) to afford methyl (R)-6- chloro-3-((1-(3,6-dimethyl-2-(1-methylcyclobutyl)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (125 mg, 79%) as a yellow solid. LCMS: (M + H) + =455.1 [0728] Step 8: To a mixture of methyl (R)-6-chloro-3-((1-(3,6-dimethyl-2-(1-methylcyclobutyl)-4-ox o-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (125 mg, 0.28 mmol) in MeOH (8 ml) and H 2 O (2 ml) was added LiOH (67 mg, 2.8 mmol). The mixture was stirred at 50 °C for 4 h. The mixture was adjusted to pH 4-5 with 1 M HCl and extracted with DCM (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to afford (R)-6-chloro-3-((1-(3,6-dimethyl-2- (1-methylcyclobutyl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl) amino)picolinic acid (79.4 mg, 66%) as a white solid. LCMS: (M + H) + =441.2 EXAMPLE 95 (R)-6-chloro-3-((1-(2-cyclopentyl-3,6-dimethyl-4-oxo-3,4-dih ydroquinazolin-8-yl)ethyl)amino)picolinic acid [0729] Step 1: To a mixture of 2-amino-3-bromo-N,5-dimethylbenzamide (2.0 g, 8.3 mmol) and TEA (1.68 g, 16.6 mmol) in DCM (50 ml) was added cyclopentanecarbonyl chloride (1.64 g, 12.45 mmol) dropwise. The mixture was stirred at RT overnight. Water (50 ml) was added and the separated aqueous was extracted with DCM (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (DCM: MeOH = 50:1) to afford 3-bromo-2-(cyclopentanecarboxamido)- N,5-dimethylbenzamide (2.5 g, 89%) as a yellow solid. LCMS: (M + H)+ =339.1 [0730] Step 2: To a mixture of 3-bromo-2-(cyclopentanecarboxamido)-N,5-dimethylbenzamide (2.5 g, 7.4 mmol) and I2 (1.88 g, 7.4 mmol) in DCM (50 ml) was added HMDS (3.57 g, 22.2 mmol). The mixture was stirred at 50 °C overnight. Cooling to RT, the mixture was washed with a saturated solution of Na 2 S 2 SO 3 (50 ml*2) and washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE:EA = 5:1) to afford 8-bromo-2-cyclopentyl-3,6-dimethylquinazolin-4(3H)-one (2.1 g, 89%) as a white solid. LCMS: (M + H)+ =321.0 [0731] Step 3: To a mixture of 8-bromo-2-cyclopentyl-3,6-dimethylquinazolin-4(3H)-one (2.1 g, 6.6 mmol) and tributyl(1-ethoxyvinyl)stannane (4.78 g, 13.2 mmol) in dioxane (50 ml) was added Pd(PPh 3 ) 2 Cl 2 (463 mg, 0.66 mmol). The mixture was stirred at 100 °C under N 2 overnight. HCl (7 ml, 1 M) was added into the mixture and stirred at 50 °C for 0.5 hour, then a saturated solution of KF (40 ml) and stirred at RT for 0.5 hour. The gray suspension was filtered. The filter cake was washed with EtOAc (50 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE:EA = 10:1-5:1) to afford 8-acetyl-2-cyclopentyl-3,6-dimethylquinazolin-4(3H)-one (1.8 g, 95%) as a white solid. LCMS: (M + H)+ =285.1 [0732] Step 4: To a mixture of 8-acetyl-2-cyclopentyl-3,6-dimethylquinazolin-4(3H)-one (1.8 g, 6.3 mmol) and (R)-2-methylpropane-2-sulfinamide (1.52 g, 12.6 mmol) in THF (50 ml) was added Ti(O-iPr) 4 (17.89 g, 63 mmol), the mixture was stirred at 75 °C for 48 h. Cooling to RT, Brine (100 ml) was added and stirred at RT for 0.5 hour, the mixture was filtrated and the cake was washed with EtOAc (50 ml*3), the separated aqueous was extracted with EA (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,E)-N-(1-(2-cyclopentyl-3,6-dimethyl-4-oxo-3,4-dihydroquin azolin-8-yl)ethylidene)-2- methylpropane-2-sulfinamide (2.45 g, 100%) as a yellow oil for the next step without further purification. LCMS: (M + H)+ =388.0 [0733] Step 5: To a mixture of (R,E)-N-(1-(2-cyclopentyl-3,6-dimethyl-4-oxo-3,4-dihydroquin azolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (2.45 g, 6.3 mmol) and HOAc (3.02 g, 50.4 mmol) in DCM (30 ml) and MeOH (30 ml) was added NaBH 3 CN (1.19 g, 18.9 mmol) slowly at 0 °C, the mixture was stirred for 2 h. A saturate solution of NH 4 Cl (100 ml) was added and stirred for 0.5 hour, the separated aqueous was extracted with DCM (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (method A) to afford (R)-N-((R)-1-(2-cyclopentyl-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (900 mg, 36%) as a yellow solid. LCMS: (M + H)+ =390.1 [0734] Step 6: A mixture of (R)-N-((R)-1-(2-cyclopentyl-3,6-dimethyl-4-oxo-3,4-dihydroqu inazolin-8-yl)ethyl)-2- methylpropane-2-sulfinamide (900 mg, 2.31 mmol) in a solution of HCl in MeOH (15 ml, 4 M) was stirred at RT for 10 min. The mixture was poured into ice-water and adjusted PH= 8-9 with a saturate solution of NaHCO 3 , the mixture was extracted with DCM/MeOH (50 ml*3, 10/1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford (R)-8-(1-aminoethyl)-2-cyclopentyl-3,6-dimethylquinazolin-4( 3H)- one (600 mg, 91%) as a yellow solid. LCMS: (M + H)+ =286.0 [0735] Step 7: To a mixture of (R)-8-(1-aminoethyl)-2-cyclopentyl-3,6-dimethylquinazolin-4( 3H)-one (100 mg, 0.35 mmol) and methyl 6-chloro-3-fluoropicolinate (99 mg, 0.53 mmol) in DMSO (5 ml) was added DIPEA (135 mg, 1.05 mmol), the mixture was heated to 100 °C for 3 h. Cooling to RT, water (30 ml) was added and the mixture was extracted with EtOAc (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-TLC (PE:EA = 5:1) to afford methyl (R)-6-chloro-3- ((1-(2-cyclopentyl-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin- 8-yl)ethyl)amino)picolinate (120 mg, 75%) as a yellow solid. LCMS: (M + H) + =455.1 [0736] Step 8: To a mixture of methyl (R)-6-chloro-3-((1-(2-cyclopentyl-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (120 mg, 0.26 mmol) in MeOH (8 ml) and H 2 O (2 ml) was added LiOH (62 mg, 2.6 mmol). The mixture was stirred at 50 °C for 4 h. The mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to afford (R)-6-chloro-3-((1-(2- cyclopentyl-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)et hyl)amino)picolinic acid (81.2 mg, 71%) as a white solid. LCMS: (M + H) + =441.2 EXAMPLE 96 (R)-2-((1-(2-(4-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydro quinazolin-8-yl)ethyl)amino)benzoic acid [0737] Step 1: To a solution of (R)-8-(1-aminoethyl)-2-(4-fluorophenyl)-3,6-dimethylquinazol in-4(3H)-one (100 mg, 0.32 mmol) in dioxane (10 mL) were added methyl 2-iodobenzoate (175 mg, 0.669 mmol), Pd2(dba) 3 (29 mg, 0.032 mmol), Xant-Phos (111 mg, 0.172 mmol) and Cs 2 CO 3 (313 mg, 0.96 mmol). The mixture was stirred at 100 °C for 12 h. The mixture was diluted with water (40 mL) and extracted with EtOAc (40 mL×3), the combined organics were dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (PE: EA=3:1) to give methyl (R)-2-((1-(2-(4-fluorophenyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate (70 mg, 48.1 %) as a yellow solid. LCMS: (M + H) + =446.2 [0738] Step 2: To a solution of methyl methyl (R)-2-((1-(2-(4-fluorophenyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate (70 mg, 0.154 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (37 mg, 1.54 mmol). The mixture was stirred at 50 °C for 4 h. The mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM (40 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to give (R)-2-((1-(2-(4- fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl) ethyl)amino)benzoic acid (30.8 mg, 46.1 %) as a white solid. LCMS: (M + H) + =432.2 EXAMPLE 97 (R)-6-chloro-3-((1-(3,6-dimethyl-4-oxo-2-(1,1,1-trifluoro-2- methylpropan-2-yl)-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0739] Step 1: To a mixture of 2-amino-3-bromo-N,5-dimethylbenzamide (1.7 g, 7.0 mmol), 3,3,3-trifluoro-2,2- dimethylpropanoic acid (1.64 g, 10.5 mmol) and CMPI (1.81 g, 14 mmol) in THF (50 ml) was added DIPEA (2.08 g, 16.11 mmol). The mixture was stirred at 75 °C for 24 h. Cooling to RT, water (50 ml) was added and the mixture was extracted with EtOAc (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (DCM: MeOH = 50:1) to afford 3-bromo- N,5-dimethyl-2-(3,3,3-trifluoro-2,2-dimethylpropanamido)benz amide (2.2 g, 83%) as a yellow solid. LCMS: (M + H) + =381.0 [0740] Step 2: To a mixture of 3-bromo-N,5-dimethyl-2-(3,3,3-trifluoro-2,2-dimethylpropanam ido)benzamide (1.9 g, 5 mmol) and I2 (1.27 g, 5 mmol) was added HMDS (15 ml). The mixture was stirred in a microwave at 150 °C for 3 h. Cooling to RT, the mixture was diluted with DCM (80 ml), washed with a saturated solution of Na 2 S 2 SO 3 (50 ml*2) and h brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (DCM:EA = 20:1) to afford 8-bromo-3,6-dimethyl-2-(1,1,1-trifluoro-2-methylpropan-2- yl)quinazolin-4(3H)-one (1.3 g, 72%) as a white solid. LCMS: (M + H)+ =363.0 [0741] Step 3: To a mixture of 8-bromo-3,6-dimethyl-2-(2-methyltetrahydrofuran-2-yl)quinazo lin-4(3H)-one (1.3 g, 3.6 mmol) and tributyl(1-ethoxyvinyl)stannane (2.61 g, 7.2 mmol) in dioxane (30 ml) was added Pd(PPh 3 ) 2 Cl 2 (253 mg, 0.36 mmol). The mixture was stirred at 95 °C under N 2 for 6 h. HCl (4 ml, 1 M) was added into the mixture and stirred at 50 °C for 0.5 hour, then a saturated solution of KF (40 ml) and stirred at RT for 0.5 hour. The gray suspension was filtered. The filter cake was washed with EtOAc (50 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE:EA = 10:1-3:1) to afford 8-acetyl-3,6-dimethyl-2-(1,1,1-trifluoro-2-methylpropan-2-yl )quinazolin-4(3H)-one (1.0 g, 85%) as a yellow solid. LCMS: (M + H) + =327.1 [0742] Step 4: To a mixture of 8-acetyl-3,6-dimethyl-2-(1,1,1-trifluoro-2-methylpropan-2-yl )quinazolin-4(3H)-one (1.0g, 3.1 mmol) and (R)-2-methylpropane-2-sulfinamide (0.75 g, 6.2 mmol) in THF (15 ml) was added Ti(O-iPr) 4 (15 ml), the mixture was stirred at 75 °C for 24 h. Cooling to rt, Brine (50 ml) was added and stirred at RT for 0.5 hour, the mixture was filtrated and the cake was washed with EtOAc (50 ml*3), the separated aqueous was extracted with EtOAc (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)-N-(1-(3,6-dimethyl-4-oxo-2-(1,1,1-trifluoro-2-methylpr opan-2-yl)-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (1.3 g, 100%) as a yellow oil for the next step without further purification. LCMS: (M + H)+ =430.0 [0743] Step 5: To a mixture of crude (R,Z)-N-(1-(3,6-dimethyl-4-oxo-2-(1,1,1-trifluoro-2-methylpr opan-2-yl)-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (1.3 g, 3.0 mmol) and HOAc (1.44 g, 24 mmol) in DCM (30 ml) and MeOH (30 ml) was added NaBH 3 CN (567 mg, 9.0 mmol) slowly at 0 °C. the mixture was stirred for 1 hour. A saturated solution of NH 4 Cl (50 ml) was added and the mixture was extracted with DCM (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (method A) to (R)-N-((R)-1-(3,6-dimethyl-4-oxo-2-(1,1,1-trifluoro-2-methyl propan-2-yl)- 3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinam ide (850 mg, 66%) as a yellow solid. LCMS: (M + H)+ =432.0 [0744] Step 6: A mixture of (R)-N-((R)-1-(3,6-dimethyl-4-oxo-2-(1,1,1-trifluoro-2-methyl propan-2-yl)-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (850 mg, 1.97 mmol) in a solution of HCl in MeOH (15 ml, 4 M) was stirred at RT for 10 min. The mixture was poured into ice-water and adjusted PH= 8-9 with a saturate solution of NaHCO 3 , the mixture was extracted with DCM/MeOH (40 ml*3, 10/1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford (R)-8-(1-aminoethyl)-3,6-dimethyl-2- (1,1,1-trifluoro-2-methylpropan-2-yl)quinazolin-4(3H)-one (600 mg, 93%) as a yellow solid. LCMS: (M + H)+ =328.3 [0745] Step 7: To a mixture of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(1,1,1-trifluoro-2-methy lpropan-2- yl)quinazolin-4(3H)-one (100 mg, 0.31 mmol) and methyl 6-chloro-3-fluoropicolinate (89 mg, 0.47 mmol) in DMSO (5 ml) was added DIPEA (120 mg, 0.93 mmol), the mixture was heated to 100 °C for 3 h. Cooling to RT, water (30 ml) was added and the mixture was extracted with EtOAc (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-TLC (DCM: EA = 50:1) to afford methyl (R)-6-chloro-3-((1-(3,6-dimethyl-4-oxo-2-(1,1,1-trifluoro-2- methylpropan-2-yl)-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (95 mg, 69%) as a white solid. LCMS: (M + H) + =497.3 [0746] Step 8: To a mixture of methyl (R)-6-chloro-3-((1-(3,6-dimethyl-4-oxo-2-(1,1,1-trifluoro-2- methylpropan- 2-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinate (95 mg, 0.19 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (46 mg, 1.9 mmol). The mixture was stirred at 50 °C for 1 hour. The mixture was adjusted to pH = 4- 5 with 1 M HCl and extracted with DCM (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to afford (R)-6-chloro-3-((1- (3,6-dimethyl-4-oxo-2-(1,1,1-trifluoro-2-methylpropan-2-yl)- 3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinic acid (66.3 mg, 72%) as a white solid. LCMS: (M + H) + =483.1 EXAMPLE 98 (R)-6-chloro-3-((1-(3,6-dimethyl-2-(4-(methylsulfonyl)phenyl )-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0747] Step 1: To a mixture of 2-amino-3-bromo-N,5-dimethylbenzamide (1.5 g, 6.2 mmol) in DMSO (30 ml) was added 4-(methylsulfonyl)benzaldehyde (2.28 g, 12.4 mmol). The mixture was stirred at 150 °C under O 2 for 10 h. The mixture was poured into water (200 ml) and stirred for 0.5 hour, the mixture was filtered and the cake was washed with water (20 ml*3), the cake was dried under reduce pressure to afford 8-bromo-3,6-dimethyl-2-(4- (methylsulfonyl)phenyl)quinazolin-4(3H)-one (1.4 g, 55%) as a white solid. LCMS: (M+H) + = 407.1 [0748] Step 2: To a mixture of 8-bromo-3,6-dimethyl-2-(4-(methylsulfonyl)phenyl)quinazolin- 4(3H)-one (1.4 g, 3.45 mmol) and tributyl(1-ethoxyvinyl)stannane (2.5 g, 6.9 mmol) in 1.4-dioxane (40 ml) was added Pd(PPh 3 ) 2 Cl 2 (242 mg, 0.345 mmol). The mixture was heated to 95 °C and stirred under N 2 for 16 h. HCl (4 ml, 1 M) was added into the mixture and stirred at 50 °C for 0.5 hour, then a saturated solution of KF (40 ml) and stirred at RT for 0.5 hour. The gray suspension was filtered. The filter cake was washed with EtOAc (50 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH= 30: 1) to 8-acetyl-3,6-dimethyl-2-(4- (methylsulfonyl)phenyl)quinazolin-4(3H)-one (900 mg, 70%) as a yellow solid. LCMS: (M + H) + = 371.1 [0749] Step 3: To a mixture of 8-acetyl-3,6-dimethyl-2-(4-(methylsulfonyl)phenyl)quinazolin -4(3H)-one (900 mg, 2.43 mmol) and (R)-2-methylpropane-2-sulfinamide (588 mg, 4.86 mmol) in THF (15 ml) was added Ti(i- PrO) 4 (15 ml). the mixture was stirred at 75 °C under N 2 for 16 h. The mixture was diluted with EtOAc (50 ml) and was a saturated solution of NaCl (50 ml) was added, the mixture was stirred at RT for 0.5 hour. The resulting mixture was filtered and the filter cake was washed with EtOAc (30 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)-N-(1-(3,6-dimethyl-2-(4- (methylsulfonyl)phenyl)-4-oxo-3,4-dihydroquinazolin-8-yl)eth ylidene)-2-methylpropane-2-sulfinamide (1.15 mg, 100% yield) as a yellow oil for the next step without further purification. LCMS: (M + H) + = 474.0 [0750] Step 4: To a mixture of crude (R,Z)-N-(1-(3,6-dimethyl-2-(4-(methylsulfonyl)phenyl)-4-oxo- 3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (1.15 mg, 2.43 mmol) and HOAc (1.16 g, 19.44 mmol) in DCM (20 ml) and MeOH (20 ml) at 0°C was added NaBH 3 CN (459 mg, 7.29 mmol) slowly. The mixture was stirred for 3 h. A saturated solution of NH 4 Cl (40 ml) was added and the mixture was extracted with DCM (40 ml * 3), the combined organic phase was washed with brine, dried with Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (method A) to afford (R)-N-((R)-1-(3,6-dimethyl-2-(4-(methylsulfonyl)phenyl)-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulf inamide (80 mg, 7%) as a white solid. LCMS: (M + H) + = 475.9 [0751] Step 5: A mixture of (R)-N-((R)-1-(3,6-dimethyl-2-(4-(methylsulfonyl)phenyl)-4-ox o-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (75 mg, 0.16 mmol) in a solution of HCl in MeOH (3 ml, 4 M) was stirred at RT for 10 min. the mixture was poured into ice-water and adjusted pH = 8-9 with a saturated solution of NaHCO 3 , the mixture was extracted with DCM/MeOH (20 ml*5, 10/1), the combined organic phase was dried over Na 2 SO 4 and concentrated to afford (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(4- (methylsulfonyl)phenyl)quinazolin-4(3H)-one (60 mg, 100%) as a yellow solid. LCMS: (M + H) + = 372.1 [0752] Step 6: To a mixture of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(4-(methylsulfonyl)pheny l)quinazolin-4(3H)- one (60 mg, 0.16 mmol) and methyl 6-chloro-3-fluoropicolinate (45 mg, 0.24 mmol) in DMSO (4 ml) was added DIPEA (62 mg, 0.48 mmol), the mixture was heated to 100 °C for 5 h. Cooling to RT, water (20 ml) was added and the mixture was extracted with EtOAc (20 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-TLC (DCM: EA = 10:1) to afford methyl (R)-6- chloro-3-((1-(3,6-dimethyl-2-(4-(methylsulfonyl)phenyl)-4-ox o-3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinate (45 mg, 52%) as a white solid. LCMS: (M + H) + =541.2 [0753] Step 7: To a mixture of methyl (R)-6-chloro-3-((1-(3,6-dimethyl-2-(4-(methylsulfonyl)phenyl )-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (45 mg, 0.08 mmol) in MeOH (4 ml) and H 2 O (1 ml) was added LiOH (20 mg, 0.8 mmol). The mixture was stirred at 50 °C for 4 h. Cooling to RT, the mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM (20 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to afford (R)-6-chloro-3-((1- (3,6-dimethyl-2-(4-(methylsulfonyl)phenyl)-4-oxo-3,4-dihydro quinazolin-8-yl)ethyl)amino)picolinic acid (20.3 mg, 48%) as a white solid. LCMS: (M + H) + =527.0 EXAMPLE 99 (R)-6-chloro-3-((1-(2-(4-cyanophenyl)-3,6-dimethyl-4-oxo-3,4 -dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0754] Step 1: To a mixture of 2-amino-3-bromo-N,5-dimethylbenzamide (1.5 g, 6.2 mmol) in DMSO (30 ml) was added 4-formylbenzonitrile (1.22 g, 9.3 mmol). The mixture was stirred at 145 °C under O 2 for 8 h. The mixture was poured into water (200 ml) and stirred for 0.5 hour, the mixture was filtered and the cake was washed with water (20 ml*3), the cake was dried under reduce pressure to afford 4-(8-bromo-3,6-dimethyl-4-oxo- 3,4-dihydroquinazolin-2-yl)benzonitrile (1.7 g, 78%) as a white solid. LCMS: (M+H) + = 354.0 [0755] Step 2: To a mixture of 4-(8-bromo-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)ben zonitrile (1.7 g, 4.8 mmol) and tributyl(1-ethoxyvinyl)stannane (3.48 g, 9.6 mmol) in 1.4-dioxane (50 ml) was added Pd(PPh 3 ) 2 Cl 2 (337 mg, 0.48 mmol). The mixture was heated to 95 °C and stirred under N 2 for 16 h. HCl (5 ml, 1 M) was added into the mixture and stirred at 50 °C for 0.5 hour, then a saturated solution of KF (40 ml) and stirred at RT for 0.5 hour. The gray suspension was filtered. The filter cake was washed with EtOAc (50 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH= 30: 1) to afford 4-(8-acetyl-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2- yl)benzonitrile (1.3 g, 86%) as a yellow solid. LCMS: (M + H) + = 318.1 [0756] Step 3: To a mixture of 4-(8-acetyl-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)be nzonitrile (1.3 g, 4.1 mmol) and (R)-2-methylpropane-2-sulfinamide (992 mg, 8.2 mmol) in THF (20 ml) was added Ti(i-PrO) 4 (20 ml). the mixture was stirred at 75 °C under N 2 for 16 h. The mixture was diluted with EtOAc (50 ml) and a saturated solution of NaCl (50 ml) was added, the mixture was stirred at RT for 0.5 hour. The resulting mixture was filtered and the filter cake was washed with EtOAc (30 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)-N-(1-(2-(4-cyanophenyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (1.72 g, 100% yield) as a yellow oil for the next step without further purification.LCMS: (M + H) + = 421.0 [0757] Step 4: To a mixture of crude (R,Z)-N-(1-(2-(4-cyanophenyl)-3,6-dimethyl-4-oxo-3,4-dihydro quinazolin- 8-yl)ethylidene)-2-methylpropane-2-sulfinamide (1.72 g, 4.1 mmol) and HOAc (1.97 g, 32.8 mmol) in DCM (40 ml) and MeOH (40 ml) at 0°C was added NaBH 3 CN (459 mg, 7.29 mmol) slowly. The mixture was stirred for 4 h. A saturated solution of NH 4 Cl (80 ml) was added and the mixture was extracted with DCM (50 ml * 3), the combined organic phase was washed with brine, dried with Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (method A) to afford (R)-N-((R)-1-(2-(4-cyanophenyl)-3,6-dimethyl-4-oxo-3,4-dihyd roquinazolin-8- yl)ethyl)-2-methylpropane-2-sulfinamide (630 mg, 36%) as a white solid. LCMS: (M + H) + = 423.0 [0758] Step 5: A mixture (R)-N-((R)-1-(2-(4-cyanophenyl)-3,6-dimethyl-4-oxo-3,4-dihyd roquinazolin-8-yl)ethyl)- 2-methylpropane-2-sulfinamide (630 mg, 1.49 mmol) in a solution of HCl in MeOH (10 ml, 4 M) was stirred at RT for 10 min. the mixture was poured into ice-water and adjusted pH = 8-9 with a saturated solution of NaHCO 3 , the mixture was extracted with DCM/MeOH (20 ml*5, 10/1), the combined organic phase was dried over Na 2 SO 4 and concentrated to afford (R)-4-(8-(1-aminoethyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinaz olin-2-yl)benzonitrile (450 mg, 100%) as a yellow solid. LCMS: (M + H) + = 319.2 [0759] Step 6: To a mixture of (R)-4-(8-(1-aminoethyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinaz olin-2- yl)benzonitrile (100 mg, 0.31 mmol) and methyl 6-chloro-3-fluoropicolinate (88 mg, 0.47 mmol) in DMSO (4 ml) was added DIPEA (120 mg, 0.93 mmol), the mixture was heated to 100 °C for 4 h. Cooling to RT, water (20 ml) was added and the mixture was extracted with EtOAc (20 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-TLC (DCM: EA = 10:1) to afford methyl (R)-6-chloro-3-((1-(2-(4-cyanophenyl)-3,6-dimethyl-4-oxo-3,4 -dihydroquinazolin-8- yl)ethyl)amino)picolinate (100 mg, 79%) as a yellow solid. LCMS: (M + H) + =488.1 [0760] Step 7: To a mixture of methyl (R)-6-chloro-3-((1-(2-(4-cyanophenyl)-3,6-dimethyl-4-oxo-3,4 - dihydroquinazolin-8-yl)ethyl)amino)picolinate (100 mg, 0.21 mmol) in MeOH (4 ml) and H 2 O (1 ml) was added LiOH (50 mg, 2.1 mmol). The mixture was stirred at 50 °C for 0.5 hour. Cooling to RT, the mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM (20 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to afford (R)-6- chloro-3-((1-(2-(4-cyanophenyl)-3,6-dimethyl-4-oxo-3,4-dihyd roquinazolin-8-yl)ethyl)amino)picolinic acid (48.9 mg, 49%) as a white solid. LCMS: (M + H) + =474.0 EXAMPLE 100 (R)-6-chloro-3-((1-(2-(1-hydroxy-2-methylpropan-2-yl)-3,6-di methyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0761] Step 1: To a mixture of methyl 3-hydroxy-2,2-dimethylpropanoate (10.0 g, 75.7 mmol) and imidazole (15.5 g, 227 mmol) in DCM (200 mL) was added TBDPSCl (41.7 g, 152 mmol) dropwise at 0 °C. The mixture was stirred at RT for 16 h. Water (200 mL) was added, the separated aqueous layer was extracted with DCM (100 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated, The residue was purified by chromatography (PE: EA =3:1) to afford methyl 3-((tert-butyldiphenylsilyl)oxy)-2,2- dimethylpropanoate (7.4 g, 26.4%) as a yellow oil. LCMS: (M + H) + =371.2 [0762] Step 2: To a solution of methyl 3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropanoate (7.4 g, 20.0 mmol) in EtOH : H 2 O (1:1, 100 mL) was added KOH (4.48 g, 80.0 mmol) at RT. The mixture was heated to 100 °C and stirred overnight. The mixture was extracted with DCM (100 mL*3), the separated aqueous layer was frozen-drying with lyophilizer to give a crude 3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropanoic acid (6.2 g, purity 76% (214 nm)) as a yellow solid for the next step without further purification. LCMS: (M – H) + =355.0 [0763] Step 3: To a solution of 2-amino-3-bromo-N,5-dimethylbenzamide (3.55 g, 14.7 mmol) in acetonitrile (50 mL) were added 3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropanoic acid (6.27 g, 17.6 mmol), TCFH (6.18 g, 22.0 mmol) and NMI (4.21 g, 17.6 mmol) at RT. The mixture was stirred at RT overnight. Water (100 mL) was added and the mixture was extracted with DCM (100 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (DCM : MeOH = 20:1) to afford 3-bromo-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylprop anamido)-N,5-dimethylbenzamide (5.3 g, 91.6%) as a yellow solid. LCMS: (M + H) + =580.9 [0764] Step 4: To a solution of 3-bromo-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylprop anamido)-N,5- dimethylbenzamide (4.8 g, 8.27 mmol) in DMF (25 mL) were added ZnCl 2 (1M, 30 mL) and HMDS (13.4 g, 82.7 mmol) at RT. The mixture was heated to 100 °C and stirred for 3 hours. Cooling to RT, water (150 mL) was added and the mixture and filtered. The filtrate was diluted with EtOAc (100 mL), the aqueous phase was extracted with EtOAc (100 mL*3). The combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 5:1) to afford 8-bromo-2-(1-((tert- butyldiphenylsilyl)oxy)-2-methylpropan-2-yl)-3,6-dimethylqui nazolin-4(3H)-one (3.2 g, 68.8%) as a yellow solid. LCMS: (M + H) + =562.9 [0765] Step 5: To a solution of 8-bromo-2-(1-((tert-butyldiphenylsilyl)oxy)-2-methylpropan-2 -yl)-3,6- dimethylquinazolin-4(3H)-one (2.6 g, 4.63 mmol) in dioxane:H 2 O (5:1, 20 mL) was added 4,4,5,5-tetramethyl-2- vinyl-1,3,2-dioxaborolane (1.42 g, 9.25 mmol), Pd(PPh 3 ) 2 Cl 2 (1.62 g, 2.31 mmol) and K3PO 4 (2.24 g, 9.25 mmol) in portions at RT. The mixture was heated to 100 °C and stirred at 100 °C for 4 h. The mixture was diluted with water (50 mL) and extracted with DCM (100 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to get residue which was purified by chromatography (PE : EA = 5:1) to afford 2- (1-((tert-butyldiphenylsilyl)oxy)-2-methylpropan-2-yl)-3,6-d imethyl-8-vinylquinazolin-4(3H)-one (1.9 g, 80.5%) as a yellow oil. LCMS: (M + H) + = 511.3 [0766] Step 6: To a solution of 2-(1-((tert-butyldiphenylsilyl)oxy)-2-methylpropan-2-yl)-3,6 -dimethyl-8- vinylquinazolin-4(3H)-one (1.6 g, 3.14 mmol) in THF : H 2 O (1:1, 20 mL) was added NaIO 4 (2.7 g, 12.5 mmol) and K 2 OsO 4 (0.927 g, 1.57 mmol) at RT, the mixture was stirred at RT for 5 h. The mixture was cooled to 0 °C, Water (100 mL) was added the mixture and the mixture was diluted with DCM (200 mL), then organic layer was washed with NaHSO 3 (100 mL *2) and the aqueous layer was extracted with DCM (100 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated, the residue was purified by chromatography (PE:EA = 3:1) to afford 2-(1-((tert-butyldiphenylsilyl)oxy)-2-methylpropan-2-yl)-3,6 -dimethyl-4- oxo-3,4-dihydroquinazoline-8-carbaldehyde (1.1 g, 68.5%) as a yellow oil. LCMS: (M +1) + =513.0 [0767] Step 7: To a mixture of 2-(1-((tert-butyldiphenylsilyl)oxy)-2-methylpropan-2-yl)-3,6 -dimethyl-4-oxo-3,4- dihydroquinazoline-8-carbaldehyde (1.1 g, 2.15 mmol) and (R)-2-methylpropane-2-sulfinamide (0.779 g, 6.45 mmol) in THF (20 mL) was added Ti(O-iPr) 4 (3.89 g, 10.7 mmol). The mixture was stirred at 75 °C overnight. Cooling to RT, Brine (20 mL) was added and the mixture and filtered. The filtrate was extracted with DCM (100 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 3:1) to afford (R,Z)-N-((2-(1-((tert-butyldiphenylsilyl)oxy)-2- methylpropan-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin- 8-yl)methylene)-2-methylpropane-2-sulfinamide (1.0 g, 75.7%) as a yellow solid. LCMS: (M + H) + =616.2 [0768] Step 8: To a solution of (R,Z)-N-((2-(1-((tert-butyldiphenylsilyl)oxy)-2-methylpropan -2-yl)-3,6-dimethyl-4- oxo-3,4-dihydroquinazolin-8-yl)methylene)-2-methylpropane-2- sulfinamide (1.1 g, 1.79 mmol) in THF (20 mL) was added MeMgBr (1M, 17.8 mL) and dimethylzinc (1.2 M, 14.9 mL) at 0 °C. the mixture was stirred for 2 h. The mixture was quenched with NH 4 Cl (10 mL) and extracted with DCM (100 mL *3). Combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method A) to afford (R)-N-((R)-1-(2-(1-((tert-butyldiphenylsilyl)oxy)-2-methylpr opan-2-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (390 mg, 34.6%) as a white solid. LCMS: (M + H) + =632.0 [0769] Step 9: To a solution of ((R)-N-((R)-1-(2-(1-((tert-butyldiphenylsilyl)oxy)-2-methylp ropan-2-yl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpro pane-2-sulfinamide (390 mg, 0.618 mmol) in MeOH (5 mL) was added HCl/MeOH (4M, 5mL) at RT. The mixture was stirred at RT for 30 minutes. The mixture was adjusted to pH = 9 with NaHCO 3 (20 mL) and extracted with DCM (50 mL *3). The combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford (R)-8-(1-aminoethyl)-2-(1-((tert- butyldiphenylsilyl)oxy)-2-methylpropan-2-yl)-3,6-dimethylqui nazolin-4(3H)-one (130 mg, 39.9%) as a yellow oil. LCMS: (M + H) + = 528.1 [0770] Step 10: To a solution of (R)-8-(1-aminoethyl)-2-(1-((tert-butyldiphenylsilyl)oxy)-2-m ethylpropan-2-yl)- 3,6-dimethylquinazolin-4(3H)-one (130 mg, 0.247 mmol) in DMSO (5 mL) were added DIPEA (63.6 mg, 0.493 mmol) and methyl 6-chloro-3-fluoropicolinate (69.9 mg, 0.370 mmol) at RT. The mixture was heated to 100 °C and stirred at 100°C for 2 h. Cooling to RT, water (50 mL) was added the mixture and extracted with EtOAc (40 mL *3). The combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE:EA=5:1) to afford methyl (R)-3-((1-(2-(1-((tert-butyldiphenylsilyl)oxy)-2- methylpropan-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin- 8-yl)ethyl)amino)-6-chloropicolinate (90 mg, 52.4%) as a yellow oil. LCMS: (M + H) + =697.0 [0771] Step 11: To a solution of ((R)-3-((1-(2-(1-((tert-butyldiphenylsilyl)oxy)-2-methylprop an-2-yl)-3,6-dimethyl- 4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)-6-chloropicoli nate (90 mg, 0.129 mmol) in THF (20 mL) was added TBAF (1 M, 2 mL) at RT. The mixture was stirred at RT for 2 h. Water (30 ml) was added and the mixture was extracted with DCM (50 mL *3). The combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-TLC (DCM: MeOH = 20:1) to afford methyl (R)-6-chloro-3-((1-(2- (1-hydroxy-2-methylpropan-2-yl)-3,6-dimethyl-4-oxo-3,4-dihyd roquinazolin-8-yl)ethyl)amino)picolinate (22 mg, 37.1%) as a yellow oil. LCMS: (M + H) + =459.2 [0772] Step 12: To a solution of methyl (R)-6-chloro-3-((1-(2-(1-hydroxy-2-methylpropan-2-yl)-3,6-di methyl-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinate (22 mg, 0.0480 mmol) in MeOH:H 2 O (5:1, 5 mL) was added LiOH (10.09 mg, 0.241 mmol) at RT. The mixture was heated to 50 °C and stirred at 50 °C for 2 h. The mixture was neutralized with HCl (1M, 2 mL) and the mixture was extracted with DCM:MeOH (10:1, 50 mL *3). The combined the organic layer was dried with over Na 2 SO 4 , filtered and concentrated. The residue was purified by Pre-HPLC (method B) to afford (R)-6-chloro-3-((1-(2-(1-hydroxy-2-methylpropan-2-yl)-3,6-di methyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinic acid (15 mg, 70.3%) as a white solid. LCMS: (M + H) + =445.2 EXAMPLE 101 (R)-6-chloro-3-(1-(2-cyclopropyl-3,6-dimethyl-4-oxo-3,4-dihy droquinazolin-8-yl)ethylamino)picolinic acid [0773] Step 1: To a mixture of 2-amino-3-bromo-N,5-dimethylbenzamide (1.2 g, 4.96 mmol) and DIPEA (1.28 g, 9.92 mmol) in THF (20 ml) was added cyclopropanecarbonyl chloride (774 mg, 7.44 mmol). The mixture was stirred at RT for 3 h. The mixture was filtered and the collected solid was dried under reduce pressure to afford 3- bromo-2-(cyclopropanecarboxamido)-N,5-dimethylbenzamide (1 g, 78%) as a white solid. LCMS: (M + H) + = 311.0 [0774] Step 2: To a mixture of 3-bromo-2-(cyclopropanecarboxamido)-N,5-dimethylbenzamide (1.2 g, 4.96 mmol) in DCM (20 ml) was added I 2 (983 mg, 3.87 mmol) and HMDS (1.87 g, 11.61 mmol). The mixture was stirred at 50 °C for 16 h. The mixture was washed with a saturated solution of sodium thiosulfate, the organic phase was concentrated and purified by flash (DCM: EA = 20: 1) to afford 8-bromo-2-cyclopropyl-3,6- dimethylquinazolin-4(3H)-one (1.0 g, 88%) as a white solid. LCMS: (M +2+ H) + =296.0 [0775] Step 3: To a mixture of 8-bromo-2-cyclopropyl-3,6-dimethylquinazolin-4(3H)-one (1.0 g, 3.42 mmol) and tributyl(1-ethoxyvinyl)stannane (2.47 g, 6.84 mmol) in 1.4-dioxane (20 ml) was added Pd(PPh 3 ) 2 Cl 2 (360 mg, 0.513 mmol). The mixture was stirred at 95 °C under N 2 for 16 h. HCl (4 ml, 1 M) was added into the mixture and the mixture was stirred at 50 °C for 0.5 hour, then 20 ml sat KF was added and the mixture was stirred at RT for 0.5 hour. The gray suspension was filtered, the filter cake was washed with DCM, the separated aqueous phase was extracted with DCM (50 ml * 3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated, the residue was purified by flash (DCM: EA = 10: 1) to afford 8-acetyl-2-cyclopropyl-3,6- dimethylquinazolin-4(3H)-one (850 mg, 97%) as a yellow solid. LCMS: (M + H) + =257.1 [0776] Step 4: To a mixture of 8-acetyl-2-cyclopropyl-3,6-dimethylquinazolin-4(3H)-one (850 mg, 3.32 mmol) and (R)-2-methylpropane-2-sulfinamide (803 mg, 6.64 mmol) in THF (15 ml) was added Ti(Oi-Pr) 4 (15 ml). the mixture was stirred at 75 °C under N 2 for 16 h. The mixture was diluted with EtOAc (50 ml) and a saturated solution of NaCl (30 ml) was added, the mixture was stirred at RT for 0.5 hour. The mixture was filtered and filter cake was washed with EtOAc (20 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)-N-(1-(2-cyclopropyl-3,6-dimethyl-4-oxo-3,4-dihydroquin azolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (850 mg, 71%) as a yellow oil. LCMS: (M + H) + =360.1 [0777] Step 5: To a mixture of crude (R,Z)-N-(1-(2-cyclopropyl-3,6-dimethyl-4-oxo-3,4-dihydroquin azolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (1.2 g, 3.34 mmol) and AcOH (1.6 g, 26.72 mmol) in DCM (15 ml) and MeOH (15 ml) was added NaBH 3 CN (631 mg, 10.02 mmol) stirred 0 °C. The mixture was stirred at 0 °C for 2 h. A saturated solution of NH 4 Cl was added and the mixture was extracted with DCM (30 ml * 3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre- HPLC (Method A) to afford (R)-N-((R)-1-(2-cyclopropyl-3,6-dimethyl-4-oxo-3,4-dihydroqu inazolin-8-yl)ethyl)-2- methylpropane-2-sulfinamide (550 mg, 46%) as a white solid. LCMS: (M + H) + =362.2 [0778] Step 6: A mixture of (R)-N-((R)-1-(2-cyclopropyl-3,6-dimethyl-4-oxo-3,4-dihydroqu inazolin-8-yl)ethyl)-2- methylpropane-2-sulfinamide (550 mg, 1.52 mmol) in HCl (3 M in MeOH) (10 ml) was stirred at RT for 0.5 hour. The mixture was poured into ice-water and adjusted pH 8 with a saturated solution of NaHCO 3 , The mixture was extracted with DCM/MeOH (30 ml*3, 10/1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford (R)-8-(1-aminoethyl)-2-cyclopropyl-3,6-dimethylquinazolin-4( 3H)-one (390 mg, 100%) as a yellow solid. LCMS: (M + H) + =258.1 [0779] Step 7: To a mixture of (R)-8-(1-aminoethyl)-2-cyclopropyl-3,6-dimethylquinazolin-4( 3H)-one (150 mg, 0.58 mmol) and methyl 6-chloro-3-fluoropicolinate (164 mg, 0.87 mmol) in DMSO (5 ml) was added DIPEA (150 mg, 1.16 mmol). The mixture was stirred at 100 °C for 16 h. Water (30 ml) was added and the mixture was extracted with EtOAc (30 ml*3), The combine organic phase was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated to afford (R)-methyl 6-chloro-3-(1-(2-cyclopropyl-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethylamino)picolinate (240 mg, 97%) as yellow oil. LCMS: (M + H) + =427.2 [0780] Step 8: To a solution of (R)-methyl 6-chloro-3-(1-(2-cyclopropyl-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethylamino)picolinate (240 mg, 0.56 mmol) in MeOH (5 ml) and H 2 O (1 ml). the mixture was stirred at 50 °C for 1 hour. The mixture was adjusted pH 5 – 6 with HCl (1 M). The mixture was concentrated and purified by Pre-HPLC (Method B) to afford (R)-6-chloro-3-(1-(2-cyclopropyl-3,6-dimethyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethylamino)picolinic acid (147.9 mg, 64% yield) as a white solid. LCMS: (M + H) + = 413.1 EXAMPLE 102 (R)-6-chloro-3-((1-(3,6-dimethyl-2-(3-methyloxetan-3-yl)-4-o xo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0781] Step 1: To a solution of 2-amino-3-bromo-N,5-dimethylbenzamide (3.0 g, 12.4 mmol) in anhydrous Acetonitrile (30 mL) were added 3-methyloxetane-3-carboxylic acid (2.88 g, 24.8 mmol), TCFH (10.5 g, 37.2 mmol) and 1-methylimidazole (5.08 g, 61.9 mmol) at RT. The mixture was heated to 80 °C and stirred overnight. Water (50 mL) was added and the mixture was extracted with DCM (80 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated, The residue was purified by chromatography (PE: EA = 3:1) to afford N-(2-bromo-4-methyl-6-(methylcarbamoyl)phenyl)-3-methyloxeta ne-3-carboxamide (2.0 g, 47.5%) as a yellow solid. LCMS: (M + H) + =341.2 [0782] Step 2: To a solution of N-(2-bromo-4-methyl-6-(methylcarbamoyl)phenyl)-3-methyloxeta ne-3- carboxamide (2.0 g, 5.88 mmol) in DMF (20 mL) were added a solution of ZnCl 2 in THF (11.7 Ml, 1 M) and HMDS (2.84 g, 17.6 mmol) at RT. The mixture was stirred at 100 °C for 3 h. Cooling to RT, the resulting mixture was filtered through a pad of Celite and filter cake was washed with DCM (100 mL x 3). The filteres were washed with brine, dried over Na 2 SO 4 and concentrated under vacuum to get a residue which was purified by chromatography (PE : EA = 5:1) to afford 8-bromo-3,6-dimethyl-2-(3-methyloxetan-3-yl)quinazolin-4(3H) -one (1.5 g, 79.2%) as a yellow solid. LCMS: (M + H) + =323.1 [0783] Step 3: To a mixture of 8-bromo-3,6-dimethyl-2-(3-methyloxetan-3-yl)quinazolin-4(3H) -one (1.5 g, 4.66 mmol) and ethyl tributylstannanecarboxylate (2.53 g, 6.98 mmol) in dioxane (40 mL) was added Pd(PPh 3 ) 2 Cl 2 (682 mg, 0.932 mmol). The mixture was stirred at 105 °C under N 2 for 6 h. HCl (5 mL, 1 M) was added into the mixture and the mixture was stirred at 50 °C for 0.5 hour, then 10 mL sat. KF was added and the mixture was stirred at RT for 0.5 hour. The gray was filtered, the filter cake was washed with EtOAc (50 mL*3), the separated aqueous phase was extracted with EtOAc (50 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 30%) to afford 8-acetyl- 3,6-dimethyl-2-(3-methyloxetan-3-yl)quinazolin-4(3H)-one (100 mg, 7.5%) as a yellow solid. LCMS: (M + H) + =287.0 [0784] Step 4: To a mixture of 8-acetyl-3,6-dimethyl-2-(3-methyloxetan-3-yl)quinazolin-4(3H )-one (100 mg, 0.349 mmol) and (R)-2-methylpropane-2-sulfinamide (84.6 mg, 0.699 mmol) in THF (10 mL) atRT was added Ti(i-PrO) 4 (1.26 g, 3.49 mmol). The mixture was stirred at 75 °C for 48 hours. Cooling to RT, brine (10 mL) was added and the mixture was stirred for 0.5 hour. The resulting mixture was filtrated and the cake was washed with EtOAc (20 mL*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)-N-(1-(3,6-dimethyl-2-(3-methyloxetan-3-yl)-4-oxo-3,4-d ihydroquinazolin-8-yl)ethylidene)-2- methylpropane-2-sulfinamide (136 mg, crude) as a yellow oil for the next step without further purification. LCMS: (M + H) + =390.1 [0785] Step 5: To a solution of crude (R,Z)-N-(1-(3,6-dimethyl-2-(3-methyloxetan-3-yl)-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (136 mg, 0.349 mmol) and CeCl 3 .7H 2 O (65.2 mg, 0.175 mmol) in MeOH (10 mL) was added NaBH 4 (39.9 mg, 1.05 mmol) in portions at -78 ° C. The mixture was warmed to RT and stirred overnight. The mixture was quenched with a saturated solution of NH 4 Cl (20 mL) and extracted with DCM (20 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method A) to afford (R)-N-((R)-1-(3,6-dimethyl-2-(3- methyloxetan-3-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2 -methylpropane-2-sulfinamide (54 mg, 39.5%) as a yellow solid. LCMS: (M + H) + =392.2 [0786] Step 6: A mixture (R)-N-((R)-1-(3,6-dimethyl-2-(3-methyloxetan-3-yl)-4-oxo-3,4 -dihydroquinazolin-8- yl)ethyl)-2-methylpropane-2-sulfinamide (54 mg, 0.138 mmol) in a solution of HCl in MeOH (2 mL, 4 M) was stirred at RT for 30 min. The mixture was poured into ice-water and adjusted pH = 8 with a saturated solution of NaHCO 3 , The mixture was extracted with DCM: MeOH (20 mL*3, 10/1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(3- methyloxetan-3-yl)quinazolin-4(3H)-one (40 mg, crude) as a yellow solid. LCMS: (M + H) + =288.3 [0787] Step 7: To a mixture of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(3-methyloxetan-3-yl)qui nazolin-4(3H)-one (40 mg, 0.139 mmol) and methyl 6-chloro-3-fluoropicolinate (39.5 mg, 0.209 mmol) in DMSO (3 mL) was added DIPEA (53.9 mg, 0.418 mmol), the mixture was heated to 100 °C and stirred for 3 h. Cooling to RT, H 2 O (20 mL) was added and the mixture was extracted with EtOAc (20 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford methyl (R)-6-chloro-3-((1-(3,6-dimethyl-2-(3-methyloxetan-3- yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinate (50 mg, 78.7%) as a yellow solid. LCMS: (M + H) + = 457.1 [0788] Step 8: To a solution of methyl (R)-6-chloro-3-((1-(3,6-dimethyl-2-(3-methyloxetan-3-yl)-4-o xo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (50 mg, 0.109 mmol) in MeOH (5 mL) and H 2 O (1 mL) was added LiOH (23.0 mg, 0.548 mmol). The mixture was stirred at 50 °C for 2 h. The mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM/MeOH (20 mL*3, 10/1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to afford (R)-6- chloro-3-((1-(3,6-dimethyl-2-(3-methyloxetan-3-yl)-4-oxo-3,4 -dihydroquinazolin-8-yl)ethyl)amino)picolinic acid (9.4 mg, 19.4%) as a white solid. LCMS: (M + H) + = 443.1 EXAMPLE 103 6-chloro-3-(((1R)-1-(3,6-dimethyl-2-(3-methyltetrahydrofuran -3-yl)-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0789] Step 1: To a mixture of 2-amino-3-bromo-N,5-dimethylbenzamide (1.1 g, 4.55 mmol), 3- methyltetrahydrofuran-3-carboxylic acid (0.71 g, 5.46 mmol) and CMPI (2.32 g, 9.1 mmol) in THF (50 ml) was added DIPEA (1.76 g, 13.65 mmol). The mixture was stirred at 75 °C overnight. Cooling to RT, water (50 ml) was added and the mixture was extracted with EtOAc (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (DCM: MeOH = 50:1) to afford N-(2-bromo-4-methyl-6-(methylcarbamoyl)phenyl)-3-methyltetra hydrofuran-3-carboxamide (1.5 g, 93%) as a pale solid. LCMS: (M + H) + =355.1 [0790] Step 2: To a mixture of N-(2-bromo-4-methyl-6-(methylcarbamoyl)phenyl)-3-methyltetra hydrofuran-3- carboxamide (1.5 g, 4.2 mmol) and I2 (1.07 g, 4.2 mmol) in DCM (50 ml) was added HMDS (2.03 g, 12.6 mmol). The mixture was stirred at 50 °C overnight. Cooling to RT, the mixture was washed with a saturated solution of Na 2 S 2 SO 3 (50 ml*2) and washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE:EA = 5:1) to afford 8-bromo-3,6-dimethyl-2-(3-methyltetrahydrofuran-3-yl)quinazo lin-4(3H)- one (1.3 g, 92%) as a white solid. LCMS: (M + H)+ =337.0 [0791] Step 3: To a mixture of 8-bromo-3,6-dimethyl-2-(3-methyltetrahydrofuran-3-yl)quinazo lin-4(3H)-one (1.3 g, 3.9 mmol) and tributyl(1-ethoxyvinyl)stannane (2.82 g, 7.8 mmol) in dioxane (50 ml) was added Pd(PPh 3 ) 2 Cl 2 (274 mg, 0.39 mmol). The mixture was stirred at 100 °C under N 2 for 6 h. HCl (4 ml, 1 M) was added into the mixture and stirred at 50 °C for 0.5 hour, then a saturated solution of KF (40 ml) and stirred at RT for 0.5 hour. The gray suspension was filtered. The filter cake was washed with EtOAc (50 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE:EA = 10:1-4:1) to afford 8-acetyl-3,6-dimethyl-2-(3-methyltetrahydrofuran-3-yl)quinaz olin-4(3H)-one (1.1 g, 94%) as a yellow solid. LCMS: (M + H) + =301.1 [0792] Step 4: To a mixture of 8-acetyl-3,6-dimethyl-2-(3-methyltetrahydrofuran-3-yl)quinaz olin-4(3H)-one (1.1 g, 3.7 mmol) and (R)-2-methylpropane-2-sulfinamide (0.895 g, 7.4 mmol) in THF (20 ml) was added Ti(O-iPr) 4 (20 ml), the mixture was stirred at 75 °C for 24 h. Cooling to RT, Brine (50 ml) was added and stirred at RT for 0.5 hour, the mixture was filtrated and the cake was washed with EtOAc (50 ml*3), the separated aqueous was extracted with EtOAc (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R)-N-((Z)-1-(3,6-dimethyl-2-(3-methyltetrahydrofuran-3-yl)- 4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (1.5 g, 100%) as a yellow oil for the next step without further purification. LCMS: (M + H)+ =404.0 [0793] Step 5: To a mixture of crude (R)-N-((Z)-1-(3,6-dimethyl-2-(3-methyltetrahydrofuran-3-yl)- 4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (1.5 g, 3.7 mmol) and HOAc (1.79 g, 29.76 mmol) in DCM (40 ml) and MeOH (40 ml) was added NaBH 3 CN (703 mg, 11.16 mmol) slowly at 0 °C. the mixture was stirred for 2 h. A saturated solution of NH 4 Cl (50 ml) was added and the mixture was extracted with DCM (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (method A) to (R)-N-((1R)-1-(3,6-dimethyl-2-(3-methyltetrahydrofuran-3-yl) -4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (700 mg, 46%) as a yellow solid. LCMS: (M + H)+ =406.0 [0794] Step 6: A mixture of (R)-N-((1R)-1-(3,6-dimethyl-2-(3-methyltetrahydrofuran-3-yl) -4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (250 mg, 0.62 mmol) in a solution of HCl in MeOH (10 ml, 4 M) was stirred at RT for 10 min. The mixture was poured into ice-water and adjusted PH= 8-9 with a saturate solution of NaHCO 3 , the mixture was extracted with DCM/MeOH (30 ml*3, 10/1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford 8-((R)-1-aminoethyl)-3,6-dimethyl-2- (3-methyltetrahydrofuran-3-yl)quinazolin-4(3H)-one (180 mg, 96%) as a yellow solid. LCMS: (M + H)+ =302.3 [0795] Step 7: To a mixture of 8-((R)-1-aminoethyl)-3,6-dimethyl-2-(3-methyltetrahydrofuran -3-yl)quinazolin- 4(3H)-one (180 mg, 0.6 mmol) and methyl 6-chloro-3-fluoropicolinate (170 mg, 0.9 mmol) in DMSO (10 ml) was added DIPEA (232 mg, 1.8 mmol), the mixture was heated to 90 °C for 16 h. Cooling to RT, water (50 ml) was added and the mixture was extracted with EtOAc (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-TLC (DCM: EA = 10:1) to afford methyl 6- chloro-3-(((1R)-1-(3,6-dimethyl-2-(3-methyltetrahydrofuran-3 -yl)-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinate (190 mg, 67%) as a white solid. LCMS: (M + H) + =471.1 [0796] Step 8: To a mixture of methyl 6-chloro-3-(((1R)-1-(3,6-dimethyl-2-(3-methyltetrahydrofuran -3-yl)-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinate (190 mg, 0.4 mmol) in MeOH (10 ml) and H 2 O (2 ml) was added LiOH (96 mg, 4.0 mmol). The mixture was stirred at 50 °C for 4 h. The mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to afford 6-chloro-3-(((1R)-1-(3,6- dimethyl-2-(3-methyltetrahydrofuran-3-yl)-4-oxo-3,4-dihydroq uinazolin-8-yl)ethyl)amino)picolinic acid (122.8 mg, 66%) as a white solid. LCMS: (M + H) + =457.1 EXAMPLE 104 (R)-6-chloro-3-((1-(2-ethyl-3,6-dimethyl-4-oxo-3,4-dihydroqu inazolin-8-yl)ethyl)amino)picolinic acid [0797] Step 1: To a solution of 2-amino-3-bromo-N,5-dimethylbenzamide (2 g, 8.2 mmol) and DIPEA (4.3 mL) in THF (60 mL) was added propionyl chloride (1.13 g, 12.3 mmol) in portions at 0 °C. The resulting mixture was stirred at 0 °C for 3 h. Water (60 mL) was added and the mixture was extracted with DCM (100 mL×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by silica gel column chromatography (DCM: MeOH=20:1) to give 3-bromo-N,5-dimethyl-2- propionamidobenzamide (1.5 g, 61%) as a white solid. LCMS (ESI) m/z: [M+H] + = 299.1 [0798] Step 2: To a solution of 3-bromo-N,5-dimethyl-2-propionamidobenzamide (1.5 g, 7.5 mmol) in DCM (50 mL) were added I2 (1.9 g, 7.5 mmol) and HMDS (3.6 g, 22.5 mmol) at RT. The resulting mixture was heated to 50 °C and stirred overnight. Cooling to RT, a saturated aqueous Na 2 S 2 O 3 (40 mL) solution was added and the mixture was extracted with DCM (100 mL×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by silica gel column chromatography (PE: EA=5:1) to give 8-bromo-2-ethyl-3,6-dimethylquinazolin-4(3H)-one (1.4 g, 67%) as a white solid. LCMS (ESI) m/z: [M+H] + = 281.1 [0799] Step 3: To a solution of 8-bromo-2-ethyl-3,6-dimethylquinazolin-4(3H)-one (1.4 g, 5 mmol) in dioxane (30 mL) were added tributyl(1-ethoxyvinyl)stannane (3.6 g, 10 mmol) and Pd(PPh 3 ) 2 Cl 2 (350 mg, 0.5 mmol) at RT. The resulting mixture was heated to 95 °C and stirred for 12 h under N 2 . HCl (8 mL, 1 M) was added into the mixture and the mixture was stirred at 50 °C for 0.5 hour., then saturated KF (100 mL) was added and the resulting mixture was stirred at RT for 0.5 hour. The gray suspension was filtered, the filter cake was washed with EtOAc (80 mL×3), the aqueous phase was extracted with EtOAc (60 mL×3) and the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by silica gel column chromatography (PE: EA=3:1) to give 8-acetyl-2-ethyl-3,6-dimethylquinazolin-4(3H)-one (1 g, 82%) as a white solid. LCMS (ESI) m/z: [M+H] + = 245.2 [0800] Step 4: To a solution of 8-acetyl-2-ethyl-3,6-dimethylquinazolin-4(3H)-one (1 g, 4.1 mmol) in THF (15 mL) were added Ti(i-PrO) 4 (15 mL) and (R)-2-methylpropane-2-sulfinamide (993 mg, 8.2 mmol) at RT. The resulting mixture was heated to 75 °C and stirred overnight. Cooling to RT, brine (15 mL) was added into the mixture. The suspension was filtered. The filter cake was washed with EtOAc (80 mL×3). The aqueous phase was extracted with EtOAc (50 mL×3) and the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give (R,Z)-N-(1-(2-ethyl-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (1.2 g, 87%) as a yellow oil. LCMS (ESI) m/z: [M+H] + = 348.1 [0801] Step 5: To a mixture of (R,Z)-N-(1-(2-ethyl-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin -8-yl)ethylidene)-2- methylpropane-2-sulfinamide (1.2 g, 3.6 mmol) and HOAc (2.0 mL) in DCM (15 mL) and MeOH (15 mL) was added NaBH 3 CN (670 mg, 10.8 mmol) in portions at 0 °C. The mixture was stirred at 20 °C for 3 h. The mixture was quenched with saturated NH 4 Cl (70 mL) and extracted with DCM (100 mL x 2). The combined extract was washed with brine, dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by Prep-HPLC (Method A) to give (R)-N-((R)-1-(2-ethyl-3,6-dimethyl-4-oxo-3,4-dihydroquinazol in-8-yl)ethyl)-2-methylpropane-2- sulfinamide (800 mg, 63.6%) as a white solid. LCMS (ESI) m/z: [M+H] + = 350.0 [0802] Step 6: A mixture (R)-N-((R)-1-(2-ethyl-3,6-dimethyl-4-oxo-3,4-dihydroquinazol in-8-yl)ethyl)-2- methylpropane-2-sulfinamide (800 mg, 2.29 mmol) in a solution of HCl in MeOH (3M, 15 mL) was stirred at RT for 10 minutes. The mixture was adjusted to pH = 9 with saturated aqueous NaHCO 3 solution and the mixture was extracted with DCM (50 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give (R)-8-(1-aminoethyl)-2-ethyl-3,6-dimethylquinazolin-4(3H)-on e (250 mg, 44.5%) as a yellow solid. LCMS (ESI) m/z: [M+H] + = 246.3 [0803] Step 7: To a solution of (R)-8-(1-aminoethyl)-2-ethyl-3,6-dimethylquinazolin-4(3H)-on e (100 mg, 0.41 mmol) in DMSO (3 mL) were added methyl 6-chloro-3-fluoropicolinate (154 mg, 0.82 mmol) and DIPEA (0.25 mL) at RT. The resulting mixture was stirred at 100 °C overnight. The mixture was diluted with water (20 mL) and extracted with EtOAc (40 mL×3), washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give methyl (R)-6-chloro-3-((1-(2-ethyl-3,6-dimethyl-4-oxo-3,4-dihydroqu inazolin-8- yl)ethyl)amino)picolinate (150 mg, 88%) as a yellow solid. LCMS (ESI) m/z: [M+H] + = 415.1 [0804] Step 8: To a solution of methyl (R)-6-chloro-3-((1-(2-ethyl-3,6-dimethyl-4-oxo-3,4-dihydroqu inazolin-8- yl)ethyl)amino)picolinate (150 mg, 0.36 mmol) in MeOH (2 mL) and THF(2 mL) were added LiOH (76 mg, 1.8 mmol) and H 2 O (1 mL) at RT. The resulting mixture was heated to 50 °C and stirred for 1 hour. The mixture was adjusted to pH = 4 with HCl solution and diluted with water (40 mL), the mixture was extracted with DCM (40 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by Prep-HPLC (Method B) to give (R)-6-chloro-3-((1-(2-ethyl-3,6-dimethyl-4-oxo-3,4-dihydroqu inazolin-8- yl)ethyl)amino)picolinic acid (56.2 mg, 39%) as a white solid. LCMS (ESI) m/z: [M+H] + = 401.1 EXAMPLE 105 (R)-6-chloro-3-((1-(2-(2-chlorophenyl)-3,6-dimethyl-4-oxo-3, 4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0805] Step 1: To a solution of 2-amino-3-bromo-N,5-dimethylbenzamide (2 g, 8.3 mmol) in DMSO (40 mL) was added 2-chlorobenzaldehyde (1.74 g, 12.4 mmo) at RT. The resulting mixture was heated to 130 °C and stirred overnight under O 2 . Cooling to RT, the mixture was poured into water (200 mL) and stirred for 15 minutes, the suspension was filtered and the collected solid was dried to provide 8-bromo-2-(2-chlorophenyl)-3,6- dimethylquinazolin-4(3H)-one (1.5 g, 50%) as a white solid. LCMS (ESI) m/z: [M+H] + = 362.8 [0806] Step 2: To a solution of 8-bromo-2-(2-chlorophenyl)-3,6-dimethylquinazolin-4(3H)-one (1.4 g, 3.8 mmol) in dioxane (30 mL) were added tributyl(1-ethoxyvinyl)stannane (2.8 g, 10 mmol) and Pd(PPh 3 ) 2 Cl 2 (280 mg, 0.4 mmol) at RT. The resulting mixture was heated to 95 °C and stirred for 12 h under N 2 . HCl (4 mL, 1 M) was added into the mixture and the mixture was stirred at 50 °C for 0.5 hour. A saturated KF (100 mL) was added and the resulting mixture was stirred at 20 °C for 0.5 hour. The gray suspension was filtered and the filter cake was washed with EtOAc (80 mL×3). The aqueous phase was extracted with EtOAc (60 mL×3) and the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by silica gel column chromatography (PE: EA=3:1) to give 8-acetyl-2-(2-chlorophenyl)-3,6-dimethylquinazolin-4(3H)- one (1.2 g, 82%) as a white solid. LCMS (ESI) m/z: [M+H] + = 327.2 [0807] Step 3: To a solution of 8-acetyl-2-(2-chlorophenyl)-3,6-dimethylquinazolin-4(3H)-one (1.2 g, 3.6 mmol) in THF (15 mL) were added Ti(i-PrO) 4 (15 mL) and (R)-2-methylpropane-2-sulfinamide (580 mg, 7.2 mmol) at RT. The resulting mixture was heated to 75 °C and stirred overnight. Brine (15 mL) was added into the mixture. The suspension was filtered and the filter cake was washed with EtOAc (80 mL×3). The aqueous phase was extracted with EtOAc (100 mL×3) and the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give (R,Z)-N-(1-(2-(2-chlorophenyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (1.5 g, 97%) as a yellow solid. LCMS (ESI) m/z: [M+H] + = 430.0 [0808] Step 4: To a solution of (R,Z)-N-(1-(2-(2-chlorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydr oquinazolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (1.5 g, 3.5 mmol) and CeCl 3 .7H 2 O (651 mg, 1.75 mmol) in MeOH (15 mL) was added NaBH 4 (400 mg, 10.5 mmol) in portions at -78 °C slowly. The resulting mixture was warmed RT and stirred overnight. The mixture was quenched with saturated NH 4 Cl (100 mL) and extracted with DCM (100 mL x 2), the combined extract was washed with brine, dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by Prep-HPLC (Method A) to give (R)-N-((R)-1-(2-(2-chlorophenyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (800 mg, 53%) as a white solid. LCMS (ESI) m/z: [M+H] + = 432.1 [0809] Step 5: A mixture (R)-N-((R)-1-(2-(2-chlorophenyl)-3,6-dimethyl-4-oxo-3,4-dihy droquinazolin-8-yl)ethyl)- 2-methylpropane-2-sulfinamide (800 mg, 1.86 mmol) in a solution of HCl in MeOH (3M, 8 mL) was stirred at RT for 10 minutes. The mixture was adjusted to pH = 9 with saturated aqueous NaHCO 3 solution and extracted with DCM (150 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give (R)-8-(1-aminoethyl)-2-(2-chlorophenyl)-3,6-dimethylquinazol in-4(3H)-one (300 mg, 49.3%) as a yellow solid. LCMS (ESI) m/z: [M+H] + = 328.2 [0810] Step 6: To a solution of (R)-8-(1-aminoethyl)-2-(2-chlorophenyl)-3,6-dimethylquinazol in-4(3H)-one (150 mg, 0.46 mmol) in DMSO (3 mL) were added methyl 6-chloro-3-fluoropicolinate (174 mg, 0.92 mmol) and DIPEA (0.25 mL) at RT. The resulting mixture was stirred at 100 °C for 12 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (70 mL×3), the combined organic phase was washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give methyl (R)-6-chloro-3-((1-(2-(2-chlorophenyl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picoli nate (150 mg, 65%) as a yellow solid. LCMS (ESI) m/z: [M+H] + = 496.9 [0811] Step 7: To a solution of methyl (R)-6-chloro-3-((1-(2-(2-chlorophenyl)-3,6-dimethyl-4-oxo-3, 4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (150 mg, 0.3 mmol) in MeOH (2 mL) and THF (2 mL) were added LiOH (76 mg, 1.8 mmol) and H 2 O (1 mL) at RT. The resulting mixture was heated to 50 °C and stirred for 1 hour. The mixture was adjusted to pH = 4 with HCl solution and diluted with water (40 mL), the mixture was extracted with DCM (40 mL x 3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by Prep-HPLC (Method B) to give (R)-6-chloro-3-((1-(2-(2-chlorophenyl)- 3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)pi colinic acid (56.8 mg, 39%) as a white solid. LCMS (ESI) m/z: [M+H] + = 483.1 EXAMPLE 106 (R)-3-((1-(2-(bicyclo[1.1.1]pentan-1-yl)-3,6-dimethyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)-6- chloropicolinic acid [0812] Step 1: To a solution of 2-amino-3-bromo-N,5-dimethylbenzamide (1.6 g, 6.61 mmol) in anhydrous THF (20 mL) were added bicyclo[1.1.1]pentane-1-carboxylic acid (1.48 g, 13.2 mmol), CMPI (5.06 g, 19.8 mmol) and DIPEA (2.56 g, 19.8 mmol) at RT. The mixture was heated to 80 °C and stirred overnight. Water (50 mL) was added and the mixture was extracted with DCM (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated, The residue was purified by chromatography (PE: EA = 3:1) to afford N-(2- bromo-4-methyl-6-(methylcarbamoyl)phenyl)bicyclo[1.1.1]penta ne-1-carboxamide (2.1 g, 94.5%) as a yellow solid. LCMS: (M + H) + =339.0 [0813] Step 2: To a solution of N-(2-bromo-4-methyl-6-(methylcarbamoyl)phenyl)bicyclo[1.1.1] pentane-1- carboxamide (2.1 g, 6.25 mmol) in DCM (50 mL) were added I2 (1.75 mg, 6.88 mmol) and HMDS (3.02 g, 18.7 mmol) at room temperature. The mixture was stirred at 50 °C for 5 h. Cooling to RT, the mixture was washed with a saturated solution of Na 2 S 2 O 3 (200 mL x3) and brine, dried over Na 2 SO 4 and concentrated under vacuum to get a residue which was purified by chromatography (PE: EA = 5:1) to afford 2-(bicyclo[1.1.1]pentan-1-yl)-8- bromo-3,6-dimethylquinazolin-4(3H)-one (1.9 g, 95.6%) as a yellow solid. LCMS: (M + H) + =321.0 [0814] Step 3: To a mixture of 2-(bicyclo[1.1.1]pentan-1-yl)-8-bromo-3,6-dimethylquinazolin -4(3H)-one (1.9 g, 5.97 mmol) and ethyl tributylstannanecarboxylate (4.33 g, 11.9 mmol) in Dioxane (40 mL) was added Pd(PPh 3 ) 2 Cl 2 (875 mg, 1.19 mmol). The mixture was stirred at 105 °C under N 2 overnight. HCl (6 mL, 1 M) was added into the mixture and stirred at 50 °C for 30 min, then 30 mL sat. KF was added and the mixture was stirred at RT for 30 min. the gray was filtered, the filter cake was washed with EtOAc (50 mL*3), the separated aqueous phase was extracted with EtOAc (50 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 30%) to afford 8-acetyl-2- (bicyclo[1.1.1]pentan-1-yl)-3,6-dimethylquinazolin-4(3H)-one (1.4 g, 83.1%) as a yellow solid. LCMS: (M + H) + =283.2 [0815] Step 4: To a mixture of 8-acetyl-2-(bicyclo[1.1.1]pentan-1-yl)-3,6-dimethylquinazoli n-4(3H)-one (1.4 g, 4.96 mmol) and (R)-2-methylpropane-2-sulfinamide (1.20 g, 9.93 mmol) in THF (30 mL) at RT was added Ti(i- PrO) 4 (17.9 g, 49.6 mmol). The mixture was stirred at 75 °C for 48 h. Cooling to RT, brine (50 mL) was added and the mixture was stirred for 0.5 hour. The resulting mixture was filtrated and the cake was washed with EtOAc (80 mL*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)-N-(1-(2-(bicyclo[1.1.1]pentan-1-yl)-3,6-dimethyl-4-oxo -3,4-dihydroquinazolin-8-yl)ethylidene)-2- methylpropane-2-sulfinamide (2.2 g, crude) as a yellow oil for the next step without further purification. LCMS: (M + H) + =386.3 [0816] Step 5: To a solution of crude (R,Z)-N-(1-(2-(bicyclo[1.1.1]pentan-1-yl)-3,6-dimethyl-4-oxo -3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (2.2 g, 5.71 mmol) and HOAc (3.89 g, 39.7 mmol) in DCM (20 mL) and MeOH (20 mL) was added NaBH 3 CN (923 mg, 14.9 mmol) in portions at 0 °C, the mixture was stirred at RT overnight. The mixture was quenched with a saturated solution of NH 4 Cl (50 ml) and extracted with DCM (80 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (method A) to afford (R)-N-((R)-1-(2-(bicyclo[1.1.1]pentan- 1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2 -methylpropane-2-sulfinamide (670 mg, 34.9%) as a yellow solid. LCMS: (M + H) + =388.2 [0817] Step 6: A mixture (R)-N-((R)-1-(2-(bicyclo[1.1.1]pentan-1-yl)-3,6-dimethyl-4-o xo-3,4-dihydroquinazolin- 8-yl)ethyl)-2-methylpropane-2-sulfinamide (670 mg, 1.73 mmol) in a solution of HCl in MeOH (10 mL, 4 M) was stirred at RT for 30 min. The mixture was poured into ice-water and adjusted pH= 8 with a saturated solution of NaHCO 3 , The mixture was extracted with DCM/MeOH (60 mL*5, 10/1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford (R)-8-(1-aminoethyl)-2-(bicyclo[1.1.1]pentan-1-yl)-3,6- dimethylquinazolin-4(3H)-one (520 mg, crude) as a yellow solid. LCMS: (M + H) + =284.1 [0818] Step 7: To a mixture of (R)-8-(1-aminoethyl)-2-(bicyclo[1.1.1]pentan-1-yl)-3,6-dimet hylquinazolin-4(3H)- one (200 mg, 0.707 mmol) and methyl 6-chloro-3-fluoropicolinate (200 mg, 1.06 mmol) in DMSO (10 mL) was added DIPEA (273 mg, 2.12 mmol). The mixture was heated to 100 °C and stirred for 12 h. Cooling to RT, H 2 O (100 mL) was added and the mixture was extracted with EtOAc (50 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford methyl (R)-3-((1-(2-(bicyclo[1.1.1]pentan-1-yl)- 3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)-6 -chloropicolinate (230 mg, 72.0%) as a yellow solid. LCMS: (M + H) + = 453.1 [0819] Step 8: To a solution of methyl (R)-3-((1-(2-(bicyclo[1.1.1]pentan-1-yl)-3,6-dimethyl-4-oxo- 3,4- dihydroquinazolin-8-yl)ethyl)amino)-6-chloropicolinate (230 mg, 0.509 mmol) in MeOH (10 mL) and H 2 O (2 mL) was added LiOH (107 mg, 2.54 mmol). The mixture was stirred at RT for 3 h. The mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM (40 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to afford (R)-3-((1-(2- (bicyclo[1.1.1]pentan-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroqu inazolin-8-yl)ethyl)amino)-6-chloropicolinic acid (106.8 mg, 47.9%) as a white solid. LCMS: (M + H) + = 439.2 EXAMPLE 107 (R)-6-chloro-3-((1-(2-(1-fluorocyclopropyl)-3,6-dimethyl-4-o xo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0820] Step 1: To a solution of 2-amino-3-bromo-N,5-dimethylbenzamide (1.5 g, 6.20 mmol) in anhydrous THF (20 mL) were added 1-fluorocyclopropane-1-carboxylic acid(967 mg, 9.30 mmol), CMPI (4.74 g, 18.6 mmol) and DIPEA (2.40 g, 18.6 mmol) at RT. The mixture was stirred at 100 °C for 5 h in a microwave in sealed tube. Water (100 mL) was added, the separated aqueous layer was extracted with DCM (100 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated, The residue was purified by chromatography (PE: EA = 3:1) to afford 3-bromo-2-(1-fluorocyclopropane-1-carboxamido)-N,5- dimethylbenzamide (1.0 g, 49.2%) as a yellow solid. LCMS: (M + H) + =331.0 [0821] Step 2: To a solution of 3-bromo-2-(1-fluorocyclopropane-1-carboxamido)-N,5-dimethylb enzamide (1.0 g, 3.05 mmol) in DCM (50 mL) were added I2 (852 mg, 3.35 mmol) and HMDS (1.47g, 9.15 mmol) at RT. The mixture was stirred at 50 °C for 5 h. Cooling to RT, the resulting mixture was washed with a saturated solution of Na 2 S 2 O 3 (100 mL x3) and brine, dried over Na 2 SO 4 and concentrated under vacuum to get a residue which was purified by chromatography (PE: EA = 5:1) to afford 8-bromo-2-(1-fluorocyclopropyl)-3,6-dimethylquinazolin- 4(3H)-one (900 mg, 95.2%) as a yellow solid. LCMS: (M + H) + =313.1 [0822] Step 3: To a mixture of 8-bromo-2-(1-fluorocyclopropyl)-3,6-dimethylquinazolin-4(3H) -one (900 mg, 2.90 mmol) and ethyl tributylstannanecarboxylate (1.58 g, 4.35 mmol) in dioxane (20 mL) was added Pd(PPh 3 ) 2 Cl 2 (425 mg, 0.581 mmol). The mixture was stirred at 105 °C under N 2 overnight. HCl (3 mL, 1 M) was added and the mixture was stirred at 50 °C for 0.5 hour, then 15 ml sat. KF was added and the mixture was stirred at rt for 0.5 hour. The gray was filtered, the filter cake was washed with EtOAc (50 mL*3), the separated aqueous phase was extracted with EtOAc (50 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 30%) to afford 8-acetyl-2-(1- fluorocyclopropyl)-3,6-dimethylquinazolin-4(3H)-one (430 mg, 54.1%) as a yellow solid. LCMS: (M + H) + =275.1 [0823] Step 4: To a mixture of 8-acetyl-2-(1-fluorocyclopropyl)-3,6-dimethylquinazolin-4(3H )-one (430 mg, 1.57 mmol) and (R)-2-methylpropane-2-sulfinamide (380 mg, 3.14 mmol) in THF (20 mL) at RT was added Ti(i-PrO) 4 (5.67 g, 15.7 mmol). The mixture was stirred at 75 °C for 48 h. Cooling to RT, brine (50 mL) was added and the mixture was stirred for 0.5 hour. The resulting mixture was filtrated and the cake was washed with EtOAc (100 mL*3), the filters were washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)-N-(1-(2-(1- fluorocyclopropyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin- 8-yl)ethylidene)-2-methylpropane-2-sulfinamide (700 mg, crude) as a yellow oil for the next step without further purification. LCMS: (M + H) + =378.3 [0824] Step 5: To a mixture of (R,Z)-N-(1-(2-(1-fluorocyclopropyl)-3,6-dimethyl-4-oxo-3,4-d ihydroquinazolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (700 mg, 1.86 mmol) and HOAc (1.23 g, 12.6 mmol) in DCM (20 mL) and MeOH (20 mL) was added NaBH 3 CN (292 mg, 4.71 mmol) in portions at 0 °C. the mixture was stirred at RT overnight. The reaction was quenched with a saturated solution of NH 4 Cl (50 mL) and extracted with DCM (50 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method A) to afford (R)-N-((R)-1-(2-(1-fluorocyclopropyl)-3,6-dimethyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinam ide (240 mg, 40.4%) as a yellow solid. LCMS: (M + H) + =380.1 [0825] Step 6: A mixture (R)-N-((R)-1-(2-(1-fluorocyclopropyl)-3,6-dimethyl-4-oxo-3,4 -dihydroquinazolin-8- yl)ethyl)-2-methylpropane-2-sulfinamide (240 mg, 0.633 mmol) in a solution of HCl in MeOH (5 mL, 4 M) was stirred at RT for 10 min. The mixture was poured into ice-water and adjusted pH= 8 with a saturated solution of NaHCO 3 , the mixture was extracted with DCM/MeOH (30 mL*3, 10/1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford (R)-8-(1-aminoethyl)-2-(1-fluorocyclopropyl)-3,6- dimethylquinazolin-4(3H)-one (220 mg, crude) as a yellow solid. LCMS: (M + H) + =276.1 [0826] Step 7: To a mixture of (R)-8-(1-aminoethyl)-2-(1-fluorocyclopropyl)-3,6-dimethylqui nazolin-4(3H)-one (200 mg, 0.727 mmol) and methyl 6-chloro-3-fluoropicolinate (206 mg, 1.09 mmol) in DMSO (10 mL) was added DIPEA (281 mg, 2.18 mmol). The mixture was heated to 100 °C and stirred for 12 h. Cooling to RT, H 2 O (50 mL) was added and the mixture was extracted with EtOAc (50 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford methyl (R)-6-chloro-3-((1-(2-(1-fluorocyclopropyl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picoli nate (150 mg, 46.5%) as a yellow solid. LCMS: (M + H) + = 455.2 [0827] Step 8: To a solution of methyl (R)-6-chloro-3-((1-(2-(1-fluorocyclopropyl)-3,6-dimethyl-4-o xo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (150 mg, 0.338 mmol) in MeOH (5 mL) and H 2 O (1 mL) was added LiOH (70.9 mg, 1.69 mmol). The mixture was stirred at 50 °C for 3 h. The mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM: MeOH (30 mL*3, 10/1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to afford (R)-6-chloro-3- ((1-(2-(1-fluorocyclopropyl)-3,6-dimethyl-4-oxo-3,4-dihydroq uinazolin-8-yl)ethyl)amino)picolinic acid (58.6 mg, 40.3%) as a white solid. LCMS: (M + H) + = 431.1 EXAMPLE 108 6-chloro-3-(((1R)-1-(3,6-dimethyl-2-(2-methyltetrahydrofuran -2-yl)-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0828] Step 1: To a mixture of 2-amino-3-bromo-N,5-dimethylbenzamide (1.3 g, 5.37 mmol), 2- methyltetrahydrofuran-2-carboxylic acid (838 mg, 6.44 mmol) and CMPI (2.74 g, 10.74 mmol) in THF (50 ml) was added DIPEA (2.08 g, 16.11 mmol). The mixture was stirred at 75 °C for 24 h. Cooling to RT, water (50 ml) was added and the mixture was extracted with EtOAc (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (DCM: MeOH = 50:1) to afford N-(2-bromo-4-methyl-6-(methylcarbamoyl)phenyl)-2-methyltetra hydrofuran-2-carboxamide (1.3 g, 68%) as a yellow solid. LCMS: (M + H) + =355.1 [0829] Step 2: To a mixture of N-(2-bromo-4-methyl-6-(methylcarbamoyl)phenyl)-2-methyltetra hydrofuran-2- carboxamide (1.3 g, 3.67 mmol) and I 2 (0.93 g, 3.67 mmol) in DCM (50 ml) was added HMDS (1.77 g, 11.01 mmol). The mixture was stirred at 50 °C overnight. Cooling to RT, the mixture was washed with a saturated solution of Na 2 S 2 SO 3 (50 ml*2) and washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (DCM:EA = 20:1) to afford 8-bromo-3,6-dimethyl-2-(2-methyltetrahydrofuran-2- yl)quinazolin-4(3H)-one (1.0 g, 81%) as a white solid. LCMS: (M + H)+ =337.1 [0830] Step 3: To a mixture of 8-bromo-3,6-dimethyl-2-(2-methyltetrahydrofuran-2-yl)quinazo lin-4(3H)-one (1.0 g, 3.0 mmol) and tributyl(1-ethoxyvinyl)stannane (2.17 g, 6.0 mmol) in dioxane (30 ml) was added Pd(PPh 3 ) 2 Cl 2 (211 mg, 0.3 mmol). The mixture was stirred at 100 °C under N 2 for 16 h. HCl (3 ml, 1 M) was added into the mixture and stirred at 50 °C for 0.5 hour, then a saturated solution of KF (40 ml) and stirred at RT for 0.5 hour. The gray suspension was filtered. The filter cake was washed with EtOAc (50 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE:EA = 10:1-4:1) to afford 8-acetyl-3,6-dimethyl-2-(2-methyltetrahydrofuran-2-yl)quinaz olin-4(3H)-one (0.8 g, 88%) as a yellow solid. LCMS: (M + H) + =301.2 [0831] Step 4: To a mixture of 8-acetyl-3,6-dimethyl-2-(2-methyltetrahydrofuran-2-yl)quinaz olin-4(3H)-one (0.8 g, 2.67 mmol) and (R)-2-methylpropane-2-sulfinamide (0.65 g, 5.34 mmol) in THF (15 ml) was added Ti(O-iPr) 4 (15 ml), the mixture was stirred at 75 °C for 24 h. Cooling to rt, Brine (50 ml) was added and stirred at RT for 0.5 hour, the mixture was filtrated and the cake was washed with EtOAc (50 ml*3), the separated aqueous was extracted with EtOAc (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R)-N-((Z)-1-(3,6-dimethyl-2-(2-methyltetrahydrofuran-2-yl)- 4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (1.07 g, 100%) as a yellow oil for the next step without further purification. LCMS: (M + H)+ =404. [0832] Step 5: To a mixture of crude (R)-N-((Z)-1-(3,6-dimethyl-2-(2-methyltetrahydrofuran-2-yl)- 4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (1.07 g, 2.67 mmol) and HOAc (1.28 g, 21.36 mmol) in DCM (20 ml) and MeOH (20 ml) was added NaBH 3 CN (505 mg, 8.01 mmol) slowly at 0 °C. the mixture was stirred for 2 h. A saturated solution of NH 4 Cl (50 ml) was added and the mixture was extracted with DCM (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (method A) to (R)-N-((1R)-1-(3,6-dimethyl-2-(2-methyltetrahydrofuran-2-yl) -4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (330 mg, 31%) as a yellow solid. LCMS: (M + H)+ =406.0 [0833] Step 6: A mixture of to (R)-N-((1R)-1-(3,6-dimethyl-2-(2-methyltetrahydrofuran-2-yl) -4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (330 mg, 0.81 mmol) in a solution of HCl in MeOH (10 ml, 4 M) was stirred at rt for 1 hour. The mixture was poured into ice-water and adjusted PH= 8-9 with a saturate solution of NaHCO 3 , the mixture was extracted with DCM/MeOH (40 ml*3, 10/1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford 8-((R)-1-aminoethyl)-3,6-dimethyl-2- (2-methyltetrahydrofuran-2-yl)quinazolin-4(3H)-one (240 mg, 98%) as a yellow solid. LCMS: (M + H)+ =302.3 [0834] Step 7: To a mixture of 8-((R)-1-aminoethyl)-3,6-dimethyl-2-(2-methyltetrahydrofuran -2-yl)quinazolin- 4(3H)-one (240 mg, 0.8 mmol) and methyl 6-chloro-3-fluoropicolinate (227 mg, 1.2 mmol) in DMSO (10 ml) was added DIPEA (310 mg, 2.4 mmol), the mixture was heated to 100 °C for 16 h. Cooling to RT, water (50 ml) was added and the mixture was extracted with EtOAc (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-TLC (DCM: EA = 50:1) to afford methyl 6- chloro-3-(((1R)-1-(3,6-dimethyl-2-(2-methyltetrahydrofuran-2 -yl)-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinate (260 mg, 69%) as a white solid. LCMS: (M + H) + =471.1 [0835] Step 8: To a mixture of methyl 6-chloro-3-(((1R)-1-(3,6-dimethyl-2-(2-methyltetrahydrofuran -2-yl)-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinate (260 mg, 0.55 mmol) in MeOH (15 ml) and H 2 O (3 ml) was added LiOH (132 mg, 5.5 mmol). The mixture was stirred at 50 °C for 2 h. The mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to afford 6-chloro-3-(((1R)-1-(3,6- dimethyl-2-(2-methyltetrahydrofuran-2-yl)-4-oxo-3,4-dihydroq uinazolin-8-yl)ethyl)amino)picolinic acid (208.3 mg, 83%) as a white solid. LCMS: (M + H) + =457.2 EXAMPLE 109 (R)-6-chloro-3-((1-(2-(3,3-difluorocyclobutyl)-3,6-dimethyl- 4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0836] Step 1: To a solution 2-amino-3-bromo-N,5-dimethylbenzamide (3 g, 12.35 mmol) and 3,3- difluorocyclobutane-1-carboxylic acid (3.36 g, 24.70 mmol) in THF (60 mL) were added CMPI (4.72 g, 18.53 mmol) and DIEA (3.19 g, 24.7 mmol) at RT. The resulting mixture was heated to 80 °C and stirred overnight. Cooling to RT, water (100 mL) was added and the mixture was extracted with DCM (100 mL×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by silica gel column chromatography (PE: EA=4:1) to give 3-bromo-2-(3,3-difluorocyclobutane-1- carboxamido)-N,5-dimethylbenzamide (3.1 g, 69.6 %) as a white solid. LCMS (ESI) m/z: [M+H] + = 361.1 [0837] Step 2: To a solution of 3-bromo-2-(3,3-difluorocyclobutane-1-carboxamido)-N,5-dimeth ylbenzamide (3.1 g, 8.59 mmol) in DCM (30 mL) were added I 2 (2.62 g, 10.31 mmol) and HMDS (4.15 g, 25.77 mmol) at RT. The resulting mixture was heated to 50 °C and stirred overnight. Cooling to RT, saturated aqueous Na 2 S 2 O 3 (40 mL) solution was added and the mixture was extracted with DCM (150 mL×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by silica gel column chromatography (PE: EA=5:1) to give 8-bromo-2-(3,3-difluorocyclobutyl)-3,6-dimethylquinazolin-4( 3H)- one (2.65 g, 90.0 %) as a yellow solid. LCMS (ESI) m/z: [M+H] + = 343.1 [0838] Step 3: To a solution of 8-bromo-2-(3,3-difluorocyclobutyl)-3,6-dimethylquinazolin-4( 3H)-one (2.65 g, 7.73 mmol) in dioxane (20 mL) were added tributyl(1-ethoxyvinyl)stannane (5.58 g, 15.46 mmol) and Pd(PPh 3 ) 2 Cl 2 (543 mg, 0.77 mmol) at RT. The resulting mixture was heated to 95 °C and stirred at the for 12 h under N 2 . HCl (8 mL, 1 M) was added and the mixture was stirred at 50 °C for 0.5 hour. A saturated KF (60 mL) was added and the mixture was stirred at RT for 0.5 hour. The gray suspension was filtered. The filter cake was washed with EtOAc (50 mL×3). The aqueous phase was extracted with EtOAc (200 mL×3) and the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by silica gel column chromatography (PE: EA=4:1) to give 8-acetyl-2-(3,3-difluorocyclobutyl)-3,6-dimethylquinazolin- 4(3H)-one (2.2 g, 98.6 %) as a yellow solid. LCMS (ESI) m/z: [M+H] + = 307.1 [0839] Step 4: To a solution of 8-acetyl-2-(3,3-difluorocyclobutyl)-3,6-dimethylquinazolin-4 (3H)-one (2.2 g, 7.20 mmol) in THF (20 mL) were added Ti(i-PrO) 4 (20 mL) and (R)-2-methylpropane-2-sulfinamide (1.76 g, 14.40 mmol) at RT. The resulting mixture was heated to 75 °C and stirred for 12 h. Cooling to RT, brine (50 ml) was added and the mixture was stirred for 0.5 hour. The resulting mixture was filtrated and the cake was washed with EtOAc (200 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)-N-(1-(2-(3,3-difluorocyclobutyl)-3,6-dimethyl-4-oxo-3, 4-dihydroquinazolin-8-yl)ethylidene)-2- methylpropane-2-sulfinamide (2.1 g) as a yellow oil for the next step without further purification. LCMS (ESI) m/z: [M+H] + = 409.9 [0840] Step 5: To a solution of (R,Z)-N-(1-(2-(3,3-difluorocyclobutyl)-3,6-dimethyl-4-oxo-3, 4-dihydroquinazolin- 8-yl)ethylidene)-2-methylpropane-2-sulfinamide (2.1 g, 5.13 mmol) in DCM (20 mL) and MeOH(20 mL) were added NaBH 3 CN (322 mg, 10.26 mmol) and HOAc (0.2 mL) at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction was quenched with saturated NH 4 Cl solution (100 ml) and extracted with DCM (200 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre- HPLC (method A) to give the target (R)-N-((R)-1-(2-(3,3-difluorocyclobutyl)-3,6-dimethyl-4-oxo- 3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (2.10 g, 96.2 %) as a white solid. LCMS (ESI) m/z: [M+H] + = 410.2 [0841] Step 6: A mixture (R)-N-((R)-1-(2-(3,3-difluorocyclobutyl)-3,6-dimethyl-4-oxo- 3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (2.10 g, 5.10 mmol) in a solution of HCl in MeOH (3M, 15 mL) was stirred at RT for 20 minutes. The mixture was adjusted to pH 9 with saturated aqueous NaHCO 3 solution and extracted with DCM (200 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give the crude product (R)-8-(1-aminoethyl)-2-(3,3- difluorocyclobutyl)-3,6-dimethylquinazolin-4(3H)-one (1.2 g, 76.7 %) as a yellow oil. LCMS (ESI) m/z: [M+H] + = 308.3 [0842] Step 7: To a solution of (R)-8-(1-aminoethyl)-2-(2,5-dimethylthiazol-4-yl)-3,6-dimeth ylquinazolin-4(3H)- one (150 mg, 0.49 mmol) in DMSO (3 mL) were added methyl 6-chloro-3-fluoropicolinate (140 mg, 0.74 mmol) and DIPEA (190 mg, 1.47 mmol) at RT. The resulting mixture was stirred at 100 °C for 4 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (70 mL×3), the combined organic phase was washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give methyl (R)-6-chloro-3-((1-(2-(3,3-difluorocyclobutyl)- 3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)pi colinate (120 mg, 51.0%) as a yellow oil. LCMS (ESI) m/z: [M+H] + = 477.1 [0843] Step 8: To a solution of methyl (R)-6-chloro-3-((1-(2-(3,3-difluorocyclobutyl)-3,6-dimethyl- 4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (120 mg, 0.25 mmol) in MeOH (3 mL) and THF (2 mL) were added LiOH (60 mg, 2.50 mmol) and H 2 O (0.5 mL) and at RT. The resulting mixture was stirred at RT for 1 hour. The mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM (20 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to give (R)-6-chloro-3-((1-(2-(3,3-difluorocyclobutyl)-3,6-dimethyl- 4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid (57.7 mg, 48.0 %) as a white solid. LCMS (ESI) m/z: [M+H] + = 463.1 EXAMPLE 110 (R)-6-chloro-3-((1-(2-(1-cyanocyclopropyl)-3,6-dimethyl-4-ox o-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0844] Step 1: To a solution of 2-amino-3-bromo-N,5-dimethylbenzamide (1.8 g, 7.404 mmol) in THF (100 mL) were added DIEA (5 mL), 1-cyanocyclopropane-1-carboxylic acid (920 mg, 8.281 mmol) and CMPI (4.85 g, 18.984 mmol) at RT. The mixture was stirred at 70 °C for 2 h. The mixture was concentrated to remove THF, the mixture was added water (150 mL) and extracted with EtOAc (150 mL×2). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was washed with cool EA (15 mL×2) and filtered to give 3-bromo-2-(1-cyanocyclopropane-1-carboxamido)-N,5-dimethylbe nzamide (1630 mg, 65.5 %) as a white solid. LCMS: (M + H) + =338.0 [0845] Step 2: To a solution of 3-bromo-2-(1-cyanocyclopropane-1-carboxamido)-N,5-dimethylbe nzamide (1.546 g, 4.599 mmol) in DCM (60 mL) were added HMDS (2.25 g, 13.941 mmol,) and I 2 (1.2 g, 4.728 mmol) at RT. The mixture was stirred at 50 °C for 16 h. After cooling with ice bath, the mixture was added saturated aqueous Na 2 S 2 O 3 solution (80 mL×2), the organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by silica gel column chromatography (DCM: EA=10:1) to give 1-(8-bromo-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)cyc lopropane-1-carbonitrile (1.45 g, 99.4 %) as a white solid. LCMS: (M + H) + =317.9 [0846] Step 3: To a solution of 1-(8-bromo-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)cyc lopropane-1- carbonitrile (1.384 g, 4.35 mmol) in dioxane (66 mL) were added tributyl(1-ethoxyvinyl)stannane (3.17 g, 8.78 mmol) and Pd(PPh 3 ) 2 Cl 2 (328 mg, 0.47 mmol) at RT. The mixture was stirred at 100 °C for 16 h under N 2 . The mixture was added HCl (4 mL, 1M) and stirred at 50 °C for 0.5 hour. The mixture was added saturated aqueous KF solution (20 mL) and stirred at RT for 0.5 hour. The gray suspension was filtered. The filter cake was washed with H 2 O (10 mL×2) and EtOAc (20 mL×2). The aqueous phase was extracted with EtOAc (120 mL×2). The combined organic layers were washed with H 2 O (150 mL) and then brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by silica gel column chromatography (DCM: EA=10:1) to give 1-(8-acetyl-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)cy clopropane-1-carbonitrile (1.2 g, 98.2 %) as a white solid. LCMS: (M + H) + =282.0 [0847] Step 4: To a solution of 1-(8-acetyl-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)cy clopropane-1- carbonitrile (1.2 g, 4.266 mmol) in THF (16 mL) were added (R)-2-methylpropane-2-sulfinamide (1.05 g, 8.663 mmol) and Ti(Oi-Pr) 4 (16 mL) at RT. The mixture was stirred at 75 °C for 16 h under N 2 . After cooling with ice bath, the mixture was added saturated aqueous NaCl solution (20 mL) and stirred at RT for 5 mins. The suspension was filtered. The filter cake was washed with H 2 O (10 mL×2) and EtOAc (20 mL×2). The aqueous phase was extracted with EtOAc (120 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give crude (R,Z)-N-(1-(2-(1-cyanocyclopropyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (1.6 g, 97.5 %) as a red solid. LCMS: (M + H) + =385.0 [0848] Step 5: To a solution of crude (R,Z)-N-(1-(2-(1-cyanocyclopropyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (1.6 g, 4.161 mmol) in MeOH (18 mL) were added DCM (18 mL), AcOH (1.8 mL) and NaBH 3 CN (800 mg, 12.731 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour. The mixture was added with aqueous NH 4 Cl solution (15 mL), extracted with DCM (50 mL×2). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by Prep-HPLC (method A) to give (R)-N-((R)-1-(2-(1-cyanocyclopropyl)-3,6-dimethyl- 4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-su lfinamide (650 mg, 40.4 %) as a white solid. LCMS: (M + H) + =387.1 [0849] Step 6: To a solution of (R)-N-((R)-1-(2-(1-cyanocyclopropyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin- 8-yl)ethyl)-2-methylpropane-2-sulfinamide (650 mg, 1.682 mmol, 1.0 eq) in MeOH (10 mL) was added HCl (4 mL, 3M in MeOH) at RT. The mixture was stirred at RT for 1 hour. The mixture was neutralized with aqueous NaHCO 3 solution to pH = 8 and extracted with DCM (100 mL×2), the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give (R)-1-(8-(1-aminoethyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-2-yl)cyclopropane-1-carbonitrile (470 mg, 99.0 %) as a yellow solid. LCMS: (M + H) + =283.1 [0850] Step 7: To a solution of (R)-1-(8-(1-aminoethyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinaz olin-2- yl)cyclopropane-1-carbonitrile (135 mg, 0.478 mmol, 1.0 eq) in DMSO (4 mL) were added methyl 6-chloro-3- fluoropicolinate (135 mg, 0.712 mmol, 1.5 eq) and DIEA (0.4 mL). The mixture was stirred at 100 °C for 4 h. After cooling to RT, the mixture was added water (50 mL), filtered and washed with water to give methyl (R)-6-chloro- 3-((1-(2-(1-cyanocyclopropyl)-3,6-dimethyl-4-oxo-3,4-dihydro quinazolin-8-yl)ethyl)amino)picolinate (200 mg, 92.5 %) as a white solid. LCMS: (M + H) + = 451.9 [0851] Step 8: To a solution of methyl (R)-6-chloro-3-((1-(2-(1-cyanocyclopropyl)-3,6-dimethyl-4-ox o-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (200 mg, 0.442 mmol) in MeOH (2 mL) were added THF (2 mL), H 2 O (2 mL) and LiOH•H 2 O (50 mg, 1.192 mmol) at RT. The mixture was stirred at RT for 0.5 hour. The mixture was neutralized with HCl (1M) to pH = 6. The mixture was purified by Prep-HPLC (method B) to give (R)-6- chloro-3-((1-(2-(1-cyanocyclopropyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinic acid (60 mg, 31.0 %) as a white solid. LCMS: (M + H) + = 438.1 EXAMPLE 111 (R)-6-chloro-3-((1-(3,6-dimethyl-4-oxo-2-(pyrimidin-5-yl)-3, 4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0852] Step 1: To a solution of 2-amino-3-bromo-N,5-dimethylbenzamide (3.5 g, 14.4 mmol,) in DMSO (100 mL) was added pyrimidine-5-carbaldehyde (3.1g, 28.80 mmol,). The mixture was stirred under O 2 at 120 °C for 2 h. The mixture was diluted with water (500 mL) and extracted with EtOAc (200 mL×3). The combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated, the cured was purified by silica gel column chromatography (PE: EA=5：2) to give 8-bromo-3,6-dimethyl-2-(pyrimidin-5-yl)quinazolin-4(3H)-one (4.0 g, 83.8 %) as a yellow solid. LCMS: (M + H) + =330.9 [0853] Step 2: To a mixture of 8-bromo-3,6-dimethyl-2-(pyrimidin-5-yl)quinazolin-4(3H)-one (4.0 g, 12.08 mmol) and tributyl(1-ethoxyvinyl)stannane (8.72 g, 24.16 mmol) in dioxane (25 ml) was added Pd(PPh 3 ) 2 Cl 2 (848 mg, 1.21 mmol,). The mixture was stirred at 95 °C under N 2 for 16 h. HCl (12.0 ml, 1 M) was added into the mixture and stirred at 50 °C for 0.5 hour, then 50 ml sat KF was added and the mixture was stirred at RT for 0.5 hour. The gray was filtered, the filter cake was washed with EtOAc (100 ml*3), the separated aqueous phase was extracted with EtOAc (100 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 3:1) to give 8-acetyl-3,6-dimethyl-2- (pyrimidin-5-yl)quinazolin-4(3H)-one (2.1 g, 59.1%) as s yellow solid. LCMS: (M + H) + =295.1 [0854] Step 3: To a mixture of 8-acetyl-3,6-dimethyl-2-(pyrimidin-5-yl)quinazolin-4(3H)-one (1 g, 3.40 mmol) and (R)-2-methylpropane-2-sulfinamide (823 mg, 6.80 mmol) in THF (20 ml) at RT was added Ti(i-PrO) 4 (20 ml). The mixture was stirred at 75 °C for 16 h. Cooling to RT, brine (100 ml) was added and the mixture was stirred for 0.5 hour. The resulting mixture was filtrated and the cake was washed with EtOAc (100 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)-N-(1- (3,6-dimethyl-4-oxo-2-(pyrimidin-5-yl)-3,4-dihydroquinazolin -8-yl)ethylidene)-2-methylpropane-2-sulfinamide (1.5 g) as a yellow oil for the next step without further purification. LCMS: (M + H) + = 398.2 [0855] Step 4: To a solution of (R,Z)-N-(1-(3,6-dimethyl-4-oxo-2-(pyrimidin-5-yl)-3,4-dihydr oquinazolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (1.5 g, 3.78 mmol) in DCM (20 mL) and MeOH(20 mL) were added NaBH 3 CN (476 mg, 5.76 mmol) and HOAc (0.2 mL) at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction was quenched with saturated NH 4 Cl solution (50 ml) and extracted with DCM (100 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (method A) to give (R)-N-((R)-1-(3,6-dimethyl-4-oxo-2-(pyrimidin-5-yl)-3,4-dihy droquinazolin-8-yl)ethyl)-2- methylpropane-2-sulfinamide (300 mg, 19.8%) as a white solid. LCMS: (M + H) + = 400.0 [0856] Step 5: To a solution of (R)-N-((R)-1-(3,6-dimethyl-4-oxo-2-(pyrimidin-5-yl)-3,4-dihy droquinazolin-8- yl)ethyl)-2-methylpropane-2-sulfinamide (300 mg, 0.75 mmol) in MeOH (4 mL) was added a solution of HCl in MeOH (10 ml, 4 M).The mixture was stirred at RT for 5 min. The mixture was poured into ice-water and adjusted PH=8 with a saturated solution of NaHCO 3 , the mixture was extracted with DCM/MeOH (50 ml*3, 10/1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (DCM: MeOH=10:1) to give (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(pyrimidin- 5-yl)quinazolin-4(3H)-one (200 mg, 90.7 %) as a white solid. LCMS: (M + H) + =296.3 [0857] Step 6: To a solution of methyl (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(pyrimidin-5-yl)quinazol in-4(3H)-one (100 mg, 0.215 mmol) in DMSO (5 mL) were added methyl methyl 6-chloro-3-fluoropicolinate (97 mg, 0.51 mmol) and DIEA (132 mg, 1.02 mmol). The mixture was stirred at 100 °C for 2 h. The mixture was diluted with water (30 ml) and extracted with EtOAc (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The cured was purified by silica gel column chromatography (PE: EA=4:1) to give methyl (R)- 6-chloro-3-((1-(3,6-dimethyl-4-oxo-2-(pyrimidin-5-yl)-3,4-di hydroquinazolin-8-yl)ethyl)amino)picolinate (100 mg, 63.2 %) as a yellow oil. LCMS: (M + H) + =465.1 [0858] Step 7: To a solution of methyl (R)-6-chloro-3-((1-(3,6-dimethyl-4-oxo-2-(pyrimidin-5-yl)-3, 4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (100 mg, 0.215 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (52 mg, 2.15 mmol). The mixture was stirred at 50 °C for 1 hour. The mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to give (R)-6-chloro-3-((1-(3,6- dimethyl-4-oxo-2-(pyrimidin-5-yl)-3,4-dihydroquinazolin-8-yl )ethyl)amino)picolinic acid (61.2 mg, 62.8%) as a white solid. LCMS: (M + H) + =451.1 EXAMPLE 112 (R)-6-chloro-3-((1-(2,3,6-trimethyl-4-oxo-3,4-dihydroquinazo lin-8-yl)ethyl)amino)picolinic acid [0859] Step 1: To a mixture of 2-amino-3-bromo-N,5-dimethylbenzamide (2.0 g, 8.26 mmol) and DIPEA (3.19 mg, 24.8 mmol) in anhydrous DCM (50 mL) was added dropwise acetyl chloride (967 mg, 12.4 mmol) at 0 °C, then the mixture was warmed to RT and stirred for 3 h. Water (100 mL) was added, the separated aqueous layer was extracted with DCM (80 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated, The residue was purified by chromatography (PE: EA = 3:1) to afford 2-acetamido-3-bromo-N,5- dimethylbenzamide (560 mg, 23.9%) as a yellow solid. LCMS: (M + H) + =285.0 [0860] Step 2: To a solution of 2-acetamido-3-bromo-N,5-dimethylbenzamide (560 mg, 1.97 mmol) in DCM (10 mL) were added HMDS (952 mg, 5.92 mmol) and I2 (501 mg, 1.97 mmol), the mixture was stirred at 50 °C for 4 h. Cooling to RT, the resulting mixture was quenched with saturated Na 2 S 2 O 3 (100 mL*3), the organic phase was washed with brine, dried over Na 2 SO 4 and concentrated under vacuum to get a residue which was purified by chromatography (PE: EA = 5:1) to afford 8-bromo-2,3,6-trimethylquinazolin-4(3H)-one (480 mg, 91.5%) as a yellow solid. LCMS: (M + H) + =267.0 [0861] Step 3: To a mixture of 8-bromo-2,3,6-trimethylquinazolin-4(3H)-one (480 mg, 1.80 mmol) and ethyl tributylstannanecarboxylate (979.8 mg, 2.71 mmol) in dioxane (10 ml) was added Pd(PPh 3 ) 2 Cl 2 (264 mg, 0.361 mmol). The mixture was stirred at 105 °C under N 2 overnight. HCl (5.0 mL, 1 M) was added into the mixture and the mixture was stirred at 50 °C for 0.5 hour, then 40 ml sat. KF was added and the mixture was stirred at RT for 0.5 hour. The gray was filtered, the filter cake was washed with EtOAc (100 mL*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 30%) to afford 8-acetyl-2,3,6-trimethylquinazolin-4(3H)-one (380 mg, 91.6%) as a yellow solid. LCMS: (M + H) + =231.2 [0862] Step 4: To a mixture of 8-acetyl-2,3,6-trimethylquinazolin-4(3H)-one (380 mg, 1.65 mmol) and (R)-2- methylpropane-2-sulfinamide (400 mg, 3.30 mmol) in THF (10 mL) at RT was added Ti(i-PrO) 4 (5.96 g, 16.5 mmol). The mixture was stirred at 75 °C for 48 h. Cooling to RT, brine (10 mL) was added and the mixture was stirred for 0.5 hour. The resulting mixture was filtrated and the cake was washed with EtOAc (50 mL*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)-2- methyl-N-(1-(2,3,6-trimethyl-4-oxo-3,4-dihydroquinazolin-8-y l)ethylidene)propane-2-sulfinamide (950 mg, crude) as a yellow oil for the next step without further purification. LCMS: (M + H) + =334.1 [0863] Step 5: To a mixture crude (R,Z)-2-methyl-N-(1-(2,3,6-trimethyl-4-oxo-3,4-dihydroquinaz olin-8- yl)ethylidene)propane-2-sulfinamide (950 mg, 2.85 mmol) and HOAc (1.295 g, 13.2 mmol) in DCM (10 mL) and MeOH (10 mL) was added NaBH 3 CN (307 mg, 4.96 mmol) in portions at 0 °C, the mixture was stirred at RT overnight. The reaction was quenched with a saturate of NH 4 Cl (20 mL) and extracted with DCM (30 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (method A) to afford (R)-2-methyl-N-((R)-1-(2,3,6-trimethyl-4-oxo-3,4-dihydroquin azolin-8- yl)ethyl)propane-2-sulfinamide (110 mg, 19.9%) as a yellow solid. LCMS: (M + H) + =336.3 [0864] Step 6: A mixture (R)-2-methyl-N-((R)-1-(2,3,6-trimethyl-4-oxo-3,4-dihydroquin azolin-8-yl)ethyl)propane- 2-sulfinamide (110 mg, 0.328 mmol) in a solution of HCl in MeOH (5 mL, 4 M) was stirred at RT for 30 min. The mixture was poured into ice-water and adjusted pH= 8 with a saturated solution of NaHCO 3 , The mixture was extracted with DCM:MeOH (50 mL*3, 10:1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford (R)-8-(1-aminoethyl)-2,3,6-trimethylquinazolin-4(3H)-one (80 mg, crude) as a yellow oil. LCMS: (M + H) + =232.2 [0865] Step 7: To a mixture of (R)-8-(1-aminoethyl)-2,3,6-trimethylquinazolin-4(3H)-one (80 mg, 0.346 mmol) and methyl 6-chloro-3-fluoropicolinate (98.2 mg, 0.519 mmol) in DMSO (5 mL) was added DIPEA (134 mg, 1.04 mmol), the mixture was heated to 100 °C and stirred for 4 h. Cooling to RT, H 2 O (50 mL) was added and the mixture was extracted with EtOAc (30 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford methyl (R)-6-chloro-3-((1-(2,3,6-trimethyl-4-oxo-3,4-dihydroquinazo lin-8- yl)ethyl)amino)picolinate (130 mg, 93.8%) as a yellow solid. LCMS: (M + H) + = 401.0 [0866] Step 8: To a mixture of methyl (R)-6-chloro-3-((1-(2,3,6-trimethyl-4-oxo-3,4-dihydroquinazo lin-8- yl)ethyl)amino)picolinate (130 mg, 0.325 mmol) in MeOH (5 mL) and H 2 O (1 mL) was added LiOH (68.3 mg, 1.625 mmol). The mixture was stirred at 50 °C for 2 h. The mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM:MeOH (30 mL*3, 10:1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to afford (R)-6-chloro-3-((1-(2,3,6- trimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picol inic acid (46.9 mg, 37.4%) as a white solid. LCMS: (M + H) + = 387.3 EXAMPLE 113 (R)-6-chloro-3-((1-(3,6-dimethyl-2-(1-methylcyclopentyl)-4-o xo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0867] Step 1: To a mixture of 2-amino-3-bromo-N,5-dimethylbenzamide (1.0 g, 4.13 mmol), 1- methylcyclopentane-1-carboxylic acid (1.05 g, 8.26 mmol) and CMPI (2.11 g, 8.26 mmol) in THF (20 mL) was added DIPEA (1.60 g, 12.4 mmol). The mixture was stirred at 80 °C overnight. Water (100 ml) was added, the mixture was extracted with EtOAc (50 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated, The residue was purified by chromatography (PE: EA = 3:1) to afford 3-bromo-N,5- dimethyl-2-(1-methylcyclopentane-1-carboxamido)benzamide (480 mg, 33%) as a yellow solid. LCMS: (M + H) + =353.0 [0868] Step 2: To a solution of 3-bromo-N,5-dimethyl-2-(1-methylcyclopentane-1-carboxamido)b enzamide (480 mg, 1.36 mmol) in DCM (20 mL) were added HMDS (658.6 mg, 4.09 mmol) and I2 (346.3 mg, 1.36 mmol). The mixture was stirred at 50 °C for 4 h. Cooling to RT, the mixture was washed with a saturated solution of Na 2 S 2 O 3 (50 mL x3) and brine, dried over Na 2 SO 4 and concentrated under vacuum to get a residue which was purified by chromatography (PE: EA = 5:1) to afford 8-bromo-3,6-dimethyl-2-(1-methylcyclopentyl)quinazolin-4(3H) -one (380 mg, 83.4%) as a yellow solid. LCMS: (M + H) + =337.0 [0869] Step 3: To a mixture of 8-bromo-3,6-dimethyl-2-(1-methylcyclopentyl)quinazolin-4(3H) -one (380 mg, 1.14 mmol) and ethyl tributylstannanecarboxylate (618 mg, 1.71 mmol) in dioxane (10 mL) was added Pd(PPh 3 ) 2 Cl 2 (167 mg, 0.227 mmol). The mixture was stirred at 95 °C under N 2 for 16 h. HCl (2.0 mL, 1 M) was added into the mixture and the mixture was stirred at 50 °C for 0.5 hour, then 10 ml sat. KF was added and the mixture was stirred at RT for 0.5 hour. The gray was filtered, the filter cake was washed with EtOAc (50 mL*3), the separated aqueous phase was extracted with EtOAc (20 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 30%) to afford 8-acetyl-3,6-dimethyl-2-(1-methylcyclopentyl)quinazolin-4(3H )-one (320 mg, 94.4%) as a yellow solid. LCMS: (M + H) + =299.3 [0870] Step 4: To a mixture of 8-acetyl-3,6-dimethyl-2-(1-methylcyclopentyl)quinazolin-4(3H )-one (320 mg, 1.07 mmol) and (R)-2-methylpropane-2-sulfinamide (259 mg, 2.15 mmol) in THF (10 mL) at RT was added Ti(i- PrO) 4 (3.88 g, 10.7 mmol). The mixture was stirred at 75 °C for 48 h. Cooling to RT, brine (50 mL) was added and the mixture was stirred for 0.5 hour. The resulting mixture was filtrated and the cake was washed with EtOAc (40 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)-N-(1-(3,6-dimethyl-2-(1-methylcyclopentyl)-4-oxo-3,4-d ihydroquinazolin-8-yl)ethylidene)-2-methylpropane- 2-sulfinamide (550 mg, crude) as a yellow oil for the next step without further purification. LCMS: (M + H) + =402.3 [0871] Step 5: To a mixture of crude (R,Z)-N-(1-(3,6-dimethyl-2-(1-methylcyclopentyl)-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (550 mg, 1.37 mmol) and HOAc (1.08 g, 10.9 mmol) in DCM (10 mL) and MeOH (10 mL) was added NaBH 3 CN (170 mg, 2.74 mmol) in portions at 0 °C, the mixture was stirred at 0 °C for 1 hour. The reaction was quenched with a saturated solution of NH 4 Cl (20 mL) and extracted with DCM (30 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (method A) to afford (R)-N-((R)-1-(3,6-dimethyl-2-(1- methylcyclopentyl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2 -methylpropane-2-sulfinamide (110 mg, 25.4%) as a yellow solid. LCMS: (M + H) + =404.3 [0872] Step 6: A mixture (R)-N-((R)-1-(3,6-dimethyl-2-(1-methylcyclopentyl)-4-oxo-3,4 -dihydroquinazolin-8- yl)ethyl)-2-methylpropane-2-sulfinamide (110 mg, 0.273 mmol) in a solution of HCl in MeOH (5 mL, 4 M) was stirred at RT for 10 min. The mixture was poured into ice-water and adjusted pH=8 with a saturated solution of NaHCO 3 , The mixture was extracted with DCM/MeOH (20 mL*3, 10/1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(1- methylcyclopentyl)quinazolin-4(3H)-one (85 mg, crude) as a yellow oil. LCMS: (M + H) + =300.2 [0873] Step 7: To a mixture of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(1-methylcyclopentyl)qui nazolin-4(3H)-one (85 mg, 0.284 mmol) and methyl 6-chloro-3-fluoropicolinate (80.6 mg, 0.426 mmol) in DMSO (5 mL) was added DIPEA (73.3 mg, 0.569 mmol), the mixture was heated at 100 °C and stirred for 4 h. Cooling to RT, H 2 O (25 mL) was added and the mixture was extracted with EtOAc (30 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford methyl (R)-6-chloro-3-((1-(3,6-dimethyl-2-(1- methylcyclopentyl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)am ino)picolinate (150 mg, crude) as a white solid. LCMS: (M + H) + = 469.1 [0874] Step 8: To a mixture of methyl (R)-6-chloro-3-((1-(3,6-dimethyl-2-(1-methylcyclopentyl)-4-o xo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (150 mg, 0.321 mmol) in MeOH (5 mL) and H 2 O (1 mL) was added LiOH (67.3 mg, 1.60 mmol). The mixture was stirred at 50 °C for 3 h. The mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM\MeOH (50 mL*3, 10\1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to afford (R)-6-chloro-3- ((1-(3,6-dimethyl-2-(1-methylcyclopentyl)-4-oxo-3,4-dihydroq uinazolin-8-yl)ethyl)amino)picolinic acid (43.7 mg, 30.0%) as a white solid. LCMS: (M + H) + = 455.0 EXAMPLE 114 (R)-6-chloro-3-((1-(2-(1-fluorocyclobutyl)-3,6-dimethyl-4-ox o-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0875] Step 1: To a solution of 2-amino-3-bromo-N, 5-dimethylbenzamide (1.2 g, 5 mmol) and 1- fluorocyclobutane-1-carboxylic acid (878 mg, 7.5 mmol) in THF (25 mL) were added CMPI (1.9 g, 7.5 mmol) and DIPEA (2.6 mL) at RT. The resulting mixture was heated to 80 °C and stirred overnight. Cooling to RT, water (40 mL) was added and the mixture was extracted with DCM (150 mL×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by silica gel column chromatography (PE: EA=2:1) to give 3-bromo-2-(1-fluorocyclobutane-1-carboxamido)-N,5-dimethylbe nzamide (1.3 g, 76%) as a white solid. LCMS (ESI) m/z: [M+H] + = 343.1 [0876] Step 2: To a solution of 3-bromo-2-(1-fluorocyclobutane-1-carboxamido)-N,5-dimethylbe nzamide (1.3 g, 3.8 mmol) in DCM (30 mL) were added I 2 (965 mg, 3.8 mmol) and HMDS (1.8 g, 11.4 mmol) at RT. The resulting mixture was heated to 50 °C and stirred overnight. Cooling to RT, a saturated aqueous Na 2 S 2 O 3 (40 mL) solution was added and the mixture was extracted with DCM (150 mL×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by silica gel column chromatography (PE: EA=5:1) to give 8-bromo-2-(1-fluorocyclobutyl)-3,6-dimethylquinazolin-4(3H)- one (1.1 g, 89%) as a white solid. LCMS (ESI) m/z: [M+H] + = 325.1 [0877] Step 3: To a solution of 8-bromo-2-(1-fluorocyclobutyl)-3,6-dimethylquinazolin-4(3H)- one (1.1 g, 3.4 mmol) in Dioxane (25 mL) were added tributyl(1-ethoxyvinyl)stannane (2.5 g, 6.8 mmol) and Pd(PPh 3 ) 2 Cl 2 (280 mg, 0.4 mmol) at RT. The resulting mixture was heated to 95 °C and stirred overnight under N 2 . HCl (4 mL, 1 M) was added and the mixture was stirred at 50 °C for 0.5 hour. A saturated KF (100 mL) was added and the mixture was stirred at RT for 0.5 hour. The gray suspension was filtered. The filter cake was washed with EtOAc (80 mL×3). The aqueous phase was extracted with EtOAc (100 mL×3) and the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by silica gel column chromatography (PE: EA=4:1) to give 8-acetyl-2-(1-fluorocyclobutyl)-3,6-dimethylquinazolin-4(3H) -one (1.2 g, 86%) as a white solid. LCMS (ESI) m/z: [M+H] + = 289.3 [0878] Step 4: To a solution of 8-acetyl-2-(1-fluorocyclobutyl)-3,6-dimethylquinazolin-4(3H) -one (900 mg, 3.1 mmol) in THF (15 mL) were added Ti(i-PrO) 4 (15 mL) and (R)-2-methylpropane-2-sulfinamide (750 mg, 6.2 mmol) at RT. The resulting mixture was heated to 75 °C and stirred overnight. Brine (15 mL) was added into the mixture. The suspension was filtered. The filter cake was washed with EtOAc (40 mL×3). The aqueous phase was extracted with EtOAc (50 mL×3) and the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give (R,Z)-N-(1-(2-(1-fluorocyclobutyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (1.2 g, 97%) as a yellow solid. LCMS (ESI) m/z: [M+H] + = 391.1 [0879] Step 5: To a solution of (R,Z)-N-(1-(2-(1-fluorocyclobutyl)-3,6-dimethyl-4-oxo-3,4-di hydroquinazolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (1.2 g, 3 mmol) and HOAc (1.5 mL) in DCM (15 mL) and MeOH (15 mL) was added NaBH 3 CN (570 mg, 9 mmol) in portions at 0 °C, the mixture was warmed up to RT and stirred for 3 h. The reaction was quenched with saturated aqueous NH 4 Cl (100 mL) solution and extracted with DCM (150 mL x 2). The combined extract was washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give a residue which was purified by Prep-HPLC (Method A) to give (R)-N-((R)-1-(2-(1-fluorocyclobutyl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpro pane-2-sulfinamide (590 mg, 50%) as a white solid. LCMS (ESI) m/z: [M+H] + = 394.1 [0880] Step 6: A mixture (R)-N-((R)-1-(2-(1-fluorocyclobutyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8- yl)ethyl)-2-methylpropane-2-sulfinamide (590 mg, 1.5 mmol) ) in a solution of HCl in MeOH (3M, 8 mL) was stirred at RT for 30 minutes. The reaction mixture was adjusted to pH = 9 with a saturated aqueous NaHCO 3 solution and the mixture was extracted with DCM (150 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give (R)-8-(1-aminoethyl)-2-(1-fluorocyclobutyl)-3,6-dimethylquin azolin- 4(3H)-one (400 mg, 92%) as a white solid. LCMS (ESI) m/z: [M+H] + = 290.4 [0881] Step 7: To a solution of (R)-8-(1-aminoethyl)-2-(1-fluorocyclobutyl)-3,6-dimethylquin azolin-4(3H)-one (100 mg, 0.35 mmol) in DMSO (2 mL) were added methyl 6-chloro-3-fluoropicolinate (131mg, 0.69 mmol) and DIPEA (0.2 mL) at RT. The resulting mixture was stirred at 100 °C overnight. Cooling to RT, the mixture was diluted with water (20 mL) and extracted with EtOAc (70 mL×3), the combined organic phase was washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give methyl (R)-6-chloro-3-((1-(2- (1-fluorocyclobutyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazoli n-8-yl)ethyl)amino)picolinate (150 mg, 94%) as a yellow solid. LCMS (ESI) m/z: [M+H] + = 459.1 [0882] Step 8: To a solution of methyl (R)-6-chloro-3-((1-(2-(1-fluorocyclobutyl)-3,6-dimethyl-4-ox o-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (150 mg, 0.32 mmol) in MeOH (2 mL) and THF (2 mL) were added LiOH (81 mg, 1.92 mmol) and H 2 O (0.5 mL) at RT. The resulting mixture was stirred at the RT for 15 minutes. The mixture was adjusted to pH = 4 with HCl solution and diluted with water (20 mL), the mixture was extracted with DCM (80 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by Prep-HPLC (Method B) to give (R)-6-chloro-3-((1-(2-(1-fluorocyclobutyl)-3,6-dimethyl-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinic acid (66.8 mg, 47%) as a white solid. LCMS (ESI) m/z: [M+H] + = 445.1 EXAMPLE 115 (R)-6-chloro-3-((1-(2-(2-cyanopropan-2-yl)-3,6-dimethyl-4-ox o-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0883] Step 1: To a solution of 2-amino-3-bromo-N,5-dimethylbenzamide (1.76 g, 7.24 mmol) in THF (100 mL) were added DIEA (5 mL), 2-cyano-2-methylpropanoic acid (930 mg, 8.22 mmol) and CMPI (4.79 g, 18.75 mmol) at RT. The mixture was stirred at 70 °C for 18 h. The mixture was concentrated to remove THF, water (150 mL) was added and the mixture was extracted with EtOAc (150 mL×2). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was washed with cool EtOAc (15 mL×2) and filtered to give 3-bromo-2-(2-cyano-2-methylpropanamido)-N,5-dimethylbenzamid e (1500 mg, 61.2 %) as a white solid. LCMS: (M + H) + =338.1 [0884] Step 2: To a solution of 3-bromo-2-(2-cyano-2-methylpropanamido)-N,5-dimethylbenzamid e (1.4 mg, 4.139 mmol) in DCM (60 mL) were added HMDS (2.0 g, 12.392 mmol) and I2 (1.1 g, 4.334 mmol) at RT. The mixture was stirred at 50 °C for 96 h. After cooling with ice bath, the mixture was added saturated aqueous Na 2 S 2 O 3 solution (80 mL×2), the organic layer war washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by silica gel column chromatography (DCM: EA=10:1) to give 2-(8-bromo-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-2- methylpropanenitrile (960 mg, 72.4 %) as a white solid. LCMS: (M + H) + =319.9 [0885] Step 3: To a solution of 2-(8-bromo-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-2- methylpropanenitrile (960 mg, 2.998 mmol) in dioxane (35 mL) were added tributyl(1-ethoxyvinyl)stannane (2.2 g, 6.091 mmol) and Pd(PPh 3 ) 2 Cl 2 (230 mg, 0.328 mmol) at RT. The mixture was stirred at 100 °C for 16 h under N 2 . The mixture was added HCl (3 mL, 1M) and stirred at 50 °C for 0.5 hour. The mixture was added saturated aqueous KF solution (15 mL) and stirred at RT for 0.5 hour. The gray suspension was filtered. The filter cake was washed with H 2 O (10 mL×2) and EtOAc (20 mL×2). The aqueous phase was extracted with EA (120 ml). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by silica gel column chromatography (DCM: EA=10:1) to give 2-(8-acetyl-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylpropaneni trile (810 mg, 95.4 %) as a white solid. LCMS: (M + H) + =284.0 [0886] Step 4: To a solution of 2-(8-acetyl-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-2 - methylpropanenitrile (810 mg, 2.859 mmol) in THF (10 mL) were added (R)-2-methylpropane-2-sulfinamide (700 mg, 5.775 mmol) and Ti(Oi-Pr) 4 (10 mL) at RT. The mixture was stirred at 75 °C for 16 h under N 2 . After cooling with ice bath, the mixture was added saturated aqueous NaCl solution (16 mL) and stirred at RT for 5 mins. The suspension was filtered. The filter cake was washed with H 2 O (10 mL×2) and EtOAc (20 mL×2). The aqueous phase was extracted with EtOAc (100 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give crude (R,Z)-N-(1-(2-(2-cyanopropan-2-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (1.1 g, 99.5 %) as a red solid. LCMS: (M + H) + =387.0 [0887] Step 5: To a solution of crude (R,Z)-N-(1-(2-(2-cyanopropan-2-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (1.1 g, 2.846 mmol) in MeOH (12 mL) were added DCM (12 mL), AcOH (1.4 mL) and NaBH 3 CN (530 mg, 8.434 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour. The mixture was added with aqueous NH 4 Cl solution (12 mL) and extracted with DCM (100 mL×2), the combined organic layers were washed with H 2 O (80 mL) and then brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by Prep-HPLC (method A) to give (R)-N-((R)-1-(2-(2- cyanopropan-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8 -yl)ethyl)-2-methylpropane-2-sulfinamide (700 mg, 63.3 %) as a white solid. LCMS: (M + H) + =389.0 [0888] Step 6: To a solution of (R)-N-((R)-1-(2-(2-cyanopropan-2-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin- 8-yl)ethyl)-2-methylpropane-2-sulfinamide (700 mg, 1.802 mmol) in MeOH (10 mL) was added HCl (4 mL, 3M in MeOH) at RT. The mixture was stirred at RT for 1 hour. The mixture was neutralized with aqueous NaHCO 3 solution to pH = 8 and extracted with DCM (100 mL×2), the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give (R)-2-(8-(1-aminoethyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-2-yl)-2-methylpropanenitrile (500 mg, 97.5 %) as a yellow solid. LCMS: (M + H) + =285.0 [0889] Step 7: To a solution of (R)-2-(8-(1-aminoethyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinaz olin-2-yl)-2- methylpropanenitrile (150 mg, 0.528 mmol) in DMSO (4 mL) were added methyl 6-chloro-3-fluoropicolinate (140 mg, 0.739 mmol) and DIEA (0.4 mL). The mixture was stirred at 100 °C for 4 h. After cooling to RT, water (40 mL) was added and the mixture was extracted with EtOAc (40 mL×2). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by silica gel column chromatography (PE: EA=1:1) to give methyl (R)-6-chloro-3-((1-(2-(2-cyanopropan-2-yl)-3,6-dimethyl- 4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinate (200 mg, 83.5 %) as a colorless oil. LCMS: (M + H) + = 454.0 [0890] Step 8: To a solution of methyl (R)-6-chloro-3-((1-(2-(2-cyanopropan-2-yl)-3,6-dimethyl-4-ox o-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (200 mg, 0.441 mmol) in THF (4 mL) were added H 2 O (4 mL) and LiOH•H 2 O (50 mg, 1.192 mmol) at RT. The mixture was stirred at RT for 0.5 hour. The mixture was neutralized with HCl (1M) to pH = 6. The mixture was purified by Prep-HPLC (method B) to give (R)-6-chloro-3-((1-(2-(2- cyanopropan-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8 -yl)ethyl)amino)picolinic acid (95 mg, 49.0 %) as a white solid. LCMS: (M + H) + = 440.1 EXAMPLE 116 (R)-3-((1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydroquinazolin -8-yl)ethyl)amino)-6-fluoropicolinic acid [0891] Step 1: To a mixture of methyl 6-aminopicolinate (4 g, 26.3 mmol) in DMF (10 mL) was added NIS (17.8 g, 78.9 mmol). The mixture was stirred at RT for 48 h. Water (200 mL) was added and the mixture was extracted with EtOAc (200 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated under vacuum to give a residue which was purified by chromatography (PE : EA = 5:1) to afford methyl 6-amino-3-iodopicolinate (3.5 g, 47.8%) as a yellow oil. LCMS: (M + H) + =279.0 [0892] Step 2: To a solution of methyl 6-amino-3-iodopicolinate (2.6 g, 9.35 mmol) in Pyridine hydrofluoride (30 mL) was added NaNO 2 (1.29 g, 18.7 mmol) at 0 °C. The mixture was warmed to RT and stirred overnight. The mixture was poured into water (100 mL) and extracted with EtOAc (200 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 10:1) to afford methyl 6-fluoro-3-iodopicolinate (2.3 g, 87.5%) as a yellow solid. LCMS: (M + H) + =282.0 [0893] Step 3: To a solution of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-phenylquinazolin-4(3H)-o ne (200 mg, 0.683 mmol) in dioxane (10 mL) were added methyl 6-fluoro-3-iodopicolinate (384 mg, 1.37 mmol), Pd 2 (dba) 3 (125 mg, 0.137 mmol), XantPhos (78.9 mg, 0.137 mmol) and Cs 2 CO 3 (445 mg, 1.37 mmol), the mixture was heated at 120 ° C and stirred for 24 h. Cooling to RT, H 2 O (40 mL) was added and the mixture was extracted with EtOAc (40 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to give a residue which was purified by Prep-TLC (DCM: MeOH = 20:1) and SFC to afford (R)-3-((1-(3,6-dimethyl-4- oxo-2-phenyl-3,4-dihydroquinazolin-8-yl)ethyl)amino)-6-fluor opicolinic acid (8 mg, 4.1%) as a yellow solid. LCMS: (M + H) + = 433.1 EXAMPLE 117 (R)-6-chloro-3-((1-(3,6-dimethyl-2-(1-methyl-1H-pyrazol-5-yl )-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0894] Step 1: To a solution of 2-amino-3-bromo-N,5-dimethylbenzamide (2.5 g, 10.3 mmol) in DMSO (50 mL) was added 1-methyl-1H-pyrazole-5-carbaldehyde (1.7 g, 15.5 mmol) at RT. The resulting mixture was heated to 130 °C and stirred for 12 h under O 2 . The mixture was poured into water (250 mL) and stirred for 15 minutes, the suspension was filtered and the collected solid was dried to provide 8-bromo-3,6-dimethyl-2-(1-methyl-1H- pyrazol-5-yl)quinazolin-4(3H)-one (2.2 g, 64%) as a white solid. LCMS (ESI) m/z: [M+H] + = 333.1 [0895] Step 2: To a solution of 8-bromo-3,6-dimethyl-2-(1-methyl-1H-pyrazol-5-yl)quinazolin- 4(3H)-one (2.2 g, 6.6 mmol) in dioxane (50 mL) were added tributyl(1-ethoxyvinyl)stannane (4.8 g, 13.2 mmol) and Pd(PPh 3 ) 2 Cl 2 (490 mg, 0.7 mmol) at RT. The resulting mixture was heated to 95 °C and stirred for 12 h under N 2 . HCl (7 mL, 1 M) was added into the mixture and the mixture was stirred at 50 °C for 0.5 hour. Then a saturated KF (200 mL) was added and the resulting mixture was stirred at 20 °C for 0.5 hour. The gray suspension was filtered and the filter cake was washed with EtOAc (100 mL×3). The aqueous phase was extracted with EtOAc (100 mL×3) and the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by silica gel column chromatography (PE: EA=4:1) to give 8-acetyl-3,6-dimethyl-2-(1-methyl-1H- pyrazol-5-yl)quinazolin-4(3H)-one (1.8 g, 92%) as a white solid. LCMS (ESI) m/z: [M+H] + = 297.2 [0896] Step 3: To a solution of 8-acetyl-3,6-dimethyl-2-(1-methyl-1H-pyrazol-5-yl)quinazolin -4(3H)-one (1.8 g, 3.1 mmol) in THF (20 mL) were added Ti(i-PrO) 4 (20 mL) and (R)-2-methylpropane-2-sulfinamide (1.4 g, 12.2 mmol) at RT. The resulting mixture was heated to 75 °C and stirred overnight. Brine (20 mL) was added into the mixture. The suspension was filtered and the filter cake was washed with EtOAc (80 mL×3). The aqueous phase was extracted with EtOAc (150 mL×3) and the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give (R,Z)-N-(1-(3,6-dimethyl-2-(1-methyl-1H- pyrazol-5-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethylidene)-2 -methylpropane-2-sulfinamide (1.5 g, 62%) as a yellow solid. LCMS (ESI) m/z: [M+H] + = 400.0 [0897] Step 4: To a solution of (R,Z)-N-(1-(3,6-dimethyl-2-(1-methyl-1H-pyrazol-5-yl)-4-oxo- 3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (1.5 g, 3.7 mmol) and HOAc (1.8 mL) in DCM (15 mL) and MeOH (15 mL) was added NaBH 3 CN (688 mg, 11.1 mmol) in portions at 0 °C, the resulting mixture was warmed up to 20 °C and for 3 h. The mixture was quenched with saturated aqueous NH 4 Cl (100 mL) solution and extracted with DCM (150 mL x 2), the combined extract was washed with brine, dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by Prep-HPLC (Method A) to give (R)-N-((R)-1-(3,6-dimethyl- 2-(1-methyl-1H-pyrazol-5-yl)-4-oxo-3,4-dihydroquinazolin-8-y l)ethyl)-2-methylpropane-2-sulfinamide (650 mg, 44%) as a white solid. LCMS (ESI) m/z: [M+H] + = 402.3 [0898] Step 5: A mixture (R)-N-((R)-1-(3,6-dimethyl-2-(1-methyl-1H-pyrazol-5-yl)-4-ox o-3,4-dihydroquinazolin- 8-yl)ethyl)-2-methylpropane-2-sulfinamide (650 mg, 1.62 mmol) in a solution of HCl in MeOH (3M, 7mL) was stirred at RT for 30 minutes. The mixture was adjusted to pH = 9 with saturated aqueous NaHCO 3 solution and the mixture was extracted with DCM (150 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(1-methyl-1H-pyrazol-5- yl)quinazolin-4(3H)-one (450 mg, 94%) as a white solid. LCMS (ESI) m/z: [M+H] + = 298.3 [0899] Step 6: To a solution of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(1-methyl-1H-pyrazol-5-y l)quinazolin-4(3H)- one (100 mg, 0.34 mmol) in DMSO (2 mL) were added methyl 6-chloro-3-fluoropicolinate (127 mg, 0.67 mmol) and DIPEA (0.2 mL) at RT. The resulting mixture was stirred at 100 °C overnight. The mixture was diluted with water (20 mL) and extracted with EtOAc (70 mL×3), the combined organic phase was washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give methyl (R)-6-chloro-3-((1-(3,6-dimethyl-2- (1-methyl-1H-pyrazol-5-yl)-4-oxo-3,4-dihydroquinazolin-8-yl) ethyl)amino)picolinate (150 mg, 95%) as a yellow solid. LCMS (ESI) m/z: [M+H] + = 467.2 [0900] Step 7: To a solution of methyl (R)-6-chloro-3-((1-(3,6-dimethyl-2-(1-methyl-1H-pyrazol-5-yl )-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (150 mg, 0.32 mmol) in MeOH (2 mL) and THF (2 mL) were added LiOH (81 mg, 1.92 mmol) and H 2 O (0.5 mL) at RT. The resulting mixture was stirred at the RT for 15 minutes. The mixture was adjusted to pH = 4 with HCl solution and diluted with water (20 mL), the mixture was extracted with DCM (80 mL x 3), the combined organic layers were dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by Prep-HPLC (Method B) to give (R)-6-chloro-3-((1-(3,6-dimethyl-2-(1-methyl-1H-pyrazol-5- yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinic acid (60.2 mg, 42%) as a white solid. LCMS (ESI) m/z: [M+H] + = 453.1 EXAMPLE 118 (R)-6-chloro-3-((1-(3,6-dimethyl-2-(1-methyl-1H-imidazol-2-y l)-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0901] Step 1: To a solution of 2-amino-3-bromo-N,5-dimethylbenzamide (3 g, 12.40 mmol,) in DMSO (60 mL) was added 1-methyl-1H-imidazole-2-carbaldehyde (2.73 g, 24.80 mmol,). The mixture was stirred under O 2 at 120 °C for 2 h. The mixture was diluted with water (300 mL) and extracted with EtOAc (100 mL×3). The combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (PE: EA=5：2) to give 8-bromo-3,6-dimethyl-2-(1-methyl-1H-imidazol-2- yl)quinazolin-4(3H)-one (3.0 g, 71.3 %) as a yellow solid. LCMS: (M + H) + =333.1 [0902] Step 2: To a mixture of 8-bromo-3,6-dimethyl-2-(1-methyl-1H-imidazol-2-yl)quinazolin -4(3H)-one (3.0 g, 8.85 mmol) and tributyl(1-ethoxyvinyl)stannane (6.39 g, 17.70 mmol) in dioxane (30 ml) was added Pd(PPh 3 ) 2 Cl 2 (621 mg, 0.89 mmol,). The mixture was stirred at 95 °C under N 2 for 16 h. HCl (9 ml, 1 M) was added into the mixture and the mixture was stirred at 50 °C for 0.5 hour, then 50 ml sat KF was added and the mixture was stirred at RT for 0.5 hour. The gray was filtered, the filter cake was washed with EtOAc (100 ml*3), the separated aqueous phase was extracted with EtOAc (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 3:1) to give 8-acetyl-3,6- dimethyl-2-(1-methyl-1H-imidazol-2-yl)quinazolin-4(3H)-one (2.5 g, 95.5%) as a yellow solid. LCMS: (M + H) + = 297.3 [0903] Step 3: To a mixture of 8-acetyl-3,6-dimethyl-2-(1-methyl-1H-imidazol-2-yl)quinazoli n-4(3H)-one (2.5 g, 8.45 mmol) and (R)-2-methylpropane-2-sulfinamide (2.05 mg, 16.90 mmol) in THF (20 ml) at RT was added Ti(i-PrO) 4 (20 ml). The mixture was stirred at 75 °C for 12 h. Cooling to RT, brine (150 ml) was added and the mixture was stirred for 0.5 hour. The resulting mixture was filtrated and the cake was washed with EtOAc (100 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)-N-(1-(3,6-dimethyl-2-(1-methyl-1H-imidazol-2-yl)-4-oxo -3,4-dihydroquinazolin-8-yl)ethylidene)-2- methylpropane-2-sulfinamide (3 g) as a yellow oil for the next step without further purification. LCMS: (M + H) + = 399.9 [0904] Step 4: To a solution of (R,Z)-N-(1-(3,6-dimethyl-2-(1-methyl-1H-imidazol-2-yl)-4-oxo -3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (3 g, 8.84 mmol) in DCM (20 mL) and MeOH(20 mL) were added NaBH 3 CN (1.1 g, 17.68 mmol) and HOAc (0.2 mL) at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction was quenched with saturated NH 4 Cl solution (150 ml) and extracted with DCM (150 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (method A) to give (R)-N-((R)-1-(3,6-dimethyl-2-(1-methyl-1H-imidazol-2-yl)-4-o xo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (850 mg, 24.0%) as a white solid. LCMS: (M + H) + = 402.0 [0905] Step 5: To a solution of (R)-N-((R)-1-(3,6-dimethyl-2-(1-methyl-1H-imidazol-2-yl)-4-o xo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (850 mg, 2.12 mmol) in MeOH (4 mL) was added HCl in MeOH (10 ml, 4 M).The mixture was stirred at RT for 5 minutes. The mixture was poured into ice-water and adjusted pH=8 with a saturated solution of NaHCO 3 , the mixture was extracted with DCM/MeOH (50 ml*3, 10/1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (DCM: MeOH=10:1) to give (R)-8-(1-aminoethyl)-3,6-dimethyl- 2-(1-methyl-1H-imidazol-2-yl)quinazolin-4(3H)-one (230 mg, 77.8 %) as a white solid. LCMS: (M + H) + =298.3 [0906] Step 6: To a solution of methyl (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(1-methyl-1H-imidazol-2- yl)quinazolin-4(3H)-one (230 mg, 0.77 mmol) in DMSO (5 mL) were added methyl methyl 6-chloro-3- fluoropicolinate (293 mg, 1.54 mmol) and DIEA (298 mg, 2.31 mmol). The mixture was stirred at 100 °C for 2 h. The mixture was diluted with water (50 ml) and extracted with EtOAc (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (PE: EA=4:1) to give methyl (R)-6-chloro-3-((1-(3,6-dimethyl-2-(1-methyl-1H-imidazol-2-y l)-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinate (150 mg, 41.5 %) as a yellow solid. LCMS: (M + H) + =467.2 [0907] Step 7: To a solution of methyl (R)-6-chloro-3-((1-(3,6-dimethyl-2-(1-methyl-1H-imidazol-2-y l)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (150 mg, 0.32 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (77 mg, 3.20 mmol). The mixture was stirred at 50 °C for 1 hour. The mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM (40 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to give (R)-6-chloro-3-((1-(3,6- dimethyl-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-3,4-dihydroquin azolin-8-yl)ethyl)amino)picolinic acid (54.3 mg, 37.5%) as a white solid. LCMS: (M + H) + =453.1

EXAMPLE 119 (R)-6-chloro-3-(1-(3,6-dimethyl-2-(1-methyl-1H-imidazol-5-yl )-4-oxo-3,4-dihydroquinazolin-8- yl)ethylamino)picolinic acid [0908] Step 1: To a mixture of 2-amino-3-bromo-N,5-dimethylbenzamide (1.4 g, 5.79 mmol) in DMSO (20 ml) was added 1-methyl-1H-imidazole-5-carbaldehyde (1.27 g, 11.58 mmol) , the mixture was stirred at 135 °C for 16 h under O 2 . The mixture was poured into water (100 ml), and stirred for 0.5 hour. The mixture was filtered and the filter cake was washed water (40 ml * 3), the collected solid was dried under reduce pressure to afford 8- bromo-3,6-dimethyl-2-(1-methyl-1H-imidazol-5-yl)quinazolin-4 (3H)-one (850 mg, 44%) as a white solid. LCMS: (M+ 2+ H) + = 335.1 [0909] Step 2: To a mixture of 8-bromo-3,6-dimethyl-2-(1-methyl-1H-imidazol-5-yl)quinazolin -4(3H)-one (850 mg, 2.56 mmol) and tributyl(1-ethoxyvinyl)stannane (1.85 g, 5.12 mmol) in 1.4-dioxane (10 ml) was added and Pd(PPh 3 ) 2 Cl 2 (270 mg, 0.384 mmol). The mixture was stirred at 100 °C under N 2 for 16 h. HCl (3 ml, 1 M) was added into the mixture and the mixture was stirred at 50 °C for 0.5 hour. Then 30 ml sat KF was added and the mixture was stirred at RT for 0.5 hour. The gray suspension was filtered. The filter cake was washed with DCM, the separated aqueous phase was extracted with DCM (20 ml * 3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated, the residue was purified by flash (DCM: EA = 10: 1) to afford 8- acetyl-3,6-dimethyl-2-(1-methyl-1H-imidazol-5-yl)quinazolin- 4(3H)-one (420 mg, 55%) as a yellow oil. LCMS: (M + H) + = 297.0 [0910] Step 3: To a mixture of 8-acetyl-3,6-dimethyl-2-(1-methyl-1H-imidazol-5-yl)quinazoli n-4(3H)-one (420 mg, 1.42 mmol) and (R)-2-methylpropane-2-sulfinamide (344 mg, 2.84 mmol) and THF (8 ml) was added Ti(Oi- Pr) 4 (8 ml). the mixture was stirred at 75 °C under N 2 for 16 h. Cooling to RT, the mixture was diluted with EtOAc (30 ml) and brine (10 mL) was added, the mixture was stirred for 0.5 hour. The resulting mixture was filtrated and the cake was washed with EtOAc (50 mL*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)-N-(1-(3,6-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-4-oxo -3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (500 mg, 88%) as a yellow oil. LCMS: (M + H) + = 400.2 [0911] Step 4: To a mixture of crude (R,Z)-N-(1-(3,6-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-4-oxo -3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (500 mg, 1.25 mmol) and AcOH (600 mg, 10 mmol) in DCM (8 ml) and MeOH (8 ml) was added NaBH 3 CN (236 mg, 3.75 mmol) 0 °C. The mixture was stirred at 0 °C for 2 h. A saturated solution of NH 4 Cl (30 ml) was added and the mixture was extracted with DCM (30 ml * 3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method A) to afford (R)-N-((R)-1-(3,6-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-4-o xo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (250 mg, 50%) as a white solid. LCMS: (M + H) + = 402.0 [0912] Step 5: A mixture of (R)-N-((R)-1-(3,6-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-4-o xo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (250 mg, 0.62 mmol) in HCl (3 M in MeOH) (5 ml) was stirred at RT for 0.5 hour. The mixture was poured into ice-water and adjusted pH= 8 with a saturated solution of NaHCO 3 , The mixture was extracted with DCM:MeOH (30 mL*3, 10:1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(1- methyl-1H-imidazol-5-yl)quinazolin-4(3H)-one (170 mg, 92%) as a yellow solid. LCMS: (M + H) + = 298.0 [0913] Step 6: To a mixture of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(1-methyl-1H-imidazol-5- yl)quinazolin- 4(3H)-one (100 mg, 0.34 mmol) and methyl 6-chloro-3-fluoropicolinate (96 mg, 0.51 mmol) in DMSO (5 ml) was added DIPEA (88 mg, 0.68 mmol). The mixture was stirred at 100 °C for 16 h. Cooling to RT, H 2 O (50 mL) was added and the mixture was extracted with EtOAc (30 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford (R)-methyl 6-chloro-3-(1-(3,6-dimethyl-2-(1-methyl-1H-imidazol-5- yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethylamino)picolinate (120 mg, 76% yield) as a yellow oil. LCMS: (M + H) + = 466.9 [0914] Step 7: A mixture of (R)-methyl 6-chloro-3-(1-(3,6-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-4- oxo-3,4- dihydroquinazolin-8-yl)ethylamino)picolinate (120 mg, 0.26 mmol) in MeOH/H 2 O (5: 1) (5 ml) was added LiOH (62 mg, 2.6 mmol). The mixture stirred at 50 °C for 1 hour. Cooling to rt, the mixture was adjusted to pH= 5 – 6 with HCl (1 M). The mixture was concentrated and purified by Pre-HPLC (Method B) to afford (R)-6-chloro-3-(1- (3,6-dimethyl-2-(1-methyl-1H-imidazol-5-yl)-4-oxo-3,4-dihydr oquinazolin-8-yl)ethylamino)picolinic acid (54.4 mg, 46% yield) as a white solid. LCMS: (M + H) + = 453.1 EXAMPLE 120 (R)-6-chloro-3-((1-(3,6-dimethyl-2-(1-methyl-1H-imidazol-4-y l)-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0915] Step 1: To a mixture of 2-amino-3-bromo-N,5-dimethylbenzamide (2 g, 8.26 mmol) in DMSO (50 mL) was added 1-methyl-1H-imidazole-4-carbaldehyde (1.82 g, 16.5 mmol), The suspension was degassed under vacuum and purged with O 2 . The mixture was heated to 150°C and stirred at 150°C overnight. Cooling to RT, the mixture was filtered and the filter cake was washed with water. The collected solid was dried under vacuum to afford 8-bromo-3,6-dimethyl-2-(1-methyl-1H-imidazol-4-yl)quinazolin -4(3H)-one (1.5 g, 54.7%) as a yellow solid. LCMS: (M + H) + =333.0 [0916] Step 2: To a mixture of 8-bromo-3,6-dimethyl-2-(1-methyl-1H-imidazol-4-yl)quinazolin -4(3H)-one (1.5 g, 4.52 mmol) and ethyl tributylstannanecarboxylate (2.45 g, 6.78 mmol) in Dioxane (30 mL) was added Pd(PPh 3 ) 2 Cl 2 (661 mg, 0.904 mmol). The mixture was stirred at 105 °C under N 2 overnight. HCl (5 mL, 1 M) was added into the mixture and stirred at 50 °C for 0.5 hour, then 50 ml sat KF was added and the mixture was stirred at RT for 0.5 hour. The gray was filtered, the filter cake was washed with EtOAc (800 mL*3), the separated aorganic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 3:1) to afford 8-acetyl-3,6-dimethyl-2-(1-methyl-1H-imidazol-4-yl)quinazoli n-4(3H)- one (1.2 g, 89.7%) as a yellow solid. LCMS: (M + H) + =297.3 [0917] Step 3: To a mixture of 8-acetyl-3,6-dimethyl-2-(1-methyl-1H-imidazol-4-yl)quinazoli n-4(3H)-one (1.2 g, 4.05 mmol) and (R)-2-methylpropane-2-sulfinamide (981 mg, 8.11 mmol) in THF (20 mL) at RT was added Ti(i- PrO) 4 (14.6 g, 40.5 mmol). The mixture was stirred at 75 °C overnight. Cooling to RT, brine (50 mL) was added and the mixture was stirred for 0.5 hour. The resulting mixture was filtrated and the cake was washed with EtOAc (80 mL*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)-N-(1-(3,6-dimethyl-2-(1-methyl-1H-imidazol-4-yl)-4-oxo -3,4-dihydroquinazolin-8-yl)ethylidene)-2- methylpropane-2-sulfinamide (2.0 g, crude) as a yellow oil for the next step without further purification. LCMS: (M + H) + =400.3 [0918] Step 4: To a mixture of crude (R,Z)-N-(1-(3,6-dimethyl-2-(1-methyl-1H-imidazol-4-yl)-4-oxo -3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (2.0 g, 5.01 mmol) and HOAc (3.18 g, 32.4 mmol) in DCM (20 ml) and MeOH (20 ml) was added NaBH 3 CN (754 mg, 12.2 mmol) in portions at 0 °C, the mixture was stirred at RT overnight. The reaction was quenched with a saturated solution of NH 4 Cl (20 mL) and extracted with DCM (80 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method A) to afford (R)-N-((R)-1-(3,6-dimethyl-2-(1- methyl-1H-imidazol-4-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)et hyl)-2-methylpropane-2-sulfinamide (600 mg, 36.9%) as a yellow solid. LCMS: (M + H) + =402.1 [0919] Step 5: A mixture (R)-N-((R)-1-(3,6-dimethyl-2-(1-methyl-1H-imidazol-4-yl)-4-o xo-3,4-dihydroquinazolin- 8-yl)ethyl)-2-methylpropane-2-sulfinamide (600 mg, 1.49 mmol) in a solution of HCl in MeOH (15 mL, 4 M) was stirred at RT for 30 min. The mixture was poured into ice-water and adjusted pH= 8 with a saturated solution of NaHCO 3 , The mixture was extracted with DCM:MeOH (60mL*3, 10:1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(1-methyl-1H- imidazol-4-yl)quinazolin-4(3H)-one (500 mg, crude) as a yellow oil. LCMS: (M + H) + =298.1 [0920] Step 6: To a mixture of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(1-methyl-1H-imidazol-4- yl)quinazolin- 4(3H)-one (100 mg, 0.337 mmol) and methyl 6-chloro-3-fluoropicolinate (95.5 mg, 0.505 mmol) in DMSO (5 mL) was added DIPEA (130.3 mg, 1.01 mmol), the mixture was heated to 100 °C and stirred for 3 h. Cooling to RT, H 2 O (30 mL) was added and the mixture was extracted with EtOAc (30 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford methyl (R)-6-chloro-3-((1-(3,6-dimethyl-2-(1- methyl-1H-imidazol-4-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)et hyl)amino)picolinate (120 mg, 76.5%) as a yellow solid. LCMS: (M + H) + = 467.0 [0921] Step 7: To a solution of methyl (R)-6-chloro-3-((1-(3,6-dimethyl-2-(1-methyl-1H-imidazol-4-y l)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (120 mg, 0.258 mmol) in MeOH (5 mL) and H 2 O (1 mL) was added LiOH (54.1 mg, 1.28 mmol). The mixture was stirred at 50 °C for 3 h. The mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM (30 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to afford (R)-6-chloro-3-((1-(3,6- dimethyl-2-(1-methyl-1H-imidazol-4-yl)-4-oxo-3,4-dihydroquin azolin-8-yl)ethyl)amino)picolinic acid (57.1 mg, 49.1%) as a white solid. LCMS: (M + H) + = 453.1 EXAMPLE 121 (R)-6-chloro-3-((1-(2-(cyclopropylmethyl)-3,6-dimethyl-4-oxo -3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0922] Step 1: To a mixure of 2-amino-3-bromo-N,5-dimethylbenzamide (2 g, 8.2 mmol) and 2- cyclopropylacetic acid (1.9 g, 16.5 mmol) in ACN (50 mL) were added TCFH (4.6 g, 16.5 mmol) and NMI (2.03 g, 16.5 mmol) at RT. The resulting mixture was heated to 90 °C and stirred overnight. Cooling to RT, water (40 mL) was added and the mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by silica gel column chromatography (PE: EA=4:1) to give 8-bromo-2-(cyclopropylmethyl)-3,6-dimethylquinazolin-4(3H)-o ne (2.0 g, 79.26%) as a white solid. LCMS (ESI) m/z: [M+H] + = 307.1 [0923] Step 2: To a solution of 8-bromo-2-(cyclopropylmethyl)-3,6-dimethylquinazolin-4(3H)-o ne (2 g, 6.5 mmol) in dioxane (60 mL) were added tributyl(1-ethoxyvinyl)stannane (4.6 g, 12.5 mmol) and Pd(PPh 3 ) 2 Cl 2 (490 mg, 0.7 mmol) at RT. The resulting mixture was heated to 95 °C and stirred overnight under N 2 . HCl (7 mL, 1 M) was added into the mixture and the mixture was stirred at 50 °C for 0.5 hour. Saturated aqueous KF (100 mL) solution was added and the resulting mixture was stirred at 20 °C for 0.5 hour. The gray suspension was filtered and the filter cake was washed with EtOAc (80 mL×3). The aqueous phase was extracted with EtOAc (60 mL×3) and the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by silica gel column chromatography (PE: EA=5:1) to give 8-acetyl-2-(cyclopropylmethyl)- 3,6-dimethylquinazolin-4(3H)-one (1.7 g, 50.4%) as a white solid. LCMS (ESI) m/z: [M+H] + = 271.3 [0924] Step 3: To a solution of 8-acetyl-2-(cyclopropylmethyl)-3,6-dimethylquinazolin-4(3H)- one (1.7 g, 6.3 mmol) in THF (15 mL) were added Ti(i-PrO) 4 (15 mL) and (R)-2-methylpropane-2-sulfinamide (1.5 g, 12.6 mmol) at RT. The resulting mixture was heated to 75 °C and stirred overnight. Brine (80 mL) was added into the mixture. The suspension was filtered. The filter cake was washed with EtOAc (100 mL×3). The aqueous phase was extracted with EtOAc (100 mL×3) and the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give (R,Z)-N-(1-(2-(cyclopropylmethyl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethylidene)-2-meth ylpropane-2-sulfinamide (2.3 g, 98%) as a yellow solid. LCMS (ESI) m/z: [M+H] + = 347.2; Retention time = 1.82 min. LCMS CP Method N [0925] Step 4: To a solution of (R,Z)-N-(1-(2-(cyclopropylmethyl)-3,6-dimethyl-4-oxo-3,4-dih ydroquinazolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (2.3 g, 6.2 mmol) and HOAc (3 mL) in DCM (20 mL) and MeOH (20 mL) was added NaBH 3 CN (1.15 g, 18.6 mmol) in portions at 0 °C, the resulting mixture was warmed up to 20 °C and stirred for 1 hour. The mixture was quenched with saturated NH 4 Cl (100 mL) and extracted with DCM (100 mL x 2), the combined extract was washed with brine, dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by Prep-HPLC (Method A) to give (R)-N-((R)-1-(2-(cyclopropylmethyl)-3,6-dimethyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinam ide (670 mg, 28.9%) as a white solid. LCMS (ESI) m/z: [M+H] + = 376.3; Retention time = 1.66 min. LCMS CP Method O [0926] Step 5: A mixture (R)-N-((R)-1-(2-(cyclopropylmethyl)-3,6-dimethyl-4-oxo-3,4-d ihydroquinazolin-8- yl)ethyl)-2-methylpropane-2-sulfinamide (670 mg, 1.79 mmol) in a solution of HCl in MeOH (3M, 15 mL) was stirred at the RT for 20 minutes. The mixture was adjusted to pH = 9 with saturated aqueous NaHCO 3 solution and the mixture was extracted with DCM (100 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give (R)-8-(1-aminoethyl)-2-(cyclopropylmethyl)-3,6- dimethylquinazolin-4(3H)-one (480 mg, 99%) as a yellow solid. LCMS (ESI) m/z: [M+H] + = 272.3 [0927] Step 6: To a solution of (R)-8-(1-aminoethyl)-2-(cyclopropylmethyl)-3,6-dimethylquina zolin-4(3H)-one (100 mg, 0.37 mmol) in DMSO (3 mL) were added methyl 6-chloro-3-fluoropicolinate (140 mg, 0.74 mmol) and DIPEA (143 mg, 1.11 mmol) at RT. The resulting mixture was stirred at the 100 °C overnight. The mixture was diluted with water (50 mL) and extracted with EtOAc (70 mL×3), the combned organic phase was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give methyl (R)-6-chloro-3-((1-(2- (cyclopropylmethyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin -8-yl)ethyl)amino)picolinate (150 mg, 92%) as a yellow solid. LCMS (ESI) m/z: [M+H] + = 441.3 [0928] Step 7: To a solution of methyl (R)-6-chloro-3-((1-(2-(cyclopropylmethyl)-3,6-dimethyl-4-oxo -3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (150 mg, 0.34 mmol) in THF (2mL) and MeOH (2 mL) were added LiOH (33 mg, 1.36 mmol) and H 2 O (2 mL) at RT, The resulting mixture was stirred at the 45 °C for 2 h. The mixture was adjusted to 4 with HCl solution and diluted with water (40 mL), the mixture was extracted with DCM (40 mL x 3), the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by Prep-HPLC (Method B) to give (R)-6-chloro-3-((1-(2-(cyclopropylmethyl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picoli nic acid (116.6 mg, 81%) as a white solid. LCMS (ESI) m/z: [M+H] + = 427.1 EXAMPLE 122 and EXAMPLE 123 (R)-6-chloro-3-((1-(2-(2-hydroxyphenyl)-3,6-dimethyl-4-oxo-3 ,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid (R)-6-chloro-3-((1-(2-(2-methoxyphenyl)-3,6-dimethyl-4-oxo-3 ,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0929] Step 1: To a solution of 2-amino-3-bromo-N,5-dimethylbenzamide (3 g, 12.40 mmol,) in DMSO (60 mL) was added 2-methoxybenzaldehyde (3.37 g, 24.80 mmol,). The mixture was stirred under O 2 at 120 °C for 2 h. The mixture was diluted with water (300 mL) and extracted with EtOAc (100 mL×3). The combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (PE: EA=5：2) to give 8-bromo-2-(2-methoxyphenyl)-3,6-dimethylquinazolin-4(3H)-one (3.0 g, 67.4 %) as a yellow solid. LCMS: (M + H) + =359.0 [0930] Step 2: To a mixture of 8-bromo-2-(2-methoxyphenyl)-3,6-dimethylquinazolin-4(3H)-one (3.0 g, 8.36 mmol) and tributyl(1-ethoxyvinyl)stannane (6.04 g, 16.72 mmol) in dioxane (30 ml) was added Pd(PPh 3 ) 2 Cl 2 (590 mg, 0.84 mmol,). The mixture was stirred at 95 °C under N 2 for 16 h. HCl (9.0 ml, 1 M) was added into the mixture and the mixture was stirred at 50 °C for 0.5 hour, then 50 ml sat KF was added and the mixture was stirred at RT for 0.5 hour. The gray was filtered, the filter cake was washed with EtOAc (100 ml*3), the separated aqueous phase was extracted with EtOAc (80 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 3:1) to give 8-acetyl-2- (2-methoxyphenyl)-3,6-dimethylquinazolin-4(3H)-one (2.5 g, 92.8%) as a yellow solid. LCMS: (M + H) + =323.2 [0931] Step 3: To a mixture of 8-acetyl-2-(2-methoxyphenyl)-3,6-dimethylquinazolin-4(3H)-on e (2.5 g, 7.76 mmol) and (R)-2-methylpropane-2-sulfinamide (1.88 g, 15.52 mmol) in THF (20 ml) at RT was added Ti(i-PrO) 4 (20 ml). The mixture was stirred at 75 °C for 12 h. Cooling to RT, brine (150 ml) was added and the mixture was stirred for 0.5 hour. The resulting mixture was filtrated and the cake was washed with EtOAc (100 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)-N-(1- (2-(2-methoxyphenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazoli n-8-yl)ethylidene)-2-methylpropane-2-sulfinamide (3 g) as a yellow oil for the next step without further purification. LCMS: (M + H) + = 426.0 [0932] Step 4: To a solution of (R,Z)-N-(1-(2-(2-methoxyphenyl)-3,6-dimethyl-4-oxo-3,4-dihyd roquinazolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (3 g, 7.04 mmol) in DCM (20 mL) and MeOH(20 mL) were added NaBH 3 CN (855 mg, 14.08 mmol) and HOAc (0.2 mL) at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction was quenched with saturated NH 4 Cl solution (60 ml) and extracted with DCM (100 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (method A) to give (R)-N-((R)-1-(2-(2-methoxyphenyl)-3,6-dimethyl-4-oxo-3,4-dih ydroquinazolin-8-yl)ethyl)-2- methylpropane-2-sulfinamide (650 mg, 21.6%) as a white solid. LCMS: (M + H) + = 428.0 [0933] Step 5: To a solution of (R)-N-((R)-1-(2-(2-methoxyphenyl)-3,6-dimethyl-4-oxo-3,4-dih ydroquinazolin-8- yl)ethyl)-2-methylpropane-2-sulfinamide (250 mg, 0.58 mmol) in MeOH (4 mL) was added HCl in MeOH (10 ml, 4 M).The mixture was stirred at RT for 5 minutes. The mixture was poured into ice-water and adjusted pH = 8 with a saturated solution of NaHCO 3 , the mixture was extracted with DCM/MeOH (60 ml*3, 10/1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (DCM: MeOH=10:1) to give (R)-8-(1-aminoethyl)-2-(2-methoxyphenyl)-3,6- dimethylquinazolin-4(3H)-one (180 mg, 96.5 %) as a white solid. LCMS: (M + H) + =324.2 [0934] Step 6: To a solution of (R)-8-(1-aminoethyl)-2-(2-methoxyphenyl)-3,6-dimethylquinazo lin-4(3H)-one (180 mg, 0.56 mmol) in DMSO (5 mL) were added methyl 6-chloro-3-fluoropicolinate (160 mg, 0.84 mmol) and DIEA (217 mg, 1.68 mmol). The mixture was stirred at 100 °C for 2 h. The mixture was diluted with water (30 ml) and extracted with EtOAc (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (PE: EA=4:1) to give the target methyl (R)-6-chloro-3-((1-(2-(2-methoxyphenyl)-3,6-dimethyl-4-oxo-3 ,4-dihydroquinazolin-8- yl)ethyl)amino)picolinate (200 mg, 73.2 %) as a yellow solid. LCMS: (M + H) + =493.2 [0935] Step 7: To a solution of methyl (R)-6-chloro-3-((1-(2-(2-methoxyphenyl)-3,6-dimethyl-4-oxo-3 ,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (100 mg, 0.20 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (48 mg, 2.00mmol). The mixture was stirred at 50 °C for 1 hour. The mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM (80 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to give (R)-6-chloro-3-((1-(2-(2- methoxyphenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl )ethyl)amino)picolinic acid (53.9 mg, 55 %) as a white solid. LCMS: (M + H) + =479.0 [0936] Step 8: To a solution of methyl (R)-6-chloro-3-((1-(2-(2-methoxyphenyl)-3,6-dimethyl-4-oxo-3 ,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (100 mg, 0.20 mmol) in DCM (2 ml) was added BBr 3 (2 ml, 1M in DCM) at 0 °C. The mixture was stirred at RT for 1 hour. The mixture was poured into ice-water and adjusted pH = 8 with a saturated solution of NaHCO 3 , the mixture was extracted with DCM/MeOH (40 ml*3, 10/1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to give (R)-6-chloro-3-((1-(2-(2-hydroxyphenyl)-3,6-dimethyl-4-oxo-3 ,4- dihydroquinazolin-8-yl)ethyl)amino)picolinic acid (36.5 mg, 39.2 %) as a white solid. LCMS: (M + H) + =465.1 EXAMPLE 124 (R)-6-chloro-3-((1-(2-(2,5-dimethyloxazol-4-yl)-3,6-dimethyl -4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0937] Step 1: To a solution of 2-amino-3-bromo-N,5-dimethylbenzamide (1.43 g, 5.882 mmol) in DMSO (15 mL) was added 2,5-dimethyloxazole-4-carbaldehyde (1.0 g, 7.992 mmol). The mixture was stirred at 135 °C for 16 h under O 2 . After cooled to RT, the mixture was filtered and washed with water, the collected solid was dried under reduce pressure to give 8-bromo-2-(2,5-dimethyloxazol-4-yl)-3,6-dimethylquinazolin-4 (3H)-one (450 mg, 22.0 %) as a white solid. LCMS: (M + H) + =350.0 [0938] Step 2: To a solution of 8-bromo-2-(2,5-dimethyloxazol-4-yl)-3,6-dimethylquinazolin-4 (3H)-one (450 mg, 1.292 mmol) in dioxane (15 mL) were added tributyl(1-ethoxyvinyl)stannane (950 mg, 2.630 mmol) and Pd(PPh 3 ) 2 Cl 2 (123 mg, 0.175 mmol) at RT. The mixture was stirred at 100 °C for 4 h under N 2 . The mixture was added HCl (2 mL, 1M) and stirred at 50 °C for 0.5 hour, then the mixture was added saturated aqueous KF solution (14 mL) and stirred at RT for 0.5 hour. The gray suspension was filtered, the filter cake was washed with H 2 O (10 mL×2) and EtOAc (20 mL×2). The separated aqueous phase was extracted with EtOAc (80 mL×2). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by silica gel column chromatography (DCM: EA=5:1) to give 8-acetyl-2-(2,5- dimethyloxazol-4-yl)-3,6-dimethylquinazolin-4(3H)-one (380 mg, 94.5 %) as a gray solid. LCMS: (M + H) + =312.0 [0939] Step 3: To a solution of 8-acetyl-2-(2,5-dimethyloxazol-4-yl)-3,6-dimethylquinazolin- 4(3H)-one (380 mg, 1.221 mmol) in THF (7 mL) were added (R)-2-methylpropane-2-sulfinamide (300 mg, 2.475 mmol) and Ti(Oi-Pr) 4 (7 mL) at RT. The mixture was stirred at 75 °C for 18 h under N 2 . After cooling with ice bath, the mixture was added saturated aqueous NaCl solution (15 mL) and stirred at RT for 5 mins. The suspension was filtered, the filter cake was washed with EtOAc (20 mL×2). The aqueous phase was extracted with EtOAc (80 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give crude (R,Z)-N-(1-(2-(2,5-dimethyloxazol-4-yl)-3,6-dimethyl-4-oxo-3 ,4-dihydroquinazolin-8-yl)ethylidene)-2- methylpropane-2-sulfinamide (500 mg, 98.8 %) as a yellow solid. LCMS: (M + H) + =415.0 [0940] Step 4: To a solution of crude (R,Z)-N-(1-(2-(2,5-dimethyloxazol-4-yl)-3,6-dimethyl-4-oxo-3 ,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (500 mg, 1.206 mmol) in MeOH (5 mL) were added DCM (5 mL), AcOH (0.6 mL) and NaBH 3 CN (228 mg, 3.628 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour. The mixture was added with aqueous NH 4 Cl solution (14 mL), extracted with DCM (100 mL×2). The combined organic layers were washed brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by Prep-HPLC (method A) to give (R)-N-((R)-1-(2-(2,5-dimethyloxazol-4-yl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpro pane-2-sulfinamide (305 mg, 60.7 %) as a white solid. LCMS: (M + H) + =417.0 [0941] Step 5: To a solution of (R)-N-((R)-1-(2-(2,5-dimethyloxazol-4-yl)-3,6-dimethyl-4-oxo -3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (305 mg, 0.732 mmol) in MeOH (4 mL) was added HCl (2 mL, 3M in MeOH) at RT. The mixture was stirred at RT for 1 hour. The mixture was neutralized with aqueous NaHCO 3 solution to pH = 8, extracted with DCM (80 mL×2). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give (R)-8-(1-aminoethyl)-2-(2,5-dimethyloxazol-4-yl)-3,6- dimethylquinazolin-4(3H)-one (225 mg, 98.4 %) as a white solid. LCMS: (M + H) + =313.0 [0942] Step 6: To a solution of (R)-8-(1-aminoethyl)-2-(2,5-dimethyloxazol-4-yl)-3,6-dimethy lquinazolin-4(3H)- one (85 mg, 0.272 mmol) in DMSO (2 mL) were added methyl 6-chloro-3-fluoropicolinate (77 mg, 0.406 mmol) and DIEA (0.4 mL). The mixture was stirred at 100 °C for 4 h. After cooling to RT, the mixture was added water (25 mL), filtered and washed with water to give methyl (R)-6-chloro-3-((1-(2-(2,5-dimethyloxazol-4-yl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picoli nate (120 mg, 91.5 %) as a yellow solid. LCMS: (M + H) + =482.0 [0943] Step 7: To a solution of methyl (R)-6-chloro-3-((1-(2-(2,5-dimethyloxazol-4-yl)-3,6-dimethyl -4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (120 mg, 0.249 mmol) in MeOH (0.8 mL) were added THF (0.8 mL), H 2 O (0.6 mL) and LiOH•H 2 O (42 mg, 1.001 mmol) at RT. The mixture was stirred at RT for 1 hour. The mixture was neutralized with HCl (1M) to pH = 6 and concentrated, the residue was purified by Prep-HPLC (method B) to give (R)-6-chloro-3-((1-(2-(2,5-dimethyloxazol-4-yl)-3,6-dimethyl -4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid (60 mg, 51.4 %) as a white solid. LCMS: (M + H) + = 468.1 EXAMPLE 125 (R)-3-((1-(3,6-dimethyl-2-(1-methylcyclopropyl)-4-oxo-3,4-di hydroquinazolin-8-yl)ethyl)amino)-6- fluoropicolinic acid [0944] Step1: To a mixture of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(1-methylcyclopropyl)qui nazolin-4(3H)-one (300 mg, 1.1 mmol), methyl 6-fluoro-3-iodopicolinate (618 mg, 2.2 mmol) and Cs 2 CO 3 (717 mg, 2.2 mmol) in dioxane (10 ml) were added Pd 2 (dba) 3 (201 mg, 0.22 mmol) and XantPhos (253 mg, 0.44 mmol). The mixture was stirred at 120 °C under N 2 for 24 h. Cooling to RT, water (20 ml) was added and the mixture was extracted with DCM (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (DCM: EA = 30:1) to afford methyl (R)-3-((1-(3,6-dimethyl-2-(1- methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)am ino)-6-fluoropicolinate (240 mg, 52%) as a brown oil. LCMS: (M + H) + =425.3 [0945] Step2: To a mixture of methyl (R)-3-((1-(3,6-dimethyl-2-(1-methylcyclopropyl)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)-6-fluoropicolinate (240 mg, 0.57 mmol) in MeOH (8 ml) and H 2 O (2 ml) was added LiOH (68 mg, 2.85 mmol), the mixture was stirred at 50 °C for 3 h. Cooling to RT, the mixture was adjusted to pH = 5-6 with 1 M HCl and extracted with DCM (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (method B) and SFC to afford (R)-3-((1-(3,6-dimethyl-2-(1-methylcyclopropyl)-4-oxo-3,4-di hydroquinazolin-8-yl)ethyl)amino)-6- fluoropicolinic acid (22.6 mg, 10%) as a white solid. LCMS: (M + H)+ =411.1 EXAMPLE 126 (R)-6-chloro-3-((1-(2-(4,6-dimethylpyridin-3-yl)-3,6-dimethy l-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0946] Step 1: To a solution of 2-amino-3-bromo-N,5-dimethylbenzamide (1.43 g, 5.882 mmol) in DMSO (19 mL) was added 4,6-dimethylnicotinaldehyde (1.11 g, 8.212 mmol). The mixture was stirred at 135 °C for 24 h under O 2 . After cooling to RT, the mixture was filtered and washed with H 2 O (10 mL×2) and EtOAc (20 mL×2). The aqueous phase was extracted with EtOAc (120 mL×2). The combined organic layers were washed brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by silica gel column chromatography (DCM: EA=1:1) to give 8-bromo-2-(4,6-dimethylpyridin-3-yl)-3,6-dimethylquinazolin- 4(3H)-one (395 mg, 18.8 %) as a white solid. LCMS: (M + H) + =357.9 [0947] Step 2: To a solution of 8-bromo-2-(4,6-dimethylpyridin-3-yl)-3,6-dimethylquinazolin- 4(3H)-one (395 mg, 1.103 mmol) in dioxane (10 mL) were added tributyl(1-ethoxyvinyl)stannane (800 mg, 2.215 mmol) and Pd(PPh 3 ) 2 Cl 2 (100 mg, 0.142 mmol) at RT. The mixture was stirred at 100 °C for 4 h under N 2 . The mixture was added HCl (1.5 mL, 1M) and stirred at 50 °C for 0.5 hour, then the mixture was added saturated aqueous KF solution (12 mL) and stirred at RT for 0.5 hour. The gray suspension was filtered, the filter cake was washed with H 2 O (10 mL×2) and EtOAc (20 mL×2). The aqueous phase was extracted with EtOAc (80 mL×2). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by silica gel column chromatography (DCM: EA=1:1) to give 8-acetyl-2-(4,6-dimethylpyridin-3-yl)- 3,6-dimethylquinazolin-4(3H)-one (350 mg, 98.7 %) as a yellow oil. LCMS: (M + H) + =322.0 [0948] Step 3: To a solution of 8-acetyl-2-(4,6-dimethylpyridin-3-yl)-3,6-dimethylquinazolin -4(3H)-one (350 mg, 1.089 mmol) in THF (7 mL) were added (R)-2-methylpropane-2-sulfinamide (270 mg, 2.228 mmol) and Ti(Oi-Pr) 4 (7 mL) at RT. The mixture was stirred at 75 °C for 18 h under N 2 . After cooling with ice bath, the mixture was added saturated aqueous NaCl solution (10 mL) and stirred at RT for 5 mins. The suspension was filtered, the filter cake was washed with (20 mL×2). The aqueous phase was extracted with EtOAc (80 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give crude (R,Z)-N-(1-(2- (4,6-dimethylpyridin-3-yl)-3,6-dimethyl-4-oxo-3,4-dihydroqui nazolin-8-yl)ethylidene)-2-methylpropane-2- sulfinamide (460 mg, 99.4 %) as a yellow solid. LCMS: (M + H) + =425.0 [0949] Step 4: To a solution of crude (R,Z)-N-(1-(2-(4,6-dimethylpyridin-3-yl)-3,6-dimethyl-4-oxo- 3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (460 mg, 1.083 mmol) in MeOH (5 mL) were added DCM (5 mL), AcOH (0.6 mL) and NaBH 3 CN (108 mg, 1.719 mmol, 1.6 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hour. The mixture was added with aqueous NH 4 Cl solution (6 mL), extracted with DCM (40 mL×2). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by Prep-HPLC (method A) to give (R)-N-((R)-1-(2-(4,6-dimethylpyridin-3-yl)- 3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methy lpropane-2-sulfinamide (85 mg, 18.4 %) as a white solid. LCMS: (M + H) + =427.1 [0950] Step 5: To a solution of (R)-N-((R)-1-(2-(4,6-dimethylpyridin-3-yl)-3,6-dimethyl-4-ox o-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (85 mg, 0.199 mmol) in MeOH (3 mL) was added HCl (1 mL, 3M in MeOH) at RT. The mixture was stirred at RT for 1 hour. The mixture was neutralized with aqueous NaHCO 3 solution to pH = 8. The mixture was concentrated to provide a residue which was extracted with THF to give (R)-8-(1-aminoethyl)-2-(4,6-dimethylpyridin-3-yl)-3,6-dimeth ylquinazolin-4(3H)-one (58 mg, 90.4 %) as a white solid. LCMS: (M + H) + =323.0 [0951] Step 6: To a solution of (R)-8-(1-aminoethyl)-2-(4,6-dimethylpyridin-3-yl)-3,6-dimeth ylquinazolin-4(3H)- one (58 mg, 0.180 mmol) in DMSO (1.5 mL) were added methyl 6-chloro-3-fluoropicolinate (51 mg, 0.269 mmol) and DIEA (0.3 mL). The mixture was stirred at 100 °C for 4 h. After cooling to RT, the mixture was added water (20 mL), filtered and washed with water to give methyl (R)-6-chloro-3-((1-(2-(4,6-dimethylpyridin-3-yl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picoli nate (82 mg, 92.8 %) as a yellow solid. LCMS: (M + H) + =492.0 [0952] Step 7: To a solution of methyl (R)-6-chloro-3-((1-(2-(4,6-dimethylpyridin-3-yl)-3,6-dimethy l-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (82 mg, 0.167 mmol) in MeOH (0.8 mL) were added THF (0.8 mL), H 2 O (0.5 mL) and LiOH•H 2 O (28 mg, 0.667 mmol) at RT. The mixture was stirred at RT for 1 hour. The mixture was neutralized with HCl (1M) to pH = 6. The mixture was purified by Prep-HPLC (FA) to give (R)-6-chloro-3-((1- (2-(4,6-dimethylpyridin-3-yl)-3,6-dimethyl-4-oxo-3,4-dihydro quinazolin-8-yl)ethyl)amino)picolinic acid (33.5 mg, 41.9 %) as a white solid. LCMS: (M + H) + = 478.1 EXAMPLE 127 (R)-3-(1-(2-(benzo[d]thiazol-7-yl)-3,6-dimethyl-4-oxo-3,4-di hydroquinazolin-8-yl)ethylamino)-6- chloropicolinic acid [0953] Step 1: To a mixture of 2-amino-3-bromo-N,5-dimethylbenzamide (1.2 g, 4.96 mmol) in DMSO (30 ml) was added benzo[d]thiazole-7-carbaldehyde (1.62 g, 9.92 mmol). The mixture was stirred at 135 °C for 16 h under O 2 . The mixture was poured into water (200 ml) and stirred for 0.5 hour, the resulting mixture was filtered and the filter cake was washed with water (50 ml * 3), the collected solid was dried under reduce pressure to afford 2-(benzo[d]thiazol-7-yl)-8-bromo-3,6-dimethylquinazolin-4(3H )-one (1.9 g, 99%) as a white solid. LCMS: (M +2+ H) + = 388.1 [0954] Step 2: To a mixture of 2-(benzo[d]thiazol-7-yl)-8-bromo-3,6-dimethylquinazolin-4(3H )-one (1.9 g, 4.94 mmol) and tributyl(1-ethoxyvinyl)stannane (3.57 g, 9.88 mmol) in 1.4-dioxane (30 ml) was added Pd(PPh 3 ) 2 Cl 2 (519 mg, 0.74 mmol). The mixture was stirred at 95 °C under N 2 for 16 h. HCl (5 ml, 1 M) was added into the mixture and the mixture was stirred at 50 °C for 0.5 hour. Then 50 ml sat KF was added and the resulting mixture stirred at RT for 0.5 hour. The gray suspension was filtered and the filter cake was washed with EtOAc (60 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by flash (DCM: EA = 10: 1) to afford 8-acetyl-2-(benzo[d]thiazol-7-yl)-3,6-dimethylquinazolin-4(3 H)-one (1.3 g, 76%) as a yellow solid. LCMS: (M + H) + = 350.0 [0955] Step 3: To a mixture of 8-acetyl-2-(benzo[d]thiazol-7-yl)-3,6-dimethylquinazolin-4(3 H)-one (1.3 g, 3.72 mmol) and (R)-2-methylpropane-2-sulfinamide (900 mg, 7.44 mmol) in THF (20 ml) was added Ti(Oi-Pr) 4 (20 ml). the mixture was stirred at 75 °C under N 2 for 16 h. Cooling to RT, the mixture was diluted with EtOAc (50 ml) and brine (50 mL) was added, the mixture was stirred for 0.5 hour. The resulting mixture was filtrated and the cake was washed with EtOAc (40 mL*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)-N-(1-(2-(benzo[d]thiazol-7-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (1.4 g, 71 % yield) as a yellow oil. LCMS: (M + H) + = 453.0 [0956] Step 4: To a mixture of (R,Z)-N-(1-(2-(benzo[d]thiazol-7-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (1.4 g, 3.1 mmol) and CeCl 3 .7H 2 O (578 mg, 1.55 mmol) in MeOH (15 ml) was added NaBH 4 (353 mg, 9.3 mmol) was added in batches -75 °C. The mixture was stirred at RT for 16 h. The reaction was quenched with a saturated solution of NH 4 Cl (40 ml) and the mixture was extracted with DCM (50 ml * 3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method A) to afford (R)-N-((R)-1-(2-(benzo[d]thiazol-7-yl)-3,6-dimethyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinam ide (500 mg, 36%) as a white solid. LCMS: (M + H) + = 454.9 [0957] Step 5: A mixture of (R)-N-((R)-1-(2-(benzo[d]thiazol-7-yl)-3,6-dimethyl-4-oxo-3, 4-dihydroquinazolin-8- yl)ethyl)-2-methylpropane-2-sulfinamide (500 mg, 1.1 mmol) in HCl (3 M in MeOH) (5 ml) was stirred at RT for 0.5 hour. The mixture was poured into ice-water and adjusted pH= 8 with a saturated solution of NaHCO 3 , The mixture was extracted with DCM: MeOH (50 mL*3, 10:1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford (R)-8-(1-aminoethyl)-2-(benzo[d]thiazol-7-yl)-3,6- dimethylquinazolin-4(3H)-one (380 mg, 98% yield) as a yellow solid. LCMS: (M + H) + = 351.0 [0958] Step 6: To a mixture of (R)-8-(1-aminoethyl)-2-(benzo[d]thiazol-7-yl)-3,6-dimethylqu inazolin-4(3H)-one (380 mg, 1.09 mmol) and methyl 6-chloro-3-fluoropicolinate (310 mg, 1.64 mmol) in DMSO (5 ml) was added DIPEA (281 mg, 2.18 mmol). The mixture was stirred at 100 °C for 16 h. H 2 O (50 mL) was added and the mixture was extracted with EtOAc (40 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by flash (PE: EA= 5: 1) to afford (R)-methyl 3-(1-(2-(benzo[d]thiazol- 7-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethylami no)-6-chloropicolinate (247 mg, 44%) as a yellow solid. LCMS: (M + H) + = 520.0 [0959] Step 7: To a mixture of (R)-methyl 3-(1-(2-(benzo[d]thiazol-7-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethylamino)-6-chloropicolinate (100 mg, 0.19 mmol) in MeOH/H 2 O (5: 1) (5 ml) was added LiOH (23 mg, 0.95 mmol). The mixture was stirred at 50 °C for 1.5 h. The mixture was adjusted to pH = 5 – 6 with HCl (1 M) and concentrated, the residue was purified by Pre-HPLC (Method B) to afford (R)-3-(1-(2- (benzo[d]thiazol-7-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazo lin-8-yl)ethylamino)-6-chloropicolinic acid (56 mg, 58%) as a white solid. LCMS: (M + H) + = 506.0 EXAMPLE 128 (R)-3-(1-(2-(6-bromopyridin-3-yl)-3,6-dimethyl-4-oxo-3,4-dih ydroquinazolin-8-yl)ethylamino)-6- chloropicolinic acid [0960] Step 1: To a mixture of (R)-methyl 6-chloro-3-(1-(2-(6-chloropyridin-3-yl)-3,6-dimethyl-4-oxo-3 ,4- dihydroquinazolin-8-yl)ethylamino)picolinate (60 mg, 0.12 mmol) in DCM (10 ml) was added a solution of BBr 3 (17% in methylene chloride) (530 mg, 0.36 mmol) 0 °C, The mixture was stirred at RT for 16 h. DCM (20 ml) was added and the mixture was washed with a saturated solution of NaHCO 3 (20 ml*2). The organic phase was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to afford (R)-3-(1-(2-(6-bromopyridin-3-yl)-3,6-dimethyl-4-oxo-3,4-dih ydroquinazolin-8-yl)ethylamino)- 6-chloropicolinic acid (18.1 mg, 29%) as a white solid. LCMS: (M + H) + = 530.1 EXAMPLE 129 (R)-6-chloro-3-((1-(2-(2,6-dimethylpyridin-3-yl)-3,6-dimethy l-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0961] Step 1: To a solution of 2-amino-3-bromo-N,5-dimethylbenzamide (800 mg, 3.291 mmol) in DMSO (18 mL) was added 2,6-dimethylnicotinaldehyde (685 mg, 5.068 mmol). The mixture was stirred at 140 °C for 11 h under O 2 . After cooling to RT, the mixture was filtered and washed with water to give 8-bromo-2-(2,6- dimethylpyridin-3-yl)-3,6-dimethylquinazolin-4(3H)-one (720 mg, 61.1 %) as a yellow solid. LCMS: (M + H) + =357.9 [0962] Step 2: To a solution of 8-bromo-2-(2,6-dimethylpyridin-3-yl)-3,6-dimethylquinazolin- 4(3H)-one (430 mg, 1.200 mmol) in dioxane (12 mL) were added tributyl(1-ethoxyvinyl)stannane (880 mg, 2.437 mmol) and Pd(PPh 3 ) 2 Cl 2 (89 mg, 0.127 mmol) at RT. The mixture was stirred at 100 °C for 4 h under N 2 . The mixture was added HCl (1.5 mL, 1M) and stirred at 50 °C for 0.5 h. The mixture was added saturated aqueous KF solution (12 mL) and stirred at RT for 0.5 hour. The gray suspension was filtered, the filter cake was washed with H 2 O (10 mL×2) and EtOAc (20 mL×2). The aqueous phase was extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by silica gel column chromatography (DCM: EA=1:1) to give 8-acetyl-2-(2,6-dimethylpyridin-3-yl)-3,6- dimethylquinazolin-4(3H)-one (370 mg, 95.9 %) as a yellow solid. LCMS: (M + H) + =322.0 [0963] Step 3: To a solution of 8-acetyl-2-(2,6-dimethylpyridin-3-yl)-3,6-dimethylquinazolin -4(3H)-one (370 mg, 1.151 mmol) in THF (7 mL) were added (R)-2-methylpropane-2-sulfinamide (290 mg, 2.393 mmol) and Ti(Oi-Pr) 4 (7 mL) at RT. The mixture was stirred at 75 °C for 18 h under N 2 . After cooling with ice bath, the mixture was added saturated aqueous NaCl solution (10 mL) and stirred at RT for 5 mins. The suspension was filtered, the filter cake was washed with EtOAc (20 mL×2). The aqueous phase was extracted with EtOAc (80 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give (R,Z)-N- (1-(2-(2,6-dimethylpyridin-3-yl)-3,6-dimethyl-4-oxo-3,4-dihy droquinazolin-8-yl)ethylidene)-2-methylpropane-2- sulfinamide (440 mg, 90.0 %) as a yellow solid. LCMS: (M + H) + =425.0 [0964] Step 4: To a solution of (R,Z)-N-(1-(2-(2,6-dimethylpyridin-3-yl)-3,6-dimethyl-4-oxo- 3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (440 mg, 1.036 mmol) in MeOH (9 mL) were added CeCl 3 •7H 2 O (185 mg, 0.497 mmol) and NaBH 4 (85 mg, 2.247 mmol) at -70 °C. After addition, the mixture was stirred for 2 h. The mixture was added with aqueous NH 4 Cl solution (5 mL) and extracted with DCM (40 mL×2), the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by Prep-HPLC (method A) to give (R)-N-((R)-1-(2-(2,6-dimethylpyridin-3-yl)- 3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methy lpropane-2-sulfinamide (190 mg, 43.0 %) as a white solid. LCMS: (M + H) + =427.0 [0965] Step 5: To a solution of (R)-N-((R)-1-(2-(2,6-dimethylpyridin-3-yl)-3,6-dimethyl-4-ox o-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (190 mg, 0.445 mmol) in MeOH (3 mL) was added HCl (2 mL, 3M in MeOH) at RT. The mixture was stirred at RT for 1 hour. The mixture was neutralized with aqueous NaHCO 3 solution to pH = 8. The mixture was concentrated to provide a residue which was extracted with THF to give (R)-8-(1-aminoethyl)-2-(2,6-dimethylpyridin-3-yl)-3,6-dimeth ylquinazolin-4(3H)-one (140 mg, 97.5 %) as a white solid. LCMS: (M + H) + =323.0 [0966] Step 6: To a solution of (R)-8-(1-aminoethyl)-2-(2,6-dimethylpyridin-3-yl)-3,6-dimeth ylquinazolin-4(3H)- one (80 mg, 0.248 mmol) in DMSO (2 mL) were added methyl 6-chloro-3-fluoropicolinate (71 mg, 0.375 mmol) and DIEA (0.3 mL). The mixture was stirred at 100 °C for 4 h. After cooling to RT, the mixture was added water (25 mL), filtered and washed with water to give methyl (R)-6-chloro-3-((1-(2-(2,6-dimethylpyridin-3-yl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picoli nate (100 mg, 81.9 %) as a yellow solid. LCMS: (M + H) + =492.0 [0967] Step 7: To a solution of methyl (R)-6-chloro-3-((1-(2-(2,6-dimethylpyridin-3-yl)-3,6-dimethy l-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (100 mg, 0.203 mmol) in MeOH (0.8 mL) were added THF (0.8 mL), H 2 O (0.5 mL) and LiOH•H 2 O (34 mg, 0.810 mmol) at RT. The mixture was stirred at RT for 1 hour. The mixture was neutralized with HCl (1M) to pH = 6 and concentrated, the residue was purified by Prep-HPLC (method B) to give (R)-6-chloro-3-((1-(2-(2,6-dimethylpyridin-3-yl)-3,6-dimethy l-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid (50.5 mg, 52.2 %) as a white solid. LCMS: (M + H) + = 478.1 EXAMPLE 130 (R)-6-chloro-3-((1-(2-(2,4-dimethyloxazol-5-yl)-3,6-dimethyl -4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0968] Step 1: To a solution of 2-amino-3-bromo-N,5-dimethylbenzamide (3 g, 12.4 mmol) in DMSO (50 mL) was added 2,4-dimethyloxazole-5-carbaldehyde (2.3 g, 18.6 mmol) at RT. The resulting mixture was heated to 130 °C and stirred overnight under O 2 . Cooling to RT, the mixture was poured into water (250 mL) and stirred for 15 minutes, the suspension was filtered and the collected solid was dried to give 8-bromo-2-(2,4-dimethyloxazol- 5-yl)-3,6-dimethylquinazolin-4(3H)-one (3.6 g, 84%) as a yellow solid. LCMS (ESI) m/z: [M+H] + =348.1 [0969] Step 2: To a solution of 8-bromo-2-(2,4-dimethyloxazol-5-yl)-3,6-dimethylquinazolin-4 (3H)-one (3.6 g, 10.4 mmol) in dioxane (50 mL) were added tributyl(1-ethoxyvinyl)stannane (7.5 g, 20.8 mmol) and Pd(PPh 3 ) 2 Cl 2 (730 mg, 1.04 mmol) at RT. The resulting mixture was heated to 95 °C and stirred for 12 h under N 2 . HCl (11 mL, 1 M) was added into the mixture and the mixture was stirred at 50 °C for 0.5 hour, then saturated KF (200 mL) was added and the resulting mixture was stirred at 20 °C for 0.5 hour. The gray suspension was filtered and the filter cake was washed with EtOAc (150 mL×3). The aqueous phase was extracted with EtOAc (80 mL×3) and the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by silica gel column chromatography (PE: EA=4:1) to give 8-acetyl-2-(2,4-dimethyloxazol-5-yl)-3,6- dimethylquinazolin-4(3H)-one (1.5 g, 46%) as a white solid. LCMS (ESI) m/z: [M+H] + =312.2 [0970] Step 3: To a solution of 8-acetyl-2-(2,4-dimethyloxazol-5-yl)-3,6-dimethylquinazolin- 4(3H)-one (1.5 g, 4.8 mmol) in THF (15 mL) were added Ti(i-PrO) 4 (15 mL) and (R)-2-methylpropane-2-sulfinamide (1.2 g, 9.6 mmol) at RT. The resulting mixture was heated to 75 °C and stirred for 12 h. Brine (15 mL) was added into the mixture and the mixture was stirred at RT for 0.5 hour, the suspension was filtered and the filter cake was washed with EtOAc (80 mL×3). The aqueous phase was extracted with EtOAc (50 mL×3) and the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give (R,Z)-N-(1-(2-(2,4-dimethyloxazol-5-yl)-3,6-dimethyl-4-oxo-3 ,4-dihydroquinazolin-8-yl)ethylidene)-2- methylpropane-2-sulfinamide (1.8 g, 91%) as a yellow solid. LCMS (ESI) m/z: [M+H] + =415.1 [0971] Step 4: To a solution of (R,Z)-N-(1-(2-(2,4-dimethyloxazol-5-yl)-3,6-dimethyl-4-oxo-3 ,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (1.8 g, 4.3 mmol) and HOAc (2.0 mL) in DCM (20 mL) and MeOH (20 mL) was added NaBH 3 CN (800 mg, 12.9 mmol) in portions at 0 °C, the resulting mixture was warmed up to 20 °C and stirred for 1 hour. The reaction was quenched with saturated NH 4 Cl (100 mL) and extracted with DCM (100 mL x 2). The combined extract was washed with brine, dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by Prep-HPLC (Method A) to give (R)-N-((R)-1-(2-(2,4-dimethyloxazol-5- yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-m ethylpropane-2-sulfinamide (1 g, 56%) as a white solid. LCMS (ESI) m/z: [M+H] + =417.3 [0972] Step 5: A mixture (R)-N-((R)-1-(2-(2,4-dimethyloxazol-5-yl)-3,6-dimethyl-4-oxo -3,4-dihydroquinazolin-8- yl)ethyl)-2-methylpropane-2-sulfinamide (1 g, 2.4 mmol) in a solution of HCl in MeOH (3M, 15 mL) was stirred at RT for 20 minutes. The mixture was adjusted to pH = 9 with saturated aqueous NaHCO 3 solution and the mixture was extracted with DCM (100 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give (R)-8-(1-aminoethyl)-2-(2,4-dimethyloxazol-5-yl)-3,6- dimethylquinazolin-4(3H)-one (700 mg, 94%) as a yellow solid. LCMS (ESI) m/z: [M+H] + =313.3 [0973] Step 6: To a solution of (R)-8-(1-aminoethyl)-2-(2,4-dimethyloxazol-5-yl)-3,6-dimethy lquinazolin-4(3H)- one (100 mg, 0.32 mmol) in DMSO (5 mL) was added methyl 6-chloro-3-fluoropicolinate (121 mg, 0.64 mmol) and DIPEA (124 mg, 0.96 mmol) at RT. The resulting mixture was stirred at the 100 °C for 12 h. The mixture was diluted with water (30 mL), extracted with EtOAc (40 mL×3), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give methyl (R)-6-chloro-3-((1-(2-(2,4-dimethyloxazol-5-yl)-3,6-dimethyl -4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (150 mg, 97%) as a yellow solid. LCMS (ESI) m/z: [M+H] + =482.0 [0974] Step 7: To a solution of methyl (R)-6-chloro-3-((1-(2-(2,4-dimethyloxazol-5-yl)-3,6-dimethyl -4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (150 mg, 0.31 mmol) in THF (2mL) and MeOH (2 mL) were added LiOH (29 mg, 1.24 mmol) and H 2 O (1 mL) at RT, The resulting mixture was stirred at the 50 °C for 1 hour. The mixture was adjusted to 4 with HCl solution and diluted with water (40 mL), the mixture was extracted with DCM (40 mL x 3), the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by Prep-HPLC (Method B) to give (R)-6-chloro-3-((1-(2-(2,4-dimethyloxazol-5-yl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picoli nic acid (129.4 mg, 89%) as a white solid. LCMS (ESI) m/z: [M+H] + =468.0 EXAMPLE 131 (R)-6-chloro-3-((1-(3,6-dimethyl-2-(oxetan-3-yl)-4-oxo-3,4-d ihydroquinazolin-8-yl)ethyl)amino)picolinic acid [0975] Step 1: T o a mixture of 2-amino-3-bromo-N,5-dimethylbenzamide (1.50 g, 6.198 mmol), oxetane-3- carboxylic acid (1.264 g, 12.4 mmol), CMPI (3.16 g, 12.39 mmol) in THF (50 mL) was added DIPEA (2.39 g, 18.60 mmol) and the mixture was stirred at 80 °C overnight. Water (100 mL) was added, the mixture was extracted with ethyl aceate (100 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated, The residue was purified by chromatography (PE: EA = 3:1) to afford N-(2-bromo-4-methyl-6- (methylcarbamoyl)phenyl)oxetane-3-carboxamide (600 mg, 29.7%) as a yellow solid. LCMS: (M + H) + =327.2 [0976] Step 2: To a solution of N-(2-bromo-4-methyl-6-(methylcarbamoyl)phenyl)oxetane-3-carb oxamide (585 mg, 1.79 mmol) in DCM (20 ml) were added HMDS (866.7 mg, 5.38 mmol) and I2 (455.7 mg, 1.79 mmol) and the mixture was stirred at 50 °C for 2 h. Cooling to RT, the mixture was diluted with DCM (20 ml) and washed with saturated Na 2 S 2 O 3 (50 mL x3), the organic phase was washed with brine, dried over Na 2 SO 4 and concentrated under vacuum to get a residue which was purified by chromatography (PE: EA = 5:1) to afford 8-bromo-3,6- dimethyl-2-(oxetan-3-yl)quinazolin-4(3H)-one (280 mg, 50.6%) as a yellow solid. LCMS: (M + H) + =311.0 [0977] Step 3: To a mixture of 8-bromo-3,6-dimethyl-2-(oxetan-3-yl)quinazolin-4(3H)-one (280 mg, 0.909 mmol) and ethyl tributylstannanecarboxylate (656.4 mg, 1.818 mmol) in dioxane (10 mL) was added Pd(PPh 3 ) 2 Cl 2 (132.9 mg, 0.182 mmol). The mixture was stirred at 105 °C under N 2 for 16 h. HCl (1 mL, 1 M) was added into the mixture and stirred at 50 °C for 0.5 hour, then 20 mL sat KF was added and the mixture was stirred at rt for 0.5 hour. the gray was filtered, the filter cake was washed with EtOAc (50 mL*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 1:1) to afford 8-acetyl-3,6-dimethyl-2-(oxetan-3-yl)quinazolin-4(3H)-one (230 mg, 93.0%) as a yellow solid. LCMS: (M + H) + =273.2 [0978] Step 4: To a mixture of 8-acetyl-3,6-dimethyl-2-(oxetan-3-yl)quinazolin-4(3H)-one (230 mg, 0.845 mmol) and (R)-2-methylpropane-2-sulfinamide (204.6 mg, 1.691 mmol) in THF (20 mL) was added Ti(i-PrO) 4 (3.05 g, 8.45 mmol). The mixture was stirred at 75 °C for 48 h. Cooling to RT, brine (50 mL) was added and the mixture was stirred for 0.5 hour. The resulting mixture was filtrated and the cake was washed with EtOAc (40 mL*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)-N-(1- (3,6-dimethyl-2-(oxetan-3-yl)-4-oxo-3,4-dihydroquinazolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (500 mg, crude) as a yellow oil for the next step without further purification. LCMS: (M + H) + =376.2 [0979] Step 5: To a mixture of crude (R,Z)-N-(1-(3,6-dimethyl-2-(oxetan-3-yl)-4-oxo-3,4-dihydroqu inazolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (500 mg, 1.33 mmol) and HOAc (1.05 g, 10.6 mmol) in DCM (10 mL) and MeOH (10 mL) was added NaBH 3 CN (252 mg, 4.00 mmol) in portions at 0 °C, the mixture was stirred for 1 hour. The reaction was quenched with NH 4 Cl (50 mL) and extracted with DCM (30 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre- HPLC (Method A) to afford (R)-N-((R)-1-(3,6-dimethyl-2-(oxetan-3-yl)-4-oxo-3,4-dihydro quinazolin-8-yl)ethyl)-2- methylpropane-2-sulfinamide (80 mg, 25.1%) as a yellow solid. LCMS: (M + H) + =378.3 [0980] Step 6: A mixture (R)-N-((R)-1-(3,6-dimethyl-2-(oxetan-3-yl)-4-oxo-3,4-dihydro quinazolin-8-yl)ethyl)-2- methylpropane-2-sulfinamide (80 mg, 0.212 mmol) in a solution of HCl in MeOH (3 mL, 4 M) was stirred at RT for 10 min. The mixture was poured into ice-water and adjusted pH= 8 with a saturated solution of NaHCO 3 , The mixture was extracted with DCM: MeOH (20 mL*3, 10:1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(oxetan-3-yl)quinazolin- 4(3H)- one (70 mg, crude) as a yellow oil. LCMS: (M + H) + =310.3 [0981] Step 7: To a mixture of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(oxetan-3-yl)quinazolin- 4(3H)-one (70 mg, 0.256 mmol) and methyl 6-chloro-3-fluoropicolinate (72.7 mg, 0.384 mmol) in DMSO (5 mL) was added DIPEA (33.1 mg, 0.769 mmol), the mixture was heated to 100 °C and stirred for 2 h. Cooling to RT, H 2 O (50 mL) was added and the mixture was extracted with EtOAc (20 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford methyl (R)-6-chloro-3-((1-(3,6-dimethyl-2-(oxetan-3-yl)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (90 mg, crude) as a white solid. LCMS: (M + H) + = 443.2 [0982] Step 8: To a mixture of methyl (R)-6-chloro-3-((1-(3,6-dimethyl-2-(oxetan-3-yl)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (90 mg, 0.203 mmol) in MeOH (5 mL) and H 2 O (1 mL) was added LiOH (34.2 mg, 0.814 mmol). The mixture was stirred at 50 °C for 1 hour. The mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM (20 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to afford (R)-6-chloro-3-((1-(3,6- dimethyl-2-(oxetan-3-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)et hyl)amino)picolinic acid (34.3 mg, 39.4%) as a white solid. LCMS: (M + H) + = 429.0 EXAMPLE 132 (R)-6-chloro-3-((1-(3,6-dimethyl-2-(1-methyl-1H-indazol-3-yl )-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [0983] Step 1: To a mixture of 2-amino-3-bromo-N,5-dimethylbenzamide (1.5 g, 6.19 mmol) in DMSO (30 mL) was added 1-methyl-1H-indazole-3-carbaldehyde (1.98 g, 12.4 mmol). The suspension was degassed under vacuum and purged with O 2 , The mixture was heated to 130°C and stirred at 130°C overnight. Cooling to RT, the mixture was filtered, the filter cake was washed with water to remove solvent. The filter cake was dried under vacuum to afford 8-bromo-3,6-dimethyl-2-(1-methyl-1H-indazol-3-yl)quinazolin- 4(3H)-one (1.1 g, 46.4%) as a yellow solid. LCMS: (M + H) + =383.1 [0984] Step 2: To a mixture of 8-bromo-3,6-dimethyl-2-(1-methyl-1H-indazol-3-yl)quinazolin- 4(3H)-one (1.3 g, 3.40 mmol) and ethyl tributylstannanecarboxylate (2.46 g, 6.81 mmol) in Dioxane (20 mL) was added Pd(PPh 3 ) 2 Cl 2 (497 mg, 0.681 mmol). The mixture was stirred at 105 °C under N 2 for 16 h. HCl (4 mL, 1 M) was added into the mixture and the mixture was stirred at 50 °C for 0.5 hour, then 50 ml sat KF was added and the mixture was stirred at RT for 0.5 hour. The gray was filtered, the filter cake was washed with EtOAc (100 mL*3), the separated organic was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 1:1) to afford 8-acetyl-3,6-dimethyl-2-(1-methyl-1H-indazol-3-yl)quinazolin -4(3H)-one (1 g, 84.9%) as a yellow solid. LCMS: (M + H) + =347.2 [0985] Step 3: To a mixture of 8-acetyl-3,6-dimethyl-2-(1-methyl-1H-indazol-3-yl)quinazolin -4(3H)-one (1 g, 2.89 mmol) and (R)-2-methylpropane-2-sulfinamide (699.4 mg, 5.78 mmol) in THF (20 mL) was added Ti(i- PrO) 4 (10.46 g, 28.9 mmol). The mixture was stirred at 75 °C for 48 h. Cooling to RT, brine (50 mL) was added and the mixture was stirred for 0.5 hour. The resulting mixture was filtrated and the cake was washed with EtOAc (100 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)-N-(1-(3,6-dimethyl-2-(1-methyl-1H-indazol-3-yl)-4-oxo- 3,4-dihydroquinazolin-8-yl)ethylidene)-2- methylpropane-2-sulfinamide (2.0 g, crude) as a yellow oil for the next step without further purification. LCMS: (M + H) + =450.0 [0986] Step 4: To a mixture of crude (R,Z)-N-(1-(3,6-dimethyl-2-(1-methyl-1H-indazol-3-yl)-4-oxo- 3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (2 g, 4.45 mmol) and HOAc (3.49 g, 35.6 mmol) in DCM (20 mL) and MeOH (20 mL) was added NaBH 3 CN (842 mg, 13.4 mmol) in portions at 0 °C, the mixture was stirred for 1 hour. The reaction was quenched with a saturated solution of NH 4 Cl (20 mL) and extracted with DCM (50 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (method A) to afford (R)-N-((R)-1-(3,6-dimethyl-2-(1- methyl-1H-indazol-3-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)eth yl)-2-methylpropane-2-sulfinamide (320 mg, 24.5%) as a yellow solid. LCMS: (M + H) + = 452.0 [0987] Step 5: A mixture (R)-N-((R)-1-(3,6-dimethyl-2-(1-methyl-1H-indazol-3-yl)-4-ox o-3,4-dihydroquinazolin- 8-yl)ethyl)-2-methylpropane-2-sulfinamide (320 mg, 0.709 mmol) in a solution of HCl in MeOH (10 mL, 4 M) was stirred at RT for 10 min. The mixture was poured into ice-water and adjusted pH= 8 with a saturated solution of NaHCO 3 , The mixture was extracted with DCM: MeOH (50 mL*3, 10:1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(1-methyl- 1H-indazol-3-yl)quinazolin-4(3H)-one (280 mg, crude) as a yellow oil. LCMS: (M + H) + =348.3 [0988] Step 6: To a mixture of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(1-methyl-1H-indazol-3-y l)quinazolin-4(3H)- one (150 mg, 0.432 mmol) and methyl 6-chloro-3-fluoropicolinate (122.5 mg, 0.648 mmol) in DMSO (5 mL) was added DIPEA (167.3 mg, 1.29 mmol), the mixture was heated to 100 °C and stirred for 2 h. Cooling to RT, H 2 O (30 mL) was added and the mixture was extracted with EtOAc (30 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford methyl (R)-6-chloro-3-((1-(3,6-dimethyl-2-(1- methyl-1H-indazol-3-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)eth yl)amino)picolinate (200 mg, crude) as a white solid. LCMS: (M + H) + = 517.2 [0989] Step 7: To a solution of methyl (R)-6-chloro-3-((1-(3,6-dimethyl-2-(1-methyl-1H-indazol-3-yl )-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (200 mg, 0.387 mmol) in MeOH (8 mL) and H 2 O (2 mL) was added LiOH (65 mg, 1.55 mmol). The mixture was stirred at 50 °C for 1 hour. The mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM (40 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to afford (R)-6-chloro-3-((1-(3,6- dimethyl-2-(1-methyl-1H-indazol-3-yl)-4-oxo-3,4-dihydroquina zolin-8-yl)ethyl)amino)picolinic acid (104 mg, 53.4%) as a white solid. LCMS: (M + H) + = 503.1 EXAMPLE 133 (R)-6-chloro-3-((1-(2-(2-cyanophenyl)-3,6-dimethyl-4-oxo-3,4 -dihydroquinazolin-8-yl)ethyl)amino)picolinic acid [0990] Step 1: To a solution of 2-amino-3-bromo-N,5-dimethylbenzamide (1.075 g, 4.422 mmol) in DMSO (20 mL) was added 2-formylbenzonitrile (940 mg, 7.168 mmol). The mixture was stirred at 140 °C for 3 h under O 2 . After cooling to RT, the mixture was added water (90 mL), filtered and washed with water to give 2-(8-bromo-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)benzonitrile (1.3 g, 83.0 %) as a red solid. LCMS: (M + H) + =353.9 [0991] Step 2: To a solution of 2-(8-bromo-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)ben zonitrile (1.3 g, 3.67 mmol) in dioxane (30 mL) were added tributyl(1-ethoxyvinyl)stannane (2.7 g, 7.476 mmol) and Pd(PPh 3 ) 2 Cl 2 (310 mg, 0.442 mmol) at RT. The mixture was stirred at 100 °C for 5 h under N 2 . The mixture was added HCl (4 mL, 1M) and stirred at 50 °C for 0.5 hour. The mixture was added saturated aqueous KF solution (18 mL) and stirred at RT for 0.5 hour. The gray suspension was filtered. The filter cake was washed with H 2 O (10 mL×2) and EtOAc (20 mL×2). The aqueous phase was extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by silica gel column chromatography (DCM: EA=20:1) to give 2-(8-acetyl-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin- 2-yl)benzonitrile (1.09 g, 93.6 %) as a yellow solid. LCMS: (M + H) + =318.0 [0992] Step 3: To a solution of 2-(8-acetyl-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)be nzonitrile (770 mg, 2.426 mmol) in THF (10 mL) were added (R)-2-methylpropane-2-sulfinamide (595 mg, 4.909 mmol) and Ti(Oi- Pr) 4 (10 mL) at RT. The mixture was stirred at 75 °C for 18 h under N 2 . After cooling with ice bath, the mixture was added saturated aqueous NaCl solution (18 mL) and stirred at RT for 5 mins. The suspension was filtered. The filter cake was washed with EtOAc (20 mL×2). The aqueous phase was extracted with (100 mL). The organic layer was washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give crude (R,Z)-N-(1-(2-(2- cyanophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)e thylidene)-2-methylpropane-2-sulfinamide (950 mg, 93.1 %) as a yellow solid. LCMS: (M + H) + =421.0 [0993] Step 4: To a solution of crude (R,Z)-N-(1-(2-(2-cyanophenyl)-3,6-dimethyl-4-oxo-3,4-dihydro quinazolin- 8-yl)ethylidene)-2-methylpropane-2-sulfinamide (950 mg, 2.259 mmol) in MeOH (30 mL) were added CeCl 3 •7H 2 O (440 mg, 1.181 mmol) and NaBH 4 (260 mg, 6.873 mmol) at -70 °C. After addition, the mixture was stirred for 3 h. The mixture was added with aqueous NH 4 Cl solution (6 mL) and extracted with DCM (100 mL×2), the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by Prep-HPLC (method A) to give (R)-N-((R)-1-(2-(2-cyanophenyl)-3,6-dimethyl-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulf inamide (550 mg, 57.6 %) as a white solid. LCMS: (M + H) + =423.0 [0994] Step 5: To a solution of (R)-N-((R)-1-(2-(2-cyanophenyl)-3,6-dimethyl-4-oxo-3,4-dihyd roquinazolin-8- yl)ethyl)-2-methylpropane-2-sulfinamide (550 mg, 1.302 mmol) in MeOH (10 mL) was added HCl (1.5 mL, 3M in MeOH) at RT. The mixture was stirred at RT for 1 hour. The mixture was neutralized with aqueous NaHCO 3 solution to pH = 8. The mixture was concentrated to provide a residue which was extracted with THF to give (R)- 2-(8-(1-aminoethyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin -2-yl)benzonitrile (400 mg, 96.5 %) as a yellow solid. LCMS: (M + H) + =319.0 [0995] Step 6: To a solution of (R)-2-(8-(1-aminoethyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinaz olin-2- yl)benzonitrile (400 mg, 1.256 mmol) in DMSO (5 mL) were added methyl 6-chloro-3-fluoropicolinate (340 mg, 1.794 mmol) and DIEA (1.5 mL). The mixture was stirred at 100 °C for 4 h. After cooling to RT, the mixture was added water (50 mL), filtered and washed with water to give methyl (R)-6-chloro-3-((1-(2-(2-cyanophenyl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picoli nate (490 mg, 79.9 %) as a yellow solid. LCMS: (M + H) + =487.9 [0996] Step 7: To a solution of methyl (R)-6-chloro-3-((1-(2-(2-cyanophenyl)-3,6-dimethyl-4-oxo-3,4 - dihydroquinazolin-8-yl)ethyl)amino)picolinate (145 mg, 0.297 mmol) in MeOH (1 mL) were added THF (1 mL), H 2 O (1 mL) and LiOH•H 2 O (50 mg, 1.192 mmol) at RT. The mixture was stirred at RT for 1 hour. The mixture was neutralized with HCl (1M) to pH = 6. The mixture was purified by Prep-HPLC (method B) to give (R)-6- chloro-3-((1-(2-(2-cyanophenyl)-3,6-dimethyl-4-oxo-3,4-dihyd roquinazolin-8-yl)ethyl)amino)picolinic acid (72 mg, 0.152 mmol, 51.2 %) as a white solid. LCMS: (M + H) + = 473.9 EXAMPLE 134 (R)-6-chloro-3-(1-(2-(2,4-dimethylthiazol-5-yl)-3,6-dimethyl -4-oxo-3,4-dihydroquinazolin-8- yl)ethylamino)picolinic acid [0997] Step 1: To a mixture of 2-amino-3-bromo-N,5-dimethylbenzamide (1.3 g, 5.37 mmol) in DMSO (30 ml) was added 2,4-dimethylthiazole-5-carbaldehyde (1.51 g, 10.74 mmol). The mixture was stirred at 135 °C for 16 h under O 2 . The mixture was poured into water (150 ml) and stirred for 0.5 hour, the resulting mixture was filtered and the filter cake was washed with water (50 ml * 3), the collected solid was dried under reduce pressure to to afford 8-bromo-2-(2,4-dimethylthiazol-5-yl)-3,6-dimethylquinazolin- 4(3H)-one (1.49 g, 76%) as a yellow solid. LCMS: (M + H) + = 364.0 [0998] Step 2: To a mixture of 8-bromo-2-(2,4-dimethylthiazol-5-yl)-3,6-dimethylquinazolin- 4(3H)-one (1.49 g, 4.1 mmol) and tributyl(1-ethoxyvinyl)stannane (2.96 g, 8.2 mmol) in 1.4-dioxane (30 ml) was added Pd(PPh 3 ) 2 Cl 2 (576 mg, 0.82 mmol). The mixture was stirred at 95 °C under N 2 for 16 h. HCl (5 ml, 1 M) was added into the mixture and the mixture was stirred at 50 °C for 0.5 hour, then sat KF (30 ml) and the resulting mixture was stirred at RT for 0.5 hour. The gray suspension was filtered and the filter cake was washed with DCM (30 ml*3), the separated organic was washed with brine, dried over Na 2 SO 4 and concentrated, the residue was purified by flash (DCM: EA = 10: 1) to afford 8-acetyl-2-(2,4-dimethylthiazol-5-yl)-3,6-dimethylquinazolin -4(3H)-one (930 mg, 69%) as a yellow solid. LCMS: (M + H) + = 328.1 [0999] Step 3: To a mixture of 8-acetyl-2-(2,4-dimethylthiazol-5-yl)-3,6-dimethylquinazolin -4(3H)-one (930 mg, 2.84 mmol) and (R)-2-methylpropane-2-sulfinamide (687 mg, 5.68 mmol) in THF (20 ml) was added Ti(Oi-Pr) 4 (20 ml). the mixture was stirred at 75 °C under N 2 for 16 h. Cooling to RT, brine (50 mL) was added and the mixture was stirred for 0.5 hour. The resulting mixture was filtrated and the cake was washed with EtOAc (100 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)-N-(1-(2-(2,4-dimethylthiazol-5-yl)-3,6-dimethyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethylidene)-2- methylpropane-2-sulfinamide (1 g, 82 %) as a yellow oil. LCMS: (M + H) + = 430.9 [01000] Step 4: To a mixture of (R,Z)-N-(1-(2-(2,4-dimethylthiazol-5-yl)-3,6-dimethyl-4-oxo- 3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (1 g, 2.33 mmol) and CeCl 3 .7H 2 O (436 mg, 1.17 mmol) in MeOH (20 ml) was added NaBH 4 (266 mg, 6.99 mmol) in batches -75 °C. The mixture was stirred at RT for 16 h. The reaction was quenched with a saturated solution of NH 4 Cl (40 mL) and extracted with DCM (50 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method A) to afford (R)-N-((R)-1-(2-(2,4-dimethylthiazol-5-yl)-3,6-dimethyl-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulf inamide (380 mg, 39%) as a white solid. LCMS: (M + H) + = 433.0 [01001] Step 5: A mixture of (R)-N-((R)-1-(2-(2,4-dimethylthiazol-5-yl)-3,6-dimethyl-4-ox o-3,4-dihydroquinazolin- 8-yl)ethyl)-2-methylpropane-2-sulfinamide (380 mg, 0.88 mmol) in HCl (3 M in MeOH) (5 ml) was stirred at RT for 0.5 hour. The mixture was poured into ice-water and adjusted pH= 8 with a saturated solution of NaHCO 3 , The mixture was extracted with DCM: MeOH (50 mL*3, 10:1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford (R)-8-(1-aminoethyl)-2-(2,4-dimethylthiazol-5-yl)-3,6- dimethylquinazolin-4(3H)-one (288 mg, 100% yield) as a yellow solid. LCMS: (M + H) + = 329.1 [01002] Step 6: To a mixture of (R)-8-(1-aminoethyl)-2-(2,4-dimethylthiazol-5-yl)-3,6-dimeth ylquinazolin-4(3H)- one (288 mg, 0.88 mmol) and methyl 6-chloro-3-fluoropicolinate (333 mg, 1.76 mmol) in DMSO (5 ml) was added DIPEA (341 mg, 2.64 mmol). The mixture was stirred at 100 °C for 16 h. Cooling to RT, H 2 O (30 mL) was added and the mixture was extracted with EtOAc (30 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated, the residue was purified by flash (PE: EA= 2: 1) to afford (R)-methyl 6-chloro-3- (1-(2-(2,4-dimethylthiazol-5-yl)-3,6-dimethyl-4-oxo-3,4-dihy droquinazolin-8-yl)ethylamino)picolinate (300 mg, 69%) as a yellow solid. LCMS: (M + H) + = 498.0 [01003] Step 7: To a solution of (R)-methyl 6-chloro-3-(1-(2-(2,4-dimethylthiazol-5-yl)-3,6-dimethyl-4-o xo-3,4- dihydroquinazolin-8-yl)ethylamino)picolinate (300 mg, 0.6 mmol) in MeOH/H 2 O (5: 1) (10 ml) was added LiOH (72 mg, 3.0 mmol). The mixture was stirred at 50 °C for 1.5 h. The mixture was adjusted to pH = 5 – 6 with HCl (1 M) and concentrated, the residue was purified by Pre-HPLC (method B) to afford (R)-6-chloro-3-(1-(2-(2,4- dimethylthiazol-5-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazol in-8-yl)ethylamino)picolinic acid (98.8 mg, 34%) as a white solid. LCMS: (M + H) + = 484.1 EXAMPLE 135 (R)-3-((1-(2-(benzofuran-7-yl)-3,6-dimethyl-4-oxo-3,4-dihydr oquinazolin-8-yl)ethyl)amino)-6-chloropicolinic acid [01004] Step 1: To a solution of 2-amino-3-bromo-N,5-dimethylbenzamide (1.5 g, 6.17 mmol) in DMSO (30 mL) was added benzofuran-7-carbaldehyde (1.80 g, 13.34 mmol). The mixture was stirred under O 2 at 120 °C overnight. The mixture was diluted with water (150 mL) and extracted with EtOAc (80 mL×3). The combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (PE: EA=5：1) to give 2-(benzofuran-7-yl)-8-bromo-3,6-dimethylquinazolin-4(3H)- one (2.0 g, 87.8%) as a yellow solid. LCMS: (M + H) + =371.0 [01005] Step 2: To a mixture of 2-(benzofuran-7-yl)-8-bromo-3,6-dimethylquinazolin-4(3H)-one (3.0 g, 8.36 mmol) and tributyl(1-ethoxyvinyl)stannane (2.0 g, 5.42 mmol) in dioxane (30 ml) was added Pd(PPh 3 ) 2 Cl 2 (379 mg, 0.54 mmol,). The mixture was stirred at 95 °C under N 2 for 16 h. HCl (9 ml, 1 M) was added into the mixture and the mixture was stirred at 50 °C for 0.5 hour, then 50 ml sat KF was added and the mixture was stirred at RT for 0.5 hour. The gray was filtered and the filter cake was washed with EtOAc (100 ml*3). The separated aqueous phase was extracted with EtOAc (50 ml*3). The combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 3:1) to give the target 8- acetyl-2-(benzofuran-7-yl)-3,6-dimethylquinazolin-4(3H)-one (1.5 g, 83.4%) as a yellow solid. LCMS: (M + H) + =333.0 [01006] Step 3: To a mixture of 8-acetyl-2-(benzofuran-7-yl)-3,6-dimethylquinazolin-4(3H)-on e (1.5 g, 4.52 mmol) and (R)-2-methylpropane-2-sulfinamide (1.09 g, 9.04 mmol) in THF (20 ml) at RT was added Ti(i-PrO) 4 (20 ml). The mixture was stirred at 75 °C for 12 h. Cooling to RT, brine (50 ml) was added and the mixture was stirred for 0.5 hour. The resulting mixture was filtrated and the cake was washed with EtOAc (100 ml*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude ((R,Z)-N- (1-(2-(benzofuran-7-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinaz olin-8-yl)ethylidene)-2-methylpropane-2-sulfinamide (2.0 g) as a yellow oil for the next step without further purification. LCMS: (M + H) + = 436.2 [01007] Step 4: To a solution of (R,Z)-N-(1-(2-(benzofuran-7-yl)-3,6-dimethyl-4-oxo-3,4-dihyd roquinazolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (2.0 g, 4.59 mmol) in DCM (20 mL) and MeOH (20 mL) were added NaBH 3 CN (578 mg, 9.18 mmol) and HOAc (0.2 mL) at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction was quenched with saturated NH 4 Cl solution (100 ml) and extracted with DCM (100 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre- HPLC (method A) to give (R)-N-((R)-1-(2-(benzofuran-7-yl)-3,6-dimethyl-4-oxo-3,4-dih ydroquinazolin-8- yl)ethyl)- 2-methylpropane-2-sulfinamide (200 mg, 10 %) as a white solid. LCMS: (M + H) + = 438.1 [01008] Step 5: To a solution of (R)-N-((R)-1-(2-(benzofuran-7-yl)-3,6-dimethyl-4-oxo-3,4-dih ydroquinazolin-8- yl)ethyl)-2-methylpropane-2-sulfinamide (200 mg, 0.46 mmol) in MeOH (4 mL) was added HCl in MeOH (10 ml, 4 M).The mixture was stirred at RT for 5 minutes. The mixture was poured into ice-water and adjusted pH = 8 with a saturated solution of NaHCO 3 , the mixture was extracted with DCM/MeOH (50 ml*3, 10/1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (DCM: MeOH=10:1) to give (R)-8-(1-aminoethyl)-2-(benzofuran-7-yl)-3,6- dimethylquinazolin-4(3H)-one (110 mg, 71.7 %) as a white solid. LCMS: (M + H) + =334.0 [01009] Step 6: To a solution of (R)-8-(1-aminoethyl)-2-(benzofuran-7-yl)-3,6-dimethylquinazo lin-4(3H)-one (110 mg, 0.33 mmol) in DMSO (5 mL) were added methyl 6-chloro-3-fluoropicolinate (95 mg, 0.50 mmol) and DIEA (128 mg, 0.99 mmol). The mixture was stirred at 100 °C for 2 h. The mixture was diluted with water (30 ml) and extracted with EtOAc (40 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The cured was purified by silica gel column chromatography (PE: EA=4:1) to give methyl (R)-3-((1- (2-(benzofuran-7-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazoli n-8-yl)ethyl)amino)-6-chloropicolinate (130 mg, 78.8 %) as a yellow solid. LCMS: (M + H) + =503.1 [01010] Step 7: To a solution of methyl (R)-3-((1-(2-(benzofuran-7-yl)-3,6-dimethyl-4-oxo-3,4-dihydr oquinazolin- 8-yl)ethyl)amino)-6-chloropicolinate (130 mg, 0.26 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (63 mg, 2.60 mmol). The mixture was stirred at 50 °C for 1 hour. The mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM (40 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to give (R)-3-((1-(2-(benzofuran-7-yl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)-6-chl oropicolinic acid (96.7 mg, 76.9 %) as a white solid. LCMS: (M + H) + =489.0 EXAMPLE 136 (R)-3-((1-(2-(benzofuran-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydr oquinazolin-8-yl)ethyl)amino)-6-chloropicolinic acid [01011] Step 1: To a mixture of 2-amino-3-bromo-N,5-dimethylbenzamide (1 g, 4.13 mmol) in DMSO (10 mL) was added benzofuran-2-carbaldehyde (1.21 g, 8.26 mmol), The suspension was degassed under vacuum and purged with O 2 . The mixture was heated to 130°C and stirred at 130°C overnight. Cooling to RT, the mixture was filtered, the filter cake was washed with water. The filter cake was dried under vacuum to afford 2-(benzofuran-2- yl)-8-bromo-3,6-dimethylquinazolin-4(3H)-one (1.1 g, 72.3%) as a yellow solid. LCMS: (M + H) + =369.0 [01012] Step 2: To a mixture of 2-(benzofuran-2-yl)-8-bromo-3,6-dimethylquinazolin-4(3H)-one (1.1 g, 2.99 mmol) and ethyl tributylstannanecarboxylate (2.16 g, 5.98 mmol) in Dioxane (20 mL) was added Pd(PPh 3 ) 2 Cl 2 (437 mg, 0.598 mmol). The mixture was stirred at 105 °C under N 2 for 16 h. HCl (3 mL, 1 M) was added into the mixture and the mixture was stirred at 50 °C for 0.5 hour, then 40 ml sat KF was added and the mixture was stirred at RT for 0.5 hour. The gray was filtered, the filter cake was washed with EtOAc (60 mL*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 1:1) to afford 8-acetyl-2-(benzofuran-2-yl)-3,6-dimethylquinazolin-4(3H)-on e (900 mg, 90.7%) as a yellow solid. LCMS: (M + H) + =333.3 [01013] Step 3: To a mixture of 8-acetyl-2-(benzofuran-2-yl)-3,6-dimethylquinazolin-4(3H)-on e (900 mg, 2.71 mmol) and (R)-2-methylpropane-2-sulfinamide (656 mg, 5.42 mmol) in THF (20 mL) was added Ti(i-PrO) 4 (9.786 g, 27.1 mmol). The mixture was stirred at 75 °C for 48 h. Cooling to RT, brine (50 mL) was added and the mixture was stirred for 0.5 hour. The resulting mixture was filtered and the cake was washed with EtOAc (80 mL*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)-N-(1-(2-(benzofuran-2-yl)-3,6-dimethyl-4-oxo-3,4-dihyd roquinazolin-8-yl)ethylidene)-2-methylpropane-2- sulfinamide (1.5 g, crude) as a yellow oil for the next step without further purification. LCMS: (M + H) + = 436.3 [01014] Step 4: To a mixture of crude (R,Z)-N-(1-(2-(benzofuran-2-yl)-3,6-dimethyl-4-oxo-3,4-dihyd roquinazolin- 8-yl)ethylidene)-2-methylpropane-2-sulfinamide (1.5 g, 3.45 mmol) and HOAc (2.66 g, 27.1 mmol) in DCM (20 mL) and MeOH (20 mL) was added NaBH 3 CN (336 mg, 5.42 mmol) in portions at 0 °C, the mixture was stirred at RT for 1 hour. The mixture was quenched with a saturated solution of NH 4 Cl (40 mL) and extracted with DCM (50 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method A) to afford (R)-N-((R)-1-(2-(benzofuran-2-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (300 mg, 25.3%) as a yellow solid. LCMS: (M + H) + = 438.0 [01015] Step 5: A mixture (R)-N-((R)-1-(2-(benzofuran-2-yl)-3,6-dimethyl-4-oxo-3,4-dih ydroquinazolin-8-yl)ethyl)- 2-methylpropane-2-sulfinamide (300 mg, 0.686 mmol) in a solution of HCl in MeOH (10 mL, 4 M) was stirred at RT for 10 min. The mixture was poured into ice-water and adjusted pH= 8 with a saturated solution of NaHCO 3 , The mixture was extracted with DCM: MeOH (40 mL*3, 10:1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford (R)-8-(1-aminoethyl)-2-(benzofuran-2-yl)-3,6- dimethylquinazolin-4(3H)-one (280 mg, crude) as a yellow oil. LCMS: (M + H) + =334.1 [01016] Step 6: To a mixture of (R)-8-(1-aminoethyl)-2-(benzofuran-2-yl)-3,6-dimethylquinazo lin-4(3H)-one (280 mg, 0.841 mmol) and methyl 6-chloro-3-fluoropicolinate (238.4 mg, 1.26 mmol) in DMSO (10 mL) was added DIPEA (325 mg, 2.52 mmol), the mixture was heated to 100 °C and stirred for 2 h. Cooling to RT, H 2 O (50 mL) was added and the mixture was extracted with EtOAc (40 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford methyl (R)-3-((1-(2-(benzofuran-2-yl)-3,6-dimethyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)-6-chloropicolinate (340 mg, 80.5%) as a yellow solid. LCMS: (M + H) + = 503.2 [01017] Step 7: To a solution of methyl (R)-3-((1-(2-(benzofuran-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydr oquinazolin- 8-yl)ethyl)amino)-6-chloropicolinate (340 mg, 0.677 mmol) in MeOH (10 mL) and H 2 O (2 mL) was added LiOH (142 mg, 3.386 mmol). The mixture was stirred at 50 °C for 1 hour. The mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM (40 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to afford (R)-3-((1-(2-(benzofuran- 2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)am ino)-6-chloropicolinic acid (158 mg, 47.8%) as a white solid. LCMS: (M + H) + = 489.1 EXAMPLE 137 (R)-3-((1-(2-(benzofuran-3-yl)-3,6-dimethyl-4-oxo-3,4-dihydr oquinazolin-8-yl)ethyl)amino)-6-chloropicolinic acid [01018] Step 1: To a solution of 2-amino-3-bromo-N,5-dimethylbenzamide (730 mg, 3.003 mmol) in DMSO (12 mL) was added benzofuran-3-carbaldehyde (720 mg, 4.926 mmol). The mixture was stirred at 135 °C for 16 h under O 2 . Cooling to RT, the mixture was added H 2 O (100 mL), the aqueous phase was extracted with EtOAc (120 mL×2). The combined organic layers were washed brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by silica gel column chromatography (PE: EA=5:1) to 269iperi 2- (benzofuran-3-yl)-8-bromo-3,6-dimethylquinazolin-4(3H)-one (594 mg, 53.6 %) as a white solid. LCMS: (M + H) + =368.8 [01019] Step 2: To a solution of 2-(benzofuran-3-yl)-8-bromo-3,6-dimethylquinazolin-4(3H)-one (594 mg, 1.609 mmol) in dioxane (16 mL) were added tributyl(1-ethoxyvinyl)stannane (1160 mg, 3.212 mmol) and Pd(PPh 3 ) 2 Cl 2 (130 mg, 0.185 mmol) at RT. The mixture was stirred at 100 °C for 5 h under N 2 . The mixture was added HCl (1.8 mL, 1M) and stirred at 50 °C for 0.5 hour, then the mixture was added saturated aqueous KF solution (10 mL) and stirred at RT for 0.5 hour. The gray suspension was filtered. The filter cake was washed with EtOAc (20 mL×2). The separated aqueous phase was extracted with EtOAc (80 mL×2). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by silica gel column chromatography (PE: EA=1:1) to afford 8-acetyl-2-(benzofuran-3-yl)-3,6-dimethylquinazolin-4(3H)- one (530 mg, 99.1 %) as a yellow solid. LCMS: (M + H) + =333.0 [01020] Step 3: To a solution of 8-acetyl-2-(benzofuran-3-yl)-3,6-dimethylquinazolin-4(3H)-on e (530 mg, 1.595 mmol) in THF (8 mL) were added (R)-2-methylpropane-2-sulfinamide (395 mg, 3.259 mmol) and Ti(Oi-Pr) 4 (8 mL) at RT. The mixture was stirred at 75 °C for 18 h under N 2 . Cooling to RT, the mixture was added a saturated aqueous NaCl solution (25 mL) and stirred at RT for 5 mins. The suspension was filtered, the filter cake was washed with EtOAc (20 mL×2). The aqueous phase was extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over Na 2 SO 4 , filtered and concentrated to afford crude (R,Z)-N-(1-(2-(benzofuran-3-yl)- 3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethylidene)-2- methylpropane-2-sulfinamide (690 mg, 99.3 %) as a yellow solid. LCMS: (M + H) + =436.0 [01021] Step 4: To a solution of crude (R,Z)-N-(1-(2-(benzofuran-3-yl)-3,6-dimethyl-4-oxo-3,4-dihyd roquinazolin- 8-yl)ethylidene)-2-methylpropane-2-sulfinamide (690 mg, 1.584 mmol) in MeOH (8 mL) and DCM (8 mL) were added AcOH (0.8 mL) and NaBH 3 CN (300 mg, 4.774 mmol, 3.0 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hour. The mixture was added with aqueous NH 4 Cl solution (6 mL) and extracted with DCM (50 mL×2). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by Prep-HPLC to afford (method A) (R)-N-((R)-1-(2-(benzofuran-3-yl)-3,6-dimethyl-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulf inamide (250 mg, 36.0 %) as a white solid. LCMS: (M + H) + =438.0 [01022] Step 5: To a solution of (R)-N-((R)-1-(2-(benzofuran-3-yl)-3,6-dimethyl-4-oxo-3,4-dih ydroquinazolin-8- yl)ethyl)-2-methylpropane-2-sulfinamide (250 mg, 0.571 mmol) in MeOH (3 mL) was added HCl (0.8 mL, 3M in MeOH) at RT. The mixture was stirred at RT for 1 hour. The mixture was neutralized with aqueous NaHCO 3 solution to pH = 7-8. The mixture was concentrated to provide a residue which was extracted with THF to afford (R)-8-(1-aminoethyl)-2-(benzofuran-3-yl)-3,6-dimethylquinazo lin-4(3H)-one (190 mg, 99.8 %) as a yellow solid. LCMS: (M + H) + =334.0 [01023] Step 6: To a solution of (R)-8-(1-aminoethyl)-2-(benzofuran-3-yl)-3,6-dimethylquinazo lin-4(3H)-one (105 mg, 0.315 mmol) in DMSO (2 mL) were added methyl 6-chloro-3-fluoropicolinate (90 mg, 0.475 mmol) and DIEA (0.3 mL). The mixture was stirred at 100 °C for 4 h. After cooled to RT, the mixture was added water (25 mL), filtered and washed with water to provide a crude which was purified by silica gel column chromatography (PE: EA=3:2) to give methyl (R)-3-((1-(2-(benzofuran-3-yl)-3,6-dimethyl-4-oxo-3,4-dihydr oquinazolin-8-yl)ethyl)amino)- 6-chloropicolinate (85 mg, 53.7 %) as a colorless viscous oil. LCMS: (M + H) + =502.9 [01024] Step 7: To a solution of methyl (R)-3-((1-(2-(benzofuran-3-yl)-3,6-dimethyl-4-oxo-3,4-dihydr oquinazolin- 8-yl)ethyl)amino)-6-chloropicolinate (85 mg, 0.169 mmol) in MeOH (0.8 mL) were added THF (0.8 mL), H 2 O (0.4 mL) and LiOH•H 2 O (28 mg, 0.667 mmol) at RT. The mixture was stirred at RT for 1 hour. The mixture was neutralized with HCl (1M) to pH = 6 and concentrated, the residue was purified by Prep-HPLC (method B) to give (R)-3-((1-(2-(benzofuran-3-yl)-3,6-dimethyl-4-oxo-3,4-dihydr oquinazolin-8-yl)ethyl)amino)-6-chloropicolinic acid (51 mg, 61.5 %) as a white solid. LCMS: (M + H) + = 489.0 EXAMPLE 138 (R)-6-chloro-3-((1-(3,6-dimethyl-2-(1-methyl-1H-pyrazol-4-yl )-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [01025] Step 1: To a solution of 2-amino-3-bromo-N,5-dimethylbenzamide (2.0 g, 8.3 mmol) in DMSO (50 mL) was added 1-methyl-1H-pyrazole-4-carbaldehyde (1.37 g, 12.45 mmol) at RT. The resulting mixture was heated to 120 °C and stirred for 16 h under O 2 . The mixture was poured into water (250 mL) and stirred for 0.5 hour, the suspension was filtered and the collected solid was dried to provide 8-bromo-3,6-dimethyl-2-(1-methyl-1H- pyrazol-4-yl)quinazolin-4(3H)-one (2.0 g, 72%) as a yellow solid. LCMS (ESI) m/z: [M+H] + = 333.0 [01026] Step 2: To a solution of 88-bromo-3,6-dimethyl-2-(1-methyl-1H-pyrazol-4-yl)quinazolin -4(3H)-one (2.0 g, 6.0 mmol) in dioxane (40 mL) were added tributyl(1-ethoxyvinyl)stannane (4.33 g, 12 mmol) and Pd(PPh 3 ) 2 Cl 2 (421 mg, 0.6 mmol) at RT. The resulting mixture was heated to 95 °C and stirred for 16 h under N 2 . HCl (6 mL, 1 M) was added into the mixture and the mixture was stirred at 50 °C for 0.5 hour. Then a saturated KF (200 mL) was added and the resulting mixture was stirred at 20 °C for 0.5 hour. The gray suspension was filtered and the filter cake was washed with EtOAc (100 mL×3). The aqueous phase was extracted with EtOAc (50 mL×3) and the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by silica gel column chromatography (PE: EA=4:1) to afford 8-acetyl-3,6-dimethyl-2-(1-methyl-1H- pyrazol-4-yl)quinazolin-4(3H)-one (1.6 g, 90%) as a white solid. LCMS (ESI) m/z: [M+H] + = 297.0 [01027] Step 3: To a solution of 8-acetyl-3,6-dimethyl-2-(1-methyl-1H-pyrazol-4-yl)quinazolin -4(3H)-one (1.6 g, 5.4 mmol) in THF (20 mL) were added Ti(i-PrO) 4 (20 mL) and (R)-2-methylpropane-2-sulfinamide (1.31 g, 10.8 mmol) at RT. The resulting mixture was heated to 75 °C and stirred overnight. Brine (50 mL) was added into the mixture. The suspension was filtered and the filter cake was washed with EtOAc (80 mL×3). The aqueous phase was extracted with EtOAc (50 mL×3) and the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford (R,Z)-N-(1-(3,6-dimethyl-2-(1-methyl-1H- pyrazol-4-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethylidene)-2 -methylpropane-2-sulfinamide (1.5 g, 70%) as a yellow solid. LCMS (ESI) m/z: [M+H] + = 400.0 [01028] Step 4: To a solution of (R,Z)-N-(1-(3,6-dimethyl-2-(1-methyl-1H-pyrazol-4-yl)-4-oxo- 3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (1.5 g, 3.7 mmol) in EtOH (20 mL) was added a solution of LiBH 4 in THF (3.7 ml, 3.7 mmol, 1 M) dropwise at -20 °C, the resulting mixture was warmed up to RT and stirred for 3 h. The mixture was quenched with saturated aqueous NH 4 Cl (100 mL) solution and extracted with DCM (100 mL x 2), the combined extract was washed with brine, dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by Prep-HPLC (Method A) to afford (R)-N-((R)-1-(3,6-dimethyl-2-(1- methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)eth yl)-2-methylpropane-2-sulfinamide (450 mg, 30%) as a white solid. LCMS (ESI) m/z: [M+H] + = 402.0 [01029] Step 5: A mixture (R)-N-((R)-1-(3,6-dimethyl-2-(1-methyl-1H-pyrazol-4-yl)-4-ox o-3,4-dihydroquinazolin- 8-yl)ethyl)-2-methylpropane-2-sulfinamide (450 mg, 1.12 mmol) in a solution of HCl in MeOH (3M, 5 mL) was stirred at RT for 30 minutes. The mixture was adjusted to pH = 9 with saturated aqueous NaHCO 3 solution and the mixture was extracted with DCM (100 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(1-methyl-1H-pyrazol-4- yl)quinazolin-4(3H)-one (300 mg, 90%) as a yellow solid. LCMS (ESI) m/z: [M+H] + = 298.3 [01030] Step 6: To a solution of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(1-methyl-1H-pyrazol-4-y l)quinazolin-4(3H)- one (150 mg, 0.51 mmol) in DMSO (5 mL) were added methyl 6-chloro-3-fluoropicolinate (145 mg, 0.77 mmol) and DIPEA (197 mg, 1.53 mmol) at RT. The resulting mixture was stirred at 100 °C overnight. The mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL×3), the combined organic phase was washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by Pre-TLC (PE: EA = 3:1) to afford methyl (R)-6-chloro-3-((1-(3,6-dimethyl-2-(1-methyl-1H-pyrazol-4-yl )-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinate (100 mg, 42%) as a yellow solid. LCMS (ESI) m/z: [M+H] + = 466.9 [01031] Step 7: To a solution of methyl (R)-6-chloro-3-((1-(3,6-dimethyl-2-(1-methyl-1H-pyrazol-4-yl )-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (100 mg, 0.21 mmol) in MeOH (2 mL) and THF (2 mL) were added LiOH (25 mg, 1.05 mmol) and H 2 O (0.5 mL). The resulting mixture was stirred at the RT for 1 hour. The mixture was adjusted to pH = 4 with HCl solution and diluted with water (20 mL), the mixture was extracted with DCM (50 mL x 3), the combined organic layers were dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by Prep-HPLC (Method B) to afford (R)-6-chloro-3-((1-(3,6-dimethyl-2-(1-methyl-1H-pyrazol-4-yl )-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinic acid (54.1 mg, 57%) as a white solid. LCMS (ESI) m/z: [M+H] + = 453.2 EXAMPLE 139 2-(1-(3,6-dimethyl-4-oxo-2-(piperidine-1-yl)-3,4-dihydroquin azolin-8-yl)ethoxy)benzamide [01032] To a solution of 2-(1-(3,6-dimethyl-4-oxo-2-(piperidine-1-yl)-3,4-dihydroquin azolin-8-yl)ethoxy)benzoic acid (52 mg, 0.12 mmol) in DMF (5 ml) was added NH 4 Cl (10 mg, 0.18 mmol), DMAP (29 mg, 0.24 mmol) and EDCI (28 mg, 0.182 mmol). The mixture was stirred at RT for 1 hour. Water (50 ml) was added, the separated aqueous layer was extracted with EtOAc (20 ml *3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated, The residue was purified by Pre-HPLC (Method A) to afford 2-(1-(3,6-dimethyl-4- oxo-2-(piperidine-1-yl)-3,4-dihydroquinazolin-8-yl)ethoxy)be nzamide (13.6 mg, 27% yield) as a white solid. LCMS: (M + H) + = 421.0 EXAMPLE 140 (R)-2-((1-(3,6-dimethyl-2-(1-methylcyclobutyl)-4-oxo-3,4-dih ydroquinazolin-8-yl)ethyl)amino)benzoic acid [01033] Step1: To a mixture of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(1-methylcyclobutyl)quin azolin-4(3H)-one (150 mg, 0.53 mmol), methyl 2-iodobenzoate (278 mg, 1.06 mmol) and Cs 2 CO 3 (346 mg, 1.06 mmol) in dioxane (10 ml) were added Pd2(dba)3 (97 mg, 0.106 mmol) and XantPhos (122 mg, 0.212 mmol). The mixture was stirred at 100 °C under N 2 for 24 h. Cooling to RT, water (20 ml) was added and the mixture was extracted with DCM (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-TLC (PE:EA = 4:1) to afford methyl (R)-2-((1-(3,6-dimethyl-2-(1-methylcyclobutyl)-4- oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (90 mg, 41%) as a yellow oil. LCMS: (M + H) + =420.1 [01034] Step2: To a mixture of methyl (R)-2-((1-(3,6-dimethyl-2-(1-methylcyclobutyl)-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate (90 mg, 0.21 mmol) in MeOH (5 ml) and H 2 O (1 ml) was added LiOH (50 mg, 2.1 mmol), the mixture was stirred at 50 °C for 4 h. Cooling to RT, the mixture was adjusted to pH = 5-6 with 1 M HCl and extracted with DCM (30 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (method B) to afford (R)-2-((1-(3,6- dimethyl-2-(1-methylcyclobutyl)-4-oxo-3,4-dihydroquinazolin- 8-yl)ethyl)amino)benzoic acid (49 mg, 58%) as a white solid. LCMS: (M + H)+ =406.2 EXAMPLE 141 (R)-6-chloro-3-((1-(2-(1-(2,2-difluoroethyl)-3-methylazetidi n-3-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinic acid [01035] Step 1: To a mixture of 2-amino-3-bromo-N,5-dimethylbenzamide (2 g, 8.3 mmol) and 1-(tert- butoxycarbonyl)-3-methylazetidine-3-carboxylic acid (2.6 g, 12.5 mmol) in THF (40 mL) were added CMPI (3.17 g, 12.5 mmol) and DIPEA (4.2 mL) at RT. The resulting mixture was heated to 75 °C and stirred overnight. Cooling to RT, water (40 mL) was added and the mixture was extracted with EtOAc (40 mL×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by silica gel column chromatography (PE: EA=5:1) to give tert-butyl 3-((2-bromo-4-methyl-6- (methylcarbamoyl)phenyl)carbamoyl)-3-methylazetidine-1-carbo xylate (2.5 g, 68.7%) as a white solid. LCMS (ESI) m/z: [M+H-Boc] + = 384.0 [01036] Step 2: To a mixture of tert-butyl 3-((2-bromo-4-methyl-6-(methylcarbamoyl)phenyl)carbamoyl)-3- methylazetidine-1-carboxylate (2.5 g, 5.7 mmol) in DCM (50 mL) were added I 2 (1.5 g, 5.7 mmol) and HMDS (2.8 g, 17.1 mmol) at RT. The resulting mixture was heated to 50 °C and stirred for 4 h. Cooling to RT, a saturated aqueous Na 2 S 2 O 3 (80 mL) solution was added and the mixture was extracted with DCM (150 mL×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by silica gel column chromatography (PE: EA=5:1) to give tert-butyl 3-(8-bromo-3,6-dimethyl-4-oxo- 3,4-dihydroquinazolin-2-yl)-3-methylazetidine-1-carboxylate (1.5 g, 62.5%) as a white solid LCMS (ESI) m/z: [M+H] + = 421.9 [01037] Step 3: To a solution of tert-butyl 3-(8-bromo-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-3- methylazetidine-1-carboxylate (1.5 g, 3.6 mmol) in dioxane (30 mL) were added tributyl(1-ethoxyvinyl)stannane (2.6 g, 7.2 mmol) and Pd(PPh 3 ) 2 Cl 2 (280 mg, 0.4 mmol) at RT. The resulting mixture was heated to 95 °C and stirred at the same temperature for 6 h under N 2 . HCl (4 mL, 1 M) was added into the mixture and the mixture was stirred at 50 °C for 0.5 hour. Then saturated KF (100 mL) was added and the mixture was stirred at RT for 0.5 hour. The gray suspension was filtered. The filter cake was washed with EtOAc (80 mL×3). The aqueous phase was extracted with EtOAc (100 mL×3) and the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by silica gel column chromatography (PE: EA=3:1) to give tert-butyl 3-(8-acetyl-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-3 -methylazetidine-1- carboxylate (1.2 g, 86%) as a white solid. LCMS (ESI) m/z: [M+H] + = 381.6 [01038] Step 4: To a solution of tert-butyl 3-(8-acetyl-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-3 - methylazetidine-1-carboxylate (1.2 g, 3.1 mmol) in DCM (15 mL) was added TFA (5 mL) at RT. The resulting mixture was stirred at RT for 3 h. Water (40 mL) was added and the mixture was extracted with DCM (150 mL×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by silica gel column chromatography (DCM: MeOH=20:1) to give 8-acetyl- 3,6-dimethyl-2-(3-methylazetidin-3-yl)quinazolin-4(3H)-one (800 mg, 90%) as a white solid. LCMS (ESI) m/z: [M+H] + = 286.3 [01039] Step 5: To a mixture of 8-acetyl-3,6-dimethyl-2-(3-methylazetidin-3-yl)quinazolin-4( 3H)-one (400 mg, 1.4 mmol) and 2-bromo-1,1-difluoroethane (303 mg, 2.1 mmol) in DMF (10mL) was added K 2 CO 3 (581 mg, 4.2 mmol) at RT. The resulting mixture was heated to 100 °C and stirred overnight. Cooling to RT, water (50 mL) was added and the mixture was extracted with EtOAc (150 mL×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by silica gel column chromatography (PE: EA=4:1) to give 8-acetyl-2-(1-(2,2-difluoroethyl)-3-methylazetidin-3-yl)-3,6 - dimethylquinazolin-4(3H)-one (190 mg, 39%) as a white solid. LCMS (ESI) m/z: [M+H] + = 350.0 [01040] Step 6: To a solution of 8-acetyl-2-(1-(2,2-difluoroethyl)-3-methylazetidin-3-yl)-3,6 -dimethylquinazolin- 4(3H)-one (190 mg, 0.54 mmol) in THF (5 mL) were added Ti(i-PrO) 4 (5 mL) and (R)-2-methylpropane-2- sulfinamide (130 mg, 1.08 mmol) at RT. The resulting mixture was heated to 75 °C and stirred for 12 h. Brine (5 mL) was added into the mixture and the mixture was stirred at RT for 0.5 hour. The suspension was filtered. The filter cake was washed with EtOAc (40 mL×3). The separated aqueous phase was extracted with EtOAc (30 mL×3) and the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give crude (R,Z)-N-(1-(2-(1-(2,2-difluoroethyl)-3-methylazetidin-3-yl)- 3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (200 mg, 82%) as a yellow solid for the next step without further purification. LCMS (ESI) m/z: [M+H] + = 394.0 [01041] Step 7: To a mixture of (R,Z)-N-(1-(2-(1-(2,2-difluoroethyl)-3-methylazetidin-3-yl)- 3,6-dimethyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sul finamide (200 mg, 0.44 mmol) and HOAc (0.25 mL) in DCM (5 mL) and MeOH (5 mL) was added NaBH 3 CN (82 mg, 1.32 mmol) in portions at 0 °C, the mixture was stirred at RT for 3 h. The reaction was quenched with saturated NH 4 Cl (30 mL) and extracted with DCM (40 mL x 3). The combined organic phase was washed with brine, dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by Prep-HPLC (Method A) to give (R)-N-((R)-1-(2-(1-(2,2-difluoroethyl)-3-methylazetidin-3- yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-m ethylpropane-2-sulfinamide (50 mg, 25%) as a white solid. LCMS (ESI) m/z: [M+H] + = 455.0 [01042] Step 8: A mixture (R)-N-((R)-1-(2-(1-(2,2-difluoroethyl)-3-methylazetidin-3-yl )-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (50 mg, 0.11 mmol) ) in a solution of HCl in MeOH (3M, 2 mL) was stirred at RT for 10 minutes. The mixture was adjusted to pH = 9 with saturated aqueous NaHCO 3 solution and extracted with DCM (50 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give the crude product (R)-8-(1-aminoethyl)-2-(1-(2,2-difluoroethyl)-3-methylazetid in- 3-yl)-3,6-dimethylquinazolin-4(3H)-one (35 mg, 91%) as a white solid. LCMS (ESI) m/z: [M+H] + = 351.3 [01043] Step 9: To a solution of (R)-8-(1-aminoethyl)-2-(1-(2,2-difluoroethyl)-3-methylazetid in-3-yl)-3,6- dimethylquinazolin-4(3H)-one (35 mg, 0.1 mmol) in DMSO (2 mL) were added methyl 6-chloro-3-fluoropicolinate (95 mg, 0.2 mmol) and DIPEA (0.06 mL) at RT. The resulting mixture was stirred at 100 °C overnight. Cooling to RT, the mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL×3), washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give methyl (R)-6-chloro-3-((1-(2-(1-(2,2-difluoroethyl)-3- methylazetidin-3-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazoli n-8-yl)ethyl)amino)picolinate (50 mg, 90%) as a yellow solid. LCMS (ESI) m/z: [M+H] + = 520.0 [01044] Step 10: To a solution of methyl (R)-6-chloro-3-((1-(2-(1-(2,2-difluoroethyl)-3-methylazetidi n-3-yl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picoli nate (50 mg, 0.09 mmol, 1.0 eq) in MeOH (1 mL) and THF(1 mL) were added LiOH (23 mg, 0.54 mmol, 6.0 eq) and H 2 O (0.5 mL) at RT. The resulting mixture was stirred at the RT for 15 minutes. The mixture was adjusted to pH = 4 with 1 M HCl solution and diluted with water (10 mL), the mixture was extracted with DCM (30 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated, the residue was purified by Prep-HPLC (Method B) to give (R)-6-chloro-3-((1- (2-(1-(2,2-difluoroethyl)-3-methylazetidin-3-yl)-3,6-dimethy l-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinic acid (24.1 mg, 53%) as a white solid. LCMS (ESI) m/z: [M+H] + = 506.2 EXAMPLE 142 (R)-6-chloro-3-((1-(3,6-dimethyl-2-(1-methyl-1H-pyrazol-3-yl )-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [01045] Step 1: To a solution of 2-amino-3-bromo-N,5-dimethylbenzamide (2.18 g, 8.968 mmol) in DMSO (25 mL) was added 1-methyl-1H-pyrazole-3-carbaldehyde (2.33 g, 21.159 mmol). The mixture was stirred at 135 °C for 18 h under O 2 . After cooling to RT, the mixture was filtered and washed with water to give 8-bromo-3,6- dimethyl-2-(1-methyl-1H-pyrazol-3-yl)quinazolin-4(3H)-one (1.95 g, 65.3 %) as a white solid. LCMS: (M + H) + =333.0 [01046] Step 2: To a solution of 8-bromo-3,6-dimethyl-2-(1-methyl-1H-pyrazol-3-yl)quinazolin- 4(3H)-one (800 mg, 2.401 mmol) in dioxane (30 mL) were added tributyl(1-ethoxyvinyl)stannane (1740 mg, 4.818 mmol) and Pd(PPh 3 ) 2 Cl 2 (190 mg, 0.271 mmol) at RT. The mixture was stirred at 100 °C for 16 h under N 2 . The mixture was added HCl (2.5 mL, 1M) and stirred at 50 °C for 0.5 hour. The mixture was added saturated aqueous KF solution (12.5 mL) and stirred at RT for 0.5 hour. The gray suspension was filtered. The filter cake was washed with H 2 O (10 mL×2) and EtOAc (20 mL×2). The aqueous phase was extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by silica gel column chromatography (DCM: EA=4:1) to give 8-acetyl-3,6-dimethyl-2-(1-methyl-1H- pyrazol-3-yl)quinazolin-4(3H)-one (230 mg, 32.3 %) as a white solid. LCMS: (M + H) + =297.0 [01047] Step 3: To a solution of 8-acetyl-3,6-dimethyl-2-(1-methyl-1H-pyrazol-3-yl)quinazolin -4(3H)-one (230 mg, 0.776 mmol) in THF (5 mL) were added (R)-2-methylpropane-2-sulfinamide (190 mg, 1.568 mmol) and Ti(Oi- Pr) 4 (5 mL) at RT. The mixture was stirred at 75 °C for 18 h under N 2 . After cooling with ice bath, the mixture was added saturated aqueous NaCl solution (10 mL) and stirred at RT for 5 mins. The suspension was filtered. The filter cake was washed with H 2 O (10 mL×2) and EtOAc (20 mL×2). The aqueous phase was extracted with EtOAc (80 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give crude (R,Z)-N-(1-(3,6-dimethyl-2-(1-methyl-1H-pyrazol-3-yl)-4-oxo- 3,4-dihydroquinazolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (310 mg, 100 %) as a yellow solid. LCMS: (M + H) + =400.0 [01048] Step 4: To a solution of crude (R,Z)-N-(1-(3,6-dimethyl-2-(1-methyl-1H-pyrazol-3-yl)-4-oxo- 3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (310 mg, 0.776 mmol) in MeOH (3 mL) were added DCM (3 mL), AcOH (0.4 mL) and NaBH 3 CN (150 mg, 2.387 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour. The mixture was added with aqueous NH 4 Cl solution (4 mL), extracted with DCM (50 mL×2). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by Prep-HPLC (method A) to give (R)-N-((R)-1-(3,6-dimethyl-2-(1-methyl-1H-pyrazol- 3-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropan e-2-sulfinamide (85 mg, 27.3 %) as a white solid. LCMS: (M + H) + =402.0 [01049] Step 5: To a solution of (R)-N-((R)-1-(3,6-dimethyl-2-(1-methyl-1H-pyrazol-3-yl)-4-ox o-3,4- dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (85 mg, 0.212 mmol) in MeOH (4 mL) was added HCl (2 mL, 3M in MeOH) at RT. The mixture was stirred at RT for 1 hour. The mixture was neutralized with aqueous NaHCO 3 solution to pH = 8, and extracted with DCM (50 mL×2), the combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(1-methyl-1H-pyrazol-3- yl)quinazolin-4(3H)-one (58 mg, 92.0 %) as a yellow solid. LCMS: (M + H) + =298.1 [01050] Step 6: To a solution of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(1-methyl-1H-pyrazol-3-y l)quinazolin-4(3H)- one (58 mg, 0.195 mmol) in DMSO (2 mL) were added methyl 6-chloro-3-fluoropicolinate (58 mg, 0.306 mmol) and DIEA (0.2 mL). The mixture was stirred at 100 °C for 4 h. After cooling to RT, the mixture was added water (25 mL), filtered and washed with water to give methyl (R)-6-chloro-3-((1-(3,6-dimethyl-2-(1-methyl-1H-pyrazol-3- yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinate (80 mg, 0.171 mmol, 87.7 %) as a white solid. LCMS: (M + H) + =466.9 [01051] Step 7: To a solution of methyl (R)-6-chloro-3-((1-(3,6-dimethyl-2-(1-methyl-1H-pyrazol-3-yl )-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (80 mg, 0.171 mmol) in MeOH (1 mL) were added THF (1 mL), H 2 O (1 mL) and LiOH•H 2 O (30 mg, 0.715 mmol) at RT. The mixture was stirred at RT for 1 hour. The mixture was neutralized with HCl (1M) to pH = 6. The mixture was purified by Prep-HPLC (method B) to give (R)-6-chloro-3- ((1-(3,6-dimethyl-2-(1-methyl-1H-pyrazol-3-yl)-4-oxo-3,4-dih ydroquinazolin-8-yl)ethyl)amino)picolinic acid (39.5 mg, 50.9 %) as a white solid. LCMS: (M + H) + = 440.1 EXAMPLE 143 (R)-6-chloro-3-((1-(2-(2,5-dimethylthiazol-4-yl)-3,6-dimethy l-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid [01052] Step 1: To a mixture of 2-amino-3-bromo-N, 5-dimethylbenzamide (2 g, 8.5 mmol) and 2,5- dimethylthiazole-4-carboxylic acid (2 g, 12.7mmol) in ACN (50 mL) were added TCFH (3.6 g, 12.7 mmol) and NMI (2.1 g, 25.5 mmol) at RT. The resulting mixture was heated to 90 °C and stirred overnight. Cooling to RT, water (60 mL) was added and the mixture was extracted with DCM (150 mL×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by silica gel column chromatography (PE: EA=4:1) to give N-(2-bromo-4-methyl-6-(methylcarbamoyl)phenyl)-2- methylthiazole-4-carboxamide (1.5 g, 46%) as a white solid. LCMS (ESI) m/z: [M+H] + = 382.1 [01053] Step 2: To a solution of N-(2-bromo-4-methyl-6-(methylcarbamoyl)phenyl)-2-methylthiaz ole-4- carboxamide (1.5 g, 3.9 mmol) in DCM (30 mL) were added I2(990 mg, 3.9 mmol) and HMDS (1.9 g, 11.7 mmol) at RT. The resulting mixture was heated to 50 °C and stirred overnight. Cooling to RT, saturated aqueous Na 2 S 2 O 3 (40 mL) solution was added and the mixture was extracted with DCM (150 mL×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by silica gel column chromatography (PE: EA=5:1) to give 8-bromo-2-(2,5-dimethylthiazol-4-yl)-3,6- dimethylquinazolin-4(3H)-one (950 mg, 67%) as a white solid. LCMS (ESI) m/z: [M+H] + =364.7 [01054] Step 3: To a solution of 8-bromo-2-(2,5-dimethylthiazol-4-yl)-3,6-dimethylquinazolin- 4(3H)-one (950 mg, 2.6 mmol) in dioxane (20 mL) were added tributyl(1-ethoxyvinyl)stannane (1.8 g, 5.2 mmol) and Pd(PPh 3 ) 2 Cl 2 (210 mg, 0.3 mmol) at RT. The resulting mixture was heated to 95 °C and stirred for 12 h under N 2 . HCl (4 mL, 1 M) was added and the mixture was stirred at 50 °C for 0.5 hour, then saturated KF (60 mL) was added and the resulting mixture was stirred at rom temperature for 0.5 hour. The gray suspension was filtered. The filter cake was washed with EtOAc (50 mL×3). The aqueous phase was extracted with EtOAc (60 mL×3) and the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by silica gel column chromatography (PE: EA=4:1) to give 8-acetyl-2-(1-fluorocyclobutyl)-3,6- dimethylquinazolin-4(3H)-one (700 mg, 82%) as a white solid. LCMS (ESI) m/z: [M+H] + = 328.0 [01055] Step 4: To a solution of 8-acetyl-2-(2,5-dimethylthiazol-4-yl)-3,6-dimethylquinazolin -4(3H)-one (700 mg) in THF (10 mL) were added Ti(i-PrO) 4 (10 mL) and (R)-2-methylpropane-2-sulfinamide (508 mg, 4.2 mmol) at RT. The resulting mixture was heated to 75 °C and stirred for 12 h. Brine (10 mL) was added into the mixture. The suspension was filtered. The filter cake was washed with EtOAc (40 mL×3). The aqueous phase was extracted with EtOAc (150 mL×3) and the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue under reduced pressure to give (R,Z)-N-(1-(2-(2,5-dimethylthiazol- 4-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethylide ne)-2-methylpropane-2-sulfinamide (900 mg, 99%) as a yellow solid. LCMS (ESI) m/z: [M+H] + = 431.0 [01056] Step 5: To a mixture of (R,Z)-N-(1-(2-(2,5-dimethylthiazol-4-yl)-3,6-dimethyl-4-oxo- 3,4- dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfina mide (800 g, 1.9 mmol) and CeCl 3 .7H 2 O (346 mg, 0.9 mmol) in MeOH (20 mL) was added NaBH 4 (212 mg, 5.6 mmol) in portions at -78 °C. The resulting mixture was warmed to RT and stirred overnight. The mixture was quenched with saturated aqueous NH 4 Cl (100 mL) solution and extracted with DCM (300 mL x 2), the combined extract was washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give a residue which was purified by Prep-HPLC (Method A) to give (R)-N-((R)-1-(2- (2,5-dimethylthiazol-4-yl)-3,6-dimethyl-4-oxo-3,4-dihydroqui nazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (250 g, 30%) as a white solid. LCMS (ESI) m/z: [M+H] + 433.2 [01057] Step 6: A mixture (R)-N-((R)-1-(2-(2,5-dimethylthiazol-4-yl)-3,6-dimethyl-4-ox o-3,4-dihydroquinazolin-8- yl)ethyl)-2-methylpropane-2-sulfinamide (250 mg, 0.58 mmol) in a solution of HCl in MeOH (3M, 5 mL) was stirred at RT for 20 minutes. The mixture was adjusted to pH = 9 with saturated aqueous NaHCO 3 solution and the mixture was extracted with DCM (100 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give (R)-8-(1-aminoethyl)-2-(2,5-dimethylthiazol-4-yl)-3,6- dimethylquinazolin-4(3H)-one (150 mg, 79%) as a white solid. LCMS (ESI) m/z: [M+H] + =329.2 [01058] Step 7: To a solution of (R)-8-(1-aminoethyl)-2-(2,5-dimethylthiazol-4-yl)-3,6-dimeth ylquinazolin-4(3H)- one (150 mg, 0.45 mmol) in DMSO (3 mL) were added methyl 6-chloro-3-fluoropicolinate (170 mg, 0.9 mmol) and DIPEA (0.2 mL) at RT. The resulting mixture was stirred at 100 °C for 12 h. Water (20 mL) was added and the mixture was extracted with EtOAc (70 mL×3), the combined organic phase was washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give methyl (R)-6-chloro-3-((1-(2-(2,5- dimethylthiazol-4-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazol in-8-yl)ethyl)amino)picolinate (200 mg, 89%) as a white solid. LCMS (ESI) m/z: [M+H] + =498.1 [01059] Step 8: To a solution of methyl (R)-6-chloro-3-((1-(2-(2,5-dimethylthiazol-4-yl)-3,6-dimethy l-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (200 mg, 0.4 mmol) in MeOH (3 mL) and THF (2 mL) were added LiOH (58 mg, 2.4 mmol) and H 2 O (0.5 mL) and at RT. The resulting mixture was stirred at RT for 15 minutes. The mixture was adjusted to pH = 5 with 1 M HCl solution AND extracted with DCM (80 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by Prep-HPLC (Method B) to give (R)-6-chloro-3-((1-(2-(2,5-dimethylthiazol-4-yl)-3,6-dimethy l-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinic acid (84.3 mg, 43%) as a white solid. LCMS (ESI) m/z: [M+H] + = 484.0 EXAMPLE 144 (R)-6-chloro-3-((1-(4-(dimethylamino)-2-phenyl-6-methylquina zolin-8-yl)ethyl)amino)picolinic acid [01060] Step 1: To a solution of 2-amino-3-bromo-5-methylbenzoic acid (5 g, 23.3 mmol) in DMF (40 mL) were added MeNH 2 (3.14 g, 34.9 mmol), DIPEA (20 mL, 69.8 mmol) and HATU (10.61 g, 27.9 mmol). The mixture was stirred for 4 h at RT. The mixture was diluted with water (50 mL) and extracted with EtOAc (80 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford 2-amino-3- bromo-N-methylbenzamide (5.1 g, 96 %) as a white solid for the next step without further purification. LCMS: (M + H) + = 229.0 [01061] Step 2: To a solution of 2-amino-3-bromo-5-methylbenzamide (3.07 g, 13.5 mmol) in DMSO (20 mL) was added benzaldehyde (2.14 g, 20.2 mmol). The mixture was stirred at 140 °C under O 2 for 16 h. Cooling to RT, the mixture was filtrated and the cake was washed with PE, dried under reduce pressure to afford 8-bromo- 3-methyl-2-phenylquinazolin-4(3H)-one (2.67 g, 63.0 %) as a yellow solid. LCMS: (M + H) + = 315.1 [01062] Step 3: To a mixture of 8-bromo-3-methyl-2-phenylquinazolin-4(3H)-one (2.67 g, 8.50 mmol) and tributyl(1-ethoxyvinyl)stannane (4.64 g, 12.8 mmol) in dioxane (15 ml) was added Pd(PPh 3 ) 2 Cl 2 (598 mg, 0.85 mmol). The mixture was stirred at 95 °C under N 2 for 16 h. HCl (9.0 mL, 1 M) was added into the mixture and stirred at 50 °C for 0.5 hour, then 50 ml sat KF was added and the mixture was stirred at RT for 0.5 hour. The gray mixture was filtered, the filter cake was washed with EtOAc (30 mL*3), the separated aqueous phase was extracted with EtOAc (30 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by chromatography (PE: EA = 5:1) to afford 8-acetyl-3-methyl-2- phenylquinazolin-4(3H)-one (2.17 g, 92%) as a brown oil. LCMS: (M + H) + =279.3 [01063] Step 4: To a mixture of 8-acetyl-3-methyl-2-phenylquinazolin-4(3H)-one (2.17 g 7.80 mmol) and (R)-2- methylpropane-2-sulfinamide (1.89 g, 15.6 mmol) in THF (40 ml) was added Ti(i-PrO) 4 (4.97 g, 17.5 mmol). The mixture was stirred at 75 °C under N 2 for 16 h. Cooling to RT, brine (50 mL) was added and the mixture was stirred for 0.5 hour, the resulting mixture was filtrated and the cake was washed with EtOAc (40 mL*3), the separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford crude (R,Z)-2- methyl-N-(1-(3-methyl-4-oxo-2-phenyl-3,4-dihydroquinazolin-8 yl) ethylidene) propane-2-sulfinamide (2.09 g) as a yellow oil for the next step without further purification. LCMS: (M + H) + = 382.2 [01064] Step 5: To a mixture of (R,Z)-2-methyl-N-(1-(3-methyl-4-oxo-2-phenyl-3,4-dihydroquin azolin-8 yl) ethylidene) propane-2-sulfinamide (2.09 g, 5.48 mmol) and CeCl 3 ·7H 2 O (1.02 g, 2.74 mmol) in MeOH (20 mL) was added NaBH 4 (621 mg, 16.4 mmol) at -75 °C. then the mixture was warmed roon temperature and stirred for 16 h. The mixture was diluted with water (50 mL) and extracted with DCM (80 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre – HPLC (method A) to afford (R)-2-methyl-N-((R)-1-(3-methyl-4-oxo-2-phenyl-3,4-dihydroqu inazolin-8-yl) ethyl) propane- 2-sulfinamide (780 mg, 51.8%) as a white solid. LCMS: (M + H) + = 384.0 [01065] Step 6: A mixture of (R)-2-methyl-N-((R)-1-(3-methyl-4-oxo-2-phenyl-3,4-dihydroqu inazolin-8- yl)ethyl)propane-2-sulfinamide (780 mg, 2.04 mmol) in a solution of HCl in MeOH (5 mL, 4 M) was stirred at RT for 10 min. The mixture was poured into ice-water and adjusted PH=8 with a saturated solution of NaHCO 3 , the mixture was extracted with DCM/MeOH (20 mL*3, 10/1), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford (R)-8-(1-aminoethyl)-3-methyl-2-phenylquinazolin-4(3H)-one (500 mg, 88%) as a colorless oil. LCMS: (M + H) + = 280.3 [01066] Step 7: To a mixture of (R)-8-(1-aminoethyl)-3-methyl-2-phenylquinazolin-4(3H)-one (500 mg, 1.79 mmol) and methyl 6-chloro-3-fluoropicolinate (372 mg, 1.97 mmol) in DMSO (15 mL) was added DIPEA (694 mg, 5.37 mmol), the mixture was heated to 100 °C and stirred for 16 h. Cooling to RT, H 2 O (60 mL) was added and the mixture was extracted with EA (60 ml*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to afford methyl (R)-6-chloro-3-((1-(3-methyl-4-oxo-2-phenyl-3,4-dihydroquina zolin-8- yl)ethyl)amino)picolinate (800 mg, 88%) as a white solid. LCMS: (M + H) + = 449.1 [01067] Step 8: To a mixture of methyl (R)-6-chloro-3-((1-(3-methyl-4-oxo-2-phenyl-3,4-dihydroquina zolin-8- yl)ethyl)amino)picolinate (800 mg, 1.79 mmol) in MeOH (10 mL) and H 2 O (2 mL) was added LiOH (430 mg, 17.9 mmol). The mixture was stirred for 2 h at RT. The mixture was adjusted to pH = 4-5 with 1 M HCl and extracted with DCM (40 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to afford (R)-6-chloro-3-((1-(4-(dimethylamino)-2-phenyl-6- methylquinazolin-8-yl)ethyl)amino)picolinic acid (299.3 mg, 38.5%) as a yellow solid. LCMS: (M + H) + =435.1 EXAMPLE 145 (R)-6-chloro-3-((1-(6-chloro-3-methyl-4-oxo-2-phenyl-3,4-dih ydroquinazolin-8-yl)ethyl)amino)picolinic acid [01068] Step 1: To a mixture of 2-amino-3-bromo-5-chlorobenzoic acid (5 g, 20 mmol) and MeNH 2 (930 mg, 30 mmol) in DMF (70 mL) were added HATU (11.4 g, 30 mmol) and DIEA (10 mL) at RT. The resulting mixture was stirred at the RT for 2 h. Water (400 mL) was added and the mixture was extracted with EtOAc (150 mL×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by silica gel column chromatography (PE: EA=4:1) to give 2-amino-3-bromo-5-chloro- N-methylbenzamide (5 g, 95%) as a white solid. LCMS (ESI) m/z: [M+H] + 263.0 [01069] Step 2: To a solution of 2-amino-3-bromo-5-chloro-N-methylbenzamide (3 g, 11.4 mmol) in DMSO (50 mL) was added benzaldehyde (1.8 g, 17.2 mmol) at RT. The resulting mixture was heated to 135 °C and stirred for 12 h under O 2 . Cooling to RT, the mixture was poured into water (250 mL) and stirred for 15 minutes, then filtered and the collected solid was dried under reduce pressure to give 8-bromo-6-chloro-3-methyl-2- phenylquinazolin-4(3H)-one (4 g, 96%yield) as a yellow solid. LCMS (ESI) m/z: [M+H] + 349.0 [01070] Step 3: To a solution of 8-bromo-6-chloro-3-methyl-2-phenylquinazolin-4(3H)-one (4 g, 11mmol) in dioxane (20 mL) were added tributyl(1-ethoxyvinyl)stannane (7.9 g, 22 mmol) and Pd(PPh 3 ) 2 Cl 2 (771 mg, 1.1 mmol) at RT. The resulting mixture was heated to 100 °C and stirred overnight under N 2 . HCl (11 mL, 1 M) was added into the mixture and the mixture was stirred at 50 °C for 0.5 hour. Then a saturated KF (100 mL) was added and the resulting mixture was stirred at RT for 0.5 hour. The gray suspension was filtered. The filter cake was washed with EtOAc (150 mL×3). The aqueous phase was extracted with EtOAc (200 mL×3), the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by silica gel column chromatography (PE: EA=4:1) to give 8-acetyl-6-chloro-3-methyl-2- phenylquinazolin-4(3H)-one (1.7 g, 49%) as a white solid. LCMS (ESI) m/z: [M+H] + 313.0 [01071] Step 4: To a solution of 8-acetyl-6-chloro-3-methyl-2-phenylquinazolin-4(3H)-one (1.7 g, 5.4 mmol) in THF (15 mL) were added Ti(i-PrO) 4 (15 mL) and (R)-2-methylpropane-2-sulfinamide (1.3 g, 10.9 mmol) at RT. The resulting mixture was heated to 75 °C and stirred overnight. Brine (15 mL) was added into the mixture. The suspension was filtered. The filter cake was washed with EtOAc (70 mL×3). The aqueous phase was extracted with EtOAc (50 mL×3) and the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue under reduced pressure to give crude (R,Z)-N-(1-(6-chloro-3-methyl-4-oxo-2- phenyl-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropan e-2-sulfinamide (2.2 g, 98%) as a yellow solid. LCMS (ESI) m/z: [M+H] + 416.1. [01072] Step 5: To a mixture of crude (R,Z)-N-(1-(6-chloro-3-methyl-4-oxo-2-phenyl-3,4-dihydroquin azolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (2 g, 4.8 mmol) and CeCl 3 .7H 2 O (897 mg, 2.7 mmol) in MeOH (30 mL) was added NaBH 4 (547 mg, 14.4 mmol) in portions at -78 °C. The resulting mixture was warmed up to RT and stirred overnight. The mixture was quenched with saturated aqueous NH 4 Cl (100 mL) solution and extracted with DCM (300 mL x 2), the combined organic phase was washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give a residue which was purified by Prep-HPLC (Method A) to give (R)-N-((R)-1-(6-chloro-3- methyl-4-oxo-2-phenyl-3,4-dihydroquinazolin-8-yl)ethyl)-2-me thylpropane-2-sulfinamide (700 mg, 35%) as a white solid. LCMS (ESI) m/z: [M+H] + 418.0 [01073] Step 6: A mixture (R)-N-((R)-1-(6-chloro-3-methyl-4-oxo-2-phenyl-3,4-dihydroqu inazolin-8-yl)ethyl)-2- methylpropane-2-sulfinamide (700 mg, 1.68 mmol) ) in a solution of HCl in MeOH (3M, 8 mL) was stirred at the RT for 30 minutes. The mixture was adjusted to pH = 9 with saturated aqueous NaHCO 3 solution and extracted with DCM (150 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give the crude product (R)-8-(1-aminoethyl)-6-chloro-3-methyl-2-phenylquinazolin-4( 3H)-one (500 mg, 95%) as a white solid. LCMS (ESI) m/z: [M+H] + 313.9. [01074] Step 7: To a solution of (R)-8-(1-aminoethyl)-6-chloro-3-methyl-2-phenylquinazolin-4( 3H)-one (500 mg, 1.59 mmol) in DMSO (7 mL) were added methyl 6-chloro-3-fluoropicolinate (600 mg, 3.18 mmol) and DIPEA (0.6 mL) at RT. The resulting mixture was stirred at 100 °C overnight. Water (40 mL) was added and the mixture was extracted with EtOAc (100 mL×3), the combined organic phase was washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford methyl (R)-6-chloro-3-((1-(6-chloro-3-methyl-4-oxo-2- phenyl-3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinate (450 mg, 58%) as a yellow solid. LCMS (ESI) m/z: [M+H] + 482.8 [01075] Step 8: To a solution methyl (R)-6-chloro-3-((1-(6-chloro-3-methyl-4-oxo-2-phenyl-3,4- dihydroquinazolin-8-yl)ethyl)amino)picolinate (450 mg, 0.93 mmol) in MeOH (2 mL) and THF (4 mL) were added LiOH (134 mg, 5.58 mmol) and H 2 O (1 mL) at RT. The resulting mixture was stirred at 50 °C for 2 h. Cooling to RT, the mixture was adjusted to pH = 5-6 with 1 M HCl and extracted with DCM (150 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by Prep-HPLC (Method B) to give (R)-6-chloro-3-((1-(6-chloro-3-methyl-4-oxo-2-phenyl-3,4-dih ydroquinazolin-8- yl)ethyl)amino)picolinic acid (262.4 mg, 61%) as a white solid. LCMS (ESI) m/z: [M+H] + 469.2 EXAMPLE 146 (R)-3,6-dimethyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl )-2-phenylquinazolin-4(3H)-one [01076] Step 1: To a solution of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-phenylquinazolin-4(3H)-o ne (100 mg, 0.341 mmol) in dioxane (4 mL) were added 1-bromo-2-(methylsulfonyl)benzene (150 mg, 0.638 mmol), BINAP (65 mg, 0.104 mmol), Cs 2 CO 3 (333 mg, 1.023 mmol) and Pd2(dba)3 (65 mg, 0.071 mmol) at RT. The mixture was stirred at 120 °C for 40 h under N 2 . The mixture was purified by silica gel column chromatography (PE:EA= 2:1) and Prep-HPLC (method A) to afford (R)-3,6-dimethyl-8-(1-((2-(methylsulfonyl)phenyl)amino)ethyl )-2- phenylquinazolin-4(3H)-one (10.3 mg, 6.7 %) as a white solid. LCMS: (M + H) + =448.3 EXAMPLE 147 (R)-2-((1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydroquinazolin -8-yl)ethyl)amino)-6-fluorobenzoic acid [01077] Step 1: To a mixture of 2-fluoro-6-iodobenzoic acid (1 g, 3.76 mmol) in DMF (10 ml) were added CH 3 I (0.801 g, 5.64 mmol) and K 2 CO 3 (1.56 g, 11.3 mmol). The mixture was stirred at RT overnight. H 2 O (100 mL) was added and the mixture was extracted with EtOAc (50 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography (PE: EA= 10:1) to afford methyl 2-fluoro-6-iodobenzoate (1 g, 95.0%) as a yellow oil. LCMS: (M + H) + =281.1 [01078] Step 2: To a mixture of (R)-8-(1-aminoethyl)-3,6-dimethyl-2-phenylquinazolin-4(3H)-o ne (250 mg, 0.853 mmol) in dioxane (5 mL) were added methyl 2-fluoro-6-iodobenzoate (477.8 mg, 1.706 mmol), Pd2(dba)3 (156.3 mg, 0.171 mmol), Xant-phos (98.6 mg, 0.171 mmol) and Cs 2 CO 3 (556.3 mg, 1.706 mmol) at RT, then the mixture was heated to 100 °C and stirred overnight. Cooled to RT, H 2 O (100 mL) was added to the mixture and the mixture was extracted with EtOAc (40 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography (PE: EA = 5:1) to afford methyl (R)-2-((1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydroquinazolin -8-yl)ethyl)amino)-6-fluorobenzoate (130 mg, 34.2%) as a yellow solid. LCMS: (M + H) + = 446.3 [01079] Step 3: To a solution of methyl (R)-2-((1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydroquinazolin -8- yl)ethyl)amino)-6-fluorobenzoate (130 mg, 0.292 mmol) in THF (5 mL) and H 2 O (1 mL) was added LiOH (61.3 mg, 1.461 mmol). The mixture was stirred at 50 °C for 3 h. The mixture was adjusted to pH 4-5 with 1 M HCl and extracted with DCM (30 mL*3), the combined organic phase was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by Pre-HPLC (Method B) to afford (R)-2-((1-(3,6-dimethyl-4-oxo-2- phenyl-3,4-dihydroquinazolin-8-yl)ethyl)amino)-6-fluorobenzo ic acid (39.0 mg, 31.0%) as a white solid. LCMS: (M + H) + = 432.1 EXAMPLE 148 (R)-3-((1-(2-(1H-indol-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroq uinazolin-8-yl)ethyl)amino)-6-chloropicolinic acid [01080] Step 1: To a solution of 2-amino-3-bromo-N,5-dimethylbenzamide (7 g, 28.9 mmol) in DMSO (100 mL) was added 1H-indole-2-carbaldehyde (6.3 g, 43.35 mmol) at RT. The resulting mixture was heated to 130 °C and stirred for 16 h under O 2 . The mixture was cooled to RT, and water (500 mL) was added. The mixture was extracted with EtOAc (250 mL×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by silica gel column chromatography (PE: DCM=3:1) to give 8-bromo-2-(1H-indol-2-yl)-3,6-dimethylquinazolin-4(3H)-one (4 g, 38%) as a white solid. LCMS (ESI) m/z: [M+H] + 368.0 [01081] Step 2: To a solution of 8-bromo-2-(1H-indol-2-yl)-3,6-dimethylquinazolin-4(3H)-one (4 g, 10.9 mmol) in dioxane (100 mL) were added tributyl(1-ethoxyvinyl)stannane (7.8 g, 21.8 mmol) and Pd(PPh 3 ) 2 Cl 2 (764 mg, 1.09 mmol) at RT. The resulting mixture was heated to 95 °C and stirred for 12 h under N 2 . HCl (11 mL, 1 M) was added to the mixture and stirred at 50 °C for 0.5 hour. Saturated KF (200 mL) was added and the resulting mixture was stirred at RT for 0.5 hour. The gray suspension was filtered. The filter cake was washed with EtOAc (150 mL×3). The aqueous phase was extracted with EtOAc (200 mL×3) and the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by silica gel column chromatography (PE: EA=4:1) to give 8-acetyl-2-(1H-indol-2-yl)-3,6-dimethylquinazolin-4(3H)-one (3 g, 83%) as a white solid. LCMS (ESI) m/z: [M+H] + 332.1 [01082] Step 3: To a solution of 8-acetyl-2-(1H-indol-2-yl)-3,6-dimethylquinazolin-4(3H)-one (3 g, 9.1 mmol) in Ti(i-PrO) 4 (80 mL) was added and (R)-2-methylpropane-2-sulfinamide (2.19 g, 18.1 mmol) at RT. The resulting mixture was heated to 75 °C and stirred for 12 h. Brine (80 mL) was added to the mixture. The suspension was filtered. The filter cake was washed with EtOAc (120 mL×3). The aqueous phase was extracted with EtOAc (250 mL×3) and the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue. The residue was purified by silica gel column chromatography (PE: EA=10:1) to give (R,Z)-N- (1-(2-(1H-indol-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazol in-8-yl)ethylidene)-2-methylpropane-2-sulfinamide (1 g, 25%) as a white solid. LCMS (ESI) m/z: [M+H] + 435.1 [01083] Step 4: To a solution of (R,Z)-N-(1-(2-(1H-indol-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydro quinazolin-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (1 g, 2.3 mmol) and CeCl 3 .7H 2 O (427 mg, 1.2 mmol) in MeOH (50 mL) added NaBH 4 (700 mg, 18.4 mmol) in portions at -78 °C. The resulting mixture was warmed to RT and stirred overnight. The mixture was quenched with saturated aqueous NH 4 Cl (250 mL) solution and extracted with DCM (250 mL x 2). The combined extract was washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give a residue which was purified by Prep-HPLC (Method A) to give (R)-N-((R)-1-(2-(1H-indol-2-yl)-3,6- dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpro pane-2-sulfinamide (400 mg, 40%) as a white solid. LCMS (ESI) m/z: [M+H] + 437.1 [01084] Step 5: A mixture -N-((R)-1-(2-(1H-indol-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroq uinazolin-8-yl)ethyl)-2- methylpropane-2-sulfinamide (400 mg, 0.91 mmol) in a solution of HCl in MeOH (3M, 8 mL) was stirred at RT for 15 minutes. The mixture was adjusted to pH 9 with saturated aqueous NaHCO 3 solution and the mixture was extracted with DCM (250 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give the crude (R)-8-(1-aminoethyl)-2-(1H-indol-2-yl)-3,6- dimethylquinazolin-4(3H)-one (300 mg, 98%) as a white solid. LCMS (ESI) m/z: [M+H] + 333.3 [01085] Step 6: To a solution of (R)-8-(1-aminoethyl)-2-(1H-indol-2-yl)-3,6-dimethylquinazoli n-4(3H)-one (100 mg, 0.3 mmol) in DMSO (2 mL) was added methyl 6-chloro-3-fluoropicolinate (114 mg, 0.6 mmol) and DIPEA (0.2 mL) at RT. The resulting mixture was stirred at 100 °C overnight. The mixture was diluted with water (30 mL) and extracted with EtOAc (70 mL×3). Tthe combined organics were washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give methyl (R)-3-((1-(2-(1H-indol-2-yl)-3,6-dimethyl-4-oxo- 3,4-dihydroquinazolin-8-yl)ethyl)amino)-6-chloropicolinate (150 mg, 99%) as a yellow solid. LCMS (ESI) m/z: [M+H] + 502.2 [01086] Step 7: To a solution of methyl (R)-3-((1-(2-(1H-indol-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroq uinazolin-8- yl)ethyl)amino)-6-chloropicolinate (150 mg, 0.3 mmol) in THF (4 mL) and H 2 O (1 mL) was added LiOH (29 mg, 1.2 mmol) at RT, The resulting mixture was stirred at the 45 °C for 2 h. The mixture was adjusted to pH 4 with 1 M HCl solution extracted with DCM (40 mL x 3), the combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to provide a residue which was purified by Prep-HPLC (Method B) to give (R)- 3-((1-(2-(1H-indol-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquina zolin-8-yl)ethyl)amino)-6-chloropicolinic acid (30.3 mg, 20%) as a white solid. LCMS (ESI) m/z: [M+H] + 488.3 [01087] The following compounds were prepared by methods similar to the procedures described above: EXAMPLE 158 [01088] Step 1: To a mixture of (R)-N-((R)-1-(2-amino-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (3 g, 7.89 mmol), 2-bromo-1H-imidazole (1.73 g, 11.84 mmol) and K 2 CO 3 (2.18 g, 15.78 mmol) in 1.4-dioxane (40 ml) and H 2 O (8 ml) was added Pd(dppf)Cl 2 (1.15 g, 1.58 mmol), the mixture was stirred at 100 °C under N 2 for 16 h. DCM (200 ml) was added and the gray suspension was filtered, the filter cake was washed with DCM (30 ml*3), the separated organic phase was concentrated to afford crude (R)-N-((R)-1-(2-amino-3-(1H-imidazol-2-yl)-5-methylphenyl)et hyl)-2-methylpropane-2-sulfinamide (2.52 g, 100%, purify: 51% (254 nm)) as a black oil for the next step without further purification. LCMS: (M + H) + = 321.3. [01089] Step 2: To a solution of (R)-N-((R)-1-(2-amino-3-(1H-imidazol-2-yl)-5-methylphenyl)et hyl)-2- methylpropane-2-sulfinamide (2.52 g, 7.89 mmol) in DMF (25 ml) was added 1,1,1-triethoxypropane (6.94 g, 39.45 mmol), the mixture was stirred at 100 °C for 16 h. EA (150 ml) was added. The mixture was washed with brine (150 ml * 2), the organic phase was dried over anh. Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (PE: MeCN= 2: 1) to afford (R)-N-((R)-1-(5-ethyl-9-methyl-imidazo[1,2- c]quinazolin-7-yl)ethyl)-2-methylpropane-2-sulfinamide (750 mg, 27%) as a white solid. LCMS: (M + H) + = 359.4. [01090] Step 3: A mixture of (R)-N-((R)-1-(5-ethyl-9-methylimidazo[1,2-c]quinazolin-7-yl) ethyl)-2-methylpropane- 2-sulfinamide (220 mg, 0.61 mmol) in HCl (3 M in MeOH) (5 ml) was stirred at RT for 0.5 hour. The reaction mixture was concentrated to afford (R)-1-(5-ethyl-9-methylimidazo[1,2-c]quinazolin-7-yl)ethanam ine (150 mg, 97%) as a yellow solid. LCMS: (M + H) + = 255.3. [01091] Step 4: To a mixture of (R)-1-(5-ethyl-9-methylimidazo[1,2-c]quinazolin-7-yl)ethanam ine (150 mg, 0.59 mmol) and methyl 6-chloro-3-fluoropicolinate (167 mg, 0.89 mmol) in DMSO (5 ml) was added DIPEA (228 mg, 1.77 mmol), the mixture was stirred at 100 °C for 16 h. EA (50 ml) was added. The mixture was washed with brine (50 ml * 2). The organic phase was dried over anh. Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (PE: EA= 2: 1) to afford (R)-methyl 6-chloro-3-(1-(5-ethyl-9-methyl- imidazo[1,2-c]quinazolin-7-yl)ethylamino)picolinate (220 mg, 88%) as a white solid. LCMS: (M + H) + = 424.3. [01092] Step 5: A solution of (R)-methyl 6-chloro-3-(1-(5-ethyl-9-methylimidazo[1,2-c]quinazolin-7- yl)ethylamino)picolinate (680 mg, 1.61 mmol) in MeCN (15 ml) was stirred at 0 °C, NBS (286 mg, 1.61 mmol) was added. The mixture was stirred at 0 °C for 2 h. The mixture was concentrated and purified by silica gel column chromatography (DCM: EA= 5: 1) to afford (R)-methyl 3-(1-(2-bromo-5-ethyl-9-methylimidazo[1,2- c]quinazolin-7-yl)ethylamino)-6-chloropicolinate (650 mg, 81 %) as a yellow solid. LCMS: (M + H) + = 502.2. [01093] Step 6: To a solution of (R)-methyl 3-(1-(2-bromo-5-ethyl-9-methylimidazo[1,2-c]quinazolin-7- yl)ethylamino)-6-chloropicolinate (60 mg, 0.12 mmol) in NMP (3 ml) were added ), DMAP (29 mg, 0.24 mmol) and CuCN (14 mg, 0.12 mmol), the mixture was stirred at 150 °C for 2 h. Water (20 ml) was added and the mixture was extracted with EA (20 ml*3). The combined organic phase was washed with brine, dried over anh. Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography (PE: EA= 2: 1) to afford (R)-methyl 6-chloro-3-(1-(2-cyano-5-ethyl-9-methylimidazo[1,2-c]quinazo lin-7-yl)ethylamino)picolinate (25 mg, 46 %) as a white solid. LCMS: (M + H) + = 449.3. [01094] Step 7: To a solution of (R)-methyl 6-chloro-3-(1-(2-cyano-5-ethyl-9-methylimidazo[1,2-c]quinazo lin-7- yl)ethylamino)picolinate (25 mg, 0.06 mmol) in THF (5 ml) and H 2 O (1ml) was added LiOH (7.2 mg, 0.3 mmol), the mixture was stirred at 50 °C for 1 h. The reaction mixture was adjusted pH= 5 - 6 with HCl (1 M) and concentrated, the residue was purified by Pre-HPLC (Method B) to afford (R)-6-chloro-3-(1-(2-cyano-5-ethyl-9- methylimidazo[1,2-c]quinazolin-7-yl)ethylamino)picolinic acid (5.0 mg, 19%) as a white solid. LCMS: (M + H) + = 435.1. EXAMPLE 220 Assay for PI3K-Alpha kinase (PIK3CA) activity, wild-type and H1047R mutant inhibitors: [01095] PI3Kα(p110a/p85a) [Invitrogen] and BTN-PIK3CA[H1047R]/PIK3R1 mutant [Carna] were used in an ADP-Glo Kinase Assay. The enzyme stocks were diluted in 1x kinase buffer at 2-fold the final concentration of each reagent in the assay. Compounds were diluted to 100X of the final desired highest inhibitor concentration with DMSO. Compound [100 µL] was transferred to wells in a 96-well source plate [Corning 3365]. An intermediate dilution plate was prepared by transferring compound [40 µL] from first plate to a new 384-well plate. Assay reaction plates were prepared by transferring 50 nL from intermediate compounds late to assay plate [Echo] in DMSO. Kinase solution was added to each well of the assay plate, except for control wells without enzyme where kinase buffer [2.5 µL] was added instead. The solutions were mixed by plate shaking. A PIP2 substrate solution was prepared by adding PIP2 [Life Technologies] and ATP in 1x kinase reaction buffer at 2-fold of the final concentration of each reagent desired in the assay. The substrate solution [2.5 µL] was added to each well of the assay plate to start the reaction. The reaction was mixed by shaking. The assay plate was covered and reacted at RT for 1 hour. The RT ADP-Glo reagent [5 µL] was added to each well. The plates were mixed and shaken slowly to stop the reaction and the plates. After equilibrating for 2 hours, the Kinase Detection reagent [10 µL] was added to the wells and mixed. After 30 minutes the plates were read for luminescence [RLU] on the Envision instrument. Percent inhibition values were calculated. Percent inhibition = (RLU max – RLU sample /RLU DMSOcontrol -RLU no_enzyme . The present inhibition data was fit with XLFit Excel to obtain IC 50 values (Y=Bottom + (Top-Bottom) / 1 + IC 50 /X) ^HillSlope) which were recorded in Tables 1 and 3. Table 1. EXAMPLE 221 Cellular Assay for Mutant PI3Ka H1047R in MDA-MB-453 Cells [01096] MDA-MB-453 breast cancer cells (ATCC) were cultured in Dulbecco’s modified Eagle’s medium (DMEM, Gibco) + 10% FBS (Fetal Bovine Serum, Gibco) + 5% Penicillin-Streptomycin (Gibco), at 37°C with 5% CO 2 . The assay was run per manufacturer’s protocol (Protocol for AlphaScreen® SureFire® Akt 1/2/3 (p- Thr308) Assay Kits (perkinelmer.com). Buffers were prepared as follows: Lysis Buffer – Diluted 5X Lysis Buffer in deionized water to a final concentration of 1X. Acceptor Mix – Diluted Activation Buffer 25-fold in combined Reaction Buffer 1 and Reaction Buffer 2. Diluted Acceptor Beads 50-fold in combined Reaction Buffers. Donor Mix: Diluted Donor Beads 50-fold in Dilution Buffer. Positive Control Lysate: Reconstitute with 250 µL deionized water. [01097] Cells were plated (60k/well, 100 µL of cells) in a 96 well plate. And incubated at 37°C overnight in serum-containing media. Compound was first diluted to 10 mM in DMSO then diluted in a 3-fold dilution scheme, starting at 10 µM and ending with 0.17 nM. Dilutions were done in a 96 well Costar clear flat bottom plate (Corning). The culture media was removed and replaced with 45 µL of inhibitors prepared at 1X in serum-free media then incubated at 37°C for 2 hrs. The media was removed from the wells and fresh 1 X Lysis Buffer (50 µL) was added. The plates were shaken on a plate shaker for 10 minutes or until all the cells were lysed. The lysates (10 µL) were transferred into the white 384 OptiPlate (Corning). Acceptor Mix (5 µL) was added to wells and mixed. The plates were sealed with Topseal-A adhesive film, covered with foil, and incubated for 1 hour at room temperature. Donor Mix (5 µL) was added to wells under subdued light and mixed. Seal plate with Topseal-A adhesive film, and cover plate with foil. Incubate for 1 hour at room temperature in the dark. Values were measured with the AlphaLISA protocol settings on the Envision. Data was normalized and IC 50 values were calculated with Prism and recorded in Tables 2-3. Table 2. Cellular Assay for Mutant PI3Ka H1047R in MDA-MB-453 Cells Table 3. Cellular Assay for Mutant PI3Ka H1047R in MDA-MB-453 Cells [01098] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes. [01099] The details of one or more embodiments of the disclosure are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. EMBODIMENTS [01100] The following non-limiting embodiments provide illustrative examples of the invention, but do not limit the scope of the invention. 1. A compound, or a pharmaceutically acceptable salt thereof, of Formula 1A, 1B, 1C or 1D: wherein: X 1 , X 2 , and X 3 is each independently -CR 5 - or -N-; X 5 is a carbon atom when a double bond is attached or is -CR 5 - or -N- when a single bond is attached; R is oxo or -OR x ; R x is H, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; or R together with R 2 and the carbon and nitrogen to which they are attached forms a 5-6 membered heteroaryl ring; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , - C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , NR 1a S(O) 2 R 1a ; -S(O) 2 R 1a , aralkyl, heteroarylalkyl, heterocyclylalkyl, C 3-8 -cycloalkyl-alkyl, aryl, C 4 - 8 -cycloalkenyl, C 3-8 -cycloalkyl, 4-10 membered oxygen containing heterocyclyl; nitrogen containing heteroaryl, and nitrogen containing heterocyclyl; wherein the aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, aryl, aralkyl, C 3-8 -cycloalkyl and C 1 - C 6 hydroxyalkyl; R 1a and R 1b are each independently selected from H, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, aryl, heteroaryl, heterocyclyl and C 3 - 8 -cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and –(CH 2 ) n -SO 2 R 7 ; wherein when R 1 is -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , two R 1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, which is substituted with 0, 1, 2, or 3 substituents independently selected from halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and –(CH 2 ) n -SO 2 R 7 ; R 2 is selected from H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 - C 6 alkoxy, C 1 -C 6 alkylsulfonyl, C 1 -C 6 hydroxyalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, C 3-8 -cycloalkyl-alkyl, aryl, heteroaryl, heterocyclyl, C 3-8 -cycloalkyl, alkylaminoalkyl, aminoalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl and alkylaminocarbonylalkyl; or R together with R 2 and the atoms to which they are attached forms a 5-6 membered ring; or when R is oxo, R 1 and R 2 together with the atoms to which they are attached can form a heterocyclyl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 - C 4 haloalkoxy, and -SO 2 R 7 ; R 3 is selected from H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 - C 6 alkoxy, C 1 -C 6 alkylsulfonyl, C 1 -C 6 hydroxyalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, C 3 - 8 -cycloalkyl-alkyl, aryl, heteroaryl, heterocyclyl, C 3 - 8 -cycloalkyl, alkylaminoalkyl, aminoalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, and alkylaminocarbonylalkyl; L is a bivalent group selected from C 1 -C 6 alkylene, -NH-C 1 -C 6 alkylene, -C 1 -C 6 alkylene-NH-, -N(CH 3 )- C 1 -C 6 alkylene, -C 1 -C 6 alkylene-N(CH 3 )-, C 3 -C 10 cycloalkyl, 5-10 membered heteroaryl and 5-6 membered heterocyclyl, wherein the alkylene group is optionally substituted with 1-6 substituents independently selected from halo, cyano and C 1 -C 6 alkoxy; A is selected from 5-6 membered heterocyclyl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl and aryl; R 4 is selected from H, –(CH 2 ) n -C(O)OR 7 , -(CH 2 ) n -C(O)N(R 7 ) 2 , -(CH 2 ) n -C(O)NHR 7 , -(CH 2 ) n -C(O)NHOR 7 , -(CH 2 ) n -SO 2 R 7 , -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 and heteroaryl, wherein the heteroaryl is substituted with 0, 1, 2, or 3 substituents independently selected from halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 - C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and –(CH 2 ) n -SO 2 R 7 ; R 5 is selected from H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 - C 6 alkoxy, C 1 -C 6 alkylsulfonyl, C 1 -C 6 hydroxyalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaminoalkyl, aminoalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, and alkylaminocarbonylalkyl; Each R 6 is independentlyselected from oxo, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 - C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, -(CH 2 ) n -OR 7 , -(CH 2 ) n -N(R 7 ) 2 , -(CH 2 ) n -C(O)R 7 , -(CH 2 ) n -C(O)OR 7 , - (CH 2 ) n -C(O)N(R 7 ) 2 , -(CH 2 ) n -SO 2 R 7 , C 3 -C 10 cycloalkyl, 5-10 membered heterocyclyl, -(CH 2 ) n -aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl is substituted with 0, 1, 2, or 3 substituents independently selected from with halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 - C 6 alkoxy, C 1 -C 6 haloalkoxy, and–(CH 2 ) n -SO 2 R 7 ; Each R 7 is independently selected from H, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 5-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; and p is 0, 1, 2 or 3; provided that (1) when X 1 and X 2 are each CR 5 , X 3 is N, and R is oxo in Formula 1A or 1B, then R 1 is not morpholino; and (2) when R 2 is 2-cyanobenzyl and R is oxo in Formula 1C, then R 1 is not 3-aminopiperdinyl. 2. The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein R 4 is -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, –(CH 2 ) 1-2 -C(O)OH, -C(O)O-C 1 -C 4 alkyl, –(CH 2 ) 1-2 -C(O)O-C 1 - C 4 alkyl, --C(O)NH 2 , -(CH 2 ) 1-2 -C(O)NH 2 , -C(O)N(C 1 -C 4 alkyl) 2 , -(CH 2 ) 1-2 -C(O)N(C 1 -C 4 alkyl) 2 , -C(O)NHO-C 1 - C 4 alkyl, -C(O)NH-C 1 -C 4 alkyl, -(CH 2 ) 1-2 -C(O)NH-C 1 -C 4 alkyl, C 1 -C 4 alkylsulfonyl, or 5-10 membered nitrogen containing heteroaryl. 3. The compound of Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 4 is - COOH. 4. The compound of any of embodiments 1-3, or a pharmaceutically acceptable salt thereof, wherein each R 6 is independently selected from H, oxo, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 - C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, -(CH 2 ) n -OR 7 , -(CH 2 ) n -N(R 7 ) 2 , -(CH 2 ) n -C(O)R 7 , -(CH 2 ) n -C (O)N(R 7 ) 2 , -(CH 2 ) n - SO 2 R 7 , C 3 - C 10 cycloalkyl, 5-10 membered heterocyclyl, -(CH 2 ) n -aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, or –(CH 2 ) n -SO 2 R 7 ; Each R 7 is independently selected from H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 5-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl Each n is independently 0 or 1; and p is 0 or 1. 5. The compound of any of embodiments 1-3, or a pharmaceutically acceptable salt thereof, wherein each R 6 is selected from H, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, hydroxymethyl, methoxymethyl, methylamino, dimethylamino, methylaminomethyl, dimethylaminomethyl, methylaminocarbonyl, aminocarbonyl, methylsulfonyl, methoxy and cyclopropyl, and p is 1. 6. The compound of any one of embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein each R 2 , R 3 and R 5 is independently selected from H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 hydroxyalkyl, -(CH 2 ) n -OR 7 , -(CH 2 ) n -C(O)R 7 , phenyl- C 1 -C 6 alkyl, 5-6 membered heteroaryl-C 1 -C 6 alkyl, 5-6 membered heterocyclyl- C 1 -C 6 alkyl, C 5 -C 6 cycloalkyl- C 1 -C 6 alkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl, C 5 -C 6 cycloalkyl, C 1 -C 6 alkylamino- C 1 -C 6 alkyl, amino- C 1 -C 6 alkyl, C 1 -C 6 alkoxy- C 1 -C 6 alkyl, carboxy C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonyl C 1 -C 6 alkyl, aminocarbonylalkyl and C 1 -C 6 alkylaminocarbonyl- C 1 -C 6 alkyl; R 7 is selected from H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 5-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl; and n is 0, 1 or 2. 7. The compound of any one of embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from H, cyano, fluoro, chloro, C 1 -C 3 alkyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, -(CH 2 ) n -OR 7 , -(CH 2 ) n -C(O)R 7 , C 3 -C 10 cycloalkyl, phenyl and 5-6 membered heteroaryl; R 7 is selected from methyl, ethyl, cyclohexyl, and phenyl; and n is 0 or 1. 8. The compound of any one of embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from H, fluoro, chloro, cyano, methyl, ethyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy, benzyl, phenyl, and cyclopropyl. 9. The compound of any one of embodiments 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from H, cyano, fluoro, chloro, C 1 -C 3 alkyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, -(CH 2 ) n -OR 7 , -(CH 2 ) n -C(O)R 7 , C 3 -C 6 cycloalkyl, phenyl and 5-6 membered heteroaryl; R 7 is selected from methyl, ethyl, cyclohexyl, and phenyl; and n is 0 or 1. 10. The compound of any one of embodiments 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from H, fluoro, chloro, cyano, methylsulfonyl, hydroxymethyl, methoxy, methyl, trifluoromethyl and cyclopropyl. 11. The compound of any one of embodiments 1 to 10, or pharmaceutically acceptable salt thereof, wherein R 5 is selected from H, cyano, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl. 12. The compound of any one of embodiments 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from H, fluoro, chloro, cyano, methyl, trifluoromethyl, methoxy and cyclopropyl. 13. The compound of any one of embodiments 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R 5 is H. 14. The compound of any one of embodiments 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R together with R 2 and the carbon and nitrogen to which they are attached forms a triazolyl ring. 15. The compound of any one of embodiments 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R is oxo. 16. The compound of any one of embodiments 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R is selected from hydroxy, methoxy, ethoxy, -OCH 2 CF 3 , -OCH 2 CF 2 H, -OCH 2 CFH 2 and -OCF 3 . 17. The compound of any one of embodiments 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from 5-10 membered nitrogen containing heteroaryl, 4-10 membered nitrogen containing heterocyclyl, 4-10 membered oxygen containing heterocyclyl, 6-10 membered aryl, C 4 -C 6 cycloalkenyl and C 3 -C 6 cycloalkyl; wherein the nitrogen containing heteroaryl, nitrogen containing heterocyclyl, aryl, cycloalkenyl or cycloalkyl is substituted with 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 -C 3 alkyl, C 1 - C 2 haloalkyl, C 1 - C 4 alkoxy, hydroxy, phenyl, aralkyl, C 3-6 -cycloalkyl and C 1 -C 3 hydroxyalkyl. 18. The compound of any one of embodiments 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from 1-piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, 2-tetrahydroisoquinolinyl, 2- tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1- imidazolidinyl, 2-tetrahydronaphthyridinyl, 2-isoindolinyl, dihydroindolyl, 2-tetrahydroisoquinolinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, oxetanyl, tetrahydrofuranyl, and 1-azetidinyl; wherein R 1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, methyl,, difluoromethyl, trifluormethyl,, hydroxy, methoxy, ethoxy, , methylsulfonyl, carboxyl, amino, dimethylamino, Boc, and a ring independently selected from morpholinyl, pyrazolyl, 1-methyl-4-pyrazolyl, benzyl, phenyl, 3-pyridinyl, pyrimidinyl, 2-methoxy-4-pyrmidinyl, 5-methoxy-4- pyrmidinyl, 1,3,6-triazanaphth-5-yl, 1-thia-4,6-diazainden-7-yl and cyclopropyl, wherein the ring is unsubstituted or substituted. 19. The compound of any one of embodiments 1 to 16, wherein R 1 is selected from pyridyl, pyrimidinyl, pyrazolyl, thienyl, oxazolyl, thiazolyl, imidazolyl, quinolinyl, 2-isoindolyl, indolyl, indazolyl, benzothiazolyl, benzofuryl, phenyl and naphthyl, cyclohexenyl, cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, and cyclohexyl; wherein the ring has one, two or three substituents independently selected from halo, cyano, C 1 - C 3 alkyl, C 1 -C 2 haloalkyl, C 1 - C 4 alkoxy, hydroxy, phenyl, aralkyl, C 3-6 -cycloalkyl and hydroxy-C 1 -C 3 alkyl. 20. The compound of any one of embodiments 1 to 16, wherein R 1 is selected from C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 1 -C 3 haloalkyl, -OR 1a , -SR 1a , - NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , -OC(O)R 1a , -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , -NR 1a S(O) 2 R 1a ; -S(O) 2 R 1a , benzyl, and pyridylmethyl; each R 1a is independently selected from H, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C 3 - 6 - cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 - C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -(CH 2 ) n -SO 2 R 7 ; each R 1b is independently selected from H, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C 3-6 - cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -(CH 2 ) n -SO 2 R 7 ; and when R 1 is - C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , or NR 1a S(O) 2 NR 1b R 1b , two R 1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 0, 1, 2, or 3 substituents independently selected from halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 - C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 . 21. The compound of any one of embodiments 1 to 20, or a pharmaceutically acceptable salt thereof, wherein L is selected from -NH-C 1 -C 4 alkylene, and -C 1 -C 4 alkylene-NH-; wherein each alkylene group is optionally substituted with 1-4 substituents independently selected from halo, cyano and C 1 -C 2 alkoxy. 22. The compound of any one of embodiments 1 to 20, or a pharmaceutically acceptable salt thereof, wherein L is C 3 -C 10 cycloalkyl, 5-10 membered heteroaryl or 5-6 membered heterocyclyl. 23. The compound of any one of embodiments 1 to 22, or a pharmaceutically acceptable salt thereof, wherein A is 5-10 membered heteroaryl, or phenyl. 24. The compound of any one of embodiments 1 to 22, or a pharmaceutically acceptable salt thereof, wherein A is selected from phenyl, pyridyl, benzothienyl, pyrazinyl and pyrimidinyl. 25. The compound of any one of embodiments 1 to 24, or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 are each -CR 5 - and X 3 is N. 26. The compound of any one of embodiments 1 to 24, or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 are each -N- and X 3 is N. 27. The compound of any one of embodiments 1 to 24, or a pharmaceutically acceptable salt thereof, wherein X 1 is -CR 5 -, X 2 is -N- and X 3 is N. 28. The compound of any one of embodiments 1 to 24, or a pharmaceutically acceptable salt thereof, wherein X 1 is -N-, X 2 is -CR 5 - and X 3 is N. 29. The compound of any one of embodiments 1 to 24, or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 are each -CR 5 - and X 3 is -CR 5 -. 30. The compound of any one of embodiments 1 to 24, or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 are each -N- and X 3 is -CR 5 -. 31. The compound of any one of embodiments 1 to 24, or a pharmaceutically acceptable salt thereof, wherein X 1 is -CR 5 -, X 2 is -N- and X 3 is -CR 5 -. 32. The compound of any one of embodiments 1 to 24, or a pharmaceutically acceptable salt thereof, wherein X 1 is -N-, X 2 is -CR 5 - and X 3 is -CR 5 -. 33. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, selected from: 2-((1-(3-methyl-4-oxo-2-(piperidin-1-yl)-3,4-dihydrothieno[3 ,2-d]pyrimidin-7-yl)ethyl)amino)benzoic acid; 2-((1-(7-methyl-4-oxo-2-(piperidin-1-yl)-4H-pyrido[1,2-a]pyr imidin-9-yl)ethyl)amino)benzoic acid; 6-chloro-3-((1-(3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4-di hydroquinazolin-8-yl)ethyl)amino)picolinic acid; 2-((1-(3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4-dihydroquin azolin-8-yl)ethyl)amino)benzamide; 2-((1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydroquinazolin-8-y l)ethyl)amino)benzoic acid; 2-((1-(2-(4,4-difluoropiperidin-1-yl)-6-methoxy-3-methyl-4-o xo-3,4-dihydropyrido[3,2-d]pyrimidin-8- yl)ethyl)amino)benzoic acid; o-(1-{12-Methyl-7-piperidino-3,4,6,8-tetraazatricyclo[7.4.0. 0 2,6 ]trideca-1(9),2,4,7,10,12-hexaen-10- yl}ethylamino)benzoic acid ; o-{1-[2-(4,4-Difluoro-1-piperidyl)-3-methyl-6-methyl-4-oxo-3 H-1,3,5-triazanaphth-8- yl]ethylamino}benzoic acid; o-[1-(6-Methyl-7-oxo-5-piperidino-6H-1-thia-4,6-diazainden-3 -yl)ethylamino]benzoic acid; o-[1-(2-Methyl-7-methyl-8-oxo-6-piperidino-7H-1,3,5,7-tetraa zanaphth-4-yl)ethylamino]benzoic acid; o-[1-(6-Methyl-4-oxo-2-piperidino-3,8a-dihydro-1,4a-diaza-8- naphthyl)ethylamino]benzoic acid; 6-Chloro-3-{1-[2-(4,4-difluoro-1-piperidyl)-6-methyl-4-oxo-1 ,4a-diaza-8-naphthyl]ethylamino}-2- pyridinecarboxylic acid; 6-Chloro-3-{1-[2-(4,4-difluoro-1-piperidyl)-3-methyl-6-methy l-4-oxo-3H-1,3,7-triazanaphth-8- yl]ethylamino}-2-pyridinecarboxylic acid; o-{1-[2-(1-piperidyl)-3,6-dimethyl-4-oxo-3H-1,3,7-triazanaph th-8-yl]ethylamino}benzoic acid; 6-Chloro-3-{1-[2-(4,4-difluoro-1-piperidyl)-3,6-dimethyl-4-o xo-1,4a-diaza-8-naphthyl]ethylamino}-2- pyridinecarboxylic acid; o-{1-[2-(1-piperidyl)-3,6-dimethyl-4-oxo-1,4a-diaza-8-naphth yl]]ethylamino}benzoic acid; 2-((1-(3,6-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4-dihydroquin azolin-8-yl)ethyl)amino)benzoic acid; 3,6-dimethyl-8-(1-(phenylamino)ethyl)-2-(piperidin-1-yl)quin azolin-4(3H)-one; 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4 -dihydroquinazolin-8-yl)ethyl)amino)benzoic acid; and 2-((1-(2-(isoindolin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroqui nazolin-8-yl)ethyl)amino)benzoic acid. 34. The compound of embodiment 1 or pharmaceutically acceptable salt thereof, having a structure of Formula 2a or 2b: Wherein R is oxo; wherein: R is -OR x ; R x is selected from H, methyl, ethyl, -CH 2 CF 3 , CH 2 CF 2 H, CH 2 CFH 2 and CF 3 ; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 2 - C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , - OC(O)R 1a , -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , NR 1a S(O) 2 R 1a ; -S(O) 2 R 1a , benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3-6 -cycloalkyl-C 1 -C 4 alkyl, phenyl, naphthyl, C 5 - C 6 cycloalkenyl, C 3 -C 6 -cycloalkyl, 5-10 membered nitrogen containing heteroaryl, 4-10 membered oxygen containing heterocyclyl and 4-10 membered nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C 1 -C 6 hydroxyalkyl; R 1a and R 1b are each independently selected from H, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C 3-6 - cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; when R 1 is -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , or NR 1a S(O) 2 NR 1b R 1b , two R 1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 2 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; or when R is oxo, R 1 and R 2 together with the nitrogen and carbon atoms to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 - C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 3 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 3 - C 6 cycloalkyl; L is C 1 -C 4 alkylene, -NH-C 1 -C 4 alkylene, or -C 1 -C 4 alkylene-NH-, and the alkylene group is optionally substituted with 1-4 substituents independently selected from halo, cyano and C 1 -C 4 alkoxy; R 4 is selected from H, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, –(CH 2 ) 1-2 -C(O)OH, - C(O)O-C 1 -C 4 alkyl, –(CH 2 ) 1-2 -C(O)O-C 1 -C 4 alkyl, --C(O)NH 2 , -(CH 2 ) 1-2 -C(O)NH 2 , -C(O)N(C 1 -C 4 alkyl) 2 , -(CH 2 ) 1-2 - C(O)N(C 1 -C 4 alkyl) 2 , -C(O)NHO-C 1 -C 4 alkyl, -C(O)NH-C 1 -C 4 alkyl, -(CH 2 ) 1-2 -C(O)NH-C 1 -C 4 alkyl, C 1 - C 4 alkylsulfonyl, and 5-membered nitrogen containing heteroaryl; R 5 is selected from H, halo, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; Each R 6 is independently selected from H, halo, cyano, C 1 -C 4 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl- C 1 -C 4 alkyl, phenyl, heteroaryl, heterocyclyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkylamino- C 1 - C 4 alkyl, amino- C 1 -C 4 alkyl, and C 1 -C 4 alkoxy-C 1 -C 4 alkyl; R 7 is selected from H, C 1 -C 2 alkyl, C 5 -C 6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; and p is 0, 1, 2 or 3. 35. The compound of Embodiment 34 or pharmaceutically acceptable salt thereof, wherein R is oxo or methoxy; R 1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2-hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl-2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2- trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1-piperidinyl, 1-piperazinyl, 2-isoindolyl, 2- isoindolinyl, indolyl, indazolyl, benzothiazolyl, benzofuryl, dihydroindolyl, 2-tetrahydroisoquinolinyl, 2- tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1- imidazolidinyl, 1-azetidinyl, oxetanyl, tetrahydrofuranyl, phenyl, 2-pyridyl, 3-pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, and cyclohexyl; wherein the ring substituent in R 1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, methyl, difluoromethyl, trifluormethyl, hydroxy, methoxy, ethoxy, methylsulfonyl, carboxyl, amino, dimethylamino, Boc, and a ring selected from morpholinyl, pyrazolyl, 1-methyl-4- pyrazolyl, benzyl, phenyl, 3-pyridinyl, pyrimidinyl, 2-methoxy-4-pyrmidinyl, 5-methoxy-4-pyrmidinyl, 1,3,6- triazanaphth-5-yl, 1-thia-4,6-diazainden-7-yl and cyclopropyl, wherein the ring is unsubstituted or substituted; R 2 is selected from H, fluoro, chloro, cyano, methyl, ethyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R 3 is selected from H, fluoro, chloro, cyano, methyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is selected from phenyl, 2-pyridyl, 3-pyridyl, and 1-benzimidazolyl; L is selected from ethylenyl, 1-methylethylenyl, -NH-CH 2 - and -NHCH(CH 3 )- , and wherein the ethylenyl, or - NHCH 2 - group is optionally substituted with 1-4 substituents independently selected from fluoro, cyano and methoxy; R 5 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methoxy and cyclopropyl; R 4 is selected from methylsulfonyl, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, -C(O)O-C 1 -C 4 alkyl, - C(O)NHO-C 1 -C 4 alkyl, -C(O)NH 2 , -C(O)NH-ethyl, -C(O)NH-isopropyl,triazolyl and tetrazolyl; R 6 is selected from H, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and methoxy; and p is 0 or 1. 36, The compound of Embodiment 34 or pharmaceutically acceptable salt thereof, wherein R is oxo; A is benzotriazolyl and R 4 is H. 36. The compound of any of Embodiments 34-35 or pharmaceutically acceptable salt thereof, wherein R 4 is -COOH. 37. The compound of Embodiment 34 or pharmaceutically acceptable salt thereof, wherein R is oxo. 37. The compound of embodiment 1 or pharmaceutically acceptable salt thereof, having a structure of Formula 3a or 3b: Wherein R is oxo wherein: R is -OR x ; R x is selected from H, methyl, ethyl, -CH 2 CF 3 , CH 2 CF 2 H, CH 2 CFH 2 and CF 3 ; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 2 - C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , - OC(O)R 1a , -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , NR 1a S(O) 2 R 1a ; -S(O) 2 R 1a , benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3-6 -cycloalkyl-C 1 -C 4 alkyl, phenyl, naphthyl, C 5 - C 6 cycloalkenyl, C 3 -C 6 cycloalkyl, 5-10 membered nitrogen containing heteroaryl, 4-10 membered oxygen containing heterocyclyl and 4-10 membered nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C 1 -C 6 hydroxyalkyl; R 1a and R 1b are each independently selected from H, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C 3 - 6 - cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; when R 1 is -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , or NR 1a S(O) 2 NR 1b R 1b , two R 1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 2 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; or when R is oxo, R 1 and R 2 together with the nitrogen and carbon atoms to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 - C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 3 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 3 - C 6 cycloalkyl; L is C 1 -C 4 alkylene, -NH-C 1 -C 4 alkylene, or -C 1 -C 4 alkylene-NH-, and the alkylene group is optionally substituted with 1-4 substituents independently selected from halo, cyano and C 1 -C 4 alkoxy; R 4 is selected from -H, SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, –(CH 2 ) 1-2 -C(O)OH, - C(O)O-C 1 -C 4 alkyl, –(CH 2 ) 1-2 -C(O)O-C 1 -C 4 alkyl, --C(O)NH 2 , -(CH 2 ) 1-2 -C(O)NH 2 , -C(O)N(C 1 -C 4 alkyl) 2 , -(CH 2 ) 1-2 - C(O)N(C 1 -C 4 alkyl) 2 , -C(O)NHO-C 1 -C 4 alkyl, -C(O)NH-C 1 -C 4 alkyl, -(CH 2 ) 1-2 -C(O)NH-C 1 -C 4 alkyl, C 1 - C 4 alkylsulfonyl, and 5-membered nitrogen containing heteroaryl; R 5 is selected from H, halo, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; Each R 6 is independently selected from H, halo, cyano, C 1 -C 4 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl- C 1 -C 4 alkyl, phenyl, heteroaryl, heterocyclyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkylamino- C 1 - C 4 alkyl, amino- C 1 -C 4 alkyl, and C 1 -C 4 alkoxy-C 1 -C 4 alkyl; R 7 is selected from H, C 1 -C 2 alkyl, C 5 -C 6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; and p is 0, 1, 2 or 3. 38. The compound of Embodiment 37 or pharmaceutically acceptable salt thereof, wherein R is oxo or methoxy; R 1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2-hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl-2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2- trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1-piperidinyl, 1-piperazinyl, 2-isoindolyl, 2- isoindolinyl, indolyl, indazolyl, benzothiazolyl, benzofuryl, dihydroindolyl, 2-tetrahydroisoquinolinyl, 2- tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1- imidazolidinyl, 1-azetidinyl, oxetanyl, tetrahydrofuranyl, phenyl, 2-pyridyl, 3-pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, and cyclohexyl; wherein the ring substituent in R 1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, methyl, difluoromethyl, trifluormethyl, hydroxy, methoxy, ethoxy, methylsulfonyl, carboxyl, amino, dimethylamino, Boc, and a ring selected from morpholinyl, pyrazolyl, 1-methyl-4- pyrazolyl, benzyl, phenyl, 3-pyridinyl, pyrimidinyl, 2-methoxy-4-pyrmidinyl, 5-methoxy-4-pyrmidinyl, 1,3,6- triazanaphth-5-yl, 1-thia-4,6-diazainden-7-yl and cyclopropyl, wherein the ring is unsubstituted or substituted; R 2 is selected from H, fluoro, chloro, cyano, methyl, ethyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R 3 is selected from H, fluoro, chloro, cyano, methyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is selected from phenyl, 2-pyridyl, 3-pyridyl, and 1-benzimidazolyl; L is selected from ethylenyl, 1-methylethylenyl, -NH-CH 2 - and -NHCH(CH 3 )- , and wherein the ethylenyl, or - NHCH 2 - group is optionally substituted with 1-4 substituents independently selected from fluoro, cyano and methoxy; R 5 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methoxy and cyclopropyl; R 4 is selected from methylsulfonyl, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, -C(O)O-C 1 -C 4 alkyl, - C(O)NHO-C 1 -C 4 alkyl, -C(O)NH 2 , -C(O)NH-ethyl, -C(O)NH-isopropyl,triazolyl and tetrazolyl; R 6 is selected from H, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and methoxy; and p is 0 or 1. 39. The compound of any of Embodiments 38-39 or pharmaceutically acceptable salt thereof, wherein R 4 is -COOH. 40. The compound of embodiment 1 or pharmaceutically acceptable salt thereof, having a structure of Formula 4a or 4b: Wherein R is oxo wherein: R is -OR x ; R x is selected from H, methyl, ethyl, -CH 2 CF 3 , CH 2 CF 2 H, CH 2 CFH 2 and CF 3 ; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 2 - C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , - OC(O)R 1a , -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , NR 1a S(O) 2 R 1a ; -S(O) 2 R 1a , benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3-6 -cycloalkyl-C 1 -C 4 alkyl, phenyl, naphthyl, C 5 - C 6 cycloalkenyl, C 3 -C 6 cycloalkyl, 5-10 membered nitrogen containing heteroaryl, 4-10 membered oxygen containing heterocyclyl; and 4-10 membered nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C 1 -C 6 hydroxyalkyl; R 1a and R 1b are each independently selected from H, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C 3-6 - cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; when R 1 is -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , or NR 1a S(O) 2 NR 1b R 1b , two R 1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 2 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; or when R is oxo, R 1 and R 2 together with the nitrogen and carbon atoms to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 - C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 3 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 3 - C 6 cycloalkyl; L is C 1 -C 4 alkylene, -NH-C 1 -C 4 alkylene, or -C 1 -C 4 alkylene-NH-, and the alkylene group is optionally substituted with 1-4 substituents independently selected from halo, cyano and C 1 -C 4 alkoxy; R 4 is selected from H, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, –(CH 2 ) 1-2 -C(O)OH, - C(O)O-C 1 -C 4 alkyl, –(CH 2 ) 1-2 -C(O)O-C 1 -C 4 alkyl, --C(O)NH 2 , -(CH 2 ) 1-2 -C(O)NH 2 , -C(O)N(C 1 -C 4 alkyl) 2 , -(CH 2 ) 1-2 - C(O)N(C 1 -C 4 alkyl) 2 , -C(O)NHO-C 1 -C 4 alkyl, -C(O)NH-C 1 -C 4 alkyl, -(CH 2 ) 1-2 -C(O)NH-C 1 -C 4 alkyl, C 1 - C 4 alkylsulfonyl, and 5-membered nitrogen containing heteroaryl; Each R 6 is independently selected from H, halo, cyano, C 1 -C 4 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl- C 1 -C 4 alkyl, phenyl, heteroaryl, heterocyclyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkylamino- C 1 - C 4 alkyl, amino- C 1 -C 4 alkyl, and C 1 -C 4 alkoxy-C 1 -C 4 alkyl; R 7 is selected from H, C 1 -C 2 alkyl, C 5 -C 6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; and p is 0, 1, 2 or 3. 41. The compound of Embodiment 40 or pharmaceutically acceptable salt thereof, wherein R is oxo or methoxy; R 1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2-hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl-2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2- trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1-piperidinyl, 1-piperazinyl, 2-isoindolyl, 2- isoindolinyl, indolyl, indazolyl, benzothiazolyl, benzofuryl, dihydroindolyl, 2-tetrahydroisoquinolinyl, 2- tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1- imidazolidinyl, 1-azetidinyl, oxetanyl, tetrahydrofuranyl, phenyl, 2-pyridyl, 3-pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, and cyclohexyl; wherein the ring substituent in R 1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, methyl, difluoromethyl, trifluormethyl, hydroxy, methoxy, ethoxy, methylsulfonyl, carboxyl, amino, dimethylamino, Boc, and a ring selected from morpholinyl, pyrazolyl, 1-methyl-4- pyrazolyl, benzyl, phenyl, 3-pyridinyl, pyrimidinyl, 2-methoxy-4-pyrmidinyl, 5-methoxy-4-pyrmidinyl, 1,3,6- triazanaphth-5-yl, 1-thia-4,6-diazainden-7-yl and cyclopropyl, wherein the ring is unsubstituted or substituted; R 2 is selected from H, fluoro, chloro, cyano, methyl, ethyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R 3 is selected from H, fluoro, chloro, cyano, methyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is selected from phenyl, 2-pyridyl, 3-pyridyl, and 1-benzimidazolyl; L is selected from ethylenyl, 1-methylethylenyl, -NH-CH 2 - and -NHCH(CH 3 )- , and wherein the ethylenyl, or - NHCH 2 - group is optionally substituted with 1-4 substituents independently selected from fluoro, cyano and methoxy; R 5 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methoxy and cyclopropyl; R 4 is selected from methylsulfonyl, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, -C(O)O-C 1 -C 4 alkyl, - C(O)NHO-C 1 -C 4 alkyl, -C(O)NH 2 , -C(O)NH-ethyl, -C(O)NH-isopropyl,triazolyl and tetrazolyl; R 6 is selected from H, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and methoxy; and p is 0 or 1. 42. The compound of either Embodiment 40 or 41 or pharmaceutically acceptable salt thereof, wherein R 4 is -COOH. 43. The compound of embodiment 1 or pharmaceutically acceptable salt thereof, having a structure of Formula 5a or 5b: Wherein R is oxo;

wherein: R is -OR x ; R x is selected from H, methyl, ethyl, -CH 2 CF 3 , CH 2 CF 2 H, CH 2 CFH 2 and CF 3 ; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 2 - C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , - OC(O)R 1a , -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , NR 1a S(O) 2 R 1a ; -S(O) 2 R 1a , benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3-8 -cycloalkyl-C 1 -C 4 alkyl, phenyl, naphthyl, C 5 - C 6 cycloalkenyl, C 3 -C 6 cycloalkyl, 5-10 membered nitrogen containing heteroaryl, 4-10 membered oxygen containing heterocyclyl; and 4-10 membered nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C 1 -C 6 hydroxyalkyl; R 1a and R 1b are each independently selected from H, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C 3-6 - cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; when R 1 is -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , or NR 1a S(O) 2 NR 1b R 1b , two R 1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 2 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; or when R is oxo, R 1 and R 2 together with the nitrogen and carbon atoms to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 - C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 3 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 3 - C 6 cycloalkyl; L is C 1 -C 4 alkylene, -NH-C 1 -C 4 alkylene, or -C 1 -C 4 alkylene-NH-, and the alkylene group is optionally substituted with 1-4 substituents independently selected from halo, cyano and C 1 -C 4 alkoxy; R 4 is selected from H, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, –(CH 2 ) 1-2 -C(O)OH, - C(O)O-C 1 -C 4 alkyl, –(CH 2 ) 1-2 -C(O)O-C 1 -C 4 alkyl, --C(O)NH 2 , -(CH 2 ) 1-2 -C(O)NH 2 , -C(O)N(C 1 -C 4 alkyl) 2 , -(CH 2 ) 1-2 - C(O)N(C 1 -C 4 alkyl) 2 , -C(O)NHO-C 1 -C 4 alkyl, -C(O)NH-C 1 -C 4 alkyl, -(CH 2 ) 1-2 -C(O)NH-C 1 -C 4 alkyl, C 1 - C 4 alkylsulfonyl, and 5-membered nitrogen containing heteroaryl; Each R 6 is independently selected from H, halo, cyano, C 1 -C 4 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl- C 1 -C 4 alkyl, phenyl, heteroaryl, heterocyclyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkylamino- C 1 - C 4 alkyl, amino- C 1 -C 4 alkyl, and C 1 -C 4 alkoxy-C 1 -C 4 alkyl; R 7 is selected from H, C 1 -C 2 alkyl, C 5 -C 6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; and p is 0, 1, 2 or 3. 44. The compound of Embodiment 43 or pharmaceutically acceptable salt thereof, wherein R is oxo or methoxy; R 1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2-hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl-2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2- trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1-piperidinyl, 1-piperazinyl, 2-isoindolyl, 2- isoindolinyl, indolyl, indazolyl, benzothiazolyl, benzofuryl, dihydroindolyl, 2-tetrahydroisoquinolinyl, 2- tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1- imidazolidinyl, 1-azetidinyl, oxetanyl, tetrahydrofuranyl, phenyl, 2-pyridyl, 3-pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, and cyclohexyl; wherein the ring substituent in R 1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, methyl, difluoromethyl, trifluormethyl, hydroxy, methoxy, ethoxy, methylsulfonyl, carboxyl, amino, dimethylamino, Boc, and a ring selected from morpholinyl, pyrazolyl, 1-methyl-4- pyrazolyl, benzyl, phenyl, 3-pyridinyl, pyrimidinyl, 2-methoxy-4-pyrmidinyl, 5-methoxy-4-pyrmidinyl, 1,3,6- triazanaphth-5-yl, 1-thia-4,6-diazainden-7-yl and cyclopropyl, wherein the ring is unsubstituted or substituted; R 2 is selected from H, fluoro, chloro, cyano, methyl, ethyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R 3 is selected from H, fluoro, chloro, cyano, methyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is selected from phenyl, 2-pyridyl, 3-pyridyl, and 1-benzimidazolyl; L is selected from ethylenyl, 1-methylethylenyl, -NH-CH 2 - and -NHCH(CH 3 )- , and wherein the ethylenyl, or - NHCH 2 - group is optionally substituted with 1-4 substituents independently selected from fluoro, cyano and methoxy; R 5 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methoxy and cyclopropyl; R 4 is selected from methylsulfonyl, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, -C(O)O-C 1 -C 4 alkyl, - C(O)NHO-C 1 -C 4 alkyl, -C(O)NH 2 , -C(O)NH-ethyl, -C(O)NH-isopropyl,triazolyl and tetrazolyl; R 6 is selected from H, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and methoxy; and p is 0 or 1. 45. The compound of either Embodiment 43 or 44 or pharmaceutically acceptable salt thereof, wherein R 4 is -COOH. 46. The compound of embodiment 1 or pharmaceutically acceptable salt thereof, having a structure of Formula 6a, 6b or 6c: wherein: X 1 , X 2 , X 3 and X 4 is each independently -CR 5 - or -N-; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 2 - C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , - OC(O)R 1a , -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , NR 1a S(O) 2 R 1a ; -S(O) 2 R 1a , benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3 - 8 -cycloalkyl-C 1 -C 4 alkyl, phenyl, naphthyl, C 5 - C 6 cycloalkenyl, C 3 -C 6 cycloalkyl, 5-10 membered nitrogen containing heteroaryl, 4-10 membered oxygen containing heterocyclyl and 4-10 membered nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C 1 -C 6 hydroxyalkyl; R 1a and R 1b are each independently selected from H, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C 3-6 - cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; when R 1 is -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , or NR 1a S(O) 2 NR 1b R 1b , two R 1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 3 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 3 - C 6 cycloalkyl; L is C 1 -C 4 alkylene, -NH-C 1 -C 4 alkylene, or -C 1 -C 4 alkylene-NH-, and the alkylene group is optionally substituted with 1-4 substituents independently selected from halo, cyano and C 1 -C 4 alkoxy; R 4 is selected from H, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, –(CH 2 ) 1-2 -C(O)OH, - C(O)O-C 1 -C 4 alkyl, –(CH 2 ) 1-2 -C(O)O-C 1 -C 4 alkyl, --C(O)NH 2 , -(CH 2 ) 1-2 -C(O)NH 2 , -C(O)N(C 1 -C 4 alkyl) 2 , -(CH 2 ) 1-2 - C(O)N(C 1 -C 4 alkyl) 2 , -C(O)NHO-C 1 -C 4 alkyl, -C(O)NH-C 1 -C 4 alkyl, -(CH 2 ) 1-2 -C(O)NH-C 1 -C 4 alkyl, C 1 - C 4 alkylsulfonyl, and 5-membered nitrogen containing heteroaryl; R 5 is selected from H, halo, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; Each R 6 is independently selected from H, halo, cyano, C 1 -C 4 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl- C 1 -C 4 alkyl, phenyl, heteroaryl, heterocyclyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkylamino- C 1 - C 4 alkyl, amino- C 1 -C 4 alkyl, and C 1 -C 4 alkoxy-C 1 -C 4 alkyl; R 7 is selected from H, C 1 -C 2 alkyl, C 5 -C 6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; R 10 is selected from H, halo, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, benzyl, phenyl, substituted or unsubstituted 5-6 membered heteroaryl, and cyclopropyl; and p is 0, 1, 2 or 3. 47. The compound of Embodiment 46 or pharmaceutically acceptable salt thereof, wherein R 1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2-hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl-2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1-piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, indolyl, indazolyl, benzothiazolyl, benzofuryl, dihydroindolyl, 2-tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, oxetanyl, tetrahydrofuranyl, phenyl, 2-pyridyl, 3-pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, and cyclohexyl; wherein the ring substituent in R 1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, methyl, difluoromethyl, trifluormethyl, hydroxy, methoxy, ethoxy, methylsulfonyl, carboxyl, amino, dimethylamino, Boc, and a ring selected from morpholinyl, pyrazolyl, 1-methyl-4-pyrazolyl, benzyl, phenyl, 3-pyridinyl, pyrimidinyl, 2- methoxy-4-pyrmidinyl, 5-methoxy-4-pyrmidinyl, 1,3,6-triazanaphth-5-yl, 1-thia-4,6-diazainden-7-yl and cyclopropyl, wherein the ring is unsubstituted or substituted; R 2 is selected from H, fluoro, chloro, cyano, methyl, ethyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R 3 is selected from H, fluoro, chloro, cyano, methyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is selected from phenyl, 2-pyridyl, 3-pyridyl, and 1-benzimidazolyl; L is selected from ethylenyl, 1-methylethylenyl, -NH-CH 2 - and -NHCH(CH 3 )- , and wherein the ethylenyl, or -NHCH 2 - group is optionally substituted with 1-4 substituents independently selected from fluoro, cyano and methoxy; R 5 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methoxy and cyclopropyl; R 4 is selected from methylsulfonyl, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , - SO(=NH)CH 3 , -C(O)OH, -C(O)O-C 1 -C 4 alkyl, -C(O)NHO-C 1 -C 4 alkyl, -C(O)NH 2 , -C(O)NH-ethyl, -C(O)NH- isopropyl,triazolyl and tetrazolyl; R 6 is selected from H, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and methoxy; R 10 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, ethenyl, propynyl, methoxy, 1- methyl-3-pyrazolyl, 1-methyl-4-pyrazolyl, and cyclopropyl; X 1 and X 2 are each -CH-; X 3 is -N-; X 4 is -CR 5 - or -N- ; and p is 0 or 1. 48. The compound of either Embodiment 46 or 47 or pharmaceutically acceptable salt thereof, wherein R 4 is -COOH. 49. The compound of embodiment 1 or pharmaceutically acceptable salt thereof, having a structure of Formula 7: wherein: X 1 and X 2 is each independently -CR 5 - or -N-; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 2 - C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , - OC(O)R 1a , -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , NR 1a S(O) 2 R 1a ; -S(O) 2 R 1a , benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3-8 -cycloalkyl-C 1 -C 4 alkyl, phenyl, naphthyl, C 5 - C 6 cycloalkenyl, C 3 -C 6 cycloalkyl, 5-10 membered nitrogen containing heteroaryl, 4-10 membered oxygen containing heterocyclyl; and 4-10 membered nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C 1 -C 6 hydroxyalkyl; R 1a and R 1b are each independently selected from H, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C 3-6 - cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; when R 1 is -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , or NR 1a S(O) 2 NR 1b R 1b , two R 1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 2 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; or R 1 and R 2 together with the nitrogen and carbon atoms to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 3 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 3 - C 6 cycloalkyl; L is C 1 -C 4 alkylene, -NH-C 1 -C 4 alkylene, or -C 1 -C 4 alkylene-NH-, and the alkylene group is optionally substituted with 1-4 substituents independently selected from halo, cyano and C 1 -C 4 alkoxy; R 4 is selected from H, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, –(CH 2 ) 1-2 -C(O)OH, - C(O)O-C 1 -C 4 alkyl, –(CH 2 ) 1-2 -C(O)O-C 1 -C 4 alkyl, --C(O)NH 2 , -(CH 2 ) 1-2 -C(O)NH 2 , -C(O)N(C 1 -C 4 alkyl) 2 , -(CH 2 ) 1-2 - C(O)N(C 1 -C 4 alkyl) 2 , -C(O)NHO-C 1 -C 4 alkyl, -C(O)NH-C 1 -C 4 alkyl, -(CH 2 ) 1-2 -C(O)NH-C 1 -C 4 alkyl, C 1 - C 4 alkylsulfonyl, and 5-membered nitrogen containing heteroaryl; R 5 is selected from H, halo, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; Each R 6 is independently selected from H, halo, cyano, C 1 -C 4 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl- C 1 -C 4 alkyl, phenyl, heteroaryl, heterocyclyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkylamino- C 1 - C 4 alkyl, amino- C 1 -C 4 alkyl, and C 1 -C 4 alkoxy-C 1 -C 4 alkyl; R 7 is selected from H, C 1 -C 2 alkyl, C 5 -C 6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; and p is 0, 1, 2 or 3. 50. The compound of Embodiment 49 or pharmaceutically acceptable salt thereof, wherein R 1 is selected methyl, ethyl, isopropyl, 1,1-dimethyl-2-hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl-2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1-piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, indolyl, indazolyl, benzothiazolyl, benzofuryl, dihydroindolyl, 2-tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, oxetanyl, tetrahydrofuranyl, phenyl, 2-pyridyl, 3-pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, and cyclohexyl; wherein the ring substituent in R 1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, methyl, difluoromethyl, trifluormethyl, hydroxy, methoxy, ethoxy, methylsulfonyl, carboxyl, amino, dimethylamino, Boc, and a ring selected from morpholinyl, pyrazolyl, 1-methyl-4-pyrazolyl, benzyl, phenyl, 3-pyridinyl, pyrimidinyl, 2- methoxy-4-pyrmidinyl, 5-methoxy-4-pyrmidinyl, 1,3,6-triazanaphth-5-yl, 1-thia-4,6-diazainden-7-yl and cyclopropyl, wherein the ring is unsubstituted or substituted; R 2 is selected from H, fluoro, chloro, cyano, methyl, ethyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R 3 is selected from H, fluoro, chloro, cyano, methyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is selected from phenyl, 2-pyridyl, 3-pyridyl, and 1-benzimidazolyl; L is selected from ethylenyl, 1-methylethylenyl, -NH-CH 2 - and -NHCH(CH 3 )- , and wherein the ethylenyl, or -NHCH 2 - group is optionally substituted with 1-4 substituents independently selected from fluoro, cyano and methoxy; R 5 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methoxy and cyclopropyl; R 4 is selected from methylsulfonyl, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , - SO(=NH)CH 3 , -C(O)OH, -C(O)O-C 1 -C 4 alkyl, -C(O)NHO-C 1 -C 4 alkyl, -C(O)NH 2 , -C(O)NH-ethyl, -C(O)NH- isopropyl,triazolyl and tetrazolyl; R 6 is selected from H, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and methoxy; X 1 and X 2 are each -CH-; and p is 0 or 1. 51. The compound of either Embodiment 49 or 50 or pharmaceutically acceptable salt thereof, wherein R 4 is -COOH. 52. The compound of Embodiment 1 or pharmaceutically acceptable salt thereof, having a structure of of Formula 8a or 8b, or a pharmaceutically acceptable salt thereof: wherein R is oxo;

wherein: R is -OR x ; R x is selected from H, methyl, ethyl, -CH 2 CF 3 , CH 2 CF 2 H, CH 2 CFH 2 and CF 3 ; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, , C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 2 - C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , - OC(O)R 1a , -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , NR 1a S(O) 2 R 1a ; -S(O) 2 R 1a , benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3-8 -cycloalkyl-C 1 -C 4 alkyl, phenyl, naphthyl, C 5 - C 6 cycloalkenyl, C 3 -C 6 cycloalkyl, 5-10 membered nitrogen containing heteroaryl, 4-10 membered oxygen containing heterocyclyl; and 4-10 membered nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C 1 -C 6 hydroxyalkyl; R 1a and R 1b are each independently selected from H, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C 3-6 - cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; when R 1 is -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , or NR 1a S(O) 2 NR 1b R 1b , two R 1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 2 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; or when R is oxo, R 1 and R 2 together with the nitrogen and carbon atoms to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 - C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 3 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 3 - C 6 cycloalkyl; L is C 1 -C 4 alkylene, -NH-C 1 -C 4 alkylene, or -C 1 -C 4 alkylene-NH-, and the alkylene group is optionally substituted with 1-4 substituents independently selected from halo, cyano and C 1 -C 4 alkoxy; R 4 is selected from H, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, –(CH 2 ) 1-2 -C(O)OH, - C(O)O-C 1 -C 4 alkyl, –(CH 2 ) 1-2 -C(O)O-C 1 -C 4 alkyl, --C(O)NH 2 , -(CH 2 ) 1-2 -C(O)NH 2 , -C(O)N(C 1 -C 4 alkyl) 2 , -(CH 2 ) 1-2 - C(O)N(C 1 -C 4 alkyl) 2 , -C(O)NHO-C 1 -C 4 alkyl, -C(O)NH-C 1 -C 4 alkyl, -(CH 2 ) 1-2 -C(O)NH-C 1 -C 4 alkyl, C 1 - C 4 alkylsulfonyl, and 5-membered nitrogen containing heteroaryl; R 5 is selected from H, halo, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; Each R 6 is independently selected from H, halo, cyano, C 1 -C 4 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl- C 1 -C 4 alkyl, phenyl, heteroaryl, heterocyclyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkylamino- C 1 - C 4 alkyl, amino- C 1 -C 4 alkyl, and C 1 -C 4 alkoxy-C 1 -C 4 alkyl; R 7 is selected from H, C 1 -C 2 alkyl, C 5 -C 6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; and p is 0, 1, 2 or 3. 53. The compound of Embodiment 52 or pharmaceutically acceptable salt thereof, wherein R is oxo or methoxy; R 1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2-hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl-2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2- trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1-piperidinyl, 1-piperazinyl, 2-isoindolyl, 2- isoindolinyl, indolyl, indazolyl, benzothiazolyl, benzofuryl, dihydroindolyl, 2-tetrahydroisoquinolinyl, 2- tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1- imidazolidinyl, 1-azetidinyl, oxetanyl, tetrahydrofuranyl, phenyl, 2-pyridyl, 3-pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, and cyclohexyl; wherein the ring substituent in R 1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, methyl, difluoromethyl, trifluormethyl, hydroxy, methoxy, ethoxy, methylsulfonyl, carboxyl, amino, dimethylamino, Boc, and a ring selected from morpholinyl, pyrazolyl, 1-methyl-4- pyrazolyl, benzyl, phenyl, 3-pyridinyl, pyrimidinyl, 2-methoxy-4-pyrmidinyl, 5-methoxy-4-pyrmidinyl, 1,3,6- triazanaphth-5-yl, 1-thia-4,6-diazainden-7-yl and cyclopropyl, wherein the ring is unsubstituted or substituted; R 2 is selected from H, fluoro, chloro, cyano, methyl, ethyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R 3 is selected from H, fluoro, chloro, cyano, methyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is selected from phenyl, 2-pyridyl, 3-pyridyl, and 1-benzimidazolyl; L is selected from ethylenyl, 1-methylethylenyl, -NH-CH 2 - and -NHCH(CH 3 )- , and wherein the ethylenyl, or - NHCH 2 - group is optionally substituted with 1-4 substituents independently selected from fluoro, cyano and methoxy; R 5 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methoxy and cyclopropyl; R 4 is selected from methylsulfonyl, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, -C(O)O-C 1 -C 4 alkyl, - C(O)NHO-C 1 -C 4 alkyl, -C(O)NH 2 , -C(O)NH-ethyl, -C(O)NH-isopropyl,triazolyl and tetrazolyl; R 6 is selected from H, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and methoxy; and p is 0 or 1. 54. The compound of either Embodiment 52 or 53 or pharmaceutically acceptable salt thereof, wherein R 4 is -COOH. 55. The compound of embodiment 1 or pharmaceutically acceptable salt thereof, having a structure of Formula 9: wherein: R is oxo or -OR x ; R x is selected from H, methyl, ethyl, -CH 2 CF 3 , CH 2 CF 2 H, CH 2 CFH 2 and CF 3 ; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 2 - C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , - OC(O)R 1a , -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , NR 1a S(O) 2 R 1a ; -S(O) 2 R 1a , benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3-8 -cycloalkyl-C 1 -C 4 alkyl, phenyl, naphthyl, C 5 - C 6 cycloalkenyl, C 3 -C 6 cycloalkyl, 5-10 membered nitrogen containing heteroaryl, 4-10 membered oxygen containing heterocyclyl; and 4-10 membered nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C 1 -C 6 hydroxyalkyl; R 1a and R 1b are each independently selected from H, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C 3 - 6 - cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; when R 1 is -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , or NR 1a S(O) 2 NR 1b R 1b , two R 1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 2 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; or when R is oxo, R 1 and R 2 together with the nitrogen and carbon atoms to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 - C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 3 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 3 - C 6 cycloalkyl; L is C 1 -C 4 alkylene, -NH-C 1 -C 4 alkylene, or -C 1 -C 4 alkylene-NH-, and the alkylene group is optionally substituted with 1-4 substituents independently selected from halo, cyano and C 1 -C 4 alkoxy; R 4 is selected from H, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, –(CH 2 ) 1-2 -C(O)OH, - C(O)O-C 1 -C 4 alkyl, –(CH 2 ) 1-2 -C(O)O-C 1 -C 4 alkyl, --C(O)NH 2 , -(CH 2 ) 1-2 -C(O)NH 2 , -C(O)N(C 1 -C 4 alkyl) 2 , -(CH 2 ) 1-2 - C(O)N(C 1 -C 4 alkyl) 2 , -C(O)NHO-C 1 -C 4 alkyl, -C(O)NH-C 1 -C 4 alkyl, -(CH 2 ) 1-2 -C(O)NH-C 1 -C 4 alkyl, C 1 - C 4 alkylsulfonyl, and 5-membered nitrogen containing heteroaryl; Each R 6 is independently selected from H, halo, cyano, C 1 -C 4 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl- C 1 -C 4 alkyl, phenyl, heteroaryl, heterocyclyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkylamino- C 1 - C 4 alkyl, amino- C 1 -C 4 alkyl, and C 1 -C 4 alkoxy-C 1 -C 4 alkyl; R 7 is selected from H, C 1 -C 2 alkyl, C 5 -C 6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; and p is 0, 1, 2 or 3. 56. The compound of Embodiment 55 or pharmaceutically acceptable salt thereof, wherein R is oxo or methoxy; R 1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2-hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl-2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2- trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1-piperidinyl, 1-piperazinyl, 2-isoindolyl, 2- isoindolinyl, indolyl, indazolyl, benzothiazolyl, benzofuryl, dihydroindolyl, 2-tetrahydroisoquinolinyl, 2- tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1- imidazolidinyl, 1-azetidinyl, oxetanyl, tetrahydrofuranyl, phenyl, 2-pyridyl, 3-pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, and cyclohexyl; wherein the ring substituent in R 1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, methyl, difluoromethyl, trifluormethyl, hydroxy, methoxy, ethoxy, methylsulfonyl, carboxyl, amino, dimethylamino, Boc, and a ring selected from morpholinyl, pyrazolyl, 1-methyl-4- pyrazolyl, benzyl, phenyl, 3-pyridinyl, pyrimidinyl, 2-methoxy-4-pyrmidinyl, 5-methoxy-4-pyrmidinyl, 1,3,6- triazanaphth-5-yl, 1-thia-4,6-diazainden-7-yl and cyclopropyl, wherein the ring is unsubstituted or substituted; R 2 is selected from H, fluoro, chloro, cyano, methyl, ethyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R 3 is selected from H, fluoro, chloro, cyano, methyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is selected from phenyl, 2-pyridyl, 3-pyridyl, and 1-benzimidazolyl; L is selected from ethylenyl, 1-methylethylenyl, -NH-CH 2 - and -NHCH(CH 3 )- , and wherein the ethylenyl, or - NHCH 2 - group is optionally substituted with 1-4 substituents independently selected from fluoro, cyano and methoxy; R 5 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methoxy and cyclopropyl; R 4 is selected from methylsulfonyl, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, -C(O)O-C 1 -C 4 alkyl, - C(O)NHO-C 1 -C 4 alkyl, -C(O)NH 2 , -C(O)NH-ethyl, -C(O)NH-isopropyl,triazolyl and tetrazolyl; R 6 is selected from H, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and methoxy; and p is 0 or 1. 57. The compound of either Embodiment 55 or 56 or pharmaceutically acceptable salt thereof, wherein R 4 is -COOH. 58. The compound of embodiment 1 or pharmaceutically acceptable salt thereof, having a structure of Formula 10a, 10b or 10c: wherein: X 1 , X 2 , X 3 , and X 6 is each independently -CR 5 - or -N-; R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C 2 - C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, -OR 1a , -SR 1a , -NR 1a R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1a , - OC(O)R 1a , -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , NR 1a S(O) 2 NR 1b R 1b , NR 1a S(O) 2 R 1a ; -S(O) 2 R 1a , benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3-8 -cycloalkyl-C 1 -C 4 alkyl, phenyl, naphthyl, C 5 - C 6 cycloalkenyl, C 3 -C 8 cycloalkyl, 5-10 membered nitrogen containing heteroaryl, 4-10 membered oxygen containing heterocyclyl and 4-10 membered nitrogen containing heterocyclyl; wherein the phenyl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl has 0, 1, 2 or 3 substituents independently selected from halo, cyano, C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxy, phenyl, benzyl, cyclopropyl and C 1 -C 6 hydroxyalkyl; R 1a and R 1b are each independently selected from H, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and C 3 - 6 - cycloalkyl; wherein each of the alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0, 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; when R 1 is -C(O)NR 1b R 1b , -NR 1a C(O)NR 1b R 1b , -S(O) 2 NR 1b R 1b , or NR 1a S(O) 2 NR 1b R 1b , two R 1b together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl ring, and the ring is substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and -SO 2 R 7 ; R 3 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; A is a ring selected from phenyl, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 3 - C 6 cycloalkyl; L is C 1 -C 4 alkylene, -NH-C 1 -C 4 alkylene, or -C 1 -C 4 alkylene-NH-, and the alkylene group is optionally substituted with 1-4 substituents independently selected from halo, cyano and C 1 -C 4 alkoxy; R 4 is selected from H, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, –(CH 2 ) 1-2 -C(O)OH, - C(O)O-C 1 -C 4 alkyl, –(CH 2 ) 1-2 -C(O)O-C 1 -C 4 alkyl, --C(O)NH 2 , -(CH 2 ) 1-2 -C(O)NH 2 , -C(O)N(C 1 -C 4 alkyl) 2 , -(CH 2 ) 1-2 - C(O)N(C 1 -C 4 alkyl) 2 , -C(O)NHO-C 1 -C 4 alkyl, -C(O)NH-C 1 -C 4 alkyl, -(CH 2 ) 1-2 -C(O)NH-C 1 -C 4 alkyl, C 1 - C 4 alkylsulfonyl, and 5-membered nitrogen containing heteroaryl; R 5 is selected from H, halo, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, phenyl, and cyclopropyl; Each R 6 is independently selected from H, halo, cyano, C 1 -C 4 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 - C 2 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyl, heteroaryl- C 1 -C 4 alkyl, heterocyclyl- C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl- C 1 -C 4 alkyl, phenyl, heteroaryl, heterocyclyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkylamino- C 1 - C 4 alkyl, amino- C 1 -C 4 alkyl, and C 1 -C 4 alkoxy-C 1 -C 4 alkyl; R 7 is selected from H, C 1 -C 2 alkyl, C 5 -C 6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each n is independently 0, 1 or 2; R 10 is selected from H, halo, cyano, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, benzyl, phenyl, substituted or unsubstituted 5-6 membered heteroaryl, and cyclopropyl; and p is 0, 1, 2 or 3. 47. The compound of Embodiment 46 or pharmaceutically acceptable salt thereof, wherein R 1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2-hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl-2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, dimethylaminocarbonyl, 1-piperidinyl, 1-piperazinyl, 2-isoindolyl, 2-isoindolinyl, indolyl, indazolyl, benzothiazolyl, benzofuryl, dihydroindolyl, 2-tetrahydroisoquinolinyl, 2-tetrahydronaphthyridinyl, 1-pyrrolindinyl, 1-pyrrolinyl, 2-pyrazolinyl, 1-pyrazolidinyl, 1-imidazolinyl, 1-imidazolidinyl, 1-azetidinyl, oxetanyl, tetrahydrofuranyl, phenyl, 2-pyridyl, 3-pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, and cyclohexyl; wherein the ring substituent in R 1 is substituted with 0, 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, methyl, difluoromethyl, trifluormethyl, hydroxy, methoxy, ethoxy, methylsulfonyl, carboxyl, amino, dimethylamino, Boc, and a ring selected from morpholinyl, pyrazolyl, 1-methyl-4-pyrazolyl, benzyl, phenyl, 3-pyridinyl, pyrimidinyl, 2- methoxy-4-pyrmidinyl, 5-methoxy-4-pyrmidinyl, 1,3,6-triazanaphth-5-yl, 1-thia-4,6-diazainden-7-yl and cyclopropyl, wherein the ring is unsubstituted or substituted; R 2 is selected from H, fluoro, chloro, cyano, methyl, ethyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; R 3 is selected from H, fluoro, chloro, cyano, methyl, trifluoromethyl, methylsulfonyl, hydroxymethyl, methoxy and cyclopropyl; A is selected from phenyl, 2-pyridyl, 3-pyridyl, and 1-benzimidazolyl; L is selected from ethylenyl, 1-methylethylenyl, -NH-CH 2 - and -NHCH(CH 3 )- , and wherein the ethylenyl, or -NHCH 2 - group is optionally substituted with 1-4 substituents independently selected from fluoro, cyano and methoxy; R 5 is selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methoxy and cyclopropyl; R 4 is selected from methylsulfonyl, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , - SO(=NH)CH 3 , -C(O)OH, -C(O)O-C 1 -C 4 alkyl, -C(O)NHO-C 1 -C 4 alkyl, -C(O)NH 2 , -C(O)NH-ethyl, -C(O)NH- isopropyl,triazolyl and tetrazolyl; R 6 is selected from H, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, and methoxy; each R 10 is independently selected from H, fluoro, chloro, cyano, C 1 -C 4 alkyl, trifluoromethyl, methoxy, ethoxy and cyclopropyl; X 1 and X 2 are -CH-; X 3 is -N-; X 6 is -CR 10 - or -N- ; and p is 0 or 1. 48. The compound of either Embodiment 46 or 47 or pharmaceutically acceptable salt thereof, wherein R 4 is -COOH. 58. The compound of any one of embodiments 1, 34, 37, 40, 43, 46, 49, 52 and 55 or pharmaceutically acceptable salt thereof, wherein R 4 -A- is selected from wherein R 6 is halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, or C 3 -C 5 cycloalkyl; and p is 0, 1, or 2. 59. The compound of embodiment 58 or pharmaceutically acceptable salt thereof, wherein R 4 -A- is ; wherein R 6 is fluoro, chloro, bromo or trifluoromethyl; and p is 0 or 1. 60. The compound of embodiment 1 or pharmaceutically acceptable salt thereof, wherein R 1 is selected from methyl, ethyl, isopropyl, 1,1-dimethyl-2-hydroxyethyl, 1,1-dimethyl-2-cyanoethyl, butyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, 1-methyl-2,2,2-trifluoroethyl, 1,1-dimethyl-2,2,2-trifluoroethyl, pentafluoroethyl, ethyloxymethyl, ethylthiomethyl, butoxy, propylthio, cyclopropylmethyl, benzyl, benzyloxy, cyclohexylamino, ethylsulfonyl, and dimethylaminocarbonyl. 61. The compound of any one of embodiments 1 to 22, or a pharmaceutically acceptable salt thereof, wherein A is selected from phenyl, benzothienyl, pyrazinyl, pyrimidinyl, 2-pyridyl, 3-pyridyl, and 1-benzimidazolyl. 62. The compound of any one of embodiments 1 to 20, or a pharmaceutically acceptable salt thereof, wherein L is selected from ethylenyl, 1-methylethylenyl, -NH-CH 2 - and -NHCH(CH 3 )-, wherein the ethylenyl, or - NHCH 2 - group is optionally substituted with 1-4 substituents independently selected from fluoro, cyano and methoxy. 63. The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein R 4 is - selected from methylsulfonyl, -SO 3 H, -PO 2 (OH) 2 , -SO 2 NH 2 , -SO(=NH)CH 3 , -C(O)OH, -C(O)O-C 1 -C 4 alkyl, - C(O)NHO-C 1 -C 4 alkyl, -C(O)NH 2 , -C(O)NH-ethyl, -C(O)NH-isopropyl, triazolyl and tetrazolyl. 64. The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from Examples 1-217. 65. A pharmaceutical composition comprising, a compound of any one of embodiments 1 to 64, and a pharmaceutically acceptable carrier. 66. A method of treating a disease or disorder associated with modulation of phosphoinositide 3 -kinase alpha (PI3K ^), comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of embodiments 1 to 64 or a pharmaceutical composition of embodiment 65. 67. The method of embodiment 66, wherein the compound has greater selectivity for mutant PI3Kα over wild-type PI3Kα. 68. The method of embodiment 66 or embodiment 67, wherein the PI3K associated with the disease or disorder has a H1047R mutation. 69. The method of any one of embodiments 66-68, wherein the disease or disorder is a cancer. 70. The method of embodiment 69, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer. 71. The method of any one of embodiments 66-68, wherein the disease or disorder is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome), or PIK3CA-related overgrowth syndrome (PROS). 72. A method of inhibiting phosphoinositide 3-kinase (PI3K), comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of embodiments 1 to 64 or a pharmaceutical composition of embodiment 65. 73. A method of treating cancer or a disorder, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of embodiments 1 to 64 or a pharmaceutical composition of embodiment 65. 74. The method of embodiment 73, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer. 75 The method of embodiment 73, wherein the disorder is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) or PIK3CA-related overgrowth syndrome (PROS). 76. A compound of any one of embodiments 1 to 64 or a pharmaceutical composition of embodiment 65, for use in treating a disease or disorder associated with modulating PI3K. 77. The compound for use of embodiment 76, wherein the disease associated with modulating PI3K is a cancer. 78. The compound for use of embodiment 77, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer. 79. The compound for use of embodiment 71, wherein the disorder is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) or PIK3CA-related overgrowth syndromes (PROS). 80. Use of a compound of any one of embodiments 1 to 64 or a pharmaceutical composition of embodiment 65, in the manufacture of a medicament for the treatment of a disease associated with modulating PI3K. 81. The use of a compound of embodiment 80, wherein the disease associated with modulating PI3K is a cancer. 82. The use of a compound of embodiment 80, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer. 83. The use of a compound of embodiment 80 wherein the disease is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) or PIK3CA-related overgrowth syndromes (PROS).




 
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