1,6−NAPHTHYRIDINE DERIVATIVES AS ANTIDIABETICS

Title:

1,6−NAPHTHYRIDINE DERIVATIVES AS ANTIDIABETICS

Document Type and Number:

WIPO Patent Application WO/2003/027113

Kind Code:

Abstract:

The invention relates generally to naphthyridine derivatives of the formula (A), wherein one of U, X, Y and Z is nitrogen and the others are C−R, where R is hydrogen or a substituent. More specifically, the invention relates to 1,6−naphthyridine derivatives and pharmaceutical compositions containing such derivatives. Methods of the invention comprise administration of a naphthyridine derivative of the invention for the treatment of diabetes and related disorders.

Inventors:

WANG YAMIN (US)
BULLOCK WILLIAM H (US)
CHEN LIBING (US)

Application Number:

PCT/US2002/030376

Publication Date:

April 03, 2003

Filing Date:

September 23, 2002

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Assignee:

BAYER AG (US)
WANG YAMIN (US)
BULLOCK WILLIAM H (US)
CHEN LIBING (US)

International Classes:

A61K31/133; A61K31/155; A61K31/195; A61K31/198; A61K31/435; A61K31/4375; A61K31/44; A61K31/4439; A61K31/444; A61K31/445; A61K31/4453; A61K31/4545; A61K31/455; A61K31/4709; A61K31/4725; A61K31/4745; A61K31/496; A61K31/5355; A61K31/5377; A61K31/541; A61K31/64; A61K31/7034; A61K38/22; A61K38/28; A61K45/00; A61K45/06; A61P3/04; A61P3/10; A61P5/12; A61P5/42; A61P9/12; A61P35/00; A61P37/06; A61P43/00; C07D471/02; C07D471/04; (IPC1-7): C07D471/04; A61K31/44; A61P3/10

Domestic Patent References:

WO2000008026A2

2000-02-17

Foreign References:

EP0227088A1

1987-07-01

Other References:

PATENT ABSTRACTS OF JAPAN vol. 015, no. 206 27 May 1991 (1991-05-27)
PATENT ABSTRACTS OF JAPAN vol. 015, no. 508 24 December 1991 (1991-12-24)
I. HERMECZ, A. HORVATH: "Nitrogen bridgehead compounds. Part 83. Synthesis and ring transformation of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-acrylates", J. HET. CHEM., vol. 29, no. 2, 1992, pages 559 - 564, XP002222061
D. T. W. CHU, A. K. CLAIBORNE: "Practical Synthesis of Iminochlorothioformates: Application of Iminochlorothioformates in the Synthesis of Novel 2,3,4,9-Tetrahydroisothiazolo[5,4-b][1,8]naphthyridine-3,4-diones and 2,3,4,9-Tetrahydroisothiazolo[5,4-b]quinoline-3,4-dione Derivatives", J. HET. CHEM., vol. 27, no. 5, 1990, pages 1191 - 1195, XP002222062
Y.-F. MING ET AL.: "Heterocyclic .beta.-enamino esters. 48. Heterocondensed pyridines by cycloaddition-extrusion sequence of bi- and tricyclic 1,3-oxazinones with N,N-diethyl-1-propynylamine", CHEMISCHE BERICHTE, vol. 120, no. 8, 1987, pages 1427 - 1431, XP001119052
R. J. FRIARY ET AL.: "Intramolecular Transaminations of Enaminones: A Synthesis of Fused, Polycyclic, N-Aryl Pyridones", TETRAHEDRON, vol. 49, no. 33, 1993, pages 7169 - 7178, XP001119983
A. G. OSBORNE, Z. GOOLAMALI: "1H and 13C NMR spectral studies of some 4H-3,1-benzoxazin-4-ones and their 2-acylaminobenzoic acid precursors", SPECTROCHIMICA ACTA PART A, vol. 56, no. 6, 2000, pages 1079 - 1100, XP002222063

Attorney, Agent or Firm:

Greenman, Jeffrey M. (400 Morgan Lane West Haven, CT, US)

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Claims:

CLAIMS What is claimed is:

A compound of the formula II wherein R"is selected from alkyl of 18 carbon atoms, alkenyl of 28 carbon atoms, alkynyl of 28 carbon atoms, and AR9, or R"is selected from aryl of 610 carbon atoms, heteroaryl of 29 carbon atoms and 14 heteroatoms selected from N, S (=O) o2 and 0, cycloalkyl of 38 carbon atoms, cycloalkenyl of 48 carbon atoms, 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 56 membered heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02 and 0, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), all of which may be substituted with 13 of Rlo ; Rlo is selected from nitro, nitrile, hydroxy, halogen, acyl of 16 carbon atoms, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, haloalkyl of 16 carbon atoms, alkoxy of 16 carbon atoms, haloalkoxy of 16 carbon atoms, cycloalkoxy of 36 carbon atoms, aryl of 610 carbon atoms, heteroaryl of 29 carbon atoms and 14 heteroatoms selected from N, S (=O) 02 and 0, NR11R12, C (=O) OR", C (=O) NHR, NHC (=O) R13, NHS (=0) 2R, S (=0) 02R13, S (=0) 2NHR11, cycloalkyl of 36 carbon atoms, cycloalkenyl of 36 carbon atoms, 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=0) 02 and 0, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 56 membered heteroaryl of 25 carbon atoms and 1 3 heteroatoms selected from N, S (=O) 02 and 0, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O) ; R13 is selected from alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, haloalkyl of 16 carbon atoms, cycloalkyl of 36 carbon atoms, and cycloalkenyl of 46 carbon atoms; Rll and R12 are independently selected from hydrogen, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, haloalkyl of 16 carbon atoms, cycloalkyl of 36 carbon atoms, and cycloalkenyl of 46 carbon atoms; A is selected from alkyl of 18 carbon atoms, alkenyl of 28 carbon atoms, alkynyl of 28 carbon atoms, and haloalkyl of 18 carbon atoms; R9 is selected from hydroxy, alkoxy of 16 carbon atoms, cycloalkoxy of 3 6 carbon atoms, OAR, NR11R12 ; or R9 is selected from aryl of 610 carbon atoms, heteroaryl of 29 carbon atoms and 14 heteroatoms selected from N, S (=O) 02 and 0, cylcoalkyl of 38 carbon atoms, cycloalkenyl of 58 carbon atoms, all of which may be substituted with 13 of R10, or R9 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 0 2 and O and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=0) 02 and 0, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 56 membered heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02 and 0, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1 3 of Rlo ; R14 is selected from cylcoalkyl of 38 carbon atoms, cycloalkenyl of 58 carbon atoms, 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) o2 and 0, all of which may be substituted with 13 of R10 ; with the proviso for R1 that when A is CH2, R9 is not optionally substituted biphenyl; R2 is selected from NR15R16, S (0) o 2Rl7, and OR17 ; R15 is selected from hydrogen, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, cylcoalkyl of 38 carbon atoms, cycloalkenyl of 48 carbon atoms, 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=0) 02 and 0, AR9, C (=O) R18, C (=O) NHR18, S (=0) 2NHR18 ; R'8 is selected from aryl of 610 carbon atoms, heteroaryl of 29 carbon atoms and 14 heteroatoms selected from N, S (=O) 02 and 0, cylcoalkyl of 38 carbon atoms, cycloalkenyl of 48 carbon atoms, 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, all of which may be substituted with 13 of R10, or R'8 is selected from alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, and alkynyl of 26 carbon atoms, all of which may be substituted with 13 of halogen or alkoxy of 16 carbon atoms, or R"is AR' ; R16 is selected from alkyl of 18 carbon atoms, alkenyl of 28 carbon atoms, alkynyl of 28 carbon atoms, and AR9, or R16 is selected from aryl of 610 carbon atoms, heteroaryl of 29 carbon atoms and 14 heteroatoms selected from N, S (=O) 02 and 0, cycloalkyl of 38 carbon atoms, cycloalkenyl of 48 carbon atoms, 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, all of which may be substituted with 13 of R10, or R15 and R16 combine, together with the nitrogen atom to which they are attached, to form a heteroaryl of 29 carbon atoms and 14 heteroatoms selected from N, S (=O) o2 and 0, or a 57 membered heterocycloalkyl of 3 6 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) o2 and 0, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 56 membered heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02 and 0, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), all of which may be substituted with 13 of R10 ; R17 is selected from alkyl of 18 carbon atoms, alkenyl of 28 carbon atoms, and alkynyl of 28 carbon atoms, haloalkyl of 18 carbon atoms, AR9, or R17 is selected from aryl of 610 carbon atoms, heteroaryl of 29 carbon atoms and 14 heteroatoms selected from N, S (=O) 02 and 0, cylcoalkyl of 38 carbon atoms, cycloalkenyl of 48 carbon atoms, 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, all of which may be substituted with 13 of R10 ; R3 is selected from aryl of 610 carbon atoms, heteroaryl of 29 carbon atoms and 14 heteroatoms selected from N, S (=O) 02 and 0, cylcoalkyl of 38 carbon atoms, heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (O) o 2, and 0, cycloalkenyl of 48 carbon atoms, and heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, S (O) o2 and 0, all of which may be substituted with 13 of R10, or R3 is selected from alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, haloalkyl of 16 carbon atoms, hydrogen, nitro, halogen, NR19R20, AOR19, ANR19R20, and AR20 ; Rl9 and R20 are independently selected from hydrogen, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, haloalkyl of 16 carbon atoms, and AR9, or R19 and R20 are independently selected from aryl of 610 carbon atoms, heteroaryl of 29 carbon atoms and 14 heteroatoms selected from N, S (O) o 2 and 0, cylcoalkyl of 38 carbon atoms, cycloalkenyl of 58 carbon atoms, 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (0) 02 and 0, 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, S (O) 02 and 0, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 56 membered heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02 and 0, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), all of which may be substituted with 13 of R10 ; R4'is selected from =0, =S, and OR21 ; R21 is hydrogen, or R21 is selected from alkyl of 18 carbon atoms, alkenyl of 28 carbon atoms, alkynyl of 28 carbon atoms, cycloalkyl of 38 carbon atoms, cycloalkenyl of 48 carbon atoms, 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=0) 02 and 0, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, all of which may be substituted with 13 of R10 ; Rs, R7', and R8 are independently selected from cycloalkyl of 38 carbon atoms, cycloalkenyl of 48 carbon atoms, aryl of 610 carbon atoms, and heteroaryl of 29 carbon atoms and 14 heteroatoms, all of which may be substituted with 13 of R10, or R5', R7', and R8 are independently selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and O and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 56 membered heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02 and 0, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 13 of R10, AR23, ANR24R25, C (=O) R24, C (=O) OR24, C (=O) NR24R25, S (=0) 2R26, AC (=O) R24, AC (=O) OR24, or AC(=O)NR24R25, or Rus', R7', and R8 are independently selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 18 carbon atoms, alkenyl of 28 carbon atoms, alkynyl of 28 carbon atoms, haloalkyl of 18 carbon atoms, alkoxy of 18 carbon atoms, haloalkoxy of 18 carbon atoms, cycloalkoxy of 38 carbon atoms, AR23, A (OR22)R23, NR27R28, ANR27R28, AQR29, QR29, QANR24R25, C(=O)R24, C (=O) OR24, C (=o) NR24R25, A_C (=O) R24, AC(=O)OR24, and AC(=O)NR24R25 ; Q is selected from O and S (=O) 02 ; R22 is selected from hydrogen, alkyl of 18 carbon atoms, haloalkyl of 18 carbon atoms, and cycloalkyl of 38 carbon atoms; R23 is selected from hydroxy, alkoxy of 18 carbon atoms, haloalkoxy of 1 8 carbon atoms, and cycloalkoxy of 38 carbon atoms, or R23 is selected from cycloalkyl of 38 carbon atoms, cycloalkenyl of 48 carbon atoms, aryl of 610 carbon atoms, and heteroaryl of 29 carbon atoms and 14 heteroatoms selected from N, S (=0) 02, and 0, all of which may be substituted with 13 of R10, or R23 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 56 membered heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02 and 0, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 13 of R10; with the proviso for A (OR22)R23 that when R23 is selected from hydroxy, alkoxy of 18 carbon atoms, haloalkoxy of 18 carbon atoms, and cycloalkoxy of 38 carbon atoms, A is not CH; R24 and R25 are independently selected from hydrogen, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, haloalkyl of 16 carbon atoms, and AR23, or R24 and R25 are independently selected from cycloalkyl of 36 carbon atoms, cycloalkenyl of 36 carbon atoms, aryl of 610 carbon atoms, and heteroaryl of 29 carbon atoms and 14 heteroatoms selected from N, S (=0) o2, and 0, all of which may be substituted with 13 of R10, or R24 and R25 are independently selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) o2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 56 membered heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02 and 0, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 13 of R10, or R24 and R25 combine, together with the nitrogen atom to which they are attached, to form a 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02, and 0, a 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02, and 0, or a heteroaryl of 29 carbon atoms and 14 heteroatoms, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 56 membered heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02 and 0, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), all of which may be substituted with 13 of R10 ; R26 is selected from alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, haloalkyl of 16 carbon atoms, A (OR22)R23, and AR23, or R26 is selected from cycloalkyl of 36 carbon atoms, cycloalkenyl of 36 carbon atoms, aryl of 610 carbon atoms, and heteroaryl of 29 carbon atoms and 14 heteroatoms selected from N, S (=O) 02, and 0, all of which may be substituted with 13 of R10, or R26 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 56 membered heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02 and 0, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 13 of R10; R27 is selected from hydrogen, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, haloalkyl of 16 carbon atoms, and AR23, or R27 is selected from cycloalkyl of 36 carbon atoms, cycloalkenyl of 36 carbon atoms, aryl of 610 carbon atoms, and heteroaryl of 29 carbon atoms and 14 heteroatoms selected from N, S (=O) 02, and 0, all of which may be substituted with 13 of R10, or R27 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 56 membered heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02 and 0, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 13 of Rio ; R28 is selected from hydrogen, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, haloalkyl of 16 carbon atoms, AR23, C(=O0R24, C(=O)OR26, C(=O)NR25R30, S(=O)2R26, AC(=O)R24, A C(=O)OR24, and AC(=O)NR24R25, or R28 is selected from cycloalkyl of 36 carbon atoms, cycloalkenyl of 36 carbon atoms, aryl of 610 carbon atoms, heteroaryl of 29 carbon atoms and 14 heteroatoms selected from N, S (=O) 02, and 0, all of which may be substituted with 13 of R10, or R28 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=0) 02, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=0) 02, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 56 membered heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02 and 0, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 13 of R10; R30 is selected from alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, haloalkyl of 16 carbon atoms, A (OR22)R23, and AR23, or R30 is selected from cycloalkyl of 36 carbon atoms, cycloalkenyl of 36 carbon atoms, aryl of 610 carbon atoms, and heteroaryl of 29 carbon atoms and 14 heteroatoms selected from N, S (=O) 02, and 0, all of which may be substituted with 13 of R10, or Wo is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=0) 02, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) o2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 56 membered heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02 and 0, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 13 of R, or R25 and R30 combine, together with the nitrogen atom to which they are attached, to form a 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02, and 0, a 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02, and 0, or a heteroaryl of 29 carbon atoms and 14 heteroatoms, all of which may be substituted with 13 of R01 ; R29 is selected from alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, haloalkyl of 16 carbon atoms, AR23, A C(=O)R24, AC(=O)OR24, AC(=O)NR24R25, ANR27R28, or R29 is selected from cycloalkyl of 36 carbon atoms, cycloalkenyl of 36 carbon atoms, aryl of 610 carbon atoms, heteroaryl of 29 carbon atoms and 14 heteroatoms selected from N, S (=O) 02, and 0, all of which may be substituted with 13 of R10, or R29 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected fiom N, O, S (=0) 02, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 56 membered heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02 and 0, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 13 of R10; and pharmaceutically acceptable salts thereof.

2.	The compound of claim 1, wherein R4'is =0.

The compound of claim 1, wherein R3' is selected from cycloalkyl of 36 carbon atoms, heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (O) 02 and 0, both of which may be substituted with 13 of R10, or R3 is selected from alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, hydrogen, nitro, halogen, NR19R20, AOR19, ANR19R20 and AR20,.

The compound of claim 3, wherein R19 and R20 are independently selected from hydrogen, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms and AR9, or wherein Rl9 and R20 are independently selected from phenyl, monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (O) 02 and 0, cycloalkyl of 36 carbon atoms, 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (0) 02 and 0, wherein one or more of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), all of which may be substituted with 13 of Rlo.

The compound of claim 1, wherein R3 is selected from cycloalkyl of 36 carbon atoms, heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (O) 02 and 0, both of which may be substituted with 13 of R10, or R3 is selected from alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, hydrogen, nitro, halogen, NR19R20, AORl9, ANR19R2o and AR20 ; and R4' is =O.

The compound of claim 5, wherein Rl9 and Wo are independently selected from hydrogen, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms and AR9, or wherein Rl9 and R20 are independently selected from phenyl, monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (O) o2 and 0, cycloalkyl of 36 carbon atoms, 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (O) 02 and 0, wherein one or more of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), all of which may be substituted with 13 of R10.

7.	The compound of claim 1, wherein R2' is NR15R16.

The compound of claim 7, wherein Rls is selected from hydrogen, alkyl of 16 carbon atoms, cylcoalkyl of 38 carbon atoms, 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, AR9, C (=O) R18, C (=O) NHR18, and S (=0) 2NHR18 ; R18 is selected from phenyl, monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02 and 0, cylcoalkyl of 36 carbon atoms, and 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, all of which may be substituted with 13 of R10, or R18 is alkyl of 16 carbon atoms, which may be substituted with 13 of halogen or alkoxy of 16 carbon atoms, or R18 iS AR9 ; and R16 is selected from alkyl of 16 carbon atoms and AR9, or R16 is selected from phenyl, monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02 and 0, cycloalkyl of 38 carbon atoms, and 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=0) 02 and 0, all of which may be substituted with 13 of R10, or Rls and R16 combine, together with the nitrogen atom to which they are attached, to form a monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02 and 0, or a 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), all of which may be substituted with 13 of Rlo.

The compound of claim 1, wherein R2' is NR15R16 ; R3 is selected from cycloalkyl of 36 carbon atoms, heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (O) 02 and 0, both of which may be substituted with 13 of R10, or R3 is selected from alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, hydrogen, nitro, halogen, NR19R20, AORl9, ANR19R20 and AR20 ; and R4'is =O.

10.

The compound of claim 9, wherein Rls is selected from hydrogen, alkyl of 16 carbon atoms, cylcoalkyl of 38 carbon atoms, 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, AR9, C (=O) R18, C (=O) NHR18, and S (=0) 2NHR18 ; R18 is selected from phenyl, monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02 and 0, cylcoalkyl of 36 carbon atoms, and 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, all of which may be substituted with 13 of R10, or R'8 is alkyl of 16 carbon atoms, which may be substituted with 13 of halogen or alkoxy of 16 carbon atoms, or R18 iS AR9 ; and Ruz is selected from alkyl of 16 carbon atoms and AR9, or Ruz is selected from phenyl, monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02 and 0, cycloalkyl of 38 carbon atoms, and 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, all of which may be substituted with 13 of R10, or Rls and R16 combine, together with the nitrogen atom to which they are attached, to form a monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02 and 0, or a 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), all of which may be substituted with 13 of R10.

11.	The compound of claim 10, selected from the group consisting of :.

12.

The compound of claim 9, wherein Rl9 and R20 are independently selected from hydrogen, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms and AR9, or wherein Rl9 and R20 are independently selected from phenyl, monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (0) 02 and 0, cycloalkyl of 36 carbon atoms, 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (O) 02 and 0, wherein one or more of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), all of which may be substituted with 13 of R10.

13.

The compound of claim 1 or 9, wherein Rs is selected from cycloalkyl of 36 carbon atoms, cycloalkenyl of 46 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms, all of which may be substituted with 13 of R10, or Rs is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and O and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 13 of R'O, AR23, ANR24R25, C(=O)R24, C(=O)OR24, C(=O)NR24R25, S(=O)2R26, AC(=O)R24, AC(=O)OR24, or AC (=O) NR24R25, or Rs is selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, haloalkyl of 16 carbon atoms, alkoxy of 16 carbon atoms, haloalkoxy of 16 carbon atoms, cycloalkoxy of 36 carbon atoms, AR23, A (oR22)R23, NR27R28, ANR27R28, AQ R29, QR29, QANR24R25, C(=O)R24, C(=O)OR24, C(=O)NR24R25, AC(=O)R24, AC (=O) OR24, and A C (=o) NR24R25 ; R22 is selected from hydrogen, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, and cycloalkyl of 36 carbon atoms; R23 is selected from hydroxy, alkoxy of 16 carbon atoms, haloalkoxy of 1 6 carbon atoms, and cycloalkoxy of 36 carbon atoms, or R23 is selected from cycloalkyl of 36 carbon atoms, cycloalkenyl of 46 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=0) 02, and 0, all of which may be substituted with 13 of R10, or R23 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=0) 02, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=0) 02, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1 3 of R10; with the proviso for A (oR22)R23 that when R23 is selected from hydroxy, alkoxy of 16 carbon atoms, haloalkoxy of 16 carbon atoms, and cycloalkoxy of 36 carbon atoms, A is not CH; R24 and R25 are independently selected from hydrogen, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, haloalkyl of 16 carbon atoms, and AR23, or R24 and R25 are independently selected from cycloalkyl of 36 carbon atoms, cycloalkenyl of 36 carbon atoms, phenyl,, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02, and 0, all of which may be substituted with 13 of R10, or R24 and R25 are independently selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=0) 02, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=0) 02, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 13 of R10, or R24 and R25 combine, together with the nitrogen atom to which they are attached, to form a 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02, and 0, a 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02, and 0, or a monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), all of which may be substituted with 13 of R10 ; Ra6 is selected from alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, haloalkyl of 16 carbon atoms, A (OR22)R23, and AR23, or R26 is selected from cycloalkyl of 36 carbon atoms, cycloalkenyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02, and 0, all of which may be substituted with 13 of R10, or R26 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=0) 02, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1 3 of Rlo ; R27 is selected from hydrogen, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, haloalkyl of 16 carbon atoms, and AR23, or R27 is selected from cycloalkyl of 36 carbon atoms, cycloalkenyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 0 2, and 0, all of which may be substituted with 13 of R10, or R27 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=0) 02, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1 3 of R" ; R28 is selected from hydrogen, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, haloalkyl of 16 carbon atoms, AR23, C(=O)R24, C(=O)OR26, C(=O)NR25R30, S(=O)2R26, AC(=O)R24, A C(=O)OR24, and AC(=O)NR24R25, or R28 is selected from cycloalkyl of 36 carbon atoms, cycloalkenyl of 36 carbon atoms, phenyl, monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=0) 02, and 0, all of which may be substituted with 13 of Rio, or R28 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1 3 of Rio ; Wo is selected from alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, haloalkyl of 16 carbon atoms, A (OR22)R23, and AR23, or R30 is selected from cycloalkyl of 36 carbon atoms, cycloalkenyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02, and 0, all of which may be substituted with 13 of Rio, or R30 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=0) 02, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1 3 of R10, or R25 and R30 combine, together with the nitrogen atom to which they are attached, to form a 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=0) 02, and 0, a 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=0) 02, and 0, or a monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms, all of which may be substituted with 13 of Rio ; and R29 is selected from alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, haloalkyl of 16 carbon atoms, AR23, A C (=O) R24 AC (=O) OR24, AC (=O) NR24R25, ANR27R28, or R29 is selected from cycloalkyl of 36 carbon atoms, cycloalkenyl of 36 carbon atoms, phenyl, monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=0) 02, and 0, all of which may be substituted with 13 of R10, or R29 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=0) 02, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1 3 of Rlo.

14.

The compound of claim 13, wherein Rs is selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms, all of which may be substituted with 13 of R10, or Rus ils 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10, AR23, ANR24R25, C (=O) R24, C(=O)OR24, C(=O)NR24R25, S(=O)2R26, AC(=O)R24, AC(=O)OR24, or AC(=O)NR24R25, or R"is selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, alkoxy of 16 carbon atoms, haloalkoxy of 16 carbon atoms, cycloalkoxy of 36 carbon atoms, AR23, NR27R28, ANR27R28, AQR29, QR29, QANR24R25, C(=O)R24, and AC (=O) R R22 is selected from hydrogen, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, and cycloalkyl of 36 carbon atoms; R23 is selected from hydroxy, alkoxy of 16 carbon atoms, haloalkoxy of 1 6 carbon atoms, and cycloalkoxy of 36 carbon atoms, or R23 is selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02, and 0, all of which may be substituted with 13 of R10, or R23 is 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=0) 02, wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of Rio ; R24 and R25 are independently selected from hydrogen, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, and AR23, or R24 and R25 are independently selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=0) 02, and 0, all of which may be substituted with 13 of R01, or R24 and R25 are independently selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10, or R24 and R25 combine, together with the nitrogen atom to which they are attached, to form a 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02, and 0, or a monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms, wherein one or more of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), all of which may be substituted with 13 of R10; R26 is selected from alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, and AR23, or R26 is selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=0) 02, and 0, all of which may be substituted with 13 of R10, or R26 is 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10 ; R27 is selected from hydrogen, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, and AR23, or R27 is selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02, and 0, all of which may be substituted with 13 of R10, or R27 is 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of Rio ; R8 is selected from hydrogen, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, AR23, C (=O) R24 C (=O) OR26, C (=O) RN25R30, S (=O) 2ruz AC(=O)R24, AC(=O)OR24, and AC (=O) NR24R25, or R28 is selected from cycloalkyl of 36 carbon atoms, phenyl, monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02, and 0, all of which may be substituted with 13 of R10, or R28 is 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10 ; Wo is selected from alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, and AR23, or R30 is selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) o2, and 0, all of which may be substituted with 13 of R10, or Wo is 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10, or R25 and Wo combine, together with the nitrogen atom to which they are attached, to form a 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) o2, and 0, or a monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms, all of which may be substituted with 13 of Rl° ; and R29 is selected from alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, AR23, AC (=O) R24, AC (=o) OR24, AC(=O)NR24R25, ANR27R28, or R29 is selected from cycloalkyl of 36 carbon atoms, phenyl, monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) o2, and 0, all of which may be substituted with 13 of Rl°, or R29 is 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=0) 0 2, wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of Rlo.

15.	The compound of claim 14 selected from the group consisting of :.

16.

The compound of claim 1 or 9, wherein R7 is selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms, all of which may be substituted with 13 of R10, or R7 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10, AR23, ANR24R25, C (=O) R24 C (=O) OR24, C(=O)NR24R25, S(=O)2R26, AC(=O)R24, AC(=O)OR24, or AC(=O)NR24R25, or R7' is selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, alkoxy of 16 carbon atoms, haloalkoxy of 16 carbon atoms, cycloalkoxy of 36 carbon atoms, AR23, A (OR22)R23, NR27R28, ANR27R28, AQR9, QR29, QANR24R25, C(=O0R24, C(=O)OR24, C (=o) NR24R25, AC(=O)R24, AC(=O)OR24, and AC (=O) NR24R25; R22 is selected from hydrogen, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, and cycloalkyl of 36 carbon atoms; R23 is selected from hydroxy, alkoxy of 16 carbon atoms, haloalkoxy of 1 6 carbon atoms, and cycloalkoxy of 36 carbon atoms, or R23 is selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) o2, and 0, all of which may be substituted with 13 of RIO, or R23 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=0) 02, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of Rio ; with the proviso for A (OR22)R23 that when R23 is selected from hydroxy, alkoxy of 16 carbon atoms, haloalkoxy of 16 carbon atoms, and cycloalkoxy of 36 carbon atoms, A is not CH; R24 and R25 are independently selected from hydrogen, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, and AR23, or R24 and R25 are independently selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02, and 0, all of which may be substituted with 13 of Rio, or R24 and R25 are independently selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=0) 02, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10, or R24 and R25 combine, together with the nitrogen atom to which they are attached, to form a 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02, or a monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), all of which may be substituted with 13 of R10 ; R26 is selected from alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, A (and A, or R26 is selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=0) 02, and 0, all of which may be substituted with 13 of R10, or R26 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10 ; R27 is selected from hydrogen, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, and AR23, or R27 is selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02, and 0, all of which may be substituted with 13 of R10, or R27 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=0) 02, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10 ; R28 is selected from hydrogen, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, AR23, C (=O) R24 C (=O) OR26, C (=O) NR25R30 S (26 AC (=O) R24, AC (=O) OR24, and AC (=O) NR24R25, or R28 is selected from cycloalkyl of 36 carbon atoms, phenyl, monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02, and 0, all of which may be substituted with 13 of R10, or R28 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10 ; R30 is selected from alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, A (OR22)R23, and AR23, or R30 is selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=0) 02, and 0, all of which may be substituted with 13 of R10, or Wo is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10, or R25 and R30 combine, together with the nitrogen atom to which they are attached, to form a 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=0) 02, and 0, or a monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms, all of which may be substituted with 13 of R10 ; R29 is selected from alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, AR23, AC (=O) R24, AC(=O)OR24, AC(=O)NR24R25, ANR27R28, or R29 is selected from cycloalkyl of 36 carbon atoms, phenyl, monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02 and 0, all of which may be substituted with 13 of R10, or R29 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10.

17.

The compound of claim 16, wherein R7 iS selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms, all of which may be substituted with 13 of R10, or R7 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S(=O)02, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R'O, AR23, ANR24R25, C (=O) R24 C (=O) OR C (=O) NR24R25, or S (=0) 2ruz6,, or R7 is selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, alkoxy of 16 carbon atoms, haloalkoxy of 16 carbon atoms, cycloalkoxy of 36 carbon atoms, AR23, NR27R28, ANR27R28, 29 QR29, QANR24R25, C(=O)R24, C(=O)NR24R25, AC(=O)R24, and A C (=O) NR24R25 ; R22 is selected from hydrogen, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, and cycloalkyl of 36 carbon atoms; R23 is selected from hydroxy, alkoxy of 16 carbon atoms, haloalkoxy of 1 6 carbon atoms, and cycloalkoxy of 36 carbon atoms, or R23 is selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02, and 0, all of which may be substituted with 13 Of R10, or R23 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10 ; R24 and R25 are independently selected from hydrogen, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, and AR23, or R24 and R25 are independently selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=0) 02, and 0, all of which may be substituted with 13 of R10, or R24 and R25 are independently selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10, or R24 and R25 combine, together with the nitrogen atom to which they are attached, to form a 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=0) 02, or a monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), all of which may be substituted with 13 of R10 ; R26 is selected from alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, and AR23, or R26 is selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02, and 0, all of which may be substituted with 13 of R10, or R26 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of Rio ; R27 is selected from hydrogen, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, and AR23, or R7 is selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02, and 0, all of which may be substituted with 13 of R10, or R27 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=0) 02, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10 ; R 8 is selected from hydrogen, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, AR23, AC (=O) R24, AC (=O) OR24, and AC (=O) NR24R25, or R28 is selected from cycloalkyl of 36 carbon atoms, phenyl, monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=0) o2, and 0, all of which may be substituted with 13 of R10, or R8 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of Rio ; R30 is selected from alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, and AR23, or R30 is selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=0) 02, and 0, all of which may be substituted with 13, of R10, or R30 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) o2, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10, or R25 and R30 combine, together with the nitrogen atom to which they are attached, to form a 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02, and 0, or a monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms, all of which may be substituted with 13 of Rio ; R29 is selected from alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, AR23, AC (=O) R24 AC (=O) OR24, AC (=O) NR24R25, ANR27R28, or R29 is selected from cycloalkyl of 36 carbon atoms, phenyl, monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=0) 02, and 0, all of which may be substituted with 13 of R10, or R29 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=0) 02, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10.

18.	The compound of claim 17 selected from the group consisting of :.

19.

The compound of claim 1 or 9, wherein R8 is selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms, all of which may be substituted with 13 of R10, or R8 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10, AR23, ANR24R25, C (=O) R24, C (=O) OR 24, C(=O)NR24R25, S(=O02R26, AC(=O)R24, AC(=O)OR24, or AC(=O)NR24R25, or R8' is selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, alkoxy of 16 carbon atoms, haloalkoxy of 16 carbon atoms, cycloalkoxy of 36 carbon atoms, AR23, A (OR22)R23, NR27R28, ANR27R28, AQR29, QR29, QANR24R25, C(=O)R24, C(=O)OR24, C(=O)NR24R25, AC(=O)R24, AC(=O)OR24, and AC(=O)NR24R25; R22 is selected from hydrogen, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, and cycloalkyl of 36 carbon atoms; R23 is selected from hydroxy, alkoxy of 16 carbon atoms, haloalkoxy of 1 6 carbon atoms, and cycloalkoxy of 36 carbon atoms, or R23 is selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=0) 02, and 0, all of which may be substituted with 13 of R10, or R23 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10 ; with the proviso for A (OR22)R23 that when R23 is selected from hydroxy, alkoxy of 16 carbon atoms, haloalkoxy of 16 carbon atoms, and cycloalkoxy of 36 carbon atoms, A is not CH; R24 and R25 are independently selected from hydrogen, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, and AR23, or R24 and R25 are independently selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02, and 0, all of which may be substituted with 13 of R10, or R24 and R25 are independently selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) o2, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10, or R24 and R25 combine, together with the nitrogen atom to which they are attached, to form a 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02, or a monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), all of which may be substituted with 13 of R10 ; R26 is selected from alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, A (OR22)R23, and AR23, or R26 is selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02, and 0, all of which may be substituted with 13 of R10, or R26 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10 ; R27 is selected from hydrogen, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, and AR23, or R27 is selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=0) 02, and 0, all of which may be substituted with 13 of Rio, or R27 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=0) o2, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10 ; R28 is selected from hydrogen, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, AR23, C (=O) R24 C (=O) OR26, C (=O) NR25R30 S (=O)2R26, AC (=O) R24, AC (=O) OR24, and AC (=O) NR24R25, or R28 is selected from cycloalkyl of 36 carbon atoms, phenyl, monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02, and 0, all of which may be substituted with 13 of R10, or R28 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) o2, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O) wherein said heterocycloalkyl may be substituted with 13 of Rio ; R30 is selected from alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, A (OR22)R23, and AR23, or R30 is selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02, and 0, all of which may be substituted with 13 of R10, or R30 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) o2, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10, or R25 and R30 combine, together with the nitrogen atom to which they are attached, to form a 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=0) 02, and 0, or a monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms, all of which may be substituted with 13 of R10 ; R29 is selected from alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, AR23, AC (=O) R24, AC (=O) OR24, AC (=O) NR24R25, ANR27R28, or R29 is selected from cycloalkyl of 36 carbon atoms, phenyl, monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02, and 0, all of which may be substituted with 13 of R10, or R29 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) o2, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10.

20.

The compound of claim 1 or 9, wherein R8 is selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms, all of which may be substituted with 13 of R10, or R8 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10, AR23, ANR24R25, C (=O) R24, C(=O)OR24, C (=O) NR24R25, or S(=O)2R26,, or R8 is selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, AR23, NR27R28, ANR27R28, AQR29, S(=O)02R29, S(=O)02ANR24R25, C(=O)NR24R25, AC(=O)OR24, and A C (=O)NR24R25; R22 is selected from hydrogen, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, and cycloalkyl of 36 carbon atoms ; R23 is selected from hydroxy, alkoxy of 16 carbon atoms, haloalkoxy of 1 6 carbon atoms, and cycloalkoxy of 36 carbon atoms, or R3 is selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02, and 0, all of which may be substituted with 13 of R10, or R23 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=0) 02, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10 ; R24 and R25 are independently selected from hydrogen, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, and AR23, or R24 and R25 are independently selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02, and 0, all of which may be substituted with 13 of R10, or R24 and R25 are independently selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, 0, S (=O) O 2, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10, or R24 and R25 combine, together with the nitrogen atom to which they are attached, to form a 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=0) 02, and 0, monocyclic heteroaryland/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), all of which may be substituted with 13 of R10 ; R26 is selected from alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, and AR23, or R26 is selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=0) 02, and 0, all of which may be substituted with 13 of R10, or R26 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of Rlo ; R7 is selected from hydrogen, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, and AR23, or R27 is selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=0) 02, and 0, all of which may be substituted with 13 of R10, or R27 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) o2, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of RIO ; R28 is selected from hydrogen, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, AR23, AC (=O) R24, AC (=O) OR24, and AC (=O) NR24R25, or R8 is selected from cycloalkyl of 36 carbon atoms, phenyl, monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02, and 0, all of which may be substituted with 13 of R10, or R28 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=0) 02, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10 ; R30 is selected from alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, and AR23, or R30 is selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02, and 0, all of which may be substituted with 13 of R10, or R30 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10, or R25 and R30 combine, together with the nitrogen atom to which they are attached, to form a 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02, and 0, or a monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms, all of which may be substituted with 13 of R10 ; R29 is selected from alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, , AR23, AC (=o) R24, AC(=O)OR24, AC(=O)NR24R25, ANR27R28, or R29 is selected from cycloalkyl of 36 carbon atoms, phenyl, monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=0) 02, and 0, all of which may be substituted with 13 of R10, or R29 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=0) 02, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10.

21.	The compound of claim 20 selected from the group consisting of :.

22.

A compound of the formula II wherein R"is selected from alkyl of 18 carbon atoms, alkenyl of 28 carbon atoms, alkynyl of 28 carbon atoms, and AR9, or R1 is selected from aryl of 610 carbon atoms, heteroaryl of 29 carbon atoms and 14 heteroatoms selected from N, S (=O) 02 and 0, cycloalkyl of 38 carbon atoms, cycloalkenyl of 48 carbon atoms, 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 56 membered heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02 and 0, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), all of which may be substituted with 13 of Rio ; Rio is selected from nitro, nitrile, hydroxy, halogen, acyl of 16 carbon atoms, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, haloalkyl of 16 carbon atoms, alkoxy of 16 carbon atoms, haloalkoxy of 16 carbon atoms, cycloalkoxy of 36 carbon atoms, aryl of 610 carbon atoms, heteroaryl of 29 carbon atoms and 14 heteroatoms selected from N, S (=O) 02 and 0, NR11R12, C (=O) OR", C (=O) NHR11, NHC (=O) R13, NHS (=0) 2R13, S (=0) 02R13, S (=0) 2NHR11, cycloalkyl of 36 carbon atoms, cycloalkenyl of 36 carbon atoms, 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=0) 02 and 0, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 56 membered heteroaryl of 25 carbon atoms and 1 3 heteroatoms selected from N, S (=O) 02 and 0, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O) ; R13 is selected from alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, haloalkyl of 16 carbon atoms, cycloalkyl of 36 carbon atoms, and cycloalkenyl of 46 carbon atoms; Rll and R12 are independently selected from hydrogen, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, haloalkyl of 16 carbon atoms, cycloalkyl of 36 carbon atoms, and cycloalkenyl of 46 carbon atoms; A is selected from alkyl of 18 carbon atoms, alkenyl of 28 carbon atoms, alkynyl of 28 carbon atoms, and haloalkyl of 18 carbon atoms; R9 is selected from hydroxy, alkoxy of 16 carbon atoms, cycloalkoxy of 3 6 carbon atoms, OAR, NRllRl2 ; or R9 is selected from aryl of 610 carbon atoms, heteroaryl of 29 carbon atoms and 14 heteroatoms selected from N, S (=O) 02 and 0, cylcoalkyl of 38 carbon atoms, cycloalkenyl of 58 carbon atoms, all of which may be substituted with 13 of Rl°, or R9 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=0) 02 and O and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 56 membered heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02 and 0, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1 3 of R10 ; R14 is selected from cylcoalkyl of 38 carbon atoms, cycloalkenyl of 58 carbon atoms, 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) o2 and 0, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, all of which may be substituted with 13 of R10 ; with the proviso for R1 that when A is CH2, R9 is not optionally substituted biphenyl; R2'is NRlSRIS ; R15 is selected from hydrogen, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, cylcoalkyl of 38 carbon atoms, cycloalkenyl of 48 carbon atoms, 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=0) 02 and 0, AR9, C (=O) R18, C (=O) NHR18, S (=0) 2NHR ; R18 is selected from aryl of 610 carbon atoms, heteroaryl of 29 carbon atoms and 14 heteroatoms selected from N, S (=0) 02 and 0, cylcoalkyl of 38 carbon atoms, cycloalkenyl of 48 carbon atoms, 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) o2 and 0, all of which may be substituted with 13 of R10, or R18 is selected from alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, and alkynyl of 26 carbon atoms, all of which may be substituted with 13 of halogen or alkoxy of 16 carbon atoms, or R18 is AR9 ; R6 is selected from alkyl of 18 carbon atoms, alkenyl of 28 carbon atoms, alkynyl of 28 carbon atoms, and AR9, or R16 is selected from aryl of 610 carbon atoms, heteroaryl of 29 carbon atoms and 14 heteroatoms selected from N, S (=0) 02 and 0, cycloalkyl of 38 carbon atoms, cycloalkenyl of 48 carbon atoms, 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=0) 02 and 0, all of which may be substituted with 13 of Rio, or R15 and R16 combine, together with the nitrogen atom to which they are attached, to form a heteroaryl of 29 carbon atoms and 14 heteroatoms selected from N, S (=O) 02 and 0, or a 57 membered heterocycloalkyl of 3 6 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 56 membered heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02 and 0, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), all of which may be substituted with 13 of Rio ; R3 is selected from cycloalkyl of 36 carbon atoms, heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (O) 02 and 0, both of which may be substituted with 13 of R10, or R3 is selected from alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, hydrogen, nitro, halogen, NR19R20, AORl9, ANR19R20 and AR20 ; Rl9 and R20 are independently selected from hydrogen, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, haloalkyl of 16 carbon atoms, and AR9, or Rl9 and Wo are independently selected from aryl of 610 carbon atoms, heteroaryl of 29 carbon atoms and 14 heteroatoms selected from N, S (O) o 2 and 0, cylcoalkyl of 38 carbon atoms, cycloalkenyl of 58 carbon atoms, 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (O) 02 and 0, 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, S (0) 02 and 0, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 56 membered heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=0) 02 and 0, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), all of which may be substituted with 13 of R10; R4 is selected from =0, =S, and OR2' ; Rl is hydrogen, or R21 is selected from alkyl of 18 carbon atoms, alkenyl of 28 carbon atoms, alkynyl of 28 carbon atoms, cycloalkyl of 38 carbon atoms, cycloalkenyl of 48 carbon atoms, 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02, and 0, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=0) 02 and 0, all of which may be substituted with 13 of R10 ; Rs is selected from cycloalkyl of 36 carbon atoms, cycloalkenyl of 46 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms, all of which may be substituted with 13 of Rl°, or Rs is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02, and O and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 13 of Rl°, AR23, ANR24R25, C(=O)R24, C(=O)OR24, C(=O)NR24R25, S(=O)2R26, AC(=O)R24, AC(=O)OR24, or AC(=O)NR24R25, or Rs is selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, haloalkyl of 16 carbon atoms, alkoxy of 16 carbon atoms, haloalkoxy of 16 carbon atoms, cycloalkoxy of 36 carbon atoms, AR23, A (OR22)R23, NR27R28, ANR27R28, AQ R29, QR29, QANR24R25, C(=O)R24, C(=O)OR24, C(=O)NR24R25, AC(=O)R24, AC (=O) OR24, and AC (=O) NR24RZS ; Q is selected from O and S (=O) 02, ; R22 is selected from hydrogen, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, and cycloalkyl of 36 carbon atoms; R23 is selected from hydroxy, alkoxy of 16 carbon atoms, haloalkoxy of 1 6 carbon atoms, and cycloalkoxy of 36 carbon atoms, or R23 is selected from cycloalkyl of 36 carbon atoms, cycloalkenyl of 46 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=0) 02, and 0, all of which may be substituted with 13 of Rl°, or R23 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) o2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1 3 of R10 ; with the proviso for A (oR22)R23 that when R23 is selected from hydroxy, alkoxy of 16 carbon atoms, haloalkoxy of 16 carbon atoms, and cycloalkoxy of 36 carbon atoms, A is not CH; R24 and R25 are independently selected from hydrogen, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, haloalkyl of 16 carbon atoms, and AR23, or R24 and R25 are independently selected from cycloalkyl of 36 carbon atoms, cycloalkenyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02, and 0, all of which may be substituted with 13 of Rl°, or R24 and R25 are independently selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 13 of Rl°, or R24 and R25 combine, together with the nitrogen atom to which they are attached, to form a 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02, and 0, a 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02, and 0, or a monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), all of which may be substituted with 13 of Rio ; R26 is selected from alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, haloalkyl of 16 carbon atoms, A (OR22)R23, and AR23, or R26 is selected from cycloalkyl of 36 carbon atoms, cycloalkenyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=0) 02, and 0, all of which may be substituted with 13 of Rl°, or R26 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=0) 02, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1 3 of R10 ; R27 is selected from hydrogen, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, haloalkyl of 16 carbon atoms, and ARa3, or R27 is selected from cycloalkyl of 36 carbon atoms, cycloalkenyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02, and 0, all of which may be substituted with 13 of Rl°, or R27 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=0) o2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1 3 of R10; R28 is selected from hydrogen, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, haloalkyl of 16 carbon atoms, AR23, C (=O)R24, C (=O) OR26, C(=O)NR25R30, S(=O)2R26, AC(=O)R24, A C (=o) OR24, and AC(=O)NR24R25, or R28 is selected from cycloalkyl of 36 carbon atoms, cycloalkenyl of 36 carbon atoms, phenyl, monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=0) 02, and 0, all of which may be substituted with 13 of R10, or W8 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=0) 02, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=0) 02, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1 3 of R10; R30 is selected from alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, haloalkyl of 16 carbon atoms, A (OR22)R23, and AR23, or R30 is selected from cycloalkyl of 36 carbon atoms, cycloalkenyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02, and 0, all of which may be substituted with 13 of R10, or R30 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=0) 02, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1 3 of R10 or R25 and Wo combine, together with the nitrogen atom to which they are attached, to form a 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=0) 02, and 0, a 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02, and 0, or a monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms, all of which may be substituted with 13 of R10 ; and R29 is selected from alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, haloalkyl of 16 carbon atoms, AR23, A C(=O)R24, AC(=O)OR24, AC(=O)NR24R25, ANR27R28, or R29 is selected from cycloalkyl of 36 carbon atoms, cycloalkenyl of 36 carbon atoms, phenyl, monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02, and 0, all of which may be substituted with 13 of R10, or R29 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, and 57 membered heterocycloalkenyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=0) 02, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1 3 of R10. R7 and R8 are independently selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms, all of which may be substituted with 13 of R10, or R7 and R8 are independently selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=0) 02, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10, AR23, ANR24R25, C(=O)R24, C(=O)OR24, C(=O)NR24R25, S(=O)2R26, AC(=O)R24, AC(=O)OR24, or AC(=O)NR24R25, or R7' and R8' are independently selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, alkoxy of 16 carbon atoms, haloalkoxy of 16 carbon atoms, cycloalkoxy of 36 carbon atoms, AR23, A (OR22)R23, NR27R28, ANR27R28, AQR29 QR29, QANR24R25, C(=O)R24, C(=O)OR24, C(=O)NR2425, AC(=O)R24, AC(=O)OR24,' and A C (=O) NR24R21. and pharmaceutically acceptable salts thereof.

23.

The compound of claim 22, wherein R4' is =O ; Rls is selected from hydrogen, alkyl of 16 carbon atoms, cylcoalkyl of 38 carbon atoms, 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=0) 02 and 0, AR9, C (=O) R18, C (=O) NHR18, and S (=0) 2NHR18; R'8 is selected from phenyl, monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02, and 0, cylcoalkyl of 36 carbon atoms, and 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, all of which may be substituted with 13 of R10, or R18 is alkyl of 16 carbon atoms, which may be substituted with 13 of halogen or alkoxy of 16 carbon atoms, or R18 iS AR9 ; and R16 is selected form alkyl of 16 carbon atoms and AR9, or R16 is selected from phenyl, monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02, and 0, cycloalkyl of 38 carbon atoms, and 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, all of which may be substituted with 13 of R10 or Rl5 and R16 combine, together with the nitrogen atom to which they are attached, to form a monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=0) 02, and 0, or a 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), all of which may be substituted with 13 of R10 ; Rl9 and R20 are independently selected from hydrogen, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms and AR9, or wherein R19 and R20 are independently selected from phenyl, monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (O) o2 and 0, cycloalkyl of 3 6 carbon atoms, 57 membered heterocycloalkyl of 36 carbon atoms and 1 2 heteroatoms selected from N, S (O) 02 and 0, wherein one or more of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), all of which may be substituted with 13 of R10 ; and Rus ils selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms, all of which may be substituted with 13 of R10, or Rs is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02 and 0, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10, AR23, ANR24R25, C (=O) R24, C(=O)OR24, C(=O)NR24R25, S(=O)2R26 AC(=O)R24, AC(=O)OR24, or A C(=O)NR24R25, or Rs is selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, alkoxy of 16 carbon atoms, haloalkoxy of 16 carbon atoms, cycloalkoxy of 36 carbon atoms, AR23, NR27R28, ANR27R28, AQR29, QR29, QANR24R25, C(=O)R24, and AC (=O) R ; R22 is selected from hydrogen, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, and cycloalkyl of 36 carbon atoms; R23 is selected from hydroxy, alkoxy of 16 carbon atoms, haloalkoxy of 1 6 carbon atoms, and cycloalkoxy of 36 carbon atoms, or R23 is selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=0) 02, and 0, all of which may be substituted with 13 of R10, or R23 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=0) 02, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10 ; R24 and R25 are independently selected from hydrogen, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, and AR23, or R24 and R25 are independently selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) o2, and 0, all of which may be substituted with 13 of R10, or R24 and R25 are independently selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10, or R24 and R5 combine, together with the nitrogen atom to which they are attached, to form a 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02, or a monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), all of which may be substituted with 13 of R10 ; R26 is selected from alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, and AR23, or R26 is selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02, and 0, all of which may be substituted with 13 of R10, or R26 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10; selected from hydrogen, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, and AR23, or R27 is selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=0) 02, and 0, all of which may be substituted with 13 of R10, or R27 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) o2, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10 ; R28 is selected from hydrogen, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, AR23, AC (=O) R24, AC (=O) OR24, and AC (=O) NR24R25, or R28 is selected from cycloalkyl of 36 carbon atoms, phenyl, monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=0) 02, and 0, all of which may be substituted with 13 of R10, or W8 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of ; R30 is selected from alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, and AR23, or Wo is selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) o2, and 0, all of which may be substituted with 13 of R10, or R30 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=0) 02, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10, or R25 and Wo combine, together with the nitrogen atom to which they are attached, to form a 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02, and 0, or a monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms, all of which may be substituted with 13 of R10 ; R29 is selected from alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, AR23, AC(=O)R24, AC(=O)OR24, AC(=O)NR24R25, ANR27R28, or R29 is selected from cycloalkyl of 36 carbon atoms, phenyl, monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=0) 02, and 0, all of which may be substituted with 13 of R10, or R29 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, O, S (=O) 02, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10 ; R7 is selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms, all of which may be substituted with 13 of R10, or R7 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=O) 02, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R'O, AR23, ANR24R25 C (=O) R24 C (=O) OR24, C(=O)NR24R25, or S (=0) 2R26,, or R7 is selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, alkoxy of 16 carbon atoms, haloalkoxy of 16 carbon atoms, cycloalkoxy of 36 carbon atoms, AR23, NR27R28, ANR27R28, AQR, QR29, QA NR24R25, C(=O)R24, C(=O)NR24R25, AC(=O)R24, and A C (=o) NR24R25; R8 is selected from cycloalkyl of 36 carbon atoms, phenyl, and monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms, all of which may be substituted with 13 of R10, or R8 is selected from 57 membered heterocycloalkyl of 36 carbon atoms and 12 heteroatoms selected from N, S (=0) 02, and 0, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 13 of R10, AR23, ANR24R25, C(=O)R24, C (=o) oR24, C (=o) NR24R25, or S (=0) 2R26,, or R8 is selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 16 carbon atoms, haloalkyl of 16 carbon atoms, AR23, NR27R28, ANR27R28, AQR29, S(=O)02R29, S(=O)02ANR24R25, C(=O)NR24R25, AC(=O)OR24, and A C(=O)NR24R25.

24.

The compound of claim 23, wherein R"is selected from alkyl of 18 carbon atoms, and AR9, or R"is selected from phenyl, monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02 and 0, cycloalkyl of 36 carbon atoms, all of which may be substituted with 13 of R10 ; A is selected from alkyl of 16 carbon atoms, and haloalkyl of 18 carbon atoms; R9 is selected from hydroxy, alkoxy of 16 carbon atoms, cycloalkoxy of 3 6 carbon atoms, OAR14, NR11R12 ; or R9 is selected from phenyl, monocyclic heteroaryl of 25 carbon atoms and 13 heteroatoms selected from N, S (=O) 02, and 0, cylcoalkyl of 36 carbon atoms, all of which may be substituted with 13 of Rlo.

25.	The compound of claim 24, wherein R"is phenyl, which may be substituted with 13 of R10.

26.

A method of treating or preventing a disease or condition selected from the group consisting of diabetes (Type 1 or Type 2), maturityonset diabetes of the young (MODY), latent autoimmune diabetes adult (LADA), impaired glucose tolerance (IGT), impaired fasting glucose (IFG), gestational diabetes, and metabolic syndrome X, comprising administering to a mammal an effective amount of a compound of claim 1 or 22.

27.	The method of claim 26, wherein said disease or condition is diabetes (Type 1 or Type 2).

28.	The method of claim 27, wherein said disease or condition is Type 2 diabetes.

29.	The method of claim 26, further comprising administering a PPARagonist, an insulin sensitizer, a sulfonylurea, an insulin secretagogue, a hepatic glucose output lowering compound, an aglucosidase inhibitor or insulin in combination with said compound of claim 1 or 22.

30.	The method of claim 29, wherein said PPARagonist is selected from rosiglitazone and pioglitazone.

31.	The method of claim 29, wherein said sulfonylurea is selected from glibenclamide, glimepiride, chlorpropamide, and glipizide.

32.	The method of claim 29, wherein said insulin secretagogue is selected from GLP 1, GIP, PAC/VPAC receptor agonists, secretin, nateglinide, meglitinide, repaglinide, glibenclamide, glimepiride, chlorpropamide, and glipizide.

33.	The method of claim 29, wherein said aglucosidase inhibitor is selected from acarbose, miglitol and voglibose.

34.	The method of claim 29, wherein said hepatic glucose output lowering compound is metformin.

35.	The method of claim 26, further comprising administering an HMGCoA reductase inhibitor, nicotinic acid, a bile acid sequestrant, a fibric acid derivative, antihypertensive drug, or an antiobesity drug in combination with said compound of claim 1 or 22.

36.	The method of claim 35, wherein said antiobesity drug is selected from a B3 agonist, a CB1 antagonist, and a lipase inhibitor.

37.	A method of treating or preventing secondary causes of diabetes selected from glucocorticoid excess, growth hormone excess, pheochromocytoma, and drug induced diabetes, comprising administering to a mammal an effective amount of a compound of claim 1 or 22. 38.

38.	A method of increasing the sensitivity of pancreatic beta cells to an insulin secretagogue, comprising administering to a mammal an effective amount of a compound of claim 1 or 22.

39.	The method of claim 38, wherein said insulin secretagogue is selected from GLP 1, GIP, PAC/VPAC receptor agonists, secretin, nateglinide, meglitinide, repaglinide, glibenclamide, glimepiride, chlorpropamide, and glipizide.

40.	A pharmaceutical composition, comprising a compound according to claim 1 or 22 and a pharmaceutically acceptable carrier.

Description:

1, 6-NAPHTHYRIDINE DERIVATIVES AS ANTIDIABETICS The present invention relates to 1,6-naphthyridine derivatives, pharmaceutical compositions containing them, and their use for treating diabetes and related disorders in a subject.

DESCRIPTION OF THE RELATED ART Diabetes is characterized by impaired glucose metabolism manifesting itself among other things by an elevated blood glucose level in the diabetic patient. Underlying defects lead to a classification of diabetes into two major groups: type 1 diabetes, or insulin dependent diabetes mellitus (IDDM), arises when patients lack insulin-producing beta-cells in their pancreatic glands. Type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), occurs in patients with impaired beta-cell function and alterations in insulin action.

The current treatment for type 1 diabetic patients is the injection of insulin, while the majority of type 2 diabetic patients are treated with agents that stimulate beta-cell function or with agents that enhance the tissue sensitivity of the patients towards insulin.

The drugs presently used to treat type 2 diabetes include alpha-glucosidase inhibitors, insulin sensitizers, insulin secretagogues, and metformin.

Over time almost one-half of type 2 diabetic subjects lose their response to these agents. Insulin treatment is instituted after diet, exercise, and oral medications have failed to adequately control blood glucose. The drawbacks of insulin treatment are the need for drug injection, the potential for hypoglycemia, and weight gain.

Because of the problems with current treatments, new therapies to treat type 2 diabetes are needed. In particular, new treatments to retain normal (glucose-dependent) insulin secretion are needed. Such new drugs should have the following characteristics: dependency on glucose for promoting insulin secretion, i. e. , compounds that stimulate insulin secretion only in the presence of elevated blood glucose; low primary and secondary failure rates; and preservation of islet cell function. The strategy to develop the new therapy disclosed herein is based on the cyclic adenosine monophosphate (cAMP) signaling mechanism and its effects on insulin secretion.

Metabolism of glucose promotes the closure of ATP-dependent K+ channels, which leads to cell depolarization and subsequent opening of Ca++ channels. This in turn results in the exocytosis of insulin granules. cAMP is a major regulator of glucose- stimulated insulin secretion. However, it has little if any effects on insulin secretion in the absence of or at low glucose concentrations (Weinhaus, A., et al., Diabetes 47: 1426-1435 (1998) ). The effects of cAMP on insulin secretion are thought to be mediated by a protein kinase A pathway.

Endogenous secretagogues like pituitary adenylate cyclase activating peptide (PACAP), VIP, and GLP-1 use the cAMP system to regulate insulin secretion in a glucose-dependent fashion (Komatsu, M., et al., Diabetes 46: 1928-1938, (1997) ). Also, phosphodiesterases (PDEs) are known to be involved in the regulation of the cAMP system.

PACAP is a potent stimulator of glucose-dependent insulin secretion from pancreatic beta cells. Three different PACAP receptor types (Rl, R2, and R3) have been described (Harmar, A. , et al., Pharmacol. Reviews 50: 265-270 (1998) ). The insulinotropic action of PACAP is mediated by the GTP binding protein Gs. Accumulation of intracellular cAMP in turn activates nonselective cation channels in beta cells increasing [Ca++] i, and promoting the exocytosis of insulin-containing secretory granules.

Vasoactive intestinal peptide (VIP) is a 28 amino acid peptide that was first isolated from hog upper small intestine (Said and Mutt, Science 169: 1217-1218,1970 ; U. S. Patent No. 3,879, 371). This peptide belongs to a family of structurally related, small polypeptides that includes helodermin, secretin, the somatostatins, and glucagon. The biological effects of VIP are mediated by the activation of membrane-bound receptor proteins that are coupled to the intracellular cAMP signaling system. These receptors were originally known as VIP-R1 and VIP-R2, however, they were later found to be the same receptors as PACAP-R2 and PACAP-R3.

GLP-1 is released from the intestinal L-cell after a meal and functions as an incretin hormone (i. e. , it potentiates glucose-induced insulin release from the pancreatic beta cell). It is a 37-amino acid peptide that is differentially expressed by the glucagon gene, depending upon tissue type. The clinical data that support the beneficial effect of raising cAMP levels in ß-cells have been collected with GLP-1. Infusions of GLP-1 in poorly controlled type 2 diabetics normalized their fasting blood glucose levels (Gutniak, M. , et al., New Eng. J. Med. 326: 1316-1322, (1992)) and with longer infusions improved the beta cell function to those of normal subjects (Rachman, J. et al., Diabetes 45: 1524- 1530, (1996) ). A recent report has shown that GLP-1 improves the ability of 8-cells to respond to glucose in subjects with impaired glucose tolerance (Byrne M. , et al., Diabetes 47: 1259-1265 (1998) ). All of these effects, however, are short-lived because of the short half-life of the peptide.

SUMMARY OF THE INVENTION The invention provides compounds, pharmaceutical compositions, and methods of using the same for treating diabetes and related disorders. Compounds of the invention include compounds of formula (II) wherein R"is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and A-R9, or Rl is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S (=O) 0-2 and O, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 02 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S (=O) 0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), all of which may be substituted with 1-3 of Rio ; Rl° is selected from nitro, nitrile, hydroxy, halogen, acyl of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S (=O) 02 and O, NR11R12, C (=O) OR", C (=O) NHR11, NHC (=O) R13, NHS (=O) 2RI3, S (=O) 0-2R13, S (=O) 2NHR11, cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S (=O) 0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O) ; R13 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, and cycloalkenyl of 4-6 carbon atoms; Rll and R12 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, and cycloalkenyl of 4-6 carbon atoms; A is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and haloalkyl of 1-8 carbon atoms; R9 is selected from hydroxy, alkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, O-A-R14, NR11R12 ; or R9 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S (=O) 0-2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, all of which may be substituted with 1-3 of Rl°, or R9 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2 and O and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 02 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S (=O) 0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10 ; R14 is selected from cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2 and 0, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 02 and O, all of which may be substituted with 1-3 of R10: with the proviso for Rl that when A is CH2, R9 is not optionally substituted biphenyl; R'is selected from NR15R16, S (O) o-2R, and OR17 ; Rls is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2 and O, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 02 and O, A-R9, C (=O) R18, C (=O) NHR18, S (=0) 2NHR ; R18 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S (=O) 02 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2 and O, all of which may be substituted with 1-3 of Rl°, or R18 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, and alkynyl of 2-6 carbon atoms, all of which may be substituted with 1-3 of halogen or alkoxy of 1-6 carbon atoms, or Rl8 is A-R9 ; R16 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and A-R9, or R16 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S (=O) 02 and O, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2 and O, all of which may be substituted with 1-3 of R10, or Rls and R16 combine, together with the nitrogen atom to which they are attached, to form a heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S (=O) 0-2 and 0, or a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2 and O, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S (=O) 0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), all of which may be substituted with 1-3 of R10 ; R17 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, and alkynyl of 2-8 carbon atoms, haloalkyl of 1-8 carbon atoms, A-R9, or R17 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S (=O) 02 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2 and O, all of which may be substituted with 1-3 of Rio ; R3 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S (=O) 0-2 and O, cylcoalkyl of 3-8 carbon atoms, heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 02, and O, cycloalkenyl of 4-8 carbon atoms, and heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2 and O, all of which may be substituted with 1-3 of R", or R3 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, hydrogen, nitro, halogen, NR19R20, A-OR19, A-NR19R20, and A-R20; Rl9 and R20 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A- R9, or Rl9 and R20 are independently selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S (O) 0-2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (O) 0-2 and O, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (O) 0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S (=O) 0-2 and 0, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), all of which may be substituted with 1-3 of R10 ; R4'is selected from =0, =S, and OR21 ; R21 is hydrogen, or R21 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2 and O, all of which may be substituted with 1-3 of R10, Rs, R7, and R8 are independently selected from cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms, all of which may be substituted with 1-3 of R10, or Rs, R", and R8 are independently selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2 and O and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S (=O) o-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, A-R23, A- NR24R25, C(=O)R24, C(=O)OR24, C(=O)NR24R25 S(=O)2R26, A-C(=O)R24, A-C(=O)OR24, or A-C (=O) NR24R25, or R5, R", and R8 are independently selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, haloalkyl of 1-8 carbon atoms, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms, cycloalkoxy of 3-8 carbon atoms, A-R23, A (OR22)-R23, NR27R28, A-NR27R28, A-Q- R29 Q-R29, Q-A-NR24Ras, C(=O)R24, C(=O)OR24, C(=O)NR24R25, A-C(=O)R24, C (=O) OR24, and A-C (=O) NR24R25 ; Q is selected from O and S (-O) 0-2 ; R22 is selected from hydrogen, alkyl of 1-8 carbon atoms, haloalkyl of 1-8 carbon atoms, and cycloalkyl of 3-8 carbon atoms; R23 is selected from hydroxy, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms, and cycloalkoxy of 3-8 carbon atoms, or R23 is selected from cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S (=0) 02, and O, all of which may be substituted with 1-3 of R10, or R23 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S (=0) 02, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S (=O) 0-2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S (=O) 0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of Rio ; with the proviso for A (OR22)-R23 that when R23 is selected from hydroxy, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms, and cycloalkoxy of 3-8 carbon atoms, A is not CH; R24 and R25 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A- R, or R24 and R25 are independently selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1- 4 heteroatoms selected from N, S (=O) 02, and O, all of which may be substituted with 1-3 of R10, or R24 and R25 are independently selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S (=O) 02, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, 0, S (=O) 0-2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S (=O) 0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, or R24 and R25 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 02, and O, a 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 02, and O, or a heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S (=O) 0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), all of which may be substituted with 1-3 of R10 ; R26 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A (QR22)-R23, and A-R23, or R26 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S (=0) 02, and O, all of which may be substituted with 1-3 of Rl°, or R26 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S (=O) 02, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, 0, S (=O) 02, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S (=O) 0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10 ; R27 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R23, or R27 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S (=O) 0-2, and O, all of which may be substituted with 1-3 of R10, or R27 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S (=O) 0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S (=O) 02, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S (=O) 0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10 ; R28 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R23, C (=O) R24, C (=O) C(=O)NR25R30, S(=O)2R26, A-C(=O)R24, A-C(=O)OR24, and A- C (=O) NR24R25, or R28 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S (=O) 0-2, and O, all of which may be substituted with 1-3 of R10, or R28 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S (=O) o-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S (=O) 02, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S (=O) 0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of Rio ; R30 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A (OR22)-R23, and A-R23, or Wo is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S (=O) o-2, and O, all of which may be substituted with 1-3 of Rl°, or R30 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S (=O) 0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S (=O) 02, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S (=O) 0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of Rio, or R25 and R30 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 02, and O, a 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 02, and O, or a heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms, all of which may be substituted with 1-3 of R10 ; R29 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R23, A-C (=O) R24, A-C (=O) OR24, A- C(=O)NR24R25, A-NR27R28, or R29 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S (=O) 0-2, and O, all of which may be substituted with 1-3 of RIO, or R29 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S (=O) 0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S (=O) 02, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S (=O) 0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of Rio and pharmaceutically acceptable salts thereof.

Another aspect of the invention includes compounds of formula (II), wherien Rl is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and A-R9, or Rl is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S (=O) o-2 and O, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S (=O) 0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), all of which may be substituted with 1-3 of R10; Rio is selected from nitro, nitrile, hydroxy, halogen, acyl of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S (=O) 02 and O, NR11R12, C (=O) ORll, C (=O) NHRll, NHC (=O) R13, NHS (=O) 2R13, S (=O) o 2Rl3 S (=O) 2NHR11, cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 02 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S (=O) 0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O) ; R13 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, and cycloalkenyl of 4-6 carbon atoms; Rl l and R12 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, and cycloalkenyl of 4-6 carbon atoms; A is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and haloalkyl of 1-8 carbon atoms; R9 is selected from hydroxy, alkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, O-A-R14, NR11R12 ; or R9 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S (=O) 02 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, all of which may be substituted with 1-3 of Rl°, or R9 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2 and O and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 02 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S (=O) 0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10; R14 is selected from cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2 and O, all of which may be substituted with 1-3 of Rio. with the proviso for Rl that when A is CH2, R9 is not optionally substituted biphenyl; R2' is NR15R16 ; Rl5 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2 and O, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) o-2 and O, A-R9, C (=O) R18, C (=O) NHR18, S (=O) 2NHR ; Rl8 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S (=O) 0-2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2 and O, all of which may be substituted with 1-3 of R10, or R18 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, and alkynyl of 2-6 carbon atoms, all of which may be substituted with 1-3 of halogen or alkoxy of 1-6 carbon atoms, or R18 is A-R9; R16 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and A-R9, or R16 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S (=O) 02 and O, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 02 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2 and O, all of which may be substituted with 1-3 of R10, or Rls and R16 combine, together with the nitrogen atom to which they are attached, to form a heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S (=O) 0-2 and O, or a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2 and O, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S (=O) 02 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), all of which may be substituted with 1-3 of R10 ; R3 is selected from cycloalkyl of 3-6 carbon atoms, heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (O) 0-2 and O, both of which may be substituted with 1-3 of Rl°, or R3 is selected from alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, hydrogen, nitro, halogen, NR19R20, A-ORl9, A-NR19R20 and A-R20 ; Rl9 and Wo are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A- R9, or Rl9 and R20 are independently selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S (O) 0-2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (O) 0-2 and O, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (O) 0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S (=O) 02 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), all of which may be substituted with 1-3 of R10 ; R4 is selected from =0, =S, and OR21 ; R21 is hydrogen, or R21 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) o-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2 and O, all of which may be substituted with 1-3 of R10 ; Rs is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 4-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, all of which may be substituted with 1-3 of Rl°, or Rs is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2 and O and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) o-2 and O, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, A-R23, A-NR24R25, C(=O)R24, C(=O)OR24, C(=O)NR24R25, S(=O)2R26, A- C (=O) R24, A-C (=O) OR24, or A-C (=O) NR24R25, or R5 is selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, A-R", A (OR22)-R23, NR27R28, A-NR27R28, A-Q-R29, Q-R29, Q-A-NR24R25, C(=O)R24, C(=O)OR24, C(=O)NR24R25, A-C(=O)R24, A-C(=O)OR24, and A- C(=O)NR24R25; Q is selected from O and S (=O) 02 ; R22 is selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and cycloalkyl of 3-6 carbon atoms; R23 is selected from hydroxy, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, and cycloalkoxy of 3-6 carbon atoms, or R23 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 4-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S (=0) 02, and O, all of which may be substituted with 1-3 of Rl°, or R23 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S (=O) 02, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S (=O) o-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10 ; with the proviso for A (OR22)-R23 that when R23 is selected from hydroxy, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, and cycloalkoxy of 3-6 carbon atoms, A is not CH; R24 and R25 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A- R, or R24 and R25 are independently selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S (=O) 0-2, and O, all of which may be substituted with 1-3 of R, or R24 and R25 are independently selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S (=O) 0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S (=O) 0-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of Rl°, or R24 and R25 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 02, and O, a 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 0-2, and O, or a monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), all of which may be substituted with 1-3 of R10 ; R26 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A (OR22)-R23, and A-R23, or R26 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S (=O) 02, and O, all of which may be substituted with 1-3 of Rl°, or R26 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S (=O) 0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S (=O) 02, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10 ; R27 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R23, or R27 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S (=O) o-2, and O, all of which may be substituted with 1-3 of Rl°, or R27 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S (=O) o-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S (=O) 0-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of Rl° ; R28 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R23, C (=O) R24, C(=O)OR26, C(=O)NR25R30, R(=O)2R26, A-C(=O)R24, A-C(=O)OR24, and A- C(=O)NR24R25, or R28 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S (=O) 0-2, and O all of which may be substituted with 1-3 of Rl°, or R28 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S (=O) 0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S (=O) o-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of Rl° ; R30 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A (OR22)-R23, and A-R23, or R30 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S (=O) 0-2, and O, all of which may be substituted with 1-3 of R10, or Wo is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S (=0) 0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S (=O) o-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of Rl°, or R25 and R33 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) o-2, and O a 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 02, and O, or a monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, all of which may be substituted with 1-3 of Rl° ; and R29 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R23, A-C (=O) R24, A-C(=O)OR24, A- C (=O) NR24R25, A-NR27R28, or R29 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S (=O) o-2, and O, all of which may be substituted with 1-3 of R10 or R29 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S (=O) o-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S (=O) 0-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (=O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, R7 and R8 are independently selected from cycloalkyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, all of which may be substituted with 1-3 of R10, or R7 and R8 are independently selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S (=O) 02, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C (=O), wherein said heterocycloalkyl may be substituted with 1-3 of Rl°, A-R23, A-NR24R25, C (=O) R24, C (=O) OR24, C(=O)NR24R25, S(=O)2R26, A-C(=O)R24, A-C(=O)OR24, or A-C(=O)NR24R25, or R7' and R8' are independently selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, A-R23, A (OR22)-R23, NR27R28, A-NR27R28, A-Q-R29, Q-R29, Q-A-NR24R25, C(=O)R24, C( C (=O) NR24R2$, A-C (=O) R24 A-C (=O) OR24, and A-C (=O) NR24R25 ; and pharmaceutically acceptable salts thereof.

Methods of the invention provide for the treatment or prevention of diabetes, inlcuding Type 1 and Type 2 diabetes, and related disorders by administration of a compound of the invention. Related disorders include maturity-onset diabetes of the young (MODY), latent autoimmune diabetes adult (LADA), impaired glucose tolerance (IGT), impaired fasting glucose (IFG), gestational diabetes, and metabolic syndrome X.

In other embodiments, methods of the invention provide for the administration of a compound of the invention in combination with a PPAR agonist, an insulin sensitizer, a sulfonylurea, an insulin secretagogue, a hepatic glucose output lowering compound, an a- glucosidase inhibitor or insulin. PPAR agonist includes rosiglitazone and pioglitazone.

Sulfonylureas include glibenclamide, glimepiride, chlorpropamide, and glipizide. Insulin secretagogues include GLP-1, GIP, PAC/VPAC receptor agonists, secretin, nateglinide, meglitinide, repaglinide, glibenclamide, glimepiride, chlorpropamide, and glipizide. oc- glucosidase inhibitors include acarbose, miglitol and voglibose. A hepatic glucose output lowering compound is metformin.

In another embodiment, methods of the invention provide for the administration of a compound of the invention in combination with an HMG-CoA reductase inhibitor, nicotinic acid, a bile acid sequestrant, a fibric acid derivative, antihypertensive drug, or an anti-obesity drug. Anti-obesity drugs include a p-3 agonist, a CB-1 antagonist, and a lipase inhibitor.

In another embodiment of the invention, methods are provided for the treatment or prevention of secondary causes of diabetes, such as glucocorticoid excess, growth hormone excess, pheochromocytoma, and drug-induced diabetes.

Finally, methods of the invention provide for increasing the sensitivity of pancreatic beta cells to an insulin secretagogue, by administering a compound of the invention. Insulin secretagogues include GLP-1, GIP, PAC/VPAC receptor agonists, secretin, nateglinide, meglitinide, repaglinide, glibenclamide, glimepiride, chlorpropamide, and glipizide.

The present invention therefore provides compounds and methods for the treatment of diabetes and related disorders. These and other aspects of the invention will be more apparent from the following description and claims.

DETAILED DESCRIPTION OF THE INVENTION The invention relates generally to naphthyridine derivatives of the formula wherein one of U, X, Y and Z is nitrogen and the others are C-R, where R is hydrogen or a substituent such as R5', R7 or R8, as described above for formula (II). R1', Ruz', R3 and R4 are as defined above for formula (II). The invention relates to compounds of formula (II), as described above, and to compounds of formula (I) wherein Ru, R2, R3, R4, R5, R6 and R7 correspond to R1', R2, R3, R4, Rs, R7 and R8, respectively, of formula (II). Such compounds may be used in the treatment of diabetes and related disorders.

In one embodiment, the invention relates to compounds of formula (II), as described above. In another embodiment, the invention relates to compounds of formula (II), wherein R1 is phenyl, which may be substituted with 1-3 of R", R"is NR"R 16, W'is selected from cycloalkyl of 3-6 carbon atoms, heterocycloalkyl of 3-6 carbon atoms and 1- 2 heteroatoms selected from N, S (O) 0-2 and O, both of which may be substituted with 1-3 of R10, or R3 is selected from alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, hydrogen, nitro, halogen, NR19R20, A-OR19, A-NR19R20 and A-R20, and R4'is =O.

In another embodiment, the invention relates to methods of treating diabetes and related disorders by administration of compounds of formula (II). Preferred methods relate to the treatment of Type 2 diabetes. In methods of the invention, compounds of formula (II) may be administered in combination with PPAR agonist, insulin sensitizers, sulfonylureas, insulin secretagogues, metformin, a-glucosidase inhibitors and insulin. In another embodiment, compounds of formula (II) are administered in combination with an HMG-CoA reductase inhibitor, nicotinic acid, a bile acid sequestrant, a fibric acid derivative, an anti-hypertensive drug or an anti-obesity drug.

In other methods of the invention, compounds of formula (II) are administered to treat or prevent secondary causes of diabetes or to increase the sensitivity of pancreatic beta cells to an insulin secretagogue.

General Preparative Methods The compounds of the invention may be prepared by use of known chemical reactions and procedures. Nevertheless, the following general synthetic schemes are presented to aid the reader in synthesizing compounds of this invention, with more detailed particular examples being presented below in the experimental section describing the working examples.

In general, compounds of Formula (I) (R4 is =O) may be prepared from the appropriately substituted nicotinic acid through several routes summarized in Flow Diagram I to IV. Compounds of Formula (II) (R4'is =O) may be prepared from the appropriately substituted nicotinic acid through the route summarized in Flow diagram V.

The close analogy between Flow Diagram I and V demonstrates that the routes used to synthesize Formula (I) may be applied to synthesize Formula (II). The routes shown in Flow Diagram II to IV maybe used to synthesize Formula (II) from appropriately substituted nicotinic acid.

Flow Diagram I Ru 0 X X R6 \ \ X AIC13, R N X X 5 5 'r< N v SOCIz s R RNH R or (COCI) 2 R) 1NH Z R5 O rus R R6 NR15RI6 X = halogen R N RHN N X base base I R5 0 R6 RUZ \N N NR5R6 R1 R (I) when R2 = NR1SR16 R3 = H R4 = =0 Flow Diagram II 0 0 5 ? 9 R o o 6 1 J) JJ R6 n-BuLi 6 Base, CW R W ORa J. Med. Chem. R17x 7 1 1986, 29, 2363 R N 17 RNH ? 1 RRNH | R15R% NH R5 O R5 O O R5 O O R6 HCI/AcOH FZ6, ORa Base R6-ORa R N N NR15R16 R N IN NR15R16 R1HN NR R R ho R (I) when R2=NR15Rl6'-NR15R'+ R15R' R4 =0 M = K, Na, Li R6, ORa 17 R N WR17 R R hydrolysis and decarboxylation such as HC !/HOAc R5 0 R5 0 R5 o mCPBA or oxone R5 o or HZOp/HOAc 7 17 when W = S N N S (=0) 1-2-R R7 N N R (I) when R2 = S (=0) 1 2 R17 (I) when R2=SR17orOR17 R3 = H R3 = H p4==o R"==0 5 5 R5 o o mCPBA or oxone R5 O O R5 O O R a or H2021HOAc, R I __ I I a ORa 6 6. R WH R R N N S-R R N N-R R NN WR R1 R1 R1 , hydro ! ys ! sanddecarboxy ! at ! on such as HCI/HOAc W=SorO Ra = alkyl, aryl Rb = alkyl R50 Rb = alkyl 6 R O R R7ANlNAWR17 R1 (I) when R2=SR17orOR17 R3=H R4 = =0 Flow Diagram III R5 o RS 0 0 6 6 SOC12 or 6XI OH OH (COCI) 2 ci R X R NR1 R N NR1 Rz R2 R5 0 R5 0 6 6 acid, base, or heat 1 R N N R NR R'N N R R'''"N NR R1 R4-=o H202/HoAcz R2-SR17 - p RZ = $ (=p_2R17 Flow Diagram IV R5 0 R5 0 R5 0 OH OH R Rc 1 R N+X R N NR1 R N NR 0 base I <-kORd CN alkylation or reductive amination R 0 -mediated coupling R6 acid/heat A R6AoRd N N NR R R N N NH2 R1 R1 7n (ì) when R2 = NR15R16 R3 = H-C (=O) RC = activated ester such as-C (=O) OPh-N02 or-C (=O) CI R4 = =o Rd = alkyl, aryl X = halogen Flow Diagram V t f, x X X N >--X AICI3, II R7 /X $, X x L X) R SOCIZ R O N OH or (COCI) 2 N Cil 15 16 R R NH ex RS'R8' R5'o R16R15N NHR< Nr'NR''SRl6 X = halogen R, R HN Rua RS base l base base R5' O N R7'N NR15RI6 (II) when R2'~ NR15R16 R=H R4'= =0 The nicotinic acids used in the above flow diagrams could be purchased from commercial sources, prepared according to Flow Diagram VI, or prepared according to literature in this field (Biorg. Med. Chem. Lett. 2001,475-477 ; J. Prakt. Chem. 2002,33 ; Eur. J. Org. Chem. 2001,1371 ; J. Org. Claim. 2000, 65, 4618; J. Med. Chem. 1997, 40, 2674; Bioorg. Med. Claim. Lett. 2000, 10, 1151 ; US patent 3838156, etc. ).

Flow Diagram VI 5 5 O O O R6 CN halogenation R6 CN such as POLI3 Ho N O R N X H Re = alkyl acid or base conc. H2S04 7C = halogen hydrolysis heat 6 R acid or baseR0 acid or base R'0 ORe hydrolysis R6 hydrolysis R6 NH I ! -oH l R7+N X R7+NJXX R7/RN X Further manipulations of Formula (I) (when R4 is =O) and (II) (when R4'is =O) could lead to more diversely substituted compounds. These manipulations include aromatic nucleophilic substitutions, metal-mediated couplings, reductions, oxidations, amide fonnations, etc.

Flow Diagram VII illustrates alkylation, and amide, urea, and sulfonamide formations in Formula (I) when R2 = NHR16. Similar transformations could be carried out in Formula (II) when R2' = NHR16, Flow Diagram VII 5 4 R6 R3 R1 R 5 R5 R4 @ R6o, R' R1 R15 aWa R6 R3 R5 R 4 R N N N' R1 H \ < o R6s, R3 R R am R10Rs I II 16 I NJNJN. R H ation Rs Rs I NNN. Rs 0/ R N N N' %'1 18 "Q, O R0--l-N'R R5 R4 R6 3 1 16 'D R R N N R 18 R SO2R Flow Diagram VIII and IX illustrate transformations at R3 in Formula (I). These transformations could also be applied to R3 in Formula (II).

Flow Diagram VIII Rs Ra Rs R4 R6 alkylation or 4 Mitsunobu 2 1 1 R1 R IN R2 R1 R R'R' R9 = alkyl or aryl Flow Diagram IX Rs R4 Rs R4 Rs Ra metal-mediated halogenation R6 I I X coupling reaction R6 R R F N NR2 R N N'R R R R R5 R4 R5 R4 R RfZ4 R6 R6 NO reduction R6 NH R N Nl R2 R N lN R2 R N N R2 R1 R R NOR R R R metal-mediated coupling or alkylaton or reductive amination R5 R4 R6JkJ, NR19R20 R I N-N'_R2 11 R Flow Diagram X illustrates manipulations of R4 in formula (I), which could also be used on R4 in formula (II).

Flow Diagram X Rs OR2 alkylation or Rs Rs reduction Mitsunobu R1 R N R2 R R'R'R' R5 0 6 S Ra R3 R6 R3 NN R 2 7 N N-R4 '1'1 Flow Diagram XI illustrates manipulations of R6 in formula (I). These manipulations could also be applied to R5 and R7 in formula (1), Rs, R7', and R8 in formula (II).

Flow Diagram XI R5 R4 3 H2, Pd/C RNN 1 R R5 R4 Suzuki reaction R6 R3 R6B (OH) 2, R I N' N I R2 R1 R Rh R5 R4 Heck reaction Rì\+, R3 Rh = H or aìkyl R5 R4 RUZ h R', R = H, aryl, heteroaryl, C (=0) R24, C (=O) OR4 X F2 R R3 Rh Ft7 N N1 R2 x R' 2-R5 Ra YTTi R ! J L JL"R'P R N R1 R 1. halogen-metal E R3 E+ could be alkyl halid, aldehyde, exchange C02, disufide, RCOCI etc. R N N R R1 R Metal-mediated amination R5 R4 R27R28NH R27R28NDeCR3 R N NR2 n R Metal-mediated R5 R4 ether formation R290, R3 R N !"1if R1 Ri Flow Diagram XII illustrates manipulations on R7 of formula (I). These manipulations could also be applied to Rs in formula (I), R5' and R7' in formula (II).

Flow Diagram XII R5 R4 CO, catalyst R6 R 3 ligand, base R 04Ni IN R NON R OH R5 R4 6 Ni (dppp) CI2 \ RMgBr R R5 R 4 R R5 R4 R6 R3 base, Ra90H R1 Rs. Rs R X I N N I R2 R5 R4 R base, R29SH X = halogen or-OS02CF3 R29S NNR2 R1 R R5 R4 R27R28NH R6) R3 27R28RN N R Ri R R5 R4 CN-Rs Rs NC N N R2 R1 R Flow Diagram XIII illustrates manipulations on Rus ouf formula (I). These manipulations could also be applied to R7 in formula (I), R5' and R7' in formula (II).

Flow Diagram XIII H R4 E Ruz R6 R3 R6 R3 base such as LDA R N R2 E+ R N N R2 RUZ Ra R P' base such as LDA R Nj 1 R E+ R R1 R Ru ruz E+ is alkyl halide, aldehydes, halogen, CO2, 02, activated ester, etc.

Flow Diagram XIV illustrates the transformations of some functional groups which are present in Formula (I) or (II).

Flow Diagram XIV amide formation Oq/Rm \, N, 5 urea formation 0 yN, Rm H \, N/ t,. N./- sulfonamide formation SO2Rm > I R alkylation \ (Rl Rk X j R, R'= H, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl reductive R I kk N Rm = alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl amination X = halogen Nu Nu-= nucleophiles such as carbanion, amine, alcohol, thiol , \--OH reduction OR'< O amide formation x Nu halogenation ! Nu- OH oxidation reductive amination reduction HNRkRi OR"' alkylation or Mitsunobu 0,. \,.. OMe R'"MgBr H 0 0 oxidation oxidation t reduction, reduction,, ;', reduction -1-N02-1-NH2 Alternative Forms Of Novel Compounds Also included in the compounds of the present invention are (a) the stereoisomers thereof, (b) the pharmaceutically-acceptable salts thereof, (c) the tautomers thereof, (d) the protected acids and the conjugate acids thereof, and (e) the prodrugs thereof.

(a) The Stereoisomers The stereoisomers of these compounds may include, but are not limited to, enantiomers, diastereomers, racemic mixtures and combinations thereof. Such stereoisomers can be prepared and separated using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present invention. Isomers may include geometric isomers. Examples of geometric isomers include, but are not limited to, cis isomers or trans isomers across a double bond.

Other isomers are contemplated among the compounds of the present invention. The isomers may be used either in pure form or in admixture with other isomers of the inhibitors described above.

(b) The Pharmaceutically-Acceptable Salts Pharmaceutically-acceptable salts of the compounds of the present invention include salts commonly used to form alkali metal salts or form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically- acceptable. Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.

Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic,, heterocyclic, carboxylic and sulfonic classes of organic acids. Examples of organic and sulfonic classes of organic acids includes, but are not limited to, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicyclic, 4- hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, N-hydroxybutyric, salicyclic, galactaric and galacturonic acid and combinations thereof.

(c) The Tautomers Tautomers of the compounds of the invention are encompassed by the present invention. Thus, for example, a carbonyl includes its hydroxy tautomer.

(d) The Protected Acids and the Conjugate Acids The protected acids include, but are not limited to, esters, hydroxyamino derivatives, amides and sulfonamides.

(e) The Prodrugs The present invention includes the prodrugs and salts of the prodrugs. Formation of prodrugs is well known in the art in order to enhance the properties of the parent compound ; such properties include solubility, absorption, biostability and release time (see "Pharmaceutical Dosage Form and Drug Delivery Systems" (Sixth Edition), edited by Ansel et al. , publ. by Williams & Wilkins, pgs. 27-29, (1995) which is hereby incorporated by reference). Commonly used prodrugs are designed to take advantage of the major drug biotransformation reactions and are also to be considered within the scope of the invention. Major drug biotransformation reactions include N-dealkylation, O- dealkylation, aliphatic hydroxylation, aromatic hydroxylation, N-oxidation, S-oxidation, deamination, hydrolysis reactions, glucuronidation, sulfation and acetylation (see Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al. , publ. by McGraw-Hill, pages 11-13, (1996), which is hereby incorporated by reference).

Dosages And Treatment Regimen Dosage levels of the compounds of this invention typically are from about 0.001 mg to about 10,000 mg daily, preferably from about 0.005 mg to about 1,000 mg daily.

On the basis of mg/kg daily dose, either given in a single dose or in divided doses, dosages typically range from about 0. 001/75 mg/kg to about 10,000/75 mg/kg, preferably from about 0.005/75 mg/kg to about 1,000/75 mg/kg.

The total daily dose of each drug can be administered to the patient in a single dose, or in multiple subdoses. Typically, subdoses can be administered two to six times per day, preferably two to four times per day, and even more preferably two to three times per day. Doses can be in immediate release form or sustained release form sufficiently effective to obtain the desired control over the diabetic condition.

The dosage regimen to prevent, treat, give relief from, or ameliorate a diabetic condition or disorder, or to otherwise protect against or treat a diabetic condition with the combinations and compositions of the present invention is selected in accordance with a variety of factors. These factors include, but are not limited to, the type, age, weight, sex, diet, and medical condition of the subject, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetics and toxicology profiles of the particular inhibitors employed, whether a drug delivery system is utilized, and whether the inhibitors are administered with other active ingredients. Thus, the dosage regimen actually employed may vary widely and therefore deviate from the preferred dosage regimen set forth above.

Pharmaceutical Compositions For the prophylaxis or treatment of the conditions and disorders referred to above, the compounds of this invention can be administered as the compound per se.

Alternatively, pharmaceutically-acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to that of the parent compound.

The compounds of the present invention also can be administered with an acceptable carrier in the form of a pharmaceutical composition. The carrier must be acceptable in the sense of being compatible with the other ingredients of the composition and must not be intolerably deleterious to the recipient. The carrier can be a solid or a liquid, or both, and preferably is formulated with the compound as a unit-dose composition, for example, a tablet, which can contain from about 0.05% to about 95% by weight of the active compound (s) based on a total weight of the dosage form. Other pharmacologically active substances can also be present, including other compounds useful in the treatment of a diabetic condition.

The active compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a therapeutically effective dose for the treatment intended. The active compounds and compositions, for example, may be administered orally, sublingually, nasally, pulmonarily, mucosally, parenterally, intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically. Unit dose formulations, particularly orally administrable unit dose formulations such as tablets or capsules, generally contain, for example, from about 0.001 to about 500 mg, preferably from about 0.005 mg to about 100 mg, and more preferably from about 0.01 to about 50 mg, of the active ingredient. In the case of pharmaceutically acceptable salts, the weights indicated above for the active ingredient refer to the weight of the pharmaceutically active ion derived from the salt.

For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, a capsule, a suspension, an emulsion, a paste, a solution, a syrup or other liquid form. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. If administered by mouth, the compounds may be admixed with, for example, lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.

Oral delivery of the compounds of the present invention can include formulations, as are well known in the art, to provide immediate delivery or prolonged or sustained delivery of the drug to the gastrointestinal tract by any number of mechanisms. Immediate delivery formulations include, but are not limited to, oral solutions, oral suspensions, fast- dissolving tablets or capsules, sublingual tablets, disintegrating tablets and the like.

Prolonged or sustained delivery formulations include, but are not limited to, pH sensitive release of the active ingredient from the dosage form based on the changing pH of the small intestine, slow erosion of a tablet or capsule, retention in the stomach based on the physical properties of the formulation, bioadhesion of the dosage form to the mucosal lining of the intestinal tract, or enzymatic release of the active drug from the dosage form.

The intended effect is to extend the time period over which the active drug molecule is delivered to the site of action by manipulation of the dosage form. Thus, enteric-coated and enteric-coated controlled release formulations are within the scope of the present invention. Suitable enteric coatings include cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethyl-cellulose phthalate and anionic polymers of methacrylic acid and methacrylic acid methyl ester.

Pharmaceutical compositions suitable for oral administration can be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present invention; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil- in-water or water-in-oil emulsion. As indicated, such compositions can be prepared by any suitable method of pharmacy which includes the step of bringing into association the inhibitor (s) and the carrier (which can constitute one or more accessory ingredients). In general, the compositions are prepared by uniformly and intimately admixing the inhibitor (s) with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product. For example, a tablet can be prepared by compressing or molding a powder or granules of the inhibitors, optionally with one or more accessory ingredients.

Compressed tablets can be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent (s). Molded tablets can be made, for example, by molding the powdered compound in a suitable machine.

Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.

Pharmaceutical compositions suitable for buccal (sub-lingual) administration include lozenges comprising a compound of the present invention in a flavored base, usually sucrose, and acacia or tragacanth, and pastilles comprising the inhibitors in an inert base such as gelatin and glycerin or sucrose and acacia.

Formulations for parenteral administration, for example, may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.

Pharmaceutically acceptable carriers encompass all the foregoing and the like. The pharmaceutical compositions of the invention can be prepared by any of the well-known techniques of pharmacy, such as admixing the components. The above considerations in regard to effective formulations and administration procedures are well known in the art and are described in standard textbooks.

Methods Of Use The present invention also includes methods for the treatment of diabetes and related diseases and conditions. One such method comprises the step of administering to a subject in need thereof, a therapeutically effective amount of one or more compounds of formula (II).

Compounds of formula (II) may be used in methods of the invention to treat diseases, such as diabetes, including both Type 1 and Type 2 diabetes. Such methods may also delay the onset of diabetes and diabetic complications. Other diseases and conditions that may be treated or prevented using compounds of formula (II) in methods of the invention include: Maturity-Onset Diabetes of the Young (MODY) (Herman, et al., Diabetes 43: 40 (1994) ), Latent Autoimmune Diabetes Adult (LADA) (Zimmet, et al., Diabetes Med. 11: 299 (1994) ), impaired glucose tolerance (IGT) (Expert Committee on Classification of Diabetes Mellitus, Diabetes Care 22 (Supp. 1) S5 (1999) ), impaired fasting glucose (IFG) (Charles, et al., Diabetes 40: 796 (1991) ), gestational diabetes (Metzger, Diabetes, 40: 197 (1991), and metabolic syndrome X.

Compounds of formula (II) may also be used in methods of the invention to treat secondary causes of diabetes (Expert Committee on Classification of Diabetes Mellitus, Diabetes Care 22 (Supp. 1), S5 (1999) ). Such secondary causes include glucocorticoid excess, growth hormone excess, pheochromocytoma, and drug-induced diabetes. Drugs that may induce diabetes include, but are not limited to, pyriminil, nicotinic acid, glucocorticoids, phenytoin, thyroid hormone, (3-adrenergic agents, a-interferon and drugs used to treat HIV infection.

The methods and compounds of the present invention may be used alone or in combination with additional therapies and/or compounds known to those skilled in the art in the treatment of diabetes and related disorders. Alternatively, the methods and compounds described herein may be used, partially or completely, in combination therapy.

Compounds of formula (II) may also be administered in combination with other known therapies for the treatment of diabetes, including PPAR agonists, sulfonylurea drugs, non-sulfonylurea secretagogues, a-glucosidase inhibitors, insulin sensitizers, insulin secretagogues, hepatic glucose output lowering compounds, insulin and anti- obesity drugs. Such therapies may be administered prior to, concurrently with or following administration of the compound of formula (II). Insulin includes both long and short acting forms and formulations of insulin. PPAR agonist may include agonists of any of the PPAR subunits or combinations thereof. For example, PPAR agonist may inlcude agonists of PPAR-a, PPAR-y, PPAR-6 or any combination of two or three of the subunits of PPAR. PPAR agonists include, for example, rosiglitazone and pioglitazone.

Sulfonylurea drugs include, for example, glyburide, glimepiride, chlorpropamide, and glipizide. a-glucosidase inhibitors that may be useful in treating diabetes when administered with a compound of formula (II) include acarbose, miglitol and voglibose.

Insulin sensitizers that may be useful in treating diabetes when administered with a compound of formula (II) include thiazolidinediones and non-thiazolidinediones. Hepatic glucose output lowering compounds that may be useful in treating diabetes when administered with a compound of formula (II) include metformin, such as Glucophage and Glucophage XR. Insulin secretagogues that may be useful in treating diabetes when administered with a compound of formula (II) include sulfonylurea and non-sulfonylurea drugs: GLP-1, GIP, PAC/VPAC receptor agonists, secretin, nateglinide, meglitinide, repaglinide, glibenclamide, glimepiride, chlorpropamide, glipizide. GLP-1 includes derivatives of GLP-1 with longer half-lives than native GLP-1, such as, for example, fatty- acid derivatized GLP-1 and exendin. In one embodiment of the invention, compounds of formula (II) are used in combination with insulin secretagogues to increase the sensitivity of pancreatic beta cells to the insulin secretagogue.

Compounds of formula (II) may also be used in methods of the invention in combination with anti-obesity drugs. Anti-obesity drugs include P-3 agonists, CB-1 antagonists, appetite suppressants, such as, for example, sibutramine (Meridia), and lipase inhibitors, such as, for example, orlistat (Xenical).

Compounds of formula (II) may also be used in methods of the invention in combination with drugs commonly used to treat lipid disorders in diabetic patients. Such drugs include, but are not limited to, HMG-CoA reductase inhibitors, nicotinic acid, bile acid sequestrants, and fibric acid derivatives. Compounds of formula (II) may also be used in combination with anti-hypertensive drugs, such as, for example, (3-blockers and ACE inhibitors.

Such co-therapies may be administered in any combination of two or more drugs (e. g. , a compound of formula (I) in combination with an insulin sensitizer and an anti- obesity drug). Such co-therapies may be administered in the form of pharmaceutical compositions, as described above.

Terms As used herein, various terms are defined below.

When introducing elements of the present invention or the preferred embodiment (s) thereof, the articles"a","an","the"and"said"are intended to mean that there are one or more of the elements. The terms"comprising","including"and"having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.

The tenn"subject"as used herein includes mammals (e. g, humans and animals).

The term"treatment"includes any process, action, application, therapy, or the like, wherein a subject, including a human being, is provided medical aid with the object of improving the subject's condition, directly or indirectly, or slowing the progression of a condition or disorder in the subject.

The phrase"therapeutically-effective"means the amount of each agent administered that will achieve the goal of improvement in a diabetic condition or disorder severity, while avoiding or minimizing adverse side effects associated with the given therapeutic treatment.

The term"pharmaceutically acceptable"means that the subject item is appropriate for use in a pharmaceutical product.

The term"prodrug"includes a compound that is a drug precursor that, following administration to a subject and subsequent absorption, is converted to an active species in vivo. Conversion to the active, species in vivo is typically via some process, such as metabolic conversion. An example of a prodrug is an acylated form of the active compound.

The following definitions pertain to the structure of the compounds: In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified, for example, alkyl of 1-8 carbon atoms or Cl-C8 alkyl. The use of a term designating a monovalent radical where a divalent radical is appropriate shall be construed to designate the divalent radical and vice versa. Unless otherwise specified, conventional definition of terms controls and conventional stable atom valences are presumed and achieved in all formulas and groups.

When symbols such as"A-Q-R"is used, it refers to a group which is formed by linking group A, group Q and group R in the designated order and the attachment of this group"A-Q-R"is any position on group A to form a stable structure. Group Q may be linked to any position on group A to form a stable structure and group R may be linked to any position on group Q to form a stable structure.

When symbols such as"A (OR')-R" is used, it refers to a group which is formed by susbstituting group A with both group OR'and group R and the attachment of this group "A (OR')-R" is any position on group A to form a stable structure. Group OR'and group R maybe linked to any position on group A to form a stable structure.

The term"halogen"refers to a halogen radical selected from fluoro, chloro, bromo or iodo.

The term"alkyl"refers to a saturated aliphatic hydrocarbon radical."Alkyl"refers to both branched and unbranched alkyl groups. Examples of"alkyl"include alkyl groups that are straight chain alkyl groups containing from one to ten carbon atoms and branched alkyl groups containing from three to ten carbon atoms. Other examples include alkyl groups that are straight chain alkyl groups containing from one to six carbon atoms and branched alkyl groups containing from three to six carbon atoms. This term is examplified by groups such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), 1, 1-dimethylethyl (tert-butyl), and the like. It may be abbreviated"Alk". It should be understood that any combination term using an"alk"or"alkyl"prefix refers to analogs according to the above definition of"alkyl". For example, terms such as"alkoxy","alkylthio","alkylamino" refer to alkyl groups linked to a second group via an oxygen, sulfur, or nitrogen atom, respectively.

The term"haloalkyl"refers to an alkyl group in which one or more hydrogen atoms are replaced with halogen atoms. This term in examplified by groups such as trifluomethyl. The more preferred haloalkyl groups are alkyl groups substituted with one or more fluro or chloro. The term"haloalkoxy"refers to haloalkyl groups linked to a second group via an oxygen atom.

The term"alkenyl"refers to a mono or polyunsatuarted aliphatic hydrocarbon radical. The mono or polyunsaturated aliphatic hydrocarbon radical contains at least one carbon-carbon double bond."Alkenyl"refers to both branched and unbranched alkenyl groups, each optionally partially or fully halogenated. Examples of"alkenyl"include alkenyl groups that are straight chain alkenyl groups containing from two to ten carbon atoms and branched alkenyl groups containing from three to ten carbon atoms. Other examples include alkenyl groups which are straight chain alkenyl groups containing from two to six carbon atoms and branched alkenyl groups containing from three to six carbon atoms. This term is exemplified by groups such as ethenyl, propenyl, n-butenyl, isobutenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, decenyl, and the like.

The term"alkynyl"refers to a mono or polyunsatuarted aliphatic hydrocarbon radical. The mono or polyunsaturated aliphatic hydrocarbon radical contains at least one carbon-carbon triple bond. "Alkynyl"refers to both branched and unbranched alkynyl groups, each optionally partially or fully halogenated. Examples of"alkynyl"include alkynyl groups that are straight chain alkynyl groups containing from two to ten carbon atoms and branched alkynyl groups containing from four to ten carbon atoms. Other examples include alkynyl groups that are straight chain alkynyl groups containing from two to six carbon atoms and branched alkynyl groups containing from four to six carbon atoms. This term is exemplified by groups such as ethynyl, propynyl, octynyl, and the like.

The term"cycloalkyl"refers to the mono-or polycyclic analogs of an alkyl group, as defined above. Unless otherwise specified, the cycloalkyl ring may be attached at any carbon atom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom which results in a stable structure. Examples of cycloalkyl groups are saturated cycloalkyl groups containing from three to ten carbon atoms. Other examples include cycloalkyl groups containing three to six carbon atoms. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclononyl, cyclodecyl, norbornane, adamantyl, and the like.

The term"cycloalkenyl"refers to the mono-or polycyclic analogs of an alkenyl group, as defined above. Unless otherwise specified, the cycloalkenyl ring may be attached at any carbon atom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom which results in a stable structure. Examples of cycloalkenyl groups are cycloalkenyl groups containing from four to ten carbon atoms.

Other examples include cycloalkenyl groups containing four to six carbon atoms.

Exemplary cycloalkenyl groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornene, and the like.

The term"heterocycloalkyl"refers to the mono-or polycyclic structures of "cycloalkyl"where one or more of the carbon atoms are replaced by one or more atoms independently chosen from nitrogen, oxygen, or sulfur atoms. Any nitrogen atom maybe optionally oxidized or quanternized, and any sulfur atom maybe optionally oxidized.

Unless otherwise specified, the heterocycloalkyl ring may be attached at any carbon atom or heteroatom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom or heteroatom which results in a stable structure. Examples of heterocycloalkyl groups are saturated heterocycloalkyl groups containing from two to nine carbon atoms and one to four heteroatoms chosen independently from nitrogen, oxygen, or sulfur atoms. Examples of heterocycloalkyl groups include morpholino, pyrazino, tetrahydrofurano, and the like.

The term"heterocycloalkenyl"refers to the mono-or polycyclic structures of "cycloalkenyl"where one or more of the carbon atoms are replaced by one or more atoms independently chosen from nitrogen, oxygen, or sulfur atoms. Any nitrogen atom maybe optionally oxidized or quanternized, and any sulfur atom maybe optionally oxidized.

Unless otherwise specified, the heterocycloalkenyl ring may be attached at any carbon atom or heteroatom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom or heteroatom which results in a stable structure. Examples of heterocycloalkenyl groups are saturated heterocycloalkenyl groups containing from two to nine carbon atoms and one to four heteroatoms chosen independently from nitrogen, oxygen, or sulfur atoms. Examples of heterocycloalkenyl groups include dihydropyran, dihydrofuran, and the like.

The term"cycloalkyloxy"refers to a monovalent radical of the formula-0- cycloalkyl, i. e. , a cycloalkyl group linked to a second group via an oxygen atom.

The term"acyl"refers to a monovalent radical of the formula-C (=O)-alkyl and- C (=O)-cycloalkyl, i. e. , an alkyl or cycloakyl group linked to a second group via caronyl group C (=O), wherein said alkyl maybe further substituted with cycloalkyl, aryl, or heteroaryl. Examples of acyl groups include-C (=O) Me (acetyl),-C (=O) CH2-cyclopropyl (cyclopropylacetyl), -C (=O) CH2Ph (phenylacetyl), and the like.

The term"aryl"refers to 6-10 membered mono-or polycyclic aromatic carbocycles, for example, phenyl and naphthyl. Unless otherwise specified, the aryl ring may be attached at any carbon atom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom which results in a stable structure. The term"aryl"refers to non-substituted aryls and aryls optionally substituted with one or more of the following groups: halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C4-C6 cycloalkenyl, C2-C6 alkynyl, nitro, cyano, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, amino, C1-C6 alkylamino (for example,-NHMe and-N (Me) 2), C1-C6 acyl, thiol, alkylthio, carboxylic acid. All the above subtsitutions can further be substituted with optionally selected groups to form a stable structure. It may be abbreviated"Ar". It should be understood that any combination term using an"ar"or"aryl"prefix refers to analogs according to the above definition of"aryl". For example, terms such as"aryloxy", "arylthio", "arylamino"refer to aryl groups linked to a second group via an oxygen, sulfur, or nitrogen atom, respectively.

The term"heteroaryl"refers to a stable 5-8 membered (but preferably, 5 or 6 membered) monocyclic or 8-11 membered bicyclic aromatic heterocycle radical. Each heteroaryl contains 1-10 carbon atoms and from 1 to 5 heteroatoms independently chosen from nitrogen, oxygen and sulfur, wherein any sulfur heteroatom may optionally be oxidized and any nitrogen heteroatom may optionally be oxidized or quaternized. Unless otherwise specified, the heteroaryl ring may be attached at any suitable heteroatom or carbon atom that results in a stable structure and, if substituted, may be substituted at any suitable heteroatom or carbon atom which results in a stable structure. The term"heteroaryl" includes heteroaryl groups that are non-substituted or those optionally substituted with one or more of the following groups: halogen, Cl-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C4-C6 cycloalkenyl, C2-C6 alkynyl, nitro, cyano, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, amino, C1-C6 alkylamino (for example,-NHMe and-N (Me) 2), C1-C6 acyl, thiol, alkylthio, carboxylic acid. Examples of"heteroaryl"include radicals such as furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzisothiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl. Terms such as"heteroaryloxy","heteroarylthio","heteroarylamino" refer to heteroaryl groups linked to a second group via an oxygen, sulfur, or nitrogen atom, respectively.

The terms"optional"or"optionally"mean that the subsequently described event or circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example,"optionally substituted aryl"means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.

A comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry ; this list is typically presented in a table entitled Standard List of Abbreviations.

The abbreviations contained in said list, and all abbreviations utilized by organic chemists of ordinary skill in the art are hereby incorporated by reference.

For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed. , 1986-87, inside cover.

Abbreviations and Acronyms When the following abbreviations are used throughout the disclosure, they have the following meaning: CHzClz methylene chloride THF tetrahydrofuran CH3CN acetonitrile Na2S04 anhydrous sodium sulfate MgS04 anhydrous magnesium sulfate DMSO dimethylsulfoxide EtOAc ethyl acetate Et2O diethyl ether Et3N triethylamine H2 hydrogen CO carbon monoxide HCl hydrochloric acid Hex hexanes 1H NMR proton nuclear magnetic resonance HPLC high performance liquid chromatography K2C03 potassium carbonate Cs2CO3 cesium carbonate NHLtCl ammonium chloride LC/MS liquid chromatography/mass spectroscopy MeOH methanol MS ES mass spectroscopy with electrospray NaHC03 sodium bicarbonate NaOH sodium hydroxide RT retention time h hour min minutes Pd (OAc) 2 palladium acetate Ni (dppp) Cl2 [1,3-bis (diphenylphosphino) propane] dichloronickel (II) DMF N, N-dimethylformamide EDCI 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride LTMP Lithium tetramethylpiperidine BuLi butyllithium TLC thin layer chromatography TFA trifluoacetic acid TMEDA tetramethylethylenediamine BINAP 2,2'-bis (diphenylphosphino)-1, 1'binaphthyl HOBt 1-hydroxybenzotriazole hydrate NaH sodium hydride MeMgBr methylmagnesium bromide DPPP (diphenylphosphino) propane DME dimethoxyethane Aids aluminum chloride TEA triethyl amine CS2 carbon disulfide MeI methyl iodide t-BuOK potassium tert-butoxide KHMDS potassium hexamethyldisilazide LiHMDS lithium hexamethyldisilazide NaOBr sodium hypobromite Br2 bromine Conc. Concentrated Pd/C palladium on carbon EtOH ethanol NH3 ammonia NaOMe sodium methoxide PPh3 triphenylphosine NaH sodium hydride LDA lithium diisopropylamide SOC12 thionyl chloride MsCl methanesulfonyl chloride DMAP 4-dimethylaminopyridine NMM 4-methylmorpholine AcOH acetic acid Na2S203 sodium thiosulfate H2SO4 sulfuric acid CHC13 chloroform MnO2 manganese (IV) oxide LAH lithium aluminum hydride ADDP 1, 1'- (azodicarbonyl)-dipiperidine EDTA ethylenediaminetetraacetic acid CC12FCClF2 1,1, 2-trichlorotrifluoroethane NaN02 sodium nitrite Preparative Examples Examples of preparations of compounds of the invention are provided in the following detailed synthetic procedures. In tables 1A and 2A, the synthesis of each compound is referenced back to these exemplary preparative steps. In tables 1B and 2B, the proposed synthesis of each compound is referenced back to these exemplary preparative steps.

All reactions were carried out under a positive pressure of dry argon or dry nitrogen, and were stirred magnetically unless otherwise indicated. Sensitive liquids and solutions were transferred via syringe or cannula, and introduced into reaction vessels through rubber septa. Commercial grade reagents and solvents were used without further purification.

Unless otherwise stated, the term'concentration under reduced pressure'refers to use of a Buchi rotary evaporator at approximately 15 mm of Hg. All temperatures are reported uncorrected in degrees Celsius (°C). Unless otherwise indicated, all parts and percentages are by volume.

Proton (tH) nuclear magnetic resonance (NMR) spectra were measured with a Varian Mercury (300 MHz) or a Bruker Avance (500 MHz) spectrometer with either Me4Si (8 0.00) or residual protonated solvent (CHC13 8 7.26 ; MeOH 8 3.30 ; DMSO 8 2.49) as standard. The NMR data of the synthesized examples, which are not disclosed in the following detailed charaterizations, are in agreements with their corresponding structural assignements.

The HPLC-MS spectra were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a YMC pro C-18 column (2 x 23 mm, 120A), and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-1200 amu using a variable ion time according to the number of ions in the source. The eluents were A: 2% CH3CN in water with 0.02% TFA and B: 2% water in CH3CN with 0.018% TFA. Gradient elution from 10% B to 95% over 3.5 minutes at a flow rate of 1.0 mL/min was used with an initial hold of 0.5 minutes and a final hold at 95% B of 0.5 minutes. Total run time was 6.5 minutes.

Elemental analyses were conducted by Robertson Microlit Labs, Madison NJ. The results of elemental analyses, if conducted but not disclosed in the following detailed charaterizations, are in agreements with their corresponding structural assignements.

The following specific examples are presented to illustrate the invention related to Formula (1) as described herein, but they should not be construed as limiting the scope of the invention in any way.

Intermediate A: 2,6-dichloro-4-methyl-nicotinic acid Method 1 A solution of sodium nitrite (2.73 g, 39.6 mmol) in water (15 mL) was added slowly to a solution of commercially available (Maybridge) 2,6-dichloro-4-methyl- nicotinamide (4.5 g, 22 mmol) in concentrated sulfuric acid resulting in evolution of heat and brown gas. The mixture was stirred at room temperature for 15 min, and then heated to 60 °C for 7 h. The solution was cooled to 0 °C and then water (15 mL) was added. The resulting white precipitate was collected by filtration and washed with hexane. The aqueous filtrate was extracted with EtOAc (3X) and the combined organic extracts were dried over MgS04 and concentrated in vacuo. The residue was combined with the white precipitate to afford 2,6-dichloro-4-methyl-nicotinic acid (4.39 g, 97%) as a white solid: LCMS RT: 1.20 min, MH+ : 206.3.

Method 2 Concentrated nitric acid (14 mL) was added to cooled (0 °C) concentrated sulfuric acid (43 mL) maintaining the internal temperature below 10 °C. After addition, the acid mixture was heated to 70 °C and commercially available (Avocado) 2,6-dichloro-4- methylnicotinonitrile (20.0 g, 107 mmol) was added. The temperature was raised until the internal temperature of the reaction reached 105 °C. At this point the heating was stopped and after 2 h, TLC analysis revealed that the reaction was complete. The reaction mixture was cooled to room temperature, and slowly added to ice (100 g) with strong agitation.

The solid was filtered and washed with cold water (10 mL). The solid was dissolved in EtOAc (100 mL) and the solution was dried over Na2S04 and concentrated to give 2,6- dichloro-4-methyl-nicotinic acid (21.0 g, 96%) as a white solid: Rf = 0.20 (1: 1 EtOAc: Hex).

Intermediate B: 2, 6-dichloro-4-methyl-nicotinoyl chloride A solution of 2, 6-dichloro-4-methyl-nicotinic acid (3.94 g, 19.1 mmol) in thionyl chloride (18 mL) was heated to 80 °C for 2 h. After cooling, the solution was concentrated in vacua to give 2,6-dichloro-4-methyl-nicotinoyl chloride as yellow oil. It was carried on to the next step without further purification. This transformation can also be accomplished using oxalyl chloride with catalytic DMF in place of thionyl chloride.

Intermediate C: 3, 3-dichloro-1-(2, 6-dichloro-4-methyl-pyridin-3-yl)-propenone A solution of the 2,6-dichloro-4-methyl-nicotinoyl chloride from the previous reaction in CHzClz (10 mL) was added slowly to a cooled (0 °C) and stirred slurry solution of Aids (2.54 g, 19.1 mmol) in CH2C12 (54 mL). After 15 min, vinylidene chloride (1.5 mL, 1.85 g, 19.1 mmol) was added to the mixture dropwise. The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was poured over ice and the ice slurry was acidified using 1 N HC1 (50 mL). Stirring was continued for 20 min and then the product was extracted with CH2C12 (3X). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give 3, 3-dichloro-1-(2, 6-dichloro-4- methyl-pyridin-3-yl) -propenone (4.22 g, 77 %) as a yellow oil: LCMS RT: 3.25, MH+ : 284.3, Rf= 0.47 (4: 1 Hex: EtOAc).

Intermediate D: 1- (2, 6-Dichloro-4-methyl-pyridin-3-yl)-3, 3-bis-phenylamino-propenone A solution of aniline (4.04 mL, 44.4 mmol) in TEA (6.2 mL, 44.4 mmol) was added slowly to a cooled (0 °C) and stirred solution of 3, 3-dichloro-1-(2, 6-dichloro-4- methyl-pyridin-3-yl)-propenone (4.22 g, 14. 8 mmol) in dioxane (50 mL). The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was concentrated in vacuo until most of the solvent was removed and then the residue was diluted with water and extracted with EtOAc (3X). The combined organic extracts were washed with water, dried over Na2S04 and concentrated ira vacuo. Silica gel flash chromatography of the residue using 7: 1 EtOAc: Hex gave 1- (2, 6-dichloro-4-methyl- pyridin-3-yl)-3, 3-bis-phenylamino-propenone as yellow solid (2.22 g, 40 %): LCMS RT: 3.21 min; MH+ : 398.2, Rf= 0.27 (2: 1 Hex: EtOAc).

Intermediate E: 7-Chloro-5-methyl-1-phenyl-2-phenylamino-1H- [1, 8]-naphthyridin-4-one A mixture of 1- (2, 6-dichloro-4-methyl-pyridin-3-yl) -3,3-bis-phenylamino- propenone (2.17 g, 5.45 mmol) and t-BuOK (1.10 g, 9.81 mmol) in dioxane (55 mL) was heated to 80 °C overnight. The reaction was cooled, concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2S04, and concentrated in vacuo. Silica gel flash chromatography of the residue using 1 : 1 EtOAc: Hex provided 7-chloro-5-methyl-l-phenyl-2-phenylamino-lH- [1, 8] naphthyridin-4-one (1.297 g, 66%) as an orange solid: LCMS RT: 2.52 min, MH+ : 362. 3, Rf = 0.18 (1: 1 EtOAc: Hex) This transformation can also be accomplished by using the combination of other aprotic solvents such as DMF, and THF with other bases such as NaH.

Intermediate F: 2, 6-dichloro-4-(trifluoromethyl) nicotinic acid Method 1 A solution of NaN02 (9.59 g, 139 mmol) in water (95 mL) was added slowly to a solution of commercially available (Oakwood) 2,6-dichloro-4- (trifluoromethyl) nicotinamide (20.0 g, 77 mmol) in conc. H2SO4 resulting in evolution of heat and brown gas. The mixture was stirred at room temperature for 15 min, and then heated to 60 °C for 18 h. The solution was cooled to 0 °C and then water (15 mL) was added. The resulting mixture was extracted with Et2O (3X) and the combined organic extracts were dried over MgS04 and concentrated in vacuo. The residue was triturated with hexanes and vacuum-filtered to afford 2, 6-dichloro-4- (trifluoromethyl) nicotinic acid (19 g, 95%) as an off-white solid: Rf= 0.30 (9: 1 CH2Cl2 : MeOH), IH-NMR (d6-DMSO, 300 MHz) 6 8. 18 (s, 1H).

Method 2 Conc. HNO3 (13.3 mL) was added to cooled (0 °C) conc. H2SO4 (60 mL) maintaining the internal temperature below 10 °C. After addition, the acid mixture was heated to 70 °C and commercially available (Maybridge) 2,6-dichloro-4- (trifluoromethyl) nicotinonitrile (20.0 g, 83 mmol) was added. The temperature was raised until the internal temperature of the reaction reached 100 °C. After heating for 1 h TLC analysis revealed that the reaction was complete. The reaction mixture was cooled to room temperature, and slowly added to ice (100 g) with strong agitation and extracted with Et20 (3X). The organic layers were combined and washed with brine. The solution was dried over Na2S04 and concentrated in vacuo to give 2,6-dichloro-4- (trifluoromethyl) nicotinic acid (19.1 g, 89%) as an off-white solid: Rf = 0.30 (9: 1 CH2Cl2 : MeOH), 1H-NMR (d6-DMSO, 300 MHz) 8 8.18 (s, 1H).

Intermediate G: 2, 6-dichloro-4- (trifluoromethyl) nicotinoyl chloride A solution of 2, 6-dichloro-4- (trifluoromethyl) nicotinic acid (3.22 g, 13.2 mmol) in thionyl chloride (9 mL) was heated at reflux for 3 h. After cooling, the solution was concentrated in vacuo to give 2, 6-dichloro-4- (trifluoromethyl) nicotinoyl chloride as a yellow oil which was carried on to the next step without further purification. This transformation can also be accomplished using oxalyl chloride with catalytic DMF in place of thionyl chloride.

Intermediate H: 3, 3-dichloro-1-[2, 6-dichloro-4-(trifluoromethyl)-3-pyridinyl]-2-propen-1-one A solution of the 2, 6-dichloro-4- (trifluoromethyl) nicotinoyl chloride from the previous reaction in CH2C12 (14 mL) was added slowly to a cooled (0 °C) and stirred slurry solution of AlC13 (4.4 g, 33.0 mmol) in CH2C12 (14 mL). After 15 min, vinylidene chloride (2.6 mL, 33.0 mmol) was added to the mixture dropwise. The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was poured over ice and partitioned with CH2C12. The organic layer was collected and cooled to 0 °C before TEA (4.6 mL, 33 mmol) was added. After 15 min, the ice bath was removed and the reaction was allowed to warm to room temperature and stirred for an additional 30 min. The solution was washed with IN HCl, NaHC03, and water. The organic layer was passed through a pad of silica gel and concentrated in vacuo to afford 3, 3-dichloro-1- [2, 6- dichloro-4- (trifluoromethyl)-3-pyridinyl]-2-propen-1-one : (4.3 g, 95%) as a brown oil: LCMS RT: 3.59, MH : 488.1, Rf-0. 44 (EtOAc).

Intermediate I : 3, 3-dianilino-1-[2, 6-dichloro-4-(trifluoromethyl)-3-pyridinyl]-2-propen-1-one A solution of aniline (18.4 mL, 202 mmol) in TEA (28.2 mL, 202 mmol) was added slowly to a cooled (0 °C) and stirred solution of 3, 3-dichloro-l- [2, 6-dichloro-4- (trifluoromethyl)-3-pyridinyl]-2-propen-1-one (22.9 g, 67.4 mmol) in dioxane (220 mL).

The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was treated with 10% HCl and extracted with EtaO (3X). The combined organic extracts were washed with brine, dried over Na2S04 and concentrated in vacuo. Silica gel flash chromatography of the residue using 6: 1 Hex: EtOAc gave 3, 3-dianilino-l- [2, 6- dichloro-4-(trifluoromethyl)-3-pyridinyl]-2-propen-1-one as an off-white solid (13.10 g, 43%) :'H-NMR (d6-DMSO, 300 MHz) 812. 24 (br s, 1H), 9.20 (br s, 1H), 7.95 (s, 1H), 7. 12- 7. 42 (m, 10H), 4.82 (s, 1H); Rf= 0.60 (6: 1 Hex: EtOAc).

Intennediate J: 2-anilino-7-chloro-1-phenyl-5-(trifluoromethyl)-1, 8-naphthyridin-4 (1H)-one A mixture of 3, 3-dianilino-l- [2, 6-dichloro-4- (trifluoromethyl)-3-pyridinyl]-2- propen-1-one (12.9 g, 28.5 mmol) and t-BuOK (28.5 mL, 28.5 mmol, 1M in THF) in dioxane (200 mL) was heated at reflux overnight. The reaction was cooled, concentrated in vacuo, treated with saturated NFLCl and extracted with EtOAc (3X). The combined organic extracts were washed with brine, dried over MgS04, and concentrated in vacuo.

Silica gel flash chromatography of the residue using 6: 1 Hex : EtOAc provided 2-anilino-7- chloro-l-phenyl-5-(trifluoromethyl)-1, 8-naphthyridin-4 (1H)-one (11.2 g, 95%) as an off- white solid: LCMS RT: 3.00 min, MH+ : 416.7, Rf = 0.25 (3: 1 Hex: EtOAc). This transformation can be accomplished by using the combination of other aprotic solvents such as DMF, and THF with other bases such as NaH.

Intermediate K: 2,6-dichloro-5-fluoronicotinoyl chloride A solution of commercially available (Aldrich) 2,6-dichloro-5-fluoronicotinic acid (5. 00 g, 23.8 mmol) in thionyl chloride (15 mL) was heated at reflux for 3 h. After cooling, the solution was concentrated in vacuo to give 2,6-dichloro-5-fluoronicotinoyl chloride as a brown oil which was carried on to the next step without further purification. This transformation can also be accomplished using oxalyl chloride with catalytic DMF in place of thionyl chloride.

Intermediate L: 3, 3-dichloro-1-(2, 6-dichloro-5-fluoro-3-pyridinyl)-2-propen-1-one A solution of the 2,6-dichloro-5-fluoronicotinoyl chloride from the previous reaction in CH2C12 (25 mL) was added slowly to a cooled (0 °C) and stirred slurry solution of Aids (7.9 g, 59.5 mmol) in CH2C12 (25 mL). After 15 min, vinylidene chloride (4.75 mL, 59.5 mmol) was added to the mixture dropwise. The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was poured over ice and partitioned with CH2C12. The organic layer was collected and cooled to 0 °C before TEA (8.3 mL, 59.5 mmol) was added. After 15 min, the ice bath was removed and the reaction was allowed to warm to room temperature and stirred for an additional 30 min. The solution was washed with 1N HC1, NaHC03, and water. The organic layer was passed through a pad of silica gel and concentrated in vacuo to afford 3, 3-dichloro-1-(2, 6- dichloro-5-fluoro-3-pyridinyl)-2-propen-1-one : (6.1 g, 90%) as a brown oil :'H-NMR (d6- DMSO, 300 MHz) 8 8. 43 (d, 1H, J= 8.4 Hz), 7.56 (s, 1H), Rf= 0.76 (3: 1 Hex: EtOAc).

Intermediate M: 3, 3-dianilino-l- (2, 6-dichloro-5-fluoro-3-pyridinyl)-2-propen-l-one To a 0 °C solution of 3, 3-dichloro-1-(2, 6-dichloro-5-fluoro-3-pyridinyl)-2-propen- 1-one (6.70 g, 23.2 mmol) in dioxane (50 mL) was added TEA (9.7 mL, 69.6) followed by aniline (6.3 mL, 69.6 mmol). After 1 h the reaction was allowed to warm to room temperature and was stirred overnight. The mixture was concentrated in vacuo until most of the solvent was removed and then the residue was diluted with water and extracted with CH2C12 (2X). The combined organic extracts were washed with water, dried over Na2S04 and concentrated in vacuo. Purification of the residue by silica gel Biotage chromatography provided 3, 3-dianilino-1- (2, 6-dichloro-5-fluoro-3-pyridinyl)-2-propen-1- one as yellow solid (4.2 g, 49%): LCMS RT: 3.47 min; MH+ : 402.6.

Intermediate N: 2-anilino-7-chloro-6-fluoro-1-phenyl-1, 8-naphthyridin-4 (lH)-one A mixture of 3, 3-dianilino-1-(2, 6-dichloro-5-fluoro-3-pyridinyl)-2-propen-1-one (2.3 g, 5.7 mmol) and t-BuOK (1.28 g, 11.4 mmol) in dioxane (80 mL) was stirred at 80 °C overnight. The reaction was cooled, concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2S04, and concentrated in vacuo. Silica gel flash chromatography of the residue provided 2-anilino-7-chloro-6-fluoro-1-phenyl-1, 8-naphthyridin-4 (1H)-one (1.0 g, 50%) as a light yellow solid: LCMS RT: 2.60 min, MH+ : 366.8. This transformation can be accomplished by using the combination of other aprotic solvents such as DMF, and THF with other bases such as NaH.

Intermediates Ni-Niz were synthesized from 3, 3-dichloro-1-(2, 6-dichloro-5-fluoro-3- pyridinyl)-2-propen-1-one as above for Intermediate N using the appropriate amine : Intermediate N1 : LCMS RT: 2. 81 min, MH+ : 402.3 Intermediate N2 : LCMS RT: 2.73 min, MH+ : 402.4 Intermediate N3: LCMS RT: 2.30 min, MH+ : 298. 1 Intermediate N4: LCMS RT: 2.88 min, MH+ : 394.3 Intermediate N5 : LCMS RT: 2. 78 min, MH+ : 426.3 Intermediate N6 : LCMS RT: 3.09 min, MH+ : 434.5 Intermediate N7 : LCMS RT: 3.07 min, MH+ : 378.2 Intermediate N8 : LCMS RT: 3.15 min, MH+ : 422.4 Intermediate Ng : LCMS RT: 2.90 min, MH+ : 486.3 Intermediate Nlo : LCMS RT: 2.22 min, MH+ : 294.2 Intermediate Nn : LCMS RT: 3.05 min, MH+ : 430. 4 Intermediate N12 : LCMS RT: 2.51 min, MH+ : 468.3 Intermediate N13 LCMS RT: 3.10 min, MH+ : 430. 4 Intermediate O : 2,6-dichloronicotinoyl chloride A solution of commercially available (Aldrich) 2,6-dichloro-nicotinic acid (2. 0 g, 10.4 mmol) in thionyl chloride (10 mL) was heated to 80 °C for 2 h. After cooling, the solution was concentrated in vacuo to give 2,6-dichloro-nicotinoyl chloride as yellow oil which was carried on to the next step without further purification. This transformation can also be accomplished using oxalyl chloride with catalytic DMF in place of thionyl chloride.

Intermediate P: 3, 3-dichloro-1-(2, 6-dichloro-3-pyridinyl)-2-propen-l-one A solution of the 2,6-dichloro-nicotinoyl chloride (1.0 g, 4.76 mmol) from the previous reaction in CH2C12 (5 mL) was added slowly to a cooled (0 °C) and stirred slurry solution of Aids (0.64 g, 4.76 mmol) in CH2C12 (20 mL). After 15 min, vinylidene chloride (0.38 mL, 0.46 g, 4.76 mmol) was added to the mixture dropwise. The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was then poured over ice and was acidified using 1 N HCl (15 mL). Stirring was continued for 20 min and the product was extracted with CH2C12 (3X). The combined organic extracts were dried over Na2S04 and concentrated in vacuo to give 3, 3-dichloro-1- (2, 6-dichloro-3- pyridinyl)-2-propen-1-one (0.88 g, 68%) as a light yellow oil : 1H-NMR (CDC13, 300 MHz) 5 8. 38, d, J = 8.4, 1H). 7.40 (d, J = 8.4, 1H), 7.10 (s, 1H) ; Rf = 0.51 (4: 1 Hex: EtOAc).

Intermediate Q: 3, 3-dianilino-1-(2, 6-dichloro-3-pyridinyl)-2-propen-1-one A solution of aniline (1.01 mL, 11.1 mmol) in TEA (1.55 mL, 11.1 mmol) was added slowly to a cooled (0 °C) and stirred solution of 3, 3-dichloro-1-(2, 6-dichloro-3- pyridinyl)-2-propen-1-one (1.0 g, 3.69 mmol) in dioxane (20 mL). The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was concentrated in vacuo until most of the solvent was removed. The residue was diluted with water and extracted with EtOAc (3X). The combined organic extracts were washed with water, dried over Na2S04 and concentrated in vacuo. Silica gel flash chromatography of the residue using 6: 1 EtOAc: Hex gave 3, 3-dianilino-1-(2, 6-dichloro-3-pyridinyl) -2- propen-1-one as pale yellow solid (0.69 g, 49%): LCMS RT: 3.81 min; MH+ : 384.2.

Intermediate R: 2-anilino-7-chloro-1-phenyl-2, 3-dihydro-1, 8-naphthyridin-4 (lH)-one A mixture of 3, 3-dianilino-1- (2, 6-dichloro-3-pyridinyl)-2-propen-1-one (0.08 g, 0.21 mmol) and NaH (0.009 g, 0.23 mmol) in THF (6 mL) was heated to 80 °C overnight. The reaction was cooled, concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. Silica gel flash chromatography of the residue using 3: 1 Hex: EtOAc provided 2-anilino-7-chloro-1-phenyl-2, 3-dihydro-1, 8-naphthyridin-4 (1H)- one (49 mg, 68%) as an off-white solid: LC-MS RT: 2.56 min, MH+ : 348.2. This transformation can be accomplished by using the combination of other aprotic solvents such as dioxane and DMF with other bases such as t-BuOK.

Intermediate S: Ethyl 3- (2-chloro-6-methyl (3-pyridyl) )-3-oxopropanoate Ethyl 3- (2-chloro-6-methyl (3-pyridyl) ) -3-oxopropanoate was prepared by the general procedure described in the Journal of Medical Chemistry, 1986, 29, 2363. The product had: MH+ : 242.1, LCMS RT: 2.33 and 3.06 min (keto-enol).

Intermediate T: Ethyl (2Z)-2-[(2-chloro-6-methyl (3-pylidyl)) carbonyl]-3, 3-dimethylthio-prop-2- enoate Cs2CO3 (24.0 g, 72.5 mmol) was added to a solution of ethyl 3- (2-chloro-6- methyl (3-pyridyl) )-3-oxopropanoate (7.0 g, 29 mmol) in THF (290 mL). The reaction mixture was cooled to-10 °C and after 15 min, CS2 (8.7 mL, 145 mmol) was added.

Stirring was continued for 2 h and MeI (4.5 mL, 72.5 mmol) was added. The reaction was slowly warmed to room temperature over 18 h and filtered. The filtrate was concentrated in vacuo to provide ethyl (2Z)-2- [ (2-chloro-6-methyl (3-pyridyl) ) carbonyl] -3, 3- dimethylthioprop-2-enoate as a yellow oil that was used without purification. LCMS RT: 2.79 min, MH+ : 345.8. A variety of alkyl halides can be used to quench the generated sulfur anion.

Intermediate U: Ethyl (2E)-3, 3-bis (phenylamino)-2-[(2-chloro-6-methyl (3-pyridyl))-carbonyl] prop-2- enoate A solution of ethyl (2a)-2-[(2-chloro-6-methyl (3-pyridyl) ) carbonyl] -3, 3- dimethylthioprop-2-enoate (100. mg, 0.28 mmol) and aniline (0.076 mL, 0.83 mmol) in THF (1.4 mL) was heated at reflux for 18 h. The reaction was cooled to room temperature and concentrated in vacuo. Silica gel flash chromatography of the residue using 1: 1 EtOAc: Hex provided ethyl (2E)-3, 3-bis (phenylamino)-2- [ (2-chloro-6-inethyl (3- pyridyl) ) carbonyl] prop-2-enoate (55.6 mg, 44%): LCMS RT: 3.56 min, MH+ : 436.3.

Intennediate V: Ethyl 7-methyl-2-methylthio-4-oxo-1-phenylhydropyridino [2,3-b]-pyridine-3- carboxylate Aniline (3.96 mL, 43.5 mmol) was added to a solution of ethyl (2Z)-2-[(2-chloro- 6-methyl (3-pyridyl) ) carbonyl] -3, 3-dimethylthioprop-2-enoate (5.13 g, 14.5 mmol) in DMSO (72.5 mL). The reaction solution was heated to 70 °C for 18 h and then cooled to room temperature. The solution was diluted with EtOAc, washed with water and brine, dried over Na2SO4, and concentrated in vacuo. Trituration of the resulting orange oil with Et2O afforded some desired product as a yellow solid. Additional product was obtained by silica gel flash chromatography of the mother liquor using 1: 1 EtOAc: Hex. The two purifications provided ethyl 7-methyl-2-methylthio-4-oxo-1-phenylhydropyridino [2,3- b] pyridine-3-carboxylate (2.87 g, 56%) as a yellow solid: LCMS RT: 2.85 min, MH+ : 355.0.

Intermediate W: Ethyl 7-methyl-4-oxo-l-phenyl-2- (phenylamino) hydro-pyridino [2, 3-b]-pyridine-3- carboxylate A solution of ethyl (2E)-3, 3-bis (phenylamino)-2- ( (2-chloro-6-methyl (3- pyridyl) ) carbonyl) prop-2-enoate (85.0 mg, 0.195 mmol) and t-BuOK (67 mg, 0.60 mmol) in dioxane (2 mL) was heated at reflux for 48 h. The reaction was cooled to room temperature and concentrated in vacuo. Silica gel flash chromatography of the residue using 3: 1 Hex: EtOAc to 100% EtOAc gave ethyl 7-methyl-4-oxo-1-phenyl-2- (phenylamino) hydropyridino [2,3-b] pyridine-3-carboxylate (39 mg, 49%) as a white solid: LCMS RT: 2. 80 min, MH+ 400.0. This transformation can be accomplished by using the combination of other aprotic solvents such as DMF and THF with other bases such as NaH.

Intermediate X: Ethyl 2- [ (4-chlorophenyl) amino]-7-methyl-4-oxo-1-phenyl-hydropyridino- [2, 3- b] pyridine-3-carboxylate KHMDS (0.5 M in toluene, 0.84 mL, 0.42 mmol) was added to a cooled (-78 °C) solution of 4-chloroaniline (71.4 mg, 0.560 mmol) in THF (0.70 mL). After 2 h, a solution of ethyl 7-methyl-2-methylthio-4-oxo-1-phenylhydropyridino [2,3-b] pyridine-3- carboxylate (100 mg, 0. 28 mmol) in THF (0.70 mL) was added resulting in immediate formation of an orange solution. The reaction was slowly warmed to room temperature, stirred for 21 h, and quenched with saturated aqueous NH4C1. The aqueous solution was extracted with Et2O (3X) and the combined organic extracts were washed with water and brine, dried over Na2S04, and concentrated in vacuo. Silica gel flash chromatography of the residue using 1: 1 EtOAc: Hex gave ethyl 2- [ (4-chlorophenyl) amino] -7-methyl-4-oxo- l-phenylhydropyridino [2,3-b] pyridine-3-carboxylate (30.0 mg, 25%) as a white solid: LCMS RT: 2.98 min, MH+ 434. 0.

Intermediate Y: 5-Bromo-2-hydroxy-6-methylnicotinc acid A solution of NaOBr was prepared by adding Bra (11.4 g, 3.66 mL, 71.3 mmol) to a cooled (0 °C) and stirred solution of NaOH (7.8 g, 196 mmol) in water (90 mL). This solution was warmed to room temperature and was then added to a solution of commercially available (Aldrich) 2-hydroxy-6-methylpyridine-3-carboxylic acid (10.0 g, 65.1 mmol) and NaOH (7.8 g, 196 mmol) in water (30 mL). After stirring for 5 min, the mixture was cooled to 0 °C and carefully acidified with conc. HC1. The precipitate was filtered and dried over MgS04 to afford 5-bromo-2-hydroxy-6-methylnicotinc acid (15.0 g, 99%) : 1H NMR (DMSO-d6) 8.25 (s, 1H), 2.41 (s, 3H); MH 232. 0. Elemental analysis calculated for C7H6BrNO3 : C, 36.23 ; H, 2.61 ; N, 6.04 ; Br, 34.44 ; Found: C, 36.07 ; H, 2.44 ; N, 5.91 ; Br, 34.43. Intermediate Z (Same as Intermediate BA): 2, 4-dichloro-6-methylnicotinic acid A solution of commercially available (Maybridge) ethyl 2,4-dichloro-6- methylpyridine-3-carboxylate (1.0 g, 4.3 mmol) and NaOH (342 mg, 8.6 mmol) in water (1.7 mL) and MeOH (1.5 mL) was heated to 80 °C for 4 h. The mixture was acidified using 50% H2SO4 and filtered. The solid was washed with cold water and dried to give of 2, 4-dichloro-6- methylpyridine-3-carboxylic acid (582 mg, 66%): LCMS RT: 0.70 min, MH+ : 206.2.

Intermediate AA (Same as Intermediate BB): 3, 3-dichloro-l- (2, 4-dichloro-6-methyl-3-pyridinyl)-2-propen-l-one The compound was prepared according to the procedure described for Intermediate BB below. LCMS RT: 3.13 min, MH+ : 284. 6.

Intermediate AB (Same as Intermediate BC): 3, 3-dianilino-1- (2, 4-dichloro-6-methyl-3-pyridinyl)-2-propen-1-one The compound was prepared according to the procedure described for Intermediate BC below: LCMS RT: 3.06 min, MH+ : 398.7.

Intermediate AC: (2Z)-3-anilino-1-(2, 6-dichloro-5-fluoro-3-pyridinyl)-3-(isopropylamino)-2-propen -1-one 3, 3-dichloro-1-(2, 6-dichloro-5-fluoro-3-pyridinyl)-2-propen-1-one (374.0 mg, 1.29 mmol) was dissolved in CH2C12 (5 mL) and cooled to 10 °C. Aniline (120.0 mg, 1.29 mmol) and isopropylamine (76.5 mg, 1.29 mmol) were added dropwise as a mixture in 3 mL of 1,4-dioxane. TEA (0.897 mL, 6.45 mmol) was added and the reaction mixture was warmed to room temperature and left to stir for 2 h. The dioxane was removed ira vacua and the brown residue was partitioned between EtOAc and saturated aqueous NaHCO3.

The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS04 and concentrated in vacuo. Purification of the residue using Biotage silica gel chromatography eluting with 6: 1 to 7: 3 Hex: EtOAc provided (2Z)-3-anilino-1-(2, 6-dichloro-5-fluoro-3-pyridinyl)-3-(isopropylamino)-2- propen-1-one (45 mg, 10%) as an off-white solid: LCMS RT: 3.63 min, MH+ : 368.2.

Intermediate AD: 4-Nitrophenyl 2-{[3-(trifluoromethyl0phenyl]amino}nicotinate To a warmed (40 °C) suspension of niflumic acid (10.0 g, 35.4 mmol) and 4- nitrophenol (4.9 g, 35.4 mmol) in CH2Cl2 (80 mL) was added a suspension of EDCI (6. 8 g, 35.4 mmol) in CH2C12 (20 mL). The reaction was stirred for 16 h, and then cooled to room temperature. The solution was quenched with water (50 mL), and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were washed with water and dried over Na2S04. The solvent was removed in vacuo, and the residue was purified by trituration with Hex: CH2Cl2 to afford 4-Nitrophenyl 2-{[3- (trifluoromethyl) phenyl] amino} nicotinate (4.5 g, 31%): LCMS RT: 4.03 min, MH+ : 404.1.

Intermediate AE: Ethyl 2-cyano-3-oxo-3-(2-{[3-(trifluoromethyl0phenyl]amino}-3- pyridinyl) propanoate To a stirred mixture of NaH (524 mg, 21.8 mmol) in toluene (20 mL) was added dropwise ethyl cyanoacetate (3.7 g, 32.7 mmol, 3.5 mL). The slurry was stirred for 1 h and then 4-nitrophenyl 2-{[3-(trifluoromethyl) phenyl] amino} nicotinate (4.4 g, 10.9 mmol) was added. The reaction mixture was stirred for 1 h and then quenched with water (20 mL). CH2C12 (30 mL) was added and the layers were partitioned. The organic layer was washed with brine (2X) and dried over Na2S04. The solvent was removed in vacuo and the residue was purified by silica gel flash chromatography (5: 1 to 2: 1 Hex: EtOAc) to afford 3 Ethyl 2-cyano-3-oxo-3- (2- { [3- (trifluoromethyl) phenyl] amino}-3- pyridinyl) propanoate. (6 g, 87%): LCMS RT: 2.83 min, MH+ : 378.0.

Intermediate AF: 2-Amino-1- [3- (trifluoromethyl) phenyl]-1, 8-naphthyridin-4 (1H)-one Ethyl 2-cyano-3-oxo-3- (2- { [3- (trifluoromethyl) phenyl] amino}-3-pyridinyl) propanoate (2.0 g, 5.3 mmol) was heated to 120 °C in a mixture of cone. HCl (4 mL) and glacial acetic acid (2 mL) for 3 h. The reaction mixture was cooled to room temperature, and neutralized by slow addition of NaOH pellets. The mixture was extracted with CHzClz (3X). The combined organic extracts were washed with saturated aqueous NaHC03 (10 mL) and brine (10 mL), dried over MgS04, and concentrated in vacuo. The residue was purified by prep-HPLC (YMC-Pack Pro C18 Column, 150 x 20 mm I. D.; 30- 70% CH3CN in water, 20 min. ) to afford 2-Amino-l- [3- (trifluoromethyl) phenyl]-1, 8- naphthyridin-4 (1H)-one (880 mg, 55%): LCMS RT: 2.03 min, MH+ : 306.3.

Intermediate AG: 7-chloro-6-fluoro-2- (isopropylamino)-1-phenyl-1, 8-naphthyridin-4 (1)-one (2Z)-3-Anilino-l- (2, 6-dichloro-5-fluoro-3-pyridinyl)-3- (isopropylamino)-2- propen-1-one (40.0 mg, 0.109 mmol) was dissolved in 4 mL of DMF. NaH (8.70 mg, 0.217 mmol, 60% dispersion in oil) was added and the reaction was heated to 85 °C under argon for 2 h. The reaction mixture was cooled to room temperature and diluted with water and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS04 and concentrated in vacuo. Purification of the residue using Biotage silica gel chromatography eluting with 100% EtOAc to 95: 5 EtOAc: MeOH provided 7-chloro-6-fluoro-2- (isopropylamino)-1-phenyl-1, 8-naphthyridin- 4 (1H)-one (21 mg, 64%) as a white solid: LCMS RT: 2.57 min, MH+ : 332.2.

Intermediate AH: 2-anilino-7-chloro-6-fluoro-5-methyl-1-phenyl-1, 8-naphthyridin-4 (lI)-one A solution of LTMP [freshly prepared at 0 °C from tetramethylpiperidine (227.2 mg, 1.62 mmol), TMEDA (188.3 mg, 1.62 mmol) and n-BuLi (1 mL, 1.62 mmol) ] in THF (5 mL) was added to a cooled (-40 °C) and stirred solution of 2-anilino-7-chloro-6-fluoro- l-phenyl-1, 8-naphthyridin-4 (lH)-one (200 mg, 0.54 mmol) in THF (10 mL). The reaction mixture was warmed to 0 °C, for 1 h and then re-cooled to-40 °C. MeI (766 mg, 5.35 mmol) was added and the reaction mixture was allowed to warm to room temperature and was stirred overnight. The reaction was quenched carefully with water (50 mL) and then extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2S04, and concentrated izl vacuo. Silica gel flash chromatography of the residue using 1: 1 EtOAc: Hex afforded 2-anilino-7-chloro-6-fluoro-5-methyl-1-phenyl-1, 8-naphthyridin- 4 (lH)-one (184 mg, 88%) as a white solid: LCMS RT: 2.74 min, MH+ : 380.3. This transformation can also be accomplished by using other amide bases such as LDA.

Intermediate AI : 2-anilino-7-chloro-6-fluoro-1-phenyl-5- (trifluoroacetyl)-1, 8-naphthyridin-4 (1X)-one A solution of LTMP [freshly prepared at 0 °C from tetramethylpiperidine (154 mg, 1.10 mmol), TMEDA (127.8 mg, 1.10 mmol) and n-BuLi (0. 688 mL, 1.10 mmol)] in THF (5 mL) was added to a cooled (-40 °C) stirred solution of 2-anilino-7-chloro-6-fluoro-1- phenyl-1, 8-naphthyridin-4 (1H)-one (100 mg, 0.273 mmol) in THF (10 mL). The reaction was stirred for 1 h and then cooled to-78 °C. Methyl trifluoroacetate (350 mg, 2.74 mmol) was added and stirring was continued for 2 h. The reaction was quenched carefully with water (50 mL), warmed to room temperature and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2S04, and concentrated in vacuo. Silica gel flash chromatography of the residue using 3: 1 Hex: EtOAc gave 2- anilino-7-chloro-6-fluoro-1-phenyl-5- (trifluoroacetyl)-1, 8-naphthyridin-4 (lI)-one (71 mg, 56%) as a light yellow solid: LCMS RT: 3.43 min, MH+ : 462.3. The anion generated from LTMP deprotonation can be quenched with other electrophiles including carbon dioxide and 4-nitrophenyl acetate.

Intermediate AJ: 7-chloro-5-methyl-2- [methyl (phenyl) amino]-1-phenyl-1, 8-naphthyridin-4 (lI)-one MeI (0.10 mL, 228 mg, 1.6 mmol) was added to a stirred suspension of K2C03 (23.5 mg, 0.17 mmol) and 2-anilino-7-chloro-5-methyl-1-phenyl-1, 8-naphthyridin-4 (1Fy)- one (50 mg, 0.14 mmol) in THF (3 mL). The suspension was heated to 40 °C and stirred was overnight. The reaction was quenched with water (5.0 mL) and extracted with EtOAc. The combined organic extracts were dried over Na2S04 and concentrated in vacuo. Recrystallization of the residue using EtOAc afforded 7-chloro-5-methyl-2- [methyl (phenyl) amino]-l-phenyl-l8-naphthyridin-4 (liS)-one (18 mg, 35%): LCMS RT: 2.24 min, MH+ : 376.6, Riz 0.76 (4: 1 Hex: EtOAc).

Intermediate AK: N- (7-chloro-5-methyl-4-oxo-l-phenyl-1, 4-dihydro-1, 8-naphthyridin-2-yl)-N'- (4- fluorophenyl)-N-phenylurea 4-Fluorophenyl isocyanate (45.0 mg, 0.33 mmol) was added to a stirred solution of 2-anilino-7-chloro-5-methyl-1-phenyl-1, 8-naphthyridin-4 (1H)-one (100 mg, 0.276 mmol) in CH2C12 (3 mL). After 16 h, an additional equivalent of 4-fluorophenyl isocyanate (45.0 mg) was added, and the reaction stirred for an additional 16 h. The reaction was concentrated in vacuo and the residue was dissolved in EtOAc. The solution was washed with 1 N HC1, dried over MgS04, and concentrated in vacuo. Purification of the residue using reverse phase prep-HPLC afforded N- (7-chloro-5-methyl-4-oxo-1-phenyl-1, 4- dihydro-1, 8-naphthyridin-2-yl)-N'- (4-fluorophenyl)-N-phenylurea (2.2 mg, 1.6%) : LCMS RT: 3.47 min, MH+ : 499.1, Rf= 0.52 (1: 1 EtOAc: Hex).

Intermediate AL: 2-anilino-7-chloro-3-iodo-5-methyl-1-phenyl-1, 8-naphthyridin-4 (lI)-one K2C03 (210 mg, 1.52 mmol) and Is (390 mg, 1.52 mmol,) were added to a solution 2-anilino-7-chloro-5-methyl-1-phenyl-1, 8-naphthyridin-4 (1H)-one (500 mg, 1.38 mmol) in DMF (10 mL). The mixture was stirred for 30 min and then poured into an aqueous solution of saturated Na2S203 (10 mL). The aqueous solution was extracted with EtOAc.

The combined organic extracts were dried over MgS04, and concentrated in vacuo. Silica gel flash chromatography of the residue using 4: 1 to 1: 1 Hex: EtOAc afforded 2-anilino-7- chloro-3-iodo-5-methyl-1-phenyl-1, 8-naphthyridin-4 (1H)-one (380 mg, 56%): LCMS RT: 3.45 min, MH+ : 488. 2, Rf= 0.5 (2: 1 Hex: EtOAc).

Intermediate AM: 2-anilino-7-chloro-6-fluoro-5- (l-hydroxypropyl)-1-phenyl-1, 8-naphthyridin-4 (1H)- one A-40 °C solution of 2-anilino-7-chloro-6-fluoro-1-phenyl-1, 8-naphthyridin-4 (1H)- one (100 mg, 0.274 mmol) in THF (10 mL) was treated with LTMP (1.10 mmol, freshly prepared by mixing 2,2, 6,6-Tetramethyl piperidine and n-BuLi at 0 °C for 30 min. ). The mixture was then allowed to warm to 0 °C for 2 h. The reaction mixture was cooled to-30 °C and propionaldehyde (159 mg, 2.74 mmol) was added. The reaction was stirred at-30 °C for 2 h before it was slowly quenched with saturated aqueous NH4Cl. The mixture was extracted with EtOAc and the organic layer was dried over MgS04 and concentrated in vacuo. The residue was purified by silica gel flash chromatography to afford 2-anilino-7- chloro-6-fluoro-5- (l-hydroxypropyl)-1-phenyl-1, 8-naphthyridin-4 (1H)-one (120 mg, 97%) as a white solid: LCMS RT: 3.14 min, MH+ : 424.2. Other electrophiles such as disulfide may be used to quench the anion.

Example 1 : 2-anilino-5-methyl-1-phenyl-1, 8-naphthyridin-4 (1)-one A solution of 2-anilino-7-chloro-5-methyl-1-phenyl-1, 8-naphthyridin-4 (1H)-one (95.0 mg, 0.263 mmol), TEA (0.65 mmol), and 10% Pd/C in EtOAc (2.5 mL) and EtOH (2.5 mL) was stirred under H2 (1 atm) for 3.5 h. The reaction mixture was filtered through a pad of Celite using EtOH and EtOAc to rinse. The combined filtrates were concentrated in vacuo, and purified with Biotage silica gel chromatography using 1: 1 EtOAc: Hex to afford 2-anilino-5-methyl-1-phenyl-1, 8-naphthyridin-4 (1H)-one (84 mg, 98%) as a pale yellow solid. LCMS RT: 2.26 min, MH+ : 328.4, Rf = 0.1 (1: 1 EtOAc: Hex), Example 2: 5-Methyl-7-morpholin-4-yl-1-phenyl-2-phenylamino-lH- [1, 8]-naphthyridin-4one A mixture of 7-chloro-5-methyl-1-phenyl-2-phenylamino-lH- [1, 8] naphthyridin-4- one (68.3 mg, 0.189 mmol) and morpholine (0.05 mL, 0.48 mmol) in dioxane (3 mL) was heated to 80 °C for 2 d. The reaction was cooled, concentrated in vacuo, diluted with water and extracted with EtOAc (3X). The combined organic extracts were washed with brine, dried over Na2S04, and concentrated in vacuo to give 5-methyl-7-morpholin-4-yl-1- phenyl-2-phenylamino-lH- [1, 8] naphthyridin-4-one (67 mg, 92%) as yellow solid: LCMS RT: 2.33 min, MH+ : 413.4, Rf= 0.49 (EtOAc).

Example 3: 5-Methyl-l-phenyl-2, 7-bis-phenylamino-1H- [1, 8] naphthyridin-4-one A mixture of 7-chloro-5-methyl-l-phenyl-2-phenylamino-lH- [1, 8] naphthyridin-4- one (15.1 mg, 0.042 mmol), aniline (2 drops), Pd (OAc) 2 (0.27 mg, 0.001 mmol), Cs2CO3 (19.5 mg, 0.06 mmol), and BINAP (1.68 mg, 0.003 mmol) in THF (0.5 mL) was heated at reflux for 16 h. The reaction was quenched with water and extracted with EtOAc (3X).

The combined organic extracts were washed brine, dried over Na2S04, and concentrated in vacuo to give 5-methyl-l-phenyl-2, 7-bis-phenylamino-1H-[1,8] naphthyridin-4-one (6.0 mg, 38%): LCMS RT: 2.57 min, MH+ : 419.5, Rf = 0.18 (EtOAc).

Example 4: 2-anilino-1, 7-diphenyl-5-(trifluoromethyl)-1, 8-naphthyridin-4 (1H)-one A solution of 2-anilino-7-chloro-1-phenyl-5-(trifluoromethyl)-1, 8-naphthyridin- 4 (1H)-one (10.0 mg, 0.241 mmol), Ph3P (6.00 mg, 0.024 mmol) and phenylboronic acid (36.0 mg, 0.290 mmol) in DME was treated with 2M K2CO3 (0. 482 mL, 0.964 mmol) and Pd (OAc) 2 (1.35 mg, 0.006 mmol). The mixture was heated at reflux for 24 h. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over MgS04, and concentrated in vacuo. Purification by preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) provided 2-anilino-1, 7-diphenyl-5- (trifluoromethyl)-1, 8-naphthyridin-4 (1H)-one (45.0 mg, 41%): LCMS RT: 3.76 min, MH'' : 458.4.

Example 5: 2-anilino-7-benzyl-5-methyl-1-phenyl-1, 8-naphthyridin-4 (1H)-one To a solution of 2-anilino-7-chloro-5-methyl-1-phenyl-1, 8-naphthyridin-4 (1H)-one (100 mg, 0.277 mmol) in THF was added Ni (dppp) Cl2 (37.0 mg, 0.069 mmol). After stirring for 5 min, benzylmagnesium chloride (2M, 1.45 mL, 2.90 mmol) was added dropwise via syringe and the mixture was allowed to stir for 24 h. The mixture was quenched with 1 N HC1 and extracted with EtOAc. The organic layer was washed brine, dried over MgS04, and concentrated in vacuo. Purification by preparative HPLC (10% MeNC in water with 0. 1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) provided 2- anilino-7-benzyl-5-methyl-1-phenyl-1, 8-naphthyridin-4 (lH)-one (47.3 mg, 41%) : LCMS RT: 2.85 min, MH : 418. 3.

Example 6: Ethylf [7-anilino-5-oXo-8-phenyl-4-(trifluoromethyl)-5, 8-dihydro-1, 8-naphthyridin-2- yl] sulfanyl} acetate NaH (60% dispersion in oil, 18. 0 mg, 0.434 mmol) was added to a cooled (0 °C) and stirred solution of ethyl mercaptoacetate (0.05 mL, 0.434 mmol) in DMF. After 0.5 h, 2-anilino-7-chloro-1-phenyl-5- (trifluoromethyl)-1, 8-naphthyridin-4 (1H)-one (150.0 mg, 0.361 mmol) was added as a solid in a single portion. The mixture was allowed to warm to room temperature and was stirred for 24 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over MgS04, and concentrated in vacuo. Purification by preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) provided ethyl {[7-anilino-5- oxo-8-phenyl-4- (trifluoromethyl)-5, 8-dihydro-l, 8-naphthyridin-2-yl] sulfanyl} acetate (50 mg, 53%): LCMS RT: 3.91 min, MH+ : 500.2, Rf= 0.24 (1: 1 EtOAc: Hex).

Example 7: { [7-anilino-5-oxo-8-phenyl-4- (trifluoromethyl)-5, 8-dihydro-1, 8-naphthyridin-2- yl] sulfanyl} acetic acid NaOH (160 mg, 4.0 mmol) was added to a stirred solution of ethyl {[7-anilino-5- oxo-8-phenyl-4- (trifluoromethyl)-5, 8-dihydro-1, 8-naphthyridin-2-yl] sulfanyl} acetate (30.0 mg, 0.060 mmol) in aqueous EtOH (lOmL EtOH in 4mL H20). The mixture was allowed to stir for 4 h and was then concentrated in vacuo. The reaction was acidified with 1N HC1 and extracted with CH2Cl2. The organic layer was dried over MgS04, and concentrated in vacuo. Purification by preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) provided {[7-anilino-5-oxo-8- phenyl-4- (trifluoromethyl)-5, 8-dihydro-1, 8-naphthyridin-2-yl] sulfanyl} acetic acid (19.0 mg, 66%): LCMS RT: 2.50 min, MH+ : 472.1 Example 8 2-anilino-1-phenyl-7- (1-piperidinyl)-5- (trifluoromethyl)-1, 8-naphthyridin-4 (1H)-one To a solution of 2-anilino-7-chloro-1-phenyl-5- (trifluoromethyl)-1, 8-naphthyridin- 4 (lH)-one (100.0 mg, 0.241 mmol) in dioxane (2.5 mL) was added piperdine (40. 9 mg, 0.481 mmol). The mixture was left to stir at 80 °C overnight. The mixture was cooled to room temperature, poured into IN HCl (1 mL) and extracted with CH2Cl2. The organic extracts were combined, washed with saturated aqueous NaHC03, dried over Na2S04, and concentrated in vacuo. The residue was purified by Biotage silica gel chrmoatography (1: 1 EtOAc: Hex) to provide 2-anilino-1-phenyl-7-(1-piperidinyl)-5-(trifluoromethyl)-1, 8- naphthyridin-4 (1H)-one (89.5 mg, 80%) as a pale yellow solid: LCMS RT: 2.76 min, MH+ : 465.5.

Example 9: 2-anilino-7-[2-(2-oxo-1-pyrrolidinyl) ethoxy]-1-phenyl-5-(trifluoromethyl)-1, 8- naphthyridin-4 (1H)-one NaH (60% dispersion, 20.0 mg, 0.514 mmol) was added to a cooled (0 °C) and stirred solution of 1- (2-hydroxyethyl)-2-pyrrolidinone (0.06 mL, 0.514 mmol) in DMF.

After 0.5 h, 2-anilino-7-chloro-1-phenyl-5-(trifluoromethyl)-1, 8-naphthyridin-4 (1-one (178 mg, 0.428 mmol) was added as a solid in a single portion and the mixture was heated to 130 °C for 48 h. After cooling to room temperature the mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried over MgS04, and concentrated in vacuo. Purification by preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) provided 2-anilino-7-[2-(2-oxo-l-pyrrolidinyl) ethoxy]-l-phenyl-5-(trifluoromethyl)-1, 8- naphthyridin-4 (1H)-one (0.047 g, 64%): LCMS RT: 2.40 min, MH+ : 509.2. This transformation can be accomplished by using other aprotic solvents such as DMSO, THF and dioxane with temperatures appropriate for these solvents. Commercially available alkoxides can also be used in the absence of base.

Example 10: 2-anilino-5-(hydroxymethyl)-1-phenyl-1, 8-naphthyridin-4 (11l)-one A solution of LDA (38.2 mmol, freshly prepared from n-BuLi and diisopropylamine) in THF (53 mL) was added to a cooled (-78 °C) and stirred suspension of 2-anilino-5-methyl-1-phenyl-1, 8-naphthyridin-4 (1H)-one (2.50 g, 7.64 mmol) in THF (100 mL). The resulting mixture was stirred for 1 h, and then oxygen gas was bubbled, through a fritted glass tube, into the bottom of the reaction vessel. The mixture was stirred overnight, with continued bubbling of oxygen with slow warming to room temperature.

The reaction was quenched with water and 1M HC1 (5 mL), and then extracted with CH2C12. The organic phase was dried over Na2S04 and concentrated in vacuo to afford an orange solid which was recrystalized from EtOAc to obtain 2-anilino-5- (hydroxymethyl)- 1-phenyl-1, 8-naphthyridin-4 (1H)-one (1.38 g, 53%): LCMS RT: 2.01 min, MH+ : 344.3, Rf= 0.22 (95: 5 CH2Cl2 : MeOH).

Example 11: 2-anilino-1-phenyl-5- (1-piperazinylmethyl)-1, 8-naphthyridin-4 (1)-one A solution of 2-anilino-5-(hydroxymethyl)-1-phenyl-1, 8-naphthyridin-4 (1H)-one (180 mg, 0.52 mmol), N, N-diisopropylethylamine (0.10 mL, 0.52 mmol) and SOC12 (0.12 mL, 1.57 mmol) in CH2C12 (7 mL) was stirred at room temperature for 2 h. Excess SOC12 and solvent were removed in vacuo to afford a brownish solid. Crude 2-anilino-5- (chloromethyl)-l-phenyl-1, 8-naphthyridin-4 (1H)-one was used without further purification: LCMS RT: 2.50 min, MH+ : 362.3.

DMF (1 mL) was added to a stirred suspension of crude 2-anilino-5-(chloroemthyl)-1- phenyl-1, 8-naphthyridin-4 (1H)-one (15.0 mg, 0.041 mmol), N, N-diisopropylethylamine (0.036 mL, 0.21 mmol), and piperazine (36 mg, 0.21 mmol) in 1,4-dioxane (2 mL). The solution was heated to 50 °C overnight, cooled to room temperature and concentrated in vacuo. Reverse phase preparative HPLC (0. 1 % TFA in CH3CN and water) of the residue gave 2-anilino-1-phenyl-5- (1-piperazinylmethyl)-1, 8-naphthyridin-4 (1H)-one (8.0 mg, 37%) as the TFA salt: LCMS RT: 0.71 min, MH+ : 412.2.

Example 12: 5-Methyl-l-phenyl-2-phenylamino-7-piperazin-1-yl-1H- [1, 8] naphthyridin-4-one A mixture of 5-methyl-1-phenyl-2-phenylamino-7-piperazin-1-yl-1H- [1, 8] naphthyridin-4-one (22.6 mg, 0.055 mmol) and MsCI (0.083 mmol, 0.006 mL) in CH2C12 (0.8 mL) was stirred at room temperature overnight at which time the solvent was removed in vacuo. The resulting residue was purified by prep-TLC to give 7- (4- methanesulfonyl-piperazin-1-yl)-5-methyl-1-phenyl-2-phenylam ino-1H- [1, 8] naphthyridin-4-one (3.4 mg, 6%): LCMS RT : 2.36 min, MH+ : 490.3.

Example 13: 5-methyl-l-phenyl-2-phenylamino-7- (4-propionyl-piperazin-1-yl)-lH- [1, 8] naphthyridin-4-one A mixture of 5-methyl-1-phenyl-2-phenylamino-7-piperazin-1-yl-1H- [1, 8] naphthyridin-4-one (21.0 mg, 0.052 mmol), propionic acid (0.004 mL, 0.055 mmol), EDCI (11.9 mg, 0.062 mmol), DMAP (7.6 mg, 0.062 mmol), and NMM (0.006 mL, 0.062) in CH2C12 (0.8 mL) was stirred at room temperature overnight. The reaction was diluted with water and extracted with CH2Cl2. The combined organic extracts were washed with 0.5 N HCl and brine and concentrated in vacuo. The residue was purified by prep-TLC eluting with 100% EtOAc to give 5-methyl-1-phenyl-2-phenylamino-7- (4- propionyl-piperazin-1-yl)-lH- [1, 8] naphthyridin-4-one (9.0 mg, 37%): LCMS RT: 2.29 min, MH+ : 468.3.

Example 14: 2-anilino-5-bromo-6-fluoro-7-methoxy-1-phenyl-1, 8-naphthyridin-4 (1g)-one A solution of LTMP [freshly prepared at 0 °C from tetramethylpiperidine (785. 4 mg, 5.6 mmol), TMEDA (651 mg, 5.6 mmol) and n-BuLi (3.5 mL, 5.6 mmol) ] in THF (10 mL) was added to a cooled (-40 °C) stirred solution of 2-anilino-6-fluoro-7-methoxy-1- phenyl-1, 8-naphthyridin-4 (lH)-one (507 mg, 104 mmol) in THF (20 mL). The reaction mixture was warmed to room temperature. After 1 h, the mixture was cooled to-30 °C and 1,2-dibromotetrachloroethane (457 mg, 1.4 mmol) was added. After 30 min, water (50 mL) was added slowly, and then the reaction was warmed to room temperature and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2S04, and concentrated in vacuo. Silica gel flash chromatography of the residue using EtOAc afforded 2-anilino-5-bromo-6-fluoro-7-methoxy-1-phenyl-1, 8-naphthyridin-4 (lI)- one (101 mg, 16%) as a light yellow solid: LCMS RT: 2.75 min, MH+ : 440.3.

Example 15: 7-Methyl-1-phenyl-2-(phenylamino) hydropyridino [2, 3-b] pyridin-4-one Ethyl 7-methyl-4-oxo-1-phenyl-2- (phenylamino) hydropyridino [2,3-b] pyridine-3- carboxylate (67 mg, 0.17 mmol) was dissolved in a 2: 1 HCl : AcOH solution (8.5 mL). The reaction was heated to 120 °C for 5 h then cooled to room temperature. The aqueous solution was washed with Et2O and then neutralized with 2 N NaOH and extracted with EtOAc. The combined organic extracts were washed with saturated aqueous NaHC03 and brine, dried over anhydrous Na2S04, and concentrated in vacuo to provide 7-methyl-1- phenyl-2- (phenylamino) hydropyridino [2,3-b] pyridin-4-one (40 mg, 72%): LCMS RT: 2.28 min, MH+ : 328.4.

Example 16: 2-anilino-5-chloro-7-methyl-1-phenyl-1, 8-naphthyridin-4 (1H)-one A mixture of 3, 3-dianilino-l- (2, 4-dichloro-6-methyl-3-pyridinyl)-2-propen-l- one (100 mg, 0.25 mmol) and t-BuOK (42 mg, 0. 38 mmol) in anhydrous dioxane (4 mL) was heated to 80 °C for 4 h. The solvent was removed in vacuo and the residue was dissolved in EtOAc. The solution was washed with water and brine, dried over MgS04, and concentrated in vacuo. Silica gel flash chromatography of the residue using 1 : 1 EtOAc: Hex gave 2-anilino-5-chloro-7-methyl-1-phenyl-1, 8-naphthyridin-4 (lH)-one (13 mg, 14%): LCMS RT: 2. 47 min, MH+ : 362.6. 2-anilino-5-chloro-7-methyl-1-phenyl-1, 6- naphthyridin-4 (1H)-one was also isolated (68 mg, 75%): LCMS RT: 2.24 min, MH+ : 362.6. This transformation can be accomplished by using the combination of other aprotic solvents such as DMF and THF with other bases such as NaH.

Example 17: Ethyl 7-anilino-3-fluoro-5-oxo-8-phenyl-5, 8-dihydro-1, 8-naphthyridine carboxylate 2-anilino-7-chloro-6-fluoro-1-phenyl-1, 8-naphthyridin-4 (1H)-one (200 mg, 0.55 mmol), DPPP (12 mg, 0.030 mmol), Pd (OAc) 2 (6.0 mg, 0.028 mmol), and CS2CO3 (114 mg, 0.42 mmol) was dissolved in a 1: 1 mixture of EtOH (3 mL) /DMF (3 mL). A balloon filled with CO was attached to the flask and the solution was stirred vigorously. The solution was saturated with CO by evacuating the flask followed by back filling the flask with CO. This was repeated 3 times before heating the solution to 70 °C. After 4 h of stirring all of the starting material had been consumed and the reaction was cooled to room temperature. The solution was diluted with EtOAc and was washed with water. The organic layer was collected, dried over Na2S04, and concentrated in vacuo. The crude solid was triturated with Et2O, filtered and dried to give ethyl 7-anilino-3-fluoro-5-oxo-8- phenyl-5, 8-dihydro-1, 8-naphthyridine-2-carboxylate as a light brown solid (900 mg, 81%) : LCMS RT : 2.63 min, MH+ : 404.4 Example 18: 7-anilino-3-fluoro-5-oxo-8-phenyl-5, 8-dihydro-1, 8-naphthyridine-2-carboxamide A suspension of ethyl 7-anilino-3-fluoro-5-oxo-8-phenyl-5, 8-dihydro-1, 8- naphthyridine-2-carboxylate (50 mg, 0.12 mmol), and NH4C1 (10 mg, 0.19 mmol) in concentrated NH3 (3 mL) and MeOH (8 drops) was stirred for 16 h at room temperature.

The solid was collected by filtration washing with water. Trituration with Et2O, provided 7-anilino-3-fluoro-5-oxo-8-phenyl-5, 8-dihydro-1, 8-naphthyridine-2-carboxamide as a yellow solid (32 mg, 71%): LCMS RT: 1.93 min, MH : 375.3. This trasformation can also be accomplished using EDCI/HOBT coupling with NH3.

Example 19: 7-anilino-N-methoxy-N, 4-dimethyl-5-oxo-8-phenyl-5, 8-dihydro-1, 8-naphthyridine-2- carboxamide 7-anilino-4-methyl-5-oxo-8-phenyl-5, 8-dihydro-1, 8-naphthyridine-2-carboxylic acid (50 mg, 0.14 mmol), N, O-dimethylhydroxylamine hydrochloride (39 mg, 0.40 mmol), HOBT (28 mg, 0.21 mmol), EDCI (40 mg, 0.21 mmol) were dissolved in CH2C12 (3 mL). To this solution was added TEA (78 uL, 0.56 mmol). The reaction was stirred for 1 h and was diluted with CH2Cl2, washed with 0. 5N HCl, saturated NaHC03, and brine.

The organic layer was collected, dried over Na2S04, and concentrated iii vacuo. The solid obtained was triturated with Et2O and dried to give 7-anilino-N-methoxy-N, 4-dimethyl-5- oxo-8-phenyl-5, 8-dihydro-1, 8-naphthyridine-2-carboxamide as a light yellow solid (34 mg, 59%): LCMS RT: 2.28 min, MH+ : 415.2. This transformation can also be accomplished by coupling the appropriate amine with the corresponding acid chloride.

Example 20: 7-acetyl-2-anilino-5-methyl-1-phenyl-1, 8-naphthyridin-4 (1-one To a suspension of 7-anilino-N-methoxy-N, 4-dimethyl-5-oxo-8-phenyl-5,8- dihydro-1, 8-naphthyridine-2-carboxamide (100 mg, 0.24 mmol) in THF (5 mL) at 0 °C was added MeMgBr (3M in Et2O, 322 uL, 0.97 mmol). The suspension became a red solution. As the reaction proceeded the solution lost its red color. After 1 h the reaction was quenched with saturated NH4Cl, diluted with EtOAc, and washed with brine. The organic layer was dried over Na2S04 and concentrated in vacuo. The crude residue was purified by a Biotage silica gel chromatography using EtOAc to afford 7-acetyl-2-anilino- 5-methyl-1-phenyl-1, 8-naphthyridin-4 (1H)-one as a light yellow solid (65 mg, 74%): LCMS RT: 2.63 min, MH+ : 370.4.

Example 21: 2-anilino-7-(butylsulfonyl)-1-phenyl-5-(trifluoromethyl)-1, 8-naphthyridin-4 (1H)-one To a solution of montmorillonite K10 (107.5 mg) in CHC13 was added 13 uL of water. 2-anilino-7-(butylsulfanyl)-1-phenyl-5-(trifluoromethyl)-1, 8-naphthyridin-4 (lu)- one (25 mg, 0.06 mmol) was then added followed by oxone (85.2 mg, 0.14 mmol). The reaction was allowed to stir for 24 h at room temperature. After 24 h the solution was bright bluish-green in color and was filtered and washed with copious amounts of CHC13.

The filtrate was then concentrated i7 vacuo. Silica gel flash chromatography using 3: 1 Hex: EtOAc provided 2-anilino-7-(butylsulfonyl)-1-phenyl-5-(trifluoromethyl)-1, 8- naphthyridin-4 (1H)-one as a yellow oil (13.8 mg, 46%): LCMS RT: 3.14, Mu''502. 2.

Example 22: N- [7-anilino-5-oxo-8-phenyl-4- (trifluoromethyl)-5, 8-dihydro-1, 8-naphthyridin-2- yl] methanesulfonamide To a solution of 2-anilino-7-chloro-1-phenyl-5- (trifluoromethyl)-1, 8-naphthyridin- 4 (1H)-one (100 mg, 0.241 mmol) in DMSO (5 mL) was added methyl sulfonamide and K2C03 (76.5 mg, 0.554 mmol). The reaction was stirred at 120 °C for 24 h. The reaction was then cooled to room temperature, quenched with water and extracted with Et20. The organic layers were dried over MgS04, and concentrated in vacuo. The crude residue was then passed through a plug of silica gel eluting with 1: 1 Hex: EtOAc to 9: 1 CHzCMeOH to afford N- [7-anilino-5-oxo-8-phenyl-4- (trifluoromethyl)-5, 8-dihydro-1, 8-naphthyridin- 2-yl] methanesulfonamide as a white solid (4.4 mg, 4%): LCMS RT: 2.45, MH+ : 475.2.

Example 23: 7-anilino-3-fluoro-5-oxo-8-phenyl-5, 8-dihydro-1, 8-naphthyridine-2-carbaldehyde 2-anilino-6-fluoro-7- (hydroxymethyl)-1-phenyl-1, 8-naphthyridin-4 (1H)-one (100 mg, 0.277 mmol) was dissolved in 4.5 mL CHC13. MnO2 (311 mg, 3.05 mmol) was added and the reaction was heated to 70 °C under argon for 3 d. The reaction mixture was filtered through celite and concentrated in vacuo. Purification by silica gel flash chromatography eluting with 3: 1 to 100: 0 EtOAc: Hex provided 7-anilino-3-fluoro-5-oxo- 8-phenyl-5, 8-dihydro-1, 8-naphthyridine-2-carbaldehyde (15 mg, 15%) as a white solid: LCMS RT: 2. 18 min, MH+ : 360.2.

Example 24: 7-amino-2-anilino-5-methyl-1-phenyl-1, 8-naphthyridin-4 (lH)-one Pd/C (30 mg, 1.75 mmol, 10%) was added to a 25 mL round bottom flask and was blanketed with argon. 7-(allylamino)-2-anilino-5-methyl-1-phenyl-1, 8-naphthyridin- 4 (1H)-one (150 mg, 0.392 mmol) was dissolved in EtOH (2 mL) and was added to the Pd/C followed by methane sulfonic acid (0.041 mL, 0.63 mmol). The reaction was heated to 80 °C for 3 d at which time it was cooled to room temperature, diluted with EtOAc and filtered through celite. The filtrate was concentrated ita vacuo and the residue was purified by Biotage silica gel chromatrography eluting with 100% EtOAc to provide 7-amino-2- anilino-5-methyl-1-phenyl-1, 8-naphthyridin-4 (1H)-one (182 mg, 41%) as a yellow solid: LCMS RT: 2.01 min, MH+ : 343.3.

Example 25: 2-anilino-7-(hydroxymethyl)-5-methyl-1-phenyl-1, 8-naphthyridin-4 (1H)-one To a 0 °C suspension of ethyl 7-anilino-3-fluoro-5-oxo-8-phenyl-5, 8-dihydro-1, 8- naphthyridine-2-carboxylate (100.0 mg, 0.25 mmol) in THF (2.5 mL) was added LAH (0.750 mmol, 1M in THF) dropwise over 10 min. After 5 min. the reaction was slowly quenched with EtOAc (10 mL), was left to stir for 15 min and was concentrated in vacuo.

The resiude was taken up in CH2C12 (10 mL) and 1N HC1 (5 mL) and was left to stir for 30 min. The layers were separated and the aqueous layer was extracted with CH2C12. The combined organic extracts were washed with brine, dried over MgS04, and concentrated in vacuo. Trituation with EtaO provided 2-anilino-6-fluoro-7-(hydroxymethyl)-1-phenyl- 1, 8-naphthyridin-4 (1H)-one (55.2 mg, 61%) as a tan solid: LCMS RT: 2.01 min, MH : 362.3.

Example 26: 2-anilino-7- [ (4-methoxyphenoxy) methyl]-5-methyl-1-phenyl-1, 8-naphthyridin-4 (lI)- one 2-anilino-6-fluoro-7- (hydroxymethyl)-1-phenyl-1, 8-naphthyridin-4 (1 F)-one (62 mg, 0.175 mmol) was dissolved in CH2C12 (1.2 mL). 4-methoxyphenol (22 mg, 0.175 mmol) was added followed by Ph3P (91.8 mg, 0.35 mmol), and ADDP (88.31 mg, 0.35 mmol). The reaction was left to stir overnight at room temperature under argon. Hexanes (5 mL) were added and the reaction was filtered. The filtrate was concentrated in vacuo.

Purification of the residue using Biotage silica gel chromatography eluting with 7: 3 to 9: 1 EtOAc: Hex provided 2-anilino-6-fluoro-7- [ (4-methoxyphenoxy) methyl]-1-phenyl-1, 8- naphthyridin-4 (1Fi)-one (30.0 mg, 37%) as a white solid: LCMS RT 2.87 min, MH+ : 464.2.

Example 27: 7-ethoxy-5-ethyl-2-[methyl (phenyl) amino]-1-phenyl-1, 8-naphthyridin-4 (lH)-one and Example 28: 2-anilino-7-ethoxy-5-ethyl-3-methyl-1-phenyl-1, 8-naphthyridin-4 (1H)-one and Example 29: 7-ethoxy-5-ethyl-3-methyl-2- [methyl (phenyl) amino]-1-phenyl-1, 8-naphthyridin- 4 (lH)-one To a suspension of 2, 2,6, 6-tetramethylpiperidine (153 mg, 0.18 mL, 1.08 mmol) in THF (10 mL) at 0 °C, was added n-BuLi via syringe (1.6 M, 0.68 mL, 1.08 mmol) and TMEDA. The reaction mixture was stirred for 1 h under argon. The reaction mixture was cooled to-60 °C using an acetone/dry ice bath and 2-anilino-7-ethoxy-5-methyl-1-phenyl- 1, 8-naphthyridin-4 (1H)-one (100 mg, 0.269 mmol) was added via syringe as a solution in THF (5 mL). The mixture was stirred for 1 h. MeI was added via syringe and the reaction was allowed to warm to room temperature and stirred for 18 h. A saturated aqueous solution of NH4C1 (20 mL) and EtOAc (20 mL) was added, and the organic layer was separated, dried over MgS04 and concentrated in vacuo. The residue was purified by silica gel flash chromatography using 7: 3 to 100: 0 EtOAc: Hex to give 3 products as follows: Example 27: (35 mg, 32 %), Example 28: (11 mg, 10 %), Example 29: (16 mg, 14 %).

Example 30: 2-anilino-6-fluoro-7-methyl-1-phenyl-1, 8-naphthyridin-4 (111)-one To 2-anilino-7-chloro-6-fluoro-1-phenyl-1, 8-naphthyridin-4 (1H)-one (100 mg, 0.273 mmol) in THF (5 mL) was added Pd (PPh3) 4 (13 mg, 0.001 mmol) and methyl zinc chloride (2M, 0.819 mL, 1.64 mmol) and the reaction was heated to 75 °C for 18 h. The reaction was then cooled to room temperature and poured into a solution of EDTA in water (2.5 g/20 mL) and extracted with Et2O. The organic layer was washed with brine and concentrated in vacuo. The residue was then taken up in MeOH and filtered. The filtrate was concentrated in vacuo to give 2-anilino-6-fluoro-7-methyl-1-phenyl-1, 8- naphthyridin-4 (1H)-one (83. 0 mg, 89%): LCMS RT: 2.43 min, MH+ : 346.4.

Example 31 : Methyl (2E)-3- (7-anilino-2-methyl-5-oxo-8-phenyl-5, 8-dihydro-1, 8-naphthyridin-3- yl)-2-propenoate To a suspension of 2-anilino-6-bromo-7-methyl-l-phenyl-1, 8-naphthyridin-4 (1h7)- one (41 mg, 0.1 mmol) in DMF (2.0 mL) were successively added Pd (OAc) 2 (0.70 mg, 0.003 mmol), Ph3P (5.2 mg, 0.02 mmol), TEA (0.03 mL) and methyl acrylate (17.2 mg, 0.2 mmol). The suspension was heated at 120 °C in a sealed tube for 64 h. The residue obtained after concentration in vacuo was washed with water and extracted with EtOAc.

The organic layer was dried over MgS04 and concentrated in vacuo. Purification by prep- HPLC provided methyl (2E)-3- (7-anilino-2-methyl-5-oxo-8-phenyl-5, 8-dihydro-1, 8- naphthyridin-3-yl)-2-propenoate (10.0 mg, 24%): LCMS RT: 2.61 min, MH : 412. 3, Rf= 0.26 (1 : 1 EtOAc : Hex).

Example 32: (2E)-3- (7-anilino-2-methyl-5-oxo-8-phenyl-5, 8-dihydro-1, 8-naphthyridin-3-yl)-2- propenoic acid To a suspension of 2-anilino-6-[(E)-3-methoxy-3-oxo-1-propenyl]-7-methyl-1- phenyl-1, 8-naphthyridin-4 (lH)-one (10 mg, 0.025 mmol) in CH3CN (2.0 mL) was added 1N NaOH (2.0 mL). The suspension was stirred at room temperature for 18 h. The mixture was diluted with water (10 mL) and extracted with EtOAc. The organic layer was dried over MgS04 and concentrated in vacuo to afford (2E)-3- (7-anilino-2-methyl-5-oxo- 8-phenyl-5, 8-dihydro-1, 8-naphthyridin-3-yl)-2-propenoic acid (6.2 mg, 63%): LCMS RT: 2.37 min, MH+ : 398.3, Rf= 0.51 (EtOAc).

Example 33: 3- (7-anilino-2-methyl-5-oxo-8-phenyl-5, 8-dihydro-1, 8-naphthyridin-3- yl) propanoicacid To a stirred suspension of 2-amlino-6- [ ()-3-hydroxy-3-oxo-l-propenyl]-7- methyl-l-phenyl-1, 8-naphthyridin-4 (11)-one (40.0 mg, 0.100 mmol) in MeOH (2.0 mL), was added Pd/C (5.3 mg, 10% weight on carbon) under an argon atmosphere, followed by the addition of ammonia formate (19.0 mg, 0.30 mmol) in a single portion. The reaction mixture was heated at reflux for 2 h, cooled and filtered. The filtrate was diluted with water (10 mL) and extracted with EtOAc. The organic layer was dried over MgS04 and concentrated in vacuo. The residue was washed with water and dried in vacuo to afford 3- (7-anilino-2-methyl-5-oxo-8-phenyl-5, 8-dihydro-1, 8-naphthyridin-3-yl) propanoicacid (34.5 mg, 86 %): LCMS RT: 2.31 min, MH+ : 400.4, Rf= 0.61 (4: 1 EtOAc: MeOH).

Example 34: 2-anilino-6, 7-dimethyl-1-phenyl-1, 8-naphthyridin-4 (1I1 :)-one Example 35 : 2-anilino-7-ethyl-1-(3-methylphenyl)-1,8-naphthyidin-4(1H)-o ne A suspension of 2-anilino-6-bromo-7-methyl-1-phenyl-1, 8-naphthyridin-4 (1H)- one (203 mg, 0.5 mmol) in THF (10 mL) in an atmosphere of argon was cooled to-78 °C.

A solution of n-BuLi in hexanes (1.0 mL, 1.6 mmol, 1.6 M) was added and the suspension was stirred for 10 min at 0 °C until it became a clear solution. Excessive MeI (0.2 mL, 3.2 mmol) was added, and the reaction was stirred for another 10 min. The reaction was quenched with saturated aqueous NH4C1 (2.0 mL) and water (10 mL) and the mixture was extracted with EtOAc. The organic layer was dried over MgS04 and concentrated in vacuo. The residue was purified by prep-HPLC to afford 2-anilino-6, 7-dimethyl-1- phenyl-1, 8-naphthyridin-4 (lH)-one (55 mg, 32%): LCMS RT: 2.33 min, MH+ : 342.4, Rf = 0.39 (EtOAc). 2-anilino-7-ethyl-1- (3-methylphenyl)-1, 8-naphthyridin-4 (1H)-one (13.3 mg, 7.5%) was also obtained as a side product: LCMS RT: 2.54 min, MH : 356.3, Rf = 0.40 (EtOAc). Other electrophiles such as aldehydes, carbon dioxide, disulfides, trifluoroacetates acid chlorides and other alkyl halides can also be used to quench the generated aryl lithium.

Example 36: Ethyl 7-anilino-4-chloro-3-fluoro-5-oxo-8-phenyl-5, 8-dihydro-1, 8-naphthyridine-2- carboxylate A suspension of ethyl 7-anilino-3-fluoro-5-oxo-8-phenyl-5, 8-dihydro-1, 8- naphthyridine-2-carboxylate (40.0 mg, 0.099 mmol) in anhydrous THF (10 mL) in an atmosphere of argon was cooled to-78 °C. LiHMDS (5 mL, 5 mmol) was then added to the suspension, and the suspension was stirred for 2 h at 0 °C and then cooled to-78 °C and treated with CC12FCClF2 (94 mg, 0.5 mmol). The reaction was stirred for another hour at 0 °C before being quenched with saturated aqueous NH4C1 (2.0 mL) and water (10 mL) and extracted with EtOAc. The organic layer was dried over MgS04 and concentrated in vacuo. Purification of the residue by prep-HPLC provided Ethyl 7- anilino-4-chloro-3-fluoro-5-oxo-8-phenyl-5, 8-dihydro-1, 8-naphthyridine-2-carboxylate (13. 2 mg, 31%): LCMS RT: 2.80 min, MH+ : 437.1, Rf= 0.78 (EtOAc).

Example 37: 7-anilino-4-chloro-3-fluoro-N, N-diisopropyl-5-oxo-8-phenyl-5, 8-dihydro-1, 8- naphthyridine-2-carboxamide LDA was made by adding n-BuLi (0.31 mL, 0.5 mmol, 1.6 M) to diisopropylamine (50 mg, 0.5 mmol) in THF (15 mL) at-15 °C. A suspension of ethyl 7- anilino-3-fluoro-5-oxo-8-phenyl-5, 8-dihydro-1, 8-naphthyridine-2-carboxylate (40.0 mg, 0.915 mmol) in anhydrous THF (10 mL) in an atmosphere of argon was cooled to-78 °C.

LDA was added and the suspension was stirred for 2 h at 0 °C and then cooled to-78 °C and treated with CCl2FCClF2 (94 mg, 0.5 mmol). The reaction was stirred for another hour at 0 °C before being quenched with saturated aqueous NH4C1 (2.0 mL) and water (10 mL). The aqueous solution was extracted with EtOAc and the organic layer was dried over MgS04 and concentrated i71 vacuo. Purification of the residue by prep-HPLC provided 7-anilino-3-bromo-4-chloro-N, N-diisopropyl-5-oxo-8-phenyl-5, 8-dihydro-1,8- naphthyridine-2-carboxamide (20 mg, 41%): LCMS RT: 3.02 min, MH : 493.3, Rf= 0.78 (EtOAc).

Example 38 : 2- [ (4-Methylbenzyl) amino]-1- [3- (trifluoromethyl) phenyl]-1, 8-naphthyridin-4 (1H)- one A mixture of 2-amino-1- [3- (trifluoromethyl) phenyl]-1, 8-naphthyridin-4 (1-one (50 mg, 0.16 mmol), CsC03 (160 mg, 0.49 mmol) and 4-methylbenzyl bromide (35 mg, 0.25 mmol) in THF (3 mL) was heated to 80 °C in a sealed tube for 16 h. The reaction was cooled to room temperature and quenched with water (3 mL). The mixture was extracted with CH2C12 (3X), and the combined organic extracts were dried with Na2S04 and concentrated in vacuo. The residue was purified by prep-HPLC (YMC-Pack Pro C18 Column, 150 x 20 mm I. D.; first run: 20-80% CH3CN in water, 11 min.; second run: 50- 90% MeOH in water, 20 min.) to afford 2- [ (4-Methylbenzyl) amino]-l- [3- (trifluoromethyl) phenyl]-1, 8-naphthyridin-4 (1H)-one (2.2 mg, 3%): LCMS RT: 2.75 min, MH+ : 410.2.

The following specific examples are presented to illustrate the invention related to Formula (II) as described herein, but they should not be construed as limiting the scope of the invention in any way.

Intermediate BA: 2, 4-dichloro-6-methylnicotinic acid A solution of commercially available (Maybridge) ethyl 2,4-dichloro-6- methylpyridine-3-carboxylate (1.0 g, 4.3 mmol) and NaOH (342 mg, 8. 6 mmol) in water (1.7 mL) and MeOH (1.5 mL) was heated to 80 °C for 4 h. The mixture was acidified using 50% H2SO4 and then filtered. The solid collected was washed with cold water and dried to give of 2, 4-dichloro-6- methylpyridine-3-carboxylic acid (582 mg, 66%): LCMS RT: 0.70 min, MH : 206.2.

Intermediate BB: 3, 3-dichloro-l- (2, 4-dichloro-6-methyl-3-pyridinyl)-2-propen-l-one 2,4-Dichloro-6-methylnicotinic acid (8.7 g, 43.0 mmol) was mixed with SOC12 (31 mL). The resulting mixture was heated to 80 °C for 2 h and concentrated in vacuo to give the acid chloride as yellow oil. The oil was then dissolved in CH2Cl2 (10 mL) and the solution was added to a cooled suspension of AlCl3 (21.3 g, 160.0 mmol) in CH2Cl2 (50 mL) at 0 °C. After 2 h at 0 °C, vinylidene chloride (2.16 mL, 80. 0 mmol) was added to the above suspension. The resulting mixture was then left to warm to room temperature and stirred overnight. The reaction mixture was poured into crushed ice and the resulting mixture was extracted with CH2Cl2. The combined organic layers were cooled to 0 °C and TEA (14.9 mL) was added. After 1 h of stirring, the organic layer was washed with 10% aqueous HC1 (100 mL), water (200 mL), brine (100 mL), and dried over Na2SO4.

Solvents were removed in vacuo and the residue was purified by passing it through a pad of silica gel with 15% EtOAc in Hex as the eluent to provide 3, 3-dichloro-1-(2, 4-dichloro- 6-methyl-3-pyridinyl)-2-propen-1-one (5.2 g, 46%): LCMS RT: 3.13 min, MH+ : 284.6.

Alternatively, the acid chloride could be prepared by using oxalyl chloride with a catalytic amount of DMF.

Intermediate BC: 3, 3-dianilino-l- (2, 4-dichloro-6-methyl-3-pyridinyl)-2-propen-l-one A solution of 3, 3-dichloro-1-(2, 4-dichloro-6-methyl-3-pyridinyl)-2-propen-1-one (5.2 g, 18.0 mmol) in 1,4-dioxane (25 mL) was cooled to 0 °C and aniline (5.1 mL, 55.0 mmol) and TEA (7.7 mL, 55.0 mmol) were added dropwise. The reaction mixture was stirred at 0 °C for 1 h and at room temperature for 2 h. The solvents were removed in vacuo. The residue was purified by passing it through a pad of silica gel with EtOAc: Hex (1: 5) as the eluent to provide 3, 3-dianilino-1-(2, 4-dichloro-6-methyl-3-pyridinyl) -2- propen-1-one (7.1 g, 99%): LCMS RT: 3.06 min, MH+ : 398.7.

Intermediates BA1, BB1, BC1, BA2, BB2, BC2 can be prepared in the same manner shown above for BA, BB and BC starting with the appropriate known starting nicotinic acid (Eur. J. Org. Chem. 2001, 1371).

Intermediate BA1 : 4, 6-dichloronicotinic acid Intermediate BB 1: 3, 3-dichloro-1- (4, 6-dichloro-3-pyridinyl)-2-propen-1-one Intermediate BC1 : 3, 3-dianilino-1- (4, 6-dichloro-3-pyridinyl)-2-propen-1-one Intermediate BA2: 4, 5-dichloronicotinic acid Intermediate BB2: 3, 3-dichloro-1- (4, 5-dichloro-3-pyridinyl)-2-propen-1-one Intermediate BC2: 3, 3-dianilino-1-(4, 5-dichloro-3-pyridinyl)-2-propen-1-one Example 39: 2-anilino-5-chloro-7-methyl-1-phenyl-1, 6-naphthyridin-4 (1 H)-one A mixture of 3, 3-dianilino-1-(2, 4-dichloro-6-methyl-3-pyridinyl)-2-propen-1-one (100 mg, 0.25 mmol) and t-BuOK (42 mg, 0.38 mmol) in anhydrous dioxane (4 mL) was heated to 80 °C for 4 h. The solvent was removed in vacuo and the residue was dissolved in EtOAc. The solution was washed with water and brine, dried over MgS04, and concentrated in vcaco. Silica gel flash chromatography of the residue using 1: 1 EtOAc: Hex gave 2-anilino-5-chloro-7-methyl-1-phenyl-1, 8-naphthyridin-4 (1H)-one (13 mg, 14%): LCMS RT: 2.47 min, MH+ : 362 and 2-anilino-5-chloro-7-methyl-1-phenyl- 1, 6-naphthyridin-4 (1H)-one (68 mg, 75%): LCMS RT: 2.24 min, MH+ : 362.3.

Alternatively, the cyclization could be achieved by using other bases such as NaH and other aprotic solvents such as THF and DMF.

Examples 40 and 41 can be prepared in the same manner as that for Example 39 above.

Example 40: 2-anilino-7-chloro-1-phenyl-1, 6-naphthyridin-4 (1H)-one Example 41: 2-anilino-8-chloro-1-phenyl-1, 6-naphthyridin-4 (lH)-one Example 42: 2-anilino-5-chloro-7-methyl-1-phenyl-1, 6-naphthyridin-4 (lH)-one To a solution of 2-anilino-5-chloro-7-methyl-1-phenyl-1, 6-naphthyridin-4 (1H)-one (80 mg, 0.22 mmol) in THF (3mL) was added Ni (dppp) Cl2 (24 mg, 0.044 mmol) at room temperature. After stirring for a few minutes MeMgBr (3M, 0.59 mL, 1.76 mmol) was added and the mixture was allowed to stir for 24 h. The mixture was quenched with 1N HC1 and extracted with EtOAc. The organic layer was washed with brine, dried over MgS04, and concentrated in vacuo. Purification by reverse-phase preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) provided 2-anilino-5, 7-dimethyl-1-phenyl-1, 6-naphthyridin-4 (1H)-one (31 mg, 40%): LCMS RT: 1.51 min, MH+ : 342.4.

Example 43: 2-anilino-5- (dimethylamino)-7-methyl-1-phenyl-1, 6-naphthyridin-4 (1H)-one A mixture of 2-anilino-5-chloro-7-methyl-1-phenyl-1, 6-naphthyridin-4 (lH)-one (80 mg, 0.22 mmol) and dimethylamine (3M in THF, 0.73 mL, 2.20 mmol) in dioxane (3 mL) was heated to 80 °C for 24 h. The reaction mixture was cooled, concentrated in vacuo, diluted with water and the resulting mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2S04, and concentrated in vacuo to give 2-anilino-5-(dimethylamino)-7-methyl-1-phenyl-1, 6-naphthyridin-4 (1H)- one (74 mg, 91%): LCMS RT: 1. 86 min, MH+ : 371.3 Example 44: Ethyl [ (2-anilino-7-methyl-4-oxo-1-phenyl-1, 4-dihydro-1, 6-naphthyridin-5- yl) sulfanyl] acetate A solution of 2-anilino-5-chloro-7-methyl-1-phenyl-1, 6-naphthyridin-4 (lH)-one (200 mg, 0.55 mmol) in EtOH (10 mL) was added ethyl 2-mercaptoacetate (0.12 mL, 1.10 mmol) and TEA (0.23 mL, 1.65 mmol). The reaction was heated at reflux for 24 h. The reaction mixture was cooled, concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic extracts were washed with water, brine, and dried over Na2S04. Solvents were removed in vacuo and the residue was purified by reverse-phase preparative HPLC (10% CH3CN in water with 0. 1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) to provide ethyl [(2-anilino-7-methyl-4-oxo-1-phenyl-1, 4-dihydro-1, 6- naphthyridin-5-yl) sulfanyl] acetate (120 mg, 49%): LCMS RT: 3.07 min, MH+ : 446.2.

Example 45: [(2-anilino-7-methyl-4-oxo-1-phenyl-1, 4-dihydro-1, 6-naphthyridin-5- yl) sulfanyl] acetic acid Aqueous NaOH (2N, 1 mL) was added to a stirred solution of ethyl [ (2-anilino-7- methyl-4-oxo-1-phenyl-1, 4-dihydro-1,6-naphthyridin-5-yl) sulfanyl] acetate (100 mg, 0.23 mmol) in EtOH (8 mL) at room temperature. The mixture was allowed to stir for 4 h and was concentrated in vacuo. The reaction mixture was acidified with IN HC1 and extracted with CH2C12. The organic layer was dried over MgS04 and concentrated in vacuo.

Purification by reverse-phase preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) provided [(2-anilino-7-methyl-4-oxo-1- phenyl-1, 4-dihydro-1, 6-naphthyridin-5-yl) sulfanyl] acetic acid (56 mg, 60%): LCMS RT: 2.61 min, MH+ : 418.2.

Example 46: Ethyl N-(2-anilino-7-methyl-4-oxo-1-phenyl-1, 4-dihydro-1, 6-naphthyridin-5- yl) glycinate To a solution of 2-anilino-5-chloro-7-methyl-1-phenyl-1, 6-naphthyridin-4 (1H)-one (80 mg, 0.22 mmol) in EtOH (8 mL) was added glycine ethyl ester hydrochloride (46 mg, 0.44 mmol) and TEA (0.23 mL, 1.65 mmol). The reaction was heated at reflux for 3 d.

The reaction mixture was cooled, concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over Na2S04 and concentrated in vacuo. The residue was purified by reverse-phase preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) to provide ethyl N- (2-anilino-7-methyl-4-oxo-1-phenyl-1, 4-dihydro-1, 6- naphthyridin-5-yl) glycinate (43 mg, 46%): LCMS RT: 2.16 min, MH+ : 429.3.

Example 47: 2-[(2-anilino-7-methyl-4-oXo-1-phenyl-1, 4-dihydro-1, 6-naphthyridin-5-yl) sulfanyl]-N- cyclopropylacetamide To a mixture of [(2-anilino-7-methyl-4-oxo-1-phenyl-1, 4-dihydro-1, 6- naphthyridin-5-yl) sulfanyl] acetic acid (20 mg, 0.05 mmol), EDCI (18 mg, 0.10 mmol), HOBT (13 mg, 0.10 mmol) and cyclopropylamine (0.004 mL, 0.06 mmol) in CH2C12 (5 mL) was added TEA (0.02 mL, 0.14 mmol). The reaction solution was stirred at room temperature for 24 h before the mixture was diluted with CH2C12, washed with 0. 5N HC1, saturated aqueous NaHC03, brine and dried over Na2S04. Solvents were removed in vacuo and the residue was purified by reverse-phase preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) to provide 2- [ (2- anilino-7-methyl-4-oxo-1-phenyl-1, 4-dihydro-1,6-naphthyridin-5-yl) sulfanyl] -N- cyclopropylacetamide (13 mg, 59%): LCMS RT: 2.55 min, MH+ : 457.1.

Example 48: 2-anilino-7-methyl-1-phenyl-5-(2, 2, 2-trifluoroethoxy)-1, 6-naphthyridin-4 (1)-one Trifluoroethanol (0.08 mL, 1.1 mmol) was added to a suspension of NaH (60% oil dispersion, 44 mg, 1. 1 mmol) in DMSO (4 mL) at 0 °C, and the mixture was heated at 60 °C for 1 h. The mixture was cooled to room temperature and a solution of 2-anilino-5- chloro-7-methyl-1-phenyl-1, 6-naphthyridin-4 (1H)-one (200 mg, 0.55 mmol) in DMSO (2 mL) was added. The resulting mixture was stirred at 50 °C for 16 h. The reaction mixture was cooled, poured into ice water and extracted with CH2C12. The organic layer was washed with brine, dried over MgS04, and concentrated in vacuo. The residue was purified by a Biotage silica gel chromatography (2: 1 EtOAc: Hex) to provide 2-anilino-7- methyl-l-phenyl-5-(2, 2, 2-trifluoroethoxy)-1, 6-naphthyridin-4 (1H)-one (159 mg, 68%): LCMS RT: 2.65 min, MH+ : 426.4. This transformation can be accomplished by using other aprotic solvents such as DMF, THF and dioxane with temperatures appropriate for these solvents. Commercially available alkoxides can also be used in the absence of base.

Example 49: 2-anilino-7-methyl-4-oxo-l-phenyl-1, 4-dihydro-1, 6-naphthyridine-5-carboxylic acid 2-Anilino-5-chloro-7-methyl-1-phenyl-1, 6-naphthyridin-4 (1-one (1.0 g, 2.8 mmol), DPPP (64 mg, 0.15 mmol), Pd (OAc) 2 (31 mg, 0.14 mmol), Cs2CO3 (580 mg, 4.20 mmol) were dissolved in EtOH (10 mL) and DMF (10 mL). A balloon filled with CO was attached to the flask and the solution was stirred vigorously. The flask was purged with CO for 5 min before it was heated to 70 °C. After 4 h the mixture was cooled to room temperature and diluted with EtOAc. The mixture was washed with water, brine, and dried over Na2S04. Solvents were removed iia vacuo and the residue was triturated with Et20 to give ethyl 2-anilino-7-methyl-4-oxo-1-phenyl-1, 4-dihydro-1, 6-naphthyridine-5- carboxylate (800 mg, 71%). The ethyl ester was then dissolved in MeOH (5 mL), and THF (20 mL). To this stirring solution was added KOH (3N, 10 mL) and the mixture was stirred at room temperature for 6 h before it was extracted with Et20. The aqueous layer was acidified with 2N HC1 to pH = 1 and the product precipitated out of the solution. The solid was filtered and dried to give 2-anilino-7-methyl-4-oxo-1-phenyl-1, 4-dihydro-1, 6- naphthyridine-5-carboxylic acid as a white solid (683 mg, 92%): LCMS RT: 1.75 min, MH+ : 372.9.

Example 50: 2-anilino-N-methoxy-N, 7-dimethyl-4-oxo-1-phenyl-1, 4-dihydro-1, 6 naphthyridine-5- carboxamide 2-anilino-7-methyl-4-oxo-1-phenyl-1, 4-dihydro-1, 6-naphthyridine-5-carboxylic acid (80 mg, 0.22 mmol), N, O-dimethylhydroxylamine hydrochloride (64 mg, 0.66 mmol), HOBT (89 mg, 0.66 mmol) and EDCI (126 mg, 0.66 mmol) were dissolved in CH2C12 (9 mL). To this solution was added TEA (120 uL, 0. 88 mmol). The reaction was stirred for 1 h and was diluted with CH2C12, washed with 0. 5N HCI, saturated NaHC03, and brine. The organic layer was collected, dried over Na2S04, and concentrated in vacuo.

The solid obtained was triturated with Et2O and dried to give 2-anilino-N-methoxy-N, 7- dimethyl-4-oxo-1-phenyl-1, 4-dihydro-1, 6 naphthyridine-5-carboxamide as a light yellow solid (50 mg, 55%): LCMS RT: 2.08 min, MH+ : 414.9. This transformation can also be accomplished by coupling the appropriate amine with the corresponding acid chloride.

Example 51 : 5-acetyl-2-anilino-7-methyl-1-phenyl-1, 6-naphthyridin-4 (1H)-one 2-Anilino-N-methoxy-N, 7-dimethyl-4-oxo-1-phenyl-1, 4-dihydro-1, 6- naphthyridine-5-carboxamide (60 mg, 0.14 mmol) was suspended in THF (5 mL). To this stirring suspension at 0 °C was added MeMgBr (0.19 mL, 0.56 mmol, 3M in Et20). The reaction was stirred at room temperature for 6 h and quenched with saturated aqueous NH4C1, diluted with EtOAc, and washed with brine. The organic layer was collected, dried over Na2S04, and concentrated in vacuo. The residue was purified by Biotage silica gel chromatography using EtOAc as the eluent to provide 5-acetyl-2-anilino-7-methyl-1- phenyl-1, 6-naphthyridin-4 (1H)-one as a light yellow solid (34 mg, 66%): LCMS RT: 2.20 min, MH+ : 370.4.

Example 52: 2-anilino-7-methyl-1-phenyl-5-(trifluoromethyl)-1, 6-naphthyridin-4 (1H)-one and Example 53: 7-methyl-2- [methyl (phenyl) amino]-1-phenyl-5-(trifluoromethyl)-1, 6-naphthyridin- 4 (lH)-one A mixture of methyl fluorosulphonyldifluoroacetate (0.78 mL, 6.10 mmol) and 2- anilino-5-chloro-7-methyl-1-phenyl-1, 6-naphthyridin-4 (1H)-one (2.0 g, 5.50 mmol) in DMF (15 mL) was mixed with Copper (I) iodide (1.05 g, 5.50 mmol) at 80 °C for 6 h before the mixture was filtered and concentrated in vacuo. The residue was diluted with CH2Cl2, washed with water and brine, and dried over MgS04. Solvents were removed in vacuo and the residue was purified by Biotage silica gel chromatography using 1: 1 EtOAc: Hex to provide 2-anilino-7-methyl-1-phenyl-5-(trifluoromethyl)-1, 6-naphthyridin- 4 (1H)-one as a light yellow solid (477 mg 22%): LCMS RT: 2.68 min, MH+ : 396.2. 7- Methyl-2- [methyl (phenyl) amino]-1-phenyl-5- (trifluoromethyl)-1, 6-naphthyridin-4 (1 H)- one (270 mg, 12%) was also isolated: LCMS RT: 2.32 min, MH+ : 410.4.

Example 54: 2-anilino-7-methyl-1-phenyl-1, 6-naphthyridin-4 (lH)-one To a flask containing 2-anilino-5-chloro-7-methyl-1-phenyl-1, 6-naphthyridin- 4 (1H)-one (10 mg, 0.03 mmol) in EtOAc (2 mL) and EtOH (2 mL) at room temperature was added a drop of TEA, and Pd/C (10 weight % on activated carbon Degussa type E101, 2 mg). The system was purged with H2 and left stirring at room temperature overnight.

The reaction mixture was filtered and concentrated in vacuo to provide 2-anilino-7- methyl-l-phenyl-1, 6-naphthyridin-4 (1H)-one (8 mg, 91%) : LCMS RT: 1.22 min, MH+ : 328.3.

Example 55: 2-anilino-5- (4-methoxyphenyl)-7-methyl-1-phenyl-1, 6-naphthyridin-4 (1H)-one An 8-mL amber vial was charged with 2-anilino-5-chloro-7-methyl-1-phenyl-1, 6- naphthyridin-4 (1H)-one (72 mg, 0.20 mmol), 4-methoxyphenylboronic acid (36 mg, 0.24 mmol), Pd (OAc) 2 (1 mg, 0.02 mmol), Ph3P (5 mg, 0.02 mmol), K2CO3 (110 mg, 0. 8 mmol, 2 M), and DME (2 mL). The mixture was heated to 90 °C 2 d. Water was added to the reaction mixture and it was extracted with CH2C12. The organic layer was dried over Na2S04. The residue after concentration in vacuo was triturated with Et2O to provide 2- anilino-5- (4-methoxyphenyl)-7-methyl-1-phenyl-1, 6-naphthyridin-4 (1 H)-one (54 mg, 63%) : LCMS RT: 1.92 min, MH+ : 434.5.

Utilizing the above described procedures for intermediates and examples alone or in combination, a variety of Formula I compounds were prepared using the appropriate starting material and the representative procedure described. These results are summarized in Table 1A.

Table 1A : Example Structure LCMS [M+H] Representative RT Procedure (min) 56 COX 2. 07 413. 4 Intermediate (0) Z, AA, AB N 0 and Example 16, 2 N N H ! H 57 \NH O 1. 85 357. 3 Intermediate Z, AA, AB and Example 16, 2 H 58 H 1. 67 412. 2 Intermediate Z, AA, AB N J and Example t ; XNJC NU N t 59 2. 18 411. 4 Intermediate Z, AA, AB N 0 and Example --zu 16, 2 N N N N N N"- t3 60 XO O 2. 02 358. 4 Intermediate Z, AA, AB and Example 16, 9 H W Example Structure LCMS [M+H] Representative RT Procedure (min) 61 F 2. 54 382. 3 Intermediate F, F F O G, H, I, J and Example 1 43- N N N -"61- 6202. 58 432. 4 Intermediate 0 0, P, Q, R and , Example 4 Jw 1 H IVNAN N N H 6302. 63 296. 3 Intermediate 0, P, Q, R and Example 4 d 64 F 2. 89 426. 2 Intermediate F, F F O G, H, I, J and Example 9 NN I H 4 65 F 3. 00 426. 2 Intermediate F F O Intermediate F, G, H, I, J and Example 4 zon \ \ N 66 O 3. 02 410. 4 Intermediate OH A, B, C, D, E 0 and Example 5 XNt CN N N'C H Example Structure LCMS [M+H] Representative RT Procedure (min) 67 0 F 3. 00 464. 2 Intermediate F, G, H, I, J and F F O HO F Example4 N N H 6 68 F O F 2. 98 500. 3 Intermediate F, G, H, I, J and F FO Ho F Example 4 N N NNN H O W 69 0 F 2. 57 432. 3 Intermediate O, P, Q, R and F Example 4 NNH 0 6 0J 70 0 2. 50 471. 1 Intermediate F, G, H, I, J and F F Example 6, 7 F F FO HA A i H 6 / 71 0 2. 73 390. 4 Intermediate < < O, P, Q, Rand Example 4 b Example Structure LCMS [M+H] Representative RT Procedure (min) 72 0 2. 73 408. 5 Intermediate 0, P, Q, R and Example 4 FX ß NU 7303. 30 396. 4 Intermediate 0, P, Q, R and Example 4 I _N_, N_, H e 7403. 41 370. 4 Intermediate 0, O, P, Q, Rand Example 5 SJ ß H W N N 7503. 56 396. 5 Intermediate \</% O, P, Q, R and Example 5 N N N'C H W 76 0 3. 39 404. 4 Intermediate bzw P, Q, R and Example 5 N N N H 77 0 2. 69 370. 3 Intermediate <\ A O, P, Q, R and Example 5 N N N H t Example Structure LCMS [M+H] Representative RT Procedure (min) 78 0 2. 59 356. 3 Intermediate 0, P, Q, R and Example 5 con'N rz M Y 79 0 2. 74 408. 4 Intermediate 0, P, Q, R and Example 4 X N N N d 80 N 1. 60 394. 0 Intermediate \ON 0 A, B, C, D, E and Example 1, 10, 11 N AN '\A 1 H X4OH zut F F 1 XI 81 I O 2. 88 376. 4 Intermediate S, ci T, U, W and 1N Example 15 N N N'O 6 H 8202. 42 348. 3 Intermediate S, cl T, U, W and L Example 15 NN NJO H 83 1. 69 426. 2 Intermediate zNo Z, AA, AB and Example N 0 16, 2 , N N HAN H b Example Structure LCMS [M+H] Representative RT Procedure (min) 84 3. 87 480. 4 Intermediate A, B, C, D, E, AL and r i ! ii \ ALand N N N Example 4 t \ 85 , Intermediate A, B, C, D, E, AL and N N N Example 4 I H PO 86 0 2. 43 283. 6 Intermediate S, T, V and Example 15 t3 N N S 87 | O 2. 82 620. 4 Intermediate A, B, C, D, E and Example N N N 2, 13 r o \ 88 1. 86 389. 1 Intermediate HN 90 o K, L, M, N, AM, and Example 1, 13 N N N H C 89 HO 00 2. 56 372. 3 Intermediate Z, AA, AB and Example N N 16, 17, 7 N N H H Example Structure LCMS [M+H] Representative RT Procedure (min) 90 I O 2. 41 504. 2 Intermediate S \/% A, B, C, D, E and Example r N N N N'C 2, 12 11 91 l O 2. 50 518. 3 Intermediate A, B, C, D, E and Example N N N N'C 2, 12 H ° u 92 l O 2. 71 566. 3 Intermediate 9JI % A, B, C, D, E and Example N N N N 2, 12 °a) W O 9302. 54 417. 4 Intermediate K, L, M, N, and Example 2 oJ e H ou 6 H f"1 94 | O 2. 27 342. 4 Intermediate S, T, U, W and Example 15 N N N'C H 95) 01. 71 426. 2 Intermediate A, B, C, D, E and Example 2 NJ ¢fS H H , N Example Structure LCMS [M+H] Representative RT Procedure (min) 96 0 1. 74 412. 1 Intermediate A, B, C, D, E and Example 2 ßN N N Nv HNJ H / 97 I O 2. 75 411. 2 Intermediate A, B, C, D, E and Example 2 N N G Lj 1 H 98 ß O 2. 70 397. 2 Intermediate A, B, C, D, E and Example 2 N N H 99 I O 2. 52 399. 4 Intermediate A, B, C, D, E and Example 2 N N N N H 10002. 80 488. 6 Intermediate A, B, C, D, E > > > > and Example 2 f N N N N"" q- 6" 101 I O 2. 89 459. 7 Intermediate A, B, C, D, E and Example 2 N N N N H / Example Structure LCMS [M+H] Representative RT Procedure (min) 102 0 2. 54 441. 6 Intermediate A, B, C, D, E and Example 2 'N N N OJ, H I W 103 I o 2. 40 383. 5 Intermediate A, B, C, D, E and Example 2 N N N H H 104 F 2. 44 467. 5 Intermediate F, F F O G, H, I, J and Example 8 N N N N'C n H ho 105 F 2. 51 480. 4 Intermediate F, F F 0 G, H, I, J and Example 8 N N N N rN N H W 106 F 1. 80 466. 4 Intermediate F, F F O G, H, I, J and Example 8 rN N N H N H 107 0 2. 65 433. 4 Intermediate A, B, C, D, E and Example 3 N N N N H H , W Example Structure LCMS [M+H] Representative RT Procedure (min) 108 I O 2. 60 437. 4 Intermediate F A, B, C, D, E and Example 3 N N N N H H 10902. 71 453. 4 Intermediate CI , w and Example 3 N N N N N N N N"" H H W 11002. 53 449. 4 Intermediate A, B, C, D, E and Example 3 N N N N H H 111 I I O 2. 65 433. 4 Intermediate A, B, C, D, E and Example 3 N N N H H 11202. 84 461. 5 Intermediate A, B, C, D, E 1 and Example 3 N N N N'C H H 1 6 1 113 | O 2. 08 387. 4 Intermediate A, B, C, D, E H and Example 2 N N N N H 6 H Example Structure LCMS [M+H] Representative RT Procedure (min) 114 I O 2. 46 433. 4 Intermediate A, B, C, D, E and Example 2 "I-N N N H 6 H 115 0 2. 64 451. 3 Intermediate A, B, C, D, E and Example 2 / F ß W 116 I O 2. 61 463. 4 Intermediate A, B, C, D, E j [ ! j H f H 11602. 61 463. 4 Intermediate k A, B, C, D, E and Example 2 H N N H/ H 6 H / 117 2. 03 440. 4 Intermediate A, B, C, D, E and Example 2 NH N N H H W 118 0 2. 58 372. 2 Intermediate A, B, C, D, E and Example 9 O N N N H 6 H 119 | O 2. 20 454. 4 Intermediate A, B, C, D, E and Example N N N N'C 2, 13 f N N w H ß O v _ Example Structure LCMS [M+H] Representative RT Procedure (min) 120 0 2. 55 496. 4 Intermediate A B C D E and Example /and Example r N N N 2, 13 O NJ H / 121 | O 2. 52 552. 2 Intermediate A, B, C, D, E and Example N N N N'O 2, 12 H N w 122 0 2. 44 516. 3 Intermediate A, B, C, D, E and Example N N N N'C 2, 13 O NJ H 123 2. 28 429. 3 Intermediate A, B, C, D, E and Example 3 O H ¢ H 0 H H 124 0 2. 45 431. 4 Intermediate F K, L, M, N, AH and N N N Example 2 r3 H 0 6 rf"i 12502. 45 362. 3 Intermediate K, L, M, N and Example 9 O N N N H C Example Structure LCMS [M+H] Representative RT Procedure (min) 126 > O 2. 51 360. 3 Intermediate K, L, M, N, AH and Exam le 1 N N N H 12702. 30 346. 4 Intermediate K, L, M, N, AH and N N N Example 1 ß W 128 2. 70 374. 4 Intermediate 0 K, L, M, N, 0 AH and Example 1 W H 129 2. 69 438. 3 Intermediate , J K, L, M, N and Example 9, 14, 4 O N N Nez ß W 130 2. 64 428. 3 Intermediate K, L, M, N O and Example 9, 14, 4 0 N N NO 6" Example Structure LCMS [M+H] Representative RT Procedure (min) 131"o 2. 74 468. 3 Intermediate 2 K, L, M, N and Example 9, 14, 4 F < JC O N N N H t 132 F 2. 77 456. 4 Intermediate K, L, M, N and Example 0 9, 14, 4 F I I I O N N N H fez 133 O 2. 37 364. 3 Intermediate S, F T, U, W and Example 15 N N N H F F 134 0 2. 40 362. 3 Intermediate S, T, V, X and Example 15 NN I N 6-H ! H 135 O 2. 46 362. 2 Intermediate S, A) 4 A T, V, X and Example 15 N N N H cl 6 Example Structure LCMS [M+H] Representative RT Procedure (min) 136 0 2. 28 346. 3 Intennediate S, T, V, X and Example 15 /RN N NX H F 137 O 2. 32 342. 3 Intermediate S, T, V, X and Example 15 CNAN H 138 O 2. 27 346. 3 Intermediate S, T, V, X and Example 15 N N N F H ! H 139 O 2. 41 362. 3 Intermediate S, T, V, X and Example 15 N N N CI A W 140 O | 2. 36 358. 3 Intermediate S, T V, Xand , Example 15 e H ! H 141 O 2. 32 358. 3 Intermediate S, , w T, V, X and Example 15 J : NAN N H i H Example Structure LCMS [M+H] Representative RT Procedure (min) 142 0 01--l 2. 36 358. 3 Intermediate S, T, V, X and Example 15 N N N H W 14302. 35 364. 3 Intermediate F A, B, C, D, E and Example 1 N N N H F F 144 0 2. 60 406. 3 Intermediate B Y, S, T, U, W and Example N N NO 15 H W 145 1-10 0 5. 35 434. 4 Intermediate Y, S, T, U, W and Example 15, 4 N N N'O H W 146 F 3. 43 470. 3 Intermediate F, F F O G, H, I, J and Example 6 S N N N H ¢S H 147 F 3. 43 470. 3 Intermediate F, F F O G, H, I, J and Example 6 SlNtNtNX H , ¢t Example Structure LCMS [M+H] Representative RT Procedure (min) 148 F 2. 59 541. 3 Intermediate F, F F 0 G, H, I, J and Example 6, 7, zu 13 S N N N 0 W 149 F 2. 66 525. 2 Intermediate F, F F O G, H, I, J and ON Example 6, 7, 13 SNNN o N N N 0 6 H 150 F 2. 49 483. 4 Intermediate F, F F O G, H, I, J and Example 8 N N N'C H H 151 F 2. 38 455. 3 Intermediate F, F F O G, H, I, J and Example 8, 7 HO O H 4 H 0 H 6 H 152 F 2. 60 499. 4 Intermediate F, F F O G, H, I, J and Example 6, 7, , 13 S N N N O H Example Structure LCMS [M+H] Representative RT Procedure (min) 153 F 2. 95 547. 4 Intermediate F, F F 0 G, H, I, J and H Example 6, 7, 1 13 r'YS-NN 0 H A W 154 F 2. 19 482. 3 Intermediate F, F F O G, H, I, J and Example 8, 7, . 13 O H t H 0 H 6 H 155 F 2. 07 482. 3 Intermediate F, F F O G, H, I, J and H Example 8, 7, , 13 N N N N 0 H H / 156 F 1. 95 454. 3 Intermediate F, F F O G, H, I, J and Example 8, 7, Han 13 N N N N 6 H i H U 157 F 2. 18 524. 3 Intermediate F, F F O G, H, I, J and Example 8, 7, 0-") 13 0 N N N'C 0 H 6H Example Structure LCMS [M+H] Representative RT Procedure (min) 158 F 2. 44 530. 3 Intermediate F, F F O G, H, I, J and Example 8, 7, N 13 o H H I / 159 F 1. 99 468. 3 Intermediate F, F F O G, H, I, J and Example 8, 7, H 13 N N N 0 H 6 H 160 F 2. 74 598. 3 Intermediate F, F F O G, H, I, J and Example 8, 7, 1 13 NNNN FX N N N F Q F 6 161 F 3. 15 442. 3 Intermediate F, F F 0 G, H, I, J and Example 6 S N N N H ¢ H 162 F 328 456. 2 Intermediate F, F F O G, H, I, J and Example 6 S N N N t H Example Structure LCMS [M+H] Representative RT Procedure (min) 163 F 2. 26 471. 3 Intermediate F, F F O G, H, I, J and Example 6, 7, H2N 13 S N N N o 6 1 164 F 2. 34 485. 3 Intermediate F, F F O G, H, I, J and Example 6, 7, H 13 S N N N o H _... 165 ci 0 F 2. 71 398. 4 Intermediate Z, AA, AB and Example N N Njb 16 H F 166 F 2. 88 542. 6 Intermediate F, F F O G, H, I, J and Example 8 , | | H NI-) < 167 F 2. 66 495. 6 Intermediate F, F F O G, H, I, J and Example 8 N N N N H 6 Example Structure LCMS [M+H] Representative RT Procedure (min) 168 2. 20 441. 5 Intermediate F, F F 0 G, H, I, J and HO, H00 Example 8 HO N N N N H H 169 F 2. 76 453. 5 Intermediate F, F F O G, H, I, J and Example 8 IYF 0 N N N N'O L 1 H 6 H 170 F F 3. 05 430. 3 Intermediate K, L, M, N, AI and Example 1 N N NEO A W 1 H 171 F 3. 14 428. 4 Intermediate 0 K, L, M, N, AI and Example 1 N N N'O H ! H 172 0 2. 72 477. 5 Intermediate A, B, C, D, E and Example 2 N N NJ H F F Example Structure LCMS [M+H] Representative RT Procedure (min) 173 F 2. 72 495. 5 Intermediate F, F F O G, H, I, J and Example 8 (/ N N N N 14 U 174 F 2. 72 495. 6 Intermediate F, F F 0 G, H, I, J and Example 8 N N N N H U 175 F 2. 77 487. 5 Intermediate F, F--F 0 G, H, I, J and Example 8 N N N N H H u W 176 0 2. 43 437. 4 Intermediate F A, B, C, D, E and Example 2 N N N N H H N F F 177 F 3. 13 502. 5 Intermediate F, F F 0 G, H, I, J and Example 6, 21 O X H zu \ Example Structure LCMS [M+H] Representative RT Procedure (min) 178 F 2. 93 488. 3 Intennediate F, F F 0 G, H, I, J and Example 6, 21 o"S N N 'O 6 H 179 F 2. 41 426. 3 Intermediate F, F F O G, H, I, J and Example 17, 7 HO N N N'C U / 180 HO 0 0 2. 56 372. 3 Intermediate Z, AA, AB and Example i 16, 17, 7 6 H U 181 I O 2. 19 408. 2 Intermediate F A, B, C, D, E HO cr and Example O Q H 0 H F F 182 F 2. 39 425. 4 Intermediate F, F F O G, H, I, J and Example 17, 18 N N N'C O 6H W Example Structure LCMS [M+H] Representative RT Procedure (min) 183 0 2. 18 407. 4 Intermediate F A, B, C, D, E H2N I and Example 2 WN'N 17, 18 0 H F F 184 F 2. 88 424. 4 Intermediate F, F F O G, H, I, J and Example 17, 7, (, 19, 20 N N N'O 0 H 185 2. 27 402. 2 Intermediate Z, AA, AB and Example 16, 9 N N N N H H 186 F>F 2. 41 408. 3 Intermediate Z, AA, AB O 0 and Example 16, 9 N N 6 H 187 F 2. 50 426. 3 Intermediate F-I--F Z, AA, AB 0 and Example 16, 9 N N N'C N N N H e Example Structure LCMS [M+H] Representative RT Procedure (min) 188 2. 43 386. 1 Intermediate "o O Z, AA, AB and Example 16, 9 N N N H 189 F 2. 66 456. 4 Intermediate F, F FO G, H, I, Jand Example 9 O N N N H b H 190 F 2. 88 462. 5 Intermediate F, F FO G, H, I, Jand Example 9 NN I F t3 H 191 F 2. 98 452. 4 Intermediate F, F F O G, H, I, J and Example 9 NN I 0 N NJ k" 192 F 3. 12 480. 3 Intermediate F, F F O G, H, I, J and Example 9 FO N N N F H I Example Structure LCMS [M+H] Representative RT Procedure (min) 193 F 3. 10 440. 1 Intermediate F, F F 0 G, H, I, J and Example 9 i I O N N N H 194 2. 51 398. 1 Intermediate , t Z, AA, AB O O and Example 16, 9 I I N N N H 195 F 2. 99 505. 4 Intermediate F, F F O G, H, I, J and Example 8 , L N N H XI 196 F 3. 05 513. 5 Intermediate F, F F O G, H, I, J and Example 8 N N N . 197 F 2. 47 455. 4 Intermediate F, F FO G, H, I, J and Example 8 N N N N H H Example Structure LCMS [M+H] Representative RT Procedure (min) 198 OF 2. 57 453. 4 Intermediate K, L, M, Ni I | and Example 2 N NtNsN+ ß ff"1 F 199 0 2. 70 440. 2 Intermediate F K, L, M, N2 I I ii : : r and Example 0 N N N 17 H F F 200 0 2. 19 411. 3 Intermediate F and Example 'RNAN H2N N N 17, 18 ° H F F 201 0 2. 48 453. 4 Intermediate F K, L, M, N2 and Example 2 N N N N H ( F 202 0 F 2. 76 440. 2 Intermediate K, L, M, N, 0 and Example N N N6 17 0 H zon 'F 203 0 F 2. 76 481. 5 Intermediate K, L, M, Ni and Example 2 N N N N "r N N N N " F _ 6"F Example Structure LCMS [M+H] Representative RT Procedure (min) 204 0 2. 69 481. 5 Intermediate F F K, L, M, N2 and Example 2 F r I H / F 205 0 F 2. 23 411. 3 Intermediate K, L, M, Ni I |l | | I and Example N'\ N''N 17, 18 O H F 206 0 2. 27 383. 4 Intermediate F K, L, AC, AG I I and Example 2 NrN NA N A J i H rf"i 207 F 3. 12 490. 3 Intermediate F, F F O G, H, I, J and Example 17 o I I I o I O H F 208 F 2. 55 461. 3 Intermediate F, F F O G, H, I, J and Example 17, H2N w I I 18 ° 4 H O H 0 H 209 F 2. 62 503. 4 Intermediate F, F F 0 G, H, I, J and ,., Example 8 zut N N N N F H ff"1 F Example Structure LCMS [M+H] Representative RT Procedure (min) 210 F 2. 82 531. 5 Intermediate F, F F O G, H, I, J and Example 8 I AJ N N F Dz F 211 F 2. 54 491. 4 Intermediate F, F F O G, H, I, J and Example 8 N N N N F H H F WF 212 F 2. 93 531. 4 Intermediate F, F F O G, H, I, J and F Example 8 N N N N H F F 213 F 2. 47 491. 4 Intermediate F, F F O G, H, I, J and F Example 8 /N N 1N N H 1 H H H / F 214 F 3. 02 476. 3 Intermediate F, F F O G, H, I, J and F Example 9 1 H O N N N I F F Example Structure LCMS [M+H] Representative RT Procedure (min) 215 F 2. 75 492. 3 Intermediate F, F F O G, H, I, J and F Example 9 F i H NON H 216 F 3. 14 476. 2 Intermediate F, F F O G, H, I, J and Example 9 O N N N F O N N N F ß F 217 F 2. 83 492. 3 Intermediate F, F F O G, H, I, J and Example 9 O N N N F H H 21802. 15 349. 1 Intermediate K, L, M, N3 I ! I and Example 2 CN N N N H 219 0 2. 01 362. 3 Intermediate F K, L, M, N HO and Example N N NU 17, 25 H 6 H - N N N 17, 25 220 0 2. 87 505. 4 Intermediate F F AH, K, L, M, Fuzz N N N N H t H F H H Example Structure LCMS [M+H] Representative RT Procedure (min) 221 > O 2. 90 396. 3 Intermediate AH, K, L, M, N ans N N N Example 1 F-_b H F U 222 3. 23 424. 3 Intermediate p AH, K, L, M, N and Example 1 N N Njq F_b H F 223 p 2. 67 396. 3 Intermediate AH, K, L, M, N and Example 1 N N N H F 224 3. 02 424. 4 Intermediate AH, K, L, M, N2 ans Example, 1 N N H F F 225 I O 2. 12 401. 3 Intermediate A, B, C, D, E and Example O H < H 6" Example Structure LCMS [M+H] Representative RT Procedure (min) 226 0 0 2. 45 459. 4 Intermediate | II K, L, M, N, AI F and Example 2 rN N N H H ri 227 0 0 2. 69 487. 5 Intermediate K, L, M, N, AI and Example 2 N N N N NN O' H oAJ t3 228 0 0 2. 37 447. 4 Intermediate K, L, M, N, AI and Example 2 N N N N H H W 229 0 0 2. 60 374. 3 Intermediate K, L, M, N, AI and Example 1 N N N'C H i H 230 2. 78 390. 1 Intermediate HO o Kg L, M, N, AM and Example 1 N N N H 23102. 09 421. 2 Intermediate A, B, C, D, E and Example 7-N N N 22 H H Example Structure LCMS [M+H] Representative RT Procedure (min) 232 0 2. 44 483. 2 Intermediate A, B, C, D, E and Example N N N N 22 H H / 233 0 2. 51 497. 2 Intermediate A, B, C, D, E and Example N N N N 22 H \ H / 23402. 44 383. 2 Intermediate A, B, C, D, E and Example 3 N N N N H H / 235 | O 2. 84 428. 4 Intermediate A, B, C, D, E {)) ] andExample N N NJO 17 X H \ 236 0 2. 77 400. 3 Intermediate A, B, C, D, E and Example 01"eN NA N N N'C 17 O H 237 0 2. 30 372. 2 Intermediate A, B, C, D, E and Example N N N'C 17, 7 0 H Example Structure LCMS [M+H] Representative RT Procedure (min) 238 I O 2. 50 427. 4 Intermediate A, B, C, D, E and Example Y ? NAN O H / 23902. 18 441. 5 Intermediate 0") A, B, C, D, E and Example N 17, 7, 13 O H W 240 l O 2. 44 399. 4 Intermediate A, B, C, D, E and Example OH O H 241 f O 2. 66 455. 5 Intermediate A, B, C, D, E and Example N N N 17, 7, 13 O H 242 I O 2. 79 427. 3 Intermediate A, B, C, D, E and Example O 4 H \ i H 6 243 0 2. 58 411. 3 Intermediate H, w A, B, C, D, E and Example Y ? NAN NJO 17, 7, 13 O ¢f__ / Example Structure LCMS [M+H] Representative RT Procedure (min) 244 I O 2. 58 457. 3 Intermediate A, B, C, D, E and Example N 17, 7, 13 O H 245 I O 2. 80 447. 5 Intermediate A, B, C, D, E and Example N N N 17, 7, 13 W 246 A < 2. 97 481. 8 Intermediate CI H A, B, C, D, E N and Example N''N''N \ I7 7 I3 90 4 247 I O 3. 30 481. 3 Intermediate A, B, C, D, E and Example N N N 17, 7, 13 ce 248 I O 3. 05 481. 7 Intermediate A, B, C, D, E JJ and Example ci N' H 17, 7, 13 ° " 249 0 1. 99 371. 4 Intermediate A, B, C, D, E H and Example -2N N N'O 17, 18 H 1 Example Structure LCMS [M+H] Representative RT Procedure (min) 250 0 2. 82 384. 4 Intermediate A, B, C, D, E and Example /<N N N< 17, 7, 19, 20 NN / 251 0 2. 94 398. 4 Intermediate A, B, C, D, E and Example N N-17, 7, 19, 20 H / 252 3. 22 426. 4 Intermediate A, B, C, D, E and Example SN N Nw 17, 7, 19, 20 H fi 253 0 3. 05 412. 4 Intermediate A, B, C, D, E and Example t'NXNANw 17, 7, 19, 20 H 254 0 3. 10 424. 4 Intermediate A, B, C, D, E and Example N N N'C 17, 7, 19, 20 O 6" 255 1 Jt 3. 19 438. 4 Intermediate A, B, C, D, E and Example OYNAN 48 17, 7, 19, 20 1 / Example Structure LCMS [M+H] Representative RT Procedure (min) 256 0 2. 96 432. 4 Intermediate A, B, C, D, E and Example N 17, 7, 19, 20 0 H 257 3. 16 466. 4 Intermediate CI i w I and Example N N N 17, 7, 19, 20 O ¢J) 258 I O 2. 80 398. 5 Intermediate A, B, C, D, E and Example XN N N 17, 7, 19, 20 H 259 t AR 2. 95 412. 5 Intermediate A, B, C, D, E and Example tN N Nv 17, 7, 19, 20 0 6 H 1 260 0) 2. 80 438. 6 Intermediate | A, B, C, D, E and Example s-N N NJO 17, 7, 19, 20 O H 261 F 0 3. 06 450. 3 Intermediate A, B, C, D, E and Example NN N'C 17, 7, 19, 20 O d Example Structure LCMS [M+H] Representative RT Procedure (min) 262 0 3. 05 450. 4 Intermediate A, B, C, D, E and Example N N N 17, 7, 19, 20 0 6 H 263 0 1. 94 376. 2 Intermediate F K, L, M, N HO w I , and Example O g4> H O H / 264 02. 44 374. 4 Intermediate F A</% K, L, M, N and Example N N NJO 17, 7, 19, 20 O H 1 265 0 2. 59 388. 3 Intermediate K, L, M, N and Example N N 17, 7, 19, 20 NN \ 26602. 68 442. 4 Intermediate K, < </E K, L, M, N and Example S <N N N 17, 7, 19, 20 S C/3 267 0 2. 97 470. 5 Intermediate Ci F K, L, M, N ClXlí q f and Example 'N''N''N 17, 7, 19, 20 0 43 Example Structure LCMS [M+H] Representative RT Procedure (min) 268 0 2. 53 376. 3 Intermediate F\ WS A K, L, M, N and Example 9 ß H H 6 H 269 0 2. 28 405. 4 Intermediate F K, L, M, N and Example 2 N N N N H H 27002. 35 406. 2 Intermediate K L M N and Example 9 0 N N H W 271 0 2. 70 390. 2 Intermediate K, L, M, N and Example 9 0 N'NNJ H / 272 0 2. 20 417. 3 Intermediate F K, L, M, N, AI and Example Fi2N I I I i 17, 18 N N N'C NON / 273 ! 02. 38 386. 3 Intermediate A, B, C, D, E and Example N''NI'N 1 N N N'C 17, 7, 19, 20, OH H 25 Example Structure LCMS [M+H] Representative RT Procedure (min) 274 0 2. 63 440. 3 Intermediate A, B, C, D, E and Example N 17, 7, 19, 20, H H 25 275 2. 83 468. 3 Intermediate ci A, B, C, D, E , and Example N N N 17, 7, 19, 20, OH ¢ 25 276 CF3 O 2. 79 479. 3 Intermediate F, G, H, I, J and Example 8 OJ eX H O H 277 CF3 0 2. 58 451. 2 Intermediate F, G, H, I, J and Example 8 J N N N O H ri" 278 F 2. 58 356. 4 Intermediate FY, OH Y, S, T, U, W F F 0 and Example 15, 34 N N N NN 6 H 279 < O 2. 79 404. 4 Intermediate Y, S, T, U, W and Example 15, 4 N N H v Example Structure LCMS [M+H] Representative RT Procedure (min) 280 0 2. 93 422. 4 Intermediate Y, S, T, U, W and Example 15, 4 _, NUA i H N 28102. 78 384. 4 Intermediate Y, S, T, U, W and Example N N 15, 34 OH Fui pu F 282 0 0 2. 50 442. 2 Intermediate , (423 + Y, S, T, U, W H20 + and Example NON 1) 15, 34 6 H 283 O O 2. 26 372. 4 Intermediate Ho Y, S, T, U, W nL', T. T ji n ,-, l and Example N N N 15, 34 W W+F HO HO 284 0 0 2. 29 427. 4 Intermediate Y, S, T, U, W and Example N N N 15, 31, 32, 33, 13 285002. 19 413. 4 Intermediate \nu Y, S, T, U, W and Example /N 1N N 9 15, 31, 32, 33, J, H 13 6 Example Structure LCMS [M+H] Representative RT Procedure (min) 286 0 0 2. 15 384. 4 Intermediate H Y, S, T, U, W and Example N N N 15, 31, 32 H ! ! H 287002. 01 386. 4 Intermediate Y, S, T, U, W and Example N N N 15, 31, 32, 33 ß 6 H 1 288002. 42 396. 5 Intermediate Y, S, T, U, W and Example N N N 15, 31 A i H 289 < 2. 97 430. 6 Intermediate Y S T U W Y, S, T, U, W and Example 15, 31 N NH A W 290002. 33 398. 6 Intermediate Y, S, T, U, W and Example N N N 15, 31, 33 H 6 Fi 291 2. 87 432. 4 Intermediate Y, S, T, U, W 0 and Example 15, 31, 33 N N N'O H W Example Structure LCMS [M+H] Representative RT Procedure (min) 292 O O 2. 01 3973 Intermediate H2N Y, S, T, U, W , and Example N N N 15, 31, 32, 13 ß jt H 293002. 00 399. 5 Intermediate HN i w Y, S, T, U, W , and Example N N N 15, 31, 32, 33, 6 H 13 i 294 F 2. 63 461. 3 Intermediate F, F F O G, H, I, J and F Example 17, If ou 'N'N'N O H F 295 0 2. 54 445. 5 Intermediate K, L, M, N and Example 2 N N N N I A Ruz W 296 0 0 2. 27 425. 3 Intermediate Y, S, T, U, W and Example N N N 15, 31, 32, 13 H i 29702. 43 392. 3 Intermediate Br Y, S, T, U, W and Example N N N'C 15 H AI H Example Structure LCMS [M+H] Representative RT Procedure (min) 298 0 0 2. 40 398. 5 Intermediate Y, S, T, U, W and Example N N N 15, 31 H j H 299002. 28 411. 4 Intermediate "IN Y, S, T, U, W H and Example N N N 15, 31, 32, 13 H C 300 F 3. 18 490. 0 Intermediate F, F F O G, H, I, J and Example 9 '--/0 N N N H V F 301 F 2. 90 462. 3 Intermediate F, F F O G, H, I, J and F Example 9 O N N N H F F 302 F 2. 90 418. 3 Intennediate F, F F O G, H, I, J and Example 1 4 N N N dz Example Structure LCMS [M+H] Representative RT Procedure (min) 303 F 2. 66 418. 3 Intermediate F, F F 0 G, H, I, J and F Example 1 N N N H F F 304 0 2. 70 403. 6 Intermediate FN A K, L, M, N and Example 2 N N N N H 305 F 2. 52 503. 6 Intermediate F, F F O G, H, I, J and Example 8 I 1 I N N N N zu F 306 F 3. 03 502. 2 Intermediate F, F--F 0 G, H, I, J and Example 8 I CN N N NGS ? OJ F) H F _ 307 O OH 2. 68 358. 0 Intermediate S, T, U, W and Example 25 N N N'O H 6 H Example Structure LCMS [M+H] Representative RT Procedure (min) 308 0 2. 40 358. 4 Intermediate A, B, C, D, E and Example 9 O N N N H ! H Utilizing the above described procedures for intermediates and examples alone or in combination, a variety of Formula I compounds can be prepared using the appropriate starting material and the representative procedure described. These compounds are summarized in Table 1 B.

Table 1B Example Structure Representative Procedure 309 N Intermediate Z, AA, AB and Example 16, 4 N N N'O H W 310 Intermediate Z, \+NH O AA, AB and Example 16, 2 ß H H W 311 Intermediate Z, AA, AB and N H O Example 16, 3 N N N H t Example Structure Representative Procedure 312 Intermediate Z, u AA, AB and Example 16, 2 NH O N N N H 6 H 313 HO Intermediate Z, AA, AB and NH 0 Example 16, 2, 7 N I N N H b 314 Intermediate Z, AA, AB and NH 0 Example 16, 2 N N N H f 315 Intermediate Z, AA, AB and HN Example 16, 2, 7, 13 NH 0 N N N H ! H Example Structure Representative Procedure 316 Intermediate Z, HN,, O AA, AB and Example 16, 2, NH 0 ' NH O 7, 13 N N No 6 H 317 HO O Intermediate Z, AA, AB and s 0 Example 16, 6, 7 N N N H t 318 °|+° Intermediate Z, AA, AB and S 0 Example 16, 6 t3 H 6 H 319 Intermediate Z, AA, AB and HN Example 16, 6, 7, 13 s 0 , N N Nio N N N H b H Example Structure Representative Procedure 320 Intermediate Z, HN, O AA, AB and Example 16, 6, keg o 7, 13 , NAN N"O H 321 NO O Internzediate Z, AA, AB, and 0 0 Example 16, 9, 7 N N Nl) H C 322 0 Intermediate Z, AA, AB, and 0 0 Example 16, 9 t H i H 323 Intermediate Z, T AA, AB, and Example 16, 9, QO O 7, 13 N N No N N N H t Example Structure Representative Procedure 324 Intermediate Z, HN AA, AB, and Example 16, 9, SO O 7, 13 /N<3 N N N H W 325 Intermediate Z, a AA, AB, and Example 16, 9 , NAN N" H (H 326 Intermediate Z, ON AA, AB, and Example 16, 9 N 43 - NNN" N N N'O H 327 Intermediate Z, AA, AB, and Example 16, 9 /t 0 t N N N H Example Structure Representative Procedure 328 0 Intermediate Y, S, T, U, W and Example 15, 34 N N N H X 329 O Intermediate Y, S, T, U, W and Example 15, 34 N N N H ! H 330 OH O Intermediate Y, S, T, U, W and Example 15, 34 N N N H t 331 OH O Intermediate Y, S, T, U, W and Example 15, 34 N N N H 6 H 332 N Intermediate Y, S, T, U, W and Example 15, 4 N N N'O < I H 333 I O Intermediate Y, S, T, U, W and Example 15, 4 \N N N \ H 6 H < Example Structure Representative Procedure 334 00 Intermediate Y, S, T, U, W and Example 15, 34 N N N H ! H 33500Intermediate Y, N S, T, U, W and Example 15, N N N 34, 13 H 336 0 0 Intermediate Y, S, T, U, W and Example 15, H I I I ! L H H \ 337 0 0 Intermediate Y, L\NJX N S, T, U, W and H Example 15, N N N 34, 13 H Q3 H 338 0 Intermediate K, < < L, M, N HO Example 31, 32 O ¢S H 0 6 H 339 0 Intermediate 0, P, Q, R and example 17, N N H 25, 26 H Example Structure Representative Procedure 340 F F Inten-nediate F, t ° G, H, I, J and Example 31, 32 HO y NAN 0 H 341 0 Intermediate A, B, C, D, E and Example 1 and N N N Intermediate tlk° ffi ZUT '\ 342 HO O Intermediate Z, AA, AB and 0'Example 16, 31, 32, 33 N N N ,,, a e 343 0 Intermediate A, B, C, D, E and Example 1 and N N N Intermediate AK I N H O W 344 0 Intermediate A, B, C, D, E and HO Example 31, 32 N IN N'O 0 6 H Example Structure Representative Procedure 345 ! 0 IntermediateA, B, C, D, E and Example 1 and N N Intermediate , AI h Y F 346 0 Intermediate O, P, Q, R and N O , Example 17, 2 25, 26 u-6 347 HO Intermediate Z, AA, AB, and 0 Example 16, 31, 32 N N N N N H 348 F Intermediate F, F FO G, H, I, J and Example 31, HO w, , 32, 33 HO N N NON / 349 0 Intermediate O, P, Q, R and Example 17, N N N H 25, 26 t ! t H Example Structure Representative Procedure 350 Intermediate K, L, M, N and Example 31 O ¢t H N N / 351 Intermediate F, F F O G, H, I, J and Example 31 I I I O ¢9 H O H / 352 0 Intermediate A, B, C, D, E and Example 31 O ¢ H O H / 353 1 Intermediate Z, 0s<0 AA, AB and Example 16, 31 e N N N H / 354 | O Intermediate A, B, C, D, E and Example 3 1, HO N 32, 33 O H / 355 0 Intermediate K, L, M, Nand Example 3 1, HO O H / Example Structure Representative Procedure 356 0 Intermediate O, P, Q, R and Example 17, N N 25, 26 i 357 0 Intermediate A, B, C, D, E AJ and Example 1 N N N 6 1 3 U] 358 0 Intermediate A, B, C, D, E and Example 1 and N N N Intennediate AL 359 Intermediate Z, O AA, AB, and Example 16, 5 N N N'O H i ! H 360/Intermediate Z, AA, AB, and Example 16, 5 N N N'O 6 H 361 N02 Inten--nediate Z, AA, AB, and Example 16, 4 N N N'O 6-H Example Structure Representative Procedure 362 0 Intermediate K, L, M, N, and Example 2 N N N -1-6 H 363 0 Intermediate K, L, M, N, and Example 2 C 1 H GNNNN H 0 O 364 0 Intermediate K, F ci L, M, N, and Example 2 N N NJ7 !) ! H CI 365 Intermediate K, L, M, N, and Example 2 HHHtL ! t 6" 366 0 Intermediate K, F L, M, N, and Example 2 , N N N N Y 367 O Intermediate K, F L, M, N, and Example 2 N N N G. H, o 0 Example Structure Representative Procedure 368 0 Intermediate K, F, L, M, N, and Example 2 N \N''N''N W 369 0 Intermediate K, L, M, N, and Example 2 N N N F H F 3700Intermediate K, F N L, M, N, and t Example 2 ß ZON iN 371 | O CN Intermediate A, B, C, D, E and Example 2 kJ, 4 H CON 372 0 Intermediate A, B, C, D, E and Example 2 r N N N N" - N N N ZU 373 0 intermediate A, B, C, D, E and Example 2 GN N H /, N Example Structure Representative Procedure 374 Intermediate A, B, C, D, E and Example 2 i H 1-0 0 375 0 Intermediate A, B, B, C, D, and Example 2 GNN NN f N N N N ir\ H 376 0 Intermediate A, B, C, D, E and Example 2 SN N S N~ N t 377 0 Intermediate A, B, C, D, E and Example 2 N N N X ts 378 | O Intermediate A, B, C, D, E and Example 2 GNNIVH I\ f N N N N f ! l W 379 0 Intermediate S, T, T, X and Example 15 N N N-^) / Example Structure Representative Procedure 380 0 Intermediate S, T, V, X and Example 15 N / 3810Intermediate S, T, V, X and Example 15 and N N N-Intermediate AJ , ON,-"O 3820Intermediate S, T, V, X and Example 15 and N N N-Intermediate AJ N 383 O Intermediate S, T, V and Example 15 N N S' W 384 0 Intermediate S, T, V and Example 15 4 W 385 0 Intermediate S, T, V and Example 15 "JNAN / Example Structure Representative Procedure 386 0 Intermediate S, T, V, X and t !)) ! Example 15 Example 15 t3 XN¢) 387 g O Intermediate A, B, C, D, E and !) !)} Example2 H ON- N 388 0 Intermediate S, NA T, V and I example 15 43 389 0 Intermediate S, T, V and Example 15 N N S 6 3900Intermediate S, T, V, X and Example 15 N CN W 391 0 Intermediate S, T, V, X and Example 15 N N N--') U Example Structure Representative Procedure 3920Intermediate S, T, V and Example 15, 21 N NHS ii 0 393 0 Intermediate S, T, V and Example 15, 21 N N s 11 I/ 3940Intermediate S, T, V and Example 15, 21 N N 0 b 395 0 Intermediate A, XJW B, C, D, E and Example 1, 12 N N N 0 w 396 Oz Intermediate Z, AA, AB and Example 16, 17, 7, 19 N N N'O 6 H \ 397 H2N<O O IntermediateZ, AA, AB and Example 16, 17, 18 N N N H Example Structure Representative Procedure 398) Intermediate Z, AA, AB and Example 16, 2 N O N 0 N N No H 399 Intermediate Z, , J AA, AB and Example 16, 2 N\ JSNJX3 N 0 NN N H 400 Intermediate Z, AA, AB and Example 16, 2, 13 CNJ 13 N N N H 401 Intermediate Z, AA, AB and Example 16, 2 N O N N N H ! H Example Structure Representative Procedure 402 \Nz Intermediate Z, A. A, AB and Example 16, 2 N\ /SNA3 N 0 NN NJO H ) H 403 CN O Intermediate Z, AA, AB and Example 16, 9 N N N H 404 l Intermediate A, i N p B ; C, D, E and Example 1, 10, N N N'O F 11 H 405 < Intermediate A, B, C, D, E and Example 1, 10, HN 11 N N N H C Example Structure Representative Procedure 406'"o Intermediate A, B, C, D, E and Example 1, 10, HN. 11 N N N'O N N H H 407 Intermediate A, I,-) B, C, D, E and HN Example 1, 10, 11 N N N H 408 Inten-nediate Z, AA, AB and Example 16, 2, HN\/O 7, 13 NH 0 "eN AN N H 409 Intermediate Z, AA, AB and Example 16, 6, HN 7, 13 S 0 ENAN N'0 H b Example Structure Representative Procedure 410 hitennediate Z, AA, AB and Example 16, 9, HNO 7, 13 0 0 NAN N H S 411 0 Intermediate Z, LNO AA AB and Example 16, 9, kO 0 7, 13 JXNJ 3 6 H 412 0 Intermediate Z, 4N, 0 AA, AB and Example 16, 2, NH 0 7, 13 N N N H sl 413 0 Intermediate Z, , N, 0 AA, AB and Example 16, 6, s O 7, 13 N N N'O N N N H Example Structure Representative Procedure 414 Intermediate Z, z t O AA, AB and X AA. ABand Example 16, 17, 7, 13 N N N H 415 Intermediate Z, ON AA, AB and X SNJX3 lE7x, a7m, Pll3O 16 Example 16, 17, 7, 13 N N N H i ! H 416 Intermediate Z, AA, AB and 9 Example 16, 17, 7, 13 N N N'O N N H H 417 Intermediate Z, AA, AB and Example 16, HN 0 0 17, 7, 13 N-N N'O H 418 Intermediate Z, O, O AA, AB and Example 16, 17 N N N'O N N N 6" Example Structure Representative Procedure 419 Intermediate Z, AA, AB and S 0 Example 16, 6 N N N'O H 420 Intermediate Z, AA, AB and X P Example 16, 6, 21 N N N'O H 421 Intermediate Z, AA, AB and Example 16, 6 S O JSNJS 14 H ! H 422 Intermediate Z, AA, AB and S 0 Example 16, 6 1 H H ! H 423 Intermediate Z, AA, AB and Example 16, 6, 21 0 H 6 H Example Structure Representative Procedure 424-Intermediate Z, +S O AA, AB and Example 16, 6 N N N Ksi 10 N N N' 425 NH2 O Intermediate Z, AA, AB and Example 16, 3, N N N 2, 4 N N N""24 b H 426 l l Intermediate K, L, M, N, AM and Example 1 and Intermediate AJ N N N H 427 A Intermediate K, L, M, N, AM 00 and Example 1 and Intermediate AJ N N N'O 6 H 428 Intermediate K, L, M, N, AM and Example 1, 26 NNN" N N N H 6' Example Structure Representative Procedure 429 Intermediate K, L, M, N, AM and Example 1, 0 F I I I N N N 6 H 430/Intermediate K, L, M, N, AM "and Example 1 and Intermediate AJ N N N'lo N N N H b 431 0 Intermediate Z, AA, AB and 0 Example 16, 31 N N N H b 432 l Intermediate Z, H N O AA, AB and Example 16, 0 31, 32, 13 N N N H b Example Structure Representative Procedure 433 0 Intermediate Z, AA, AB and 0 Example 16, 31, 33 N N N 6 H t H 434 Intermediate Z, HN AA, AB and Example 16, 31, 32, 33, 13 N N N'O H 435 Intermediate Z, AA, AB and Example 16, > O 31, 33 N N N H 43 H 436 Intermediate Z, AA, AB and Example 16, HN O 31, 32, 33, 13 0 N N N 6 H Example Structure Representative Procedure 437 Intermediate Z, AA, AB and Example 16, 0 31, 32, 33, 13 N N N'O H 43 H 438 Intermediate Z, AA, AB and Example 16, 17, 7, 19, 20 N N N 6 H 439 Intermediate Z, AA, AB and 0 Example 16, 17, 7, 19, 20 N N N H 440 Intermediate Z, AA, AB and Example 16, Oo 17, 7, 19, 20 N N N H t Example Structure Representative Procedure 441 \ Intermediate Z, N AA, AB and Example 16, 2, N 0 13 N N N H S 442 Intermediate Z, HN AA, AB and Example 16, 2 N and Intermediate N N N W 6 H 443 o Intermediate Z, I AA, AB and Example 16, 2, 12 N 0 NN N H W 444 Intermediate Z, J4NZ O AA, AB and Example 16, 2, r ! iii fli 13 I H H Example Structure Representative Procedure 445 0 Intermediate Z, AA AB and H T -T-i i <- Example 16, 3, 24, 13 N N N'O H U 446 0 Intermediate Z, AA, AB and Example 16, 2, 13 N N N H 447 n 1°l Intermediate Z, A, AA, AB and O Example 16, 22 N N N'O N N N"' H 448 0 Intermediate Z, - AA, ABand O Example 16, 22 N N N H b 449 I p Intermediate Z, AA, AB and N NH O Example 16, 3, "1 Lj /< i 24 and Intermediate NN N'0 AK H W Example Structure Representative Procedure 450 0 01-1 Intermediate S, T, U, W and Example 25 and Intennediate AJ H ! ! H 451 Intermediate S, T, U, W and Example 25 and Intermediate AJ N N N H t 452 Intermediate S, T, U, W and 0 10"0 Example 25, 26 FF) -NNN H 453 N Intermediate S, T, U, W and 0 0 Example 25, 26 "CN N*N'O 6 H 454 Intermediate S, T, U, W and O OH Example 25 and Intermediate AJ b H Example Structure Representative Procedure 455 Intermediate S, T, U, W and Example 15 and N N N Intermediate AL and Example 3 456 Intermediate S, T, U, W and Example 15 and Intermediate AL and N N N Example 3 H W 457 A Intermediate S, T, U, W and Example 15 and NH Intermediate AL and NN"N" Example 3 N N N Example 3 H 458 Intermediate Y, S, T, U, W and Example 15, 0 0 31, 32, 33, 195 0 20 N N N H 6 H 459 n Intermediate Y, S, T, U, W and 0<N r N <=N 3 3E1X, a3m3P1e15, Example 15, 31, 33 N N N'O 6 H H Example Structure Representative Procedure 460 | Intermediate Y, w S, T, U, W and Example 15, AXFN 31, 32, 33, 19, 20 N N NO H U \ 461 Intermediate Y, S, T, U, W and Example 15, <\N 17, 7, 19, 20 o N N N'O H i H 462 Intermediate Y, S, T, U, W and Example 15, mon 17, 7, 19, 20 N N N'O N N N H 3 463 Intermediate Y, 0 S, T, U, W and Example 15, 0 17, 7, 19, 20 N N No H i H 464 0 Intermediate Y, S, T, U, W and Example 15, N N N'O 17, 25 H Example Structure Representative Procedure 465 0 Intermediate Y, S, T, U, W and Example 15, N N N'O 17, 25 and Intermediate AJ W 4660Intermediate Y, S, T, U, W and Example 15, RN N NA/17, 25, 26 H 3 H 467 O~\ Intermediate Y, S, T, U, W and Example 15, 3 N N N'O W 468 N=\ Intermediate Y, S, T, U, W and Example 15, 3 N N N'O H t H 469 N \ Intermediate Y, S, T, U, W and Example 15, 3 N N N H 470 zozo Intermediate Y, S, T, U, W and Example 15, 3 N N NEO 3 - N N N" H Example Structure Representative Procedure 471. 0 Intermediate Y, S, T, U, W and Example 15, 3 N N N'O H 4720. Intermediate Y, S, T, U, W and Example 15, 3, nu N N N'O 6 H 473 0Intermediate Y, S, T, U, W and Example 15, 3 and H N N Intermediate razz i I AK 474 0 Intermediate Y, S, T, U, W and 0 \___/N Example 15, 3, N N N N N'O H 475 \ Intermediate Y, S, T, U, W and O N N Example 15, 3 K) K) K ! t "N N N"" H ... 476 0 Intermediate Y, < S, T, U, W and Example 15, 3 \N N N N N N"- H Example Structure Representative Procedure 477 \\ O Intermediate Y, S, T, U, W and HN Example 15, 3 N N N'O lu H 478 Intermediate Y, S, T, U, W and Example 15, 3, N N N 24 H 43 H 479 o Intermediate Y, N S, T, U, W and Example 15, 3 N N N 6 H 480 Intermediate Y, S, T, U, W and Example 15, 3 HN \ I N N N H C3 H 481 Intermediate Y, 0 S, S, T, U, and Example 15, 3 zizi N N N 6 H 482 Intermediate Y, S, T, U, W and Example 15, 3 HN-\ \ N N N N N N'O 6 H Example Structure Representative Procedure 483 Intennediate Y, N S, S, T, U, and Example 15, 3 N N N'O H 484 ~O Intermediate Y, 0 S, T, U, W and HN/X s Example 15, 3 N NEO N 485 HO Intermediate Y, S, T, U, W and //Example 15, 3, 7 N N N'O t 486 H2N Intermediate Y, S, T, U, W and HN Example 15, 3, 18 N N N'O H W 487 Intermediate Y, S, T, U, W and Example 15, 3, H N 7, 13 N N N'O H 6 H Example Structure Representative Procedure 488 Intermediate Y, S, T, U, W and Example 15, 3, 0X\ ° 7, 13 Ol/--\ Han 'N'N'N H 489 Intermediate Y, S, T, U, W and Example 15, 3, 0m 8 7, 13 HN N N N N N N'O 6 H 490 Intermediate Y, S, T, U, W and Example 15, 3, 13 N N N U / H 491 \ o o Intermediate Y, O Jt S, T, U, W and Example 15, 3, 12 A H H 492 Intermediate Y, H N O S, T, U, Wand HN Example 15, 3, 24 and N N N Intermediate 6 H AK Example Structure Representative Procedure 493 O Intermediate Y, S, T, U, W and Example 15, 34 ß H H 494 Intermediate Y, S, T, U, W and Example 15, 34 N N NO N N N H 495 0 o Intermediate Y, S, T, U, W and Example 15, N N N 34, 21 H U 496 Intem-lediate Y, \tS o S, T, U, Wand Example 15, 34, 21 N N N 6 H 497 s Intermediate Y, o S, T, U, W and Example 15, 34 Ho I ! N 1 No H U 498 0 Intermediate S, NC ; RNA T, U, W and Example 15 N N N H t t H Example Structure Representative Procedure 499 0 Intermediate Y, S, T, U, W and Example 15, N N N'O 31, 32, 33, 13 . t3 500 _ Intermediate Y, S, T, U, W and Example 15, H N N No 31, 32, 33, 13 H 5010Intermediate Y, S, T, U, W and Example 15, H N N'O 31, 32, 33, 13 H 502 F Intermediate F, F FO G, H, I, J and Example 17, 25 o 1 t t I IJ and N N N Intermediate AJ H t 503 F Intermediate F, F+F O G, H, I, J and Example 17, 25 and N Nô Intermediate AJ H 504 F Intermediate F, G, H, I, J and Example 17, 25 and N N N Intermediate AJ 6" Example Structure Representative Procedure 505 F Intermediate F, F F 0 G, H, I, J and Example 8 N N N N'JO N H ki " 506 F Intermediate F, F F 0 G, H, I, J and Example 8 eN CNlNtNkNU \ IN N N N H 507 F Intermediate F, F FO G, H, I, J and <N Example 8 tN N N N'O 6 H 508 F Intermediate F, F F O G, H, I, J and Example 9 O N N N 6 H sl 509 F Intennediate F, F FO G, H, I, Jand Example 9 O N N N H W 510 F Intermediate F, F F 0 G, H, I, J and Example 9 0 N N N'O , H Example Structure Representative Procedure 511 F Intermediate F, F F O G, H, I, J and Example 9 I I I O N N A b H 512 F Intermediate F, F FO G, H, I, J and Example 6, 21 I o I S N N N 11 H / 513 F Intermediate F, F F O G, H, I, J and aN Example 6 I S N N N H t 514 F Intermediate F, F F O G, H, I, J and Example 6 S N N // W 515 F Intermediate F, F FO G, H, I, Jand Example 9 NC N N H U 516 F Intermediate F, F F O G, H, I, J and ,, Example 8 and Intermediate H N N N N AK N II NJ H O w Example Structure Representative Procedure 517 F Intermediate F, F F O G, H, I, J and Example 8 and Intermediate H N N N Ny N H 0 b O 518 F Intermediate F, F F O G, H, I, J and Example 31, 33 < H NNN'O O ° W 519 F Intermediate F, F F 0 G, H, I, J and Example 31, 33 0 js H N N N'O NON /0 H 520 F Intermediate F, F 0 G, H, I, J and ,, Example 31, 32, 33, 13 H non 521 F Intermediate F, F 0 G, H, I, J and » \ H\ Example31, ! t ! i TT 32, 33, 13 CN NN'O H \ 522 F Intermediate F, F F 0 G, H, I, J and Example 3 1, 32, 33, 13 'N N N N H Example Structure Representative Procedure 523 F Intermediate F, F F O G, H, I, J and Example 3 1, LJ J, JJ k J. JZ, JJ, 1J 32, 33, 13 w U . H , j 524 F Intermediate F, F F 0 G, H, I, J and Example 31, 33 N N N'O NON 525 F Intermediate F, F FO G, H, I, J and Example 3, 24, 0 13 N N N H 6 H W 526 F Intermediate F, Fi Example 3, 24, 0 13 N N N N H 527 Intermediate F, F F O G, H, I, J and Example 3, 24 and H N N H Intermediate /-N H H AK H 6- 528 F Intermediate F, F F 0 G, H, I, J and Example 3, 24 and N N N Intermediate NH H Ait Example Structure Representative Procedure 529 F Intermediate F, F F O G, H, I, J and Example 9, 7 o-N H H 530 F Intermediate F, F F O G, H, I, J and Example 9 N N N N N'O oN 531 F Intermediate F, F F O G, H, I, J and Example 9, 7, 13 p N N N A H 532 Intermediate F, F F O G, H, I, J and example 9, 7, 8j OU N N N'O -C H \ ° ( 533 F Intermediate F, F F O G, H, I, J and Example 9, 7, 13 O A w Utilizing the above described procedures for intermediates and examples and Flow Diagrams I-XIV alone or in combination, a variety of Formula I compounds can be prepared using the appropriate starting material. These compounds are summarized in Table 1C.

Table 1C Example Structure 534 N02 0 N N N 6 H 535 O \N N N N H 6 H 536 (0) 0 N ton N N H 5370 537 0 /NO/ N N N 5380 \ 538 0 N N S 539 0 N N O Example Structure 540 0 NI'NI'O 5410 541 N N O b 542 0 t N ? 543 0 1 N N S n t0 544 I I XSX 545 s N N N N N'O zou 6 546 OH N N N H Example Structure 547 N N N 6 H 548 N N N'o N N N H 0 i i 0 N N N 6 H 550 OH O N l NJ 3 H 551 0 ---oI N N N H 552 I I N N N ! H \ Example Structure 553 0 O 1. H N N N 554 0 554 0 I I IN 555 N N N 6 H \ "NNN- t H 556 O O N N N H ! H po 556 0 0 N N N I ! H 558. \o 557 0 588 6 H 558 aN 0 Example Structure 559 0 . je. 6 H 560 0 I 5 0 I I C t3 H H po 561 0 N I I O N N N o\ 6 H 562 0 N N N H 562 563 I N'O H, I 563 AN 0 H N I N'O NN I I H -XNAN I N'O 6 H Example Structure 565 zozo -S, 11 ND 0 N 566 1 N'Nr'N zu 567 /\ N I NAN I N'O H 568c F zozo F I'-0 I I I N N N H 569 Fs, F ZU N N N NON 570 F F F O Zozo 'PN N IN Example Structure 571 F FF N N H N N N N 572 F F F O 0 F-o N nu 571 0 I I I N N N N 574 F F F O N 0 N N H zu 575 F F F O i i 575 N H N 6 H / \ 576 F F F O Han N N N'O 6 H i H Exam le Structure 577 FF F-o N N N H 578r : F N Y N v N X 9> N > H H N N N N N . N N N erz H t H 579c F ZU 0 S. N N N H 580 F F F O N H N N 6 H 6' 5 1 SI N N N H Utilizing the above described procedures for intermediates and examples alone or in combination, a variety of Formula II compounds were prepared using the appropriate starting material and the representative procedure described. These results are summarized in Table 2A.

Table 2A Example Structure LCMS RT [M+H] Representative (min) Procedure 582 2. 39 372. 3 Intermediate kO 0 BA, BB, BC and Example 39, 48 b H H 583 0 OH 2. 05 401. 2 Intermediate BA, BB, BC NH O and Example 39, 46, 45 N N H 584 1. 93 401. 3 Intermediate u BA, BB, BC and Example NH O 39, 43 N N N N t 585 rut 2. 04 418. 3 Intermediate BA, BB, BC and Example ß 9 39, 42 N N U 586o025358. 4 Intermediate BA, BB, BC and Example N N 39, 48 H t _ Example Structure LCMS RT [M+H] Representative (min) Procedure 587 2. 89 412. 1 Intermediate ao o BA, BB, BC and Example 39, 48 A H H 588 8 1. 89 415. 3 Intermediate BA, BB, BC and Example t 0 39, 48 39, 48 N N H 589 V 2. 57 398. 3 Intermediate BA, BB, BC 0 0 and Example 39, 48 N N N N 6 H 590 Oa 1. 92 457. 2 Intermediate BA, BB, BC and Example kO O 39, 48 O O N N H 591 F F 2. 41 408. 4 Intermediate BA, BB, BC 0 and Example 39, 48 N N H t Example Structure LCMS RT [M+H] Representative (min) Procedure 592 2. 52 386. 1 Intermediate Ro O BA, BB, BC and Example 39, 48 t H i H 593 2. 46 402. 2 Intermediate bd, BB, BC and Example O O 39, 48 N N H t H 594 2. 12 441. 1 Intermediate ON BA, BB, BC and Example So 0 39, 48 N N N / H \ 595 H2N 1. 79 371. 9 Intermediate BA, BB, BC N and Example w 39, 49, 47 ! ! H H 596 cl 0 2. 36 398. 3 Intermediate BA, BB, BC and Example L N N 39 H F F Example Structure LCMS RT [M+H] Representative (min) Procedure 597 ci O 2. 57 390. 4 Intermediate BA, BB, BC and Example N 39 H 598 3. 28 400. 2 Intermediate BA, BB, BC and Example 39, 48 b H 6 H 599 2. 56 422. 0 Intermediate 0 o BA, BB, BC and Example ? fff) fTr 39, 48 N N H F F 600 2. 74 414. 1 Intermediate 'Io 0 BA, BB, BC and Example N 39, 48 !. H H 601 CI O F 2. 43 398. 4 Intermediate N BA, BB, BC and Example N''N 39 H ZIP Example Structure LCMS RT [M+H] Representative (min) Procedure 602 l 2. 57 422. 1 Intermediate o O F BA, BB, BC and Example 39, 48 N N H / F 603 2. 45 408. 2 Intermediate O 0 F BA, BB, BC and Example I SF JE H H F 604 F P 2. 02 396. 3 Intermediate BU, BB, BC X F and Example 39, 42 , 'N'N H N 605, 2. 15 410. 3 Intermediate BA, BB, BC ou and Example 3 39, 42 nua N N b 606 1. 96 383. 3 Intermediate NH 0 BA, BB, BC NH O and Example N 39, 43 -AN 6' il Example Structure LCMS RT [M+H] Representative (min) Procedure 607 2. 20 484. 3 Intermediate BA, BB, BC 0 and Example OH 39, 43 N C N ZIZI U H 608 2. 19 411. 3 Intermediate BA, BB, BC and Example 39, 43 N H W 6090233419. 4 Intermediate BA, BB, BC F'p andExample F 39, 43 N H 0 N 'N N H 610 0 1. 86 454. 3 Intermediate FH BA, BB, BC and Example (N 39, 43 N O t SNJt3 b ! H Example Structure LCMS RT [M+H] Representative (min) Procedure 611 N 1. 22 483. 2 Intermediate BA, BB, BC and Example rua 39, 43 N 0 N N NEO H 612 2. 11 411. 4 Intermediate BA, BB, BC and Example XNJ 1 39, 43 A H W H 613 1. 55 426. 0 Intermediate CN) BA, BB, BC and Example N O 39, 43 N f H H 614 1. 98 413. 0 Intermediate BA, BB, BC N 0 and Example 39, 43 W oh Example Structure LCMS RT [M+H] Representative (min) Procedure 615 F 1. 88 370. 3 Intermediate -ou BA, BB, BC OH and Example F NN f H "N-- N N'C \ 616 0 O 1. 73 356. 3 Intermediate BA, BB, BC and Example 39, 42 A U 617 0 2. 53 488. 3 Intermediate t d F A BA, BB, BC T Fe OH and Example gNß F 39, 43 N 0 H . ! H 618 F o 2. 30 427. 3 Intermediate FH BA, BB, BC and Example 0 NH 0 39, 43 N N < 619 N 1. 68 405. 4 Intermediate BA, BB, BC and Example ! ff ! f N 39, 55 N N'C H W Example Structure LCMS RT [M+H] Representative (min) Procedure 620 02N 2. 25 449. 2 Intermediate BA, BB, BC XNX and Example N 39, 55 N N H . t H 621 2. 00 418. 5 Intermediate BA, BB, BC and Example t H I I N N N neo \ 622 ci 2. 19 438. 3 Intermediate BA, BB, BC ß and Example 39, 55 N N 6 H Utilizing the above described procedures for intermediates and examples alone or in combination, a variety of Formula II compounds can be prepared using the appropriate starting material and the representative procedure described. These compounds are summarized in Table 2B.

Table 2B Example Stucture Representative Procedure 623 0 Intermediate N BC1 and N N'Example 40, YNN Example 40, 6 H 49, 47 W 624 0 Intermediate BA1, BB1, I I BC1 and HO N N'Example 40, \ (JL H 31 37 H 31, 32 625 0 Intermediate BA1, BB1, BC 1 and N N N Example 40, t r. Ba 626 0 Intermediate BA1, BBl, I BCI and H r--N N N Example 40, N N H 43 and Intermediate 0 AK 627 0 Intermediate BAl, BB1, Bu1 ans H f N N N+/Example 40, H 43 and hitennediate v O w AK 628 0 Intermediate Nv BA1, BB1, BC1 and N N Example 40, H 17, 25 and Intermediate </AJ Example Stucture Representative Procedure 629 0 Intermediate BA1, BB1, BC1 and N-N Example 40, p, H 31, 33 630 0 Intermediate BAl, BB1, I I BCI and N N Example 40, O, H 31, 33 W 631 0 Intermediate BA1, BBl, N BCI and NON Example 40, 0 H 31, 32, 33, 47 632 0 Intermediate BA1, BB1, t, n) ! BCland N-Example 40, ° t3 H 31, 32, 33, 47 633 0 Intermediate BA1, BBI, I I BCI and N N-Example 40, ou H 31, 32, 33, 47 W 634 0 Intermediate BAl, BB1, H J i ! f i ! BCland ---N Example 40, W H 31, 32, 33, 47 Example Stucture Representative Procedure 635 0 Intermediate BA1, BB1, BCI and N Example 40, H 31, 33 636 0 Intermediate N BA1, BB1, I O I BC1 and N N Example 40, H 17, 25 and Intermediate w AJ 637 0 Intermediate N BA1, BB1, o 11 {BC1 and N N Example 40, H 17, 25 and Intermediate </AJ 638 0 Intermediate BC1 aBnd 1, BCI and N N Example 40, ß tl BC1 and J H 4g i 639 0 Intermediate eN Nv < BA1, BB1, BCI and y Example 40, 6 H. 48 i 640 O Intermediate BA1, BB1, BCI and O N N Example 40, 03 i Example Stucture Representative Procedure 641 0 Intermediate BA1, BB1, N BC1 and O N H Example 40, 0 H 48 \+/n 642 0 Intermediate BA1, BB1, BC1 and S N N Example 40, Õ H 44, 21 643 0 Intermediate BA1, BBl, BC1 and S N N Example 40, A 6 H 44 644 0 Intermediate BA1, BB1, BCI and S N N Example 40, H 44 i 645 0 Intermediate BA1, BB1, I'o BCI and NC N N Example 40, ruz i 646 0 Intermediate BA1, BB1, BC1 and , N N Example 40, H 49, 47 W Example Stucture Representative Procedure 647 0 Intermediate BA1, BB1, BC1 and YN N N Example 40, f A w 648 \O Intermediate BA, BB, BC and Example 39, 17, 25, 26 0 O O N N e / 649 HO O Intermediate BA, BB, BC 0 and Example 39, 31, 32, 33 NEZ N H H 650 0 Intermediate BA1, BBl, BC1 and N'y N N Example 40, H H 43 </ 651 0 Intermediate BAl, BB1, Bu1 an eN N N Example 40, b H 43 Example Stucture Representative Procedure 652 0 Intermediate N v A BA2 BB2 I BC2 and N N Example 40, J i H 1 Ti HO H 31, 32 Ho 653 0 Intermediate , BA1, BB1, BC1 and N N Example 40, 6 H 43 654 0 Intermediate NV/% BA1 BB1 N g BC1 and H JL JL 1 I J BCland N N Example 40, 0 H 49, 47 655 0 Intermediate BA1, BB1, BCI and 'N''N Example 40, OH 49, 50, 51 656 0 Intermediate BA1, BB1, I I BCI and S N N Example 40, H 44 i 657 0 Intermediate BA1, BB1, BCI and N N N Example 40, H H 43 i Example Stucture Representative Procedure 658 0 Intermediate BA1, BB1, JL BC1 and N N Example 40, 0 H 49, 50, 51 659 0 Intermediate Bd1, BB1, Bu1 an N N'O Example 40, HNJ t H e 660 0 Intermediate BA1, BB1, N BC1 and S < N Example 40, 6 H 44 s 661 0 Intermediate BA1, BB1, I BC1 and N N-Example 40, 6 H 49, 47 662 0 Intermediate BA1, BB1, bu1 an -S N N'C Example 40, Õ H 44, 21 663 Intermediate BA, BB, BC and Example 39, 31 N N 6 H ! H Example Stucture Representative Procedure 664 0 Intermediate BAl, BBl, BCI and N N'N Example 40, H H 43 665 w Intermediate BA, BB, BC and Example 0 Q 39, 17, 25, 26 N N N H 666 0 Intermediate BA1, BBI, 0 N BCI and S N N Example 40, 44, 21 667 0 Intermediate BAl, BB1, , BC1 and N N'C Example 40, W 0 JL H 49, 50, 51 668 0 Intermediate BA1, BB1, Bai ans O \N N HN Example 40, , H 43, 12 s \SNJ b 669 0 Intermediate BA1, BBI, BC1 and N N N Example 40, 3 A H b H Example Stucture Representative Procedure 670 Intermediate NH O BA, BB, BC and Example wN t 39, 3 N N H ! H 671 0 Intermediate BA1, BB1, I | BC1 and N N Example 40, 6 H 55 r 672 0 Intermediate BA1, BB1, 0 BCI and IS,, N N Example 40, 0 H 44, 21 i W 673 0 Intermediate BA1, BB1, Bai ans N N N Example 40, 0 NY H 43, 12 ll l ll O 0 674 0 Intermediate N BAI, BBl, N N N Example 40, ° H 31 0 675 0 Intermediate BA1, BB1, BC1 and 'N''N Example 40, 0 H 49, 50, 51 W Example Stucture Representative Procedure 676 Intermediate BA, BB, BC and Example 0 0 39, 17, 25, 26 N N N N H 677 0 Intermediate BA, BB, BC and Example N N 39, 54 and Intermediate AL 678 0 Intermediate , CI N , BA1, BB1, l I BCI and N N N Example40, 3 H H 679 0 Intermediate BAl, BB1, BC1 and N Example 40, 11, N H 43, 12 Õ 680 0 Intermediate BA1, BB1, Bu1 an 0 N N Example 40, rS'" W 681 0 Intermediate BA1, BB1, BCI and N N Example 40, 0 H 49, 50, 51 i Example Stucture Representative Procedure 682 Intermediate O=S=O BA, BB, BC and Example 39, 43, 12 N O N N H 683 0 Intermediate N BA, BB, BC and Example N i 39, 54 and Intermediate AJ 684 ci 0 Intermediate BA1, BBl, BCl and N N N Example 40, 3 H H w 685 NH2 0 Intermediate BA, BB, BC and Example N N 39, 3, 24 H < 686 0 Intermediate N BA1. BB1, 0 I | l ll BC1 and 'N''N Example 40, H 17 i 687 0 Intermediate BA1, BB1, N BCI and Example 40, O H 49, 47 i Example Stucture Representative Procedure 688 0 Intermediate N BA2, BB2, BC2 and N N Example 40, J J H 31, 32, 33 0 HO O 689 0 Intermediate BA1, BBl, BC1 and N N N Example 40, H 6 H 22 i 690 0 Intermediate BA1, BB1, BCl and N N N Example 40, 3 H H 691 0 Intermediate BA2, BB2, BC2 and N N Example 41, WU 692 0 Intermediate BA1, BBl, 0 BCI and S" N N Example 40, H 44, 21 i 693 0 Intermediate BA1, BBl, BC1 and N N Example 40, 17, 25, 26 Example Stucture Representative Procedure 694 0 Intermediate BC1 and 1 an N Example 40, O X H 17, 25, 23 QS 695 0 Intermediate BA1, BB l, j !) j BCland N NJO Example 40, O J H 17, 18 W 696 0 Intermediate BA1, BB1, BC1 and H2N N N Example 40, 3, b i 697 HO Intermediate BA, BB, BC N and Example XJ4NKNU 39, 17, 25 H U i H 698 N Intermediate BA, BB, BC and Example 0 0 39, 17, 25, 26 I I I K JXNX t 699 O Intermediate BA2, BB2, BC2 and N N Example 41, i, Sw w y I Example Stucture Representative Procedure 700 0 Intermediate 01--l N BA 1, BB 1, I BCI and N Example 40, 0 J H 49, 50 701 0 Intermediate BA, BB, BC and Example 'N N 39 54, and Intermediate NH AK k 702 0 Intermediate CI, N , BAl, BB1, Bu1 ans NH N HN Example 40, 3 H 6 H W 703 0 Intermediate BA1, BBl, , BC1 and N NJO Example 40, O JW H 49, 50, 51 w 704 0 Intermediate N BA2, BB2, BC2 and N N Example 41, 6 H 34 705 0 Intermediate N BA2, BB2, BC2 and N Example 41, 3 < L I] Nu/ NH6 H Example Stucture Representative Procedure 706 0 Intermediate BA1, BB1, Bai ans N N Example 40, ¢ ß H 17, 25, 26 W 707 0 Intermediate BA1, BB1, BC1 and S N N Example 40, 0 H 44 708 0 Intermediate BA1, BB1, BC1 and I CN N N Example 40, N J, H 43, 47 709 Intermediate f BA, BB, BC and Example °> O 39, 17, 25, 26 N N 6 H W 710 0 Intermediate BAl, BB1, BCI and O N N Example 40, 6 H 48 i 711 0 Intermediate BA2, BB2, BC2 and N N Example 41, 1°4° W Example Stucture Representative Procedure 712 0 Intermediate N BA1, BB1, I I I BCI and N N Example 40, 3 A H H 713 0 Intermediate BA, BB, BC and Example 39 54 and Intermediate NH AK W 714 0 Intermediate N BA2, BB2, BC2 and N N Example 41, 34 715 0 Intermediate BA1, BB1, BCI and N NAN'O Example 40, 3 A H H 716 0 Intermediate BAl, BB1, N I BC1 and N, \ N N Example 40, WJ t 17, 25, 26 717 0Intermediate Nv A BA1, BB1, BCI and i 1 I i 1 J BCland O N N Example 40, 6 H 48 Example Stucture Representative Procedure 718 0 Intermediate BA1, BB1, , bland "IS N Example 40, 6 H 49, 50, 51 e n 719 0 Intermediate N BA2, BB2, BC2 and N N Example 41, 3 N oFX U 0 720 0 Intermediate N BA2, BB2, BC2 and N N Example 4 1, 6 H 34 Intermediate BAl, BB1, I | 1 BC1 and s N Example 40, 6 H 55 722 0 Intermediate BA1, BBl, Bai ans S N N Example 40, 0 H 44, 45 723 Intermediate BA1, BB1, BC1 and N N N Example 40, 3 H 6H Example Stucture Representative Procedure 724 0 Intermediate BA1, BB1, Bu1 ans CN N N Example 40, N H 43, 47 o w I 725 0 Intermediate BA, BB, BC and Example N N 39, 54 and Intermediate NU AK F 726 0 Intermediate BA1, BB1, o 1 | I I BC1 and N N Example 40, Novj H 17, 25, 26 Intermediate BA1, BB1, Bu1 an Example 40, 3 N N N H H 728 0 Intermediate BA2, BB2, BC2 and N Example 41, H 34 729 0 Intermediate BA2, BB2, BC2 and N N Example 41, 3 ryN A H H I Example Stucture Representative Procedure 730 0 Intermediate BCI and N N Example 40, H 55 731 0 Intermediate BA I, BBl, Ls 14 Jl, 4 IJ BC1 and N N N Example 40, 3 H H 732 0 Intermediate BA1, BB1, BCI and O N N Example 40, F F H 48 733 0 Intermediate F N BAI, BB I, I : 01 BCI and N N N Example40, 3 H H \ 734 HO Intermediate BA, BB, BC O and Example 1 JJ. QQ 1 0 t SNX 39, 31, 32 N H b 735 0 Intermediate BAI, BBl, BC1 and L 1L Ji JL iL J. i) BCland N N N Example 40, 3 H H Example Stucture Representative Procedure 736 F 0 Intermediate BA1, BB1, BC1 and Example 40, 3 H H 737 0 Intermediate BA1, BBl, Bu1 an -/-/"N'N"" Example40, HO N N'Example 40, 0 31, 32, 33 w 738 O Intermediate Bai ans N N N Example 40, 3 H H 739 Intermediate HO O BA, BB, BC and Example 39, 49, 50, 51, 25 N N b H 740 H N a Intermediate N BA, BB, BC and Example 39, 17, 25, 11 N N H X 741 N Intermediate \ON 0 BA, BB, BC and Example N 39, 17, 25, 11 N N H t Example Stucture Representative Procedure 742 0 Intermediate BA1, BBl, BCI and N N Example 40, 42 743 0 Intermediate BA1, BB1, JL BCI and N Example 40, 42 744 0 Intermediate N BA1, BB1, BCI and N N Example 40, 42 W 745 0 Intermediate N BA 1, BB 1, L BC1 and N N Example 40, 6 H 42 746 0 Intermediate BA 1, BB 1, 1 ! l ! l I ! J BCland HO N BC1 and N N Example 40, JL H T7 0 k 17, 25 747 0 Intermediate BA1, BBl, HO BCI and 'N''N Example 40, 49, 50, 51, 25 Example Stucture Representative Procedure 748 0 Intermediate BA1, BB1, I I BCI and HO N Example 40, A A 49, 50, 51, 25 CI 749 0 Intermediate BA1, BB1, u 1 ! l) t i ! BCland HOuNXNX Example 40, S H 49, 50, 51, 25 is il 750 0 Intermediate N BA1, BB1, o BCl and Example 40, 17, 25, 26 O 751 0 Intermediate (I ( BAI, BB1, JLJL JL J'J BCland BC1 and Example 40, 6 55 752 Intermediate BA1, BB1, X CH BC1 and N N'o Example 40, F 6 55 753 0 Intermediate BA1, BB1, 11 1 BCI and N N'O Example 40, 55 754 0 Intermediate Nv A BA1, BB1, 1 BC1 and 'N''N Example 40, H 49, 50, 51 Example Stucture Representative Procedure 755 0 Intermediate N BA 1, BB 1, BC 1 and N N-Example 40, 6 H 49, 50, 51 756 0 Intermediate N\ rt BAl. BBI, HO N BCI and N N Example 40, O, H 49 U 757 0 Intermediate Nv A BA1, BB1, BA 1, BB 1, BC1 and N N N Example 40, N J, H 43 758 Intennediate J ! jj J ! ! J BCland BA1, BB1, BC1 and N N N Example 40, NJ, I H 43 759 \ o Intermediate BA1, BB1, BCl and 'N N N Example 40, ni" 760 o Intermediate BA1, BB1, BC1 and 'N N N Example 40, 6 H 43 r 761 Intermediate Nv A BA1, BB1, Bu1 an rN N N Example 40, , ONJ ß 43 0 6 Example Stucture Representative Procedure 762 0 Intermediate BA1, BB1, BC1 and N N N Example 40, , CN H 43 0 6 763 Intermediate BAI, BB1, Bu1 an N t3 Example 40, 43, 47 C : r N H 43, 47 764 0 Intermediate N BA 1, BB 1, BCl and 1 o N N N 43ample 40, 110 H 0 765 0 Intermediate < 11 1 BC1 and L. ! ! !) ! ! J BCland ° CN N N Example 40, N b H 43, 12 Wõ 766 0 Intermediate BA1, BB1, BC 1 and example 40, m" 767 0 Intermediate N BA 1, BB 1, BC1 and HN S XNg Example 40, A b H 43 w o Intermediate BA1, BB1, BCI and Example 40, 3 H H -< Example Stucture Representative Procedure 769 0 Intermediate N BAI, BBl, Example 40, N N N Example 40, 0 H H 43 \0 b H 43 Intermediate O Nv A BA1, BB1, 11 BCI and Example 40, , 22 U 771 0 Intermediate NY\ -) BA1, BB1, BCI and N N N Example 40, 46, 45 U 772 0 Intermediate BAI, BB I, BCI and N N N Example 40, o H, N H 46 0 H b H 46 i 773 0 Intermediate BA1, BB1, Bai ans NyaNLN Example 40, 0""46, 45, 47 774 0 Intermediate H N BAI, BBl, N J and H H Example 40, 46, 45, 47 Intermediate 0 NwJA A BA1, BB1, BC1 and N'Z : N I N Example 40, O 2n H 46, 45, 47 U Example Stucture Representative Procedure 776 0 Intermediate BA1, BB1, BCI and S N N Example 40, 0 ß H 44, 45, 47 W Intermediate BA1, BB1, Bu1 an If---N N Example 40, 0 H 44, 4S, 47 U 778 0 Intermediate H N BA1, BBl, LJ tHHh N BC1 and Example 40, 44, 45, 47 Intermediate BA 1, BB 1, BC1 and O N N Example 40, O rn H 48, 45 U Intermediate -- BA1, BBI, I I BCI and \/w0 N N Example 40, 0 6 H 48 U Intermediate I I BC1 and N jL JL 1 i J BCland O N N Example 40, 48, 45, 47 782 Intermediate O N BA1, BB1, BCl and if Example40, 48, 45, 47 w Example Stucture Representative Procedure 783 0 Intermediate Nv BC1 and 1, JL JL JL Ji. J BCland H example 40, 44 U 784 0 Intermediate BA1, BBl, 0 BCI and H Example 40, 0 4E4x, 44, 21 785 0 Intermediate N BA 1, BB 1, I I I BCI and O N N Example 40, 6 H 48 w 786 0 Intermediate BA1, BBl, Bu1 an O N N Example 40, b H 48 i 787 0 Intermediate BA1, BBl, 9N BC1 and O N N Example 40, ° m" 788 0 Intermediate BA1, BB1, BCI and N N Example 40, 6 789 0 Intermediate BAl, BB1, F JL JL JL Ji. J BCland F Bd1 and F Example 40, 4 Example Stucture Representative Procedure 790 Intermediate O o BA, BB, BC /< NX/3ng, d 4E8X amp 1 e and Example N, 39, 48 N N F H 791 Intermediate 0 0 BA, BB, BC and Example A H /<N w / I I N 792 Intermediate 0 0 BA, BB, BC N and Example 39, 48 N N H 793 Intermediate O 0 BA, BB, BC and Example 39, 48 N N H zu 794 Intermediate o BA, BB, BC and Example ni an N N b Example Stucture Representative Procedure 795 Intermediate WO o BA, BB, BC and Example N 39, 48 N N O N 1 H H 796 Intermediate BA, BB, BC and Example vX X 39, 48 N N F H f) 797 Intermediate WO 0 BA, BB, BC and Example 39, 48 N F F F F F 798 Intermediate 0 o BA, BB, BC and Example N 39, 48 i T f i N N N02 H 02Nt 799 Intermediate 0 o BA, BB, BC and Example N 39, 48 N N CN Nit NC NC Example Stucture Representative Procedure 800 l Intermediate BA, BB, BC and Example 39, 48 N neo d 801 Intermediate SO o BA, BB, BC and Example F 39, 48 F H I/ / 802 Intermediate wO 0 BA, BB, BC and Example 39, 48 I/ v H 803 Intermediate BA, BB, BC and Example 39, 48 0 H " 804 Intermediate BA, BB, BC and Example N 39, 48 /o " 0 Example Stucture Representative Procedure 805 ! Intermediate o BA, BB, BC and Example 3 39, 48 N NON R"" N 806 Intermediate SO 0 BA, BB, BC and Example 39, 48 ow , O Y H NU I \I iN 807 ! Intermediate BA, BB, BC N and Example X NtN F 39, 48 N N F Y H N/ I \I iN 808 l Intermediate SO 0 BA, BB, BC and Example 39, 48 W nJ N N 809 Intermediate SO o BA, BB, BC and Example N 39, 48 H N J H Example Stucture Representative Procedure 810 l Intermediate sO o BA, BB, BC and Example N 39, 48 ,"N I N H nez 811 0 Intermediate N BA, BB, BC and Example N'C 39, 54, 47 O I I, 812 0 Intermediate N BA, BB, BC and Example , IN 39, 54 and Intermediate AJ 813 0 Intermediate BU, BB, BC and Example N N 39, 54 and NH Intemiediate I AK I 8140Intermediate N BA, BB, BC and Example N N 39, 54, 12 to=s zozo 815 0 Intermediate N BA, BB, BC and Example N 39, 54, 12 Wo k3° Example Stucture Representative Procedure 816 0 Intermediate N BA, BB, BC and Example Non 39, 54, 12 i , ors °o 817 0Intermediate BA, BB, BC and Example N N 39, 54, 12 Lo=sX [ !) o 818 Intermediate N BA, BB, BC and Example N N s 39, 54, 12 s- 1 \ I 819 0 Intermediate N BA, BB, BC and Example N 39, 54 and Intermediate AL and Example 42 820 0 Intermediate N BA, BB, BC and Example N 39, 54 and Intermediate AL 821 O OH Intermediate N BA, BB, BC and Example N' 39 54 and N N Intennediate AL and Example 17, 25 Example Stucture Representative Procedure 822 0 Intermediate BA, BB, BC NX X w {vE and Example N N 39, 54 and N-N- 3 1 H Intermediate AL and WJ example 55 823 o aNg°\ Intermediate BA, BB, BC N and Example N N 39, 54 and Intermediate AL and Example 55 824 0 Intermediate BA, BB, BC and Example 39, 54 and Intermediate AL and Example 17, 25 and Intermediate AJ 825 Intermediate BA, BB, BC O o and Example 39, 54 and Intermediate AL and 1 H Example 17, 25 and Intermediate AJ 826 Intermediate BA, BB, BC 0 and Example N 39, 54 and Intermediate N N AL and H Example 17, 25, 26 Example Stucture Representative Procedure 827 Nt Intermediate BA, BB, BC 0 and Example N 39, 54 and N N H)" Intermediate AL and Example 17, 25, 26 828 O Intermediate INIC BA, BB, BC and Example - N</39, 54 and Intermediate AL and Example 3 829 A Intermediate BA, BB, BC O and Example /39, 54 and '-ir if H Intermediate N N'o AL and Example 3 U 830 A Intermediate I BA, BB, BC O and Example N N--39, 54 and Intermediate NO AL and Example 3 U 831 CN 0 Intermediate v a\ BA, BB, BC and Example N No 39, 43 H Example Stucture Representative Procedure 832 Intermediate BA, BB, BC N 0 and Example 39, 43 , IN N H < 833 Intermediate BA, BB, BC and Example HNo+° 39, 46, 45, 47 NH 0 N b H H 834 0 Intermediate BA, BB, BC and Example X N W 39, 46, 45, 47 I N H H 835 Intermediate BA, BB, BC and Example HN +O 39, 44, 45, 47 s 0 A H H Example Stucture Representative Procedure 836 09 Intermediate BA, BB, BC and Example kg o 39, 44, 45, 47 N zizi N N < 837 09 Intermediate N 0 BA, BB, BC and Example TO 0 39, 48, 45, 47 w I w N N N A H < 83 8 Intermediate BA, BB, BC and Example HN O 39, 48, 45, 47 ro 0 A H N H 839 Intermediate /w O BA, BB, BC and Example 39, 49, 47 N N H i H Example Stucture Representative Procedure 840 Intermediate BA, BB, BC and Example 39, 49, 47 W H N N H 841 H Intermediate m BA, BB, BC and Example 39, 49, 47 N N H W 842 H Intermediate mNw o BA, BB, BC and Example orin 39, 49, 47 N N'O H 843 Intermediate BA, BB, BC and Example 39, 17 N NC) 6 H H 844 Intermediate BA, BB, BC S 0 and Example N 39, 44 H U Example Stucture Representative Procedure 845 Intermediate BA, BB, BC and Example 's o 39, 44 X NJ : 3 6 H U 846 Intermediate BA, BB, BC S 0 and Example 39, 44 , IN N H 847 s Intermediate BA, BB, BC and Example 39, 44 b H H 848 Intermediate BA, BB, BC and Example 3 39, 44, 21 I I A H H 849 Intermediate BA, BB, BC and Example X NJS3 39, 44, 21 N H S Example Stucture Representative Procedure 850 Intermediate BA, BB, BC 0 0 and Example O H N N H 851 eN Intermediate I BA, BB, BC 0 0 and Example 39, 48 N H 852 Intermediate BA, BB, BC and Example N I I I 39, 49, 50, 51, . J ?, 1'. 7, U, 'i, N N"O 25 and Intermediate AJ 853 Intermediate BA, BB, BC and Example 39, 49, 50, 51, N 25 ans Intermediate N AJ H 854 Intermediate BA, BB, BC and Example 0 0 39, 49, 50, 51, 25, 26 N N N"0 Example Stucture Representative Procedure 855 A1 Intermediate BA, BB, BC and Example Ag0 o 39, 49, 50, 51, 25, 26 N N N H 856 Intermediate BA, BB, BC 0 and Example 39, 31, 33 N nit H U 857 Intermediate O O BA, BB, BC and Example xi 43 39, 31, 33 N N N U 858 H2N 0 Intermediate BA, BB, BC 0 and Example N 39, 31, 32, 33, 47 N N-10 H Example Stucture Representative Procedure 859 l Intermediate HN 0 BA, BB, BC and Example 0 39, 31, 32, 33, N 47 I I b H 6" 860 Intermediate BA, BB, BC and Example 0 39, 31, 33 N\ N N H b 861 Intermediate BA, BB, BC and Example HN O 39, 31, 32, 33, 47 b N N N 6' 862 Intermediate ON 0 BA, BB, BC and Example 0 39, 31, 32, 33, 47 N N N'O 6-H Example Stucture Representative Procedure 863 Intermediate BA, BB, BC and Example , I 39, 49, 50, 51 N No 6 H 864 Intermediate BA, BB, BC and Example 39, 49, 50, 51 N N N H 865 A Intermediate BA, BB, BC and Example Oo 39, 49, 50, 51 N I J I N N N 866 Intermediate N BA, BB, BC and Example kNJ O 39, 43, 47 N H b Example Stucture Representative Procedure 867 Intermediate Hftj o BA, BB, BC and Example gNß 39, 43 and Intermediate N 0 AK N N H N'O H 868 X Intermediate BA, BB, BC NH 0 and Example N 39, 3 N I J I N N U 869 0 Intermediate J4NZ O BA, BB, BC and Example X N43 39, 43, 47 O H H 870 0 Intermediate N O BA, BB, BC and Example 39, 43, 47 N N H Example Stucture Representative Procedure 871 Intennediate BA, BB, BC and Example 0 NH 0 39, 22 N i i I N N NU N 872 \ %0 Intermediate O'NH O BA, BB, BC and Example 39, 3, 24, 12 A H z \ z Intermediate BA, BB, BC NH and Example 0-)--N H 0 39, 3, 24 and e NJX3 AK Intermediate N AK N H 874 O Intermediate N BA2, BB2, BC2 and N No Example 4 1, < ß 34 34 8750Intermediate N BA2, BB2, BC2 and N No Example 41, H 34 i Example Stucture Representative Procedure 876 O Intermediate N BA2, BB2, Zizi BC2 and N N Example 4 1, H 34 Ha 877 0 Intermediate 877 BA2, BB2, BC2 and N N Example 41, X W 34 O, i w 878 O Intermediate BA2, BB2, Bu2 ans AL N Example 41, JLrt)-) H A H 34 0 879 0 Intermediate N BA2, BB2, BC2 and N NIO Example 41, SoU / 880 O Intermediate N BA2, BB2, BC2 and N No Example 41, 31, 33 0 I 8810Intermediate BA2, BB2, Bu2 ans Wj/N N Example 41, 31, 32, 33, 47 H 6 Example Stucture Representative Procedure 882 0 Intermediate N BA2, BB2, BC2 and 9N N Example 41, HN H 31, 32, 33, 47 HN O 883 0 Intermediate BA2, BB2, BC2 and N N Example 41, H 31, 32, 33, 47 0 884 0 Intermediate BA2, BB2, BC2 and N N Example 41, HNtO W 31, 32, 33, 47 HN O 885 0 Intermediate N BA2, BB2, BC2 and N N'O Example 41, 0 A 31, 32, 33, 47 Fi N O 886 0 Intermediate BA2, BB2, BC2 and N N Example 41, H 31, 33 Example Stucture Representative Procedure 887 O Intermediate N BA2, BB2, BC2 and N N Example 41, WU 0 0 8880Intermediate N BA2, BB2, BC2 and N N Example 41, 6 H 55 F 889 0 Intermediate BA2, BB2, Bu2 ans N No Example 4 1, 55 N A U W 890 0 Intermediate N BA2, BB2, BC2 and N No Example 41, oli HO {m 891 0 Intermediate N BA2, BB2, BC2 and N Example 41, F O H 34 XI F 892 0 Intermediate BA2, BB2, BC2 and N No Example 41, 90 0 Example Stucture Representative Procedure 893 0 Intermediate N BA2, BB2, I 11 k I IJ BC2 and N N' (Example 4 1, H 49, 47 I 894 0 Intermediate N BA2, BB2, BC2 and N N'O Example 4 1, J=oi H 49, 47 HN 895 0 Intermediate N BA2, BB2, BC2 and N N'O Example 41, 49, 47 Han W 896 0 Intermediate BA2, BB2, BC2 and N N Example 41, 49, 47 897 O Intermediate N BA2, BB2, BC2 and N N'O Example 41, HN H 49, 47 HN % w 8980Intermediate BA2, BB2, BC2 and N N'O Example 4 1, g 34 i Example Stucture Representative Procedure 899 0 Intermediate AN BA2, BB2, BC2 and N N Example 41, g H 34 w < 900 0 Intermediate BA2, BB2, BC2 and Nu - S=O H 34, 21 0 0 901 0 Intermediate N BA2, BB2, IN l BC2 and N N Example 41, Sub H 34, 21 w õ 3 9020Intermediate N BA2, BB2, BC2 and N NEO Example 41, H 31, 32, 33, 50, 51 903 0 Intermediate BA2, BB2, BC2 and N N'O Example 4 1, H 31, 33 0 904 0Intermediate BA2, BB2, BC2 and N'O Example 41, 31, 32, 33, 50, 51 0 Example Stucture Representative Procedure 905 0Intermediate N BA2, BB2, BC2 and N N Example 41, G H 49, 50, 51 906 0Intermediate N BA2, BB2, BC2 and N N'O Example 41, p H 49, 50, 51 il il 907 0 Intermediate N BA2, BB2, BC2 and NN'O Example 41, cl 49, 50, 51 908 0 Intermediate N BA2, BB2, BC2 and NN Example 41, 31, 33, 25 OH 909 0 Intermediate BA2, BB2, BC2 and N Example 41, 31, 33, 25and Intermediate AJ W I 910 0 Intermediate N BA2, BB2, BCI an vNtNX Example 41, oJ Sn H 17, 25, 26 0 Example Stucture Representative Procedure 911 0 Intermediate N BA2, BB2, I | 1 BC2 and N N'O Example 4 1, 17, 25 Ho i I 912 0 Intermediate N BA2, BB2, BC2 and NN Example 41, oJ X H 17, 25 and Intermediate w AJ 913 0 Intermediate N BA2, BB2, BC2 and N N'O Example 41, 3 NoS W (3 914 0 Intermediate N BA2, BB2, BC2 and N No Example 41, 3 H Care HNX U 915 0 Intermediate N BA2, BB2, BC2 and N Example 41, 3 CX A H H N 916 0 Intermediate BA2, BB2, BC2 and N N Example 41, 3 NX U o6 i Example Stucture Representative Procedure 917 0 Intermediate qX BA2, BB2, BC2 and 0 N N Example 41, 3 W H 918 0 Intermediate BA2, BB2, BC2 and N N Example 41, 3 N NN 6 H N of 919 0 Intermediate N BA2, BB2, BC2 and W 1 N Example 41, 3 and Intermediate N AK NH NH 920 0 Intermediate Boa2, BB2, N BC2 and N N Example 41, 3, ,-N/I H 12 o6 O=S=o 921 0 Intermediate BA2, BB2, BC2 and W 1 H Example 41, 3 H N/ Example Stucture Representative Procedure 922 0 Intermediate BA2, BB2, BC2 and N 1 H Example 41, 3 H cl 923 0 Intermediate N BA2, BB2, BC2 and N No Example 41, 3 w 924 0 Intermediate N BA2, BB2, BC2 and N N'O Example 41, 3, NHzJL 24 925 0 Intermediate N BA2, BB2, BC2 and t1N4Nw Example 41, 3 SU 926 0 Intermediate N<\ a\ BA2, BB2, BC2 and N NJO Example 41, 3 N 927 0 Intermediate BA2, BB2, BC2 and f N/\Nw Example 41, 3 H O-NH6 H Example Stucture Representative Procedure 928 Intermediate BA2, BB2, I | BC2 and N N Example 41, 3 C < NH 0 929 0 Intermediate BA2, BB2, BC2 and N Ni) Example 41, 3, NH H 45 HO4O WJ O 930 Intermediate BA2, BB2, BC2 and N N'O Example 41, 3, C n NH H 18 Han'\ 2 O 931 0 Intermediate BA2, BB2, BC2 and N N'O Example 41, 3, cNHA H 45, 47 . 932 0 Intermediate BA2, BB2, BC2 and N N'O Example 41, 3, CNXo b 45, 47 00 0 933 0 Intermediate BA2, BB2, BC2 and f N N+/Example 41, 3, 0T NH6 H 24, 47 I U Example Stucture Representative Procedure 934 0 Intermediate N BA2, BB2, BC2 and N N Example 41, 3, N H 47 "00 935 0 Intermediate N BA2, BB2, BC2 and N nez Example 41, 3, O=S-N H 12 o \ I 0 Qi 936 0 Intermediate BA2, BB2, BC2 and N NIO Example 41, 3, Os NH 1 H 24 and Intermediate AK Utilizing the above described procedures for intermediates and examples, and Flow Diagrams I-XIV alone or in combination, a variety of Formula II compounds can be prepared using the appropriate starting material. These compounds are summarized in Table 2C Table 2C Example Structure 937 0 'N N 6" 938 w I w 938 0 H N N'O N Ni / k")-6 939 0 \/O N N'O 940 I I 940 0 H N/ ou 941 0 T) i f ! l N N I N'O H HN/ 942 0 NI-1 1 0 N NJO 'N Example Structure 943 0 YNN" 'N N H NEZ 944 LL JNN0H 9450 'i 945 Ni J/ 9 N N N nez / HAN 'N'N 946 0 HN/ 947 0 N 0 N NJO an H N/ 948 0 N 'N N H N/ / Example Structure 949 0 N NN'O 'N N HN 6 6 950 0 N N N'O H HN ? 951 0 02NN N N 6 H 9520 CULJO HAN I H=SI 0 O 953 953 0 , N_ _N H YofNNtH 954, xi N N neo 'N N H N/I Ew/SSs b Example Structure 955 0 N I I N S 6 956 0 N I I fA 6 00 nez 958 0 N i I N N") 959 0 N I I N N") N 960 0 zizi NN Example structure 961 0 N I I zon 962 0 fold NS b N S 964 0 N I N S' ! O N N-S- 965 0 N'S- 6 966 Ni I N S 966/A N S\/X Example Structure 967 0 w I NS/ n !" So S 3 in O N S file ii L X 969 0 N 0 11 0 !" p 970 970 0 N 'NHS O I I to 972 0 six Example Structure 973 0 fTiof 11 il 6° amp T) i r 'N S 974 Jo t NlSX 9750 N 0"'Y 6 976 0 t 6 977 0 w I N O 978 b S Example Structure 979 0 NO N N H 980-0 0C N N W W < N H 981 O XN I 6 H H 982S 982 N N 983OH H 983 OH CNJ 3 b H H 984 H 'N N b H Example Structure 985 n u kNJ 3 0 N N H ! H 986 N02 O N N H 987 I 0 b H JL 988 p HN N XN N N H 9890 989 o HAN N N H W Example Structure 990 HO N N IN'O N N H 991OH 0 N N N 992 0 992 , N N 1-N N H 991 b3 99 I I I 6 H 994 0 994 995 N N N I N \ N 0/H 995 0 w w w NON 6-H Example Structure 996 0 wl wl N N 0 han ! H 997 H S O H 998 \N 998 998 0 9 ZU b ! ! i H I I I N N O H 1000 H2N/W NJ 3 b H 1001 ICI N N 1001 0 N acid Exam le Structure 1002 0 \/N w ! H H 1003. o I /v, N_ N u all 1004 Ni / dz NO/ Biological Evaluation Demonstration of the activity of the compounds of this invention is accomplished through in vitro, ex vivo and in vivo assays that are well known in the art. in vivo test procedure: Male Wistar rats (270-330g) were fasted overnight and then given either vehicle or compound by oral gavage. Two or three hours later, the rats were given an intraperitoneal dose of glucose (2g/kg). The rats were tail-bled for glucose using a Glucometer (Bayer Corporation, Mishawaka, IN) just prior to the glucose dose and 15,30 and 60 minutes afterward. The area under the glucose curve was calculated by the trapezoidal method for both the vehicle and treated animals, and the percent reduction in the glucose AUC by the compound calculated. A typical positive effect of the compound results in a 12-20% reduction in the AUC relative to the AUC of the vehicle-treated group. Compounds of present invention were found to have a blood glucose lowering effect in this in vivo assay.

The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing examples are included by way of illustration only. Accordingly, the scope of the invention is limited only by the scope of the appended claims.

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