Compounds and methods for treating inflammatory and fibrotic disorders

Abstract

Disclosed are compounds and methods for treating inflammatory and fibrotic disorders, including methods of modulating a stress activated protein kinase (SAPK) system with an active compound, wherein the active compound exhibits low potency for inhibition of the p38 MAPK; and wherein the contacting is conducted at a SAPK-modulating concentration that is at a low percentage inhibitory concentration for inhibition of the p38 MAPK by the compound. Also disclosed are derivatives and analogs of pirfenidone, useful for modulating a stress activated protein kinase (SAPK) system. .[.Mederski et al., Tetrahedron (1999), 55(44), 12757-12770.*.]. .[.Azuma et al., A placebo control and double blind phase II clinical study of pirfenidone in patients with idiopathic pulmonary fibrosis in Japan, Am J Respir Crit Care Med., 165:A729 (2002)..]. .[.Badger, et al., Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock and immune function, J. Pharmacol. Exp. Ther. 279:1453-61 (1996)..].

Claims

1. A compound of formula .[.II.]. .Iadd.(II) .Iaddend. ##STR00577## wherein R.sup.1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, cyano, sulfonamido, halo, alkenylenearyl, and heteroaryl; R.sup.2 is selected from the group consisting of .Iadd.substituted or unsubstituted .Iaddend.aryl; unsubstituted heteroaryl; heteroaryl substituted with one or more substituents selected from halo, unsubstituted alkyl, alkenyl, OCF.sub.3, NO.sub.2, CN, NC, OH, alkoxy, haloalkoxy, amino, CO.sub.2H, and CO.sub.2alkyl; haloalkylcarbonyl; cycloalkyl; .[.hydroxylalkyl;.]. sulfonamide; unsubstituted cycloheteroalkyl and .[.cycloheteroarlkyl.]. .Iadd.cycloheteroalkyl .Iaddend.substituted with one to three substituents independently selected from alkyleneOH, C(O)NH.sub.2, NH.sub.2, aryl, haloalkyl, halo, and OH; .[.or R.sup.2 and R.sup.1 together form an optionally substituted 5-membered nitrogen-containing heterocyclic ring.]. .Iadd.and wherein heteroaryl of R.sup.2 is selected from the group consisting of thienyl, furyl, pyridyl, oxazoly, quinolyl, thiophenyl, isoquinolyl, pyrazolyl, indolyl, triazinyl, triazolyl, isothiazolyl, isoxazolyl, benzothiazolyl, pyrazinyl, pyrimidinyl, thiazolyl, and thiadiazolyl.Iaddend.; R.sup.3 is selected from the group consisting of hydrogen, .Iadd.substituted or unsubstituted .Iaddend.aryl, alkenylenearyl, heteroaryl, alkyl, alkenyl, haloalkyl, amino, and hydroxy; R.sup.4 is selected from the group consisting of hydrogen, haloalkyl, alkoxy, alkenyl, and alkenylenearyl; X.sup.1, X.sup.2, X.sup.3, and X.sup.4 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, halo, hydroxy, amino, .Iadd.substituted or unsubstituted .Iaddend.aryl, cycloalkyl, thioalkyl, alkoxy, haloalkyl, haloalkoxy, alkoxyalkyl, cyano, .[.aldehydro.]. .Iadd.aldehydo.Iaddend., alkylcarbonyl, amido, haloalkylcarbonyl, sulfonyl, and sulfonamide, or X.sup.2 and X.sup.3 together form a 5- or 6-membered ring comprising O(CH.sub.2).sub.nO, wherein n is 1 or 2, wherein at least one of X.sup.1, X.sup.2, X.sup.3, and X.sup.4 is not hydrogen; and X.sup.5 is hydrogen, with the proviso that (a) at least one of X.sup.1, X.sup.2, X.sup.3, and X.sup.4 is not selected from the group consisting of hydrogen, halo, alkoxy, and hydroxy.Iadd.; .Iaddend.or (b) .[.at least one of.]. R.sup.1.[., R.sup.2, R.sup.3, or R.sup.4.]. is not selected from the group consisting of hydrogen, alkyl, alkenyl, .[.haloalkyl, hydroxyalkyl, alkoxy, phenyl, substituted phenyl,.]. .Iadd.and .Iaddend.halo, .[.hydroxy, and alkoxyalkyl,.]..Iadd.; or (c) R.sup.2 is not unsubstituted phenyl or substituted phenyl; or (d) R.sup.3 is not selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, unsubstituted phenyl, substituted phenyl, and hydroxy; or (e) R.sup.4 is not selected from the group consisting of hydrogen, alkenyl, haloalkyl or alkoxy; .Iaddend. or a pharmaceutically acceptable salt, or ester thereof.

2. The compound of claim 1, wherein one of X.sup.1, X.sup.2, and X.sup.3 is not hydrogen.

3. A compound having a structure of formula (III) or formula (IV) ##STR00578## ##STR00579## wherein R.sup.3 is selected from the group consisting of hydrogen, aryl, alkenylenearyl, heteroaryl, alkyl, alkenyl, haloalkyl, amino, and hydroxy; R.sup.4 is selected from the group consisting of hydrogen, haloalkyl, alkoxy, alkenyl, and alkenylenearyl; X.sup.1, X.sup.2, X.sup.3, and X.sup.4 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, halo, hydroxy, amino, aryl, cycloalkyl, thioalkyl, alkoxy, haloalkyl, haloalkoxy, alkoxyalkyl, cyano, .[.aldehydro.]. .Iadd.aldehydo.Iaddend., alkylcarbonyl, amido, haloalkylcarbonyl, sulfonyl, and sulfonamide, or X.sup.2 and X.sup.3 together form a 5- or 6-membered ring comprising O(CH.sub.2).sub.nO, wherein n is 1 or 2, wherein at least one of X.sup.1, X.sup.2, X.sup.3, and X.sup.4 is not hydrogen; X.sup.5 is hydrogen; and X.sup.8 is hydrogen or alkyl; and X.sup.6 and X.sup.7 are independently selected from the group consisting of hydrogen, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylenylaryl, alkylenylheteroaryl, alkylenylheterocycloalkyl, alkylenylcycloalkyl, or X.sup.6 and X.sup.7 together form an optionally substituted 5 or 6 membered heterocyclic ring, or a pharmaceutically acceptable salt, or ester thereof.

4. The compound of claim 3, wherein X.sup.7 is hydrogen.

5. The compound of claim 1, wherein R.sup.1 is selected from the group consisting of hydrogen, 4-pyridyl, cyclopropanyl, 2-furanyl, cyano, H.sub.2NSO.sub.2, (CH.sub.3).sub.2NSO.sub.2, fluoro, 4-(3,5-dimethyl)-isoxazolyl, 4-pyrazolyl, 4-(1-methyl)-pyrazolyl, 5-pyrimidinyl, 2-imidazolyl, and thiazolyl.

6. The compound of claim 1, wherein at least one of X.sup.1, X.sup.2, or X.sup.3 is alkyl or cycloalkyl.

7. The compound of claim 1, wherein at least one of X.sup.1, X.sup.2, or X.sup.3 is haloalkyl.

8. The compound of claim 1, wherein at least one of X.sup.1, X.sup.2, or X.sup.3 is alkenyl.

9. The compound of claim 1, wherein at least one of X.sup.1, X.sup.2, or X.sup.3 is amino.

10. The compound of claim 1 having a structure selected from the group consisting of: ##STR00580## ##STR00581## ##STR00582## ##STR00583## ##STR00584## ##STR00585## ##STR00586## ##STR00587## ##STR00588## ##STR00589## ##STR00590## ##STR00591## ##STR00592## ##STR00593## ##STR00594## ##STR00595## ##STR00596## ##STR00597## ##STR00598## or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1, wherein the compound exhibits an IC.sub.50 in a range of about 100 M to about 1000 M for inhibition of p38 MAPK.

12. The compound of claim 11, wherein the compound exhibits an IC.sub.50 is in the range of about 200 M to about 800 M.

13. The compound of claim 1, wherein the compound exhibits an EC.sub.50 in the range of about 0.1 M to about 1000 M for inhibition of TNF secretion in a bodily fluid in vivo.

14. A composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

15. The compound of claim 2, wherein R.sup.2 is selected from the group consisting of .Iadd.substituted or unsubstituted .Iaddend.aryl; unsubstituted heteroaryl; heteroaryl substituted with one or more substituents selected from halo, unsubstituted alkyl, alkenyl, OCF.sub.3, NO.sub.2, CN, NC, OH, alkoxy, haloalkoxy, amino, CO.sub.2H, and CO.sub.2alkyl; haloalkylcarbonyl; cycloalkyl; .[.hydroxylalkyl;.]. sulfonamido; and unsubstituted cycloheteroalkyl.[.; or R.sup.2 and R.sup.1 together form an optionally substituted 5-membered nitrogen-containing heterocyclic ring.]..

16. The compound of claim 15, selected from the group consisting of: ##STR00599## ##STR00600## or a pharmaceutically acceptable salt thereof.

17. A compound selected from the group consisting of: ##STR00601## or a pharmaceutically acceptable salt thereof.

18. The compound of claim 3 having a structure selected from the group consisting of: ##STR00602## ##STR00603## ##STR00604## ##STR00605## ##STR00606## ##STR00607## ##STR00608## ##STR00609## ##STR00610## ##STR00611## ##STR00612## ##STR00613## ##STR00614## ##STR00615## ##STR00616## or a pharmaceutically acceptable salt thereof.

19. A compound selected from the group consisting of: ##STR00617## ##STR00618## .[.and,.]. or a pharmaceutically acceptable salt thereof.

Description

EXAMPLES

Synthesis of Compounds of Formula (I)

(1) The following examples show the synthesis of specific compounds of Formula I, as depicted in Table 1, above.

(2) Synthesis of Compound 1: Following general procedure A, compound 1 was prepared in 50% yield as an oil. MS-ESI: m/z=200.3 [M+1].sup.+

(3) Synthesis of Compound 2: Following general procedure A, compound 2 was prepared in 73% yield as an oil. MS-ESI: m/z=200.3 [M+1].sup.+

(4) Synthesis of Compound 3: Following general procedure A, compound 3 was prepared in 78% yield as an oil. MS-ESI: m/z=200.3 [M+1].sup.+

(5) Synthesis of Compound 4: Following general procedure A, compound 4 was prepared in 46% yield as an oil. MS-ESI: m/z=214.3 [M+1].sup.+

(6) Synthesis of Compound 5: Following general procedure A, compound 5 was prepared in 52% yield as a yellowish oil. MS-ESI: m/z=214.3 [M+1].sup.+

(7) Synthesis of Compound 6: Following general procedure A, compound 6 was prepared in 86% yield as a solid. MS-ESI: m/z=214.3 [M+1].sup.+

(8) Synthesis of Compound 7: Following general procedure A, compound 7 was prepared in 50% yield as a white solid. MS-ESI: m/z=242.2 [M+1].sup.+

(9) Synthesis of Compound 8: Following general procedure A, compound 8 was prepared in 52% yield as an oil. MS-ESI: m/z=212.2 [M+1].sup.+

(10) Synthesis of Compound 9: Following general procedure A, compound 9 was prepared in 79% yield as an oil. MS-ESI: m/z=212.3 [M+1].sup.+

(11) Synthesis of Compound 10: Following general procedure A, compound 10 was prepared in 48% yield as a white solid. MS-ESI: m/z=212.3 [M+1].sup.+

(12) Synthesis of Compound 11: Following general procedure A, compound 11 was prepared in 73% yield as an oil. MS-ESI: m/z=229.2 [M+1].sup.+

(13) Synthesis of Compound 12: Following general procedure A, compound 12 was prepared in 81% yield as a white solid. MS-ESI: m/z=229.2 [M+1].sup.+

(14) Synthesis of Compound 13: Following general procedure A, compound 13 was prepared in 5.5% yield as a white solid. MS-ESI: m/z=262.3 [M+1].sup.+

(15) Synthesis of Compound 14: Following general procedure A, compound 14 was prepared in 35% yield as a white solid. MS-ESI: m/z=262.3 [M+1].sup.+

(16) Synthesis of Compound 15: Following general procedure A, compound 15 was prepared in 49% yield as a white solid. MS-ESI: m/z=262.3 [M+1].sup.+

(17) Synthesis of Compound 16: Following general procedure A, compound 16 was prepared in 75% yield as a solid. MS-ESI: m/z=268.3 [M+1].sup.+

(18) Synthesis of Compound 17: Following general procedure A, compound 17 was prepared in 40% yield as a yellowish solid. MS-ESI: m/z=232.2 [M+1].sup.+

(19) Synthesis of Compound 18: Following general procedure A, compound 18 was prepared in 79% yield as an oil. MS-ESI: m/z=232.2 [M+1].sup.+

(20) Synthesis of Compound 19: Following general procedure A, compound 19 was prepared in 85% yield as a white solid. MS-ESI: m/z=232.2 [M+1].sup.+

(21) Synthesis of Compound 20: Following general procedure A, compound 20 was prepared in 8% yield as an oil. MS-ESI: m/z=254.1 [M+1].sup.+

(22) Synthesis of Compound 21: Following general procedure A, compound 21 was prepared in 62% yield as a white solid. MS-ESI: m/z=254.2 [M+1].sup.+

(23) Synthesis of Compound 22: Following general procedure A, compound 22 was prepared in 57% yield as a white solid. MS-ESI: m/z=254.3 [M+1].sup.+

(24) Synthesis of Compound 23: Following general procedure A, compound 23 was prepared in 30% yield as a white solid. MS-ESI: m/z=278.3 [M+1].sup.+

(25) Synthesis of Compound 24: Following general procedure A, compound 24 was prepared in 93% yield as a white solid. MS-ESI: m/z=278.3 [M+1].sup.+

(26) Synthesis of Compound 25: Following general procedure A, compound 25 was prepared in 17% yield as a yellowish solid. MS-ESI: m/z=292.2 [M+1].sup.+

(27) Synthesis of Compound 26: Following general procedure A, compound 26 was prepared in 50% yield as an oil. MS-ESI: m/z=292.2 [M+1].sup.+

(28) Synthesis of Compound 27: Following general procedure A, compound 27 was prepared in 73.5% yield as a white solid. MS-ESI: m/z=292.2 [M+1].sup.+

(29) Synthesis of Compound 28: Following general procedure A, compound 28 was prepared in 4.5% yield as a white solid. MS-ESI: m/z=230.1 [M+1].sup.+

(30) Synthesis of Compound 29: Following general procedure A, compound 29 was prepared in 25% yield as an oil. MS-ESI: m/z=230.1 [M+1].sup.+

(31) Synthesis of Compound 30: Following general procedure A, compound 30 was prepared in 25% yield as an oil. MS-ESI: m/z=230.2 [M+1].sup.+

(32) Synthesis of Compound 31: Following general procedure A, compound 31 was prepared in 52% yield as a white solid. MS-ESI: m/z=260.1 [M+1].sup.+

(33) Synthesis of Compound 32: Following general procedure A, compound 32 was prepared in 23.8% yield as a solid, using triethylamine as a base, instead of pyridine. MS-ESI: m/z=241.2 [M+1].sup.+

(34) Synthesis of Compound 33: Following general procedure A, compound 33 was prepared in 81% yield as a white solid. MS-ESI: m/z=211.2 [M+1].sup.+

(35) Synthesis of Compound 34: Following general procedure A, compound 34 was prepared in 80% yield as a reddish solid, after crystallization. MS-ESI: m/z=244.4 [M+1].sup.+

(36) Synthesis of Compound 35: Following general procedure A, compound 35 was prepared in 82% yield as a yellowish solid. MS-ESI: m/z=230.4 [M+1].sup.+

(37) Synthesis of Compound 36: Following general procedure A, compound 36 was prepared in 71% yield as a solid. MS-ESI: m/z=244.2[M+1].sup.+

(38) Synthesis of Compound 37: Following general procedure A, compound 37 was prepared in 72% yield as a white solid. MS-ESI: m/z=228.0 [M+1].sup.+

(39) Synthesis of Compound 38: Following general procedure A, compound 38 was prepared in 75% yield as a white solid. MS-ESI: m/z=227.9 [M+1].sup.+

(40) Synthesis of Compound 39: Following general procedure A, compound 39 was prepared in 38% yield as a white solid. MS-ESI: m/z=242.9 [M+1].sup.+

(41) Synthesis of Compound 40: Following general procedure A, compound 40 was prepared in 81% yield as a white solid. MS-ESI: m/z=188.0 [M+1].sup.+

(42) Synthesis of Compound 41: Following general procedure A, compound 41 was prepared in 85% yield as a white solid. MS-ESI: m/z=308.2 [M+1].sup.+

(43) Synthesis of Compound 42: Following general procedure A, compound 42 was prepared in 91% yield as a white solid. MS-ESI: m/z=308.2 [M+1].sup.+

(44) Synthesis of Compound 43: Following general procedure A, compound 43 was prepared in 70% yield as a solid. MS-ESI: m/z=286.1 [M+1].sup.+

(45) Synthesis of Compound 44: Following general procedure A, compound 44 was prepared in 23.8% yield as a white solid. MS-ESI: m/z=241.2 [M+1].sup.+

(46) Synthesis of Compound 45: Following general procedure A, compound 45 was prepared in 80% yield as a solid. MS-ESI: m/z=197.3 [M+1].sup.+

(47) Synthesis of Compound 46:

(48) ##STR00507##
A solution of 1 (134 mg, 1 mmol), EtSNa (168 mg, 2 mmol) in DMF (5 ml) was heated to 60 C. for 4 h. To the reaction mixture was added HCl (aq.) until pH was about 6. The mixture was evaporated in vacuo to give 2. (110 mg, 92%). Pyridine (140 mg, 1.8 mmol) was slowly added to a mixture of 2 (110 mg, 0.9 mmol), phenylboronic acid (220 mg, 1.8 mmol) and Cu(OAc).sub.2 (18 mg) in DCM (5 mL). After the suspension was stirred overnight at room temperature, it was monitored by TLC. When no starting material was detected, the mixture was washed with saturated NaHCO.sub.3. The organic layer was dried over sodium sulfate, evaporated in vacuo to afford the crude product, which was purified by preparative TLC to give compound 46 (50 mg, 25% yield) as a white solid. MS-ESI: m/z=197.3 [M+1].sup.+

(49) Synthesis of Compound 47: Following general procedure A, compound 47 was prepared in 65% yield as a white solid. MS-ESI: m/z=251.2 [M+1].sup.+, 253.2 [M+3].sup.+

(50) Synthesis of Compound 48: Following general procedure A, compound 48 was prepared in 23% yield as a solid. MS-ESI: m/z=189.2 [M+1].sup.+

(51) Synthesis of Compound 49: Following general procedure A, compound 49 was prepared in 1% yield as a solid. MS-ESI: m/z=189.2 [M+1].sup.+

(52) Synthesis of Compound 50: Following general procedure A, compound 50 was prepared in 2% yield as a white solid. MS-ESI: m/z=203.2 [M+1].sup.+

(53) Synthesis of Compound 51: Following general procedure B, compound 51 was prepared in 34% yield as a white solid. MS-ESI: m/z=241.2 [M+1].sup.+

(54) Synthesis of Compound 52: Following general procedure B, compound 52 was prepared in 22% yield as a white solid. MS-ESI: m/z=241.2 [M+1].sup.+

(55) Synthesis of Compound 53: A mixture of 3-Bromo-1H-pyridin-2-one (150 mg, 0.6 mmol)), thienyl boromic acid (160 mg, 1.25 mmol)), Pd(PPh.sub.3).sub.2Cl.sub.2 (30 mg, 0.07 mmol) and Na.sub.2CO.sub.3 (200 mg, 1.88 mmol) in toluene (20 mL) and water (5 mL) was heated at 60 C. overnight under nitrogen atmosphere. Then, water (20 mL) was added and the aqueous layer was extracted with CH.sub.2Cl.sub.2 (30 mL2). The organics were washed by water and brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was purified by prep-TLC to give compound 52 (85 mg, 56% yields) as a yellowish solid. MS-ESI: m/z=254.3 [M+1].sup.+

(56) Synthesis of Compound 54: Following general procedure A, compound 54 was prepared in 78% yield as a white solid. MS-ESI: m/z=278.1 [M+1].sup.+

(57) Synthesis of Compound 55: Following general procedure D, compound 55 was prepared in 65% yield as a solid. MS-ESI: m/z=274.3 [M+1].sup.+

(58) Synthesis of Compound 56: Following general procedure D, compound 56 was prepared in 60% yield as a solid. MS-ESI: m/z=254.3 [M+1].sup.+

(59) Synthesis of Compound 57:

(60) ##STR00508##
Following general procedure E, compound 57 was synthesized (yield of first step 51%; yield of second step 17%). MS-ESI: m/z=274.3 [M+1].sup.+

(61) Synthesis of Compound 58: Following general procedure E, compound 58 was prepared in 61% yield as a solid. MS-ESI: m/z=254.3 [M+1].sup.+

(62) Synthesis of Compound 59:

(63) ##STR00509##
A mixture of 2, 6-dibromopyridine (1) (4 g, 17 mmol), potassium t-butoxide (20 g, 0.27 mol), and redistilled t-butyl alcohol (100 mL) was refluxed overnight. After cooling, the solvent was removed in vacuo, ice/water was carefully added, and the aqueous layer was extracted with chloroform (100 mL2), which removed the unreacted staring material. The aqueous layer was acidified with 3 N HCl, extracted with chloroform (100 mL2), washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated affording pure 6-bromo-2-pyridone (2.5 g, 85% yields) as a white solid. The preparation of 3 followed the general procedure A, in a 73% yield. 3 was then subjected to the conditions of general procedure A to prepare compound 59 in 35% yield as a yellowish oil. MS-ESI: m/z=274.3 [M+1].sup.+

(64) Synthesis of Compound 60: Compound 60 is synthesized in a similar fashion as compound 59, in 7.9% yield as a yellowish oil. MS-ESI: m/z=254.2 [M+1].sup.+

(65) Synthesis of Compound 61:

(66) ##STR00510##
To a solution of ethyl vinyl ether (1, 40 mL) in 100 ml of dichloromethane, pyridine (36 mL) was added. Then a solution of trifluoroacetic anhydride (87.6 g) in 50 mL of dichloromethane was added at 0 C. After stirring at room temperature for 30 min, the solution was poured into 40 mL of H.sub.2O. The layers were separated and the aqueous layer was extracted again with 40 mL of dichloromethane. The organic layers were combined, washed with H.sub.2O and dried over MgSO.sub.4. Removal of solvent the gave crude 3, which was used directly in the next step.

(67) ##STR00511##
Trimethylchlorosilane (26.5 mL, 150 mmol) was added to the solution of zinc powder (10 g, 150 mmol) in anhydrous THF (150 ml) under N.sub.2. After stirring for 0.5 h, a solution of chloroacetonitrile (6.35 mL, 100 mmol) and trifluoroacetylvinyl ether (8.4 g, 50 mmol) in anhydrous THF (75 mL) was added dropwise slowly to keep the temperature at 40 C. The mixture was refluxed for 2 h. After cooling to room temperature, concentrated HCl (25 mL) was added. The mixture was refluxed for 1 h, then cooled to room temperature. The reaction mixture was then poured into ice water. The product was extracted with EA, and washed with brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated to dryness to give the residue. The residue was purified by column chromatography to afford 8.3 g of 5. Following general procedure A, compound 61 was prepared in 52% yield as a white solid. MS-ESI: m/z=284.0 [M+1].sup.+

(68) Synthesis of Compound 62: Following general procedure outlined for compound 61, compound 62 was prepared in 80% yield as a solid. MS-ESI: m/z=283.0 [M+1].sup.+

(69) Synthesis of Compound 63: Following general procedure outlined for compound 61, compound 63 was prepared in 78% yield as a white solid. MS-ESI: m/z=307.9 [M+1].sup.+

(70) Synthesis of Compound 64: Following general procedure F, compound 64 was prepared in 79% for the first step and 65% for the second step, to produce an oil. MS-ESI: m/z=290.1 [M+1].sup.+

(71) Synthesis of Compound 65: Following general procedure F, compound 65 was prepared in 64% for the first step and 60% for the second step, to produce a yellowish solid. MS-ESI: m/z=290.2 [M+1].sup.+

(72) Synthesis of Compound 66: Following general procedure F, compound 66 was prepared in 80% for the first step and 56% for the second step. MS-ESI: m/z=250.2 [M+1].sup.+

(73) Synthesis of Compound 67: Following general procedure F, compound 67 was prepared in 85% for the first step. The second step was performed at 0 C., using DCM as the solvent, giving compound 67 in 76% yield for the second step. MS-ESI: m/z=268.2 [M+1].sup.+

(74) Synthesis of Compound 68: Following general procedure F, compound 68 was prepared in 10% for the first step and 15% for the second step to give a white solid. MS-ESI: m/z=222.7 [M+1].sup.+

(75) Synthesis of Compound 69: Following general procedure F, compound 69 was prepared in 79% for the first step and 59% for the second step. MS-ESI: m/z=222.7 [M+1].sup.+

(76) Synthesis of Compound 70: Following general procedure F, compound 70 was prepared in 75% for the first step and 63% for the second step. MS-ESI: m/z=223.2 [M+1].sup.+

(77) Synthesis of Compound 71: Following general procedure F, compound 71 was prepared in 85% for the first step. The second step was carried out at room temperature in a capped plastic tube for 6 hours to give an oil in a 50% yield for the second step. MS-ESI: m/z=265.2 [M+1].sup.+

(78) Synthesis of Compound 72:

(79) ##STR00512##
Following general procedure F, compound 72 was prepared in 89% for the first step and 53% for the second step, where in the second step, 4 eq of DAST was used. MS-ESI: m/z=272.0 [M+1].sup.+

(80) Synthesis of Compound 73: Following general procedure F, compound 73 was prepared in 89% for the first step and 58% for the second step to give an oil, where in the second step, 4 eq of DAST was used. MS-ESI: m/z=272.0 [M+1].sup.+

(81) Synthesis of Compound 74: Following general procedure F, compound 74 was prepared in 85% for the first step and 56% for the second step to give an oil, where in the second step, 6 eq of DAST was used. MS-ESI: m/z=286.0 [M+1].sup.+

(82) Synthesis of Compound 75: Following general procedure F, compound 75 was prepared in 71.4% for the first step and 39% for the second step to give a white solid, where in the second step, 6 eq of DAST was used. MS-ESI: m/z=286.0 [M+1].sup.+

(83) Synthesis of Compound 76: Following general procedure F, compound 76 was prepared in 89% for the first step and 57% for the second step to give a white solid. MS-ESI: m/z=290.0 [M+1].sup.+

(84) Synthesis of Compound 77: Following general procedure G, compound 77 was prepared in 20% yield as a white solid. MS-ESI: m/z=291.9 [M+1].sup.+

(85) Synthesis of Compound 78: Following general procedure G, compound 78 was prepared in 38% yield as a white solid. MS-ESI: m/z=291.0 [M+1].sup.+

(86) Synthesis of Compound 79: Following general procedure G, compound 79 was prepared in 78% yield as a white solid. MS-ESI: m/z=315.9 [M+1].sup.+

(87) Synthesis of Compound 80: Following general procedure G, compound 80 was prepared in 83% yield as a solid. MS-ESI: m/z=290.0 [M+1].sup.+

(88) Synthesis of Compound 81: Following general procedure G, compound 81 was prepared in 85% yield as a solid. MS-ESI: m/z=290.0 [M+1].sup.+

(89) Synthesis of Compound 82: Following general procedure G, compound 82 was prepared in 70% yield as a white solid. MS-ESI: m/z=304.9 [M+1].sup.+

(90) Synthesis of Compound 83: Following general procedures G then F, compound 83 was prepared in 90% for first step and 25% yield for second step (fluorination) as a yellowish oil. MS-ESI: m/z=298 [M+1].sup.+

(91) Synthesis of Compound 84: Following general procedures G then F, compound 84 was prepared in 83% for first step and 54% yield for second step (fluorination). MS-ESI: m/z=298.4 [M+1].sup.+

(92) Synthesis of Compound 85: Following general procedures G then F, compound 85 was prepared in 86% for first step and 49% yield for second step (fluorination). MS-ESI: m/z=312.0 [M+1].sup.+

(93) Synthesis of Compound 86: Following general procedures G then F, compound 86 was prepared in 82% for first step and 56% yield for second step (fluorination). MS-ESI: m/z=312.0 [M+1].sup.+

(94) Synthesis of Compound 87: Following general procedures A then F, compound 87 was synthesized in 86% yield then 20% yield for the second step (fluorination). MS-ESI: m/z=236 [M+1].sup.+

(95) Synthesis of Compound 88: Following general procedures A then F, compound 88 was synthesized in 65% yield then 25% yield for the second step (fluorination). MS-ESI: m/z=236 [M+1].sup.+

(96) Synthesis of Compound 89: Following general procedures A then F, compound 89 was synthesized in 72% yield then 26% yield for the second step (fluorination). MS-ESI: m/z=250.0 [M+1].sup.+

(97) Synthesis of Compound 90: Following general procedures A then F, compound 90 was synthesized in 75% yield then 27% yield for the second step (fluorination). MS-ESI: m/z=250.0 [M+1].sup.+

(98) Synthesis of Compound 91:

(99) ##STR00513##
3, above, was prepared using general procedure A. 4 was prepared in the following manner. To a solution of 3 (1 eq) in tetrahydrofuran-methanol (10:1) was added sodium borohydride (5 eq) at 0 C. The mixture was stirred at room temperature for 30 min. Water was added and then mixture was extracted with EA. The organics were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. 4 was isolated by prep-TLC. 5 was prepared according to general procedure F. Compound 91 was prepared under these reaction conditions to provide 86% yield of first step, 70% yield of second step, and 30% yield of third step. MS-ESI: m/z=272.2 [M+1].sup.+

(100) Synthesis of Compound 92: Similar to synthesis of compound 91, compound 92 was prepared to provide 82% yield of first step, 85% yield of second step, and 15% yield of third step. MS-ESI: m/z=272.3 [M+1].sup.+

(101) Synthesis of Compound 93: Similar to synthesis of compound 91, compound 93 was prepared to provide 80% yield of first step, 79.5% yield of second step, and 50% yield of third step. MS-ESI: m/z=232.3 [M+1].sup.+

(102) Synthesis of Compound 94: Similar to synthesis of compound 91, compound 94 was prepared to provide 82.9% yield of first step, 51% yield of second step, and 32% yield of third step. MS-ESI: m/z=250.2 [M+1].sup.+

(103) Synthesis of Compound 95:

(104) ##STR00514##
To a solution of 5-bromo-2-methoxy-pyridine (2.4 g, 8.94 mmol), (E)-prop-1-enylboronic acid (1 g, 11.6 mmol), K.sub.3PO.sub.4 (6.6 g, 31.3 mmol) and tricyclohexylphosphine (250 mg, 0.894 mmol) in toluene (40 mL) and water (2 mL) under a nitrogen atmosphere was added palladium acetate (100 mg, 0.447 mmol). The mixture was heated to 100 C. for 3 h and then cooled to room temperature. Water (100 mL) was added and the mixture extracted with EA (2150 mL), the combined organics were washed with brine (100 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The product was purified by column chromatography to give 1.3 g of compound 3 (68.4%, yield). Compound 3 (1.3 g, 8.72 mmol) was added to a stirred solution of hydrobromic acid (9.7 mL) in absolute ethanol (234 mL) under nitrogen and the mixture was heated under reflux for 5 hours. The cooled solution was evaporated in vacuo, and the residue partitioned between 10% sodium carbonate solution and DCM. The organic phase was dried with Na.sub.2SO.sub.4 and evaporated in vacuo to give 1.04 g of compound 4 as a white solid. (89% yield). Compound 5 was prepared using general procedure A. Compound 95 was prepared to give 85% yield of an oil. MS-ESI: m/z=255.3 [M+1].sup.+

(105) Synthesis of Compound 96: Similar to synthesis of compound 95, compound 96 was prepared to provide 89% yield as a white solid. MS-ESI: m/z=280.2 [M+1].sup.+

(106) Synthesis of Compound 97:

(107) ##STR00515##
Using the procedure as outlined for compound 95 and general procedure F, compound 97 was prepared in 82% yield (first step) and 59% yield (second step). MS-ESI: m/z=262.2 [M+1].sup.+

(108) Synthesis of Compound 98:

(109) ##STR00516##
Meta-chloroperbenzoic acid (mCPBA, 5 eq.) was added to the solution of 1 in DCM at 78 C. The reaction was stirred at 0 C. for 20 minutes, then filtered. The reaction filtrate was purified by prep-TLC to give 2. Following this general procedure, compound 18 was subjected to these conditions to provide compound 98 in 22% yield as a white solid. MS-ESI: m/z=263.9 [M+1].sup.+

(110) Synthesis of Compound 99: Similar to the synthesis of compound 98, compound 99 was prepared from compound 19 to provide compound 99 in 40% yield as a yellowish solid. MS-ESI: m/z=264 [M+1].sup.+

(111) Synthesis of Compound 100: Similar to the synthesis of compound 98, compound 100 was prepared from compound 67 to provide compound 100 in 80% yield as a white solid. MS-ESI: m/z=300.2 [M+1].sup.+

(112) Synthesis of Compound 101:

(113) ##STR00517##
2 is prepared using general procedure A in 84% yield. A mixture of 2 (1 g, 5 mmol) and trimethyl-trifluoromethylsilane (3.5 mL, 2M in THF, 7 mmol) in THF (20 mL) was cooled to 0 C. in an ice bath and treated with tetrabutylammonium fluoride (0.25 mL, 1 M in THF, 0.25 mmol) under nitrogen atmosphere at 0 C. for 30 min. The mixture was warmed to room temperature and stirred 24 h. Then, 1 M HCl (50 mL) was added, and the mixture was stirred overnight. The aqueous layer was extracted with EA (50 mL2) and the organic layer was concentrated. The desired product was separated by column chromatography to give pure intermediate (0.94 g, 70% yield) as yellow solid. MS-ESI: m/z=270.2 [M+1].sup.+ The intermediate (50 mg, 0.19 mmol) and manganese dioxide (165 mg, 1.9 mmol) were stirred overnight at room temperature in DCM (5 mL). The progress of the reaction was detected by TLC. Upon completion, the crude mixture was filtered through a pad of celite and the filtrate was concentrated. Compound 101 was isolated by washing the crude with petroleum ether to give pure product (36 mg, 70% yields) as a white solid. MS-ESI: m/z=268.2 [M+1].sup.+

(114) Synthesis of Compound 102: Following general procedure A, compound 102 was prepared in 80% yield as a white solid. MS-ESI: m/z=268.2 [M+1].sup.+

(115) Synthesis of Compound 103: Compound 103 was prepared from compound 102. A mixture of compound 102 (2 g, 10 mmol) and trimethyl-trifluoromethyl-silane (7 ml, 2M in THF, 15 mmol) in THF (40 mL) was cooled to 0 C. in an ice bath and then treated with tetrabutylammonium fluoride (0.5 ml, 1 M in THF, 0.5 mmol) under nitrogen atmosphere at 0 C. for 30 min. The mixture was warmed to room temperature and stirred 24 h. Then, 1 M HCl (50 mL) was added and the mixture was stirred overnight. The aqueous layer was extracted with EA (70 mL2) and the organic layer was concentrated. The desired product was separated by column chromatography to give pure compound 103 (1.5 g, 45% yields) as a white solid.

(116) MS-ESI: m/z=338.3 [M+1].sup.+

(117) Synthesis of Compound 104: Compound 104 was prepared from compound 103. Potassium bromate (16.6 g, 0.1 mol) was added over 0.5 h to a vigorously stirred mixture of 2-iodobenzoic acid (20 g, 0.08 mmol) and 180 mL 0.73 M H.sub.2SO.sub.4 (0.13 mol) in a 55 C. bath. The mixture was stirred for 4 h at 68 C., and the Br.sub.2 formed was removed by reduced pressure in the reaction process. The reaction was cooled to room temperature with an ice bath. Filtration and washing of the solid with ice water and iced ethanol gave the desired compound IBX (16 g, 70% yield). Compound 103 (1 g, 3 mmol) was dissolved in EA (50 mL), and IBX (4 g, 15 mmol) was added. The resulting suspension was immersed in an oil bath set to 80 C. and stirred vigorously open to the atmosphere overnight. The reaction was cooled to room temperature and filtered. The filter cake was washed with EA, and the combined filtrates were concentrated. The desired compound was obtained (0.98 g, 98% yields) as a white solid. MS-ESI: m/z=336 [M+1].sup.+

(118) Synthesis of Compound 105: Compound 105 was prepared from compound 104. Compound 104 (80 mg, 0.24 mmol) in dry DCM (1.5 mL) was added at the temperature of 78 C. under N.sub.2 atmosphere to a solution of DAST (50 mg, 0.31 mmol) in DCM (0.5 mL). The mixture was stirred at 78 C. for 2 h, and then warmed to room temperature overnight. The reaction mixture was diluted with DCM (20 mL), and poured into saturated NaHCO.sub.3 (30 mL). The organic phase was separated and dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Compound 105 was isolated by thin-layer chromatography (42 mg, 50% yields) as a white solid. MS-ESI: m/z=340.2 [M+1].sup.+

(119) Synthesis of Compound 106: Compound 106 was prepared from compound 104. Compound 104 (100 mg, 0.3 mmol) was dissolved in acetonitrile (1.2 mL), and DAST (100 mg, 0.6 mmol) was added. Fluorination was carried out at 80 C. in a pressure vessel for 4 h. After cooling to room temperature, the reaction mixture was diluted with DCM (20 mL), and poured into the saturated sodium bicarbonate solution (30 mL). The organic phase was separated and dried over sodium sulfate. Compound 106 was isolated by prep-TLC (20 mg, 20% yields) as a yellowish solid. MS-ESI: m/z=357.7 [M+1].sup.+

(120) Synthesis of Compound 107: Compound 107 was prepared from compound 104. A mixture of Compound 104 (80 mg, 0.24 mmol) and trimethyl-trifluoromethyl-silane (0.07 mL pure, 0.49 mmol) in THF (2.5 mL) cooled to 0 C. in an ice bath is treated with tetrabutylammonium fluoride (0.5 mL, 0.024 M in THF, 0.012 mmol) under nitrogen atmosphere at 0 C. for 30 min. The mixture was raised to room temperature and stirred 24 h. Then, 1 M HCl (20 mL) was added and the mixture was stirred overnight. The aqueous layer was extracted with EA (30 mL2) and the organic layers were concentrated. The desired product was separated out by washing the crude with EA to give Compound 107 (50 mg, 52% yield) as a yellowish solid. MS-ESI: m/z=406.2 [M+1].sup.+

(121) Synthesis of Compound 108: A slurry of pyrimidin-2(1H)-one (1 g, 10.4 mmol), triphenylbismuth (6.88 g, 15.6 mmol), anhydrous Cu(OAc).sub.2 (2.84 g,15.6 mmol) and NEt.sub.3 (2.5 mL) in anhydrous DCM (16 mL) was stirred at room temperature under a nitrogen atmosphere. After a period of two days, the solution became gelatinous and changed from deep blue to light green. The reaction mixture was diluted with DCM then filtered. The filtrate was washed with NaHCO.sub.3, EDTA and NaCl (aq) and then dried with Na.sub.2SO.sub.4. Compound 108 was isolated by flash column chromatography (358 mg, 20% yield). MS-ESI: m/z=173.2 [M+1].sup.+

(122) Synthesis of Compounds 109 & 110: Compound 109 was prepared from compound 108. Sodium borohydride (200 mg 5.26 mmol) was added slowly to a solution of Compound 108 (90 mg, 0.526 mmol) in acetic acid (32 mL) and the mixture was stirred for 30 min at room temperature. The reaction mixture was neutralized cautiously with aqueous sodium hydroxide, on an ice-water bath, and then extracted with dichloromethane and dried over anhydrous magnesium sulfate. Compound 109 (78 mg, 39%, MS-ESI: m/z=173.2 [M+1].sup.+) and Compound 110 (59 mg, 29%, MS-ESI: m/z=177.2 [M+1].sup.+) were obtained by prep-TLC.

(123) Synthesis of Compound 111: Following general procedure A, compound 112 was prepared in 45% yield as a white solid. MS-ESI: m/z=242.2 [M+1].sup.+

(124) Synthesis of Compound 112: Following general procedure A, compound 113 was prepared in 72% yield as an oil. MS-ESI: m/z=230.2 [M+1].sup.+

(125) Synthesis of Compound 113: Following general procedure A, compound 114 was prepared in 75% yield as a solid. MS-ESI: m/z=268.2 [M+1].sup.+

(126) Synthesis of Compound 114: Following General procedure H2, compound 114 was synthesized in 20% yield. .[.1H.]. .Iadd..sup.1H .Iaddend.NMR (300 MHz, DMSO-d.sub.6) ppm 7.68 (dd, 1H), 7.45-7.61 (m, 5H), 6.50 (dd, 1H), 6.33 (td, 1H)

(127) Synthesis of Compound 115: A for compound 115 was prepared in the following manner. A solution of 5-cyano-2-methoxy pyridine (1 eq), sodium ethylsulfide (EtSNa) (2 eq) in DMF (5 ml/eq) was heated to 60 C. for 4 h. To the reaction mixture was added HCl-Et.sub.2O until the mixture reached a pH of about 6, under nitrogen flush, in order to remove volatiles (.[.Et2O.]. .Iadd.Et.sub.2O .Iaddend.and EtSH). The mixture was centrifuged and filtered, which removed the sodium chloride. The DMF solution was used as prepared in General procedure H2 to provide compound 115 in 21% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.63 (d, 1H), 7.77 (dd, 1H), 7.64 (m, 2H), 7.55 (m, 2H), 6.61 (d, 1H)

(128) Synthesis of Compound 116: For compound 116, A was prepared according to general procedure I, as follows.

(129) ##STR00518##
The 5-bromo-2-methoxy-pyridine (750 mg, 4 mmol), cyclopropyl boronic acid (1.08 g, 12.5 mmol) KF (760 mg, 13 mmol) and Pd(PPh.sub.3).sub.4 were dissolved in toluene (12 ml) and the reaction mixture was heated at 150 C. by microwave for 1.5 h. The crude was purified by column chromatography to give the intermediate (1.33 g 74% yield) as colorless oil. To a magnetically stirred solution of 5-cyclopropyl-2-methoxypyridine (1.33 g, 8.9 mmol), in 30 mL of DMF, EtSNa (1.502 g, 17.8 mmol) was added. The mixture was heated at 90 C. for 24 h. The reaction was cooled at room temperature and HCl/Et.sub.2O was added until pH 6. EtSH formed. The remaining HCl/Et.sub.2O and EtSH was evaporated by bubbling N.sub.2 at 40 C. The solution of A (concentration 40 mg/ml) was use as such for the next step. Following general procedure H1A, compound 116 was prepared in 25% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.65-8.77 (m, 2H), 7.51-7.57 (m, 2H), 7.48 (d, 1H), 7.30 (dd, 1H), 6.46 (d, 1H), 1.69-1.85 (m, 1H), 0.76-0.87 (m, 2H), 0.57-0.66 (m, 2H)

(130) Synthesis of Compound 117: Compound A for compound 117 was prepared as stated for compound 116. The prepared compound A was used in General procedure H1A to provide compound 117 in 25% yield. .sup.1H NMR (300 MHz, DMSO-d.sub.6) ppm 10.10 (s, 1H), 7.65 (t, 1H), 7.51-7.61 (m, 1H), 7.36-7.45 (m, 2H), 7.25 (dd, 1H), 7.04 (ddd, 1H), 6.41 (d, 1H), 2.06 (s, 3H), 1.67-1.84 (m, 1H), 0.73-0.87 (m, 2H), 0.52-0.63 (m, 2H)

(131) Synthesis of Compound 118: Compound A for compound 118 was prepared as stated for compound 116. The prepared compound A was used in General procedure H1A to provide compound 118 in 18% yield. .sup.1H NMR (300 MHz, DMSO-d.sub.6) ppm 7.56 (m, 2H), 7.49 (m, 2H), 7.46 (d, 1H), 7.28 (dd, 1H), 6.44 (d, 1H), 1.67-1.84 (m, 1H), 0.73-0.89 (m, 2H), 0.54-0.65 (m, 2H)

(132) Synthesis of Compound 119: Following General procedure H2, compound 119 was synthesized in 45% yield. 1H NMR (300 MHz, DMSO-d.sub.6) ppm 7.63 (ddd, 1H), 7.31-7.58 (m, 6H), 6.40-6.55 (m, 1H), 6.31 (td, 1H)

(133) Synthesis of Compound 120: Following General procedure H2, compound 120 was synthesized in 30% yield. 1H NMR (300 MHz, DMSO-d.sub.6) ppm 8.03 (dd, 1H), 7.73 (dd, 1 H), 7.45-7.60 (m, 5H), 6.63 (dd, 1H), 2.71 (s, 6H)

(134) Synthesis of Compound 121: Following General procedure I, A was prepared as follows.

(135) ##STR00519##
The 5-Furan-2-yl-1H-pyridin-2-one product was obtained by reaction of 2.66 g (14 mmol) of 5-bromo-2-methoxy-pyridine. After purification (SiO.sub.2; Pet. Ether/AcOEt 9:1) 1.83 g (75% yield) of pure product were obtained as white solid. The obtained product was de-methylated using EtSNa. The obtained A in a DMF solution (10 mmol/30 ml) was used for the Chan Lam reaction, following General Procedure H2 to provide compound 121 in 19% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.85-7.94 (m, 2H), 7.66 (dd, 1H), 7.42-7.59 (m, 5H), 6.80 (dd, 1H), 6.60 (dd, 1H), 6.55 (dd, 1H)

(136) Synthesis of Compound 122: Following General procedure H1A, compound 122 was synthesized in 53% yield. .sup.1H NMR (300 MHz, DMSO-d.sub.6) ppm 10.13 (s, 1H), 7.69 (t, 1 H), 7.61 (ddd, 1H), 7.54-7.59 (m, 1H), 7.47-7.54 (m, 1H), 7.42 (t, 1H), 7.04 (ddd, 1H), 6.39-6.53 (m, 1H), 6.31 (td, 1H), 2.06 (s, 3H)

(137) Synthesis of Compound 123: Following General procedure H1A, compound 123 was synthesized in 37% yield. .sup.1H NMR (300 MHz, DMSO-d.sub.6) ppm 8.13 (d, 1H), 7.73 (dd, 1H), 7.66 (m, 2H), 7.55 (m, 2H), 6.64 (d, 1H), 2.71 (s, 6H)

(138) Synthesis of Compound 124: For compound 124, A was prepared as described for compound 121. The obtained A in a DMF solution (10 mmol/30 ml) was used for the Chan Lam reaction, following General Procedure H2 to provide compound 124 in 13% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.98 (d, 1H), 7.90 (dd, 1H), 7.66-7.68 (m, 1H), 7.66 (m, 2H), 7.54 (m, 2H), 6.81 (dd, 1H), 6.62 (dd, 1H), 6.56 (dd, 1H)

(139) Synthesis of Compound 125: Following General procedure H2, compound 125 was synthesized in 20% yield. .sup.1H NMR (300 MHz, DMSO-d.sub.6) ppm 10.16 (s, 1H), 8.02 (d, 1H), 7.75 (t, 1H), 7.72 (dd, 1H), 7.57-7.66 (m, 1H), 7.46 (t, 1H), 7.15 (ddd, 1H), 6.63 (d, 1H), 2.71 (s, 6H), 2.07 (s, 3H)

(140) Synthesis of Compound 126: Following General procedure H2, compound 126 was synthesized in 13% yield. .sup.1H NMR (300 MHz, DMSO-d.sub.6) ppm 8.73 (dd, 2H), 7.70 (ddd, 1 H), 7.49-7.60 (m, 3H), 6.52 (ddd, 1H), 6.37 (td, 1H)

(141) Synthesis of Compound 127: Compound A for compound 127 was prepared as stated for compound 115. The prepared compound A was used in General procedure H2 to provide compound 127 in 33% yield. .sup.1H NMR (300 MHz, DMSO-d.sub.6) ppm 10.15 (s, 1H), 8.58 (d, 1H), 7.75 (dd, 1H), 7.72 (t, 1H), 7.60 (ddd, 1H), 7.45 (t, 1H), 7.10 (ddd, 1H), 6.59 (dd, 1H), 2.07 (s, 3H)

(142) Synthesis of Compound 128: For compound 128, A was prepared as described for compound 121. The obtained demethylated A in a DMF solution (10 mmol/30 ml) was used for the Chan Lam reaction, following General Procedure H2 to provide compound 128 in 20% yield. 1H NMR (300 MHz, DMSO-d6) ppm 10.14 (s, 1H), 7.83-7.96 (m, 2H), 7.70-7.77 (m, 1H), 7.66 (dd, 1H), 7.60 (ddd, 1H), 7.45 (t, 1H), 7.13 (ddd, 1H), 6.80 (dd, 1H), 6.57-6.64 (m, 1H), 6.55 (dd, 1H), 2.07 (s, 3H)

(143) Synthesis of Compound 129: Compound A for compound 129 was prepared as stated for compound 116. The prepared compound A was used in General procedure H1A to provide compound 129 in 23% yield. .sup.1H NMR (300 MHz, DMSO-d.sub.6) ppm 7.92 (m, 2H), 7.62 (m, 2H), 7.41-7.53 (m, 3H), 7.29 (dd, 1H), 6.45 (d, 1H), 1.68-1.84 (m, 1H), 0.74-0.88 (m, 2H), 0.52-0.67 (m, 2H)

(144) Synthesis of Compound 130: Following General procedure I, A was prepared as follows.

(145) ##STR00520##
Following standard Suzuki coupling, the 2-Methoxy-5-phenyl-pyridine was obtained by reaction of 1.9 g (10 mmol) of 5-bromo-2-methoxy-pyridine. After purification (SiO.sub.2; Pet. Ether/EA 9:1) 1.8 g (97% yield) of pure product were obtained as white solid. The 2-Methoxy-5-phenyl-pyridine (1 g, 5.4 mmol) was added to HSO.sub.3Cl (2 ml) at 0 C. The dark solution was stirred at room temperature for 4 h and then poured onto ice. Concentrated ammonia was added, while maintaining the temperature<10 C. The intermediate was extracted with EA (1.2 g, 84% yield) and used for the next step without further purification. To a magnetically stirred solution of the intermediate (4-(6-Methoxy-pyridin-3-yl)benzenesulfonamide, 1.2 g, 4.5 mmol), in 3 mL of EtOH, 15 mL of HBr were added. The mixture was heated at 80 C. for 20 h. The reaction was cooled at room temperature and poured into KHCO.sub.3 saturated solution. EA was added and the mixture was transferred into a separator funnel. The aqueous layer was separated and extracted with additional portion of EA. The combined organics were washed once with water. The organic layer was dried with sodium sulfate, filtered and evaporated under vacuum, affording 300 mg of A. The aqueous layer was acidified and the solvent was evaporated under vacuum. Purification by flash column chromatography (EA) afforded 750 mg of A (89% of yield). A was used for the Chan Lam reaction, following General Procedure H1A to provide compound 130 in 77% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.12 (d, 1H), 8.00 (dd, 1H), 7.83 (m, 4H), 7.42-7.64 (m, 5H), 7.34 (s, 2H), 6.64 (d, 1H)

(146) Synthesis of Compound 131: Compound A for compound 131 was prepared as stated for compound 130. The prepared compound A was used in General procedure H1A to provide compound 131 in 61% yield. .sup.1H NMR (300 MHz, DMSO-d.sub.6) ppm 8.18 (d, 1H), 8.02 (dd, 1H), 7.84 (m, 4H), 7.69 (m, 2H), 7.55 (m, 2H), 7.34 (s, 2H), 6.65 (d, 1H)

(147) Synthesis of Compound 132: Compound A for compound 132 was prepared as stated for compound 116. The prepared compound A was used in General procedure H1A to provide compound 132 in 25% yield. .sup.1H NMR (300 MHz, DMSO-d.sub.6) ppm 7.42-7.57 (m, 3 H), 7.36-7.42 (m, 2H), 7.33 (dd, 1H), 7.13-7.24 (m, 1H), 6.80 (d, 1H), 1.66-1.81 (m, 1 H), 0.86-0.97 (m, 2H), 0.52-0.64 (m, 2H)

(148) Synthesis of Compound 133: For compound 133, A was prepared as described for compound 121. The obtained A in a DMF solution (10 mmol/30 ml) was used for the Chan Lam reaction, following General Procedure H2 to provide compound 133 in 17% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.87-8.96 (m, 2H), 7.79-7.85 (m, 2H), 7.69-7.77 (m, 2H), 7.44 (dd, 1H), 6.76-6.84 (m, 1H), 6.47-6.57 (m, 2H)

(149) Synthesis of Compound 134: Following General procedure I, A was prepared as follows.

(150) ##STR00521##
Following standard Suzuki coupling, an intermediate was obtained by reaction of 2.82 g (15 mmol) of 5-bromo-2-methoxy-pyridine. After purification (SiO.sub.2; Pet. Ether/EA 9:1) 2.8 g (92% yield) of pure intermediate were obtained as white solid. The intermediate (900 mg) was dissolved in HBr 48% (10 ml) and EtOH (3 ml) and the solution was heated at reflux for 3 h. After evaporation of volatiles the desired A pyridone was obtained as white solid (780 mg, 93% yield). A was used in the Chan Lam reaction, following General Procedure H1A to provide compound 134 in 33% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.02 (d, 1H), 7.87-7.99 (m, 3H), 7.73 (m, 2H), 7.69 (m, 2H), 7.50 (s, 2H), 7.25 (m, 2H), 6.62 (d, 1H)

(151) Synthesis of Compound 135: For compound 135, A was prepared as described for compound 134. A was used in the Chan Lam reaction, following General Procedure H1A to provide compound 135 in 59% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.13 (s, 1H), 7.86-7.96 (m, 2H), 7.74 (t, 1H), 7.55-7.71 (m, 3H), 7.44 (t, 1H), 7.23 (m, 2H), 7.14 (ddd, 1H), 6.55-6.64 (m, 1H), 2.06 (s, 3H)

(152) Synthesis of Compound 136: For compound 136, A was prepared as described for compound 134. A was used in the Chan Lam reaction, following General Procedure H1A to provide compound 136 in 53% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.94 (d, 1H), 7.91 (dd, 1H), 7.68 (m, 2H), 7.40-7.59 (m, 5H), 7.23 (m, 2H), 6.60 (dd, 1H)

(153) Synthesis of Compound 137: For compound 137, A was prepared as described for compound 134. A was used in the Chan Lam reaction, following General Procedure H1A to provide compound 137 in 53% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.01 (d, 1H), 7.93 (dd, 1H), 7.63-7.74 (m, 4H), 7.53 (m, 2H), 7.24 (m, 2H), 6.61 (dd, 1H)

(154) Synthesis of Compound 138: For compound 138, A was prepared as follows:

(155) ##STR00522##
1.53 g (10 mmol) of 2-methoxy-pyridine-5-boronic acid and 2.46 g (15 mmol) of 2-Bromo-thiazole and K.sub.2CO.sub.3 (3 eq) were dissolved in a 10:1 mixture of DME/H.sub.2O (4 ml/mmol). The solution was degassed by bubbling N.sub.2 for 15 min and then Pd(PPh.sub.3).sub.4 (0.05 eq) was added. The reaction mixture was heated at 90 C. for 8 h .[.an.]. .Iadd.and .Iaddend.then cooled at room temperature, diluted with EA and filtered on a celite plug. The filtrate was washed with brine. The separated organic phase was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. After purification (SiO.sub.2; Pet. Ether/EA 9:1) 1.8 g (92% yield) of a 1:1 mixture of intermediate and the dimeric 2-methoxy-pyridine were obtained and used for the next step. The mixture (1.1 g) was dissolved in HBr 48% (10 ml) and EtOH (3 ml) and the solution was heated at reflux for 3 h. After evaporation of volatiles, the crude was purified by column chromatography (SiO.sub.2; Pet. Ether/EA 9:1) leading to the desired pyridone A (350 mg). Following general .[.procued.]. .Iadd.procedure .Iaddend.H1A, compound 138 was prepared in 35% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.23 (d, 1H), 8.07 (dd, 1H), 7.84 (d, 1H), 7.70 (d, 1H), 7.41-7.63 (m, 5H), 6.64 (d, 1 H)

(156) Synthesis of Compound 139: Following general procedure I, A was prepared as follows.

(157) ##STR00523##
Following standard procedure for Suzuki coupling, the intermediate was obtained by reaction of 3 g (16 mmol) of 5-bromo-2-methoxy-pyridine. After purification (SiO.sub.2; Hexane/EA 30/1 to EA) 2.2 g (51% yield) of the intermediate were obtained as white solid. To a magnetically stirred solution of 2-Methoxy-5-(1-methyl-1H-pyrazol-4-yl)-pyridine (1.2 g, 6.3 mmol), in 3 mL of EtOH, 15 mL of HBr were added. The mixture was heated at 80 C. for 20 h. The reaction was cooled at room temperature. The solvent was evaporated under vacuum. Purification by flash column chromatography (EA) afforded 1.1 g of A (quantitative yield). Following general procedure H1A, compound 139 was prepared in 63% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.04 (d, 1H), 7.94 (dd, 1H), 7.79 (d, 1H), 7.79 (dd, 1H), 7.62 (m, 2 H), 7.54 (m, 2H), 6.56 (d, 1H), 3.82 (s, 3H)

(158) Synthesis of Compound 140: For compound 140, A was prepared as described for compound 134. A was used in the Chan Lam reaction, following General Procedure H1A to provide compound 140 in 30% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 9.26 (s, 1H), 9.08 (s, 2H), 8.18 (d, 1H), 7.99 (dd, 1H), 7.70 (m, 2H), 7.27 (m, 2H), 6.66 (d, 1H)

(159) Synthesis of Compound 141: For compound 141, A was prepared as described for compound 134. A was used in the Chan Lam reaction, following General Procedure H1A to provide compound 141 in 45% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.68-8.81 (m, 2H), 8.02 (dd, 1H), 7.94 (dd, 1H), 7.70 (m, 2H), 7.62-7.66 (m, 2H), 7.26 (m, 2H), 6.64 (dd, 1H)

(160) Synthesis of Compound 142: Compound A for compound 142 was prepared according to the following scheme.

(161) ##STR00524##
6-Methoxy-pyridin-3-ylamine (2.5 g 2 mmol) was dissolved in 48% HBF.sub.4 (10 ml) and cooled at 0 C. NaNO.sub.2 (2.4 g, 3.4 mmol) was added portionwise maintaining the temperature<5 C. The dark solution was stirred at low temperature for 1 h. The solid was collected by filtration and washed with water and then dried under vacuum. The desired diazonium salt was obtained (3.18 g, 72%) as white crystalline solid. The diazonium salt (2 g, 8.9 mmol) and celite (4 g) were finely mixed in a mortar, transferred to a reaction vessel, then gradually heated to 150 C., whereupon a rapid evolution of fumes occurred. The resulting solid was washed several times with abundant diethyl ether. The organic solution was washed with Et.sub.2O/HCl then evaporated to provide the desired intermediate as its hydrochloric salt (1.2 g) as pale yellow viscous oil. The obtained fluoromethoxy pyridine (1.2 g) was dissolved in HBr 48% (10 ml) and EtOH (3 ml) and the solution was heated at reflux for 6 h. After evaporation of volatiles the desired pyridone A was obtained as amorphous solid in quantitative yield, and used in General procedure H1A to provide compound 142 in 28% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.85-7.97 (m, 1H), 7.59-7.73 (m, 1H), 7.34-7.57 (m, 5H), 6.45-6.57 (m, 1H)

(162) Synthesis of Compound 143: Using A as prepared as described for compound 142, following General procedure H1A, compound 143 was prepared in 13% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.13 (br. s., 1H), 7.89 (ddd, 1H), 7.69-7.72 (m, 1H), 7.67 (ddd, 1 H), 7.57 (ddd, 1H), 7.35-7.48 (m, 1H), 6.97-7.16 (m, 1H), 6.51 (ddd, 1H), 2.06 (s, 3H)

(163) Synthesis of Compound 144: Using A as prepared as described for compound 142, following General procedure .[.HIA.]. .Iadd.H1A.Iaddend., compound 144 was prepared in 26% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.13 (br. s., 1H), 7.89 (ddd, 1H), 7.69-7.72 (m, 1H), 7.67 (ddd, 1 H), 7.57 (ddd, 1H), 7.35-7.48 (m, 1H), 6.97-7.16 (m, 1H), 6.51 (ddd, 1H), 2.06 (s, 3H)

(164) Synthesis of Compound 145: For compound 145, A was prepared as described for compound 139. A was used in the Chan Lam reaction, following General Procedure H1A to provide compound 145 in 42% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.04 (s, 1H), 7.88 (dd, 1H), 7.71-7.83 (m, 2H), 7.36-7.61 (m, 5H), 6.54 (dd, 1H), 3.82 (s, 3H)

(165) Synthesis of Compound 146: For compound 146, A was prepared as described for compound 121. The obtained demethylated A in a DMF solution (10 mmol/30 ml) was used for the Chan Lam reaction, following General Procedure H2 to provide compound 146 in 7% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 9.26 (s, 1H), 9.04 (s, 2H), 8.15 (d, 1H), 7.95 (dd, 1H), 7.70 (dd, 1H), 6.81 (dd, 1H), 6.67 (dd, 1H), 6.58 (dd, 1H)

(166) Synthesis of Compound 147: Following general procedure I, A was prepared as follows.

(167) ##STR00525##
The 2-methoxy-pyridine-5-boronic acid (1.9 g, 12 mmol), the 5-bromo-pyrimidine (1.2 eq) and K2CO3 (3 eq) were dissolved in a 10:1 mixture of DME/H.sub.2O (4 ml/mmol). The solution was degassed by bubbling N.sub.2 for 15 min and then Pd(PPh.sub.3).sub.4 (0.05 eq) was added. The reaction mixture was heated at 90 C. for 8 h .[.an.]. .Iadd.and .Iaddend.then cooled at room temperature, diluted with EA and filtered on a celite plug. The filtrate was washed with brine. The separated organic phase was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by column chromatography. (SiO.sub.2; Hexane/EA 30/1 to EA) 1.29 g (56% yield) of intermediate were obtained as white solid. A solution of 5-(6-Methoxy-pyridin-3-yl)-pyrimidine (1.29 g, 6.9 mmol) in EtOH (4 ml) and HBr 48% (10 ml) was stirred at 90 C. for 7 h. The solvent was evaporated and the crude A (as hydrobromide salt) was utilized in the next step without any purification. Following general procedure H1A, compound 147 was prepared in 22% yield. 1H NMR (300 MHz, DMSO-d6) ppm 9.12 (s, 2H), 9.11 (s, 1H), 8.32 (d, 1H), 8.06 (dd, 1H), 7.69 (m, 2H), 7.56 (m, 2H), 6.68 (d, 1H)

(168) Synthesis of Compound 148: For compound 148, A was prepared as stated for compound 147. Following general procedure H1A, compound 148 was prepared in 37% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.15 (br. s., 1H), 9.10 (s, 3H), 8.25 (d, 1H), 8.04 (dd, 1H), 7.76 (s, 1H), 7.61 (d, 1H), 7.46 (dd, 1H), 7.15 (ddd, 1H), 6.65 (d, 1H), 2.06 (s, 3H)

(169) Synthesis of Compound 149: For compound 149, A was prepared as stated for compound 147. Following general procedure .[.HIA.]. .Iadd.H1A.Iaddend., compound 149 was prepared in 16% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 9.12 (br. s., 3H), 8.26 (d, 1H), 8.04 (dd, 1H), 7.32-7.66 (m, 5H), 6.66 (d, 1H)

(170) Synthesis of Compound 150: For compound 150, A was prepared as stated for compound 130. The prepared A was used in General procedure H1A to provide compound 150 in 36.5% yield. .sup.1H NMR (300 MHz, DMSO-d.sub.6) ppm 9.27 (s, 1H), 9.09 (s, 2H), 8.33 (dd, 1H), 8.07 (dd, 1H), 7.86 (s, 4H), 7.36 (s, 2H), 6.70 (dd, 1H)

(171) Synthesis of Compound 151: Following general procedure I, A was prepared in the following manner.

(172) ##STR00526##
Following standard procedure for Suzuki coupling, the intermediate product was obtained by reaction of 2.5 g (13.3 mmol) of 5-bromo-2-methoxy-pyridine. After purification (SiO.sub.2; Hexane/EA 30/1 to EA) 2.1 g (87% yield) of the intermediate product were obtained as white solid. A solution of 6-Methoxy-[3,4]bipyridinyl (2.1 g, 11.3 mmol) in EtOH (6 ml) and HBr 48% (12 ml) was stirred at 90 C. for 6 h. The solvent was evaporated and crude A (as hydrobromide salt) was utilized in the next step without any purification. Following general procedure H1A, compound 151 was prepared in 12% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.15 (s, 1H), 8.57 (br. s., 2H), 8.25 (d, 1H), 8.06 (dd, 1H), 7.75 (dd, 1 H), 7.66-7.73 (m, 2H), 7.62 (ddd, 1H), 7.46 (dd, 1H), 7.15 (ddd, 1H), 6.64 (d, 1H), 2.07 (s, 3H)

(173) Synthesis of Compound 152: For compound 152, A was prepared as described for compound 151. A was used in the Chan Lam reaction, following General Procedure H1A to provide compound 152 in 29% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.45-8.64 (m, 2 H), 8.18 (dd, 1H), 8.00 (dd, 1H), 7.61-7.76 (m, 2H), 7.37-7.61 (m, 5H), 6.63 (dd, 1H)

(174) Synthesis of Compound 153: For compound 153, A was prepared as described for compound 151. A was used in the Chan Lam reaction, following General Procedure H1A to provide compound 153 in 36% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.45-8.70 (m, 2 H), 8.32 (d, 1H), 8.07 (dd, 1H), 7.63-7.77 (m, 4H), 7.55 (d, 2H), 6.66 (d, 1H)

(175) Synthesis of Compound 154: Compound 154 was synthesized in the following manner. To a solution of 2-pyridone (200 mg, 2.1 mmol) and 4-bromophenyl sulfonamide (994 mg, 4.2 mmol) in 0.9 mL NMP, K.sub.2CO.sub.3 (292 mg, 2.1 mmol) and copper (I) iodide (120 mg, 30%) were added, and the mixture heated at 160 C. for 30 seconds under MW irradiation. The crude mixture was then dissolved in EA and the product precipitated out as a solid. The solid was purified by prep-HPLC to give 31.4 mg of compound 154 as a white solid (3% yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6) ppm 7.93 (m, 2H), 7.69 (ddd, 1H), 7.63 (m, 2H), 7.53 (ddd, 1H), 7.47 (s, 2H), 6.50 (dt, 1H), 6.35 (td, 1H)

(176) Synthesis of Compound 155: For compound 155, A was prepared as described for compound 139. A was used in the Chan Lam reaction, following General Procedure H1A to provide compound 155 in 14% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.13 (s, 1H), 8.03 (s, 1H), 7.86 (dd, 1H), 7.78 (d, 1H), 7.78 (dd, 1H), 7.70 (t, 1H), 7.52-7.65 (m, 1H), 7.44 (t, 1H), 7.09 (ddd, 1H), 6.54 (dd, 1H), 3.82 (s, 3H), 2.06 (s, 3H)

(177) Synthesis of Compound 156: For compound 156, A was prepared as described for compound 139. A was used in the Chan Lam reaction, following General Procedure H1A to provide compound 156 in 20% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.04 (s, 1H), 7.90-8.00 (m, 3H), 7.79 (d, 1H), 7.81 (dd, 1H), 7.68 (m, 2H), 7.49 (br. s., 2H), 6.57 (dd, 1H), 3.83 (s, 3H)

(178) Synthesis of Compound 157: For compound 157, A was prepared in the following manner.

(179) ##STR00527##
The 2-methoxy-pyridine-5-boronic acid (1.9 g, 12 mmol), the 5-bromo-pyrimidine (1.2 eq) and K.sub.2CO.sub.3 (3 eq) were dissolved in a 10:1 mixture of DME/H.sub.2O (4 mL/mmol). The solution was degassed by bubbling nitrogen for 15 min and then Pd(PPh.sub.3).sub.4 (0.05 eq) was added. The reaction mixture was heated at 90 C. for 8 h and then cooled at room temperature, diluted with EtOAc and filtered on a celite plug. The filtrate was washed with brine. The separated organic phase was dried over Na.sub.2SO4 and concentrated under reduced pressure. The obtained residue was purified by column chromatography. (SiO.sub.2; Hexanes/EtOAc 30/1 to EtOAc) 1.29 g (56% yield) of pure product were obtained as white solid. A solution of 5-(6-Methoxy-pyridin-3-yl)-pyrimidine (1.29 g, 6.9 mmol) in EtOH (4 ml) and HBr 48% (10 ml) was stirred at 90 C. for 7 h. The solvent was evaporated and the crude compound (as hydrobromide salt) was utilized in the next step without any purification. A was used in the Chan Lam reaction, following General Procedure H1A to provide compound 157 in 11% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 9.10-9.17 (m, 3H), 8.73-8.81 (m, 2H), 8.31 (dd, 1H), 8.07 (dd, 1H), 7.63-7.70 (m, 2H), 6.70 (dd, 1H)

(180) Synthesis of Compound 158: For compound 158, A was prepared as stated for compound 147. Following general procedure .[.HIA.]. .Iadd.H1A.Iaddend., compound 158 was prepared in 37% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 9.02-9.21 (m, 3H), 8.32 (d, 1H), 8.07 (dd, 1 H), 7.97 (m, 2H), 7.75 (m, 2H), 7.51 (s, 2H), 6.69 (d, 1H)

(181) Synthesis of Compound 159: Following general procedure I, A was prepared as follows.

(182) ##STR00528##
Following standard procedure for Suzuki coupling, the intermediate was obtained by reaction of 2.82 g (15 mmol) of 5-bromo-2-methoxy-pyridine. After purification (SiO.sub.2; Hexane/EA 8/2) 1.8 g (59% yield) of pure intermediate were obtained as white solid. To a magnetically stirred solution of 2-Methoxy-5-(1-methyl-1H-pyrazol-4-yl)-pyridine (1 g, 4.9 mmol), in 3 mL of EtOH, 10 mL of HBr were added. The mixture was heated at 90 C. for 4 h. The reaction was cooled at room temperature. The solvent was evaporated under vacuum, afforded 1.34 g of A (quantitative yield). Following general procedure H1A, compound 159 was prepared in 11% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.13 (s, 1H), 7.74 (dd, 1 H), 7.69 (dd, 1H), 7.52-7.62 (m, 2H), 7.44 (dd, 1H), 7.11 (ddd, 1H), 6.58 (dd, 1H), 2.39 (s, 3H), 2.22 (s, 3H), 2.06 (s, 3H)

(183) Synthesis of Compound 160: For compound 160, A was prepared as stated for compound 159. Following general procedure H1A, compound 160 was prepared in 23% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.71 (dd, 1H), 7.42-7.61 (m, 6H), 6.58 (dd, 1 H), 2.39 (s, 3H), 2.22 (s, 3H)

(184) Synthesis of Compound 161: Compound A for compound 161 was .[.preared.]. .Iadd.prepared .Iaddend.as stated for compound 138. The prepared compound A was used in General procedure H1A to provide compound 161. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.58 (dd, 1H), 7.38-7.54 (m, 5H), 6.90 (d, 1H), 6.47 (d, 1H), 3.61-3.77 (m, 4H), 2.79-2.97 (m, 4H)

(185) Synthesis of Compound 162: Compound A for compound 162 was prepared as stated for compound 138. The prepared compound A was used in General procedure H1A to provide compound 162 in 65% yield. .sup.1H NMR (300 MHz, DMSO-d.sub.6) ppm 10.16 (s, 1H), 8.22 (dd, 1H), 8.06 (dd, 1H), 7.84 (d, 1H), 7.75 (t, 1H), 7.70 (d, 1H), 7.57-7.67 (m, 1H), 7.46 (t, 1H), 7.16 (ddd, 1H), 6.64 (dd, 1H), 2.07 (s, 3H)

(186) Synthesis of Compound 163: For compound 163, A was prepared as stated for compound 159. Following general procedure H1A, compound 163 was prepared in 33% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.77 (dd, 1H), 7.45-7.71 (m, 5H), 6.60 (dd, 1 H), 2.39 (s, 3H), 2.23 (s, 3H)

(187) Synthesis of Compound 164: For compound 164, A was prepared as stated for compound 159. Following general procedure H1A, compound 164 was prepared in 25% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.71-8.78 (m, 2H), 7.78 (dd, 1H), 7.54-7.66 (m, 3H), 6.62 (dd, 1H), 2.40 (s, 3H), 2.23 (s, 3H)

(188) Synthesis of Compound 165: For compound 165, A was prepared as described for compound 139. A was used in the Chan Lam reaction, following General Procedure H1A to provide compound 165 in 4.6% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 9.25 (s, 1H), 9.04 (s, 2H), 8.08 (dd, 1H), 8.04 (d, 1H), 7.85 (dd, 1H), 7.79 (d, 1H), 6.62 (dd, 1H), 3.84 (s, 3H)

(189) Synthesis of Compound 166: Following General procedure H1A, compound 166 was synthesized. 1H NMR (300 MHz, DMSO-d.sub.6) ppm 8.65-8.79 (m, 2H), 8.03 (dd, 1H), 7.65 (dd, 1H), 7.50-7.60 (m, 2H), 6.51 (dd, 1H)

(190) Synthesis of Compound 167: Following General Procedure L1, compound 167 was prepared in 13% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.55-7.66 (m, 3H), 7.35-7.54 (m, 2H), 6.95 (d, 1H), 6.48 (d, 1H), 3.50-3.81 (m, 4H), 2.80-2.96 (m, 4H)

(191) Synthesis of Compound 168: For compound 168, A was prepared as described for compound 139. A was used in the Chan Lam reaction, following General Procedure H1A to provide compound 168 in 7.4% yield. .sup.1H NMR (300 MHz, CDCl.sub.3) ppm 8.80 (m, 2H), 7.60 (d, 1H), 7.55 (dd, 1H), 7.49 (s, 1H), 7.46 (m, 2H), 7.41 (dd, 1H), 6.73 (dd, 1H), 3.95 (s, 3 H)

(192) Synthesis of Compound 169: Following general procedure I, A was prepared as follows.

(193) ##STR00529##
Following standard procedure for Suzuki coupling, the intermediate was obtained by reaction of 2 g (10.64 mmol) of 5-bromo-2-methoxy-pyridine. After purification (SiO.sub.2; hexane/EA 20/1 to EA) 2.1 g (87% yield) of pure intermediate were obtained as white solid. A solution of 6-methoxy-3,3-bipyridine (1.7 g, 11.3 mmol) in EtOH (6 ml) and HBr 48% (12 ml) was stirred at 80 C. for 20 h. The solvent was evaporated and crude A (as hydrobromide salt) was utilized in the next step without any purification (quantitative yield). Following general procedure H1A, with the addition of triethylamine, compound 169 was prepared in 14% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.89 (br. s., 1H), 8.51 (d, 1H), 8.18 (dd, 1H), 8.07 (ddd, 1H), 8.01 (dd, 1H), 7.64-7.74 (m, 2H), 7.49-7.60 (m, 2H), 7.44 (dd, 1H), 6.65 (dd, 1H)

(194) Synthesis of Compound 170: Compound 170 is prepared as outlined in General Procedures K and J. .[.Initialy.]. .Iadd.Initially.Iaddend., 8 is prepared according to procedure K, then 9 was prepared according to General Procedure J by reaction of 2.3 g ethyl 6-oxo-6,7-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (11.1 mmol), with 2.5 g of 4-isopropoxyphenylboronic acid (13.9 mmol). After purification (SiO.sub.2; DCM:MeOH 99:1) 2.1 g (55% yield) of 9 were obtained. Next, 10 was obtained starting from 2.1 g (6.2 mmol) of 9. After filtration 1.8 g (93.3% yield) of 10 were obtained. Then, from 10 amide formation with morpholine was performed to provide compound 170 in 46.2% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.32 (s, 1H), 7.80 (d, 1H), 7.42-7.58 (m, 4H), 6.86 (s, 1H), 6.20 (d, 1 H), 3.39-3.73 (m, 4H), 1.74-1.99 (m, 4H)

(195) Synthesis of Compound 171: For compound 171, A was prepared as stated for compound 159. Following general procedure H1A, compound 171 was prepared in 5% yield.

(196) .sup.1H NMR (300 MHz, DMSO-d6) ppm 9.25 (s, 1H), 9.03 (s, 2H), 7.90 (dd, J=2.6, 0.6 Hz, 1 H), 7.65 (dd, J=9.5, 2.5 Hz, 1H), 6.66 (dd, J=9.4, 0.6 Hz, 1H), 2.41 (s, 3H), 2.24 (s, 3H)

(197) Synthesis of Compound 172: For compound 172, A was prepared as stated for compound 169. Following general procedure H1A, compound 172 was prepared in 21% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.88 (br. s., 1H), 8.51 (br. s., 1H), 8.10 (dd, 1 H), 8.05 (dt, 1H), 7.95-8.02 (m, 1H), 7.39-7.58 (m, 6H), 6.63 (d, 1H)

(198) Synthesis of Compound 173: Compound 173 was synthesized in the following manner.

(199) ##STR00530##
6-methoxynicotinaldehyde (1.0 g, 7.2 mmol) was dissolved in HBr 48% (10 mL) and EtOH (3 mL) and the solution was heated at reflux for 2 h. After evaporation of volatiles, 1.6 g of the desired pyridone intermediate was obtained. The intermediate was used in the next step without further purification. To a solution of 6-oxo-1,6-dihydropyridine-3-carbaldehyde (640 mg, 5.2 mmol) in DCM (6 mL) and DMF (2 mL), Cu(OAc).sub.2 (1.8 g, 10.4 mmol), phenyl boronic acid (1.2 g, 10.4 mmol), pyridine (0.8 g, 10.4 mmol) and finely grounded, activated 4 molecular sieves (1 g) were added. The mixture was stirred at room temperature for 24 h. A concentrated solution of NH.sub.4OH was added. The solvents were evaporated under vacuum, and the resulting crude was purified by chromatographic column (SiO.sub.2; Pet. Ether/EtOAc 10/1 to 0/1). 300 mg (48% yield) of the second intermediate were obtained as a white solid. To a solution of the second intermediate (6-oxo-1-phenyl-1,6-dihydropyridine-3-carbaldehyde, 300 mg, 2.5 mmol) in of MeOH (20 mL), glyoxal (0.89 g, 10.4 mmol) was added at 0 C. Gaseous NH.sub.3 was bubbled into the mixture at 0 C. for 1 h. The reaction was warmed at room temperature and stirred for 24 h. The solvent was evaporated under vacuum and the resulting crude was purified by flash chromatography (SiO.sub.2, Pet. Ether/EtOAc 10/1 to 0/1) and by reverse-phase preparative HPLC. 80 mg (14% yield) of compound 173 were obtained. .sup.1H NMR (300 MHz, DMSO-d6) ppm 14.16 (br. S., 1H), 8.49 (d, 1H), 8.03 (dd, 1H), 7.66 (s, 2H, 7.44-7.63 (m, 5H), 6.75 (d, 1H)

(200) Synthesis of Compound 174: For compound 174, the iodopyridone intermediate was prepared as described for compound 189, below. The iodopyridone intermediate was then used in a Stille coupling.

(201) ##STR00531##
5-iodo-1-(pyridin-4-yl)pyridin-2(1H)-one (0.120 g, 0.4 mmol) was dissolved in dry and degassed toluene (10 mL), previously degassed. Pd(PPh.sub.3).sub.4 (0.023 g, 0.02 mmol) was then added and the mixture was stirred for 10 minutes. 2-(tributylstannyl)thiazole (0.15 g, 0.4 mmol) was added and the reaction was heated at 90 C. for 4 h under nitrogen atmosphere. A large excess of a KF/H.sub.2O solution was added and the mixture was stirred for 1 h. The aqueous phase was extracted with EtOAc. The solvent was removed under reduced pressure and the crude was purified by flash chromatography (SiO.sub.2; EtOAc/MeOH 95:5) and then through titration in CH.sub.3CN. 38.7 mg (38% yield) of compound 174 were obtained as a white solid. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.65-8.86 (m, 2H), 8.31 (dd, 1H), 8.10 (dd, 1H), 7.86 (d, 1H), 7.72 (d, 1H), 7.58-7.68 (m, 2H), 6.60-6.74 (m, 1 H)

(202) Synthesis of Compound 175: For compound 175, 10 was prepared as described for compound 170, then 10 was mixed with .[.N-methylpiperdine.]. .Iadd.N-methylpiperidine .Iaddend.under the amide formation conditions of General Procedure J to provide compound 175 in 28% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.18 (s, 1H), 7.74 (d, 1H), 7.22 (m, 2H), 7.05 (m, 2H), 6.64 (s, 1 H), 6.17 (d, 1H), 4.69 (spt, 1H), 3.42-3.80 (m, 4H), 2.25-2.36 (m, 4H), 2.19 (s, 3H), 1.34 (d, 6H)

(203) Synthesis of Compound 176: For compound 176, A was prepared as stated for compound 169. Following general procedure H1A, compound 176 was prepared in 7.6% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.89 (dd, 1H), 8.76 (dd, 2H), 8.52 (dd, 1H), 8.16 (dd, 1H), 8.07 (ddd, 1H), 8.01 (dd, 1H), 7.62-7.69 (m, 2H), 7.44 (ddd, 1H), 6.67 (dd, 1H)

(204) Synthesis of Compound 177: For compound 177, 10 was prepared as described for compound 170, then 10 was mixed with 3-methoxybenzylamine under the amide formation conditions of General Procedure J to provide compound 177 in 46.5% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm

(205) Synthesis of Compound 178: For compound 178, 10 was prepared as described for compound 170, then 10 was mixed with benzylamine under the amide formation conditions of General Procedure J to provide compound 178 in 33.8% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.94 (s, 1H), 8.65 (t, 1H), 7.78 (d, 1H), 7.15-7.39 (m, 7H), 6.96-7.12 (m, 3H), 6.18 (d, 1H), 4.68 (quin, 1H), 4.42 (d, 2H), 1.33 (d, 6H)

(206) Synthesis of Compound 179: For compound 179, 10 was prepared as described for compound 170, then 10 was mixed with 2-aminothiazole under the amide formation conditions of General Procedure J to provide compound 179 in 37% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 12.23 (br. s., 1H), 11.38 (br. s., 1H), 7.83 (d, 1H), 7.49 (d, 1H), 7.40 (s, 1H), 7.29 (m, 2H), 7.19 (d, 1H), 7.10 (m, 2H), 6.25 (d, 1H), 4.71 (spt, 1H), 1.36 (d, 6H)

(207) Synthesis of Compound 180: For compound 180, 10 was prepared as described for compound 170, then 10 was mixed with .[.N-methylpiperdine.]. .Iadd.N-methylpiperidine .Iaddend.under the amide formation conditions of General Procedure J to provide compound 180 in 33.8% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.48 (s, 1H), 7.78 (d, 1H), 7.46-7.58 (m, 4H), 6.67 (s, 1H), 6.20 (d, 1H), 3.57-3.72 (m, 4H), 2.23-2.35 (m, 4H), 2.18 (s, 3H)

(208) Synthesis of Compound 181: For compound 181, 10 was prepared as described for compound 170, then 10 was mixed with .[.pyrole.]. .Iadd.pyrrole .Iaddend.under the amide formation conditions of General Procedure J to provide compound 181 in 46.2% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.32 (s, 1H), 7.80 (d, 1H), 7.42-7.58 (m, 4H), 6.86 (s, 1H), 6.20 (d, 1H), .[.3.48-3.73.]. .Iadd.3.39-3.73 .Iaddend.(m, 4H), 1.74-1.99 (m, 4H)

(209) Synthesis of Compound 182: For compound 182, 10 was prepared as described for compound 170, then 10 was mixed with morphiline under the amide formation conditions of General Procedure J to provide compound 182 in 47% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.50 (br. s., 1H), 7.78 (d, 1H), 7.44-7.59 (m, 4H), 6.71 (s, 1H), 6.20 (d, 1H), 3.48-3.75 (m, 8H)

(210) Synthesis of Compound 183: For compound 183, the general procedure outlined for compound 189 was used.

(211) ##STR00532##
The iodopyridone intermediate above was obtained by reaction of 600 mg (2.7 mmol) of 5-iodo-2-pyridone with phenylboronic acid. After purification (SiO.sub.2; Hexane/Acetate/MeOH 1/1/0 to 0/10/1). 600 mg (75% yield) of pure intermediate were obtained as a pale yellow solid. The Suzuki coupling, as outlined for compound 189, below, provided compound 183 in 38% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.98 (s, 2H), 7.91 (dd, 1H), 7.83 (dd, 1 H), 7.36-7.62 (m, 5H), 6.54 (dd, 1H)

(212) Synthesis of Compound 184: For compound 184, intermediate sulfonamide was prepared as follows.

(213) ##STR00533##
A mixture of 2-methoxy-5-aminopyridine (10 g, 0.08 mol) in AcOH (125 mL), and concentrated HCl (150 mL) was cooled at 0 C. in an ice/water bath. A solution of NaNO.sub.2 (4.0 g, 0.058 mol) in water (15 mL) was added dropwise at 0 C. The resulting mixture was stirred for 45 minutes at 0 C. In a separate round bottom flask, 150 mL of concentrated HCl was added dropwise to a sodium bisulphite solution. The gaseous SO.sub.2 thus formed was purged for 2-3 h into a third round bottom flask containing AcOH cooled at 20 C. CuCl.sub.2 (18 g) was added, and the reaction was stirred for 20 minutes at 20 C. The mixture was added dropwise to the 2-methoxy-5-aminopyridine/AcOH/concentrated HCl mixture maintained at 0 C. The reaction was allowed to warm up to room temperature and stirred overnight. The mixture was quenched with water and the solid thus formed was filtered, re-dissolved in DCM and filtered through celite. The clear solution was dried over Na.sub.2SO.sub.4 and concentrated under vacuum to afford 10.2 g (61% yield) of pure 6-methoxy-pyridine-3-sulfonyl chloride. 6-Methoxy-pyridine-3-sulfonyl chloride (5.0 g, 0.025 mol) was dissolved in DCM and cooled at 0 C. .[.Gasseous.]. .Iadd.Gaseous .Iaddend.NH.sub.3 was bubbled in the solution for 10 min. The resulting pale brown suspension was filtered and the solid was triturated with water. The resulting white solid was filtered and dried under vacuum to afford 3.2 g (70.6% yield) of pure 6-Methoxy-pyridine-3-sulfonamide. 6-Methoxy-pyridine-3-sulfonamide (0.752 g, 4.0 mmol) was dissolved in EtOH (6 mL). An excess of 48% HBr aqueous solution (12 mL) was added and the reaction was heated at 90 C. for 20 h. The solvent was removed under reduced pressure and the residual hydrobromic acid was further dried under reduced pressure, at 40 C., to provide the intermediate sulfonamide in quantitative yield. The sulfonamide was used in General Procedure H1A to provide compound 184 in 10% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.05 (dd, 1H), 7.79 (dd, 1H), 7.62 (m, 2H), 7.55 (m, 2H), 7.36 (s, 2H), 6.67 (dd, 1H)

(214) Synthesis of Compound 185: For compound 185, A was prepared in the following manner.

(215) ##STR00534##
Following the general procedure I, 5-(2-fluorophenyl)-2-methoxypyridine was obtained by reaction of 3 g (16 mmol) of 5-bromo-2-methoxy-pyridine. After purification (SiO.sub.2; Pet. Ether/EtOAc 1/1 to 0/1), 750 mg (31% yield) of pure product was obtained as a white solid. 5-(2-fluorophenyl)-2-methoxypyridine (750 mg) was dissolved in HBr 48% (10 mL) and EtOH (3 mL) and the solution was heated at reflux for 3 h. After evaporation of volatiles, 700 mg (quantitative yield) of the desired pyridone were obtained as a white solid. Following general procedure H1A, compound 185 was prepared in 58% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.13 (s, 1H), 7.69-7.90 (m, 3H), 7.51-7.65 (m, 2H), 7.20-7.50 (m, 4 H), 7.14 (dd, 1H), 6.60 (d, 1H), 2.06 (s, 3H)

(216) Synthesis of Compound 186: For compound 186, A was prepared as described for compound 185. Following general procedure H1A, compound 186 was prepared in 43% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.82-7.88 (m, 1H), 7.78 (ddd, 1H), 7.35-7.62 (m, 7H), 7.22-7.36 (m, 2H), 6.61 (dd, 1H)

(217) Synthesis of Compound 187: For compound 187, A was prepared as described for compound 185. Following general procedure H1A, compound 187 was prepared in 58% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.90 (d, 1H), 7.79 (ddd, 1H), 7.67 (m, 2H), 7.47-7.63 (m, 3H), 7.19-7.46 (m, 3H), 6.62 (dd, 1H)

(218) Synthesis of Compound 188: The synthesis of compound 188 was achieved in the following manner.

(219) ##STR00535##
5-(1H-imidazol-2-yl)pyridin-2(1H)-one (0.097 g, 0.6 mmol) was dissolved in DCM (3 mL) and N,N-dimethylformammide (3 mL). Phenylboronic acid (0.087 g, 0.72 mmol), copper(II) acetate (0.21 g, 1.2 mmol), pyridine (0.095 g, 1.2 mmol) and 4 molecular sieves were added and the reaction was stirred at room temperature in an open vessel for nine days. The reaction was monitored by UPLC-MS. At the end of the reaction, a concentrated solution of NH.sub.4OH was added. Solvents were removed at reduced pressure, and the crude was purified by flash chromatography (SiO.sub.2; EtOAc/MeOH 1:0 to 95:5). Two main products were recovered: 24 mg of compound 173 (10% yield) and 7 mg of compound 188 (2% yield). .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.81-7.94 (m, 1H), 7.75 (d, 1H), 7.71 (br. s., 1H), 7.40-7.66 (m, 8H), 7.33 (dd, 1H), 7.22-7.30 (m, 2H), 6.50 (d, 1H)

(220) Synthesis of Compound 189: For compound 189, an iodopyridone is the intermediate of the Suzuki reaction.

(221) ##STR00536##
To a solution of 5-iodo-pyridin-2-one (1 eq) in DCM (5 mL/mmol of aryl halide) and DMF (0.7 mL/mmol of aryl halide), Cu(OAc).sub.2 (2 eq), the appropriate boronic acid (1.2 eq), pyridine (2 eq) and finely grounded, activated 4 molecular sieves were added. The mixture was stirred at room temperature in an open vessel for a variable time (from 12 hours to 7 days). Fresh Boronic acid was further added in sluggish reactions. A concentrated solution of NH.sub.4OH was added. The solvents were evaporated under vacuum and the resulting crude was absorbed on silica pad and purified by flash chromatographic column (SiO.sub.2; Pet. Ether/EtOAc mixture).
800 mg (4.2 mmol) of 5-iodo-2-pyridone with 4-pyridine-boronic acid. After purification (SiO.sub.2; Pet. Ether/EtOAc/MeOH 1/1/0 to 0/10/1). 387 mg (31% yield) of pure product were obtained as a pale yellow solid. MS-ESI.sup.+: m/z=299 [MH.sup.+]

(222) ##STR00537##
For the Suzuki coupling, the iodopyridone (1 eq), the appropriate boronic acid (1.2 eq) and K.sub.2CO.sub.3 (3 eq) were dissolved in a 10:1 mixture of DME/H.sub.2O (4 mL/mmol). The solution was degassed by bubbling N.sub.2 for 15 min and then Pd(PPh.sub.3).sub.4 (0.05 eq) was added. The reaction mixture was heated at 90 C. for 18 h, after which time, BOC protecting group was completely cleaved. Mixture was cooled at room temperature, diluted with EtOAc and filtered on a celite plug. The filtrate was washed with brine. The separated organic phase was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by column chromatography (SiO.sub.2; Pet. Ether/EtOAc mixture).
Compound 189 was obtained in 42% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.71-8.92 (m, 2H), 8.00 (s, 2H), 7.98 (dd, 1H), 7.88 (dd, 1H), 7.66-7.78 (m, 2H), 6.60 (dd, 1H), 5.74 (br. s., 1H)

(223) Synthesis of Compound 190: For compound 190, the intermediate sulfonamide was prepared as described for compound 184. The intermediate sulfonamide was used in General Procedure H1A to provide compound 190 in 9% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.99 (d, 1H), 7.78 (dd, 1H), 7.41-7.64 (m, 5H), 7.36 (s, 2H), 6.66 (d, 1H)

(224) Synthesis of Compound 191: For compound 191, A was prepared as stated for compound 147. Following general procedure H1A, compound 191 was prepared. .sup.1H NMR (300 MHz, DMSO-d6) ppm 9.13 (s, 1H), 9.12 (s, 1H), 8.76 (d, 1H), 8.67 (dd, 1H), 8.35 (dd, 1H), 8.08 (dd, 1H), 8.02 (ddd, 1H), 7.61 (ddd, 1H), 6.70 (dd, 1H)

(225) Synthesis of Compound 192: For compound 192, A was prepared as stated for compound 169. Following general procedure H1A, compound 192 was prepared in 15% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.89 (d, 1H), 8.52 (dd, 1H), 8.17 (d, 1H), 8.06 (ddd, 1H), 8.01 (dd, 1H), 7.96 (m, 2H), 7.74 (m, 2H), 7.49 (s, 2H), 7.43 (ddd, 1H), 6.66 (d, 1H)

(226) Synthesis of Compound 193: For compound 193, the iodopyridone intermediate was prepared as described for compound 189 and 183, above. The iodopyridone was then used in a Stille coupling.

(227) ##STR00538##
5-iodo-1-phenylpyridin-2(1H)-one (0.088 g, 0.3 mmol) was dissolved in dry and degassed toluene (7.5 mL/mmol). The catalyst was then added (0.017 g, 0.015 mmol) and the mixture was stirred for 10 minutes. 2-(tributylstannyl)oxazole (0.107 g, 0.3 mmol) was added and the reaction was heated at 90 C. for 18 h under nitrogen atmosphere. Conc. NH.sub.4OH was added. The solvent was removed at reduced pressure and the crude was purified by flash chromatography (SiO.sub.2; Pet. Ether/EtOAc 1:1) and then through titration in di-isopropylether. The residual product present in the mother liquor was recovered after purification with preparative. 36 mg (30% yield) of compound 193 were obtained as a pale yellow solid. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.19 (dd, 1H), 8.14 (d, 1H), 8.02 (dd, 1H), 7.43-7.61 (m, 5H), 7.32 (d, 1H), 6.66 (dd, 1H)

(228) Synthesis of Compound 194: For compound 194, 10 was prepared as described for compound 170, then 10 was mixed with .[.pyrole.]. .Iadd.pyrrole .Iaddend.under the amide formation conditions of General Procedure J to provide compound 194 in 29% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.72 (br. s., 1H), 7.76 (d, 1H), 7.22 (m, 2H), 7.05 (m, 2H), 6.85 (s, 1 H), 6.19 (d, 1 H), 4.69 (quin, 1H), 3.39-3.72 (m, 4H), 1.78-1.95 (m, 4H), 1.34 (d, 6H)

(229) Synthesis of Compound 195: For compound 195, 10 was prepared as described for compound 170, then 10 was mixed with 3-methoxyaniline under the amide formation conditions of General Procedure J to provide compound 195 in 75% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.26 (br. s., 1H), 9.86 (s, 1H), 7.83 (d, 1H), 7.37-7.41 (m, 1H), 7.14-7.32 (m, 5H), 7.08 (m, 2H), 6.63 (ddd, 1H), 6.22 (d, 1H), 4.70 (quin, 1H), 3.73 (s, 3 H), 1.35 (d, 6H)

(230) Synthesis of Compound 196: For compound 196, 10 was prepared as described for compound 170, then 10 was mixed with 3-phenoxyaniline under the amide formation conditions of General Procedure J to provide compound 196 in 20% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.64 (s, 1H), 9.94 (s, 1H), 7.86 (d, 1H), 7.28-7.57 (m, 10 H), 7.15 (dddd, 1H), 7.04 (m, 2H), 6.72 (ddd, 1H), 6.24 (d, 1H)

(231) Synthesis of Compound 197: For compound 197, 10 was prepared as described for compound 170, then 10 was mixed with 3-aminobenzenesulfonamide under the amide formation conditions of General Procedure J to provide compound 197 in 21.4% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.31 (s, 1H), 10.16 (s, 1H), 8.12-8.18 (m, 1H), 7.89-8.01 (m, 1H), 7.84 (d, 1H), 7.43-7.57 (m, 2H), 7.30-7.35 (m, 3H), 7.27 (m, 2H), 7.09 (m, 2H), 6.23 (d, 1H), 4.71 (quin, 1H), 1.35 (d, 6H)

(232) Synthesis of Compound 198: For compound 198, 10 was prepared as described for compound 170, then 10 was mixed with 3-methylaminopyridine under the amide formation conditions of General Procedure J to provide compound 198 in 28.4% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.02 (s, 1H), 8.62-8.92 (m, 1H), 8.35-8.58 (m, 2H), 7.79 (d, 1 H), 7.17-7.34 (m, 4H), 6.98-7.14 (m, 3H), 6.19 (d, 1H), 4.68 (quin, 1H), 4.43 (d, 2H), 1.33 (d, 6H)

(233) Synthesis of Compound 199: For compound 199, 10 was prepared as described for compound 170, then 10 was mixed with 3-phenoxyaniline under the amide formation conditions of General Procedure J to provide compound 199 in 47% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.28 (s, 1H), 9.92 (s, 1H), 7.81 (d, 1H), 7.35-7.49 (m, 4H), 7.31 (dd, 1H), 7.20-7.27 (m, 3H), 7.10-7.19 (m, 1H), 6.98-7.10 (m, 4H), 6.72 (.[.ddd, 1.]..Iadd.ddd, 1 H.Iaddend.), 6.21 (d, 1H), 4.69 (quin, 1H), 1.34 (d, 6H)

(234) Synthesis of Compound 200: Following General Procedure L2, compound 200 was prepared in 10% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.45-7.55 (m, 2H), 7.34-7.45 (m, 4H), 6.57 (d, 1H), 6.45 (dd, 1H), 2.99-3.12 (m, 4H), 1.78-1.97 (m, 4H)

(235) Synthesis of Compound 201: For compound 201, A was prepared as described for compound 185. Following general procedure H1A, compound 201 was prepared in 13% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 9.25 (s, 1H), 9.07 (s, 2H), 8.06 (d, 1H), 7.79-7.88 (m, 1H), 7.55-7.65 (m, 1H), 7.20-7.47 (m, 3H), 6.66 (dd, 1H)

(236) Synthesis of Compound 202: Compound A for compound 202 was prepared as stated for compound 116. The prepared compound A was used in General procedure H1A to provide compound 202 in 8% yield. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.27 (s, 1H), 8.91 (s, 2 H), 7.29-7.35 (m, 1H), 7.11 (dt, 1H), 6.71 (d, 1H), 1.63-1.83 (m, 1H), 0.86-1.02 (m, 2 H), 0.51-0.69 (m, 2H)

(237) Synthesis of Compound 203: For compound 203, the iodopyridone intermediate was obtained as described for compound 189.

(238) ##STR00539##
The product was obtained by reaction of 500 mg (2.25 mmol) of 5-iodo-2-pyridone with 4-trifluoromethoxy-phenyl-boronic acid. After flash chromatography (SiO2; Pet. Ether/EtOAc 2:1) 300 mg (35% yield) of the intermediate were obtained as a white solid. MS-ESI.sup.+: m/z=380.9 [MH.sup.+] The iodopyridone was then used in a Stille coupling.

(239) ##STR00540##
5-iodo-1-(4-(trifluoromethoxy)phenyl)pyridin-2(1H)-one (0.19 g, 0.5 mmol) was dissolved in dry and degassed toluene (10 mL). Pd(PPh.sub.3).sub.4 (0.029 g, 0.025 mmol) was then added and the mixture was stirred for 10 minutes. 2-(tributylstannyl) thiazole (0.187 g, 0.5 mmol) was added and the reaction was heated at 90 C. for 4 h under nitrogen atmosphere. A large excess of a KF/H.sub.2O solution was added and the mixture was stirred for 1 h. The aqueous phase was extracted with EtOAc. The solvent was removed under reduced pressure and the crude was purified by flash chromatography (SiO.sub.2; Pet. Ether/EtOAc 7:3 to Hex/EtOAc 1:1) and then through titration in a Pet. Ether/EtOAc mixture. 62.5 mg (37% yield) of compound 203 were obtained as a white solid. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.30 (dd, 1H), 8.09 (dd, 1H), 7.85 (d, 1H), 7.60-7.75 (m, 3H), 7.55 (m, 2H), 6.66 (dd, 1H)

(240) Synthesis of Compound 204: For compound 204, 10 was prepared as described for compound 170, then 10 was mixed with 3-chloroaniline under the amide formation conditions of General Procedure J to provide compound 204 in 32.3% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.69 (s, 1H), 10.04 (s, 1H), 7.82-7.97 (m, 2H), 7.63 (ddd, 1 H), 7.46-7.59 (m, 4H), 7.27-7.41 (m, 2H), 7.10 (ddd, 1H), 6.26 (d, 1H)

(241) Synthesis of Compound 205: For compound 205, 10 was prepared as described for compound 170, then 10 was mixed with 2-methylaminotetrahydrofuran under the amide formation conditions of General Procedure J to provide compound 205 in 16.5% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.15-11.41 (m, 1H), 8.11-8.29 (m, 1H), 7.81 (d, 1 H), 7.47-7.63 (m, 4H), 7.04 (d, 1H), 6.20 (d, 1H), 3.83-3.97 (m, 1H), 3.68-3.81 (m, 1 H), 3.53-3.67 (m, 1H), 3.18-3.37 (m, 2H), 1.69-1.98 (m, 3H), 1.43-1.60 (m, 1H)

(242) Synthesis of Compound 206: For compound 206, 10 was prepared as described for compound 170, then 10 was mixed with 4-phenoxyaniline under the amide formation conditions of General Procedure J to provide compound 206 in 34.7% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.25 (s, 1H), 9.91 (s, 1H), 7.83 (d, 1H), 7.60-7.75 (m, 2H), 7.31-7.44 (m, 2H), 7.19-7.31 (m, 3H), 7.04-7.16 (m, 3H), 6.90-7.04 (m, 4H), 6.22 (d, 1H), 4.64-4.76 (m, 1H), 1.35 (d, 6H)

(243) Synthesis of Compound 207: For compound 207, general procedures K and J were used to obtain compound 207 in 70% yield. .sup.1H NMR (300 MHz, CDCl.sub.3): ppm 1.34 (t, J=7.1 Hz, 3H); 4.30 (q, J=7.1 Hz, 2H); 6.47 (d, J=9.3 Hz, 1H); 7.03 (d, J=2.4 Hz, 1H); 7.26-7.43 (m, 2H); 7.57-7.69 (m, 4H); 8.27 (s, 1H); MS-ESI: m/z=283.1 .[.[M+1]+.]. .Iadd.[M+1].sup.+.Iaddend.

(244) Synthesis of Compound 208: For compound 208, general procedures K and J were used to obtain compound 208 in 41% yield. .sup.1H NMR (300 MHz, CDCl.sub.3): ppm 1.34 (t, J=7.2 Hz, 3H); 4.30 (q, J=7.1 Hz, 2H); 6.54 (d, J=9.3 Hz, 1H); 6.79 (d, J=8.7 Hz, 2H); 7.01-7.11 (m, 3H); 7.76 (d, J=9.0 Hz, 1H); 7.89-8.57 (br., 1H); 8.425 (s, 1H); MS-ESI: m/z=299.0 [M+1].sup.+

(245) Synthesis of Compound 209: For compound 209, the following synthesis was used.

(246) ##STR00541## ##STR00542##
To a mixture of 209-1 (45.0 g, 381.4 mmol), para-toluene-sulfonyl chloride (80.1 g, 421.6 mmol) and a catalytic amount of tetrabutyl ammonium bromide (TBABr) in toluene (540 ml) was added aq. NaOH (288.0 g in 900 ml water, 7.2 mol). The biphasic solution was stirred at ambient temperature for 4 h, and then extracted twice with toluene. The organic phase was dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The crude product was triturated in ethyl acetate/petroleum ether (V:V=1:20) and filtrated to afford the compound 209-2 (90 g, 87% yield). MS-ESI: m/z=273.1 [M+1].sup.+
A solution of 209-2 (50.0 g, 183.8 mmol) in dry THF cooled to 78 C. and n-BuLi (81 ml, 2.5 M in hexane) was added over 20 minutes. The resulted solution was maintained at 78 C. for 1 h, and then a solution of BrCl.sub.2CCCl.sub.2Br (71.0 g, 220.5 mmol) in dry THF was added. The mixture was stirred 78 C. for 30 min and allowed to warm slowly to room temperature. The solvent was removed under vacuum and the residue was partitioned between EtOAc and water. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The crude product was purified by column chromatography (5% ethyl acetate in petroleum ether to 20% ethyl acetate in petroleum ether as the eluent) to afford 209-3 (37 g, 58% yield). MS-ESI: m/z=351.0 [M+1].sup.+
A mixture of 209-3 (30 g, 0.085 mol), methanol (.[.85OmL.]..Iadd.850 mL.Iaddend.) and aqueous potassium hydroxide (5 mol/L, 100 mL) was heated under reflux overnight. The majority of the solvent was removed under vacuum, and the residue was partitioned between EtOAc and water. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated to give 209-4 (24 g, 80% yield) which was used without further purification. .[.1H.]. .Iadd..sup.1H .Iaddend.NMR (400 MHz, DMSO): 6.550 (s, 1H); 7.039 (dd, J=5.2 Hz, J=3.2 Hz, 1H); 7.857 (dd, J=1.6 Hz, J=3.2 Hz, 1H); 8.155 (q, J=1.6 Hz, 1H); 12.418 (br, 1H)
mCPBA (14.0 g, 81.4 mmol) was added into a solution of 209-4 (8.0 g, 40.8 mmol) in THF (140 ml) at 0 C., and then the reaction was warmed up the room temperature for 1 h and quenched with saturated Na.sub.2S.sub.2O.sub.3. The solution was concentrated after filtering. The crude was purified by column chromatography (0-10% methanol in ethyl acetate as the eluent) to afford 209-5 (6.3 g, 73% yield). .sup.1H NMR (400 MHz, DMSO): 6.698 (s, 1H); 7.055 (t, J=6.4 Hz, 1H); 7.660 (d, J=6.0 Hz, 1H); 8.099 (d, J=6.0 Hz, 1H)
A mixture of 209-5 (3.5 g, 16.5 mmol) and acetic acid anhydride was heated at its reflux temperature for 1.5 h. The solution was then evaporated. The residue was mixed with methanol and Et.sub.3N at room temperature for 2 h. The solution was concentrated and the residue was partitioned between EtOAc and water. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The crude product was purified by column chromatography (10% ethyl acetate/petroleum) to afford 209-6 (1.4 g, 40% yield). .sup.1H NMR (300 MHz, DMSO): 6.337 (d, J=8.1 Hz, 1H); 6.359 (s, 1H); 7.662 (d, J=8.1 Hz, 1H) MS-ESI: m/z=214.1 [M+1].sup.+
A solution of 209-6 (150 mg, 0.71 mmol) and triethylamine (470 mg, 4.2 mmol) in THF (5 mL) was stirred for 15 min before the addition of (Boc).sub.2O (0.907 g, 4.2 mmol). The solution was stirred at room temperature overnight. Most of the solvent was removed under vacuum to get a residue, then it was partitioned between water (50 mL) and DCM (100 mL), the organic layer was separated and the aqueous layer was extracted with DCM (50 mL2). The combined organic layer was washed with water (100 mL) and brine (100 mL), dried over Na.sub.2SO.sub.4 and concentrated to give a residue, which was purified by Prep-TLC (25% ethyl acetate in petroleum ether as the eluent) to give 209-7 (250 mg, yield 85%). .sup.1H NMR (400 MHz, CDCl3): 1.558 (s, 9H); 1.684 (s, 9H); 6.673(s, 1H); 6.970 (d, J=8.4 Hz, 1H); 7.824 (d, J=8.4 Hz, 1H); MS-ESI: m/z=436.9 [M+23].sup.+
A mixture of 209-7 (550 mg, 1.33 mmol), K.sub.2CO.sub.3 (200 mg, 1.45 mmol) and methanol (8 mL) was stirred at rt for 1 h. Methanol was removed before the addition of water (50 mL), then it was extracted with DCM (50 mL3). Combined DCM was washed with water and brine, dried over Na.sub.2SO.sub.4 and concentrated to give a residue, which was isolated by prep-TLC (50% ethyl acetate in petroleum ether as the eluent) to give 209-8 (130 mg, 31.2%) as a white solid.

(247) .sup.1H NMR (400 MHz, CDCl3): 1.699 (s, 9H); 6.404(d, J=9.2 Hz, 1H); 6.488 (s, 1H); 7.518 (d, J=9.2 Hz, 1H); MS-ESI: m/z=352.9 [M+39].sup.+

(248) A mixture of 209-8 (50 mg, 0.16 mmol), 4-isopropoxylbenzyl boric acid (100 mg, 0.73 mmol), pyridine (0.26 mL, 3.2 mmol) and anhydrous Cu(OAC).sub.2 (10 mg, 0.05 mmol) in DCM (2 mL) was stirred over night open to air. The mixture was filtrated and evaporated to give a residue, which was isolated by Prep-TLC (20% ethyl acetate in petroleum ether as the eluent) to give 209-9 (50 mg, 78.6%) as a white solid. .sup.1H NMR (400 MHz, CDCl3): 1.345 (d, J=8.0 Hz, 6H); 1.412 (s, 1H); 4.489 (m, J=8.0 Hz, 1H); 6.596 (s, 1H); 6.785 (d, J=11.2 Hz, 1H); 6.852-6.906 (m, 2H); 7.031-7.085 (m, 2H); 7.725 (d, J=11.2 Hz, 1H); MS-ESI: m/z=448.8 [M+1].sup.+
A solution of 209-9 (50 mg, 0.112 mmol) in DCM/TFA (V:V=1:1) was stirred at room temperature for 3 h. All the solvents were removed by evaporation to give a residue. It was isolated by Prep-TLC (25% ethyl acetate in petroleum ether as the eluent) to give compound 209 (30 mg, 68.5%) as a white solid. .sup.1H NMR (400 MHz, CDCl3): 1.350 (d, J=6.0 Hz, 6H); 4.509 (m, J=6.0 Hz, 1H); 6.440 (d, J=2.0 Hz, 1H); 6.674 (d, J=8.4 Hz, 1H); 6.899 (d, J=8.8 Hz, 2H); 7.053 (d, J=8.8 Hz, 2H); 7.774 (d, J=8.4 Hz, 1H); 8.683 (br, 1H); MS-ESI: m/z=349.2 [M+1].sup.+

(249) Synthesis of Compound 210: For compound 210, compound 247 was used as an intermediate in general procedure J amide formation to form compound 210 in 20.4% yield.

(250) .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.65 (br. s., 1H), 9.86 (s, 1H), 7.87 (d, 1H), 7.45-7.63 (m, 4H), 7.38-7.44 (m, 1H), 7.14-7.34 (m, 3H), 6.63 (ddd, 1H), 6.24 (d, 1H), 3.73 (s, 3H)

(251) Synthesis of Compound 211: For compound 211, compound 216 was used as an intermediate in general procedure J amide formation to form compound 211 in 52% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.53 (br. s., 1H), 9.84 (br. s., 1H), 7.85 (d, 1H), 7.34-7.49 (m, 5H), 7.29 (s, 1H), 7.16-7.27 (m, 2H), 6.56-6.71 (m, 1H), 6.23 (d, 1H), 3.73 (s, 3H)

(252) Synthesis of Compound 212: For compound 212, compound 216 was used as an intermediate in general procedure J amide formation to form compound 212 in 27.9% yield.

(253) .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.18 (br. s., 1H), 7.70-7.85 (m, 1H), 7.26-7.47 (m, 4H), 6.85 (s, 1H), 6.08-6.28 (m, 1H), 3.39-3.72 (m, 4H), 1.76-1.94 (m, 4H)

(254) Synthesis of Compound 213: For compound 213, general procedures K and J were used to obtain compound 213 in 61% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 12.49 (br. s., 1H), 7.92 (d, 2H), 7.82 (d, 1H), 7.61 (d, 2H), 7.01 (s, 1H), 6.24 (d, 1H)

(255) Synthesis of Compound 214: For compound 214, compound 216 was used as an intermediate in general procedure J amide formation to form compound 214 in 17.5% yield.

(256) .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.17 (br. s., 1H), 8.63 (br. s., 1H), 7.80 (d, 1H), 7.19-7.46 (m, 9H), 7.04 (s, 1H), 6.18 (d, 1H), 4.42 (d, 2H)

(257) Synthesis of Compound 215: For compound 215, general procedures K and J were used to obtain compound 215 in 93.3% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 12.41 (s, 1H), 7.76 (d, 1H), 7.20 (m, 2H), 7.04 (m, 2H), 6.97 (s, 1H), 6.20 (d, 1 H), 4.68 (quin, 1H), 1.34 (d, 6H)

(258) Synthesis of Compound 216: For compound 216, general procedures K and J were used to obtain compound 216 in 93.6% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.77 (d, 1H), 7.24-7.50 (m, 4H), 6.89 (s, 1H), 6.19 (d, 1H)

(259) Synthesis of Compound 217: For compound 217, compound 216 was used as an intermediate in general procedure J amide formation to form compound 217 in 31.6% yield.

(260) .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.60 (br. s., 1H), 10.11 (br. s., 1H), 8.18 (s, 1H), 7.92 (br. s., 1H), 7.84 (d, 1H), 7.22-7.55 (m, 9H), 6.20 (d, 1H)

(261) Synthesis of Compound 218: For compound 218, compound 216 was used as an intermediate in general procedure J amide formation to form compound 218 in 30.7% yield.

(262) .sup.1H NMR (300 MHz, DMSO-d6) pm 11.40 (br. s., 1H), 7.76 (d, 1H), 7.27-7.50 (m, 4 H), 6.66 (s, 1H), 6.18 (d, 1H), 3.51-3.75 (m, 4H), 2.23-2.37 (m, 4H), 2.18 (s, 3H)

(263) Synthesis of Compound 219: For compound 219, compound 213 was used as an intermediate in general procedure J amide formation to form compound 219 in 21.9% yield.

(264) .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.71 (s, 1H) 9.87 (s, 1H) 7.94 (d, 2H) 7.89 (d, 1H) 7.65 (d, 2H) 7.37-7.45 (m, 1H) 7.33 (s, 1H) 7.14-7.29 (m, 2H) 6.57-6.69 (m, 1H) 6.26 (d, 1H) 3.73 (s, 3H)

(265) Synthesis of Compound 220: For compound 220, compound 213 was used as an intermediate in general procedure J amide formation to form compound 220 in 47.5% yield.

(266) .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.53 (br. s., 1H) 7.92 (m, 2H) 7.80 (d, 1H) 7.62 (m, 2H) 6.72 (s, 1H) 6.21 (d, 1H) 3.49-3.72 (m, 8H)

(267) Synthesis of Compound 221: For compound 221, compound 247 was used as an intermediate in general procedure J amide formation to form compound 221 in 37.9% yield.

(268) .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.63 (s, 1H), 9.93 (s, 1H), 7.88 (d, 1H), 7.65-7.76 (m, 2H), 7.47-7.62 (m, 4H), 7.32-7.42 (m, 2H), 7.31 (d, 1H), 7.05-7.16 (m, 1H), 6.91-7.05 (m, 4H), 6.25 (d, 1H)

(269) Synthesis of Compound 222: For compound 222, compound 216 was used as an intermediate in general procedure J amide formation to form compound 222 in 30.9% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.51 (s, 1H) 9.91 (s, 1H) 7.86 (d, 1H) 7.65-7.76 (m, 2H) 7.32-7.50 (m, 6H) 7.29 (s, 1H) 7.06-7.15 (m, 1H) 6.92-7.05 (m, 4H) 6.24 (d, 1 H)

(270) Synthesis of Compound 223: For compound 223, general procedure K is modified as follows.

(271) ##STR00543##
To a solution of 4 (5 g crude) in dry DMF (50 mL) anhydrous potassium carbonate (10.9 g, 79 mmol) and methyl iodide (2.5 mL, 0.039 mol) were added. The reaction was stirred at room temperature overnight. The mixture was filtered and the residue was washed with methanol. Mother liquors were concentrated and the obtained crude product was purified by column chromatography (SiO.sub.2, hexanes:EtOAc 7:3) to obtain 1.5 g of a yellow solid (9:1 mixture of 1-Methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid methyl ester and 1-Methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester. This intermediate was then used in the subsequent reactions of general procedure K to obtain a methyl version of intermediate 8 for use in general procedure J. Following this modified procedure, compound 223 was obtained in 94% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 12.98 (br. s., 1H) 8.18 (d, 1H) 7.44 (m, 2H) 7.36 (m, 2H) 7.20 (s, 1H) 6.88 (d, 1H) 3.82 (s, 3H)

(272) Synthesis of Compound 224: For compound 224, compound 247 was used as an intermediate in general procedure J amide formation to form compound 224 in 13.4% yield.

(273) .sup.1H NMR (300 MHz, DMSO-d6) ppm 1.36 (br. s., 1H) 8.65 (t, 1H) 7.82 (d, 1H) 7.46-7.59 (m, 4H) 7.21 (t, 1H) 7.07 (s, 1H) 6.73-6.88 (m, 3H) 6.21 (d, 1H) 4.39 (d, 2H) 3.72 (s, 3 H)

(274) Synthesis of Compound 225: For compound 225, general procedures K and J were used to obtain compound 225 in 83.7% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.78 (d, 1H), 7.60 (m, 2H), 7.38 (m, 2H), 6.94 (s, 1H), 6.20 (d, 1H)

(275) Synthesis of Compound 226: For compound 226, compound 213 was used as an intermediate in general procedure J amide formation to form compound 226 in 23.5% yield.

(276) .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.44 (s, 1H) 7.91 (m, 2H) 7.82 (d, 1H) 7.60 (m, 2H) 6.87 (s, 1H) 6.21 (d, 1H) 3.39-3.73 (m, 4H) 1.77-1.98 (m, 4H)

(277) Synthesis of Compound 227: For compound 227, compound 216 was used as an intermediate in general procedure J amide formation to form compound 227 in 37.2% yield.

(278) .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.41 (br. s., 1H) 7.76 (d, 1H) 7.29-7.47 (m, 4H) 6.62-6.74 (m, 1H) 6.19 (d, 1H) 3.51-3.72 (m, 8H)

(279) Synthesis of Compound 228: For compound 228, compound 216 was used as an intermediate in general procedure J amide formation to form compound 228 in 47.6% yield.

(280) .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.58 (br. s., 1H) 10.01 (br. s., 1H) 7.80-7.94 (m, 2 H) 7.56-7.66 (m, 1H) 7.23-7.50 (m, 6H) 7.02-7.15 (m, 1H) 6.23 (d, 1H)

(281) Synthesis of Compound 229: For compound 229, compound 213 was used as an intermediate in general procedure J amide formation to form compound 229 in 19% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.55 (br. s., 1H), 7.92 (m, 2H), 7.78 (d, 1H), 7.62 (m, 2 H), 6.68 (s, 1H), 6.19 (d, 1H), 3.52-3.75 (m, 4H), 2.23-2.35 (m, 4H), 2.18 (s, 3H)

(282) Synthesis of Compound 230: For compound 230, compound 213 was used as an intermediate in general procedure J amide formation to form compound 230 in 23% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.43 (br. s., 1H), 7.92 (m, 2H), 7.80 (d, 1H), 7.62 (m, 2 H), 6.70 (s, 1H), 6.13-6.27 (m, 1H), 4.51-4.72 (m, 1H), 2.92 (s, 3H), 1.12 (d, 6H)

(283) Synthesis of Compound 231: For compound 231, compound 216 was used as an intermediate in general procedure J amide formation to form compound 231 in 23% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.23 (br. s., 1H), 7.77 (d, 1H), 7.27-7.48 (m, 4H), 6.69 (s, 1H), 6.18 (d, 1H), 4.45-4.73 (m, 1H), 2.92 (s, 3H), 1.13 (d, 6H)

(284) Synthesis of Compound 232: For compound 232, compound 213 was used as an intermediate in general procedure J amide formation to form compound 232 in 36% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.37 (br. s., 1H), 8.19 (br. s., 1H), 7.94 (m, 2H), 7.82 (d, 1H), 7.63 (m, 2H), 7.04 (s, 1H), 6.20 (d, 1H), 3.83-3.98 (m, 1H), 3.68-3.80 (m, 1H), 3.53-3.66 (m, 1H), 3.13-3.36 (m, 2H), 1.67-1.99 (m, 3H)

(285) Synthesis of Compound 233: For compound 233, compound 225 was used as an intermediate in general procedure J amide formation to form compound 233 in 19% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.34 (br. s., 1H), 7.77 (d, 1H), 7.61 (m, 2H), 7.39 (m, 2 H), 6.69 (s, 1H), 6.18 (d, 1H), 4.45-4.72 (m, 1H), 2.92 (s, 3H), 1.13 (d, 6H)

(286) Synthesis of Compound 234: For compound 234, compound 213 was used as an intermediate in general procedure J amide formation to form compound 234 in 35% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.80 (br. s., 1H), 10.01 (br. s., 1H), 7.81-8.01 (m, 4H), 7.56-7.70 (m, 3H), 7.26-7.42 (m, 2H), 7.03-7.16 (m, 1H), 6.25 (d, 1H)

(287) Synthesis of Compound 235: For compound 235, compound 225 was used as an intermediate in general procedure J amide formation to form compound 235 in 19% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.34 (br. s., 1H), 7.77 (d, 1H), 7.61 (m, 2H), 7.39 (m, 2 H), 6.69 (s, 1H), 6.18 (d, 1H), 4.45-4.72 (m, 1H), 2.92 (s, 3H), 1.13 (d, 6H)

(288) Synthesis of Compound 236: For compound 236, compound 213 was used as an intermediate in general procedure J amide formation to form compound 236 in 45% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.39 (br. s., 1H), 8.44 (br. s., 1H), 7.91 (m, 2H), 7.83 (d, 1H), 7.61 (m, 2H), 7.25-7.38 (m, 4H), 7.17-7.24 (m, 1H), 7.14 (s, 1 H), 6.21 (d, 1H), 4.99-5.21 (m, 1H), 1.44 (d, 3H)

(289) Synthesis of Compound 237: For compound 237, compound 225 was used as an intermediate in general procedure J amide formation to form compound 237 in 25.1% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.76 (d, 1H), 7.60 (m, 2H), 7.39 (m, 2H), 6.69 (s, 1 H), 6.17 (d, 1H), 3.52-3.73 (m, 8H)

(290) Synthesis of Compound 238: For compound 238, compound 213 was used as an intermediate in general procedure J amide formation to form compound 238 in 38% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.44 (br. s., 1H), 8.62 (br. s., 1H), 7.92 (m, 2H), 7.82 (d, 1H), 7.63 (m, 2H), 7.15-7.36 (m, 5H), 6.92-7.14 (m, 1H), 6.02-6.29 (m, 1H), 4.41 (d, 2H)

(291) Synthesis of Compound 239: For compound 239, compound 215 was used as an intermediate in general procedure J amide formation to form compound 239 in 34% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.91 (s, 1H), 7.75 (d, 1H), 7.22 (m, 2H), 7.06 (m, 2H), 6.67 (s, 1H), 6.17 (d, 1H), 4.64-4.75 (m, 1H), 4.53-4.64 (m, 1H), 2.91 (s, 3H), 1.33 (d, 6H), 1.12 (d, 6H)

(292) Synthesis of Compound 240: For compound 240, compound 215 was used as an intermediate in general procedure J amide formation to form compound 240 in 20% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.88 (s, 1H), 8.22 (t, 1H), 7.76 (d, 1H), 7.25 (m, 2H), 7.08 (m, 2H), 6.99 (s, 1H), 6.18 (d, 1H), 4.58-4.80 (m, 1H), 3.81-3.95 (m, 1H), 3.67-3.81 (m, 1H), 3.53-3.67 (m, 1H), 3.12-3.37 (m, 2H), 1.67-1.96 (m, 3H), 1.41-1.60 (m, 1H), 1.34 (d, 6H)

(293) Synthesis of Compound 241: For compound 241, compound 213 was used as an intermediate in general procedure J amide formation to form compound 241 in 25.3% yield.

(294) .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.23-8.33 (m, 1H), 7.84-8.00 (m, 3H), 7.72-7.80 (m, 1H), 7.69 (d, 2H), 7.49-7.58 (m, 2H), 7.14 (br. s., 1H), 6.10 (br. s., 1 H), 3.14 (s, 3H)

(295) Synthesis of Compound 242: For compound 242, compound 225 was used as an intermediate in general procedure J amide formation to form compound 242 in 31.8% yield.

(296) .sup.1H NMR (300 MHz, DMSO-d6) ppm 12.25 (br. s., 1H), 11.67 (br. s., 1H), 7.86 (d, 1H), 7.66 (m, 2H), 7.39-7.56 (m, 4H), 7.20 (d, 1H), 6.26 (d, 1H)

(297) Synthesis of Compound 243: For compound 243, compound 225 was used as an intermediate in general procedure J amide formation to form compound 243 in 31.8% yield.

(298) .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.50 (br. s., 1H), 7.75 (d, 1H), 7.59 (m, 2H), 7.39 (m, 2H), 6.65 (s, 1H), 6.15 (d, 1H), 3.53-3.80 (m, 4H), 2.23-2.35 (m, 4 H), 2.18 (s, 3H)

(299) Synthesis of Compound 244: For compound 244, compound 225 was used as an intermediate in general procedure J amide formation to form compound 244 in 19.7% yield.

(300) .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.32 (br. s., 1H), 7.79 (d, 1H), 7.60 (m, 2H), 7.38 (m, 2H), 6.86 (s, 1H), 6.20 (d, 1H), 3.56 (br. s., 4H), 1.87 (br. s., 4H)

(301) Synthesis of Compound 245: For compound 245, compound 225 was used as an intermediate in general procedure J amide formation to form compound 245 in 26.7% yield.

(302) .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.68 (br. s., 1H), 10.03 (s, 1H), 7.80-7.94 (m, 2H), 7.58-7.69 (m, 3H), 7.39-7.47 (m, 2H), 7.27-7.39 (m, 2H), 7.10 (ddd, 1H), 6.24 (d, 1H)

(303) Synthesis of Compound 246: For compound 246, compound 225 was used as an intermediate in general procedure J amide formation to form compound 246 in 31.9% yield.

(304) .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.62 (s, 1H), 9.92 (s, 1H), 7.87 (d, 1H), 7.66-7.75 (m, 2H), 7.58-7.66 (m, 2H), 7.32-7.48 (m, 4H), 7.29 (s, 1H), 7.05-7.17 (m, 1H), 6.92-7.05 (m, 4H), 6.24 (d, 1H)

(305) Synthesis of Compound 247: For compound 247, general procedures K and J were used to obtain compound 247 in 81.5% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.80 (d, 1H), 7.40-7.60 (m, 4H), 6.99 (s, 1H), 6.22 (d, 1H)

(306) Synthesis of Compound 248: For compound 248, general procedures K and J were used to obtain compound 248 in 90% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 12.32 (br. s., 1H), 9.69 (br. s., 1H), 7.76 (d, 1H), 7.33 (dd, 1H), 6.97 (s, 1H), 6.90 (ddd, 1H), 6.72 (ddd, 1H), 6.67 (t, 1H), 6.20 (d, 1H)

(307) Synthesis of Compound 249: For compound 249, compound 225 was used as an intermediate in general procedure J amide formation to form compound 249 in 15.2% yield.

(308) .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.62 (t, 1H), 7.81 (d, 1H), 7.62 (m, 2H), 7.41 (m, 2 H), 7.22 (t, 1H), 7.06 (s, 1H), 6.73-6.88 (m, 3H), 6.20 (d, 1H), 4.39 (d, 2H), 3.72 (s, 3H)

(309) Synthesis of Compound 250: For compound 250, compound 213 was used as an intermediate in general procedure J amide formation to form compound 250 in 34.2% yield.

(310) .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.12 (s, 1H), 8.76 (br. s., 1H), 8.32-8.58 (m, 2 H), 7.92 (m, 2H), 7.84 (d, 1H), 7.63 (m, 2H), 7.21-7.30 (m, 2H), 7.09 (s, 1 H), 6.21 (d, 1H), 4.33-4.53 (m, 2H)

(311) Synthesis of Compound 251: For compound 251, compound 213 was used as an intermediate in general procedure J amide formation to form compound 251 in 31.1% yield.

(312) .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.12 (s, 1H), 8.76 (br. s., 1H), 8.32-8.58 (m, 2 H), 7.92 (m, 2H), 7.84 (d, 1H), 7.63 (m, 2H), 7.21-7.30 (m, 2H), 7.09 (s, 1 H), 6.21 (d, 1H), 4.33-4.53 (m, 2H)

(313) Synthesis of Compound 252: For compound 252, compound 215 was used as an intermediate in general procedure J amide formation to form compound 252 in 27% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.73 (br. s., 1H), 8.44 (d, 1H), 7.77 (d, 1H), 7.13-7.40 (m, 7H), 7.00-7.13 (m, 3H), 6.18 (d, 1H), 4.99-5.20 (m, 1H), 4.58-4.76 (m, 1H), 1.44 (d, 3H), 1.33 (d, 6H)

(314) Synthesis of Compound 253: For compound 253, compound 225 was used as an intermediate in general procedure J amide formation to form compound 253 in 23.3% yield.

(315) .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.62 (s, 1H), 9.93 (s, 1H), 7.77-7.93 (m, 1H), 7.57-7.67 (m, 2H), 7.35-7.49 (m, 6H), 7.26-7.35 (m, 2H), 7.09-7.21 (m, 1H), 6.97-7.09 (m, 2H), 6.63-6.78 (m, 1H), 6.23 (d, 1H)

(316) Synthesis of Compound 254: For compound 254, compound 225 was used as an intermediate in general procedure J amide formation to form compound 254 in 23.6% yield.

(317) .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.07 (br. s., 1H), 8.47-8.78 (m, 1H), 7.81 (d, 1 H), 7.62 (m, 2H), 7.41 (m, 2H), 7.13-7.35 (m, 5H), 7.05 (s, 1H), 6.19 (d, 1 H), 4.34-4.49 (m, 2H)

(318) Synthesis of Compound 255: For compound 255, general procedures K and J were used to obtain compound 255 in 94.7% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.78 (d, 1H), 7.45 (dd, 1H), 7.02-7.13 (m, 1H), 6.96 (s, 1H), 6.91-6.95 (m, 1H), 6.82-6.91 (m, 1H), 6.20 (d, 1H), 3.79 (s, 3H)

(319) Synthesis of Compound 256: For compound 256, compound 215 was used as an intermediate in general procedure J amide formation to form compound 256 in 39.1% yield.

(320) .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.88 (s, 1H), 8.07 (q, 1H), 7.76 (d, 1H), 7.24 (m, 2 H), 7.07 (m, 2H), 6.92 (s, 1H), 6.17 (d, 1H), 4.69 (spt, 1H), 2.70 (d, 3H), 1.34 (d, 6H)

(321) Synthesis of Compound 257: For compound 257, compound 213 was used as an intermediate in general procedure J amide formation to form compound 257 in 21.2% yield.

(322) .sup.1H NMR (300 MHz, DMSO-d6) ppm 12.28 (s, 1H), 11.76 (br. s., 1H), 7.97 (d, 2H), 7.89 (d, 1H), 7.69 (d, 2H), 7.50 (d, 2H), 7.20 (d, 1H), 6.28 (d, 1H)

(323) Synthesis of Compound 258: For compound 258, compound 225 was used as an intermediate in general procedure J amide formation to form compound 258 in 41.6% yield.

(324) .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.25 (s, 1H), 8.19 (t, 1H), 7.80 (d, 1H), 7.64 (m, 2 H), 7.42 (m, 2H), 7.02 (s, 1H), 6.19 (d, 1H), 3.81-3.97 (m, 1H), 3.68-3.81 (m, 1H), 3.50-3.68 (m, 1H), 3.10-3.38 (m, 2H), 1.67-1.96 (m, 3H), 1.39-1.63 (m, 1H)

(325) Synthesis of Compound 259: For compound 259, compound 225 was used as an intermediate in general procedure J amide formation to form compound 259 in 28.9% yield.

(326) .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.77 (d, 1H), 7.61 (m, 2H), 7.39 (m, 2H), 6.65 (s, 1 H), 6.18 (d, 1H), 3.52-3.63 (m, 4H), 2.66-2.77 (m, 4H)

(327) Synthesis of Compound 260: For compound 260, compound 225 was used as an intermediate in general procedure J amide formation to form compound 260 in 51.9% yield.

(328) .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.27 (br. s., 1H), 7.95 (br. s., 1H), 7.77 (d, 1H), 7.61 (m, 2H), 7.40 (m, 2H), 6.90 (s, 1H), 6.14 (d, 1H), 2.70 (d, 3H)

(329) Synthesis of Compound 261: For compound 261, compound 225 was used as an intermediate in general procedure J amide formation to form compound 261 in 25% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.30 (t, 1H), 7.76-7.86 (m, 1H), 7.62 (m, 2H), 7.39 (m, 2H), 7.02 (s, 1H), 6.20 (d, 1H), 3.37-3.49 (m, 2H), 2.91 (br. s., 6H), 1.80 (br. s., 4H)

(330) Synthesis of Compound 262: For compound 262, compound 225 was used as an intermediate in general procedure J amide formation to form compound 262 in 25.4% yield.

(331) .sup.1H NMR (300 MHz, DMSO-d6) ppm 12.20 (br. s., 1H), 11.15 (br. s., 1H), 8.77 (t, 1H), 7.83 (d, 1H), 7.63 (m, 2H), 7.47-7.59 (m, 1H), 7.36-7.47 (m, 3H), 7.10-7.18 (m, 2H), 7.09 (s, 1H), 6.21 (d, 1H), 4.59-4.69 (m, 2H)

(332) Synthesis of Compound 263: For compound 263, compound 215 was used as an intermediate in general procedure J amide formation to form compound 263 in 10% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.74 (br. s., 1H), 7.63 (d, 1H), 7.27 (m, 2H), 7.05 (m, 2 H), 6.82 (s, 1H), 6.43 (d, 1H), 5.90 (br. s., 2H), 4.54-4.67 (m, 1H), 1.40 (d, 6H)

(333) Synthesis of Compound 264: For compound 264, compound 215 was used as an intermediate in general procedure J amide formation to form compound 264 in 55% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.94 (br. s., 1H), 7.74 (d, 1H), 7.22 (m, 2H), 7.05 (m, 2 H), 6.73 (s, 1H), 6.17 (d, 1H), 4.57-4.80 (m, 1H), 3.06 (br. s., 6H), 1.33 (d, 6H)

(334) Synthesis of Compound 265: For compound 265, compound 213 was used as an intermediate in general procedure J amide formation to form compound 265 in 19.3% yield.

(335) .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.75 (br. s., 1H), 9.91 (br. s., 1H), 7.78-7.99 (m, 3 H), 7.59-7.70 (m, 2H), 7.23-7.51 (m, 6H), 7.10-7.20 (m, 1H), 6.99-7.08 (m, 2H), 6.71 (dd, 1H), 6.23 (d, 1H)

(336) Synthesis of Compound 266: For compound 266, compound 213 was used as an intermediate in general procedure J amide formation to form compound 266 in 33.5% yield.

(337) .sup.1H NMR (300 MHz, DMSO-d6) ppm 12.19 (br. s., 1H), 11.36 (br. s., 1H), 8.74 (br. s., 1 H), 7.93 (m, 2H), 7.84 (d, 1H), 7.63 (m, 2H), 7.31-7.59 (m, 2H), 7.02-7.19 (m, 3H), 6.20 (d, 1H), 4.53-4.70 (m, 2H)

(338) Synthesis of Compound 267: For compound 267, compound 216 was used as an intermediate in general procedure J amide formation to form compound 267 in 25% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.55 (br. s., 1H), 9.91 (br. s., 1H), 7.83 (d, 1H), 7.21-7.52 (m, 10H), 7.10-7.21 (m, 1H), 7.04 (d, 2H), 6.63-6.80 (m, 1H), 6.10-6.33 (m, 1H)

(339) Synthesis of Compound 268: For compound 268, compound 247 was used as an intermediate in general procedure J amide formation to form compound 268 in 46% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.29 (br. s., 1H), 8.45 (d, 1H), 7.82 (d, 1H), 7.43-7.59 (m, 4H), 7.24-7.38 (m, 4H), 7.16-7.24 (m, 1H), 7.13 (s, 1H), 6.20 (d, 1 H), 5.09 (quin, 1 H), 1.44 (d, 3H)

(340) Synthesis of Compound 269: For compound 269, compound 216 was used as an intermediate in general procedure J amide formation to form compound 269 in 42% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.15 (br. s., 1H) 8.05 (br. s., 1H) 7.79 (d, 1H) 7.30-7.52 (m, 4H) 6.94 (s, 1H) 6.18 (d, 1H) 2.71 (d, 3H)

(341) Synthesis of Compound 270: For compound 270, compound 247 was used as an intermediate in general procedure J amide formation to form compound 270 in 34% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.30 (s, 1H), 7.98-8.15 (m, 1H), 7.81 (d, 1H), 7.39-7.61 (m, 4H), 6.95 (s, 1H), 6.20 (d, 1H), 2.71 (d, 3H)

(342) Synthesis of Compound 271: For compound 271, compound 247 was used as an intermediate in general procedure J amide formation to form compound 271 in 44.9% yield.

(343) .sup.1H NMR (300 MHz, DMSO-d6) ppm 12.19 (br. s., 1H), 11.36 (s, 1H), 8.80 (t, 1H), 7.84 (d, 1H), 7.31-7.61 (m, 6H), 7.11-7.19 (m, 2H), 7.10 (s, 1H), 6.22 (d, 1H), 4.62 (d, 2H)

(344) Synthesis of Compound 272: For compound 272, compound 216 was used as an intermediate in general procedure J amide formation to form compound 272 in 36% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.67 (s, 1H), 8.61 (dd, 1H), 7.80 (d, 1H), 7.32-7.49 (m, 4H), 7.22 (dd, 1H), 7.05 (s, 1H), 6.74-6.89 (m, 3H), 6.19 (d, 1H), 4.33-4.43 (m, 2 H), 3.71 (s, 3H)

(345) Synthesis of Compound 273: For compound 273, compound 247 was used as an intermediate in general procedure J amide formation to form compound 273 in 43% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.73 (br. s., 1H), 10.28 (s, 1H), 8.26-8.33 (m, 1H), 8.02-8.16 (m, 1H), 7.90 (d, 1H), 7.47-7.68 (m, 6H), 7.38 (s, 1H), 6.26 (d, 1H), 3.19 (s, 3 H)

(346) Synthesis of Compound 274: For compound 274, compound 255 was used as an intermediate in general procedure J amide formation to form compound 274 in 31.9% yield.

(347) .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.93 (br. s., 1H) 9.76 (s, 1H) 8.54-8.77 (m, 1H) 7.78 (d, 1H) 7.19-7.40 (m, 6H) 7.03 (s, 1H) 6.92 (dd, 1H) 6.76 (d, 1H) 6.70 (t, 1H) 6.18 (d, 1H) 4.42 (d, 2H)

(348) Synthesis of Compound 275: For compound 275, compound 213 was used as an intermediate in general procedure J amide formation to form compound 275 in 26% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.75 (br. s., 1H), 9.90 (br. s., 1H), 7.78-8.03 (m, 3H), 7.57-7.77 (m, 4H), 7.32-7.44 (m, 2H), 7.28 (br. s., 1H), 7.05-7.17 (m, 1 H), 6.90-7.05 (m, 4H), 6.12-6.34 (m, 1H)

(349) Synthesis of Compound 276: For compound 276, compound 215 was used as an intermediate in general procedure J amide formation to form compound 276 in 28% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.07 (br. s., 1H), 9.42 (br. s., 1H), 8.38 (t, 1H), 7.80 (d, 1H), 7.22 (m, 2H), 7.08 (m, 2H), 7.01 (d, 1H), 6.20 (d, 1H), 4.69 (quin, 1H), 3.42-3.71 (m, 4H), 3.16-3.35 (m, 2H), 2.91-3.16 (m, 2H), 1.77-2.07 (m, 4H), 1.34 (d, 6H)

(350) Synthesis of Compound 277: For compound 277, compound 216 was used as an intermediate in general procedure J amide formation to form compound 277 in 31% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.62 (br. s., 1H), 10.26 (s, 1H), 8.22-8.32 (m, 1H), 8.00-8.14 (m, 1H), 7.88 (d, 1H), 7.53-7.68 (m, 2H), 7.26-7.52 (m, 5H), 6.25 (d, 1H), 3.19 (s, 3H)

(351) Synthesis of Compound 278: For compound 278, compound 215 was used as an intermediate in general procedure J amide formation to form compound 278 in 30% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.40 (br. s., 1H), 10.24 (s, 1H), 8.14-8.24 (m, 1H), 7.91-8.06 (m, 1H), 7.85 (d, 1H), 7.59 (dd, 1H), 7.36-7.45 (m, 1H), 7.32 (s, 1H), 7.25 (m, 2H), 7.07 (m, 2H), 6.24 (d, 1H), 4.70 (quin, 1H), 2.62 (s, 6H), 1.35 (d, 6H)

(352) Synthesis of Compound 279: For compound 279, compound 215 was used as an intermediate in general procedure J amide formation to form compound 279 in 26% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.33 (br. s., 1H), 10.03 (br. s., 1H), 7.79-7.90 (m, 2H), 7.54-7.66 (m, 1H), 7.35 (dd, 1H), 7.20-7.31 (m, 3H), 7.01-7.17 (m, 3H), 6.23 (d, 1H), 4.70 (quin, 1H), 1.35 (d, 6H)

(353) Synthesis of Compound 280: For compound 280, compound 255 was used as an intermediate in general procedure J amide formation to form compound 280 in 34.9% yield.

(354) .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.69 (s, 1H), 9.75 (br. s., 1H), 7.77 (d, 1H), 7.35 (dd, 1H), 6.91 (dd, 1H), 6.85 (d, 1H), 6.71-6.79 (m, 1H), 6.69 (t, 1H), 6.19 (d, 1H), 3.66 (br. s., 2H), 3.47 (br. s., 2H), 1.88 (br. s., 2H)

(355) Synthesis of Compound 281: For compound 281, compound 215 was used as an intermediate in general procedure J amide formation to form compound 281 in 22.5% yield.

(356) .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.73 (d, 1H), 7.22 (m, 2H), 7.05 (m, 2H), 6.63 (s, 1 H), 6.17 (d, 1H), 4.56-4.79 (m, 1H), 3.54-3.64 (m, 4H), 2.66-2.79 (.[.m, 4.]..Iadd.m, 4 H.Iaddend.), 1.33 (d, 6 H)

(357) Synthesis of Compound 282: For compound 282, compound 225 was used as an intermediate in general procedure J amide formation to form compound 282 in 49% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.68 (br. s., 1H), 8.73 (br. s., 1H), 8.48 (dd, 2H), 7.81 (d, 1H), 7.61 (m, 2H), 7.41 (m, 2H), 7.25 (d, 2H), 7.06 (s, 1H), 6.19 (d, 1H), 4.43 (d, 2H)

(358) Synthesis of Compound 283: For compound 283, compound 247 was used as an intermediate in general procedure J amide formation to form compound 283 in 52% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 12.28 (s, 1H), 11.69 (s, 1H), 7.86 (d, 1H), 7.58 (s, 4H), 7.49 (d, 1H), 7.47 (br. s., 1H), 7.19 (d, 1H), 6.26 (d, 1H)

(359) Synthesis of Compound 284: For compound 284, a similar modified general procedure K and J as for compound 223 was followed. Compound 284 was obtained in 27% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 12.54 (br. s., 1H), 8.24 (d, 1H), 7.66 (s, 1H), 7.56 (d, 1H), 7.45 (m, 2H), 7.38 (m, 2H), 7.28 (d, 1H), 6.91 (d, 1H), 3.88 (s, 3H)

(360) Synthesis of Compound 285: For compound 285, compound 216 was used as an intermediate in general procedure J amide formation to form compound 285 in 33% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.14 (br. s., 1H), 8.19 (t, 1H), 7.79 (d, 1H), 7.34-7.51 (m, 4H), 7.02 (s, 1H), 6.19 (d, 1H), 3.81-3.97 (m, 1H), 3.68-3.81 (m, 1 H), 3.52-3.67 (m, 1H), 3.11-3.38 (m, 2H), 1.68-1.97 (m, 3H), 1.40-1.62 (m, 1H)

(361) Synthesis of Compound 286: For compound 286, compound 213 was used as an intermediate in general procedure J amide formation to form compound 286 in 46% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.10 (t, 1H), 7.93 (m, 2H), 7.83 (d, 1H), 7.62 (m, 2 H), 7.00 (s, 1H), 6.20 (d, 1H), 3.22-3.38 (m, 2H), 2.40-2.60 (m, 6H), 1.55-1.76 (m, 4H)

(362) Synthesis of Compound 287: For compound 287, compound 216 was used as an intermediate in general procedure J amide formation to form compound 287 in 38% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 12.20 (br. s., 1H), 11.22 (br. s., 1H), 8.75-8.82 (m, 1H), 7.83 (d, 1H), 7.29-7.60 (m, 6H), 7.04-7.19 (m, 3H), 6.21 (d, 1H), 4.55-4.68 (m, 2H)

(363) Synthesis of Compound 288: For compound 288, compound 215 was used as an intermediate in general procedure J amide formation to form compound 288 in 41.7% yield.

(364) .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.36 (s, 1H), 10.25 (s, 1H), 8.23-8.30 (m, 1H), 8.02-8.12 (m, 1H), 7.85 (d, 1H), 7.56-7.65 (m, 2H), 7.32 (s, 1H), 7.27 (m, 2H), 7.08 (m, 2 H), 6.24 (d, 1H), 4.70 (spt, 1H), 3.19 (s, 3H), 1.35 (d, 6H)

(365) Synthesis of Compound 289: For compound 289, compound 247 was used as an intermediate in general procedure J amide formation to form compound 289 in 13% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.36 (s, 1H), 8.66 (t, 1H), 7.82 (d, 1H), 7.45-7.60 (m, 4H), 7.14-7.36 (m, 5H), 7.06 (s, 1H), 6.20 (d, 1H), 4.42 (d, 2H)

(366) Synthesis of Compound 290: For compound 290, compound 225 was used as an intermediate in general procedure J amide formation to form compound 290 in 18% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.70 (br. s., 1H), 10.26 (s, 1H), 8.24-8.30 (m, 1H), 8.01-8.14 (m, 1H), 7.88 (d, 1H), 7.53-7.69 (m, 4H), 7.43 (m, 2H), 7.34-7.38 (m, 1H), 6.25 (d, 1H), 3.19 (s, 3H)

(367) Synthesis of Compound 291: For compound 291, compound 255 was used as an intermediate in general procedure J amide formation to form compound 291 in 56% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.31 (br. s., 1H), 10.04 (br. s., 1H), 9.75 (s, 1H), 7.86-7.88 (m, 1H), 7.84 (d, 1H), 7.59 (d, 1H), 7.37 (dd, 1H), 7.35 (dd, 1H), 7.28 (s, 1H), 7.05-7.15 (m, 1H), 6.88-6.99 (m, 1H), 6.77 (d, 1H), 6.70-6.74 (m, 1H), 6.23 (d, 1H)

(368) Synthesis of Compound 292: For compound 292, compound 215 was used as an intermediate in general procedure J amide formation to form compound 292 in 35.3% yield.

(369) .sup.1H NMR (300 MHz, DMSO-d6) ppm 12.20 (br. s., 1H), 10.68 (br. s., 1H), 8.80 (t, 1H), 7.79 (d, 1H), 7.32-7.62 (m, 2H), 7.25 (m, 2H), 6.99-7.17 (m, 5H), 6.19 (d, 1H), 4.64-4.74 (m, 1H), 4.56-4.64 (m, 2H), 1.32 (d, 6H)

(370) Synthesis of Compound 293: For compound 293, compound 213 was used as an intermediate in general procedure J amide formation to form compound 293 in 32.6% yield.

(371) .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.39 (br. s., 1H), 7.99-8.15 (m, 1H), 7.94 (m, 2 H), 7.83 (d, 1H), 7.62 (m, 2H), 6.96 (s, 1H), 6.21 (d, 1H), 2.71 (d, 3H)

(372) Synthesis of Compound 294: For compound 294, compound 216 was used as an intermediate in general procedure J amide formation to form compound 294 in 30.7% yield.

(373) .sup.1H NMR (300 MHz, DMSO-d6) ppm 12.25 (br. s., 1H), 11.59 (br. s., 1H), 7.85 (d, 1H), 7.36-7.57 (m, 6H), 7.19 (d, 1H), 6.26 (d, 1H)

(374) Synthesis of Compound 295: For compound 295, compound 225 was used as an intermediate in general procedure J amide formation to form compound 295 in 18% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.67 (br. s., 1H), 10.16 (br. s., 1H), 8.19 (s, 1H), 7.95 (br. s., 1H), 7.87 (d, 1H), 7.63 (m, 2H), 7.47-7.55 (m, 2H), 7.44 (m, 3H), 7.20-7.39 (m, 2H), 6.23 (d, 1H)

(375) Synthesis of Compound 296: For compound 296, compound 216 was used as an intermediate in general procedure J amide formation to form compound 296 in 31.9% yield.

(376) .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.20 (s, 1H), 8.43 (d, 1H), 7.81 (d, 1H), 7.25-7.47 (m, 8H), 7.15-7.25 (m, 1H), 7.12 (s, 1H), 6.19 (d, 1H), 5.10 (quin, 1H), 1.44 (d, 3H)

(377) Synthesis of Compound 297: For compound 297, compound 215 was used as an intermediate in general procedure J amide formation to form compound 297 in 35.8% yield.

(378) .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.25 (s, 1H), 9.90 (s, 1H), 7.83 (d, 1H), 7.60-7.70 (m, 1H), 7.30-7.41 (m, 1H), 7.19-7.30 (m, 3H), 7.01-7.19 (m, 3H), 6.22 (d, 1H), 4.70 (quin, 1H), 3.81 (s, 3H), 1.35 (d, 6H)

(379) Synthesis of Compound 298: Compound 298 was prepared by mixing a methoxy intermediate in anhydrous DCM and 2 eq of BBr.sub.3 at 0 C. After the reaction was complete (about 1-2 hours), it was washed with saturated NaHCO.sub.3 several times until neutral. Organic solution was dried (sodium sulfate) and evaporated. Compound 298 was isolated by pre-TLC to give pure product (82% yield) as a white solid. MS-ESI: m/z=202.1 [M+1].sup.+

(380) Synthesis of Compound 299: Similar to the synthesis of compound 298, compound 299 was prepared in 87% yield as a white solid. MS-ESI: m/z=202.3 [M+1].sup.+

(381) Synthesis of Compound 300: Following general procedure A, compound 300 was prepared in 42% yield as a white solid. MS-ESI: m/z=204.3 [M+1].sup.+

(382) Synthesis of Compound 301: Following general procedure A, compound 301 was prepared in 9% yield as a solid. MS-ESI: m/z=204.3 [M+1].sup.+

(383) Synthesis of Compound 302: Following general procedure A, compound 302 was prepared in 27.3% yield as a white solid. MS-ESI: m/z=220.3 [M+1].sup.+; 222.2 [M+3].sup.+

(384) Synthesis of Compound 303: Following general procedure A, compound 303 was prepared in 20% yield as a white solid. MS-ESI: m/z=216.3 [M+1].sup.+

(385) Synthesis of Compound 304: Following general procedure A, compound 304 was prepared in 66% yield as a white solid. MS-ESI: m/z=216.3 [M+1].sup.+

(386) Synthesis of Compound 305: Following general procedure A, compound 305 was prepared in 50% yield as a yellowish solid. MS-ESI: m/z=216.3 [M+1].sup.+

(387) Synthesis of Compound 306: Following general procedure A, compound 306 was prepared in 43% yield as an oil. MS-ESI: m/z=244.0 [M+1].sup.+

(388) Synthesis of Compound 307: Following general procedure A, compound 307 was prepared in 81% yield as an oil. MS-ESI: m/z=244.1 [M+1].sup.+

(389) Synthesis of Compound 308: Following general procedure A, compound 308 was prepared in 87% yield as a reddish brown solid. MS-ESI: m/z=244.2 [M+1].sup.+

(390) Synthesis of Compound 309: Following general procedure A, compound 309 was prepared in 80% yield as a yellowish solid. MS-ESI: m/z=234.3 [M+1].sup.+

(391) Synthesis of Compound 310: Following general procedure A, compound 310 was prepared in 85% yield as a light yellow solid. MS-ESI: m/z=248.2 [M+1].sup.+

(392) Synthesis of Compound 311: Following general procedure A, compound 311 was prepared in 76% yield as a white solid. MS-ESI: m/z=250.2 [M+1].sup.+

(393) Synthesis of Compound 312: Following general procedure A, compound 312 was prepared in 22% yield as a white solid. MS-ESI: m/z=266.2 [M+1].sup.+

(394) Synthesis of Compound 313: Following general procedure A, compound 313 was prepared in 25% yield as a light yellow solid. MS-ESI: m/z=230.2 [M+1].sup.+

(395) Synthesis of Compound 314: Following general procedure A, compound 314 was prepared in 27% yield as a colorless oil. MS-ESI: m/z=242.2 [M+1].sup.+

(396) Synthesis of Compound 315: Following general procedure A, compound 315 was prepared in 32% yield as a white solid. MS-ESI: m/z=240.1 [M+1].sup.+

(397) Synthesis of Compound 316: Following general procedure A, compound 316 was prepared in 92% yield as a light yellow solid. MS-ESI: m/z=202.2 [M+1].sup.+

(398) Synthesis of Compound 317: Following general procedure A, compound 317 was prepared in 28% yield as a white solid. MS-ESI: m/z=186.2 [M+1].sup.+

(399) Synthesis of Compound 318: Compound 318 was prepared as follows.

(400) ##STR00544##
Following general procedure A, the intermediate compound was prepared in 78% yield as a white solid. MS-ESI: m/z=278.1 [M+1].sup.+ To a solution of the intermediate (3.5 g, 10.8 mmol) in methanol (200 ml) was added Pd/C (300 mg) catalyst under N.sub.2 atmosphere, and then stirred for 2 h under H.sub.2 atmosphere (1 atm, 25 C.). The catalyst was filtered off through the celite pad, and the filtrate was concentrated in vacuo to give compound 318 (2.2 g, 93% yields) as a white solid. MS-ESI: m/z=188.2 [M+1].sup.+

(401) Synthesis of Compound 319: Following general procedure A, compound 319 was prepared in 85% yield as a white solid. MS-ESI: m/z=206.3 [M+1].sup.+

(402) Synthesis of Compound 320: Following general procedure A, compound 320 was prepared in 84% yield as a white solid. MS-ESI: m/z=240.3 [M+1].sup.+

(403) Synthesis of Compound 321: Following general procedure A, compound 321 was prepared in 79% yield as a solid. MS-ESI: m/z=206.2 [M+1].sup.+; 208.2 [M+3].sup.+

(404) Synthesis of Compound 322: Compound 322 was synthesized as follows.

(405) ##STR00545##
To a solution Br-substitution-1-Phenyl-1H-pyridin-2-one (1 eq), the appropriate boromic acid (1.2 eq), potassium phosphate (3.5 eq) and tricyclohexylphosphine (0.1 eq) in toluene/water (2:/1, V:V) under a nitrogen atmosphere was added palladium acetate (0.05 eq). The mixture was heated to 100 C. for 2-3 h, and then cooled to room temperature, water was added and the mixture was extracted with EtOAc, the combined organics were washed with brine and water, dried over anhydrous Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was purified by pre-TLC to afford the desired compound 322 in 70% yield as a pink solid. MS-ESI: m/z=212.2 [M+1].sup.+

(406) Synthesis of Compound 323: Similar to compound 322, compound 323 was prepared in 60% yield as a yellow solid. MS-ESI: m/z=274.3 [M+1].sup.+

(407) Synthesis of Compound 324: Compound 324 was synthesized as follows. To compound 318 (2.2 g, 11.8 mmol) in DCM (120 ml) was added .[.triethylanine.]. .Iadd.triethylamine .Iaddend.(1.7 g, 16.8 mmol) at 78 C., followed by the addition of trifluoromethanesulfonic anhydride (4.76 g, 16.9 mmol). The resulting mixture was stirred at 78 C. for 15 min and quenched with ammonium chloride solution (10 ml). After warming to room temperature, water (30 ml) and DCM (50 ml) were added and separated. The intermediate triflate was obtained by washing the crude with methanol and gave 2.12 g pure compound in 90% yield. A solution of the intermediate triflate (trifluoro-methanesulfonic acid 2-oxo-1-phenyl-1,2-dihydro-pyridin-4-yl ester) (0.79 mmol) and tetrakis(triphenylphosphine)palladium (0.011 g, 0.0095 mmol) in dimethoxyethane (1 ml) was stirred at room temperature for 15 min followed by the addition of the solution arylboronic acid (0.21 mmol) in dimethoxyethane (1 ml) and 2M sodium carbonate (1 ml). The resulting mixture was refluxed for 14 hr and cooled down to room temperature. Water and ethyl acetate were added. After separation, the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate solution was dried (Na.sub.2SO.sub.4) and filtered, and the filtrate was concentrated in vacuo to dryness. Compound 324 was obtained in 51.6% yield as a solid. MS-ESI: m/z=248.3 [M+1].sup.+

(408) Synthesis of Compound 325: Similar to compound 324, compound 325 was prepared in 60.2% yield as a solid. MS-ESI: m/z=212.2 [M+1].sup.+

(409) Synthesis of Compound 326: Following general procedure A, compound 326 was prepared in 15% yield. MS-ESI: m/z=212.3 [M+1].sup.+

(410) Synthesis of Compound 327: Compound 327 was prepared as follows.

(411) ##STR00546##
A mixture of 2,6-dibromopyridine (4 g, 17 mmol), potassium t-butoxide (20 g, 0.27 mol), and redistilled t-butyl alcohol (100 ml) was refluxed overnight. After cooling, the solvent was removed in vacuo, ice/water was carefully added, and the aqueous layer was extracted with chloroform (100 ml2), which removed the unreacted staring material. The aqueous layer was acidified with 3 N HCl, extracted with chloroform (100 ml2), washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated affording pure 6-bromo-2-pyridone (2.5 g, 85% yield) as a white solid. Intermediate 3 was prepared following general procedure A in 73% yield. Intermediate 3 was then reacted with the appropriate boronic acid, Pd (OAc).sub.2, PCy.sub.3, K.sub.3PO.sub.4 at 100 C. to afford compound 327 in 40% yield as an oil. MS-ESI: m/z=248.3 [M+1].sup.+

(412) Synthesis of Compound 328: Similar to compound 327, compound 328 was prepared in 9.48% yield as an oil. MS-ESI: m/z=212.2 [M+1].sup.+

(413) Synthesis of Compound 329: Following general procedure A, compound 329 was prepared in 90% yield as a white solid. MS-ESI: m/z=298.3 [M+1].sup.+

(414) Synthesis of Compound 330: Following general procedure A, compound 330 was prepared in 75% yield as a yellowish solid. MS-ESI: m/z=230.4 [M+1].sup.+

(415) Synthesis of Compound 331: Following general procedure A, compound 331 was prepared in 81% yield as an oil. MS-ESI: m/z=262.1 [M+1].sup.+

(416) Synthesis of Compound 332: Following general procedure A, compound 332 was prepared in 80% yield as a solid. MS-ESI: m/z=276.2 [M+1].sup.+

(417) Synthesis of Compound 333: Following general procedure F, compound 333 was prepared in 65% yield to give a yellowish solid. MS-ESI: m/z=280.1 [M+1].sup.+

(418) Synthesis of Compound 334: Following general procedure F, compound 334 was prepared in 59% yield. MS-ESI: m/z=256.2 [M+1].sup.+, 258.2. [M+3].sup.+

(419) Synthesis of Compound 335: Compound 335 was prepared as follows.

(420) ##STR00547##
A mixture of compound 1 (200 mg, 1.3 mmol) in AcOH (4 ml) was added HBr (aq. 40%, 1 ml), then heated to reflux for 2 h. The compound 2 was obtained by evaporated in vacuo (160 mg, 90%). To a mixture of compound 2 (160 mg, 1.2 mmol), phenylboronic acid (293 mg, 2.4 mmol) and Cu(OAc).sub.2 (36 mg, 0.2 mmol) in DCM, pyridine (190 mg, 2.4 mmol) was added slowly. After the suspension was stirred overnight at room temperature, it was checked by TLC and the starting material was completely vanished, and then washed with saturated NaHCO.sub.3. The DCM layer was dried over sodium sulfate, and evaporated to obtain the crude product. The crude product was purified by preparative TLC to afford the compound 3 (110 mg, 43%). A mixture of compound 3 (110 mg,0.5 mmol) in DAST (2.5 ml) was heated to 80 C. for 4 h. The reaction mixture was extracted by DCM and saturated NaHCO.sub.3, and the crude product was purified by preparative TLC to give compound 335 (40 mg, 34% yield) as yellow solid. MS-ESI: m/z=236.3 [M+1].sup.+

(421) Synthesis of Compound 336: Similar to the synthesis of compound 91, compound 336 was prepared in 63% yield as a white solid. MS-ESI: m/z=262.1 [M+1].sup.+

(422) Synthesis of Compound 337: Similar to the synthesis of compound 91, compound 337 was prepared in 70% yield to give a white solid. MS-ESI: m/z=238.2 [M+1].sup.+, 240.3 [M+3].sup.+

(423) Synthesis of Compound 338: Compound 338 was synthesized as follows.

(424) ##STR00548##
A mixture of compound 2 (1 g, 5 mmol) and trimethyl-trifluoromethyl-silane (3.5 ml, 2M in THF, 7 mmol) in THF (20 ml) cooled to 0 C. in an ice bath was treated with tetrabutylammonium fluoride (0.25 ml, 1 m in THF, 0.25 mmol) under nitrogen atmosphere at 0 C. for 30 min. The mixture was raised to room temperature and stirred 24 h. Then 1 M HCl (50 ml) was added and the mixture was stirred overnight. The aqueous layer was extracted with EtOAc (50 ml2) and the organics was concentrated. The desired product was separated by columnar chromatography to give compound 338 (0.94 g, 70% yields) as yellow solid. MS-ESI: m/z=270.2 [M+1].sup.+

(425) Synthesis of Compound 339: Compound 339 was prepared from compound 338 as follows. Compound 338 (50 mg, 0.19 mmol) and manganese dioxide (165 mg, 1.9 mmol) were stirred overnight at room temperature in DCM (5 ml). The reaction was detected by TLC. Upon completion, the crude mixture was filtered through a pad of celite and the filtrate was concentrated. The desired compound was isolated by washing the crude with PE to give pure intermediate product (36 mg, 70% yields) as a white solid. A mixture of this intermediate (100 mg, 0.37 mmol) and trimethyl-trifluoromethyl-silane (0.27 ml, 2 M in THF, 0.54 mmol) in THF (2 ml) cooled to 0 C. in an ice bath is treated with tetrabutylammonium fluoride (0.02 ml, 1 M in THF, 0.02 mmol) under nitrogen atmosphere at 0 C. for 30 min. The mixture was raised to room temperature and stirred 24 h. Then 1 M HCl (20 ml) was added and the mixture was stirred overnight. The aqueous layer was extracted with EtOAc (30 ml3) and the organics was concentrated. The desired product was separated out by washing the crude with EtOAc to give compound 339 (54 mg, 43% yield) as a white solid. MS-ESI: m/z=338.2 [M+1].sup.+

(426) Synthesis of Compound 340: Compound 340 was prepared from compound 338 as follows. Compound 338 (50 mg, 0.19 mmol) in dry DCM (1 ml) was added at the temperature of 78 C. under N.sub.2 atmosphere to a solution of DAST (34 mg, 0.21 mmol) in DCM (1 ml). The mixture was stirred at 78 C. for 2 h, and then warmed to room temperature overnight. The reaction mixture was diluted with DCM (20 ml), and poured into saturated NaHCO.sub.3 (30 ml). Organic phase was separated and dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Desired compound was isolated by thin-layer chromatography to give pure compound 340 (16 mg, 30% yields) as a yellowish solid. MS-ESI: m/z=272.2 [M+1].sup.+

(427) Synthesis of Compound 341: Compound 341 was prepared from compound 338 as follows. Compound 338 (50 mg, 0.19 mmol) and manganese dioxide (165 mg, 1.9 mmol) were stirred overnight at room temperature in DCM (5 ml). The reaction was detected by TLC. Upon completion, the crude mixture was filtered through a pad of celite and the filtrate was concentrated. The desired compound was isolated by washing the crude with PE to give pure intermediate product (36 mg, 70% yield) as a white solid.

(428) To a suspension of methyltriphosphonium bromide (336 mg, 0.96 mmol) in tetrahydrofuran (16 ml) maintained at 0 C. was added n-butyllithium (0.4 ml, 2.5 M solution in THF). The resulting solution was stirred for fifteen minutes prior to the addition of a solution of this intermediate (200 mg, 0.76 mmol.) in tetrahydrofuran (10 ml). The reaction mixture was stirred for about 1 h before quenching by dilution with water. The second intermediate product was extracted into EA and the combined organic layers were evaporated under reduced pressure, the second intermediate product was isolated by TLC (150 mg, 76% yield). 1-phenyl-5-(3,3,3-trifluoroprop-1-en-2-yl)pyridine-2(1H)-one (the second intermediate product) (100 mg, 0.38 mmol) in C.sub.2H.sub.5OH (8 ml) was added Pd/C (10 mg) under N.sub.2. The reaction mixture was stirred for 2 h under H.sub.2, then filtered, extracted by DCM, washed by brine, dried by Na.sub.2SO.sub.4. Compound 341 was isolated by TLC (79 mg, 79% yield) as oil. MS-ESI: m/z=268.3 [M+1].sup.+

(429) Synthesis of Compound 342: Compound 342 was prepared from compound 338 as follows. Compound 338 (50 mg, 0.19 mmol) and manganese dioxide (165 mg, 1.9 mmol) were stirred overnight at room temperature in DCM (5 ml). The reaction was detected by TLC. Upon completion, the crude mixture was filtered through a pad of celite and the filtrate was concentrated. The desired compound was isolated by washing the crude with PE to give pure intermediate product (36 mg, 70% yield) as a white solid. Then, following general procedure D, compound 342 was prepared in 64% yield as a white solid. MS-ESI: m/z=290.3 [M+1].sup.+

(430) Synthesis of Compound 343: Compound 343 was prepared as follows.

(431) ##STR00549##
Intermediate 3 was prepared thus. To a solution of compound 1 (3.0 g, 16 mmol), compound 2 (2.5 g, 21 mmol), K.sub.3PO.sub.4 (12.5 g, 57 mmol) in toluene/water (60 ml/3 ml) under a .[.nitro.]. .Iadd.nitrogen .Iaddend.atmosphere was added Pd(PPh.sub.3).sub.4 (2.0 g, 1.6 mmol). The mixture was heated to reflux for 3 h and then cooled to room temperature. Water was added and the mixture extracted with EtOAc, the combined organics were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The product was isolated by column chromatography afforded the compound 3. (2.1 g, 69%). Intermediate 3 (2.0 g, 11 mmol) in HBr (aq. 40%)/EtOH (20 ml/4 ml) was heated to reflux for 2 h, the reaction was monitored by TLC, when completed, the mixture was cooled to r.t. The reaction mixture was neutralized by NaHCO.sub.3, then extracted with EtOAc several times. The combined organics was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford the compound 4 (1.7 g, 91%) Following general procedure A, compound 343 was prepared from intermediate 4 in 50% as an oil. MS-ESI: m/z=306.0 [M+1].sup.+

(432) Synthesis of Compound 344: Similar to compound 343, compound 344 was prepared in 15% yield as a white solid. MS-ESI: m/z=277.9 [M+1].sup.+

(433) Synthesis of Compound 345: Similar to compound 343, compound 345 was prepared in 60% yield as a white solid. MS-ESI: m/z=281.9 [M+1].sup.+

(434) Synthesis of Compound 346: Similar to compound 343, compound 346 was prepared in 90% yield as a yellowish solid. MS-ESI: m/z=305.9 [M+1].sup.+

(435) Synthesis of Compound 347: Similar to compound 343, compound 347 was prepared in 85% yield as a solid. MS-ESI: m/z=278.0 [M+1].sup.+

(436) Synthesis of Compound 348: Similar to compound 343, compound 348 was prepared in 50% yield as a white solid. MS-ESI: m/z=331.8 [M+1].sup.+

(437) Synthesis of Compound 351: Following general procedure A, compound 351 was prepared in 55% yield as a white solid. MS-ESI: m/z=269.9 [M+1].sup.+

(438) Synthesis of Compound 352: Following general procedure A, compound 352 was prepared in 70% yield as a reddish liquid. MS-ESI: m/z=298 [M+1].sup.+

(439) Synthesis of Compound 353: Following general procedure A, compound 353 was prepared in 85% yield as a white solid. MS-ESI: m/z=270.0 [M+1].sup.+

(440) Synthesis of Compound 354: Following general procedure A, compound 354 was prepared in 78% yield as a solid. MS-ESI: m/z=273.9 [M+1].sup.+

(441) Synthesis of Compound 355: Following general procedure A, compound 355 was prepared in 68% yield as a white solid. MS-ESI: m/z=244.1 [M+1].sup.+

(442) Synthesis of Compound 356: Following general procedure A, compound 356 was prepared in 65% yield as a white solid. MS-ESI: m/z=270.0 [M+1].sup.+

(443) Synthesis of Compound 357: Following general procedure F, compound 357 was prepared in 68% yield. MS-ESI: m/z=305.9 [M+1].sup.+

(444) Synthesis of Compound 358: Similar to the synthesis of compound 100, compound 358 was prepared in 80% yield as a white solid. MS-ESI: m/z=300.2 [M+1].sup.+

(445) Synthesis of Compound 359: Compound 359 was prepared as follows.

(446) ##STR00550##
A mixture of reagent 1 (0.5-1 mmol, 1 eq.), boronic acids 2 (2 eq.), copper(II) acetate (0.4-0.6 eq.), pyridine (2 eq.) and molecular sieves 4 A in dichloromethane (5 ml/1 mmol reagent 1) was stirred for overnight at the room temperature opened to the air. The reactions were monitored by TLC, and when found to be completed washed with saturated sodium bicarbonate with EDTA and dried over sodium sulfate. Compounds 3 were isolated by pre-TLC (using EA/PE as solvent). Reagent 3 (0.3-0.5 mmol, 1 eq.) was dissolved in acetonitrile (3 mL/1 mmol reagent 3), DAST (2 eq.) was added slowly at room temperature. The resulting solution was stirred at 80 C. in a capped plastic tube overnight. After cooling to room temperature, it was diluted with DCM, washed with aqueous solution of saturated sodium bicarbonate, water and brine, dried over Na.sub.2SO.sub.4, concentrated to give a residue, which was purified by pre-TLC (using EA/PE as solvent) to give target compound. Following this procedure, compound 359 was prepared in 13.9% yield as a white solid. .sup.1H NMR (400 MHz, CDCl3): 2.98 (s, 6H); 3.3236.341 (t, J=5.6 Hz, 1H); 6.4606.599 (d, J=55.6 Hz, 1H); 6.6396.657 (d, J=7.2 Hz, 2H); 6.7656.790 (d, J=10.0 Hz, 2H); 7.3147.353 (t, J=8.0 Hz, 1H); 7.4467.464 (d, J=7.2 Hz, 1H) MS-ESI: m/z=265.1 [M+1].sup.+

(447) Synthesis of Compound 360: Similar to preparation of compound 359, compound 360 was prepared in 19.7% yield as a white solid. .sup.1H NMR (400 MHz, CDCl3): 6.2786.647 (m, 2H); 6.679 (s, 1H); 7.3147.343 (t, J=11.6 Hz, 2H); 7.3957.419 (d, J=9.6 Hz, 1H); 7.4597.498 (q, J=15.6 Hz, 2H) MS-ESI: m/z=256.3 [M+1].sup.+

(448) Synthesis of Compound 361: Similar to preparation of compound 359, compound 361 was prepared in 19.8% yield as a white solid. .sup.1H NMR (400 MHz, CDCl3): 1.3501.371 (d, J=8.4 Hz, 6H), 4.5544.594 (t, J=16 Hz, 1H), 6.2746.643 (m, 2H); 6.777 (s, 1H); 6.673 (s, 1H); 6.9506.980 (q, J=12 Hz, 2H); 7.2427.272 (q, J=12 Hz, 2H), 7.4227.446 (d, J=9.6 Hz, 1H) MS-ESI: m/z=280.2 [M+1].sup.+

(449) Synthesis of Compound 362: Similar to preparation of compound 359, compound 362 was prepared in 20.1% yield as a white solid. .sup.1H NMR (400 MHz, CDCl3): 6.2896.697 (m, 2H); 6.679 (s, 1H); 7.4107.435 (d, J=10 Hz, 1H); 7.5317.569 (d, J=15.2 Hz, 2H); 7.7707.812 (d, J=16.8 Hz, 2H) MS-ESI: m/z=290.3 [M+1].sup.+

(450) Synthesis of Compound 363: Similar to preparation of compound 359, compound 363 was prepared in 20.1% yield as a white solid. .sup.1H NMR (400 MHz, CDCl3): 3.847 (s, 1H), 6.3206.596 (m, 2H); 6.758 (s, 1H); 6.9797.018 (m, 2H); 7.2737.303 (m, 2H); 7.4207.438 (d, J=7.2 Hz, 1H) MS-ESI: m/z=252.3 [M+1].sup.+

(451) Synthesis of Compound 364: Similar to preparation of compound 359, compound 364 was prepared in 27.8% yield as a white solid. .sup.1H NMR (400 MHz, CDCl3): 6.3356.612 (m, 2H); 6.7846.786 (d, J=0.8 Hz 1H); 7.3497.372 (t, J=9.2 Hz, 2H); 7.4197.449 (m, 3H) MS-ESI: m/z=306.3 [M+1].sup.+

(452) Synthesis of Compound 367: Similar to preparation of compound 359, compound 367 was prepared in 7.8% yield as a white solid. .sup.1H NMR (400 MHz, CDCl3): 1.9071.998 (t, J=36.4 Hz, 3H), 6.3386.614 (m, 2H); 6.780 (s, 1H); 7.4367.601 (m, 5H) MS-ESI: m/z=286.3 [M+1].sup.+

(453) Synthesis of Compound 368: Similar to preparation of compound 359, compound 368 was prepared in 10.2% yield as a white solid. .sup.1H NMR (400 MHz, CDCl3): 1.9051.996 (t, J=36.4 Hz, 3H), 6.3386.614 (m, 2H); 6.788 (s, 1H); 7.4237.466 (t, J=17.2 Hz, 3H), 7.6467.668 (d, J=8.8 Hz, 2H) MS-ESI: m/z=286.3 [M+1].sup.+

(454) Synthesis of Compound 371: Similar to the synthesis of compound 95, compound 371 was prepared in 82% yield as a white solid. MS-ESI: m/z=246.2 [M+1].sup.+, 248.2 [M+3].sup.+

(455) Synthesis of Compound 372: Similar to the synthesis of compound 95, compound 372 was prepared in 86% yield as a white solid. MS-ESI: m/z=270.0[M+1].sup.+

(456) Synthesis of Compound 373: Similar to the synthesis of compound 95, compound 373 was prepared in 88% yield as a white solid. MS-ESI: m/z=242.3 [M+1].sup.+

(457) Synthesis of Compound 374: Similar to the synthesis of compound 95, compound 374 was prepared in 60% yield as a white solid. MS-ESI: m/z=296.3 [M+1].sup.+

(458) Synthesis of Compound 376: Compound 376 was prepared as follows.

(459) ##STR00551##
5-bromo-2-methoxypyridine (0.66 g, 3.49 mmol) and 1,3,5-trimethyl-1 h-pyrazole-4-boronic acid pinacol ester (0.99 g, 4.19 mmol) were dissolved in a degassed DME/H.sub.2O mixture (14 mL, 10:1 ratio). Solid Na.sub.2CO.sub.3 (1.1 g, 10.47 mmol) was added, followed by Pd(PPh.sub.3).sub.4 (0.2 g, 0.17 mmol). The reaction mixture was heated at 80 C. for 18 h. Water was added until complete dissolution of the residual carbonate and the solution was stirred for additional 6 h at the same temperature. The organic layer was separated and evaporated under reduced pressure and the resulting crude mixture was purified by flash chromatography (SiO.sub.2; DCM/MeOH 20:1). 440 mg (66% yield) of pure product were obtained as a pale yellow solid. MS-ESI: m/z=218.3 [M+1].sup.+5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2(1H)-one (0.44 g, 2.3 mmol) was dissolved in EtOH (3 mL). An excess of 48% HBr aqueous solution (10 mL) was added and the reaction was heated at 90 C. for 24 h. The solvent was removed under reduced pressure and the crude was purified by flash chromatography (SiO.sub.2; AcOEt to AcOEt/MeOH 3.5:1). 400 mg (92% yield) of pure intermediate product were obtained as an off-white foam.

(460) Following general procedure H1A, compound 376 was prepared from this intermediate in 58% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.39-7.57 (m, 7H), 6.54 (d, 1H), 3.66 (s, 3H), 2.20 (s, 3H), 2.11 (s, 3H)

(461) Synthesis of Compound 377: Similar to the procedure for compound 376, compound 377 was prepared in 30% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.11 (s, 1H), 7.73 (dd, 1H), 7.51-7.63 (m, 1H), 7.47 (dd, 1H), 7.42 (dd, 1H), 7.39 (d, 1H), 7.03-7.15 (m, 1H), 6.53 (d, 1H), 3.66 (s, 3H), 2.19 (s, 3H), 2.10 (s, 3H), 2.05 (s, 3H)

(462) Synthesis of Compound 378: Compound 378 was prepared as follows.

(463) ##STR00552##
2-bromo pyrimidine (0.55 g, 3.49 mmol) and 2-methoxy-5-pyridineboronic acid (0.53 g, 3.49 mmol) were dissolved in a degassed mixture of DME/H.sub.2O (11 mL, 10:1 ratio). Solid K.sub.2CO.sub.3 (1.4 g, 10.47 mmol) was added, followed by Pd(PPh.sub.3).sub.4 (0.2 g, 0.17 mmol). The reaction mixture was heated at 90 C. for 18 h. The organic layer was separated and evaporated under vacuum. The resulting crude was purified by flash chromatography (SiO.sub.2; Pet. Ether/AcOEt 1:1). 420 mg (65% yield) of pure product were obtained as a pale yellow solid. MS-ESI: m/z=188 [M+1].sup.+ 2-(6-methoxypyridin-3-yl)pyrimidine (0.78 g, 4 mmol) was dissolved in EtOH (5 mL). An excess of 48% HBr aqueous solution (10 mL) was added and the reaction was heated at 90 C. for 24 h. The solvent was removed under reduced pressure and the residual hydrobromic acid was stripped at reduced pressure, at 40 C. The resulting off white solid was used in the next step without further purification. MS-ESI: m/z=174 [M+1].sup.+

(464) Following general procedure H1A, compound 378 was prepared from this intermediate in 30% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.82 (d, 2H) 8.56 (dd, 1 H) 8.41 (dd, 1H) 7.70 (m, 2H) 7.51-7.60 (m, 2H) 7.38 (t, 1H) 6.66 (dd, 1 H)

(465) Synthesis of Compound 379: Compound 379 was prepared as follows.

(466) ##STR00553##
The 5-iodo-1-arylpyridin-2(1H)-one (1 eq), the boronic acid (1.2 eq) and K.sub.2CO.sub.3 (3 eq) were dissolved in a 10:1 mixture of DME/H.sub.2O (4 ml/mmol). The solution was degassed by bubbling N.sub.2 for 15 min and then Pd(PPh.sub.3).sub.4 (0.05 eq) was added. The reaction mixture was heated at 90 C. for 18 h, after which time, BOC protecting group was completely cleaved. Mixture was cooled at room temperature, diluted with AcOEt and filtered on a celite plug. The filtrate was washed with brine. The separated organic phase was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by column chromatography (EtOAc:Hexanes 3:7 to 1:1) to afford compound 379 as a pale yellow solid (11% yield). .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.12 (s, 1H), 7.98 (s, 2H), 7.80-7.87 (m, 1H), 7.69 (t, 1H), 7.56-7.64 (m, 1H), 7.10 (ddd, 1H), 6.54 (dd, 1H), 2.06 (s, 3H)

(467) Synthesis of Compound 380: Compound 380 was prepared as follows.

(468) ##STR00554##
Following the standard procedure for Suzuki coupling the intermediate was obtained by reaction of 3 g (16 mmol) of 5-bromo-2-methoxy-pyridine. After purification (SiO.sub.2; Hexanes:EtOAc 9:1) 1.4 g (31% yield) of pure product were obtained as white solid. 2-methoxy-5-(4-methoxyphenyl)pyridine (1.4 g, 4.96 mmol) was dissolved in HBr 48% (12 ml) and EtOH (6 ml) and the solution was heated at reflux for 24 h. After evaporation of volatiles the desired pyridone was obtained as white solid (0.99 g, quantitative yield).

(469) Following general procedure H1A, compound 380 was prepared in 40% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.85-7.98 (m, 2H), 7.66 (m, 2H), 7.47-7.61 (m, 4H), 6.97 (m, 2H), 6.51-6.65 (m, 1H), 3.77 (s, 3H)

(470) Synthesis of Compound 381: Compound 381 was prepared as follows.

(471) ##STR00555##
The product was obtained by reaction of 963 mg (6.3 mmol) of 2-methoxy-pyridine-5-boronic acid. After purification (SiO.sub.2; Hexanes:EtOAc 1:1) 747 mg (65% yield) of pure product were obtained as white solid. 2-(6-methoxypyridin-3-yl)pyrimidine (747 mg) was dissolved in HBr 48% (10 ml) and EtOH (5 ml) and the solution was heated at reflux overnight. After evaporation of volatiles the desired pyridone was obtained as white solid (1.016 g, quantitative yield).

(472) Following general procedure H1A, compound 381 was prepared from this intermediate in 14% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.81 (d, 2H), 8.53 (dd, 1 H), 8.40 (dd, 1H), 7.42-7.65 (m, 5H), 7.37 (dd, 1H), 6.65 (d, 1H)

(473) Synthesis of Compound 382: Similar to compound 381, compound 382 was prepared in 33% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.16 (s, 1H), 8.81 (d, 2H), 8.53 (dd, 1H), 8.39 (dd, 1H), 7.76-7.84 (m, 1H), 7.55-7.66 (m, 1H), 7.47 (dd, 1H), 7.37 (dd, 1H), 7.18 (ddd, 1H), 6.64 (dd, 1H), 2.07 (s, 3H)

(474) Synthesis of Compound 383: Compound 383 was prepared as follows.

(475) ##STR00556##
5-iodo-1-phenyl-1H-pyridin-2-one (0.34 g, 1.13 mmol) was dissolved in dry and degassed toluene 5 mL). The catalyst was then added (0.065 g, 0.057 mmol) and the mixture was stirred for 10 minutes. 1-methyl-4-(tributylstannyl)-3-(trifluoromethyl)-1H-pyrazole (0.49 g, 1.13 mmol) was added and the reaction was heated at 90 C. for 18 h under nitrogen atmosphere. Conc. NH.sub.4OH was added. The solvent was removed at reduced pressure and the crude was purified by elution through basic alumina (Hexanes:EtOAc 1:1). 37 mg (10% yield) of compound 383 were obtained as a pale yellow solid. .sup.1H NMR (300 MHz, DMSO-d6) d ppm 7.99 (d, 1H), 7.75 (dd, 1H), 7.38-7.62 (m, 5H), 6.91 (s, 1H), 6.62 (dd, 1H), 3.94 (s, 3H)

(476) Synthesis of Compound 384: Compound 384 was prepared as follows.

(477) ##STR00557##
N-(3-(5-iodo-2-oxopyridin-1(2H)-yl)phenyl)acetamide (0.050 g, 0.14 mmol) was dissolved in dry and degassed toluene (3 mL). The catalyst was then added (0.008 g, 0.007 mmol) and the mixture was stirred for 10 minutes. 2-(tributylstannyl)oxazole (0.050 g, 0.14 mmol) was added and the reaction was heated at 90 C. for 18 h under nitrogen atmosphere. Conc. NH.sub.4OH was added. The solvent was removed at reduced pressure and the crude was purified by preparative HPLC. 16 mg (38.7% yield) of compound 384 were obtained as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) ppm 10.15 (br. s., 1H), 8.16-8.21 (m, 1H), 8.14 (d, 1H), 8.02 (dd, 1H), 7.76 (t, 1H), 7.61 (ddd, 1H), 7.46 (dd, 1H), 7.32 (d, 1H), 7.16 (ddd, 1H), 6.65 (dd, 1H), 2.07 (s, 3H)

(478) Synthesis of Compound 385: Compound 385 was prepared as follows.

(479) ##STR00558##
Following standard Suzuki coupling, the product was obtained by reaction of 2.82 g (15 mmol) of 5-bromo-2-methoxy-pyridine. After purification (SiO.sub.2; Hexanes:EtOAc 9:1) 2.8 g (92% yield) of pure product were obtained as white solid. The intermediate (900 mg) was dissolved in HBr 48% (10 ml) and EtOH (3 ml) and the solution was heated at reflux for 3 h. After evaporation of volatiles the desired pyridone was obtained as white solid (780 mg, 93% yield).

(480) Following general procedure H1A, compound 385 was prepared in 35% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.86-7.99 (m, 1H), 7.82 (d, 1H), 7.58-7.73 (m, 2H), 7.12-7.30 (m, 3H), 6.94 (d, 1H), 6.87 (dd, 1H), 6.58 (d, 1H), 4.08 (q, 2H), 2.04 (s, 3H), 1.35 (t, 3H)

(481) Synthesis of Compound 386: Compound 386 was prepared as follows.

(482) ##STR00559##
Following standard procedure for Suzuki coupling, the intermediate was obtained by reaction of 3 g (16 mmol) of 5-bromo-2-methoxy-pyridine. After purification (SiO.sub.2; Hexanes:EtOAc 20:1 to 100% EtOAc) 2.2 g (51% yield) of pure product were obtained as white solid. To a magnetically stirred solution of 2-Methoxy-5-(1-methyl-1H-pyrazol-4-yl)-pyridine (1.2 g, 6.3 mmol), in 3 mL of EtOH, 15 mL of HBr were added. The mixture was heated at 80 C. for 20 h. The reaction was cooled at room temperature. The solvent was evaporated under vacuum. Purification by flash column chromatography (SiO.sub.2; 100% AcOEt) afforded 1.1 g of the intermediate compound (quantitative yield).

(483) Following general .[.provedure.]. .Iadd.procedure .Iaddend.H1A, compound 386 was prepared from this intermediate in 22% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.01 (s, 1H), 7.71-7.81 (m, 3H), 7.16 (d, 1H), 6.94 (d, 1H), 6.86 (dd, 1H), 6.52 (dd, 1H), 4.08 (q, 2H), 3.81 (s, 3 H), 2.02 (s, 3H), 1.35 (t, 3H)

(484) Synthesis of Compound 387: Compound 387 was prepared as follows.

(485) ##STR00560##
Following the standard procedure for Suzuki coupling, the intermediate was obtained by reaction of 3.2 g (16 mmol) of 5-bromo-2-methoxy-4-methylpyridine. After purification (SiO.sub.2; Hexanes:EtOAc 20:1 to 100% EtOAc) 2 g (62% yield) of pure product was obtained as white solid. A solution of 2-methoxy-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)pyridine (2 g, 9.9 mmol) in EtOH (6 ml) and HBr 48% (12 ml) was stirred at 90 C. for 24 h. The solvent was evaporated and the crude compound (as hydrobromide salt) was utilized in the next step without any purification. Quantitative yield.

(486) Following general procedure H1A, compound 387 was prepared from this intermediate in 33% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.88 (s, 1H), 7.59 (d, 1 H), 7.34-7.55 (m, 6H), 6.43 (s, 1H), 3.84 (s, 3H), 2.23 (d, 3H)

(487) Synthesis of Compound 388: Similar to compound 387, compound 388 was prepared in 41% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.10 (s, 1H), 7.87 (s, 1H), 7.69 (t, 1H), 7.51-7.61 (m, 2H), 7.48 (s, 1H), 7.41 (dd, 1H), 7.08 (ddd, 1H), 6.42 (s, 1H), 3.84 (s, 3H), 2.23 (d, 3H), 2.05 (s, 3H)

(488) Synthesis of Compound 389: Compound 389 was prepared as follows.

(489) ##STR00561##
Following standard procedure for Suzuki coupling, the intermediate was obtained by reaction of 420 mg (3 mmol) of 5-bromo-2-methoxy-pyridine. After purification (SiO.sub.2; Hexanes:EtOAc 95:5) 390 mg (65% yield) of pure product was obtained as white solid. The intermediate (390 mg) was dissolved in HBr 48% (5 ml) and EtOH (5 ml) and the solution was heated at reflux for 24 h. After evaporation of volatiles the desired pyridone was obtained as white solid (359 mg, quantitative yield).

(490) Following general procedure H1A, compound 389 was prepared from this intermediate in 51% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.06 (d, 1H), 7.97 (dd, 1 H), 7.34-7.61 (m, 8H), 7.00-7.20 (m, 1H), 6.60 (d, 1H)

(491) Synthesis of Compound 390: Similar to compound 389, compound 390 was prepared in 38% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.13 (s, 1H), 8.05 (d, 1H), 7.97 (dd, 1H), 7.70-7.77 (m, 1H), 7.58-7.65 (m, 1H), 7.49-7.58 (m, 1 H), 7.36-7.49 (m, 3H), 7.02-7.20 (m, 2H), 6.60 (d, 1H), 2.06 (s, 3H)

(492) Synthesis of Compound 391: Similar to compound 387, compound 391 was prepared in 26% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.86 (s, 1H), 7.57 (d, 1H), 7.35 (s, 1H), 7.12 (d, 1H), 6.91 (d, 1H), 6.84 (dd, 1H), 6.40 (s, 1H), 4.06 (q, 2H), 3.83 (s, 3H), 2.24 (d, 3H), 2.02 (s, 3H), 1.34 (t, 3H)

(493) Synthesis of Compound 392: Compound 392 was prepared from the intermediate aryl group as follows.

(494) ##STR00562##
Following the standard procedure for Suzuki coupling, the product was obtained by reaction of 2.7 g (14.4 mmol) of 5-bromo-2-methoxy-pyridine. After purification (SiO.sub.2; Hexanes:EtOAc 1:1 to 100% EtOAc) 1.29 g mg (48% yield) of pure product was obtained as white solid. A solution of 5-(6-Methoxy-pyridin-3-yl)-pyrimidine (1.29 g, 6.9 mmol) in EtOH (4 ml) and HBr 48% (10 ml) was stirred at 90 C. for 7 h. The solvent was evaporated and the crude compound (as hydrobromide salt) was utilized in the next step without any purification.

(495) Following general procedure H1A, compound 392 was prepared from this intermediate in 21% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 9.07-9.12 (m, 3H), 8.14 (dd, 1H), 8.06 (dd, 1H), 7.21 (d, 1H), 6.96 (d, 1H), 6.88 (dd, 1H), 6.64 (dd, 1H), 4.08 (q, 2H), 2.06 (s, 3H), 1.35 (t, 3H)

(496) Synthesis of Compound 393: Similar to synthesis of compound 380, compound 393 was prepared in 41% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.66-8.83 (m, 2H), 7.85-7.97 (m, 2H), 7.61-7.68 (m, 2H), 7.58 (m, 2H), 6.98 (m, 2H), 6.54-6.66 (m, 1H), 3.78 (s, 3H)

(497) Synthesis of Compound 394: Similar to synthesis of compound 380, compound 394 was prepared in 33% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.82-7.92 (m, 2H), 7.43-7.61 (m, 7H), 6.97 (m, 2H), 6.58 (dd, 1H), 3.77 (s, 3H)

(498) Synthesis of Compound 395: Similar to synthesis of compound 380, compound 395 was prepared in 42% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.12 (s, 1H), 7.88 (dd, 1H), 7.83 (d, 1H), 7.70-7.76 (m, 1H), 7.58-7.64 (m, 1H), 7.54 (m, 2 H), 7.44 (dd, 1 H), 7.14 (ddd, 1H), 6.97 (m, 2H), 6.57 (d, 1H), 3.77 (s, 3H), 2.06 (s, 3H)

(499) Synthesis of Compound 396: Similar to compound 387, compound 396 was prepared in 23% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.88 (s, 1H), 7.43-7.69 (m, 6H), 6.45 (s, 1H), 3.84 (s, 3H), 2.24 (d, 3H)

(500) Synthesis of Compound 397: Compound 397 was prepared from an intermediate heteroaryl prepared as follows.

(501) ##STR00563##
Following the standard procedure for Suzuki coupling, the intermediate was obtained by reaction of 3 g (16 mmol) of 5-bromo-2-methoxy-pyridine. After purification (SiO.sub.2; Hexanes:EtOAc 1:1 to 100% EtOAc) 750 mg (31% yield) of pure product was obtained as white solid. 5-(2-fluorophenyl)-2-methoxypyridine (750 mg) was dissolved in HBr 48% (10 ml) and EtOH (3 ml) and the solution was heated at reflux for 3 h. After evaporation of volatiles the desired pyridone was obtained as white solid (700 mg, quantitative yield).

(502) Following general procedure H1A, compound 397 was prepared from this intermediate in 34% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.74-7.83 (m, 1H), 7.67-7.73 (m, 1H), 7.51-7.61 (m, 1H), 7.17-7.42 (m, 4H), 6.94 (d, 1H), 6.87 (dd, 1H), 6.59 (dd, 1H), 4.08 (q, 2H), 2.05 (s, 3H), 1.35 (t, 3H)

(503) Synthesis of Compound 398: Similar to compound 389, compound 398 was prepared in 30% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.13 (d, 1H), 7.99 (dd, 1H), 7.62-7.76 (m, 2H), 7.34-7.62 (m, 5H), 7.02-7.20 (m, 1H), 6.62 (d, 1H)

(504) Synthesis of Compound 399: Following general procedure A, compound 399 was prepared in 44% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 12.24 (br. s., 1H), 10.11 (s, 1 H), 7.73 (m, 1H), 7.57 (m, 1H), 7.51 (dd, 1H), 7.35-7.47 (m, 2H), 7.10 (ddd, 1H), 6.54 (d, 1H), 2.17 (br. s., 6H), 2.06 (s, 3H)

(505) Synthesis of Compound 400: Similar to synthesis of compound 380, compound 400 was prepared in 36% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.89 (dd, 1H), 7.72 (d, 1H), 7.53 (m, 2H), 7.19 (d, 1H), 6.91-7.04 (m, 3H), 6.86 (dd, 1H), 6.56 (d, 1H), 4.08 (q, 2H), 3.77 (s, 3H), 2.04 (s, 3H), 1.35 (t, 3H)

(506) Synthesis of Compound 401: Compound 401 was synthesized as follows.

(507) ##STR00564##
6-methoxynicotinaldehyde (1.0 g, 7.2 mmol) was dissolved in HBr 48% (10 mL) and EtOH (3 mL) and the solution was heated at reflux for 2 h. After evaporation of volatiles 1.6 g of the desired pyridone was obtained. The product was used in the next step without further purification. To a solution of 6-oxo-1,6-dihydropyridine-3-carbaldehyde (300 mg, 2.4 mmol) in DMF (10 mL), Cu(OAc)2 (0.88 g, 4.8 mmol), 3-acetamidophenyl boronic acid (0.5 g, 2.8 mmol), pyridine (0.42 mL, 2.8 mmol) and finely grounded, activated 4 A molecular sieves (1 g) were added. The mixture was stirred at room temperature for 24 h. A concentrated solution of NH.sub.4OH was added. The solvents were evaporated under vacuum, and the resulting crude was purified by chromatographic column (SiO.sub.2; Hexanes:EtOAc 9:1 to 100% EtOAc). 370 mg (38.5% yield) of pure product were obtained as a white solid. To a solution of N-(3-(5-formyl-2-oxopyridin-1(2H)-yl)phenyl)acetamide (370 mg, 0.94 mmol) in MeOH (20 mL), glioxal (0.4 mL, 3.4 mmol) was added at 0 C. Gaseous NH.sub.3 was bubbled into the mixture at 0 C. for 1 h. The reaction was warmed at room temperature and stirred for 24 h. The solvent was evaporated under vacuum and the resulting crude was purified by flash chromatography (SiO.sub.2, Hexanes:EtOAc 9:1 to 100% EtOAc). 100 mg (24.6% yield) of compound 401 were obtained. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.20 (s, 1H), 8.49 (d, 1H), 8.03 (dd, 1H), 7.83-7.91 (m, 1H), 7.67 (s, 2H), 7.54-7.62 (m, 1H), 7.50 (dd, 1H), 7.15 (ddd, 1H), 6.75 (d, 1H), 2.07 (s, 3H)

(508) Synthesis of Compound 402: Following general procedure H1A, compound 402 was prepared in 17% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.16 (s, 1H), 8.24-8.34 (m, 1H), 8.19 (d, 1H), 7.69-7.79 (m, 1H), 7.56-7.65 (m, 1H), 7.38-7.51 (m, 1H), 7.16 (ddd, 1H), 2.06 (s, 3H)

(509) Synthesis of Compound 403: Similar to compound 387, compound 403 was prepared in 34% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.71 (dd, 2H), 7.90 (s, 1H), 7.54-7.64 (m, 4H), 6.47 (s, 1H), 3.85 (s, 3H), 2.24 (d, 3H)

(510) Synthesis of Compound 405: Compound 405 was prepared from an intermediate heteroaryl synthesized as follows.

(511) ##STR00565##
A mixture of 2-methoxy-5-aminopyridine (10 g, 0.08 mol) in AcOH (125 mL), and concentrated HCl (150 mL) was cooled at 0 C. in an ice/water bath. A solution of NaNO.sub.2 (4.0 g, 0.058 mol) in water (15 mL) was added dropwise at 0 C. The resulting mixture was stirred for 45 minutes at 0 C. In the meantime, in a separate round bottom flask, 150 mL of concentrated HCl was added dropwise to a sodium bisulphite solution. The gaseous SO.sub.2 thus formed was purged for 2-3 h into a third round bottom flask containing AcOH cooled at 20 C. CuCl.sub.2 (18 g) was added, and the reaction was stirred for 20 minutes at 20 C. The mixture was added dropwise to the 2-methoxy-5-aminopyridine/AcOH/concentrated HCl mixture maintained at 0 C. The reaction was allowed to warm up to room temperature and stirred overnight. The mixture was quenched with water and the solid thus formed was filtered, re-dissolved in DCM and filtered through celite. The clear solution was dried over Na.sub.2SO.sub.4 and concentrated under vacuum to afford 10.2 g (61% yield) of pure 6-methoxy-pyridine-3-sulfonyl chloride. 6-Methoxy-pyridine-3-sulfonyl chloride (5.0 g, 0.025 mol) was dissolved in DCM and cooled at 0 C. .[.Gasseous.]. .Iadd.Gaseous .Iaddend.NH.sub.3 was bubbled in the solution for 10 min. The resulting pale brown suspension was filtered and the solid was triturated with water. The resulting white solid was filtered and dried under vacuum to afford 3.2 g (70.6% yield) of pure 6-Methoxy-pyridine-3-sulfonamide. 6-Methoxy-pyridine-3-sulfonamide (0.752 g, 4.0 mmol) was dissolved in EtOH (6 mL). An excess of 48% HBr aqueous solution (12 mL) was added and the reaction was heated at 90 C. for 20 h. The solvent was removed under reduced pressure and the residual hydrobromic acid was further dried under reduced pressure, at 40 C. Quantitative yield.

(512) Following general procedure H1A, compound 405 was prepared from this intermediate in 28% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.86 (d, 1H), 7.79 (dd, 1 H), 7.35 (s, 2H), 7.19 (d, 1H), 6.96 (d, 1H), 6.88 (dd, 1H), 6.64 (d, 1H), 4.08 (q, 2H), 2.02 (s, 3H), 1.35 (t, 3H)

(513) Synthesis of Compound 406: Following general procedure H1A, compound 406 was prepared in 38% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.29 (dd, 1H), 8.20 (d, 1 H), 7.42-7.65 (m, 5H)

(514) Synthesis of Compound 407: Compound 407 was prepared as follows:

(515) ##STR00566##
Following the standard procedure for Suzuki coupling, the product was obtained by reaction of 1.02 g (5.4 mmol) of 5-bromo-2-methoxy-pyridine. After purification (SiO.sub.2; Hexanes:EtOAc 20:1 to 100% EtOAc) 1.12 g (96% yield) of pure product were obtained as white solid. A solution of 2-Methoxy-5-(4-methoxy-phenyl)-pyridine (1.12 g, 5.2 mmol) in EtOH (5 ml) and HBr 48% (10 ml) was stirred at 80 C. for 48 h. The solvent was evaporated and the crude compound (as hydrobromide salt) was utilized in the next step without any purification (quantitative yield).

(516) Compound 407 was prepared from this intermediate using general procedure H1A in 35% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.98 (dd, 1H), 7.93 (dd, 1H), 7.39-7.62 (m, 5H), 7.32 (dd, 1H), 7.13-7.23 (m, 2H), 6.81-6.92 (m, 1H), 6.59 (dd, 1H), 3.80 (s, 3H)

(517) Synthesis of Compound 408: Similar to compound 407, compound 408 was prepared in 38% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.05 (d, 1H), 7.95 (dd, 1H), 7.67 (m, 2H), 7.54 (m, 2H), 7.32 (dd, 1H), 7.15-7.24 (m, 2H), 6.83-6.93 (m, 1H), 6.61 (d, 1H), 3.80 (s, 3H)

(518) Synthesis of Compound 409: Compound 409 was prepared as follows.

(519) ##STR00567##
Following standard procedure for Suzuki coupling the intermediate was obtained by reaction of 3 g (16 mmol) of 5-bromo-2-methoxy-pyridine. After purification (SiO.sub.2; Hexanes:EtOAc 9:1) 3.1 g (70% yield) of pure product were obtained as white solid. The intermediate (3.1 g) was dissolved in HBr 48% (10 ml) and EtOH (5 ml) and the solution was heated at reflux for 24 h. After evaporation of volatiles the desired pyridone was obtained as white solid (2.9 g, quantitative yield).

(520) Compound 409 was prepared following general procedure H1A in 36% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.73 (dd, 1H), 7.69 (dd, 1H), 7.41-7.57 (m, 5H), 7.37 (dd, 1H), 7.32 (ddd, 1H), 7.09 (dd, 1H), 6.99 (ddd, 1H), 6.53 (dd, 1H), 3.80 (s, 3H)

(521) Synthesis of Compound 410: Similar to the preparation of compound 409, compound 410 was prepared in 13% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.70-7.79 (m, 2H), 7.66 (m, 2H), 7.52 (m, 2H), 7.38 (dd, 1H), 7.33 (ddd, 1H), 7.10 (dd, 1H), 6.99 (td, 1H), 6.55 (d, 1H), 3.80 (s, 3H)

(522) Synthesis of Compound 411: Following general procedure A, compound 411 was prepared in 51% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 12.24 (br. s., 1H), 7.37-7.59 (m, 7H), 6.54 (dd, 1H), 2.17 (br. s., 6H)

(523) Synthesis of Compound 412: Similar to the preparation of compound 409, compound 412 was prepared in 26% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.74 (dd, 1H), 7.55 (d, 1H), 7.25-7.38 (m, 2H), 7.18 (d, 1H), 7.08 (dd, 1H), 6.98 (ddd, 1H), 6.94 (d, 1H), 6.85 (dd, 1H), 6.52 (d, 1H), 4.07 (q, 2H), 3.79 (s, 3H), 2.06 (s, 3H), 1.35 (t, 3H)

(524) Synthesis of Compound 413: Compound 413 was prepared as follows.

(525) ##STR00568##
To a suspension of A (2.9 mmol) in a MeOH:Water (10 mL:1 mL) mixture, a solution of NaOH in water (2.9 mmol in 2 mL of Water) was added at 30 C. To the stirred reaction, a solution of 2-aminoacetamide (2.9 mmol) in MeOH (2 mL) was added. The mixture was stirred at the same temperature for 1 h, then warmed at room temperature and stirred for additional 3 h. AcOH was added until pH 5 and the volatile portion was evaporated under vacuum. The remaining mixture was portioned between Water (10 mL) and Ethyl Acetate (10 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated under vacuum.

(526) Following general procedure H1A, compound 413 was prepared from this intermediate in 51% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.26 (d, 1H), 8.21 (d, 1 H), 7.87-8.00 (m, 2H), 7.48-7.62 (m, 5H), 7.38-7.47 (m, 2H), 7.28-7.36 (m, 1H)

(527) Synthesis of Compound 415: Similar to compound 407, compound 415 was prepared in 23% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.12 (s, 1H), 7.86-8.01 (m, 2H), 7.73 (t, 1H), 7.53-7.68 (m, 1H), 7.44 (dd, 1H), 7.32 (dd, 1H), 7.10-7.23 (m, 3H), 6.80-6.93 (m, 1H), 6.59 (dd, 1H), 3.79 (s, 3H), 2.06 (s, 3H)

(528) Synthesis of Compound 416: Compound 416 was prepared as follows.

(529) ##STR00569##
Following the standard procedure for Suzuki coupling, the product was obtained by reaction of 1.02 g (5.4 mmol) of 5-bromo-2-methoxy-pyridine. After purification (SiO.sub.2; Hexanes:EtOAc 20:1 to 100% EtOAc)) 1.06 g (89% yield) of pure product were obtained as white solid. A solution of 2-Methoxy-5-(4-methoxy-phenyl)-pyridine (1.12 g, 5.2 mmol) in EtOH (5 ml) and HBr 48% (10 ml) was stirred at 80 C. overnight. The solvent was evaporated and the crude compound (as hydrobromide salt) was utilized in the next step without any purification (quantitative yield).

(530) Compound 416 was prepared from this intermediate following general procedure H1A in 41% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.00 (d, 1H), 7.93 (dd, 1H), 7.68 (m, 2H), 7.36-7.59 (m, 7H), 6.60 (d, 1H)

(531) Synthesis of Compound 417: Similar to compound 416, compound 417 was prepared in 44% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.13 (s, 1H), 7.99 (d, 1H), 7.93 (dd, 1H), 7.71-7.78 (m, 1H), 7.67 (m, 2H), 7.54-7.63 (m, 1H), 7.39-7.49 (m, 3H), 7.07-7.19 (m, 1H), 6.60 (d, 1H), 2.06 (s, 3H)

(532) Synthesis of Compound 418: Similar to compound 407, compound 418 was prepared in 16% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.95 (dd, 1H), 7.86 (d, 1H), 7.30 (dd, 1H), 7.11-7.24 (m, 3H), 6.95 (d, 1H), 6.80-6.91 (m, 2H), 6.57 (d, 1H), 4.08 (q, 2H), 3.79 (s, 3H), 2.04 (s, 3H), 1.35 (t, 3H)

(533) Synthesis of Compound 419: Following general procedure H1A, compound 419 was prepared in 28% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.33-8.44 (m, 1H), 8.21 (d, 1H), 7.68 (m, 2H), 7.56 (m, 2H)

(534) Synthesis of Compound 420: Similar to compound 416, compound 420 was prepared in 33.8% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.94 (dd, 1H), 7.89 (d, 1 H), 7.65 (m, 2H), 7.44 (m, 2H), 7.20 (d, 1H), 6.94 (d, 1H), 6.87 (dd, 1H), 6.59 (d, 1H), 4.08 (q, 2H), 2.04 (s, 3H), 1.35 (t, 3H)

(535) Synthesis of Compound 421: Similar to compound 416, compound 421 was prepared in 31.5% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.07 (d, 1H), 7.95 (dd, 1 H), 7.63-7.73 (m, 4H), 7.53 (m, 2H), 7.46 (m, 2H), 6.62 (d, 1H)

(536) Synthesis of Compound 422: Similar to compound 413, compound 422 was prepared in 35% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.25 (d, 1H), 8.23 (d, 1H), 7.91-8.03 (m, 2H), 7.44-7.65 (m, 5H), 7.17-7.33 (m, 2H)

(537) Synthesis of Compound 423: Similar to compound 407, compound 423 was prepared in 34% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.63-8.87 (m, 2H), 8.04 (d, 1H), 7.97 (dd, 1H), 7.58-7.69 (m, 2H), 7.33 (t, 1H), 7.15-7.27 (m, 2H), 6.81-6.94 (m, 1 H), 6.63 (d, 1H), 3.80 (s, 3H)

(538) Synthesis of Compound 424: Compound 424 was prepared as follows.

(539) ##STR00570##

(540) ##STR00571##
In a round bottom flask, glyoxylic acid .[.acid.]. B (22 mmol) and 4-F acetophenone A (8 mmol) were mixed together and the reaction was heated at 115 C. overnight, then allowed to cool down at room temperature. Water (5 mL) and concentrated NH.sub.4OH (1 mL), were poured into the reaction vessel and the mixture was extracted with DCM (35 mL). To the aqueous basic solution hydrazine (8 mmol) was added and the reaction was stirred at 100 C. for 2 h. The precipitate thus formed was collected by filtration and washed with plenty of water. The desired compound was recovered as a light yellow solid (45% yield). .sup.1H NMR (300 MHz, DMSO-d6) ppm 13.15 (br. s., 1H) 8.01 (d, 1H) 7.91 (m, 2H) 7.31 (m, 2H) 6.97 (d, 1H)

(541) Following general procedure .[.HIA.]. .Iadd.H1A.Iaddend., compound 424 was prepared from this intermediate in 74% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.12 (s, 1H), 8.14 (d, 1 H), 7.94-8.01 (m, 2H), 7.90-7.94 (m, 1H), 7.57-7.66 (m, 1H), 7.43 (t, 1 H), 7.28-7.39 (m, 3H), 7.18 (d, 1H), 2.06 (s, 3H)

(542) Synthesis of Compound 425: Compound 425 was prepared as follows.

(543) ##STR00572##
Following standard procedure for Suzuki coupling, the intermediate was obtained by reaction of 3 g (16 mmol) of 5-bromo-2-methoxy-pyridine. After purification (SiO.sub.2; Hexanes:EtOAc 1:1 to 100% EtOAc) 3.99 g (95% yield) of pure product was obtained as white solid. The intermediate (3.99 g) was dissolved in HBr 48% (12 ml) and EtOH (6 ml) and the solution was heated at reflux for 24 h. After evaporation of volatiles the desired pyridone was obtained as white solid (3.72 g, quantitative yield).

(544) Compound 425 was prepared following general procedure H1A with this intermediate in 42% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.74 (d, 1H), 7.67 (dd, 1 H), 7.32-7.60 (m, 9H), 6.57 (d, 1H)

(545) Synthesis of Compound 426: Following general procedure H1A, compound 426 was prepared in 8% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 9.30 (s, 1H), 9.04 (s, 2H), 8.47-8.64 (m, 1H), 8.28 (d, 1H)

(546) Synthesis of Compound 427: Similar to the preparation of compound 409, compound 427 was prepared in 45% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.67-8.79 (m, 2H), 7.68-7.82 (m, 2H), 7.59-7.68 (m, 2H), 7.39 (dd, 1H), 7.34 (ddd, 1H), 7.10 (dd, 1H), 7.00 (td, 1H), 6.54-6.61 (m, 1H), 3.80 (s, 3H)

(547) Synthesis of Compound 428: Similar to compound 424, compound 428 was prepared in 94% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.14 (d, 1H), 7.90-8.04 (m, 2 H), 7.61-7.71 (m, 2H), 7.49-7.59 (m, 2H), 7.40-7.49 (m, 1H), 7.26-7.40 (m, 2H), 7.19 (d, 1H)

(548) Synthesis of Compound 429: Following general procedure A, compound 429 was prepared in 26% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.14 (s, 1H), 8.19 (t, 1H), 8.17 (d, 1H), 7.94-8.08 (m, 2H), 7.69-7.81 (m, 2H), 7.52-7.66 (m, 2H), 7.45 (dd, 1H), 7.10-7.21 (m, 1H), 6.62 (d, 1H), 2.07 (s, 3H)

(549) Synthesis of Compound 430: Following general procedure A, compound 430 was prepared in 44% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.13 (s, 1H), 8.17 (d, 1H), 7.98-8.06 (m, 1H), 7.81-7.91 (m, 4H), 7.71-7.78 (m, 1H), 7.56-7.66 (m, 1H), 7.45 (t, 1 H), 7.15 (ddd, 1H), 6.63 (d, 1H), 2.06 (s, 3H)

(550) Synthesis of Compound 431: Similar to compound 416, compound 431 was prepared in 20.3% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 9.25 (s, 1H), 9.07 (s, 2H), 8.22 (d, 1H), 8.00 (dd, 1H), 7.69 (m, 2H), 7.48 (m, 2H), 6.66 (d, 1H)

(551) Synthesis of Compound 432: Similar to preparation of compound 433, compound 432 was prepared in 6.7% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 9.26 (s, 1H), 9.08 (s, 2H), 8.29 (d, 1H), 8.04 (dd, 1H), 7.79 (t, 1H), 7.60-7.69 (m, 1H), 7.46 (dd, 1H), 7.33-7.42 (m, 1H), 6.67 (d, 1H)

(552) Synthesis of Compound 433: Compound 433 was prepared as follows.

(553) ##STR00573##
Following standard procedure for Suzuki coupling, the product was obtained by reaction of 1.02 g (5.4 mmol) of 5-bromo-2-methoxy-pyridine. After purification (SiO.sub.2; Hexanes:EtOAc 20:1 to 100% EtOAc) 1.06 g (80% yield) of pure product were obtained as white solid. A solution of 2-Methoxy-5-(4-methoxy-phenyl)-pyridine (949 mg, 4.3 mmol) in EtOH (10 ml) and HBr 48% (10 ml) was stirred at 80 C. overnight. The solvent was evaporated and the crude compound (as hydrobromide salt) was utilized in the next step without any purification (quantitative yield).

(554) Compound 433 was prepared following general procedure H1A from this intermediate in 13% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.14 (d, 1H), 7.98 (dd, 1 H), 7.78 (t, 1H), 7.67 (m, 2H), 7.62 (ddd, 1H), 7.54 (m, 2H), 7.43 (dd, 1H), 7.35 (ddd, 1 H), 6.62 (d, 1H)

(555) Synthesis of Compound 434: Similar to the preparation of compound 425, compound 434 was prepared in 30% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.12 (br. s., 1H), 7.74-7.78 (m, 1H), 7.70-7.74 (m, 1H), 7.67 (dd, 1H), 7.47-7.62 (m, 3H), 7.35-7.47 (m, 3H), 7.14 (ddd, 1H), 6.57 (dd, 1H), 2.06 (s, 3H)

(556) Synthesis of Compound 435: Similar to the preparation of compound 409, compound 435 was prepared in 20% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.12 (s, 1 H), 7.77 (t, 1H), 7.72 (dd, 1H), 7.69 (dd, 1H), 7.52-7.61 (m, 1H), 7.43 (dd, 1H), 7.28-7.39 (m, 2H), 7.14 (ddd, 1H), 7.09 (dd, 1H), 6.99 (ddd, 1H), 6.53 (dd, 1H), 3.80 (s, 3H), 2.06 (s, 3H)

(557) Synthesis of Compound 436: Similar to the preparation of compound 409, compound 436 was prepared in 23% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 9.24 (s, 1 H), 9.06 (s, 2H), 7.89 (dd, 1H), 7.79 (dd, 1H), 7.40 (dd, 1H), 7.35 (ddd, 1H), 7.11 (dd, 1 H), 7.01 (td, 1H), 6.59 (dd, 1H), 3.81 (s, 3H)

(558) Synthesis of Compound 437: Similar to the preparation of compound 425, compound 437 was prepared in 20% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.65-8.82 (m, 2H), 7.83 (d, 1H), 7.71 (dd, 1H), 7.61-7.66 (m, 2H), 7.50-7.61 (m, 2H), 7.36-7.45 (m, 2H), 6.62 (d, 1H)

(559) Synthesis of Compound 438: Compound 438 was prepared as follows.

(560) ##STR00574##
5-bromo-2-methoxy-4-methylpyridine (1.0 g, 4.95 mmol) was dissolved in HBr 48% (10 mL) and EtOH (10 mL) and the solution was heated at 90 C. for 24 h. After evaporation of volatiles, 930 mg (quantitative yield) of the desired pyridone were obtained as a white solid. 5-bromo-4-methyl-1-phenylpyridin-2(1H)-one was obtained by reaction of 450 mg (2.39 mmol) of 5-bromo-4-methylpyridin-2(1H)-one with phenylboronic acid. After purification (SiO.sub.2; Hexanes: EtOAc 9:1 to 1:1) 250 mg (39.7% yield) of compound 438 were obtained as a white solid. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.93 (s, 1H), 7.32-7.58 (m, 5H), 6.47-6.57 (m, 1H), 2.24 (d, 3H)

(561) Synthesis of Compound 439: Similar to compound 385, compound 439 was prepared in 51% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.84-7.98 (m, 2H), 7.58-7.74 (m, 2H), 7.43 (t, 1H), 7.16-7.30 (m, 2H), 6.97-7.13 (m, 3H), 6.59 (dd, 1H), 3.81 (s, 3H)

(562) Synthesis of Compound 440: Similar to compound 385, compound 440 was prepared in 47% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.98 (dd, 1H), 7.92 (dd, 1H), 7.64-7.74 (m, 2H), 7.57 (ddd, 1H), 7.29-7.41 (m, 2H), 7.15-7.29 (m, 2H), 6.61 (dd, 1 H)

(563) Synthesis of Compound 441: Similar to compound 385, compound 441 was prepared in 55% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.95 (dd, 1H), 7.91 (dd, 1H), 7.62-7.72 (m, 2H), 7.50-7.62 (m, 2H), 7.29-7.42 (m, 2H), 7.16-7.29 (m, 2H), 6.59 (dd, 1H)

(564) Synthesis of Compound 442: Following general procedure A, compound 442 was prepared in 68% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.13 (s, 1H), 8.02 (d, 1H), 7.94-8.01 (m, 1H), 7.78 (dd, 1H), 7.71 (t, 1H), 7.56-7.65 (m, 2H), 7.52 (dd, 1H), 7.45 (t, 1H), 7.12 (ddd, 1H), 6.57 (d, 1H), 2.06 (s, 3H)

(565) Synthesis of Compound 443: Following general procedure A, compound 443 was prepared in 55% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.14 (s, 1H), 8.16 (d, 1H), 8.03 (dd, 1H), 7.93 (s, 4H), 7.76 (s, 1H), 7.61 (dt, 1H), 7.46 (t, 1H), 7.16 (ddd, 1H), 6.64 (d, 1H), 3.23 (s, 3H), 2.07 (s, 3H)

(566) Synthesis of Compound 444: Following general procedure A, compound 444 was prepared in 70% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.14 (s, 1H), 8.18 (d, 1H), 8.14 (t, 1H), 8.03 (dd, 1H), 7.94-8.01 (m, 1H), 7.79-7.88 (m, 1H), 7.75 (s, 1H), 7.68 (t, 1H), 7.60-7.65 (m, 1H), 7.46 (t, 1H), 7.09-7.23 (m, 1H), 6.64 (d, 1H), 3.25 (s, 3H), 2.07 (s, 3H)

(567) Synthesis of Compound 445: Similar to compound 385, compound 445 was prepared in 54% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 11.29 (s, 1H), 10.06 (s, 1H), 8.44 (s, 1H), 8.03-8.11 (m, 1H), 7.85 (d, 1H), 7.65-7.76 (m, 1H), 7.62 (s, 1H), 7.36-7.48 (m, 2H), 7.22-7.35 (m, 3H), 7.02-7.14 (m, 2H), 6.23 (d, 1H), 4.71 (spt, 1H), 1.35 (d, 6H)

(568) Synthesis of Compound 446: Following general procedure A, compound 446 was prepared in 78% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.19-8.21 (m, 1H), 8.17 (d, 1 H), 7.93-8.07 (m, 2H), 7.74 (ddd, 1H), 7.60 (dd, 1H), 7.43-7.58 (m, 5H), 6.62 (d, 1H)

(569) Synthesis of Compound 447: Similar to compound 385, compound 447 was prepared in 25% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.82-7.94 (m, 2H), 7.57-7.74 (m, 2H), 7.41 (m, 2H), 7.16-7.30 (m, 2H), 7.06 (m, 2H), 6.48-6.65 (m, 1H), 3.82 (s, 3H)

(570) Synthesis of Compound 448: Similar to compound 385, compound 448 was prepared in 33% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.89 (dd, 1H), 7.83 (d, 1H), 7.57-7.69 (m, 2H), 7.39-7.51 (m, 1H), 7.35 (dd, 1H), 7.14-7.28 (m, 3H), 7.08 (td, 1H), 6.56 (d, 1H), 3.77 (s, 3H)

(571) Synthesis of Compound 449: Similar to compound 385, compound 449 was prepared in 38% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.99 (d, 1H), 7.92 (dd, 1H), 7.63-7.74 (m, 3H), 7.44-7.61 (m, 3H), 7.16-7.30 (m, 2H), 6.60 (dd, 1H)

(572) Synthesis of Compound 450: Following general procedure A, compound 450 was prepared in 82% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.17-8.21 (m, 1H), 8.15 (t, 1 H), 7.97-8.07 (m, 2H), 7.83 (ddd, 1H), 7.68 (dd, 1H), 7.41-7.62 (m, 5H), 6.64 (d, 1H), 3.25 (s, 3H)

(573) Synthesis of Compound 451: Following general procedure A, compound 451 was prepared in 70% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.04 (d, 1H), 7.97 (dd, 1H), 7.78 (dd, 1H), 7.40-7.63 (m, 7H), 6.57 (dd, 1H)

(574) Synthesis of Compound 452: Following general procedure A, compound 452 was prepared in 65% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 9.40 (s, 1H), 7.43-7.64 (m, 8H), 7.40 (dd, 1H), 7.32 (td, 1H), 7.24 (td, 1H), 6.57 (dd, 1H), 1.97 (s, 3H)

(575) Synthesis of Compound 453: Similar to preparation of compound 433, compound 453 was prepared in 52% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.13 (s, 1H), 8.07 (d, 1H), 7.96 (dd, 1H), 7.69-7.78 (m, 2H), 7.56-7.67 (m, 2H), 7.45 (dd, 1H), 7.43 (dd, 1 H), 7.35 (ddd, 1H), 7.15 (ddd, 1H), 6.59 (d, 1H), 2.06 (s, 3H)

(576) Synthesis of Compound 454: Following general procedure A, compound 454 was prepared in 60% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 9.95 (s, 1H), 7.84-7.95 (m, 2 H), 7.39-7.66 (m, 9H), 6.53-6.64 (m, 1H), 2.04 (s, 3H)

(577) Synthesis of Compound 455: Following general procedure A, compound 455 was prepared in 74% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.43 (dd, 1H), 7.98 (dd, 1H), 7.96 (d, 1H), 7.87-7.94 (m, 1H), 7.36-7.59 (m, 5H), 6.85 (dd, 1H), 6.60 (dd, 1H), 3.87 (s, 3H)

(578) Synthesis of Compound 456: Following general procedure A, compound 456 was prepared in 82% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.83 (d, 1H), 7.73 (dt, 1H), 7.64 (td, 1H), 7.42-7.58 (m, 5H), 7.34 (ddd, 1H), 7.15 (dddd, 1H), 6.60 (d, 1H)

(579) Synthesis of Compound 457: Following general procedure A, compound 457 was prepared in 82% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.11 (s, 1H), 7.81-7.92 (m, 2H), 7.73 (t, 1H), 7.60 (ddd, 1H), 7.44 (dd, 1H), 7.24 (d, 1H), 7.14 (ddd, 1H), 7.08 (dd, 1 H), 6.94 (d, 1H), 6.51-6.60 (m, 1H), 6.03 (s, 2H), 2.06 (s, 3H)

(580) Synthesis of Compound 458: Following general procedure A, compound 458 was prepared in 89% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.13 (s, 1H), 9.93 (s, 1H), 7.81-7.87 (m, 1H), 7.78-7.81 (m, 1H), 7.75 (br. s., 2H), 7.57-7.65 (m, 1 H), 7.49-7.55 (m, 1H), 7.45 (dd, 1H), 7.33 (dd, 1H), 7.28 (dt, 1H), 7.14 (ddd, 1H), 6.62 (dd, 1H), 2.06 (s, 3H), 2.04 (s, 3H)

(581) Synthesis of Compound 459: Following general procedure A, compound 459 was prepared in 56% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 9.68 (s, 1H), 7.74-7.85 (m, 2H), 7.40-7.58 (m, 5H), 7.33 (dd, 1H), 7.07-7.18 (m, 1H), 6.92 (dt, 1H), 6.85 (tt, 1H), 6.54 (dd, 1H)

(582) Synthesis of Compound 460: Following general procedure A, compound 460 was prepared in 63% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.13 (br. s., 1H), 9.42 (br. s., 1H), 7.79-7.85 (m, 1H), 7.46-7.58 (m, 4H), 7.44 (dd, 1H), 7.38 (dd, 1H), 7.32 (td, 1H), 7.23 (td, 1H), 7.10 (ddd, 1H), 6.56 (d, 1H), 2.06 (s, 3H), 1.97 (s, 3H)

(583) Synthesis of Compound 461: Similar to compound 385, compound 461 was prepared in 52% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.10 (s, 1H), 7.82-7.96 (m, 2H), 7.58-7.75 (m, 4H), 7.35-7.46 (m, 2H), 7.16-7.30 (m, 2H), 6.58 (dd, 1H), 2.08 (s, 3H)

(584) Synthesis of Compound 462: Following general procedure A, compound 462 was prepared in 45% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.13 (s, 1H), 8.06-8.14 (m, 1H), 7.92 (d, 1H), 7.84 (dd, 1H), 7.65-7.73 (m, 2H), 7.57-7.65 (m, 1H), 7.44 (dd, 1H), 7.10 (ddd, 1H), 6.94 (dd, 1H), 6.56 (dd, 1H), 2.06 (s, 3H)

(585) Synthesis of Compound 463: Following general procedure A, compound 463 was prepared in 28% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.17 (d, 1H), 8.02 (dd, 1H), 7.93 (s, 4H), 7.41-7.61 (m, 5H), 6.64 (d, 1H), 3.23 (s, 3H)

(586) Synthesis of Compound 464: Following general procedure A, compound 464 was prepared in 82% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.84 (dd, 1H), 7.70 (dd, 1H), 7.44-7.57 (m, 5H), 7.43 (d, 1H), 6.60 (dd, 1H), 6.40 (d, 1H), 3.85 (s, 3 H)

(587) Synthesis of Compound 465: Following general procedure A, compound 465 was prepared in 81% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.12 (s, 1H), 7.84 (d, 1H), 7.79 (dd, 1H), 7.71 (dd, 1H), 7.56-7.63 (m, 1H), 7.44 (dd, 1H), 7.21 (d, 1H), 7.11 (ddd, 1 H), 6.97-7.06 (m, 1H), 6.56 (d, 1H), 2.19 (s, 3H), 2.06 (s, 3H)

(588) Synthesis of Compound 466: Following general procedure A, compound 466 was prepared in 74% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.12 (s, 1H), 9.44 (s, 1H), 7.78-7.92 (m, 2H), 7.74 (t, 1H), 7.60 (d, 1H), 7.44 (dd, 1H), 7.20 (dd, 1H), 7.14 (ddd, 1 H), 7.01 (d, 1H), 6.95 (dd, 1H), 6.66-6.77 (m, 1H), 6.53-6.63 (m, 1H), 2.06 (s, 3H)

(589) Synthesis of Compound 467: Following general procedure A, compound 467 was prepared in 76% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.12 (s, 1H), 8.42 (d, 1H), 7.85-8.04 (m, 3H), 7.74 (t, 1H), 7.56-7.66 (m, 1H), 7.44 (dd, 1H), 7.14 (ddd, 1H), 6.85 (dd, 1H), 6.60 (dd, 1H), 3.87 (s, 3H), 2.06 (s, 3H)

(590) Synthesis of Compound 468: Following general procedure A, compound 468 was prepared in 57% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.15 (s, 1H), 8.04-8.11 (m, 2H), 7.92-8.04 (m, 2H), 7.69-7.85 (m, 3H), 7.56-7.67 (m, 1H), 7.42-7.55 (.[.d, 2H.]..Iadd.m, 2 H.Iaddend.), 7.37 (br. s., 1H), 7.11-7.20 (m, 1H), 6.63 (d, 1H), 2.07 (s, 3H)

(591) Synthesis of Compound 469: Following general procedure A, compound 469 was prepared in 68% yield. .sup.1H H NMR (300 MHz, DMSO-d6) ppm 10.13 (s, 1H), 8.06 (d, 1H), 7.98-8.03 (m, 1H), 7.94-7.98 (m, 1H), 7.86-7.94 (m, 2H), 7.66-7.78 (m, 3H), 7.57-7.65 (m, 1H), 7.45 (dd, 1H), 7.31 (br. s., 1H), 7.11-7.20 (m, 1H), 6.62 (d, 1H), 2.07 (s, 3 H)

(592) Synthesis of Compound 470: Following general procedure A, compound 470 was prepared in 74% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.12 (s, 1H), 7.96 (dd, 1H), 7.83 (d, 1H), 7.71-7.80 (m, 2H), 7.56-7.66 (m, 1H), 7.35-7.50 (m, 3H), 7.33 (d, 1H), 7.17 (ddd, 1H), 6.59 (dd, 1H), 6.42 (dd, 1H), 3.80 (s, 3H), 2.07 (s, 3H)

(593) Synthesis of Compound 471: Following general procedure A, compound 471 was prepared in 85% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.95 (dd, 1H), 7.84 (d, 1H), 7.78 (d, 1H), 7.43-7.59 (m, 6H), 7.40 (dd, 1H), 7.33 (d, 1H), 6.60 (d, 1 H), 6.42 (dd, 1H), 3.80 (s, 3H)

(594) Synthesis of Compound 473: Following general procedure A, compound 473 was prepared in 66% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.13 (s, 1H), 7.69-7.78 (m, 1H), 7.55-7.68 (m, 3H), 7.42 (d, 1H), 7.43 (dd, 1H), 7.13 (ddd, 1H), 6.97 (d, 1H), 6.58 (d, 1H), 2.24 (s, 3H), 2.06 (s, 3H)

(595) Synthesis of Compound 474: Similar to compound 385, compound 474 was prepared in 9% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 9.36 (br. s., 1H), 7.90 (dd, 1 H), 7.72 (d, 1H), 7.54-7.70 (m, 3H), 7.29-7.50 (m, 3H), 7.13-7.29 (m, 2 H), 6.57 (d, 1 H), 1.89 (s, 3H)

(596) Synthesis of Compound 475: Following general procedure A, compound 475 was prepared in 94% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.12 (s, 1H), 7.88 (dd, 1H), 7.82 (d, 1H), 7.71-7.75 (m, 1H), 7.60 (d, 1H), 7.53 (m, 2H), 7.44 (dd, 1 H), 7.09-7.18 (m, 1H), 6.95 (m, 2H), 6.57 (d, 1H), 4.04 (q, 2H), 2.06 (s, 3H), 1.33 (t, 3H)

(597) Synthesis of Compound 476: Following general procedure A, compound 476 was prepared in 51% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 9.93 (s, 1H), 7.80-7.88 (m, 2H), 7.75 (t, 1H), 7.43-7.59 (m, 6H), 7.23-7.39 (m, 2H), 6.58-6.66 (m, 1H), 2.04 (s, 3 H)

(598) Synthesis of Compound 477: Following general procedure A, compound 477 was prepared in 41% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 9.44 (br. s., 1H), 7.85 (dd, 1 H), 7.83 (s, 1H), 7.36-7.64 (m, 5H), 7.20 (t, 1H), 7.03 (ddd, 1H), 6.96 (dd, 1H), 6.72 (ddd, 1H), 6.51-6.64 (m, 1H)

(599) Synthesis of Compound 478: Following general procedure A, compound 478 was prepared in 54% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.59-7.69 (m, 2H), 7.43-7.57 (m, 5H), 7.42 (d, 1H), 6.97 (d, 1H), 6.58 (dd, 1H), 2.25 (s, 3H)

(600) Synthesis of Compound 479: Following general procedure A, compound 479 was prepared in 64% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.86 (d, 1H), 7.79 (dd, 1H), 7.36-7.60 (m, 5H), 7.22 (d, 1H), 7.03 (t, 1H), 6.57 (d, 1H), 2.19 (d, 3 H)

(601) Synthesis of Compound 480: Following general procedure A, compound 480 was prepared in 25% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 9.45 (br. s., 1H), 7.84 (dd, 1 H), 7.77 (dd, 1H), 7.44-7.57 (m, 5H), 7.42 (m, 2H), 6.79 (m, 2H), 6.56 (dd, 1H)

(602) Synthesis of Compound 481: Following general procedure A, compound 481 was prepared in 64% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 7.78-7.94 (m, 2H), 7.37-7.61 (m, 5H), 7.26 (d, 1H), 7.09 (dd, 1H), 6.94 (d, 1H), 6.56 (d, 1H), 6.03 (s, 2H)

(603) Synthesis of Compound 482: Compound 482 was prepared as follows.

(604) ##STR00575##
Following standard procedure for Suzuki coupling, the product was obtained by reaction of 264 mg (1.0 mmol) of 3-bromo-N,N-dimethylbenzenesulfonamide. After purification (SiO.sub.2; Hexanes:EtOAc 1:1) 293 mg (quantitative yield) of pure product were obtained as white solid. A solution of 3-(6-methoxypyridin-3-yl)-N,N-dimethylbenzenesulfonamide (292 mg, 1.0 mmol) in EtOH (4 ml) and HBr 48% (4 ml) was stirred at 80 C. overnight. The solvent was evaporated and the crude compound (as hydrobromide salt) was purified by flash chromatography (DCM:MeOH 9:1). 278 mg were obtained as a pale yellow solid (quantitative yield).

(605) Following general procedure H1A, compound 482 was prepared from this intermediate in 69% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.13 (d, 1H), 7.94-8.04 (m, 2H), 7.92 (s, 1H), 7.63-7.74 (m, 2H), 7.37-7.61 (m, 5H), 6.63 (d, 1 H), 2.64 (s, 6H)

(606) Synthesis of Compound 483: Compound 483 was prepared as follows.

(607) ##STR00576##
Following the standard procedure for Suzuki coupling, the product was obtained by reaction of 264 mg (1.0 mmol) of 4-bromo-N,N-dimethylbenzenesulfonamide. After purification (SiO.sub.2; Hexanes:EtOAc 1:1) 292 mg (quantitative yield) of pure product were obtained as white solid. A solution of 4-(6-methoxypyridin-3-yl)-N,N-dimethylbenzenesulfonamide (292 mg, 1.0 mmol) in EtOH (4 ml) and HBr 48% (4 ml) was stirred at 80 C. overnight. The solvent was evaporated and the crude compound (as hydrobromide salt) was purified by flash chromatography (DCM:MeOH 9:1). 278 mg were obtained as a pale yellow solid (quantitative yield).

(608) Following general procedure H1A, compound 483 was prepared from this intermediate in 79% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 8.15 (d, 1H), 8.02 (dd, 1 H), 7.92 (m, 2H), 7.74 (m, 2H), 7.40-7.60 (m, 5H), 6.64 (d, 1H), 2.62 (s, 6H)

(609) Synthesis of Compound 484: Following general procedure H1A and similar to compound 482, compound 484 was prepared in 56% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.14 (s, 1H), 8.12 (d, 1H), 7.93-8.04 (m, 2H), 7.91 (s, 1H), 7.73-7.79 (m, 1H), 7.54-7.73 (m, 3H), 7.46 (dd, 1H), 7.09-7.21 (m, 1H), 6.63 (d, 1H), 2.64 (s, 6H), 2.07 (s, 3H)

(610) Synthesis of Compound 485: Following general procedure H1A and similar to compound 483, compound 485 was prepared in 53% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.14 (s, 1H), 8.14 (d, 1H), 7.98-8.08 (m, 1H), 7.86-7.98 (m, 2H), 7.69-7.79 (m, 3 H), 7.56-7.64 (m, 1H), 7.45 (dd, 1H), 7.15 (ddd, 1H), 6.63 (d, 1H), 2.62 .Iadd.(s, 6 H), 2.06 .Iaddend.(s, 3H)

(611) Synthesis of Compound 486: Following general procedure A, compound 486 was prepared in 58% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.12 (s, 1H), 9.69 (s, 1H), 7.70-7.85 (m, 3H), 7.52-7.63 (m, 1H), 7.43 (t, 1H), 7.31 (dd, 1H), 7.07-7.19 (m, 2H), 6.92 (dd, 1H), 6.84 (td, 1H), 6.53 (dd, 1H), 2.06 (s, 3H)

(612) Synthesis of Compound 487: Following general procedure A, compound 487 was prepared in 56% yield. .sup.1H NMR (300 MHz, DMSO-d6) ppm 10.12 (s, 1H), 7.86-8.00 (m, 2H), 7.69-7.75 (m, 1H), 7.56-7.64 (m, 1H), 7.44 (t, 1H), 7.30 (t, 1H), 7.08-7.21 (m, 3 H), 6.77-6.90 (m, 1H), 6.57 (dd, 1H), 4.07 (q, 2H), 2.06 (s, 3H), 1.32 (t, 3H)

Assessment of Biological Activity

Example 1

(613) Compounds were screened for their ability to inhibit the activity of p38 MAP kinase in vitro using the Transcreener KinasePlus assay (Madison, Wis.). This assay determines p38 activity by measuring ATP consumption in the presence of a relevant peptide substrate. This assay is commonly used in the characterization of kinases (Lowrey and Kleman-Leyer, Expert Opin Ther Targets 10(1):179-90 (2006)). The Transcreener KinasePlus assay measures the p38 catalyzed conversion of ATP to ADP using a florescence polarization-based approach. The p38 reaction is performed as usual and stopped by addition of Stop-Detect reagents. These reagents halt further conversion of ATP to ADP and facilitate quantification of product ADP. Detection of ADP is made possible by an ADP-specific antibody and corresponding fluorescently .[.lableled.]. .Iadd.labeled .Iaddend.tracer in the Stop-Detect mix. In the absence of ADP, the fluorescently labeled tracer is bound by the ADP-specific antibody resulting in a complex with high fluorescence polarization (FP). Product ADP competes with the fluorescently labeled tracer for binding to the ADP-specific antibody and results in lower fluorescence polarization.

(614) p38 gamma was obtained from Millipore, Inc (Billerica, Ma.). p38 MAP Kinases are recombinant human full-length proteins with an amino-terminal GST fusion, expressed in and purified from E. coli. Proteins were aliquoted and stored at 80 C. Assays for p38 activity were performed in the presence of an EGF receptor peptide (sequence KRELVEPLTPSGEAPNQALLRSEQ ID NO: 1) that was obtained from Midwest Biotech (Fishers, Ind.). EGFR peptide was aliquotted and stored at 20 C.

(615) p38 MAP kinase assays were performed using p38 assay buffer containing 20 mM HEPES, pH 7.5, 10 mM MgCl.sub.2, 2 mM DTT, 0.01% Triton X-100, 10% glycerol, and 0.0002% bovine serum albumin (BSA). This buffer was supplemented with 10 ATP, 25 M EGFR peptide and 1 nM p38-. Compounds were weighed and dissolved to a known final concentration in DMSO.

(616) The assay and compound dilutions were conducted on a Janus liquid handling platform (Perkin Elmer, Waltham, Mass.) at room temperature (about 25 C.). Compounds in DMSO were placed in column 1 of a Costar V-bottom 96 well plate and diluted serially across the plate (3.3 dilutions). Columns 11 and 12 contain DMSO only (no inhibitor). Each compound dilution was 30-fold higher than the desired final concentration. A daughter plate was created by placing 180 L of p38 assay buffer in each well of a second Costar V-bottom 96 well plate and 20 L of the diluted compound stocks in DMSO were transferred and mixed. The assay was conducted in a black .[.Proxipate.]. .Iadd.Proxiplate .Iaddend.F-Plus 384 well plate (Perkin Elmer, Waltham, Mass.). All subsequent transfers were conducted using a 96 well head such that the final assay was quad mapped with 4 replicates of each reaction. 5 L of the compound mixture was transferred from the daughter plate to the assay plate. 5 L of a mixture containing enzyme and EGFR peptide at 3-fold the desired final concentration in p38 assay buffer was then added to the appropriate wells. The reactions in the final two columns of the 384 well plate received a mixture of EGFR peptide in p38 assay buffer in the absence of enzyme. These wells served as a control for complete inhibition of enzyme. After the compound and EGFR/enzyme (or EGFR only) mixtures were added these component are preincubated for 5 minutes. The assay was initiated by addition of 5 L ATP in p38 assay buffer with mixing. The final reaction volume was 15 L and the reaction was allowed to run for 1 hour at room temperature. The reaction was stopped by addition of 5 L of Transcreener Stop-Detect solution containing 8 nM ADP Far Red Tracer and 41.6 g/mL ADP-Anti-body in 100 mM HEPES, pH 7.5, 0.8 M sodium chloride, 0.04% BRIJ-35, and 40 mM EDTA. Following addition of the Stop-Detect solution, the contents of the plate were mixed and incubated for 1 hour at room temperature.

(617) The plates were read for fluorescence polarization (FP) on a PerkinElmer EnVision using 3 filters (Cy5 Ex 620/40; Cy5 Em FP P-pol 688 nm; Cy5 Em FP S-pol 688 nm), and a mirror (Cy5 FP D658/fp688). Each read was integrated for 100 flashes. The formula
1000*(SG*P)/(S+G*P)
was used to convert the 2 emission readouts into mP; SS-pol filter signal, PP-pol filter signal, and G=gain.

(618) The mP output from the EnVision (a 384 matrix) was transferred to a plot of mP versus compound concentration. XLfit (IDBS, Guildford, England) was used to apply a 4-parameter logistic fit to the data and determine the median inhibitory concentration (IC.sub.50). Preferred compounds exhibit IC.sub.50 values of between about 0.05 M and about 10 M, preferably about 0.1 M to about 5 M.

Example 2

(619) Compounds were screened for the ability to inhibit TNF release from THP-1 cells stimulated with lipopolysaccharide (LPS) in vitro. The ability of compounds to inhibit TNF release in this in vitro assay was correlated with the inhibition of p38 activity and TNF expression in vivo, and was therefore an indicator of potential in vivo therapeutic activity (Lee et al. Ann. N.Y. Acad. Sci. 696:149-170 (1993); and Nature 372:739-746 (1994)).

(620) THP-1 cells from ATCC (TIB202) were maintained at 37 C., 5% CO.sub.2 in RPMI 1640 media (MediaTech, Herndon, Va.) containing 4.5 g/L glucose, supplemented with 10% fetal bovine serum, 1% penicillin/streptomycin and 50 M -mercaptoethanol.

(621) Test compounds were initially dissolved in DMSO. Compounds were then diluted in DMSO for all subsequent dilutions. The compounds were diluted in RPMI Media immediately prior the addition to the THP-1 cells to a final concentration of 1.25% DMSO (v/v) upon addition to the cells. Compounds were tested at a final concentration on cells of 750 to 1000 M. Where data indicates it was appropriate compounds were tested at a 5-10 fold lower concentration. The assay was performed under sterile conditions. THP-1 cells at a culture density of 6-810.sup.5 cells/mL were collected and resuspended in the RPMI media at 110.sup.6 cells/mL. 100 l of resuspended cells were added to each well, which contained 100 l of RPMI medium with test compound. Test compounds were prepared at 2.5 times the final concentration. Final DMSO concentration was no more than 0.5% (v/v). Cells were preincubated with compound for 60 minutes at 37 C., 5% CO.sub.2 prior to stimulation with lipopolysaccharide (LPS) (Sigma L-2880, 1 mg/ml stock in PBS). The final LPS concentration in each well was 200 ng/ml for TNF release. Unstimulated control cell suspensions received DMSO/RPMI Media vehicle only. Cell mixtures were incubated for 4 hours for TNF release. 80 l of supernatants were taken and transferred to a fresh plate and stored at 70 C. until further analysis. TNF levels were measured using ELISA kits (R&D systems PDTA00C). A SpectraMAX M5 was used as the plate reader. The calculated amount of TNF released was expressed as a percentage of the vehicle+LPS control.

(622) Some compounds were tested for a TNF dose response. Test compounds were initially dissolved in DMSO. Compounds were then serially diluted in DMSO over an appropriate range of concentrations between 2 mM and 4 M. The compounds were diluted in RPMI Media immediately prior the addition to the THP-1 cells to a final concentration of 0.5% DMSO (v/v) upon addition to the cells. The assay was performed under sterile conditions. THP-1 cells at a culture density of 6-810.sup.5 cells/mL were collected and resuspended in the RPMI media at 110.sup.6 cells/mL. 100 l of resuspended cells were added to each well, which contained 100 l of RPMI media with test compound. Test compounds were prepared at 2.5 times the final concentration. Final DMSO concentration was no more than 0.5% (v/v). Cells were preincubated with compound for 60 minutes at 37 C., 5% CO.sub.2 prior to stimulation with lipopolysaccharide (LPS) (Sigma L-2880, 1 mg/ml stock in PBS). The final LPS concentration in each well was 200 ng/ml for TNF release. Unstimulated control cell suspensions received DMSO/RPMI Media vehicle only. Cell mixtures were incubated for 4 hours for TNF release. 80 l of supernatants were taken and transferred to a fresh plate and stored at 70 C. until further analysis. TNF levels were measured using ELISA kits (R&D systems PDTA00C). A SpectraMAX M5 was used as the plate reader. Analysis was performed by non-linear regression to generate a dose response curve. The calculated IC.sub.50 value was the concentration of the test compound that caused a 50% decrease in TNF levels.

(623) Compounds inhibit the release of TNF in this in vitro assay. Preferred compounds exhibit IC.sub.50 values for TNF between about 1 M and about 1000 M, preferably about 1 M to about 800 M.

Example 3

(624) Compounds were tested for cytotoxicity using an ATPlite assay (Perkin Elmer 6016731). THP-1 cells were treated with compounds as described for TNF tests. 4 hours after LPS addition, 80 l of media is removed for ELISA. 48 hrs after LPS addition of media and cells were mixed with 100 l of ATPlite reagent. The mixture was shaken for 2 minutes then read for luminescence. A SpectraMAX M5 is used as the plate reader.

(625) The calculated cytotoxicity is expressed as a percentage of the LPS/DMSO control compound. Compounds which had a low score in ATPlite compared to the LPS/DMSO control were classified as cytotoxic rather than TNF inhibitors. Where appropriate compounds were tested at 5-10 fold lower concentrations to determine whether the compound had activity at lower, non cytotoxic concentrations.

(626) For serial dilutions of compound, analysis is performed by non-linear regression to generate a dose response curve. The calculated CC.sub.50 value is the concentration of the test compound that causes a 50% decrease in ATP levels.

(627) Compounds may exhibit cytotoxicity which can also lower TNF release in this in vitro assay. Preferred compounds show an ATPlite value which is 100% of the LPS/DMSO control. Preferred compounds exhibit CC.sub.50 values of greater than 1 mM, preferably of undetectable toxicity.

Example 4

(628) Compounds are screened for the ability to inhibit TNF release from primary human peripheral blood mononuclear cells (PBMC) stimulated with lipopolysaccharide (LPS) in vitro. The ability of compounds to inhibit TNF release in this in vitro assay is correlated with the inhibition of p38 activity and is therefore an indicator of potential in vivo therapeutic activity (Osteoarthritis & Cartilage 10:961-967 (2002); and Laufer, et al., J. Med. Chem. 45: 2733-2740 (2002)).

(629) Human peripheral blood mononuclear cells (PBMC) are isolated by differential centrifugation through a Ficoll-HyPaque density gradient from pooled serum of 3-8 individual blood donors. Isolated PBMC contain approximately 10% CD-14 positive monocytes, 90% lymphocytes and <1% granulocytes and platelets. PBMC (106/ml) are cultured in polystyrene plates and stimulated with lipopolysaccharide (LPS; 50 ng/ml; Sigma, St. Louis, Mo.) in the presence and absence of the test compound in serial dilutions, in duplicate, for 24 hr at 37 C. in GIBCO RPM1 medium (Invitrogen, Carlsbad, Calif.) without serum. The TNF level in cell supernatants is determined by ELISA using a commercially available kit (MDS Panlabs #309700).

(630) Preferred compounds inhibit the release of TNF in this assay with an IC.sub.50 value of between about 100 M and about 1000 M, preferably about 200 M to about 800 M.

Example 5

(631) Compounds are screened for the ability to inhibit the release of TNF in an in vivo animal model (See, e.g., Griswold et al. Drugs Exp. Clin. Res. 19:243-248 (1993); Badger, et al. J. Pharmacol. Exp. Ther. 279:1453-1461 (1996); Dong, et al. Annu. Rev. Immunol. 20:55-72 (2002) (and references cited therein); Ono, et al., Cellular Signalling 12:1-13 (2000) (and references cited therein); and Griffiths, et al. Curr. Rheumatol. Rep. 1:139-148 (1999)).

(632) Without being bound by any particular theory, it is believed that inhibition of TNF in this model is due to inhibition of p38 MAP kinase by the compound.

(633) Male Sprague-Dawley rats (0.2-0.35 kg) are randomly divided into groups of six or more and are dosed intravenously by infusion or bolus injection, or are dosed orally with test compounds in a suitable formulation in each case. At ten minutes to 24 hr following treatment lipopolysaccharide E. coli/0127:B8 (0.8 mg/kg) is administered IV in the presence of D-galactosamine. Blood levels are samples are collected 1.5 hours post-treatment with LPS. Serum TNF and/or IL-6 determined using an appropriate ELISA kit and compared to that from vehicle-treated control.

(634) Preferred compounds inhibit the release of TNF in this in vivo assay. Preferred compounds exhibit an ED.sub.50 value of less than 500 mg/kg, preferably less than 400 mg/kg, preferably less than 200 mg/kg, preferably less than 100 mg/kg, more preferably, less than 50 mg/kg, more preferably, less than 40 mg/kg, more preferably, less than 30 mg/kg, more preferably, less than 20 mg/kg, more preferably, less than 10 mg/kg.

(635) The methods of determining the IC.sub.50 of the inhibition of p38 by a compound include any methods known in the art that allow the quantitative detection of any of the downstream substrates of p38 MAPK as described above. Therefore, these methods additionally include but limited to detection of expression of genes known to be regulated by p38 either individually, or by gene arrays.

Results of Biological Tests

(636) The data sets for each compound assayed as described in Examples 2 (TNF inhibition) and 3 (ATPlite assay), above were binned based on percentage of control (POC) data. For a subset of compounds with data from dose response curves, calculated POC values at the 750 M screening concentration were derived from the existing EC.sub.50, CC.sub.50 and Hill Slope values using the standard .[.four-paramater.]. .Iadd.four-parameter .Iaddend.curve fit equation assuming an upper .[.asymptope.]. .Iadd.asymptote .Iaddend.of 100% and a lower .[.asymptope.]. .Iadd.asymptote .Iaddend.of 0%. The relevant equations are: POC.sub.TNF=(1000)/(1+(750/EC.sub.50)^Hill Slope) and POC.sub.ATPlite=(1000)/(1+(750/CC.sub.50)^Hill Slope). These values were averaged with existing POC determinations create a data set that could be appropriately binned.

(637) Data were binned using the following criteria: Bin A (greatest inhibition) POC<33; Bin B POC 33 and <66; Bin C 66-100, with either ATPlite POC>90 or an ATPlite POC at least two-fold above the TNF POC. When ATPlite POC for a given compound was not either 1) greater than 90, or 2) at least two-fold above the TNF POC the compound was placed in bin C regardless of the TNF POC. Adjustments were made to the binning of compounds 10, 21, 47, 160, 179, 189, 193, based on full dose response curves with CC.sub.50:EC.sub.50 ratios that were either >2 or <2, respectively. In the former case, the compounds were left in the appropriate bin based on TNF POC and in the latter case they were placed in bin C.

(638) TABLE-US-00002 TABLE 2 Example Bin 1 A 2 C 3 C 4 C 5 C 6 A 7 C 8 B 9 C 10 C 11 C 12 C 13 C 14 C 15 C 16 C 17 C 18 B 19 A 20 C 21 C 22 A 23 C 24 C 25 C 26 C 27 C 28 C 29 A 30 C 31 C 32 C 33 C 34 C 35 C 36 C 37 C 38 C 39 C 40 C 41 A 42 C 43 C 44 C 45 C 46 C 47 A 48 C 49 C 50 B 51 C 52 C 53 C 54 C 56 C 58 C 59 C 60 A 61 C 62 C 63 C 64 C 65 C 66 C 67 C 68 C 69 C 70 C 72 A 73 A 74 A 75 C 77 C 78 C 79 C 80 A 81 C 82 A 83 C 84 A 85 C 86 C 87 C 88 C 89 A 90 B 91 C 92 C 93 A 94 A 96 A 97 A 98 C 99 C 100 C 101 C 102 A 103 C 104 C 105 A 106 A 107 C 108 C 109 A 110 C 111 C 112 C 113 C 114 B 115 C 116 C 117 A 118 A 119 C 120 B 121 A 122 C 123 C 124 C 125 C 126 C 127 B 128 A 129 B 130 A 131 C 132 A 133 C 134 C 135 A 136 A 137 A 138 A 139 A 140 B 141 A 142 C 143 C 144 C 145 A 147 A 148 C 149 C 150 C 151 C 152 A 153 A 154 C 155 A 156 C 158 C 159 A 160 C 161 C 162 C 163 B 164 C 166 C 167 B 168 B 169 A 171 C 172 A 173 C 174 C 177 A 178 A 179 C 182 C 183 A 184 C 185 C 186 C 187 C 188 C 189 B 190 C 192 C 193 B 195 C 197 C 200 A 201 C 202 C 203 A 209 C 210 C 211 A 212 C 213 C 214 A 215 C 216 B 217 A 218 C 219 C 220 C 221 C 222 C 223 C 224 C 225 B 226 C 227 C 228 A 229 C 230 C 231 C 232 B 233 C 234 C 235 A 236 A 237 C 238 B 239 C 240 B 241 A 242 A 243 C 244 C 245 A 246 C 247 C 248 C 249 A 250 B 251 C 252 A 253 C 254 A 255 C 256 C 257 A 258 A 259 C 260 B 261 C 262 B 263 C 264 C 265 C 266 C 267 A 268 A 269 C 270 C 271 C 272 A 273 A 274 A 275 C 276 C 277 A 278 A 279 A 280 C 281 C 282 B 283 A 284 C 285 A 286 C 287 B 288 A 289 C 290 A 291 A 292 C 293 C 294 A 295 A 296 C 297 C

(639) While the present invention has been described in some detail for purposes of clarity and understanding, one skilled in the art will appreciate that various changes in form and detail can be made without departing from the true scope of the invention. All figures, tables, appendices, patents, patent applications and publications, referred to above, are incorporated herein by reference.