Biaryl derivatives as bromodomain inhibitors

Abstract

The present disclosure relates to compounds, which are useful for inhibition of BET protein function by binding to bromodomains, and their use in therapy.

Claims

1. A compound selected from: 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-hydroxyethoxy)pyridin-2-yl)-N,N,3-trimethylbenzamide; 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-(isopropylamino)ethoxy)pyridin-2-yl)-N,N,3-trimethylbenzamide; 3-Chloro-4-(6-(5, 7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-hydroxyethoxy)pyridin-2-yl)-N,N-dimethylbenzamide; 3-Chloro-4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-(isopropylamino)ethoxy)pyridin-2-yl)-N,N-dimethylbenzamide; (S)-7-Fluoro-5-((1-methylpyrrolidin-3-yl)oxy)-2-(6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one; 4-(6-(6, 8-Dimethoxy-1-oxo-1,2-dihydroisoquinolin-3-yl)pyridin-2-yl)-N, N-dimethylbenzamide; 6,8-Dimethoxy-3-(6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)isoquinolin-1(2H)-one; 6,8-dimethoxy-3-(6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)isoquinolin-1(2H)-one; 2-(6-(2-(Dimethylamino)ethoxy)-4′-(methylsulfinyl)biphenyl-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(6-(Azetidin-3-yloxy)-4′-(methylsulfinyl)biphenyl-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 5,7-Dimethoxy-2-(6-(1-methylazetidin-3-yloxy)-4′-(methylsulfinyl)biphenyl-3-yl)quinazolin-4(3H)-one; 2-(6-(Azetidin-3-yloxy)-4′-(methylsulfinyl)-[1,1′-biphenyl]-3-yl)-7-fluoro-5-methoxyquinazolin-4(3H)-one; 7-Fluoro-5-methoxy-2-(6-((1-methylazetidin-3-yl)oxy)-4′-(methylsulfinyl)-[1,1′-biphenyl]-3-yl)quinazolin-4(3H)-one; 2-(6-(2-Hydroxyethoxy)-4′-(methylsulfinyl)biphenyl-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(6-(2-(Isopropylamino)ethoxy)-4′-(methylsulfinyl)biphenyl-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2′-(Azetidin-3-yloxy)-5′-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-[1,1′-biphenyl]-4-carbonitrile; 5′-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2′-((1-methylazetidin-3-yl)oxy)-[1, 1′-biphenyl]-4-carbonitrile; 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)-N, N-dimethylbenzamide; 2-(5-(2-Hydroxyethoxy)-6-phenylpyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(5-(2-(Isopropylamino)ethoxy)-6-phenylpyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-hydroxyethoxy)pyridin-2-yl)-N, N-dimethylbenzamide; 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one methanesulfonate; 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-(isopropylamino)ethoxy)pyridin-2-yl)-N, N-dimethylbenzamide; 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-6(4-Acetylphenyl)-5-(2-hydroxyethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 5,7-Dimethoxy-2-(6-(4-(methylsulfonyl)phenyl)-5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-2-yl)quinazolin-4(3H)-one; 2-(5-(2-Hydroxyethoxy)-6-(2-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 5,7-Dimethoxy-2-(6-(4-(methylsulfonyl)phenyl)-5-(2-morpholinoethoxy)pyridin-2-yl)quinazolin-4(3H)-one; 2-(5-(2-(Isopropylamino)ethoxy)-6-(2-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(5-(2-(Isopropylamino)ethoxy)-6-(3-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2-hydroxyethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2-(isopropylamino)ethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(5-(2-Hydroxyethoxy)-6-(3-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one methanesulfonate; 2-(5-(2-Hydroxyethoxy)-6-(3-(methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(5-(2-Hydroxyethoxy)-6-(2-methyl-4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(5-(2-(Isopropylamino)ethoxy)-6-(3-(methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2-morpholinoethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(6-(2-(Isopropylamino)ethoxy)-4′-(methylsulfonyl)-[1,1′-biphenyl]-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(5-(2-(Isopropylamino)ethoxy)-6-(2-methyl-4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)-2-(trifluoromethyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 5,7-Dimethoxy-2-(4′-(methylsulfinyl)-[1, 1′-biphenyl]-3-yl)quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(4-(4-(methylsulfinyl)phenyl)thiophen-2-yl)quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(5-methoxy-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(3-(5-(methylsulfinyl)thiophen-2-yl)phenyl)quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(7-(4-(methylsulfinyl)phenyl)-1H-indol-5-yl)quinazolin-4(3H)-one; tert-Butyl (2-((6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(4-(methylsulfinyl)phenyl)pyridin-3-yl)oxy)ethyl)(isopropyl)carbamate; 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-methoxypyridin-2-yl)-N,N,3-trimethylbenzamide: 5,7-Dimethoxy-2-(6-(4-(methylsulfinyl)phenyl)-5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-2-yl)quinazolin-4(3H)-one; 3-Chloro-4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-methoxypyridin-2-yl)-N, N-dimethylbenzamide; 5-Methoxy-2-(5-methoxy-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(5-methoxy-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one; 2-Chloro-5′-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2′-methoxy-N,N-dimethyl-[1, 1′-biphenyl]-4-carboxamide; 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)-7-methoxyquinazolin-4(3H)-one; 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)-7-methoxyquinazolin-4-(3H)-one; 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one; 1-(2-((6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(4-(methylsulfonyl)phenyl)pyridin-3-yl)oxy)ethyl)pyrrolidine 1-oxide; 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-Yl)-5-methoxyquinazolin-4(3H)-one; 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one; 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)-7-methoxyquinazolin-4(3H)-one; 2-(5-(2-Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-7-methoxyquinazolin-4(3H)-one; 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one; and stereoisomers, tautomers, pharmaceutically acceptable salts, and hydrates thereof.

2. The compound according to claim 1, wherein the compound is selected from: 2-(5-(2-Hydroxyethoxy)-6-(4-(methyfsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyqusnazolin-4(3H)-one; 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one methanesulfonate; 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazoline-4(3H)-one; 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 5,7-Dimethoxy-2-(5-methoxy-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one; and stereoisomers, tautomers, pharmaceutically acceptable salts, and hydrates thereof.

3. A pharmaceutical composition comprising a compound according to claim 1 or claim 2.

4. A method for inhibiting BET proteins in a mammal comprising administering a therapeutically effective amount of a compound according to claim 1 or claim 2.

Description

EXEMPLARY EMBODIMENTS OF THE INVENTION

(1) One embodiment of the invention provides a compound of Formula I:

(2) ##STR00005##
or a stereoisomer, tautomer, pharmaceutical acceptable salt, or hydrate thereof,
wherein:

(3) W.sub.1 is selected from N and CR.sub.1;

(4) W.sub.2 is selected from N and CR.sub.2;

(5) W.sub.3 is selected from N and CR.sub.3;

(6) W.sub.4 is selected from N and CR.sub.4;

(7) each W may be the same or different from each other;

(8) A is selected from N and CH;

(9) R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, aryl, hydroxyl, and halogen;

(10) two adjacent substituents selected from R.sub.1, R.sub.2, R.sub.3, and R.sub.4 may be connected in a 5- or 6-membered ring to form a bicyclic carbocycle or bicyclic heterocycle;

(11) AR1 is a group selected from the following:

(12) ##STR00006##

(13) AR2 is a group selected from the following:

(14) ##STR00007##

(15) R.sub.5 is selected from hydrogen, alkyl, alkoxy, thioalkyl, amino, and halogen;

(16) R.sub.6 is selected from hydrogen, alkoxy, alkyl, aminoalkyl and thioalkyl

(17) with the proviso that if R.sub.6 is hydrogen or methyl, then at least one of R.sub.1-R.sub.4 is not hydrogen;

(18) Y is selected from NH, O, and S;

(19) W.sub.5 is selected from N and CQ.sub.1;

(20) W.sub.6 is selected from N and CQ.sub.2;

(21) W.sub.7 is selected from N and CQ.sub.3;

(22) W.sub.8 is selected from N and CQ.sub.4;

(23) W.sub.9 is selected from N and CQ.sub.5;

(24) Q.sub.1, Q.sub.2, Q.sub.3, Q.sub.4, and Q.sub.5 are independently selected from hydrogen, alkyl, halogen, —CN, —SO.sub.2Me, —SO.sub.2Et, —SO.sub.2Pr, —SO.sub.2iPr, —S(O)Me, —S(O)Et, —S(O)Pr, —S(O)iPr, amide, ketone, —COOH, and ester;

(25) with the proviso that if R.sub.2 is methoxy, hydroxyl, and R.sub.3 is methoxy, then at least one of Q.sub.1, Q.sub.2, Q.sub.3, Q.sub.4, and Q.sub.5 is different from hydrogen;

(26) with the proviso that if R.sub.1 and R.sub.3 are methoxy and Q.sub.3 is —SO.sub.2Me or —SMe, then at least one of R.sub.2, R.sub.4, R.sub.5, R.sub.6, Q.sub.1, Q.sub.2, Q.sub.4, and Q.sub.5 is different from hydrogen; and

(27) two adjacent substituents selected from R.sub.5, R.sub.6, Q.sub.1, Q.sub.2, Q.sub.3, Q.sub.4, Q.sub.5, and Q.sub.6 may be connected to form a 5- or 6-membered ring to form an unsubstituted carbocycle or heterocycle.

(28) In some embodiments, R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are selected from hydrogen, alkyl (such as methyl and ethyl), alkoxy (such as methoxy and ethoxy), and halogen (such as fluoride).

(29) In some embodiments, R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are each independently selected from alkyl or alkoxy, each of which may be optionally substituted with hydroxyl, amino, halogen, or ester.

(30) In some embodiments, R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are each independently selected from alkenyl or alkynyl, each of which may be optionally substituted with halogen.

(31) In some embodiments, R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are each independently selected from aryl or aryloxy, each of which may be optionally substituted with halogen, alkoxy, or amino.

(32) In certain embodiments, R.sub.1 and R.sub.3 in the compound of Formula I are each independently an alkoxy (such as methoxy).

(33) In other embodiments, R.sub.1 and R.sub.3 in compounds of Formula I are each methoxy and R.sub.2 and R.sub.4 are each hydrogen.

(34) In an exemplary compound of Formula I, R.sub.5 is selected from hydrogen and alkyl.

(35) In some embodiments R.sub.5 is selected from alkoxy, alkyl, or thioalkyl, each of which may be optionally substituted with halogen, alkoxy, or hydroxyl.

(36) In some embodiments R.sub.5 is selected from aryl or aryloxy, each of which may be optionally substituted with halogen or alkoxy.

(37) In some embodiments R.sub.6 is selected from hydrogen and alkoxy.

(38) In other embodiments R.sub.6 in compounds of Formula I is selected from hydrogen, methoxy, ethoxy, alkoxy optionally substituted with a hydroxyl or amino.

(39) In some embodiments R.sub.6 is selected from alkyl, alkoxy, aminoalkyl, or thioalkyl, each of which may be optionally substituted with halogen, amino, hydroxyl, or alkoxy.

(40) In certain embodiments R.sub.6 is selected from hydrogen, methoxy,

(41) ##STR00008##

(42) In some embodiments, AR1 in the compound of Formula I is selected from

(43) ##STR00009##

(44) In other embodiments, AR1 in the compound of Formula I is selected from

(45) ##STR00010##

(46) In certain exemplary compounds of Formula I, AR2 is selected from

(47) ##STR00011##

(48) In some exemplary compounds of Formula I, AR2 is

(49) ##STR00012##

(50) In some embodiments, W.sub.5 is selected from CQ.sub.1.

(51) In other embodiments, W.sub.6 is selected from CQ.sub.2.

(52) In certain compounds of Formula I W.sub.7 is selected from CQ.sub.3.

(53) In other exemplary embodiments, W.sub.8 is selected from CQ.sub.4.

(54) In other compounds of Formula I, W.sub.9 is selected from CQ.sub.5.

(55) In some embodiments, Q.sub.1, Q.sub.2, Q.sub.3, Q.sub.4, and Q.sub.5 are independently selected from hydrogen, alkyl (such as methyl, —CF.sub.3, or ethyl), halogen (such as chloro), —CN, —SO.sub.2Me, —SO.sub.2Et, —SO.sub.2Pr, —SO.sub.2iPr, —S(O)Me, —S(O)Et, —S(O)Pr, —S(O)iPr, amide, ketone, ester, and —COOH.

(56) In other compounds of Formula I, Q.sub.1, Q.sub.2, Q.sub.4, and Q.sub.5 are independently selected from hydrogen, methyl, —CF.sub.3, ethyl, —Cl, —CN, —SO.sub.2Me, —SO.sub.2Et, and —S(O)Me.

(57) In other exemplary embodiments, Q.sub.1, Q.sub.2, Q.sub.4, and Q.sub.5 are independently selected from hydrogen, methyl, —CF.sub.3, —Cl, —SO.sub.2Me, and —S(O)Me.

(58) In some embodiments, Q.sub.1, Q.sub.2, Q.sub.3, Q.sub.4, and Q.sub.5 are alkyl, optionally substituted with halogen, —CN, sulfone, sulfoxide, amide, ketone, carboxylic acid, or ester.

(59) In some embodiments, Q.sub.1, Q.sub.2, Q.sub.3, 4, and Q.sub.5 are each independently selected from amide, ester, or ketone, each of which may be optionally substituted with halogen.

(60) In some embodiments, Q.sub.3 is selected from hydrogen, —CN, —SO.sub.2Me, —SO.sub.2Et, —SO.sub.2Pr, —SO.sub.2iPr, —S(O)Me, —S(O)Et, —S(O)Pr, —S(O)iPr, amide, ketone, ester, and —COOH.

(61) In other embodiments, Q.sub.3 is selected from hydrogen, —CN, —SO.sub.2Me, —SO.sub.2Et, —S(O)Me, —C(O)N(Me).sub.2, and —C(O)Me.

(62) In certain embodiments of the invention, the compound of Formula I is selected from: 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-hydroxyethoxy)pyridin-2-yl)-N,N,3-trimethylbenzamide. (Example 3), 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-(isopropylamino)ethoxy)pyridin-2-yl)-N,N,3-trimethylbenzamide (Example 4), 3-Chloro-4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-hydroxyethoxy)pyridin-2-yl)-N,N-dimethylbenzamide (Example 5), 3-Chloro-4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-(isopropylamino)ethoxy)pyridin-2-yl)-N,N-dimethylbenzamide (Example 6), (S)-7-Fluoro-5-((1-methylpyrrolidin-3-yl)oxy)-2-(6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one (Example 7), 4-(6-(6,8-Dimethoxy-1-oxo-1,2-dihydroisoquinolin-3-yl)pyridin-2-yl)-N,N-dimethylbenzamide (Example 8), 6,8-Dimethoxy-3-(6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)isoquinolin-1(2H)-one (Example 9), 6,8-dimethoxy-3-(6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)isoquinolin-1(2H)-one (Example 10), 2-(6-(2-(Dimethylamino)ethoxy)-4′-(methylsulfinyl)biphenyl-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 11), 2-(6-(Azetidin-3-yloxy)-4′-(methylsulfinyl)biphenyl-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 12), 5,7-Dimethoxy-2-(6-(1-methylazetidin-3-yloxy)-4′-(methylsulfinyl)biphenyl-3-yl)quinazolin-4(3H)-one (Example 13), 2-(6-(Azetidin-3-yloxy)-4′-(methylsulfinyl)-[1,1′-biphenyl]-3-yl)-7-fluoro-5-methoxyquinazolin-4(3H)-one (Example 14), 7-Fluoro-5-methoxy-2-(6-((1-methylazetidin-3-yl)oxy)-4′-(methylsulfinyl)-[1,1′-biphenyl]-3-yl)quinazolin-4(3H)-one (Example 15), 2-(6-(2-Hydroxyethoxy)-4′-(methylsulfinyl)biphenyl-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 16), 2-(6-(2-(Isopropylamino)ethoxy)-4′-(methylsulfinyl)biphenyl-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 17), 2′-(Azetidin-3-yloxy)-5′-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-[1,1′-biphenyl]-4-carbonitrile (Example 18), 5′-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2′-((1-methylazetidin-3-yl)oxy)-[1,1′-biphenyl]-4-carbonitrile (Example 19), 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)-N,N-dimethylbenzamide (Example 20), 2-(5-(2-Hydroxyethoxy)-6-phenylpyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 21), 2-(5-(2-(Isopropylamino)ethoxy)-6-phenylpyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 22), 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-hydroxyethoxy)pyridin-2-yl)-N,N-dimethylbenzamide (Example 23), 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 24), 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one methanesulfonate (Example 25), 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-(isopropylamino)ethoxy)pyridin-2-yl)-N,N-dimethylbenzamide (Example 26), 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 27), 2-(6-(4-Acetylphenyl)-5-(2-hydroxyethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 28), 5,7-Dimethoxy-2-(6-(4-(methylsulfonyl)phenyl)-5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-2-yl)quinazolin-4(3H)-one hydrochloride (Example 29), 2-(5-(2-Hydroxyethoxy)-6-(2-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 30), 5,7-Dimethoxy-2-(6-(4-(methylsulfonyl)phenyl)-5-(2-morpholinoethoxy)pyridin-2-yl)quinazolin-4(3H)-one hydrochloride (Example 31), 2-(5-(2-(Isopropylamino)ethoxy)-6-(2-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 32), 2-(5-(2-(Isopropylamino)ethoxy)-6-(3-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 33), 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2-hydroxyethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 34), 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2-(isopropylamino)ethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 35), 2-(5-(2-Hydroxyethoxy)-6-(3-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one methanesulfonate (Example 36), 2-(5-(2-Hydroxyethoxy)-6-(3-(methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 37), 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 38), 2-(5-(2-Hydroxyethoxy)-6-(2-methyl-4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 39), 2-(5-(2-(Isopropylamino)ethoxy)-6-(3-(methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 40), 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 41), 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 42), 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2-morpholinoethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 43), 2-(6-(2-(Isopropylamino)ethoxy)-4′-(methylsulfonyl)-[1,1′-biphenyl]-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 44), 2-(5-(2-(Isopropylamino)ethoxy)-6-(2-methyl-4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 45), 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)-2-(trifluoromethyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 46), 5,7-Dimethoxy-2-(4′-(methylsulfinyl)-[1,1′-biphenyl]-3-yl)quinazolin-4(3H)-one (Example 47), 5,7-Dimethoxy-2-(4-(4-(methylsulfinyl)phenyl)thiophen-2-yl)quinazolin-4(3H)-one (Example 48), 5,7-Dimethoxy-2-(6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one (Example 49), 5,7-Dimethoxy-2-(5-methoxy-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one (Example 50), 5,7-Dimethoxy-2-(3-(5-(methylsulfinyl)thiophen-2-yl)phenyl)quinazolin-4(3H)-one (Example 51), 5,7-Dimethoxy-2-(7-(4-(methylsulfinyl)phenyl)-1H-indol-5-yl)quinazolin-4(3H)-one (Example 52), tert-Butyl (2-((6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(4-(methylsulfinyl)phenyl)pyridin-3-yl)oxy)ethyl)(isopropyl)carbamate (Example 53), 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-methoxypyridin-2-yl)-N,N,3-trimethylbenzamide (Example 54), 5,7-Dimethoxy-2-(6-(4-(methylsulfinyl)phenyl)-5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-2-yl)quinazolin-4(3H)-one (Example 55), 3-Chloro-4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-methoxypyridin-2-yl)-N,N-dimethylbenzamide (Example 56), 5-Methoxy-2-(5-methoxy-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one (Example 57), 5,7-Dimethoxy-2-(5-methoxy-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one (Example 58), 2-Chloro-5′-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2′-methoxy-N,N-dimethyl-[1,1′-biphenyl]-4-carboxamide (Example 59), 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)-7-methoxyquinazolin-4(3H)-one (Example 60), 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one (Example 61), 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one (Example 62), 1-(2-((6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(4-(methylsulfonyl)phenyl)pyridin-3-yl)oxy)ethyl)pyrrolidine 1-oxide (Example 63), 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one (Example 64), 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one (Example 65), 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)-7-methoxyquinazolin-4(3H)-one (Example 66), 2-(5-(2-Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-7-methoxyquinazolin-4(3H)-one (Example 67), 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one (Example 68)

(63) In certain embodiments, the compound of Formula I is selected from: 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 24), 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one methanesulfonate (Example 25), 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 27), 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 41)

(64) In selected embodiments of the compounds of Formula I, R.sub.6 is selected from the group represented by Formula II:

(65) ##STR00013##
wherein:

(66) D and E are independently selected from O, N, and S;

(67) R.sub.7 is selected from hydrogen and alkyl, and R.sub.7 is present only if D is N;

(68) R.sub.8 and R.sub.9 are independently selected from hydrogen, alkyl, and cycloalkyl, and only one of R.sub.8 and R.sub.9 is present if E is O or S;

(69) R.sub.8 and R.sub.9 may be connected to form a carbocycle or a heterocycle containing one or more heteroatoms;

(70) R.sub.8 or R.sub.9 may be connected with R.sub.7 to form a carbocycle or a heterocycle containing one or more heteroatoms; and

(71) n is selected from 1, 2, and 3. In some embodiments, D is oxygen. In some embodiments, E is selected from O and N. In some embodiments, R.sub.7 is selected from hydrogen, methyl, and ethyl. In some embodiments, n is 1.

(72) In some embodiments R.sub.7 is alkyl optionally substituted with halogen, alkoxy, amino, or hydroxyl.

(73) In some embodiments, R.sub.8 and R.sub.9 are each selected from hydrogen, and alkyl (preferably C1-C5).

(74) In some embodiments R.sub.8 and R.sub.9 are each selected from alkyl or cycloalkyl, each of which may be optionally substituted with halogen, hydroxyl, cyano, amido, sulfone, sulfonamide, or heterocycle.

(75) In certain compounds of Formula I, wherein R.sub.6 is selected from:

(76) ##STR00014##

(77) In certain embodiments, the compound of Formula I is selected from: 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-hydroxyethoxy)pyridin-2-yl)-N,N,3-trimethylbenzamide. (Example 3), 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-(isopropylamino)ethoxy)pyridin-2-yl)-N,N,3-trimethylbenzamide (Example 4), 3-Chloro-4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-hydroxyethoxy)pyridin-2-yl)-N,N-dimethylbenzamide (Example 5), 3-Chloro-4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-(isopropylamino)ethoxy)pyridin-2-yl)-N,N-dimethylbenzamide (Example 6), 2-(6-(2-(Dimethylamino)ethoxy)-4′-(methylsulfinyl)biphenyl-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 11), 2-(6-(Azetidin-3-yloxy)-4′-(methylsulfinyl)biphenyl-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 12), 5,7-Dimethoxy-2-(6-(1-methylazetidin-3-yloxy)-4′-(methylsulfinyl)biphenyl-3-yl)quinazolin-4(3H)-one (Example 13), 2-(6-(Azetidin-3-yloxy)-4′-(methylsulfinyl)-[1,1′-biphenyl]-3-yl)-7-fluoro-5-methoxyquinazolin-4(3H)-one (Example 14), 7-Fluoro-5-methoxy-2-(6-((1-methylazetidin-3-yl)oxy)-4′-(methylsulfinyl)-[1,1′-biphenyl]-3-yl)quinazolin-4(3H)-one (Example 15), 2-(6-(2-Hydroxyethoxy)-4′-(methylsulfinyl)biphenyl-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 16), 2-(6-(2-(Isopropylamino)ethoxy)-4′-(methylsulfinyl)biphenyl-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 17), 2′-(Azetidin-3-yloxy)-5′-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-[1,1′-biphenyl]-4-carbonitrile (Example 18), 5′-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2′-((1-methylazetidin-3-yl)oxy)-[1,1′-biphenyl]-4-carbonitrile (Example 19), 2-(5-(2-Hydroxyethoxy)-6-phenylpyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 21), 2-(5-(2-(Isopropylamino)ethoxy)-6-phenylpyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 22), 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-hydroxyethoxy)pyridin-2-yl)-N,N-dimethylbenzamide (Example 23), 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 24), 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one methanesulfonate (Example 25), 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-(isopropylamino)ethoxy)pyridin-2-yl)-N,N-dimethylbenzamide (Example 26), 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 27), 2-(6-(4-Acetylphenyl)-5-(2-hydroxyethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 28), 5,7-Dimethoxy-2-(6-(4-(methylsulfonyl)phenyl)-5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-2-yl)quinazolin-4(3H)-one hydrochloride (Example 29), 2-(5-(2-Hydroxyethoxy)-6-(2-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 30), 5,7-Dimethoxy-2-(6-(4-(methylsulfonyl)phenyl)-5-(2-morpholinoethoxy)pyridin-2-yl)quinazolin-4(3H)-one hydrochloride (Example 31), 2-(5-(2-(Isopropylamino)ethoxy)-6-(2-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 32), 2-(5-(2-(Isopropylamino)ethoxy)-6-(3-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 33), 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2-hydroxyethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 34), 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2-(isopropylamino)ethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 35), 2-(5-(2-Hydroxyethoxy)-6-(3-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one methanesulfonate (Example 36), 2-(5-(2-Hydroxyethoxy)-6-(3-(methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 37), 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 38), 2-(5-(2-Hydroxyethoxy)-6-(2-methyl-4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 39), 2-(5-(2-(Isopropylamino)ethoxy)-6-(3-(methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 40), 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 41), 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 42), 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2-morpholinoethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 43), 2-(6-(2-(Isopropylamino)ethoxy)-4′-(methylsulfonyl)-[1,1′-biphenyl]-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 44), 2-(5-(2-(Isopropylamino)ethoxy)-6-(2-methyl-4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 45), 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)-2-(trifluoromethyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 46), tert-Butyl (2-((6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(4-(methylsulfinyl)phenyl)pyridin-3-yl)oxy)ethyl)(isopropyl)carbamate (Example 53), 5,7-Dimethoxy-2-(6-(4-(methylsulfinyl)phenyl)-5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-2-yl)quinazolin-4(3H)-one (Example 55), 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)-7-methoxyquinazolin-4(3H)-one (Example 60), 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one (Example 61), 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one (Example 62), 1-(2-((6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(4-(methylsulfonyl)phenyl)pyridin-3-yl)oxy)ethyl)pyrrolidine 1-oxide (Example 63), 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one (Example 64), 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one (Example 65), 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)-7-methoxyquinazolin-4(3H)-one (Example 66), 2-(5-(2-Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-7-methoxyquinazolin-4(3H)-one (Example 67), 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one (Example 68).

(78) In certain embodiments, the compound of Formula I is selected from: 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 24), 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one methanesulfonate (Example 25), 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 27), 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 41).

(79) Another aspect of the invention provides a method for inhibition of BET protein function by binding to bromodomains, and their use in the treatment and prevention of diseases and conditions in a mammal (e.g., a human) comprising administering a therapeutically effective amount of a compound of Formula I.

(80) In one embodiment, because of potent effects of BET inhibitors in vitro on IL-6 and IL-17 transcription, BET inhibitor compounds of Formula I are used as therapeutics for inflammatory disorders in which IL-6 and/or IL-17 have been implicated as drivers of disease. The following autoimmune diseases are amenable to therapeutic use of BET inhibition by administration of a compound of Formula I because of a prominent role of IL-6 and/or IL-17: Acute Disseminated Encephalomyelitis [69], Agammaglobulinemia [70], Allergic Disease [71], Ankylosing spondylitis [72], Anti-GBM/Anti-TBM nephritis [73], Anti-phospholipid syndrome [74], Autoimmune aplastic anemia [75], Autoimmune hepatitis [76], Autoimmune inner ear disease [77], Autoimmune myocarditis [78], Autoimmune pancreatitis [79], Autoimmune retinopathy [80], Autoimmune thrombocytopenic purpura [81], Behcet's Disease [82], Bullous pemphigoid [83], Castleman's Disease [84], Celiac Disease [85], Churg-Strauss syndrome [856], Crohn's Disease [87], Cogan's syndrome [88], Dry eye syndrome [89], Essential mixed cryoglobulinemia [90], Dermatomyositis [91], Devic's Disease [92], Encephalitis [93], Eosinophlic esophagitis [94], Eosinophilic fasciitis [94], Erythema nodosum [95], Giant cell arteritis [96], Glomerulonephritis [97], Goodpasture's syndrome [73], Granulomatosis with Polyangiitis (Wegener's) [98], Graves' Disease [99], Guillain-Barre syndrome [100], Hashimoto's thyroiditis [101], Hemolytic anemia [102], Henoch-Schonlein purpura [103], IgA nephropathy [104], Inclusion body myositis [105], Type I diabetes [8], Interstitial cystitis [106], Kawasaki's Disease [107], Leukocytoclastic vasculitis [108], Lichen planus [109], Lupus (SLE) [110], Microscopic polyangitis [111], Multiple sclerosis [112], Myasthenia gravis [113], myositis [91], Optic neuritis [114], Pemphigus [115], POEMS syndrome [116], Polyarteritis nodosa [117], Primary biliary cirrhosis [118], Psoriasis [119], Psoriatic arthritis [120], Pyoderma gangrenosum [121], Relapsing polychondritis [122], Rheumatoid arthritis [123], Sarcoidosis [124], Scleroderma [125], Sjogren's syndrome [126], Takayasu's arteritis [127], Transverse myelitis [128], Ulcerative colitis [129], Uveitis [130], Vitiligo [131].

(81) Acute and chronic (non-autoimmune) inflammatory diseases characterized by increased expression of pro-inflammatory cytokines, including IL-6, MCP-1, and IL-17, would also be amenable to therapeutic BET inhibition. These include, but not limited to, sinusitis [132], pneumonitis [133], osteomyelitis [134], gastritis [135], enteritis [136], gingivitis [137], appendicitis [138], irritable bowel syndrome [139], tissue graft rejection [140], chronic obstructive pulmonary disease (COPD) [141], septic shock (toxic shock syndrome, SIRS, bacterial sepsis, etc) [12], osteoarthritis [142], acute gout [143], acute lung injury [141], acute renal failure [144], burns [145], Herxheimer reaction [146], SIRS associated with viral infections [8].

(82) In one embodiment, BET inhibitor compounds of Formula I are used for treating rheumatoid arthritis (RA) and multiple sclerosis (MS). Strong proprietary data exist for the utility of BET inhibitors in preclinical models of RA and MS [17]. Both RA and MS are characterized by a dysregulation of the IL-6 and IL-17 inflammatory pathways [10] and thus would be especially sensitive to BET inhibition. In another embodiment, BET inhibitor compounds of Formula I are used for treating sepsis and associated afflictions. BET inhibition has been shown to inhibit development of sepsis, in part, by inhibiting IL-6 expression, in preclinical models in both published [12] and proprietary data.

(83) In one embodiment, BET inhibitor compounds of Formula I are used to treat cancer. Cancers that have an overexpression, translocation, amplification, or rearrangement c-myc or other myc family oncoproteins (MYCN, L-myc) are particularly sensitive to BET inhibition [27, 28]. These cancers include, but are not limited to, B-acute lymphocytic leukemia, Burkitt's lymphoma, Diffuse large cell lymphoma, Multiple myeloma, Primary plasma cell leukemia, Atypical carcinoid lung cancer, Bladder cancer, Breast cancer, Cervix cancer, Colon cancer, Gastric cancer, Glioblastoma, Hepatocellular carcinoma, Large cell neuroendocrine carcinoma, Medulloblastoma, Melanoma, nodular, Melanoma, superficial spreading, Neuroblastoma, esophageal squamous cell carcinoma, Osteosarcoma, Ovarian cancer, Prostate cancer, Renal clear cell carcinoma, Retinoblastoma, Rhabdomyosarcoma, Small cell lung carcinoma [25].

(84) In one embodiment, BET inhibitor compounds of Formula I are used to treat cancers that result from an aberrant regulation (overexpression, translocation, etc) of BET proteins. These include, but are not limited to, NUT midline carcinoma (Brd3 or Brd4 translocation to nutlin 1 gene) [22], B-cell lymphoma (Brd2 overexpression) [23], non-small cell lung cancer (BrdT overexpression) [147, 148], esophageal cancer and head and neck squamous cell carcinoma (BrdT overexpression) [147], colon cancer (Brd4) [149].

(85) In one embodiment, because BET inhibitors decrease Brd-dependent recruitment of pTEFb to genes involved in cell proliferation, BET inhibitor compounds of Formula I are used to treat cancers that rely on pTEFb (Cdk9/cyclin T) and BET proteins to regulate oncogenes. These include, but are not limited to, chronic lymphocytic leukemia and multiple myeloma [150], follicular lymphoma, diffuse large B cell lymphoma with germinal center phenotype, Burkitt's lymphoma, Hodgkin's lymphoma, follicular lymphomas and activated, anaplastic large cell lymphoma [151], neuroblastoma and primary neuroectodermal tumor [152], rhabdomyosarcoma [153], prostate cancer [154], and breast cancer [45].

(86) In one embodiment, BET inhibitor compounds of Formula I are used to treat cancers in which BET-responsive genes, such as CDK6, Bcl2, TYRO3, MYB, and hTERT are up-regulated [26, 27]. These cancers include, but are not limited to, pancreatic cancer, breast cancer, colon cancer, glioblastoma, adenoid cystic carcinoma, T-cell prolymphocytic leukemia, malignant glioma, bladder cancer, medulloblastoma, thyroid cancer, melanoma, multiple myeloma, Barret's adenocarcinoma, hepatoma, prostate cancer, pro-myelocytic leukemia, chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma, small cell lung cancer, renal carcinoma [32, 155-162].

(87) Published and proprietary data have shown direct effects of BET inhibition on cell proliferation in various cancers. In one embodiment, BET inhibitor compounds of Formula I are used to treat cancers for which exist published and, for some, proprietary, in vivo and/or in vitro data showing a direct effect of BET inhibition on cell proliferation. These cancers include NMC (NUT-midline carcinoma), acute myeloid leukemia (AML), acute B lymphoblastic leukemia (B-ALL), Burkitt's Lymphoma, B-cell Lymphoma, Melanoma, mixed lineage leukemia, multiple myeloma, pro-myelocytic leukemia (PML), non-Hodgkin's lymphoma [24, 26-30, 33]. Examples provided within this application have also shown a direct effect of BET inhibition on cell proliferation in vitro for the following cancers: Neuroblastoma, Medulloblastoma, lung carcinoma (NSCLC, SCLC), colon carcinoma.

(88) In one embodiment, because of potential synergy or additive effects between BET inhibitors and other cancer therapy, BET inhibitor compounds of Formula I are combined with other therapies, chemotherapeutic agents, or anti-proliferative agents to treat human cancer and other proliferative disorders. The list of therapeutic agents which can be combined with BET inhibitors in cancer treatment includes, but is not limited to, ABT-737, Azacitidine (Vidaza), AZD1152 (Barasertib), AZD2281 (Olaparib), AZD6244 (Selumetinib), BEZ235, Bleomycin Sulfate, Bortezomib (Velcade), Busulfan (Myleran), Camptothecin, Cisplatin, Cyclophosphamide (Clafen), CYT387, Cytarabine (Ara-C), Dacarbazine, DAPT (GSI-IX), Decitabine, Dexamethasone, Doxorubicin (Adriamycin), Etoposide, Everolimus (RAD001), Flavopiridol (Alvocidib), Ganetespib (STA-9090), Gefitinib (Iressa), Idarubicin, Ifosfamide (Mitoxana), IFNa2a (Roferon A), Melphalan (Alkeran), Methazolastone (temozolomide), Metformin, Mitoxantrone (Novantrone), Paclitaxel, Phenformin, PKC412 (Midostaurin), PLX4032 (Vemurafenib), Pomalidomide (CC-4047), Prednisone (Deltasone), Rapamycin, Revlimid (Lenalidomide), Ruxolitinib (INCB018424), Sorafenib (Nexavar), SU11248 (Sunitinib), SU11274, Vinblastine, Vincristine (Oncovin), Vinorelbine (Navelbine), Vorinostat (SAHA), WP1130 (Degrasyn).

(89) In one embodiment, because of their ability to up-regulate ApoA-1 transcription and protein expression [11, 35], BET inhibitor compounds of Formula I are used to treat cardiovascular diseases that are generally associated with including dyslipidemia, atherosclerosis, hypercholesterolemia, and metabolic syndrome [8, 19]. In another embodiment, BET inhibitors would be used to treat non-cardiovascular disease characterized by deficits in ApoA-1, including Alzheimer's disease [37].

(90) In one embodiment, BET inhibitor compounds of Formula I are used in patients with insulin resistance and type II diabetes [8, 19, 38, 39]. The anti-inflammatory effects of BET inhibition would have additional value in decreasing inflammation associated with diabetes and metabolic disease [163].

(91) In one embodiment, because of their ability to down-regulate viral promoters, BET inhibitor compounds of Formula I are used as therapeutics for cancers that are associated with viruses including Epstein-Barr Virus (EBV), hepatitis virus (HBV, HCV), Kaposi's sarcoma associated virus (KSHV), human papilloma virus (HPV), Merkel cell polyomavirus, and human cytomegalovirus (CMV) [40-42, 164]. In another embodiment, because of their ability to reactivate HIV-1 in models of latent T cell infection and latent monocyte infection, BET inhibitor compounds of Formula I are used in combination with anti-retroviral therapeutics for treating HIV [43-46].

(92) In one embodiment, because of the role of epigenetic processes and bromodomain-containing proteins in neurological disorders, BET inhibitor compounds of Formula I are used to treat diseases including, but not limited to, Alzheimer's disease, Parkinson's disease, Huntington disease, bipolar disorder, schizophrenia, Rubinstein-Taybi syndrome, and epilepsy [9, 165].

(93) In one embodiment, because of the effect of BRDT depletion or inhibition on spermatid development, BET inhibitor compounds of Formula I are used as reversible, male contraceptive agents [50, 51].

Pharmaceutical Compositions

(94) Pharmaceutical compositions of the present disclosure comprise at least one compound of Formula I, or tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate thereof formulated together with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, buccal and parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) administration. The most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.

(95) Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of a compound of the present disclosure as powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As indicated, such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association at least one compound of the present disclosure as the active compound and a carrier or excipient (which may constitute one or more accessory ingredients). The carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and must not be deleterious to the recipient. The carrier may be a solid or a liquid, or both, and may be formulated with at least one compound described herein as the active compound in a unit-dose formulation, for example, a tablet, which may contain from about 0.05% to about 95% by weight of the at least one active compound. Other pharmacologically active substances may also be present including other compounds. The formulations of the present disclosure may be prepared by any of the well-known techniques of pharmacy consisting essentially of admixing the components.

(96) For solid compositions, conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid pharmacologically administrable compositions can, for example, be prepared by, for example, dissolving or dispersing, at least one active compound of the present disclosure as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. In general, suitable formulations may be prepared by uniformly and intimately admixing the at least one active compound of the present disclosure with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product. For example, a tablet may be prepared by compressing or molding a powder or granules of at least one compound of the present disclosure, which may be optionally combined with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, at least one compound of the present disclosure in a free-flowing form, such as a powder or granules, which may be optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s). Molded tablets may be made by molding, in a suitable machine, where the powdered form of at least one compound of the present disclosure is moistened with an inert liquid diluent.

(97) Formulations suitable for buccal (sub-lingual) administration include lozenges comprising at least one compound of the present disclosure in a flavored base, usually sucrose and acacia or tragacanth, and pastilles comprising the at least one compound in an inert base such as gelatin and glycerin or sucrose and acacia.

(98) Formulations of the present disclosure suitable for parenteral administration comprise sterile aqueous preparations of at least one compound of Formula I or tautomers, stereoisomers, pharmaceutically acceptable salts, and hydrates thereof, which are approximately isotonic with the blood of the intended recipient. These preparations are administered intravenously, although administration may also be effected by means of subcutaneous, intramuscular, or intradermal injection. Such preparations may conveniently be prepared by admixing at least one compound described herein with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions according to the present disclosure may contain from about 0.1 to about 5% w/w of the active compound.

(99) Formulations suitable for rectal administration are presented as unit-dose suppositories. These may be prepared by admixing at least one compound as described herein with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.

(100) Formulations suitable for topical application to the skin may take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers and excipients which may be used include Vaseline, lanoline, polyethylene glycols, alcohols, and combinations of two or more thereof. The active compound (i.e., at least one compound of Formula I or tautomers, stereoisomers, pharmaceutically acceptable salts, and hydrates thereof) is generally present at a concentration of from about 0.1% to about 15% w/w of the composition, for example, from about 0.5 to about 2%.

(101) The amount of active compound administered may be dependent on the subject being treated, the subject's weight, the manner of administration and the judgment of the prescribing physician. For example, a dosing schedule may involve the daily or semi-daily administration of the encapsulated compound at a perceived dosage of about 1 μg to about 1000 mg. In another embodiment, intermittent administration, such as on a monthly or yearly basis, of a dose of the encapsulated compound may be employed. Encapsulation facilitates access to the site of action and allows the administration of the active ingredients simultaneously, in theory producing a synergistic effect. In accordance with standard dosing regimens, physicians will readily determine optimum dosages and will be able to readily modify administration to achieve such dosages.

(102) A therapeutically effective amount of a compound or composition disclosed herein can be measured by the therapeutic effectiveness of the compound. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being used. In one embodiment, the therapeutically effective amount of a disclosed compound is sufficient to establish a maximal plasma concentration. Preliminary doses as, for example, determined according to animal tests, and the scaling of dosages for human administration is performed according to art-accepted practices.

(103) Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD.sub.50 (the dose lethal to 50% of the population) and the ED.sub.50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD.sub.50/ED.sub.50. Compositions that exhibit large therapeutic indices are preferable.

(104) Data obtained from the cell culture assays or animal studies can be used in formulating a range of dosage for use in humans. Therapeutically effective dosages achieved in one animal model may be converted for use in another animal, including humans, using conversion factors known in the art (see, e.g., Freireich et al., Cancer Chemother. Reports 50(4):219-244 (1966) and the following Table for Equivalent Surface Area Dosage Factors).

(105) Equivalent Surface Area Dosage Factors

(106) TABLE-US-00001 To: Mouse Rat Monkey Dog Human From: (20 g) (150 g) (3.5 kg) (8 kg) (60 kg) Mouse 1 ½ ¼ ⅙ 1/12 Rat 2 1 ½ ¼ 1/7 Monkey 4 2 1 ⅗ ⅓ Dog 6 4 ⅗ 1 ½ Human 12 7 3 2 1

(107) The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED.sub.50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. Generally, a therapeutically effective amount may vary with the subject's age, condition, and gender, as well as the severity of the medical condition in the subject. The dosage may be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment.

(108) In one embodiment, a compound of Formula I or a tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate thereof, is administered in combination with another therapeutic agent. The other therapeutic agent can provide additive or synergistic value relative to the administration of a compound of the present disclosure alone. The therapeutic agent can be, for example, a statin; a PPAR agonist, e.g., a thiazolidinedione or fibrate; a niacin, a RVX, FXR or LXR agonist; a bile-acid reuptake inhibitor; a cholesterol absorption inhibitor; a cholesterol synthesis inhibitor; a cholesteryl ester transfer protein (CETP), an ion-exchange resin; an antioxidant; an inhibitor of AcylCoA cholesterol acyltransferase (ACAT inhibitor); a tyrophostine; a sulfonylurea-based drug; a biguanide; an alpha-glucosidase inhibitor; an apolipoprotein E regulator; a HMG-CoA reductase inhibitor, a microsomal triglyceride transfer protein; an LDL-lowing drug; an HDL-raising drug; an HDL enhancer; a regulator of the apolipoprotein A-IV and/or apolipoprotein genes; or any cardiovascular drug.

(109) In another embodiment, a compound of Formula I or a tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate thereof, is administered in combination with one or more anti-inflammatory agents. Anti-inflammatory agents can include immunosuppressants, TNF inhibitors, corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDS), and the like. Exemplary anti-inflammatory agents include, for example, prednisone; methylprenisolone (Medrol®), triamcinolone, methotrexate (Rheumatrex®, Trexall®), hydroxychloroquine (Plaquenil®), sulfasalzine (Azulfidine®), leflunomide (Arava®), etanercept (Enbrel®), infliximab (Remicade®), adalimumab (Humira®), rituximab (Rituxan®), abatacept (Orencia®), interleukin-1, anakinra (Kineret™), ibuprofen, ketoprofen, fenoprofen, naproxen, aspirin, acetominophen, indomethacin, sulindac, meloxicam, piroxicam, tenoxicam, lornoxicam, ketorolac, etodolac, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, diclofenac, oxaprozin, apazone, nimesulide, nabumetone, tenidap, etanercept, tolmetin, phenylbutazone, oxyphenbutazone, diflunisal, salsalate, olsalazine or sulfasalazine.

(110) Specific embodiments of the invention include:

(111) 1. A compound of Formula I:

(112) ##STR00015##
or a stereoisomer, tautomer, pharmaceutical acceptable salt, or hydrate thereof,
wherein:

(113) W.sub.1 is selected from N and CR.sub.1;

(114) W.sub.2 is selected from N and CR.sub.2;

(115) W.sub.3 is selected from N and CR.sub.3;

(116) W.sub.4 is selected from N and CR.sub.4;

(117) each W may be the same or different from each other;

(118) A is selected from N and CH;

(119) R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, aryl, hydroxyl, and halogen;

(120) two adjacent substituents selected from R.sub.1, R.sub.2, R.sub.3, and Ry may be connected in a 5- or 6-membered ring to form a bicyclic carbocycle or bicyclic heterocycle;

(121) AR1 is a group selected from the following:

(122) ##STR00016##

(123) AR2 is a group selected from the following:

(124) ##STR00017##

(125) R.sub.5 is selected from hydrogen, alkyl, alkoxy, thioalkyl, amino, and halogen;

(126) R.sub.6 is selected from hydrogen, alkoxy, alkyl, aminoalkyl, and thioalkyl;

(127) Y is selected from NH, O, and S;

(128) W.sub.5 is selected from N and CQ.sub.1;

(129) W.sub.6 is selected from N and CQ.sub.2;

(130) W.sub.7 is selected from N and CQ.sub.3;

(131) W.sub.8 is selected from N and CQ.sub.4;

(132) W.sub.9 is selected from N and CQ.sub.5;

(133) Q.sub.1, Q.sub.2, Q.sub.3, Q.sub.4, and Q.sub.5 are independently selected from hydrogen, alkyl, halogen, —CN, —SO.sub.2Me, —SO.sub.2Et, —SO.sub.2Pr, —S(O)Me, —S(O)Et, —S(O)Pr, —S(O)iPr, amide, ketone, —COOH, and ester; and

(134) two adjacent substituents selected from R.sub.5, R.sub.6, Q.sub.1, Q.sub.2, Q.sub.3, Q.sub.4, Q.sub.5, and Q.sub.6 may be connected in a 5- or 6-membered ring to form an unsubstituted carbocycle or heterocycle.

(135) 2. The compound according to embodiment 1, wherein if R.sub.6 is hydrogen or methyl, then at least one of R.sub.i—R.sub.4 is not hydrogen.

(136) 3. The compound according to embodiment 1, wherein R.sub.2 is methoxy, hydroxyl, and R.sub.3 is methoxy, then at least one of Q.sub.1, Q.sub.2, Q.sub.3, Q.sub.4, and Q.sub.5 is different from hydrogen.

(137) 4. The compound according to embodiment 1, wherein if R.sub.1 and R.sub.3 are methoxy and Q.sub.3 is —SO.sub.2Me or —SMe, then at least one of R.sub.2, R.sub.4, R.sub.5, R.sub.6, Q.sub.1, Q.sub.2, Q.sub.4, and Q.sub.5 is not hydrogen.

(138) 5. The compound according to embodiment 1, wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are selected from hydrogen, alkyl, alkoxy, and halogen.

(139) 6. The compound according to embodiment 1, wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are selected from hydrogen, methyl, ethyl, methoxy, ethoxy, and fluoride.

(140) 7. The compound according to embodiment 1, wherein R.sub.1 and R.sub.3 are each independently an alkoxy.

(141) 8. The compound according to embodiment 1, wherein R.sub.1 and R.sub.3 are methoxy.

(142) 9. The compound according to embodiment 1, wherein R.sub.1 and R.sub.3 are each methoxy and R.sub.2 and R.sub.4 are each hydrogen.

(143) 10. The compound according to any one of embodiments 1-9, wherein R.sub.5 is selected from hydrogen and alkyl.

(144) 11. The compound according to any one of embodiments 1-10, wherein R.sub.6 is selected from hydrogen and alkoxy.

(145) 12. The compound according to any one of embodiments 1-10, wherein R.sub.6 is selected from hydrogen, methoxy, ethoxy, alkoxy preferable substituted with a hydroxyl or amino.

(146) 13. The compound according to any one of embodiments 1-10, wherein R.sub.6 is selected from hydrogen, methoxy,

(147) ##STR00018##

(148) 14. The compound according to any one of embodiments 1-13, wherein AR1 is selected from

(149) ##STR00019##

(150) 15. The compound according to any one of embodiments 1-13, wherein AR1 is selected from

(151) ##STR00020##

(152) 16. The compound according to any one of embodiments 1-15, wherein AR2 is selected from

(153) ##STR00021##

(154) 17. The compound according to any one of embodiments 1-15, wherein AR2 is

(155) ##STR00022##

(156) 18. The compound according to any one of embodiments 1-17, wherein W.sub.5 is selected from CQ.sub.1.

(157) 19. The compound according to any one of embodiments 1-18, wherein W.sub.6 is selected from CQ.sub.2.

(158) 20. The compound according to any one of embodiments 1-19, wherein W.sub.7 is selected from CQ.sub.3.

(159) 21. The compound according to any one of embodiments 1-20, wherein W.sub.8 is selected from CQ.sub.4.

(160) 22. The compound according to any one of embodiments 1-21, wherein W.sub.9 is selected from CQ.sub.5.

(161) 23. The compound according to any one of embodiments 1-22, wherein Q.sub.1, Q.sub.2, Q.sub.3, Q.sub.4, and Q.sub.5 are independently selected from hydrogen, alkyl, halogen, —CN, —SO.sub.2Me, —SO.sub.2Et, —SO.sub.2Pr, —SO.sub.2iPr, —S(O)Me, —S(O)Et, —S(O)Pr, —S(O)iPr, amide, ketone, ester, and —COOH.

(162) 24. The compound according to any one of embodiments 1-22, wherein Q.sub.1, Q.sub.2, Q.sub.4, and Q.sub.5 are independently selected from hydrogen, methyl, —CF.sub.3, ethyl, —Cl, —CN, —SO.sub.2Me, —SO.sub.2Et, and —S(O)Me.

(163) 25. The compound according to any one of embodiments 1-22, wherein Q.sub.1, Q.sub.2, Q.sub.4, and Q.sub.5 are independently selected from hydrogen, methyl, —CF.sub.3, —Cl, —SO.sub.2Me, and —S(O)Me.

(164) 26. The compound according to any one of embodiments 1-25, wherein Q.sub.3 is selected from hydrogen, —CN, —SO.sub.2Me, —SO.sub.2Et, —SO.sub.2Pr, —SO.sub.2iPr, —S(O)Me, —S(O)Et, —S(O)Pr, —S(O)iPr, amide, ketone, ester, and —COOH.

(165) 27. The compound according to any one of embodiments 1-25, wherein Q.sub.3 is selected from hydrogen, —CN, —SO.sub.2Me, —SO.sub.2Et, —S(O)Me, —C(O)N(Me).sub.2, and —C(O)Me.

(166) 28. The compound according to embodiment 1, wherein the compound of Formula I is selected from: 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-hydroxyethoxy)pyridin-2-yl)-N,N,3-trimethylbenzamide; 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-(isopropylamino)ethoxy)pyridin-2-yl)-N,N,3-trimethylbenzamide; 3-Chloro-4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-hydroxyethoxy)pyridin-2-yl)-N,N-dimethylbenzamide; 3-Chloro-4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-(isopropylamino)ethoxy)pyridin-2-yl)-N,N-dimethylbenzamide; (S)-7-Fluoro-5-((1-methylpyrrolidin-3-yl)oxy)-2-(6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one; 4-(6-(6,8-Dimethoxy-1-oxo-1,2-dihydroisoquinolin-3-yl)pyridin-2-yl)-N,N-dimethylbenzamide; 6,8-Dimethoxy-3-(6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)isoquinolin-1(2H)-one; 6,8-dimethoxy-3-(6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)isoquinolin-1(2H)-one; 2-(6-(2-(Dimethylamino)ethoxy)-4′-(methylsulfinyl)biphenyl-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(6-(Azetidin-3-yloxy)-4′-(methylsulfinyl)biphenyl-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 5,7-Dimethoxy-2-(6-(1-methylazetidin-3-yloxy)-4′-(methylsulfinyl)biphenyl-3-yl)quinazolin-4(3H)-one; 2-(6-(Azetidin-3-yloxy)-4′-(methylsulfinyl)-[1,1′-biphenyl]-3-yl)-7-fluoro-5-methoxyquinazolin-4(3H)-one; 7-Fluoro-5-methoxy-2-(6-((1-methylazetidin-3-yl)oxy)-4′-(methylsulfinyl)-[1,1′-biphenyl]-3-yl)quinazolin-4(3H)-one; 2-(6-(2-Hydroxyethoxy)-4′-(methyl sulfinyl)biphenyl-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(6-(2-(Isopropylamino)ethoxy)-4′-(methylsulfinyl)biphenyl-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2′-(Azetidin-3-yloxy)-5′-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-[1,1′-biphenyl]-4-carbonitrile; 5′-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2′-((1-methylazetidin-3-yl)oxy)-[1,1′-biphenyl]-4-carbonitrile; 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)-N,N-dimethylbenzamide; 2-(5-(2-Hydroxyethoxy)-6-phenylpyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(5-(2-(Isopropylamino)ethoxy)-6-phenylpyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-hydroxyethoxy)pyridin-2-yl)-N,N-dimethylbenzamide; 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one methanesulfonate; 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-(isopropylamino)ethoxy)pyridin-2-yl)-N,N-dimethylbenzamide; 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(6-(4-Acetylphenyl)-5-(2-hydroxyethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 5,7-Dimethoxy-2-(6-(4-(methylsulfonyl)phenyl)-5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-2-yl)quinazolin-4(3H)-one hydrochloride; 2-(5-(2-Hydroxyethoxy)-6-(2-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 5,7-Dimethoxy-2-(6-(4-(methylsulfonyl)phenyl)-5-(2-morpholinoethoxy)pyridin-2-yl)quinazolin-4(3H)-one hydrochloride; 2-(5-(2-(Isopropylamino)ethoxy)-6-(2-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(5-(2-(Isopropylamino)ethoxy)-6-(3-(methyl sulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2-hydroxyethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2-(isopropylamino)ethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(5-(2-Hydroxyethoxy)-6-(3-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one methanesulfonate; 2-(5-(2-Hydroxyethoxy)-6-(3-(methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(5-(2-Hydroxyethoxy)-6-(2-methyl-4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(5-(2-(Isopropylamino)ethoxy)-6-(3-(methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methyl sulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2-morpholinoethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(6-(2-(Isopropylamino)ethoxy)-4′-(methylsulfonyl)-[1,1′-biphenyl]-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(5-(2-(Isopropylamino)ethoxy)-6-(2-methyl-4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)-2-(trifluoromethyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 5,7-Dimethoxy-2-(4′-(methylsulfinyl)-[1,1′-biphenyl]-3-yl)quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(4-(4-(methylsulfinyl)phenyl)thiophen-2-yl)quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(5-methoxy-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(3-(5-(methylsulfinyl)thiophen-2-yl)phenyl)quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(7-(4-(methylsulfinyl)phenyl)-1H-indol-5-yl)quinazolin-4(3H)-one; tert-Butyl (2-((6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(4-(methylsulfinyl)phenyl)pyridin-3-yl)oxy)ethyl)(isopropyl)carbamate; 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-methoxypyridin-2-yl)-N,N,3-trimethylbenzamide; 5,7-Dimethoxy-2-(6-(4-(methylsulfinyl)phenyl)-5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-2-yl)quinazolin-4(3H)-one; 3-Chloro-4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-methoxypyridin-2-yl)-N,N-dimethylbenzamide; 5-Methoxy-2-(5-methoxy-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(5-methoxy-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one; 2-Chloro-5′-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2′-methoxy-N,N-dimethyl-[1,1′-biphenyl]-4-carboxamide; 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)-7-methoxyquinazolin-4(3H)-one; 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one; 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one; 1-(2-((6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(4-(methylsulfonyl)phenyl)pyridin-3-yl)oxy)ethyl)pyrrolidine 1-oxide; 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one; 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one; 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)-7-methoxyquinazolin-4(3H)-one; 2-(5-(2-Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-7-methoxyquinazolin-4(3H)-one; 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one; and a stereoisomer, tautomer, pharmaceutical acceptable salt, or hydrate thereof.

(167) 29. The compound according to embodiment 1, wherein the compound of Formula I is 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one.

(168) 30. The compound according to embodiment 1, wherein the compound of Formula I is 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one methanesulfonate.

(169) 31. The compound according to embodiment 1, wherein the compound of Formula I is 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one.

(170) 32. The compound according to embodiment 1, wherein the compound of Formula I is 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one.

(171) 33. The compound according to embodiment 1, wherein the compound of Formula I is 5,7-Dimethoxy-2-(5-methoxy-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one.

(172) 34. A compound according to embodiment 1, wherein R.sub.6 is selected from the group represented by Formula II:

(173) ##STR00023##
wherein:

(174) D and E are independently selected from O, N, and S;

(175) R.sub.7 is selected from hydrogen and alkyl, and R.sub.7 is present only if D is N;

(176) R.sub.8 and R.sub.9 are independently selected from hydrogen, alkyl, and cycloalkyl, wherein if E is O or S, then only one of R.sub.8 and R.sub.9 is present;

(177) R.sub.8 and R.sub.9 may be connected to form a carbocycle or a heterocycle containing one or more heteroatoms;

(178) R.sub.8 or R.sub.9 may be connected with R.sub.7 to form a carbocycle or a heterocycle containing one or more heteroatoms;

(179) n is selected from 1, 2, and 3.

(180) 35. The compound according to embodiment 34, wherein D is oxygen.

(181) 36. The compound according to embodiment 34, wherein E is selected from O and N.

(182) 37. The compound according to embodiment 34, wherein R.sub.7 is selected from hydrogen, methyl, and ethyl.

(183) 38. The compound according to embodiment 34, wherein n is 1.

(184) 39. The compound according to embodiment 34, wherein R.sub.8 and R.sub.9 are each selected from hydrogen, and alkyl.

(185) 40. The compound according to embodiment 34, wherein R.sub.6 is selected from:

(186) ##STR00024##

(187) 41. A pharmaceutical composition comprising a compound according to any one of embodiments 1-40.

(188) 42. A compound according to any one of embodiments 1-40 for use as a medicament.

(189) 43. A method for inhibiting BET proteins in a mammal comprising administering a therapeutically effective amount of a compound according to any one of embodiments 1-40.

(190) 44. A method for treating a disease that is sensitive to a BET inhibitor comprising administering a therapeutically effective amount of a compound according to any one of embodiments 1-40.

(191) 45. A method for treating an autoimmune disease in a mammal comprising administering a therapeutically effective amount of a compound according to any one of embodiments 1-40.

(192) 46. The method of embodiment 45, wherein the autoimmune disease is selected from Acute Disseminated Encephalomyelitis, Agammaglobulinemia, Allergic Disease, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, Anti-phospholipid syndrome, Autoimmune aplastic anemia, Autoimmune hepatitis, Autoimmune inner ear disease, Autoimmune myocarditis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune thrombocytopenic purpura, Behcet's Disease, Bullous pemphigoid, Castleman's Disease, Celiac Disease, Churg-Strauss syndrome, Crohn's Disease, Cogan's syndrome, Dry eye syndrome, Essential mixed cryoglobulinemia, Dermatomyositis, Devic's Disease, Encephalitis, Eosinophlic esophagitis, Eosinophilic fasciitis, Erythema nodosum, Giant cell arteritis, Glomerulonephritis, Goodpasture's syndrome, Granulomatosis with Polyangiitis (Wegener's), Graves' Disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, Hemolytic anemia, Henoch-Schonlein purpura, IgA nephropathy, Inclusion body myositis, Type I diabetes, Interstitial cystitis, Kawasaki's Disease, Leukocytoclastic vasculitis, Lichen planus, Lupus (SLE), Microscopic polyangitis, Multiple sclerosis, Myasthenia gravis, myositis, Optic neuritis, Pemphigus, POEMS syndrome, Polyarteritis nodosa, Primary biliary cirrhosis, Psoriasis, Psoriatic arthritis, Pyoderma gangrenosum, Relapsing polychondritis, Rheumatoid arthritis, Sarcoidosis, Scleroderma, Sjogren's syndrome, Takayasu's arteritis, Transverse myelitis, Ulcerative colitis, Uveitis, and Vitiligo.

(193) 47. A method for treating inflammatory diseases or disorders in a mammal comprising administering a therapeutically effective amount of a compound according to any one of embodiments 1-40.

(194) 48. The method of embodiment 47 wherein the inflammatory disease or disorder is selected from sinusitis, pneumonitis, osteomyelitis, gastritis, enteritis, gingivitis, appendicitis, irritable bowel syndrome, tissue graft rejection, chronic obstructive pulmonary disease (COPD), septic shock, toxic shock syndrome, SIRS, bacterial sepsis, osteoarthritis, acute gout, acute lung injury, acute renal failure, burns, Herxheimer reaction, and SIRS associated with viral infections.

(195) 49. A method for treating or preventing a cancer in a mammal comprising administering a therapeutically effective amount of a compound according to any one of embodiments 1-40.

(196) 50. The method of embodiment 49 wherein the cancer is a midline carcinoma.

(197) 51. The method of embodiment 49 wherein the cancer exhibits overexpression, translocation, amplification, or rearrangement of a myc family oncoproteins.

(198) 52. The method of embodiment 49 wherein the cancer is characterized by overexpression of c-myc.

(199) 53. The method of embodiment 49 wherein the cancer is characterized by is characterized by overexpression n-myc.

(200) 54. The method of embodiment 49 wherein the cancer results from aberrant regulation of BET proteins.

(201) 55. The method of embodiment 49 wherein the cancer is characterized by recruitment of pTEFb to regulate oncogenes.

(202) 56. The method of embodiment 49 wherein the cancer is characterized by upregulation of CDK6, Bcl2, TYRO3, MYB and/or hTERT.

(203) 57. The method of embodiment 49 wherein the cancer is selected from: B-acute lymphocytic leukemia, Burkitt's lymphoma, diffuse large cell lymphoma, multiple myeloma, primary plasma cell leukemia, atypical carcinoid lung cancer, bladder cancer, breast cancer, cervix cancer, colon cancer, gastric cancer, glioblastoma, hepatocellular carcinoma, large cell neuroendocrine carcinoma, medulloblastoma, melanoma, nodular melanoma, neuroblastoma, esophageal squamous cell carcinoma, osteosarcoma, ovarian cancer, prostate cancer, renal clear cell carcinoma, retinoblastoma, rhabdomyosarcoma, small cell lung carcinoma, NUT midline carcinoma, B-cell lymphoma, non-small cell lung cancer, esophageal cancer and head and neck squamous cell carcinoma, chronic lymphocytic leukemia, follicular lymphoma, diffuse large B cell lymphoma with germinal center phenotype, Burkitt's lymphoma, Hodgkin's lymphoma, follicular lymphomas, activated anaplastic large cell lymphoma, primary neuroectodermal tumor, pancreatic cancer, adenoid cystic carcinoma, T-cell prolymphocytic leukemia, malignant glioma, thyroid cancer, Barret's adenocarcinoma, hepatoma, pro-myelocytic leukemia, chronic lymphocytic leukemia, and mantle cell lymphoma.

(204) 58. The method of any one of embodiments 49-57 wherein the compound of Formula I is administered in combination with another anticancer agent.

(205) 59. The method of embodiment 58, wherein the anticancer agent is selected from ABT-737, Azacitidine (Vidaza), AZD1152 (Barasertib), AZD2281 (Olaparib), AZD6244 (Selumetinib), BEZ235, Bleomycin Sulfate, Bortezomib (Velcade), Busulfan (Myleran), Camptothecin, Cisplatin, Cyclophosphamide (Clafen), CYT387, Cytarabine (Ara-C), Dacarbazine, DAPT (GSI-IX), Decitabine, Dexamethasone, Doxorubicin (Adriamycin), Etoposide, Everolimus (RAD001), Flavopiridol (Alvocidib), Ganetespib (STA-9090), Gefitinib (Iressa), Idarubicin, Ifosfamide (Mitoxana), IFNa2a (Roferon A), Melphalan (Alkeran), Methazolastone (temozolomide), Metformin, Mitoxantrone (Novantrone), Paclitaxel, Phenformin, PKC412 (Midostaurin), PLX4032 (Vemurafenib), Pomalidomide (CC-4047), Prednisone (Deltasone), Rapamycin, Revlimid (Lenalidomide), Ruxolitinib (INCB018424), Sorafenib (Nexavar), SU11248 (Sunitinib), SU11274, Vinblastine, Vincristine (Oncovin), Vinorelbine (Navelbine), Vorinostat (SAHA), and WP1130 (Degrasyn).

(206) 60. A method of treating a cardiovascular disease comprising administering a therapeutically effective amount of a compound according to any one of embodiments 1-40.

(207) 61. The method of embodiment 60, wherein the cardiovascular disease is dyslipidemia, atherosclerosis, hypercholesterolemia, or metabolic syndrome.

(208) 62. A method of treating insulin resistance diabetes comprising administering a therapeutically effective amount of a compound according to any one of embodiments 1-40.

(209) 63. A method of treating a neurological disorder comprising administering a therapeutically effective amount of a compound according to any one of embodiments 1-40.

(210) 64. The method of embodiment 63 wherein the neurological disorder is Alzheimer's disease, Parkinson's disease, Huntington disease, bipolar disorder, schizophrenia, Rubinstein-Taybi syndrome, or epilepsy.

(211) 65. A method of male contraception comprising administering a therapeutically effective amount of a compound according to any one of embodiments 1-40.

(212) 66. A method of treating HIV comprising administering a therapeutically effective amount of a compound according to any one of embodiments 1-40.

(213) 67. A method of treating a cancer associated with a viral infection comprising administering a therapeutically effective amount of a compound according to any one of embodiments 1-40.

(214) 68. The method of embodiment 67 wherein the virus is selected from Epstein-Barr Virus, hepatitis B virus, hepatitis C virus, Kaposi's sarcoma associated virus, human papilloma virus, Merkel cell polyomavirus, and human cytomegalovirus.

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EXAMPLES

Example 1: Preparation of the intermediate 6-Bromo-5-(2-((tert-butyldimethylsilyl)-oxy)ethoxy)picolinaldehyde (4)

(216) ##STR00025##

(217) Preparation of 2-Bromo-6-(hydroxymethyl)pyridin-3-ol (2). To a solution of potassium hydroxide (1.90 g, 28.7 mmol) in water (13 mL) was added 2-bromopyridin-3-ol (1, 5.00 g, 28.7 mmol), disodium ethylenediaminetetraacetate dihydrate (0.218 g, 0.574 mmol) and 37% formaldehyde (7.8 mL, 99 mmol). The mixture was heated at 90° C. for 5 h, cooled at room temperature (rt) and acidified with acetic acid (1.73 mL, 28.7 mmol). The solution was diluted with EtOAc (200 mL), washed with water (50 mL) and brine (50 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated to afford the title compound (5.82 g, 99%) as a white solid: .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.32 (d, J=8.1 Hz, 1H), 7.20-7.27 (m, 1H), 4.81 (s, 1H), 4.56 (d, J=8.7 Hz, 2H); Multimode MS m/z 204 [M+H].sup.+.

(218) Preparation of 6-Bromo-5-hydroxypicolinaldehyde (3). To a solution of 2-bromo-6-(hydroxymethyl)pyridin-3-ol (2, 5.82 g, 28.5 mmol) in 1,4-dioxane (300 mL) was added manganese(IV) oxide (17.6 g, 85.5 mmol). The mixture was heated at 100° C. for 16 h under nitrogen. After this time, the reaction mixture was cooled to room temperature, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with hexanes to 0-70% EtOAc in hexanes to afford the title compound (2.92 g, 51%) as an off-white solid: .sup.1H NMR (300 MHz, CDCl.sub.3) δ 9.90 (s, 1H), 7.92 (d, J=8.2 Hz, 1H), 7.43 (d, J=8.2 Hz, 1H).

(219) Preparation of 6-Bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)picolinaldehyde (4). A mixture of 6-bromo-5-hydroxypicolinaldehyde (3, 2.0 g, 9.9 mmol) in DMF (20 mL) was treated with K.sub.2CO.sub.3 (4.14 g, 30.0 mmol) and heated at 80° C. for 30 min. (2-Bromoethoxy)(tert-butyl)dimethylsilane (2.87 g, 12.0 mmol) was added and the mixture was heated at 80° C. for 24 h. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography eluting with 0-20% EtOAc in hexanes to afford the title compound (3.06 g, 85%) as an off-white waxy solid: .sup.1H NMR (300 MHz, CDCl.sub.3) δ 9.93 (d, J=0.7 Hz, 1H), 7.92 (d, J=8.3 Hz, 1H), 7.33 (d, J=8.3 Hz, 1H), 4.25 (t, J=5.0 Hz, 2H), 4.06 (t, J=5.0 Hz, 2H), 0.90 (s, 9H), 0.11 (s, 6H).

Example 2: Preparation of the intermediate N,N,3-Trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (7)

(220) ##STR00026##

(221) Preparation of 4-Bromo-N,N,3-trimethylbenzamide (6). A mixture of 4-bromo-3-methylbenzoic acid (5, 5.00 g, 23.3 mmol), dimethylamine (2 M in THF, 17.4 mL, 34.9 mmol), 1-hydroxybenzotriazole (3.15 g, 23.3 mmol), and triethylamine (7.06 g, 69.9 mmol) in dichloromethane (200 mL) was treated with 1-(3-(dimethylamino)propyl)-3-ethyl carbodiimide hydrochloride (5.82 g, 30.3 mmol). The mixture was stirred at room temperature for 16 h. After diluting with EtOAc (300 mL), the mixture was washed with water (100 mL) and brine (100 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 0-20% EtOAc in hexanes to afford the title compound (4.67 g, 83%) as a yellow oil: .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.55 (d, J=8.1 Hz, 1H), 7.30 (d, J=1.6 Hz, 1H), 7.08 (dd, J=1.9, 8.1 Hz, 1H), 3.09 (s, 3H), 2.97 (s, 3H), 2.41 (s, 3H); Multimode MS m/z 242 [M+H].sup.+.

(222) Preparation of N,N,3-Trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (7). To a solution of 4-bromo-N,N,3-trimethylbenzamide (6, 2.00 g, 8.26 mmol), bis(pinacolato)diboron (2.52 g, 9.92 mmol), potassium acetate (2.43 g, 24.8 mmol), and 1,1′-bis(diphenylphosphino)ferrocene (0.046 g, 0.083 mmol) in 1,4-dioxane (100 mL) under nitrogen was added (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (0.068 g, 0.083 mmol). The mixture was heated at 100° C. for 48 h. After diluting with EtOAc (300 mL), the mixture was washed with water (100 mL) and brine (100 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated. The residue was purified by silica gel chromatography eluting with 0-60% EtOAc in hexanes to afford the title compound (2.64 g, >99%) as a brown solid: .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.76 (d, J=7.5 Hz, 1H), 7.20 (s, 1H), 7.17 (d, J=7.5 Hz, 1H), 3.09 (s, 3H), 2.93 (s, 3H), 2.54 (s, 3H), 1.34 (s, 12H); Multimode MS m/z 290 [M+H].sup.+.

Example 3: Preparation of 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-hydroxyethoxy)pyridin-2-yl)-N,N,3-trimethylbenzamide

(223) ##STR00027##

(224) Preparation of 4-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-formylpyridin-2-yl)-N,N,3-trimethylbenzamide (8). To a suspension of N,N,3-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (7, 240 mg, 0.083 mmol), 6-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)picolinaldehyde (4, 200 mg, 0.55 mmol) and potassium carbonate (115 mg, 0.83 mol) in an argon-degassed solution of 9:1 ethanol:water (5 mL) was added tetrakis(triphenylphosphine)palladium(0) (32 mg, 0.028 mmol). The mixture in a sealed tube was heated to 80° C. for 15 h. The resulting suspension was partitioned between ethyl acetate (50 mL) and water (50 mL) and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined extracts were washed with brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. Silica gel chromatography eluting with 0-40% EtOAc in hexanes afforded the title compound (0.229 g, 93%) as a white solid: .sup.1H NMR (500 MHz, CDCl.sub.3) δ 10.05 (s, 1H), 8.07 (d, J=7.5 Hz, 1H), 7.44 (d, J=7.0 Hz, 1H), 7.35-7.32 (m, 2H), 7.30-7.28 (m, 1H), 4.17 (t, J=5.5 Hz, 2H), 3.86 (t, J=5.5 Hz, 2H), 3.12 (br s, 3H), 3.02 (br s 3H), 2.12 (s, 3H), 0.83 (s, 9H), −0.6 (s, 6H).

(225) Preparation of 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-hydroxyethoxy)pyridin-2-yl)-N,N,3-trimethylbenzamide (Example 3). 2-Amino-4,6-dimethoxybenzamide (2, 237 mg, 1.20 mmol), 4-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-formylpyridin-2-yl)-N,N,3-trimethylbenzamide (8, 560 mg, 1.26 mmol), para-toluenesulfonic acid (552 mg, 2.90 mmol), sodium hydrogen sulfite (352 mg, 3.38 mmol) and anhydrous N,N-dimethylacetamide (15 mL) were mixed in a sealed tube and heated at 120° C. for 17 h. The solvent was removed in vacuo, the residue was dissolved in methanol (20 mL) and the contents were adsorbed onto silica gel (5 g). The adsorbed material was purified by silica gel chromatography eluting with 0-4% CH.sub.3OH in CH.sub.2Cl.sub.2 to afford the title compound (0.410 g, 67%) as a white solid: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 10.8 (s, 1H), 8.40 (d, J=9.0 Hz, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.33-7.30 (m, 2H), 6.81 (d, J=2.5 Hz, 1H), 6.57 (d, J=2.5 Hz, 1H), 4.85 (t, J=5.5 Hz, 1H), 4.18 (t, J=5.5 Hz, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 3.68-3.65 (m, 2H), 3.00 (s, 6H), 2.21 (s, 3H). ESI MS m/z 505 [M+H].sup.+.

Example 4: Preparation of 4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-(isopropylamino)ethoxy)pyridin-2-yl)-N,N,3-trimethylbenzamide

(226) ##STR00028##

(227) Preparation of 4-(3-(2-Bromoethoxy)-6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)-N,N,3-trimethylbenzamide (9). A solution of 4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-hydroxyethoxy)pyridin-2-yl)-N,N,3-trimethylbenzamide (Example 3, 200 mg, 0.39 mmol) in anhydrous DMF (10 mL) was cooled to 0° C. and phosphorus tribromide (161 mg, 0.59 mmol) was added dropwise over 1 min. The stirred solution under inert atmosphere was then heated to 80° C. for 8 h. The reaction solution was poured into water (30 mL) and the resulting mixture was extracted with CH.sub.2Cl.sub.2 (3×50 mL). The extracts were washed with brine (2×100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The resulting orange oil was purified by silica gel chromatography eluting with 0-3% CH.sub.3OH in CH.sub.2Cl.sub.2 to afford the title compound (0.180 g, 80%) as a white solid: .sup.1H NMR (500 MHz, DMSO-d.sub.6): δ 10.8 (s, 1H), 8.41 (d, J=9.0 Hz, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.34 (s, 1H), 7.30 (d, J=8.0 Hz, 2H), 6.81 (d, J=2.5 Hz, 1H), 6.57 (d, J=2.5 Hz, 1H), 4.50 (t, J=5.5 Hz, 2H), 3.92 (s, 3H), 3.85 (s, 3H), 3.74 (t, J=5.5 Hz, 1H), 3.00 (s, 3H), 2.99 (s, 3H), 2.26 (s, 3H).

(228) Preparation of 4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-(isopropylamino)ethoxy)pyridin-2-yl)-N,N,3-trimethylbenzamide (Example 4). A solution of 4-(3-(2-bromoethoxy)-6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)-N,N,3-trimethylbenzamide (9, 150 mg, 0.26 mmol) in DMSO (1.25 mL) under inert atmosphere was stirred as isopropylamine (0.937 mg, 15.8 mmol) was added. The reaction was heated to 40° C. for 16 h and was then cooled to rt. Water (15 mL) was added to the reaction solution and while stirring a precipitate formed. The suspension was filtered and washed with water (100 mL). The solid was placed in a vacuum oven at rt for 16 h to afford the title compound (96 mg, 88%) as a white solid: .sup.1H NMR (500 MHz, CD.sub.3OD) δ 8.49 (d, J=8.5 Hz, 1H), 7.71 (d, J=8.5 Hz, 1H), 7.45 (d, J=7.5 Hz, 1H), 7.40 (s, 1H), 7.36 (d, J=8.0 Hz, 1H), 6.82 (d, J=2.5 Hz, 1H), 6.53 (d, J=2.5 Hz, 1H), 4.21 (t, J=5.5 Hz, 2H), 3.91 (s, 3H), 3.88 (s, 3H), 3.13 (s, 3H), 3.07 (s, 3H), 2.88 (t, J=5.5 Hz, 2H), 2.71 (sept, 1H), 2.24 (s, 3H), 0.97 (d, J=6.5 Hz, 6H); ESI MS m/z 546 [M+H].sup.+.

Example 5: Preparation of 3-Chloro-4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-hydroxyethoxy)pyridin-2-yl)-N,N-dimethylbenzamide

(229) ##STR00029##

(230) Preparation of 4-Bromo-3-chloro-N,N-dimethylbenzamide (11). A solution of 4-bromo-3-chlorobenzoic acid (10, 5.00 g, 21.2 mmol), 2M dimethylamine in THF (10.6 mL, 21.2 mmol) and N,N-diisopropylethylamine (4.12 g, 31.8 mmol) in anhydrous DMF (50 mL) was cooled to 0° C. and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 12.1 g, 31.8 mmol) was added portionwise over 20 min. The reaction was allowed to warm to rt and stir for 2 h. More 2M dimethylamine in THF (5.30 mL, 10.6 mmol) was added and the reaction stirred for 5 days. The reaction suspension was poured into water (200 mL) and the mixture was extracted with EtOAc (3×100 mL). The EtOAc layer was washed with brine (2×200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to a brown oil. The product was purified by silica gel chromatography eluting with 0-3% CH.sub.3OH in CH.sub.2Cl.sub.2 to afford the title compound (5.10 g, 80%) as a brown solid: .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.73 (d, J=8.0 Hz, 1H), 7.52 (s, 1H), 7.18 (d, J=8.0 Hz, 1H), 3.10 (s, 3H), 3.01 (s, 3H).

(231) Preparation of 3-Chloro-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (12). To an argon-degassed solution of 4-bromo-3-chloro-N,N-dimethylbenzamide (11, 1.00 g, 3.81 mmol), potassium acetate (1.12 g, 11.4 mmol) and bis(pinacolato)diboron (0.968 g, 3.81 mmol) in 1,4-dioxane (20 mL) was added dichlorodiphenylphosphenylferrocenepalladium(II) (139 mg, 0.190 mmol). The mixture was stirred under nitrogen and heated at 100° C. for 14 h. The reaction was cooled to rt and water was added (50 mL). The mixture was extracted with EtOAc (3×50 mL) and the combined extracts were washed with brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and the filtrate was concentrated to a brown oil. The product was purified by silica gel chromatography eluting with 0-50% EtOAc in hexanes to afford the title compound (5.10 g, 80%) as an off-white solid: .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.71 (d, J=8.0 Hz, 1H), 7.39 (s, 1H), 7.25 (d, J=8.0 Hz, 1H), 3.09 (s, 3H), 2.93 (s, 3H), 1.37 (s, 12H).

(232) Preparation of 4-(3-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)-6-formylpyridin-2-yl)-3-chloro-N,N-dimethylbenzamide (13). Following the method described for 4-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-formylpyridin-2-yl)-N,N,3-trimethylbenzamide (8, See Example 3), compound 13 was made from 6-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)picolinaldehyde (4) and 3-chloro-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (12) in 84% yield: .sup.1H NMR (500 MHz, CDCl.sub.3) δ 10.08 (s, 1H), 8.12 (d, J=8.0 Hz, 1H), 7.59-7.52 (m, 3H), 7.47 (d, J=8.0 Hz, 1H), 4.24 (d, J=5.5 Hz, 2H), 3.93 (d, J=5.5 Hz, 2H), 3.21 (s, 3H), 3.10 (s, 3H), 0.88 (s, 9H), −0.44 (s, 6H).

(233) Preparation of 3-Chloro-4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-hydroxyethoxy)pyridin-2-yl)-N,N-dimethylbenzamide (Example 5). Following the method described for 4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-hydroxyethoxy)pyridin-2-yl)-N,N,3-trimethylbenzamide (Example 3), Example 5 was made from 4-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-formylpyridin-2-yl)-3-chloro-N,N-dimethylbenzamide (13) and 2-amino-4,6-dimethoxybenzamide (2) in 68% yield: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 10.9 (s, 1H), 8.43 (d, J=9.0 Hz, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.59 (s, 1H), 7.49 (d, J=8.0 Hz, 1H), 6.81 (d, J=2.5 Hz, 1H), 6.57 (d, J=2.5 Hz, 1H), 4.83 (t, J=5.5 Hz, 1H), 4.21 (t, J=5.5 Hz, 2H), 3.92 (s, 3H), 3.85 (s, 3H), 3.69-3.66 (m, 2H), 3.02 (s, 3H), 3.00 (s, 3H).

Example 6: Preparation of 3-Chloro-4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-(isopropylamino)ethoxy)pyridin-2-yl)-N,N-dimethylbenzamide

(234) ##STR00030##

(235) Preparation of 4-(3-(2-Bromoethoxy)-6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)-3-chloro-N,N-dimethylbenzamide (15). Following the method described for 4-(3-(2-bromoethoxy)-6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)-N,N,3-trimethylbenzamide (9, See Example 4), compound 15 was made from 3-chloro-4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-hydroxyethoxy)pyridin-2-yl)-N,N-dimethylbenzamide (Example 5) in 63% yield: .sup.1H NMR (500 MHz, DMSO-d.sub.6): δ 10.8 (s, 1H), 8.44 (d, J=9.0 Hz, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.60 (s, 1H), 7.49 (d, J=8.0 Hz, 1H), 6.82 (d, J=2.5 Hz, 1H), 6.58 (d, J=2.5 Hz, 1H), 4.52 (t, J=5.5 Hz, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 3.73 (t, J=5.5 Hz, 2H), 3.03 (s, 3H), 2.98 (s, 3H).

(236) Preparation of 3-Chloro-4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-(isopropylamino)ethoxy)pyridin-2-yl)-N,N-dimethylbenzamide (Example 6). Following the method described for 4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-(isopropylamino)ethoxy)pyridin-2-yl)-N,N,3-trimethylbenzamide (See Example 4), Example 6 was made from 4-(3-(2-bromoethoxy)-6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)-3-chloro-N,N-dimethylbenzamide (15) in 76% yield: .sup.1H NMR (500 MHz, CD.sub.3OD) δ 8.54 (d, J=8.5 Hz, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.63 (s, 1H), 7.52 (d, J=8.0 Hz, 1H), 6.85 (d, J=2.5 Hz, 1H), 6.56 (d, J=2.5 Hz, 1H), 4.25 (t, J=5.5 Hz, 2H), 3.93 (s, 3H), 3.90 (s, 3H), 3.14 (s, 3H), 3.07 (s, 3H), 2.92 (t, J=5.5 Hz, 2H), 2.76 (sept, 1H), 1.01 (d, J=6.5 Hz, 6H); ESI MS m/z 566 [M+H].sup.+.

Example 7: Preparation of (S)-7-Fluoro-5-((1-methylpyrrolidin-3-yl)oxy)-2-(6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one

(237) ##STR00031##

(238) Preparation of 6-(4-(Methylsulfonyl)phenyl)picolinaldehyde (3): A solution of 6-bromopicolinaldehyde (1, 2.00 g, 10.8 mmol), (4-(methylsulfonyl)phenyl)boronic acid (2, 2.36 g, 11.8 mmol), and potassium carbonate (2.22 g, 16.2 mmol) in ethanol/water (200/20 mL) under nitrogen was treated with tetrakis(triphenylphosphine)palladium(0) (0.62 g, 0.54 mmol). The mixture was heated at 80° C. for 5 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography eluting with) −50% EtOAc in hexanes to afford the title compound (2.66 g, 95%) as a yellow solid: .sup.1H NMR (300 MHz, CDCl.sub.3) δ 10.18 (s, 1H), 8.31 (d, J=8.5 Hz, 2H), 8.10 (d, J=8.5 Hz, 2H), 7.97-7.07 (m, 3H), 3.11 (s, 3H); Multimode MS m/z 262 [M+H].sup.+.

(239) Preparation of 5,7-Difluoro-2-(6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one (5): A solution of 6-(4-(methylsulfonyl)phenyl)picolinaldehyde (3, 1.27 g, 4.88 mmol) and 2-amino-4,6-difluorobenzamide (4, 0.600 g, 3.49 mmol) in DMA (8 mL) was treated with p-TsOH (0.796 g, 4.19 mmol) and NaHSO.sub.3 (0.726 g, 6.98 mmol) and then heated at 120° C. for 48 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography eluting with 0-5% MeOH in CH.sub.2Cl.sub.2 to afford the title compound (0.62 g, 43%) as an off-white solid: .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.47 (s, 1H), 8.74 (d, J=8.5 Hz, 2H), 8.47 (dd, J=0.8, 7.8 Hz, 1H), 8.37 (d, J=7.8 Hz, 1H), 8.23 (t, J=7.8 Hz, 1H), 8.08 (d, J=8.5 Hz, 2H), 7.38-7.52 (m, 2H), 3.30 (s, 3H); ESI MS m/z 414 [M+H].sup.+.

(240) Preparation of (S)-7-Fluoro-5-((1-methylpyrrolidin-3-yl)oxy)-2-(6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one (Example 7). To a room temperature solution of (S)-1-methylpyrrolidin-3-ol (734 mg, 7.26 mmol) in anhydrous DMF (4 mL) was added 60% sodium hydride in mineral oil (145 mg, 3.63 mmol) and the suspension stirred for 0.5 h at rt. A solution of 5,7-difluoro-2-(6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one (5, 300 mg, 0.726 mmol) in anhydrous DMF (5 mL) was then added and the reaction stirred for 17 h at rt. Water (0.5 mL) was added followed by 2 N aq. HCl until pH 7 was reached (5 mL). The solvents were removed in vacuo and methanol (5 mL), CH.sub.2Cl.sub.2 (20 mL) and silica gel (10 g) were added to the residue. The solvents were removed and the adsorbed material was purified by silica gel chromatography eluting with 0-40% CH.sub.2Cl.sub.2:CH.sub.3OH: aq. NH.sub.4OH (80/18/2) in CH.sub.2Cl.sub.2. The resulting material was purified further by prep HPLC to afford the title compound (304 mg, 85%) as a yellow solid: .sup.1H NMR (500 MHz, CDCl.sub.3) δ 10.6 (br s, 1H), 8.59 (d, J=8.5 Hz, 1H), 8.26 (d, J=8.5 Hz, 2H), 8.12 (d, J=8.5 Hz, 2H), 8.07-8.05 (m, 1H), 7.99 (d, J=8.5 Hz, 1H), 7.07 (d, J=8.5 Hz, 1H), 6.56 (d, J=8.5 Hz, 1H), 4.98-4.92 (m, 1H), 3.14 (s, 3H), 3.15-3.08 (br s, 1H), 3.92-2.88 (m, 1H), 2.88-2.80 (m, 1H), 2.70-2.59 (br s, 1H), 2.45 (s, 3H), 2.44-2.34 (m, 1H), 2.23-2.14 (m, 1H); ESI MS m/z 495 [M+H].sup.+.

Example 8: Preparation of 4-(6-(6,8-Dimethoxy-1-oxo-1,2-dihydroisoquinolin-3-yl)pyridin-2-yl)-N,N-dimethylbenzamide

(241) ##STR00032##

(242) Preparation of 4-bromo-N,N-dimethylbenzamide (2): To a solution mixture of 4-bromobenzoic acid (1, 5.0 g, 24.9 mmol), DMF (1 mL) and CH.sub.2Cl.sub.2 (125 mL) was slowly added oxalyl chloride (6.3 mL, 75 mmol) at room temperature. The reaction mixture was allowed to stir at room temperature for 2 hours before being concentrated to dryness under reduced pressure. The residue was then taken up in CH.sub.2Cl.sub.2 (125 mL) and treated with dimethyl amine (2M in THF, 125 mL, 250 mmol) at room temperature. The solution was allowed to stir for 16 h at room temperature followed by addition of water (50 mL). The organic layer was dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography eluting with 0-5% MeOH in CH.sub.2Cl.sub.2 to provide the title compound (3.1 g, 55%): .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.58-7.44 (m, 2H), 7.33-7.24 (m, 2H), 3.11 (s, 3H), 2.97 (s, 3H).

(243) Preparation of 4-bromo-N,N-dimethylbenzamide (3): A mixture of bis(pinacolato)diboron (610 mg, 2.4 mmol), 4-bromo-N,N-dimethylbenzamide (2, 500 mg, 2.19 mmol), Pd(dppf)Cl.sub.2 (18 mg, 0.02 mmol), KOAc (320 mg, 3.3 mmol) and 1,4-dioxane (18 mL) was heated at 100° C. under nitrogen for 16 h. The reaction mixture was filtered and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-5% MeOH in CH.sub.2Cl.sub.2 to provide the title compound (540 mg, 90%) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.86-7.78 (m, 2H), 7.43-7.36 (m, 2H), 3.11 (s, 3H), 2.97 (s, 3H), 1.35 (s, 12H).

(244) Preparation of 3-(6-Bromopyridin-2-yl)-6,8-dimethoxyisoquinolin-1(2H)-one (5): A solution of 2,4-dimethoxy-6-methylbenzoic acid (4, 3.0 g, 15.8 mmol) in THF (14 mL) was slowly added to a solution of n-BuLi (22.4 mL, 35.8 mmol), diisopropylamine (0.95 mL, 6.7 mmol) and THF (14 mL) at −78° C. After the addition, the solution was allowed to warm to 0° C. and stirred for 1 h. The solution was cooled to −78° C. and a solution of 6-bromo-2-pyridinecarbonitrile (2.9 g, 15.8 mmol) and THF (14 mL) was added. The reaction mixture was allowed to warm to room temperature over 24 h and was quenched by the addition of water. The mixture was extracted with CH.sub.2Cl.sub.2 (3×100 mL) and the combined organic layers were dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (0-5% methanol in CH.sub.2Cl.sub.2) to provide the title compound as a brown solid (460 mg, 8%): .sup.1H NMR (300 MHz, CDCl.sub.3) δ 9.77 (s, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.64 (t, J=7.8 Hz, 1H), 7.49 (d, J=7.8 Hz, 1H), 6.93 (s, 1H), 6.56 (s, 1H), 6.51 (s, 1H), 3.99 (s, 3H), 3.91 (s, 3H).

(245) Preparation of 4-(6-(6,8-Dimethoxy-1-oxo-1,2-dihydroisoquinolin-3-yl)pyridin-2-yl)-N,N-dimethylbenzamide (Example 8). A mixture of 3-(6-bromopyridin-2-yl)-6,8-dimethoxyisoquinolin-1(2H)-one (5, 240 mg, 0.67 mmol), N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (3, 240 mg, 0.87 mmol), K.sub.2CO.sub.3 (139 mg, 1.01 mmol), tetrakis(triphenylphosphine)palladium(0) (39 mg, 0.03 mmol), EtOH (20 mL) and water (4 mL) was heated to 80° C. under nitrogen for 18 hrs. The mixture was cooled to room temperature and diluted with CH.sub.2Cl.sub.2 (250 mL). The solution was washed with water (50 mL) and then brine (50 mL), dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue purified by silica gel chromatography eluting with 0-10% MeOH in CH.sub.2Cl.sub.2. Further purification by preparative HPLC followed by treatment with 2 N HCl provided the title compound (36 mg, 13%): .sup.1H NMR (500 MHz, CD.sub.3OD) δ 8.32 (d, J=8.14 Hz, 2H), 8.13-7.97 (m, 3H), 7.60 (d, J=8.11 Hz, 2H), 7.50 (s, 1H), 6.85 (s, 1H), 6.65 (s, 1H), 3.99-3.92 (m, 6H), 3.15 (s, 3H), 3.07 (s, 3H); ESI MS m/z 430 [M+H].sup.+.

Example 9: Preparation of 6,8-Dimethoxy-3-(6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)isoquinolin-1(2H)-one

(246) ##STR00033##

(247) Preparation of 6,8-Dimethoxy-3-(6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)isoquinolin-1(2H)-one (Example 9). A solution of 3-(6-bromopyridin-2-yl)-6,8-dimethoxyisoquinolin-1(2H)-one (5, See example 8) (1, 0.090 g, about 50% pure, 0.12 mmol), (4-(methylsulfonyl)phenyl)boronic acid (2, 0.030 g, 0.15 mmol), and potassium carbonate (0.025 g, 0.18 mmol) in ethanol/water (10/2 mL) under nitrogen was treated with tetrakis(triphenylphosphine)palladium(0) (0.007 g, 0.006 mmol). The mixture was heated at 80° C. for 16 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography eluting with 0-3% MeOH in CH.sub.2Cl.sub.2 to afford the title compound (0.046 g, 88%) as a yellow solid: .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 10.42 (s, 1H), 8.53 (d, J=8.5 Hz, 2H), 8.05-8.25 (m, 5H), 7.42 (d, J=1.6 Hz, 1H), 6.84 (d, J=2.2 Hz, 1H), 6.60 (d, J=2.2 Hz, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.29 (s, 3H); ESI MS m/z 437 [M+H].sup.+.

Example 10: Preparation of 6,8-dimethoxy-3-(6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)isoquinolin-1(2H)-one

(248) ##STR00034##

(249) Preparation of 6,8-dimethoxy-3-(6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)isoquinolin-1(2H)-one (Example 10). Following the general procedure for Example 9, the title compound (Example 10) (48 mg, 82%) was obtained as a yellow solid from 3-(6-bromopyridin-2-yl)-6,8-dimethoxyisoquinolin-1(2H)-one (1, 0.070 g, about 70% pure, 0.14 mmol) and (4-(methylsulfinyl)phenyl)boronic acid (4, 0.032 g, 0.17 mmol). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 10.42 (s, 1H), 8.45 (d, J=8.5 Hz, 2H), 8.07-8.20 (m, 3H), 7.86 (d, J=8.5 Hz, 2H), 7.42 (d, J=2.2 Hz, 1H), 6.85 (d, J=2.2 Hz, 1H), 6.59 (d, J=2.2 Hz, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 2.82 (s, 3H); ESI MS m/z 421 [M+H].sup.+.

Example 11: Preparation of 2-(6-(2-(Dimethylamino)ethoxy)-4′-(methylsulfinyl)biphenyl-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one

(250) ##STR00035##

(251) Preparation of 3-Bromo-4-(2-(dimethylamino)ethoxy)benzaldehyde (2): A mixture of 3-bromo-4-hydroxybenzaldehyde (1, 1.00 g, 5 mmol) in DMF (15 mL) was treated with K.sub.2CO.sub.3 (2.07 g, 15.0 mmol) and heated at 80° C. for 30 min. 2-Chloro-N,N-dimethylethanamine hydrochloride (0.864 g, 6.00 mmol) was added and the mixture was heated at 80° C. for 18 h. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography eluting with 0-2% MeOH in CH.sub.2Cl.sub.2 to afford the title compound (1.05 g, 77%) as light brown oil.

(252) Preparation of 6-(2-(Dimethylamino)ethoxy)-4′-(methylsulfinyl)biphenyl-3-carbaldehyde (4): A solution of 3-bromo-4-(2-(dimethylamino)ethoxy)benzaldehyde (2, 0.300 g, 1.11 mmol), 4-(methylsulfinyl)phenylboronic acid (3, 0.244 g, 1.33 mmol), and potassium carbonate (0.275 g, 1.99 mmol) in 1,4-dioxane/water (10/1 mL) under nitrogen was treated with tetrakis(triphenylphosphine)palladium(0) (0.064 g, 0.056 mmol). The mixture was heated at 100° C. for 16 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography eluting with 0-10% MeOH in CH.sub.2Cl.sub.2 to afford the title compound (0.22 g, 60%) as a light brown solid: .sup.1H NMR (500 MHz, CDCl.sub.3) δ 9.94 (s, 1H), 7.86-7.92 (m, 2H), 7.67-7.75 (m, 4H), 7.11 (d, J=8.2 Hz, 1H), 4.20 (t, J=5.8 Hz, 2H), 2.78 (s, 3H), 2.07 (t, J=5.8 Hz, 2H), 2.61 (s, 6H); ESI MS m/z 332 [M+H].sup.+.

(253) Preparation of 2-(6-(2-(Dimethylamino)ethoxy)-4′-(methylsulfinyl)biphenyl-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 11): A solution of 6-(2-(dimethylamino)ethoxy)-4′-(methylsulfinyl)biphenyl-3-carbaldehyde (4, 0.220 g, 0.663 mmol) and 2-amino-4,6-dimethoxybenzamide (5, 0.10 g, 0.51 mmol) in DMA (2 mL) was treated with p-TsOH (0.233 g, 1.22 mmol) and NaHSO.sub.3 (0.159 g, 1.53 mmol). The mixture was heated at 110° C. for 16 h, cooled to room temperature and concentrated. The residue was purified by silica gel chromatography eluting with 0-50% 92:7:1 CHCl.sub.3/MeOH/concentrated NH.sub.4OH in CH.sub.2Cl.sub.2. This material was further purified by reverse phase HPLC eluting with 10% to 90% CH.sub.3CN in H.sub.2O with 0.1% TFA. After concentration, the residue was dissolved in acetonitrile and water. The mixture was basified with concentrated NH.sub.4OH, and the precipitated solid was filtered, washed with water, and dried under vacuum to afford the title compound (0.12 g, 46%) as an off-white solid: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.05 (s, 1H), 8.20-8.25 (m, 2H), 7.89 (d, J=8.4 Hz, 2H), 7.75 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.5 Hz, 1H), 6.74 (d, J=2.2 Hz, 1H), 6.51 (d, J=2.2 Hz, 1H), 4.02 (t, J=5.7 Hz, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 2.79 (s, 3H), 2.62 (t, J=5.7 Hz, 2H), 2.18 (s, 6H); ESI MS m/z 508 [M+H].sup.+.

Example 12: Preparation of 2-(6-(Azetidin-3-yloxy)-4′-(methylsulfinyl)biphenyl-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one

(254) ##STR00036##

(255) Preparation of tert-Butyl 3-(Methylsulfonyloxy)azetidine-1-carboxylate (2): To a mixture of tert-butyl 3-hydroxyazetidine-1-carboxylate (1, 3.15 g. 18.3 mmol) and triethylamine (12.7 ml, 91.5 mmol) in CH.sub.2Cl.sub.2 (100 mL) was added dropwise methanesulfonyl chloride (4.17 g, 36.6 mmol) at room temperature. The reaction stirred for 2 h. The mixture was diluted with EtOAc (300 mL), washed with water (100 mL) and brine (100 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated to afford the title compound (4.3 g, 94%) as a light brown oil: .sup.1H NMR (500 MHz, CDCl.sub.3) δ 5.16-5.23 (m, 1H), 4.25-4.30 (m, 2H), 4.07-4.12 (m, 2H), 3.06 (s, 3H), 1.44 (s, 9H).

(256) Preparation of tert-Butyl 3-(2-Bromo-4-formylphenoxy)azetidine-1-carboxylate (4): A mixture of 3-bromo-4-hydroxybenzaldehyde (3, 1 g. 5 mmol) in DMF (20 mL) was treated with K.sub.2CO.sub.3 (1.38 g, 10.0 mmol) and heated at 80° C. for 30 min. tert-Butyl 3-(methylsulfonyloxy)azetidine-1-carboxylate (1.63 g, 6.50 mmol) was added and the mixture was heated at 80° C. for 18 h. The mixture was cooled to room temperature and water was added (100 mL). The solid was filtered, washed with water, and dried under vacuum to afford the title compound (0.34 g, 17%) as a yellow solid: .sup.1H NMR (500 MHz, CDCl.sub.3) δ 9.85 (s, 1H), 8.11 (d, I=2.0 Hz, 1H), 7.78 (dd, J=2.0, 8.4 Hz, 1H), 6.64 (d, J=8.4 Hz, 1H), 4.97-5.03 (m, 1H), 4.34-4.41 (m, 2H), 4.07-4.15 (m, 2H), 1.45 (s, 9H).

(257) Preparation of tert-Butyl 3-(5-Formyl-4′-(methylsulfinyl)biphenyl-2-yloxy)azetidine-1-carboxylate (6): A solution of tert-butyl 3-(2-bromo-4-formylphenoxy)azetidine-1-carboxylate (4, 0.300 g, 0.843 mmol), 4-(methylsulfinyl)phenylboronic acid (5, 0.155 g, 0.843 mmol), and potassium carbonate (0.209 g, 1.52 mmol) in 1,4-dioxane/water (10/1 mL) under nitrogen was treated with tetrakis(triphenylphosphine)palladium(0) (0.047 g, 0.042 mmol). The mixture was heated at 100° C. for 16 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography eluting with hexanes to 0-100% EtOAc in hexanes to afford the title compound (0.26 g, 74%) as an off-white solid: .sup.1H NMR (500 MHz, CDCl.sub.3) δ 9.96 (s, 1H), 7.91 (d, J=2.1 Hz, 1H), 7.87 (dd, J=2.1, 8.4 Hz, 1H), 7.68-7.75 (m, 4H), 6.73 (d, J=2.1 Hz, 1H), 4.95-5.03 (m, 1H), 4.30-4.38 (m, 2H), 3.95-4.02 (m, 2H), 2.80 (s, 3H), 1.44 (s, 9H).

(258) Preparation of 2-(6-(Azetidin-3-yloxy)-4′-(methylsulfinyl)biphenyl-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 12). A solution of tert-butyl 3-(5-formyl-4′-(methylsulfinyl)biphenyl-2-yloxy)azetidine-1-carboxylate (6, 0.260 g, 0.627 mmol) and 2-amino-4,6-dimethoxybenzamide (7, 0.123 g, 0.627 mmol) in DMA (2 mL) was treated with p-TsOH (0.286 g, 1.50 mmol) and NaHSO.sub.3 (0.196 g, 1.88 mmol) and then heated at 110° C. for 16 h. The reaction mixture was cooled to room temperature, trifluoroacetic acid (5 mL) added and the mixture was heated at 110° C. for 4 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography eluting with 0-50% CHCl.sub.3/MeOH/concentrated NH.sub.4OH in CH.sub.2Cl.sub.2. This material was further purified by reverse phase HPLC eluting with 10% to 90% CH.sub.3CN in H.sub.2O with 0.1% TFA. The product fractions were concentrated and the residue was dissolved in acetonitrile and water. The mixture was basified by concentrated NH.sub.4OH and the precipitate was filtered, washed with water and dried under vacuum to afford the title compound (0.225 g, 73%) as an off-white solid: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.10-8.30 (m, 2H), 7.88 (d, J=8.4 Hz, 2H), 7.78 (d, J=8.4 Hz, 2H), 6.97 (d, J=8.4 Hz, 1H), 6.73 (d, J=2.2 Hz, 1H), 6.52 (d, J=2.2 Hz, 1H), 5.10-5.20 (m, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.75-3.90 (m, 2H), 3.45-3.55 (m, 2H), 2.82 (s, 3H); ESI MS m/z 492 [M+H].sup.+.

Example 13: Preparation of 5,7-Dimethoxy-2-(6-(1-methylazetidin-3-yloxy)-4′-(methylsulfinyl)biphenyl-3-yl)quinazolin-4(3H)-one

(259) ##STR00037##

(260) Preparation of 5,7-Dimethoxy-2-(6-(1-methylazetidin-3-yloxy)-4′-(methylsulfinyl)biphenyl-3-yl)quinazolin-4(3H)-one (Example 13). To a solution of 2-(6-(azetidin-3-yloxy)-4′-(methylsulfinyl)biphenyl-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one (8, 0.080 g, 0.16 mmol), 37% formaldehyde in water (1.32 mL, 16.3 mmol), sodium acetate (0.026 g, 0.32 mmol), and acetic acid (0.192 g, 3.20 mmol) in 1,2-dichloroethane/methanol (10/5 mL) was added sodium triacetoxyborohydride (0.666 g, 3.20 mmol) and the mixture was stirred at room temperature for 16 h. After concentration, the residue was purified by silica gel chromatography eluting with 0-50% CHCl.sub.3/MeOH/concentrated NH.sub.4OH in CH.sub.2Cl.sub.2. This material was further purified by reverse phase HPLC eluting with 10% to 90% CH.sub.3CN in H.sub.2O with 0.1% TFA. The product fractions were concentrated and the residue was dissolved in acetonitrile and water. The mixture was basified with concentrated NH.sub.4OH and the precipitate was filtered, washed with water and dried under vacuum to afford the title compound (0.03 g, 37%) as an off-white solid: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.07 (s, 1H), 8.15-8.25 (m, 2H), 7.88 (d, J=8.4 Hz, 2H), 7.78 (d, J=8.4 Hz, 2H), 7.03 (d, J=8.4 Hz, 1H), 6.73 (d, J=2.2 Hz, 1H), 6.51 (d, J=2.2 Hz, 1H), 4.85-5.00 (m, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.70-3.80 (m, 2H), 2.95-3.15 (m, 2H), 2.81 (s, 3H), 2.28 (s, 3H); ESI MS m/z 506 [M+H].sup.+.

Example 14: Preparation of 2-(6-(Azetidin-3-yloxy)-4′-(methylsulfinyl)-[1,1′-biphenyl]-3-yl)-7-fluoro-5-methoxyquinazolin-4(3H)-one

(261) ##STR00038##

(262) Preparation of tert-Butyl 3-((5-(5,7-Difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-4′-(methylsulfinyl)-[1,1′-biphenyl]-2-yl)oxy)azetidine-1-carboxylate (11): A solution of tert-butyl 3-(5-formyl-4′-(methylsulfinyl)biphenyl-2-yloxy)azetidine-1-carboxylate (6, 0.531 g, 1.28 mmol) and 2-amino-4,6-difluorobenzamide (10, 0.200 g, 1.16 mmol) in DMA (4 mL) was treated with p-TsOH (0.529 g, 2.78 mmol) and NaHSO.sub.3 (0.362 g, 3.48 mmol) and then heated at 110° C. for 16 h. The reaction mixture was cooled to room temperature and diluted with water. The precipitated solid was filtered, washed with water and dried under vacuum to afford the title compound (0.925 g, >99%) as an off-white solid; ESI MS m/z 568 [M+H].sup.+.

(263) Preparation of tert-Butyl 3-((5-(7-Fluoro-5-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-4′-(methylsulfinyl)-[1,1′-biphenyl]-2-yl)oxy)azetidine-1-carboxylate (12): A solution of tert-butyl 3-((5-(5,7-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-4′-(methylsulfinyl)-[1,1′-biphenyl]-2-yl)oxy)azetidine-1-carboxylate (11, 0.480 g, 0.857 mmol) in DMF (10 mL) was treated with 25% sodium methoxide in methanol (5.49 mL, 25.4 mmol) and stirred at room temperature for 3 h. To the reaction mixture was added acetic acid to reach pH 8 and then water was added (100 mL). The solid was filtered, washed with water, and dried under vacuum to afford the title compound (0.53 g, >99%) as a gray solid; ESI MS m/z 579 [M+H].sup.+.

(264) Preparation of 2-(6-(Azetidin-3-yloxy)-4′-(methylsulfinyl)-[1,1′-biphenyl]-3-yl)-7-fluoro-5-methoxyquinazolin-4(3H)-one (Example 14). To a solution of tert-butyl 3-((5-(7-fluoro-5-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-4′-(methylsulfinyl)-[1,1′-biphenyl]-2-yl)oxy)azetidine-1-carboxylate (12, 0.53 g, 0.92 mmol) was added trifluoroacetic acid (5 mL) at room temperature and the reaction was stirred for 1 h. The mixture was concentrated and the residue was purified by reverse phase HPLC eluting with 10% to 90% CH.sub.3CN in H.sub.2O with 0.1% TFA to afford the title compound (0.151 g, 34%) as an off-white solid: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.23 (d, J=2.3 Hz, 1H), 8.19 (dd, J=2.3, 8.6 Hz, 1H), 7.88 (d, J=8.4 Hz, 2H), 7.78 (d, J=8.4 Hz, 2H), 6.95-7.01 (m, 2H), 6.90 (dd, J=2.3, 8.6 Hz, 1H), 5.10-5.20 (m, 1H), 3.90 (s, 3H), 3.79-3.85 (m, 2H), 3.47-3.55 (m, 2H), 2.81 (s, 3H); ESI MS m/z 480 [M+H].sup.+.

Example 15: Preparation of 7-Fluoro-5-methoxy-2-(6-((1-methylazetidin-3-yl)oxy)-4′-(methylsulfinyl)-[1,1′-biphenyl]-3-yl)quinazolin-4(3H)-one

(265) ##STR00039##

(266) Preparation of 7-Fluoro-5-methoxy-2-(6-((1-methylazetidin-3-yl)oxy)-4′-(methylsulfinyl)-[1,1′-biphenyl]-3-yl)quinazolin-4(3H)-one (Example 15). To a solution of 2-(6-(azetidin-3-yloxy)-4′-(methylsulfinyl)-[1,1′-biphenyl]-3-yl)-7-fluoro-5-methoxyquinazolin-4(3H)-one (13, 0.100 g, 0.209 mmol), 37% formaldehyde in water (0.17 mL, 2.09 mmol), sodium acetate (0.034 g, 0.41 mmol), acetic acid (0.246 g, 4.10 mmol) and 1,2-dichloroethane/methanol (20/10 mL) was added sodium triacetoxyborohydride (0.853 g, 4.10 mmol) and the mixture was stirred at room temperature for 16 h. After concentration, the residue was purified by silica gel chromatography eluting with 0-100% CHCl.sub.3/MeOH/concentrated NH.sub.4OH in CH.sub.2Cl.sub.2. This material was further purified by reverse phase HPLC eluting with 10% to 90% CH.sub.3CN in H.sub.2O with 0.1% TFA. The product fractions were concentrated and the residue was dissolved in acetonitrile and water. The mixture was basified with concentrated NH.sub.4OH, the precipitate filtered, washed with water, and dried under vacuum to afford the title compound (0.031 g, 30%) as an off-white solid: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.50-12.50 (br s, 1H), 8.22 (d, J=2.3 Hz, 1H), 8.19 (dd, J=2.3, 8.6 Hz, 1H), 7.88 (d, J=8.4 Hz, 2H), 7.78 (d, J=8.4 Hz, 2H), 7.04 (d, J=8.7 Hz, 1H), 6.98 (dd, J=2.3, 8.6 Hz, 1H), 6.91 (dd, J=2.3, 8.6 Hz, 1H), 4.85-5.00 (m, 1H), 3.90 (s, 3H), 3.70-3.80 (m, 2H), 2.95-3.05 (m, 2H), 2.81 (s, 3H), 2.28 (s, 3H); ESI MS m/z 494 [M+H].sup.+.

Example 16: Preparation of 2-(6-(2-Hydroxyethoxy)-4′-(methylsulfinyl)biphenyl-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one

(267) ##STR00040##

(268) Preparation of 3-Bromo-4-(2-(tert-butyldimethylsilyloxy)ethoxy)benzaldehyde (2): A mixture of 3-bromo-4-hydroxybenzaldehyde (1, 2.00 g. 9.95 mmol) in DMF (30 mL) was treated with K.sub.2CO.sub.3 (2.75 g, 12.9 mmol) was heated at 80° C. for 30 min. (2-Bromoethoxy)(tert-butyl)dimethylsilane (3.09 g, 12.9 mmol) was added and the mixture was heated at 80° C. for 24 h. The mixture was cooled to room temperature and water was added. The precipitated solid was filtered, washed with water and dried under vacuum to afford the title compound (3.75 g, >99%) as a white solid: .sup.1H NMR (500 MHz, CDCl.sub.3) δ 9.84 (s, 1H), 8.08 (d, J=2.0 Hz, 1H), 7.79 (dd, J=2.0, 8.5 Hz, 1H), 7.05 (d, J=8.5 Hz, 1H), 4.21 (t, J=5.0 Hz, 2H), 4.04 (t, J=5.0 Hz, 2H), 0.90 (s, 9H), 0.11 (s, 6H).

(269) Preparation of 6-(2-(tert-Butyldimethylsilyloxy)ethoxy)-4′-(methylsulfinyl)biphenyl-3-carbaldehyde (4): A solution of 3-bromo-4-(2-(tert-butyldimethylsilyloxy)ethoxy)benzaldehyde (2, 0.937 g, 2.61 mmol), 4-(methylsulfinyl)phenylboronic acid (3, 0.400 g, 2.17 mmol), and potassium carbonate (0.539 g, 3.91 mmol) in 1,4-dioxane/water (20/2 mL) under nitrogen was treated with tetrakis(triphenylphosphine)palladium(0) (0.125 g, 0.109 mmol). The mixture was heated at 100° C. for 16 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography eluting with 0-2% MeOH in CH.sub.2Cl.sub.2 to afford the title compound (0.78 g, 86%) as an off-white solid: .sup.1H NMR (500 MHz, CDCl.sub.3) δ 9.94 (s, 1H), 7.86-7.90 (m, 2H), 7.67-7.76 (m, 4H), 7.14 (d, J=8.3 Hz, 1H), 4.19 (t, J=5.0 Hz, 2H), 3.92 (t, J=5.0 Hz, 2H), 2.77 (s, 3H), 0.85 (s, 9H), 0.01 (s, 6H); ESI MS m/z 419 [M+H].sup.+.

(270) Preparation of 2-(6-(2-Hydroxyethoxy)-4′-(methylsulfinyl)biphenyl-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 16). A solution of 6-(2-(tert-butyldimethylsilyloxy)ethoxy)-4′-(methylsulfinyl)biphenyl-3-carbaldehyde (4, 0.703 g, 1.68 mmol) and 2-amino-4,6-dimethoxybenzamide (5, 0.300 g, 1.53 mmol) in DMA (6 mL) was treated with p-TsOH (0.698 g, 3.67 mmol) and NaHSO.sub.3 (0.477 g, 4.59 mmol) and then heated at 110° C. for 16 h. Trifluoroacetic acid was added (2 mL) and the mixture was heated at 110° C. for 2 h. The reaction mixture was cooled to room temperature and diluted with water. The precipitated solid was filtered and washed with water and purified by silica gel chromatography eluting with 0-50% MeOH in CH.sub.2Cl.sub.2 to afford (0.72 g, 98%). This material (0.05 g) was further purified by reverse phase HPLC eluting with 10% to 90% CH.sub.3CN in H.sub.2O with 0.1% TFA to afford the title compound (0.038 g, 76%) as an off-white solid: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.05-8.15 (m, 2H), 7.92 (d, J=8.4 Hz, 2H), 7.78 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 1H), 6.81 (d, J=2.2 Hz, 1H), 6.57 (d, J=2.2 Hz, 1H), 4.22 (t, J=4.6 Hz, 2H), 3.92 (s, 6H), 3.87 (t, J=4.6 Hz, 2H), 2.86 (s, 3H); ESI MS m/z 481 [M+H].sup.+.

Example 17: Preparation of 2-(6-(2-(Isopropylamino)ethoxy)-4′-(methylsulfinyl)biphenyl-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one

(271) ##STR00041##

(272) Preparation of 2-(6-(2-(Isopropylamino)ethoxy)-4′-(methylsulfinyl)biphenyl-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 17). To a mixture of 2-(6-(2-hydroxyethoxy)-4′-(methylsulfinyl)biphenyl-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one (6, 0.05 g. 0.1 mmol) and pyridine (0.08 g, 1 mmol) in CH.sub.2Cl.sub.2 (10 mL) was added dropwise with methanesulfonyl chloride (0.06 g, 0.5 mmol) at room temperature. After stirring for 16 h, the reaction was diluted with methanol (20 mL), stirred 1 h at room temperature and concentrated. To the residue was added isopropylamine (5 mL) and the mixture was heated in a sealed tube at 110° C. overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography eluting with 0-50% 92:7:1 CHCl.sub.3/MeOH/concentrated NH.sub.4OH in CH.sub.2Cl.sub.2. This material was further purified by reverse phase HPLC eluting with 10% to 90% CH.sub.3CN in H.sub.2O with 0.1% TFA. The product fractions were concentrated and the residue was dissolved in acetonitrile and water. The mixture was basified with concentrated NH.sub.4OH and the precipitate was filtered, washed with water and dried under vacuum to afford the title compound (0.023 g, 22%) as an off-white solid: .sup.1H NMR (500 MHz, CD.sub.3OD) δ 8.12-8.05 (m, 2H), 7.86 (d, J=8.4 Hz, 2H), 7.81 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.4 Hz, 1H), 6.81 (d, J=2.2 Hz, 1H), 6.57 (d, J=2.2 Hz, 1H), 4.25 (t, J=5.2 Hz, 2H), 3.93 (s, 6H), 2.97 (t, J=5.2 Hz, 2H), 2.85 (s, 3H), 2.75-2.82 (m, 1H), 1.01 (d, J=6.0 Hz, 6H); ESI MS m/z 522 [M+H].sup.+.

Example 18: Preparation of 2′-(Azetidin-3-yloxy)-5′-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-[1,1′-biphenyl]-4-carbonitrile

(273) ##STR00042##

(274) Preparation of tert-Butyl 3-((4′-Cyano-5-formyl-[1,1′-biphenyl]-2-yl)oxy)azetidine-1-carboxylate (3): A solution of tert-butyl 3-(2-bromo-4-formylphenoxy)azetidine-1-carboxylate (1, 0.50 g, 1.4 mmol), 4-cyanophenylboronic acid (2, 0.248 g, 1.69 mmol), and potassium carbonate (0.348 g, 2.52 mmol) in 1,4-dioxane/water (20/2 mL) under nitrogen was treated with tetrakis(triphenylphosphine)palladium(0) (0.081 g, 0.070 mmol). The mixture was heated at 100° C. for 3 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography eluting with 0-50% EtOAc in hexanes to afford the title compound (0.28 g, 53%) as a yellow solid.

(275) Preparation of 2′-(Azetidin-3-yloxy)-5′-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-[1,1′-biphenyl]-4-carbonitrile (Example 18). A solution of tert-butyl 3-((4′-cyano-5-formyl-[1,1′-biphenyl]-2-yl)oxy)azetidine-1-carboxylate (3, 0.280 g, 0.741 mmol) and 2-amino-4,6-dimethoxybenzamide (4, 0.145 g, 0.741 mmol) in DMA (4 mL) was treated with p-TsOH (0.338 g, 1.78 mmol) and NaHSO.sub.3 (0.231 g, 2.22 mmol), and was heated at 110° C. for 16 h. The reaction mixture was cooled to room temperature, trifluoroacetic acid was added (5 mL) and the mixture was heated at 70° C. for 16 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography eluting with 0-100% 92:7:1 CHCl.sub.3/MeOH/concentrated NH.sub.4OH in CH.sub.2Cl.sub.2. This material was further purified by reverse phase HPLC eluting with 10% to 90% CH.sub.3CN in H.sub.2O with 0.1% TFA. The product fractions were concentrated and the residue was dissolved in acetonitrile and water. The mixture was basified with concentrated NH.sub.4OH, and the precipitate was filtered, washed with water, and dried under vacuum to afford the title compound (0.079 g, 23%) as an off-white solid: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.15-8.25 (m, 2H), 7.95 (d, J=8.5 Hz, 2H), 7.90 (d, J=8.5 Hz, 2H), 6.99 (d, J=8.5 Hz, 1H), 6.73 (d, I=2.2 Hz, 1H), 6.52 (d, J=2.2 Hz, 1H), 5.10-5.20 (m, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.75-3.83 (m, 2H), 3.45-3.55 (m, 2H); ESI MS m/z 455 [M+H].sup.+.

Example 19: Preparation of 5′-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2′-((1-methylazetidin-3-yl)oxy)-[1,1′-biphenyl]-4-carbonitrile

(276) ##STR00043##

(277) Preparation of 5′-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2′-((1-methylazetidin-3-yl)oxy)-[1,1′-biphenyl]-4-carbonitrile (Example 19). To a solution of 2′-(azetidin-3-yloxy)-5′-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-[1,1′-biphenyl]-4-carbonitrile (5, 0.065 g, 0.14 mmol), 37% formaldehyde in water (0.12 mL, 1.43 mmol), sodium acetate (0.024 g, 0.28 mmol), and acetic acid (0.168 g, 2.80 mmol) in 1,2-dichloroethane/methanol (20/10 mL) was added sodium triacetoxyborohydride (0.582 g, 2.80 mmol) and the mixture was stirred at room temperature for 16 h. After concentration, the residue was purified by silica gel chromatography eluting with 0-100% 92:7:1 CHCl.sub.3/MeOH/concentrated NH.sub.4OH in CH.sub.2Cl.sub.2. This material was further purified by reverse phase HPLC eluting with 10% to 90% CH.sub.3CN in H.sub.2O with 0.1% TFA. The product fractions were concentrated and the residue was dissolved in acetonitrile and water. The mixture was basified with concentrated NH.sub.4OH and the precipitate was filtered, washed with water and dried under vacuum to afford the title compound (0.047 g, 70%) as an off-white solid: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.07 (s, 1H), 8.15-8.25 (m, 2H), 7.95 (d, J=8.4 Hz, 2H), 7.88 (d, J=8.4 Hz, 2H), 7.04 (d, J=8.4 Hz, 1H), 6.73 (d, J=2.2 Hz, 1H), 6.51 (d, J=2.2 Hz, 1H), 4.85-5.00 (m, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.70-3.80 (m, 2H), 2.95-3.05 (m, 2H), 2.80 (s, 3H); ESI MS m/z 469 [M+H].sup.+.

Example 20: 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)-N,N-dimethylbenzamide

(278) ##STR00044##

(279) To a degassed solution of 6-bromopicolinaldehyde (0.963 g, 5.18 mmol) and 4-(dimethyl carbamoyl)phenyl boronic acid (1.0 g, 5.18 mmol) in toluene (25 mL) and ethanol (25 mL), was added a solution of Na.sub.2CO.sub.3 (1.65 g, 15.54 mmol) in water (10 mL). The reaction mixture was degassed again and Pd(PPh.sub.3).sub.4 (0.299 g, 0.26 mmol) was added. The reaction mixture was heated at 90° C. for 3 h. After that time the reaction was cooled to rt and diluted with ethyl acetate (150 mL). The organic layer was separated and washed with water, brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 98:2 dichloromethane/methanol) to give 4-(6-formylpyridin-2-yl)-N,N-dimethylbenzamide as yellow oil (1.38 g, >99%): .sup.1H NMR (400 MHz, CDCl.sub.3-d) δ 10.18 (s, 1H), 8.14 (d, J=8.60 Hz, 2H), 7.93-8.01 (m, 3H), 7.59 (d, J=8.60 Hz, 2H), 3.15 (s, 3H), 3.03 (s, 3H).

(280) To a solution of 4-(6-formylpyridin-2-yl)-N,N-dimethylbenzamide (1.38 g, 5.42 mmol) and 2-amino-4,6-dimethoxybenzamide (1.06 g, 5.42 mmol) in N,N-dimethyl acetamide (30 ml), was added NaHSO.sub.3 (1.44 g, 8.14 mmol) and p-toluenesulfonic acid monohydrate (1.23 g, 6.48 mmol). The reaction mixture was heated at 120° C. for 10 h. After that time the reaction was cooled to rt and the solvent was removed under reduced pressure. Water (100 mL) was added and neutralized with NaHCO.sub.3. The precipitated solids were collected by filtration and dried. The product was purified by flash column chromatography (silica gel, 98:2 dichloromethane/methanol) to give 4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)-N,N-dimethylbenzamide (0.562 g, 24%) as white solid: mp 217-219° C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.64 (s, 1H), 8.47 (d, J=8.60 Hz, 2H), 8.40 (d, J=7.82 Hz, 1H), 8.26 (d, J=7.42 Hz, 1H), 8.16 (t, J=8.01 Hz, 1H), 7.57 (d, J=8.60 Hz, 2H), 6.84 (d, J=2.34 Hz, 1H), 6.62 (d, J=2.34 Hz, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 3.03 (br s, 3H), 2.97 (br s, 3H); ESI MS m/z 431 [M+H].sup.+.

Example 21: 2-(5-(2-Hydroxyethoxy)-6-phenylpyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one

(281) ##STR00045##

(282) To a degassed solution of 2-bromo-6-(hydroxymethyl)pyridin-3-ol (1.18 g, 5.78 mmol) and phenylboronic acid (0.705 g, 5.78 mmol) in toluene (25 mL) and ethanol (25 mL), was added a solution of Na.sub.2CO.sub.3 (1.84 g, 17.35 mmol) in water (10 mL). The reaction mixture was degassed again and Pd(PPh.sub.3).sub.4 (0.334 g, 0.289 mmol) was added. The reaction mixture was heated at 90° C. for 16 h. After that time the reaction was cooled to rt and diluted with ethyl acetate (150 mL). The organic layer was separated. The aqueous layer was neutralized with acetic acid and extracted with ethyl acetate (1×100 mL). The combined organic layers were washed with water, brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to give 6-(hydroxymethyl)-2-phenylpyridin-3-ol (1.22 g) as a yellow foam: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.98 (s, 1H), 7.99 (d, J=7.42 Hz, 2H), 7.41 (t, J=7.42 Hz, 3H), 7.24-7.37 (m, 2H), 4.51 (d, J=5.47 Hz, 2H), 4.41 (d, J=5.86 Hz, 1H); ESI MS m/z 202 [M+H].sup.+.

(283) To a solution of 6-(hydroxymethyl)-2-phenylpyridin-3-ol (1.22 g, 6.06 mmol) in DMSO (5 mL) was added IBX (1.86 g, 6.66 mmol). The reaction mixture was stirred at rt for 2 h. After that time the reaction was diluted with water (150 mL) and the precipitated solids were collected by filtration and washed with ethyl acetate (200 mL). The aqueous filtrate was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 70:30 hexanes/ethyl acetate) to give 5-hydroxy-6-phenylpicolinaldehyde (0.428 g, 37% over two steps) as a gummy yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3-d) δ 10.04 (s, 1H), 7.94 (d, J=8.59 Hz, 1H), 7.79 (d, J=7.03 Hz, 2H), 7.58 (t, J=7.42 Hz, 3H), 7.52 (d, J=7.42 Hz, 1H), 7.42 (d, J=8.20 Hz, 1H); ESI MS m/z 200 [M+H].sup.+.

(284) To a solution of 5-hydroxy-6-phenylpicolinaldehyde (0.428 g, 2.14 mmol) in DMF (5 mL), was added Cs.sub.2CO.sub.3 (1.54 g, 4.72 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (0.616 g, 2.57 mmol). The reaction mixture was stirred at rt for 16 h. After that time the reaction was diluted with water (100 mL) and the reaction was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 90:10 hexanes/ethyl acetate) to give 5-(2-(tert-butyldimethylsilyloxy)ethoxy)-6-phenylpicolinaldehyde (0.355 g, 46%) as a colorless oil: .sup.1H NMR (400 MHz, CDCl.sub.3-d) δ 10.07 (s, 1H), 8.01-8.04 (m, 2H), 7.95 (d, J=8.59 Hz, 1H), 7.45 (dd, J=9.95, 8.00 Hz, 4H), 4.19-4.24 (m, 2H), 3.97-4.01 (m, 2H), 0.88 (s, 9H), 0.04-0.06 (m, 6H).

(285) To a solution of 2-amino-4,6-dimethoxybenzamide (0.195 g, 0.99 mmol) and 5-(2-(tert-butyldimethylsilyloxy)ethoxy)-6-phenylpicolinaldehyde (0.355 g, 0.99 mmol) in N,N-dimethyl acetamide (10 ml), was added NaHSO.sub.3 (0.264 g, 1.49 mmol) and p-toluenesulfonic acid monohydrate (0.038 g, 0.198 mmol). The reaction mixture was heated at 120° C. for 16 h. After that time the reaction was cooled to rt and the solvent was removed under reduced pressure. The reaction mixture was then diluted with water (150 mL) and neutralized with NaHCO.sub.3. The precipitated solids were collected by filtration, washed with water and dried to give 2-(5-(2-(tert-butyldimethylsilyloxy)ethoxy)-6-phenylpyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.500 g, 94%) as an off-white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.08 (s, 1H), 8.35 (d, J=8.98 Hz, 1H), 8.21 (d, J=2.34 Hz, 2H), 7.82 (d, J=8.59 Hz, 1H), 7.44-7.52 (m, 3H), 6.81 (d, J=2.34 Hz, 1H), 6.58 (d, J=2.34 Hz, 1H), 4.24-4.32 (m, 2H), 3.94-4.00 (m, 2H), 3.92 (s, 3H), 3.86 (s, 3H), 0.85 (s, 9H), 0.08 (s, 6H); ESI MS m/z 534 [M+H].sup.+.

(286) To a solution of 2-(5-(2-(tert-butyldimethylsilyloxy)ethoxy)-6-phenylpyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.500 g, 0.936 mmol) in THF (20 mL) was added a 1M solution of TBAF in THF (1.87 mL, 1.87 mmol). The reaction mixture was stirred at rt for 1 h. After that time, the reaction was concentrated under reduced pressure. Water (100 mL) was then added and stirred for 30 min at rt. The precipitated solids were collected by filtration, washed with water and dried. The product was purified by flash column chromatography (silica gel, 95:5 dichloromethane/methanol) to give 2-(5-(2-hydroxyethoxy)-6-phenylpyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.220 g, 56%) as a white solid: mp 240-242° C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.09 (s, 1H), 8.35 (d, J=8.60 Hz, 1H), 8.22 (d, J=7.03 Hz, 2H), 7.81-7.83 (m, 1H), 7.42-7.55 (m, 3H), 6.81 (d, J=2.34 Hz, 1H), 6.58 (d, J=2.34 Hz, 1H), 4.98 (t, J=5.28 Hz, 1H), 4.25 (t, J=4.88 Hz, 2H), 3.92 (s, 3H), 3.86 (s, 3H), 3.79 (q, J=5.08 Hz, 2H); ESI MS m/z 420 [M+H].sup.+.

Example 22: 2-(5-(2-(Isopropylamino)ethoxy)-6-phenylpyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one

(287) ##STR00046##

(288) To a solution of 2-(5-(2-hydroxyethoxy)-6-phenylpyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.195 g, 0.465 mmol) in DMF (8 mL) was added PPh.sub.3 (0.140 g, 0.534 mmol) and CBr.sub.4 (0.177 g, 0.534 mmol). The reaction mixture was stirred at rt for 16 h. After that time the reaction was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol) to give 2-(5-(2-bromoethoxy)-6-phenylpyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.300 g) as a white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.13 (s, 1H), 8.36 (d, J=8.60 Hz, 1H), 8.26 (d, J=1.56 Hz, 1H), 7.82 (d, J=8.60 Hz, 2H), 7.40-7.56 (m, 3H), 6.82 (d, J=1.95 Hz, 1H), 6.58 (d, J=2.34 Hz, 1H), 4.57 (s, 2H), 3.81-3.94 (m, 8H).

(289) To a suspension of 2-(5-(2-bromoethoxy)-6-phenylpyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.300 g, 0.62 mmol) in DMF (5 mL) was added isopropylamine (0.367 g, 6.2 mmol). The reaction mixture was stirred at rt for 16 h and then concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 98:2 dichloromethane/methanol) to give a product that was re-purified by flash column chromatography (silica gel, 99:1 dichloromethane/7N NH.sub.3 in methanol) to give 2-(5-(2-(isopropylamino)ethoxy)-6-phenylpyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.054 g, 25% over two steps) as an off-white solid: mp 179-180° C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.36 (d, J=8.60 Hz, 1H), 8.17 (d, J=6.64 Hz, 2H), 7.81 (d, J=8.60 Hz, 1H), 7.43-7.54 (m, 3H), 6.81 (d, J=2.34 Hz, 1H), 6.58 (d, J=2.34 Hz, 1H), 4.22 (t, J=5.47 Hz, 2H), 3.92 (s, 3H), 3.86 (s, 3H), 2.91 (t, J=5.47 Hz, 2H), 2.70-2.82 (m, 1H), 0.97 (d, J=6.25 Hz, 6H); ESI MS m/z 461 [M+H].sup.+.

Example 23: 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-hydroxyethoxy)pyridin-2-yl)-N,N-dimethylbenzamide

(290) ##STR00047##

(291) To a solution of 2-bromo-6-(hydroxymethyl)pyridin-3-ol (2.00 g, 9.80 mmol) in anhydrous DMF (30 mL) was added K.sub.2CO.sub.3 (2.03 g, 14.7 mmol). The reaction mixture was stirred for 10 minutes at rt, then (2-bromoethoxy)(tert-butyl)dimethylsilane (2.31 mL, 10.8 mmol) was added. The reaction mixture was stirred at 60° C. for 16 h under nitrogen. After that time the reaction was cooled to rt and concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (200 mL). The organic phase was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 70:30 hexanes/ethyl acetate) to give (6-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-2-yl)methanol (2.98 g, 84%) as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3): δ7.19-7.25 (m, 2H), 4.68 (d, J=5.86 Hz, 2H), 4.14 (t, J=5.08 Hz, 2H), 4.02 (t, J=5.08 Hz, 2H), 2.75 (t, J=5.67 Hz, 1H), 0.90 (s, 9H), 0.11 (s, 6H). ESI MS m/z 362 and 364 [M+H].sup.+.

(292) To a solution of (6-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-2-yl)methanol (2.88 g, 7.95 mmol) in DMSO (15 mL) was added IBX (2.45 g, 8.75 mmol). The reaction mixture was stirred at rt for 3 h. After that time the reaction was diluted with water (100 mL) and the precipitated solids were collected by filtration and washed with ethyl acetate (250 ml). The organic layer was washed with water, brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to give 6-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)picolinaldehyde (2.85 g, 99%) as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3): δ9.82 (s, 1H), 7.81 (d, J=8.21 Hz, 1H), 7.23 (d, J=8.60 Hz, 1H), 4.14 (t, J=4.69 Hz, 2H), 3.95 (t, J=4.30 Hz, 2H), 0.79 (s, 9H), 0.00 (s, 6H).

(293) A mixture of 6-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)picolinaldehyde (1.62 g, 4.50 mmol), (4-(dimethylcarbamoyl)phenyl)boronic acid (0.87 g, 4.50 mmol) and Na.sub.2CO.sub.3 (1.43 g, 13.5 mmol) was degassed under nitrogen. Then toluene (25 mL), ethanol (25 mL) and water (10 mL) was added. The reaction mixture was degassed again and Pd(PPh.sub.3).sub.4 (0.26 g, 0.225 mmol) was added and the mixture was degassed again. The reaction mixture was stirred at 90° C. for 16 h under nitrogen. After that time the reaction was cooled to rt and concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (2×150 mL). The combined organic layer was washed with water and brine, dried over Na.sub.2SO.sub.4 and concentrated. The product was purified by flash column chromatography (silica gel, 70:30 hexanes/ethyl acetate to 60:40 hexanes/ethyl acetate) to give 4-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-formylpyridin-2-yl)-N,N-dimethylbenzamide (1.26 g, 65%) as a dark yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3): δ10.07 (s, 1H), 8.10 (d, J=8.60 Hz, 2H), 7.97 (d, J=8.60 Hz, 1H), 7.51 (d, J=8.60 Hz, 2H), 7.46 (d, J=8.60 Hz, 1H), 4.22 (t, J=4.69 Hz, 2H), 3.99 (t, J=4.69 Hz, 2H), 3.15 (br s, 3H), 3.03 (br s, 3H), 0.88 (s, 9H), 0.05 (s, 6H); ESI MS m/z 429 [M+H].sup.+.

(294) To a solution of 4-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-formylpyridin-2-yl)-N,N-dimethylbenzamide (1.25 g, 2.91 mmol) and 2-amino-4,6-dimethoxybenzamide (0.63 g, 3.20 mmol) in N,N-dimethylacetamide (30 ml) was added NaHSO.sub.3 (58.5 wt %, 0.80 g, 4.36 mmol) and p-toluenesulfonic acid monohydrate (0.11 g, 0.58 mmol). The reaction mixture was stirred at 120° C. for 18 h. After that time it was cooled to rt, concentrated under reduced pressure and diluted with water (100 mL). The precipitated solids were collected by filtration, washed with water and dried under vacuum. The product was then washed with ether and dried to give 4-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)-N,N-dimethylbenzamide (2.15 g) as a gray solid: ESI MS m/z: 605 [M+H].sup.+.

(295) To a solution of 4-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)-N,N-dimethylbenzamide (2.15 g, 2.91 mmol) in THF (30 mL) was added a solution of tetrabutylammoniumfluoride in THF (1 M, 6.0 mL, 6.00 mmol). The reaction mixture was stirred at rt for 2 h. After this time the reaction was concentrated under reduced pressure, diluted with water (100 mL) and stirred for 1 h at rt. The precipitated solids were collected by filtration, washed with water and dried. The product was purified by flash column chromatography (silica gel, 77:20:3 dichloromethane/ethyl acetate/methanol to 74:20:6 dichloromethane/ethyl acetate/methanol) to give 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-hydroxyethoxy)pyridin-2-yl)-N,N-dimethylbenzamide (0.495 g, 35% over two steps) as a white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ11.20 (s, 1H), 8.37 (d, J=8.60 Hz, 1H), 8.31 (d, J=8.60 Hz, 2H), 7.84 (d, J=8.60 Hz, 1H), 7.51 (d, J=8.60 Hz, 2H), 6.80 (d, J=2.34 Hz, 1H), 6.58 (d, J=2.34 Hz, 1H), 4.99 (t, J=5.28 Hz, 1H), 4.26 (t, J=4.69 Hz, 2H), 3.92 (s, 3H), 3.86 (s, 3H), 3.80 (q, J=5.08 Hz, 2H), 3.02 (br s, 3H), 2.99 (br s, 3H); ESI MS m/z: 491 [M+H].sup.+.

Example 24: 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one

(296) ##STR00048##

(297) To a solution of 2-bromo-6-(hydroxymethyl)pyridin-3-ol (2.06 g, 10.09 mmol) in acetone (100 mL) and DMF (20 mL) was added K.sub.2CO.sub.3 (2.093 g, 15.14 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (2.899 g, 12.12 mmol). The reaction mixture was heated at reflux for 48 h, then cooled to rt and filtered. The filtrate was concentrated at reduced pressure and the residue was purified by flash column chromatography (silica gel, 70:30 hexanes/ethyl acetate) to give (6-bromo-5-(2-((t-butyldimethylsilyl)oxy)ethoxy)pyridin-2-yl)methanol (2.65 g, 72%) as white solid: .sup.1H NMR (400 MHz, CDCl.sub.3-d) δ 7.22 (d, J=2.73 Hz, 2H), 4.69 (s, 2H), 4.14 (t, J=4.88 Hz, 2H), 4.02 (t, J=5.07 Hz, 2H), 0.90 (s, 9H), 0.11 (s, 6H).

(298) To a solution of (6-bromo-5-(2-((t-butyldimethylsilyl)oxy)ethoxy)pyridin-2-yl)methanol (2.65 g, 7.32 mmol) in DMSO (5 mL), was added IBX (2.25 g, 8.05 mmol). The reaction mixture was stirred at rt for 1 h. After that time the reaction was diluted with water (200 mL) and the precipitated solids were removed by filtration and washed with ethyl acetate (250 ml). The organic layer was washed with water, brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to give 6-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)picolinaldehyde (2.27 g, 86%) as white solid: .sup.1H NMR (400 MHz, CDCl.sub.3-d) δ 9.94 (s, 1H), 7.92 (d, J=8.49 Hz, 1H), 7.33 (d, J=8.49 Hz, 1H), 4.23-4.29 (m, 2H), 4.01-4.09 (m, 2H), 0.89 (s, 9H), 0.11 (s, 6H).

(299) To a degassed solution of 6-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)picolinaldehyde (2.27 g, 6.30 mmol) and 4,4,5,5-tetramethyl-2-(4-(methylsulfonyl)phenyl)-1,3,2-dioxaborolane (1.78 g, 6.30 mmol) in toluene (30 mL) and ethanol (30 mL) was added a solution of Na.sub.2CO.sub.3 (2.00 g, 18.91 mmol) in water (12 mL). The reaction mixture was degassed again and Pd(PPh.sub.3).sub.4 (0.364 g, 0.31 mmol) was added. The reaction mixture was heated at 90° C. for 16 h. After that time the reaction was cooled to rt and diluted with ethyl acetate (250 mL). The organic layer was separated and washed with water, brine, dried over Na.sub.2SO.sub.4 and concentrated. The product was purified by flash column chromatography (silica gel, 75:25 hexanes/ethyl acetate) to give 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(4-(methylsulfonyl)phenyl)picolinaldehyde (2.33 g, 85%) as an off-white solid: .sup.1H NMR (400 MHz, CDCl.sub.3-d) δ 10.06 (s, 1H), 8.27 (d, J=8.60 Hz, 2H), 8.03 (dd, J=8.79, 4.88 Hz, 3H), 7.51 (d, J=8.60 Hz, 1H), 4.22-4.30 (m, 2H), 3.94-4.03 (m, 2H), 3.09 (s, 3H), 0.87 (s, 9H), 0.045 (s, 6H).

(300) To a solution of 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(4-(methylsulfonyl)phenyl)picolinaldehyde (1.05 g, 5.35 mmol) and 2-amino-4,6-dimethoxybenzamide (2.33 g, 5.35 mmol) in N,N-dimethylacetamide (20 ml) was added NaHSO.sub.3 (1.43 g, 8.03 mmol) and p-toluenesulfonic acid monohydrate (200 mg, 1.07 mmol). The reaction mixture was heated at 120° C. for 20 h. After that time the reaction was cooled to rt, concentrated under reduced pressure, and diluted with water (150 mL). The reaction mixture was then neutralized with NaHCO.sub.3 and the precipitated solids were collected by filtration, washed with water and dried to give 2-(5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (2.7 g, 82%) as an off-white solid: .sup.1H NMR (400 MHz, CDCl.sub.3-d) δ 10.42 (s, 1H), 8.53 (d, J=8.99 Hz, 1H), 8.22 (d, J=8.60 Hz, 2H), 8.06 (d, J=8.60 Hz, 2H), 7.56 (d, J=8.99 Hz, 1H), 6.84 (d, J=2.34 Hz, 1H), 6.49 (d, J=1.95 Hz, 1H), 4.25 (t, J=4.88 Hz, 2H), 3.90-4.03 (m, 8H), 3.13 (s, 3H), 0.90 (s, 9H), 0.04 (s, 6H); ESI MS m/z 612 [M+H].sup.+.

(301) To a solution of 2-(5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (2.7 g, 4.42 mmol) in THF (30 mL), was added a 1M solution of TBAF in THF (8.84 mL, 8.84 mmol). The reaction mixture was allowed to stir at rt for 1 h. After that time the reaction was concentrated under reduced pressure, diluted with water (150 mL) and stirred for 1 h at rt. The precipitated solids were collected by filtration, washed with water and dried. The product was purified by flash column chromatography (silica gel, 98:2 dichloromethane/methanol) to give 2-(5-(2-hydroxyethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.920 g, 34% over two steps) as an off-white solid: mp>300° C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.32 (s, 1H), 8.51 (d, J=8.20 Hz, 2H), 8.39 (d, J=8.59 Hz, 1H), 8.01 (d, J=8.59 Hz, 2H), 7.86 (d, J=8.98 Hz, 1H), 6.79 (d, J=2.34 Hz, 1H), 6.56 (d, J=2.34 Hz, 1H), 5.00 (t, J=5.27 Hz, 1H), 4.26 (t, J=4.68 Hz, 2H), 3.90 (s, 3H), 3.84 (s, 3H), 3.78 (q, J=5.07 Hz, 2H), 3.28 (s, 3H); ESI MS m/z 498 [M+H].sup.+.

Example 25: 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one methanesulfonate

(302) ##STR00049##

(303) To a suspension of 2-(5-(2-hydroxyethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (50 mg, 0.10 mmol) in a mixture of dichloromethane (5 mL) and methanol (1 mL) was added a solution of 0.1 M methanesulfonic acid in dichloromethane (1.0 mL, 0.10 mmol). The reaction mixture was stirred at rt for 1 h. After that time the reaction was concentrated under reduced pressure and the residue washed with ether and dried to give 2-(5-(2-hydroxyethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one methanesulfonate (0.051 g, 86%) as a yellow solid: mp 134-136° C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.52 (d, J=8.59 Hz, 2H), 8.42 (d, J=8.59 Hz, 1H), 8.03 (d, J=8.59 Hz, 2H), 7.90 (d, J=8.98 Hz, 1H), 6.84 (d, J=2.34 Hz, 1H), 6.60 (d, J=2.34 Hz, 1H), 4.29 (t, J=4.68 Hz, 2H), 3.92 (s, 3H), 3.87 (s, 3H), 3.80 (t, J=4.68 Hz, 2H), 3.30 (s, 3H), 2.35 (s, 3H); ESI MS m/z 498 [M+H].sup.+.

Example 26: 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-(isopropylamino)ethoxy)pyridin-2-yl)-N,N-dimethylbenzamide

(304) ##STR00050##

(305) To a suspension of 4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-hydroxyethoxy)pyridin-2-yl)-N,N-dimethylbenzamide (0.471 g, 0.96 mmol) in DMF (12 mL) was added PBr.sub.3 (0.18 mL, 1.92 mmol). The reaction mixture was stirred at 60° C. for 3 h under nitrogen. After that time the reaction was cooled to rt and concentrated under reduced pressure. The residue was diluted with saturated NaHCO.sub.3 solution (50 mL). The precipitated solids were collected by filtration, washed with water and dried. The product was purified by flash column chromatography (silica gel, 95:5 dichloromethane/methanol) to give 4-(3-(2-bromoethoxy)-6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)-N,N-dimethylbenzamide (0.477 g, 90%) as a white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ11.24 (s, 1H), 8.38 (d, J=8.99 Hz, 1H), 8.33 (d, J=8.21 Hz, 2H), 7.84 (d, J=8.99 Hz, 1H), 7.52 (d, J=8.21 Hz, 2H), 6.81 (d, J=2.34 Hz, 1H), 6.58 (d, J=2.34 Hz, 1H), 4.58 (t, J=5.08 Hz, 2H), 3.89-3.95 (m, 5H), 3.87 (s, 3H), 3.02 (br s, 3H), 2.99 (br s, 3H); ESI MS m/z 553 [M+H].sup.+.

(306) To a suspension of 4-(3-(2-bromoethoxy)-6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)-N,N-dimethylbenzamide (0.470 g, 0.85 mmol) in DMSO (4 mL) was added isopropylamine (3 mL) in a sealed glass tube. The reaction mixture was stirred at 70° C. for 16 h. After that time the reaction was cooled to rt and concentrated under reduced pressure. The residue was diluted with saturated NaHCO.sub.3 solution (60 mL). The precipitated solids were collected by filtration, washed with water and dried. The product was purified by flash column chromatography (silica gel, 95:5 dichloromethane/7 N NH.sub.3 in methanol) followed by trituration with diethyl ether to give 4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2-(isopropylamino)ethoxy)pyridin-2-yl)-N,N-dimethylbenzamide (0.405 g, 89%) as a white solid: mp 214-215° C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.37 (d, J=8.60 Hz, 1H), 8.28 (d, J=8.21 Hz, 2H), 7.82 (d, J=8.60 Hz, 1H), 7.51 (d, J=8.60 Hz, 2H), 6.80 (d, J=2.34 Hz, 1H), 6.57 (d, J=2.34 Hz, 1H), 4.23 (t, J=5.47 Hz, 2H), 3.92 (s, 3H), 3.86 (s, 3H), 2.98 (s, 3H), 3.02 (s, 3H), 2.93 (t, J=5.47 Hz, 2H), 2.75 (quin, J=6.25 Hz, 1H), 0.97 (d, J=6.25 Hz, 6H); ESI MS m/z 532 [M+H].sup.+.

Example 27: 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one

(307) ##STR00051##

(308) To a suspension of 2-(5-(2-hydroxyethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.245 g, 0.493 mmol) in DMF (5 mL) was added PBr.sub.3 (0.267 g, 0.986 mmol). The reaction mixture was stirred at 60° C. for 4 h. After that time the reaction mixture was cooled to rt, concentrated under reduced pressure and diluted with saturated aqueous NaHCO.sub.3 solution. The precipitated solids were collected by filtration, washed with water and dried. The product was purified by flash column chromatography (silica gel, 98:2 dichloromethane/methanol) to give 2-(5-(2-bromoethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.236 g, 85%) as an off-white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.33 (s, 1H), 8.52 (d, J=8.99 Hz, 2H), 8.40 (d, J=8.60 Hz, 1H), 8.02 (d, J=8.60 Hz, 2H), 7.87 (d, J=8.99 Hz, 1H), 6.79 (d, J=2.34 Hz, 1H), 6.56 (d, J=2.34 Hz, 1H), 4.55-4.64 (m, 2H), 3.88-3.94 (m, 5H), 3.85 (s, 3H), 3.27 (s, 3H).

(309) To a suspension of 2-(5-(2-bromoethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.115 g, 0.205 mmol) in DMSO (1 mL) was added isopropylamine (0.727 g, 12.3 mmol). The reaction mixture was stirred at 40° C. for 16 h. After that time the reaction was cooled to rt and diluted with water (15 ml). The precipitated solids were collected by filtration, washed with water and dried. The product was purified by flash column chromatography (silica gel, 97:3 dichloromethane/7 N NH.sub.3 in methanol) to give 2-(5-(2-(isopropylamino)ethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.085 g, 77%) as a yellow solid: mp 114-116° C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.49 (d, J=8.60 Hz, 2H), 8.40 (d, J=8.99 Hz, 1H), 8.00 (d, J=8.60 Hz, 2H), 7.86 (d, J=8.99 Hz, 1H), 6.79 (d, J=2.34 Hz, 1H), 6.56 (d, J=2.34 Hz, 1H), 4.24 (t, J=5.67 Hz, 2H), 3.90 (s, 3H), 3.85 (s, 3H), 3.27 (s, 3H), 2.91 (t, J=5.67 Hz, 2H), 2.69-2.79 (m, 1H), 0.96 (d, J=6.25 Hz, 6H); ESI MS m/z 539 [M+H].sup.+.

Example 28: 2-(6-(4-Acetylphenyl)-5-(2-hydroxyethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one

(310) ##STR00052##

(311) A mixture of 6-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)picolinaldehyde (0.738 g, 2.04 mmol), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanone (0.502 g, 2.04 mmol) and Na.sub.2CO.sub.3 (0.65 g, 6.12 mmol) was degassed under nitrogen. Then toluene (20 mL), ethanol (20 mL) and water (5 mL) were added. The reaction mixture was degassed again and Pd(PPh.sub.3).sub.4 (0.12 g, 0.10 mmol) was added and the mixture was degassed again. The reaction mixture was stirred at 90° C. for 16 h under nitrogen. After that time the reaction was cooled to rt and concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layer was washed with water and brine, dried over Na.sub.2SO.sub.4 and concentrated. The product was purified by flash column chromatography (silica gel, 70:30 hexanes/ethyl acetate) to give 6-(4-acetylphenyl)-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)picolinaldehyde (0.517 g, 63%) as an off-white solid: .sup.1H NMR (400 MHz, CDCl.sub.3): δ10.02 (s, 1H), 8.11 (m, 2H), 8.13-8.09 (m, 2H), 7.95 (d, J=8.60 Hz, 1H), 7.43 (d, J=8.60 Hz, 1H), 4.19 (t, J=4.30 Hz, 2H), 3.95 (t, J=4.69 Hz, 2H), 2.61 (s, 3H), 0.83 (s, 9H), 0.00 (s, 6H).

(312) To a solution of 6-(4-acetylphenyl)-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)picolinaldehyde (0.50 g, 1.25 mmol) and 2-amino-4,6-dimethoxybenzamide (0.27 g, 1.37 mmol) in N,N-dimethyl acetamide (10 ml) was added NaHSO.sub.3 (58.5 wt %, 0.34 g, 1.87 mmol) and p-toluenesulfonic acid monohydrate (0.047 g, 0.25 mmol). The reaction mixture was stirred at 120° C. for 16 h. After that time the reaction was cooled to rt and concentrated under reduced pressure. The residue was diluted with saturated NaHCO.sub.3 solution (100 mL) and the precipitated solids were collected by filtration, washed with water and dried under vacuum. The product was purified by flash column chromatography (silica gel, 98:2 dichloromethane/methanol to 97:3 dichloromethane/methanol) to give 2-(6-(4-acetylphenyl)-5-(2-hydroxyethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.317 g, 55%) as a white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ11.23 (s, 1H), 8.42-8.38 (m, 3H), 8.06 (d, J=8.59 Hz, 2H), 7.87 (d, J=8.98 Hz, 1H), 6.81 (d, J=1.95 Hz, 1H), 6.58 (d, J=2.34 Hz, 1H), 5.00 (t, J=5.27 Hz, 1H), 4.27 (t, J=4.88 Hz, 2H), 3.92 (s, 3H), 3.87 (s, 3H), 3.80 (q, J=5.07 Hz, 2H), 2.65 (s, 3H); ESI MS m/z 462 [M+H].sup.+.

(313) 2-(6-(4-Acetylphenyl)-5-(2-hydroxyethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.046 g, 0.10 mmol) was dissolved in a mixture of dichloromethane and methanol (1:1, 10 mL). A solution of 2 N HCl in diethyl ether (0.2 mL, 0.40 mmol) was added and the reaction mixture was stirred at rt for 30 minutes. The reaction was concentrated under reduced pressure and then re-dissolved in 1 N HCl (15 mL). This mixture was lyophilized to give 2-(6-(4-Acetylphenyl)-5-(2-hydroxyethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one hydrochloride (0.043 g, 86%) as a light yellow solid: mp 232-234° C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.40 (d, J=8.21 Hz, 3H), 8.06 (d, J=8.21 Hz, 2H), 7.87 (d, J=8.99 Hz, 1H), 6.82 (d, J=2.34 Hz, 1H), 6.59 (d, J=2.34 Hz, 1H), 4.28 (t, J=4.69 Hz, 2H), 3.92 (s, 3H), 3.87 (s, 3H), 3.80 (t, J=4.88 Hz, 2H), 2.65 (s, 3H); ESI MS m/z 462 [M+H].sup.+.

Example 29: 5,7-Dimethoxy-2-(6-(4-(methylsulfonyl)phenyl)-5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-2-yl)quinazolin-4(3H)-one hydrochloride

(314) ##STR00053##

(315) To a suspension of 2-(5-(2-bromoethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.120 g, 0.214 mmol) in DMSO (1 mL) was added pyrrolidine (0.045 g, 12.3 mmol). The reaction mixture was stirred at 40° C. for 2 h. After that time the reaction was cooled to rt, diluted with water (100 mL) and neutralized with Na.sub.2CO.sub.3. The precipitated solids were collected by filtration, washed with water and dried to give an off-white solid (100 mg, 85% yield). The product was dissolved in a 9:1 mixture of dichloromethane/methanol (10 mL). A 1 M solution of HCl in ether (2 mL) was added and the reaction was allowed to stir at rt for 1 h. The reaction was concentrated under reduced pressure and then re-dissolved in 1 N HCl (15 mL). This mixture was lyophilized to give 5,7-dimethoxy-2-(6-(4-(methylsulfonyl)phenyl)-5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-2-yl)quinazolin-4(3H)-one hydrochloride (0.113 g, 90%) as a yellow solid: mp 211-213° C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.00 (br s, 1H), 8.37-8.49 (m, 3H), 8.03 (d, J=8.21 Hz, 2H), 7.93 (d, J=8.99 Hz, 1H), 6.82 (d, J=1.95 Hz, 1H), 6.58 (d, J=2.34 Hz, 1H), 4.59 (t, J=4.69 Hz, 2H), 3.90 (s, 3H), 3.85 (s, 3H), 3.47 (br s, 4H), 3.27 (s, 3H), 2.99 (br s, 2H), 1.93 (br s, 2H), 1.74-1.87 (m, 2H); ESI MS m/z 551 [M+H].sup.+.

Example 30: 2-(5-(2-Hydroxyethoxy)-6-(2-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one

(316) ##STR00054##

(317) To a solution of 2-bromo-6-hydroxymethyl-pyridin-3-ol (1.0 g, 4.90 mmol) in N,N-dimethylformamide (15 mL) under nitrogen was added potassium carbonate (1.01 g, 7.35 mmol) and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (1.12 mL, 5.39 mmol). The resulting mixture was heated at 60° C. for 20 h. After that time the reaction was cooled to rt, filtered, and diluted with ethyl acetate. The organic phase was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to give {6-bromo-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-pyridin-2-yl}-methanol (1.51 g, 85%) as a pink solid: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.19-7.25 (m, 2H), 4.69 (s, 2H), 4.14 (t, J=4.9 Hz, 2H), 4.02 (t, J=4.9 Hz, 2H), 2.77 (s, 1H), 0.90 (s, 9H), 0.11 (s, 6H); ESI MS m/z 362 and 364 (M+1).sup.+.

(318) To a solution of {6-bromo-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-pyridin-2-yl}-methanol (1.5 g, 4.14 mmol) in DMSO (4 mL) under nitrogen was added 2-iodoxybenzoic acid (1.21 g, 4.35 mmol). The reaction mixture was stirred at rt for 1.5 h. After that time the solids were removed by filtration and washed with water and ethyl acetate. The organic phase was set aside and the aqueous phase was extracted with ethyl acetate. The combined organic phase was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to give 6-bromo-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-pyridine-2-carbaldehyde (1.47 g, 99%) as a light orange oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.93 (s, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 4.25 (t, J=4.8 Hz, 2H), 4.07 (t, J=4.8 Hz, 2H), 0.90 (s, 9H), 0.11 (s, 6H).

(319) A mixture of 6-bromo-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-pyridine-2-carbaldehyde (1.47 g, 4.08 mmol), 2-(methylsulfonyl)phenylboronic acid (0.89 g, 4.49 mmol) and 2.0 M Na.sub.2CO.sub.3 solution (1.29 g, 6.1 mL, 12.24 mmol) in toluene (15 mL) and ethanol (7 mL) was degassed. Pd(PPh.sub.3).sub.4 (0.47 g, 0.408 mmol) was added and the reaction was heated at 100° C. for 20 h. After that time the reaction was cooled to rt, diluted with brine and extracted with ethyl acetate. The combined organic phase was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The product was purified by flash column chromatography (80:20 Hexanes/ethyl acetate) to give 5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-6-(2-methanesulfonyl-phenyl)-pyridine-2-carbaldehyde (1.27 g, 71%) as a yellow oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.96 (s, 1H), 8.18 (dd, J=7.8, 1.2 Hz, 1H), 8.04 (d, J=8.6 Hz, 1H), 7.66-7.64 (m, 2H), 7.59 (d, J=8.6 Hz, 1H), 7.47 (dd, J=7.8, 1.2 Hz, 1H), 4.13 (t, J=4.7 Hz, 2H), 3.82 (t, J=4.7 Hz, 2H), 3.17 (s, 3H), 0.80 (s, 9H), −0.11 (s, 6H).

(320) To a solution of 2-amino-4,6-dimethoxy-benzamide (0.57 g, 2.91 mmol) in N,N-dimethylacetamide (20 mL) was added 5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-6-(2-methanesulfonyl-phenyl)-pyridine-2-carbaldehyde (1.27 g 2.91 mmol) followed by NaHSO.sub.3 (0.60 g, 5.82 mmol) and p-toluenesulfonic acid monohydrate (0.55 g, 2.91 mmol). The reaction was heated at 130° C. for 22 h. After that time the reaction was cooled to rt, concentrated under reduced pressure, diluted with water and adjusted to pH 8 with 1 M Na.sub.2CO.sub.3. The precipitated solids were collected by filtration, washed with water and triturated with diethyl ether. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol to 95:5 dichloromethane/methanol) to give 2-(5-(2-hydroxyethoxy)-6-(2-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.20 g, 14%) as a yellow solid: mp 92-93° C.; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.46 (s, 1H), 8.57 (d, J=8.7 Hz, 1H), 8.18 (dd, J=7.8, 1.2 Hz), 7.82-7.70 (m, 2H), 7.49 (d, J=8.7 Hz, 1H), 7.42 (dd, J=7.8, 1.2 Hz, 1H), 6.84 (d, J=2.3 Hz), 6.48 (d, J=2.3 Hz), 4.27 (br s, 2H), 3.98 (s, 3H), 3.96 (s, 3H), 3.85-3.78 (m, 2H), 2.95 (s, 3H), 2.81 (t, J=6.8 Hz, 1H); ESI MS m/z 498 (M+1).

Example 31: 5,7-Dimethoxy-2-(6-(4-(methylsulfonyl)phenyl)-5-(2-morpholinoethoxy)pyridin-2-yl)quinazolin-4(3H)-one hydrochloride

(321) ##STR00055##

(322) To a suspension of 2-(5-(2-bromoethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.130 g, 0.232 mmol) in DMSO (1 mL) was added morpholine (0.060 g, 0.696 mmol). The reaction mixture was stirred at 40° C. for 2 h. After that time the reaction was cooled to rt, diluted with water (100 ml) and neutralized with Na.sub.2CO.sub.3. The precipitated solids were collected by filtration, washed with water and dried to give a white solid. The product was dissolved in a 9:1 mixture of dichloromethane/methanol (10 mL). A 1 M solution of HCl in ether (2 mL) was added and the reaction allowed to stir at rt for 1 h. The reaction was concentrated under reduced pressure and then re-dissolved in 1 N HCl (15 mL). This mixture was lyophilized to give 5,7-dimethoxy-2-(6-(4-(methylsulfonyl)phenyl)-5-(2-morpholinoethoxy)pyridin-2-yl)quinazolin-4(3H)-one hydrochloride (0.130 g, 92%) as a yellow solid: mp 226-228° C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.42 (d, J=8.60 Hz, 2H), 8.47 (d, J=8.99 Hz, 1H), 8.06 (d, J=8.60 Hz, 2H), 7.94 (d, J=8.60 Hz, 1H), 6.82 (d, J=2.34 Hz, 1H), 6.60 (d, J=2.34 Hz, 1H), 4.60-4.70 (m, 2H), 3.94-3.88 (m, 5H), 3.87 (s, 3H), 3.74 (br s, 4H), 3.64 (br s, 2H), 3.41 (br s, 2H), 3.30 (s, 3H); ESI MS m/z 567 [M+H].sup.+.

Example 32: 2-(5-(2-(Isopropylamino)ethoxy)-6-(2-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one

(323) ##STR00056##

(324) PBr.sub.3 (58.6 μL, 0.623 mmol) was added dropwise to a solution of 2-(5-(2-hydroxyethoxy)-6-(2-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.30 g, 0.71 mmol) in N,N-dimethylformamide (3 mL) under nitrogen. The reaction was heated at 60° C. for 4 h. After that time the reaction was cooled to rt and diluted with water. The pH was adjusted to 8 with 1M Na.sub.2CO.sub.3 solution and extracted three times with ethyl acetate. The combined organic phase was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The product was purified by flash column chromatography (99:1 dichloromethane/methanol to 98:2 dichloromethane/methanol) to give 2-(5-(2-bromoethoxy)-6-(2-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.13 g, 74%) as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.32 (s, 1H), 8.57 (d, J=8.7 Hz, 1H), 8.19 (dd, J=7.8, 1.2 Hz, 1H), 7.81-7.68 (m, 2H), 7.46 (dd, J=7.8, 1.2 Hz, 1H), 7.45 (d, J=8.7 Hz, 1H), 6.84 (d, J=2.2 Hz, 1H), 6.48 (d, J=2.2 Hz, 1H), 4.37 (t, J=6.3 Hz, 2H), 3.97 (s, 3H), 3.96 (s, 3H), 3.49 (t, J=6.3 Hz, 2H), 2.99 (s, 3H).

(325) To a solution of 2-(5-(2-bromoethoxy)-6-(2-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.13 g, 0.23 mmol) in THF (3 mL) was added isopropylamine (0.4 mL, 4.64 mmol). The reaction was heated at 50° C. in a sealed tube for 20 h. After that time the reaction was cooled to rt and concentrated under reduced pressure. The residue was dissolved in dichloromethane and was washed with 0.1 N HCl. The aqueous phase was extracted three times with dichloromethane and the combined organic phase was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The product was triturated in diethyl ether to give 2-(5-(2-(isopropylamino)ethoxy)-6-(2-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.090 g, 72%) as a white solid: mp 178-180° C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.43 (d, J=8.7 Hz, 1H), 8.11 (dd, J=7.8, 1.2 Hz, 1H), 7.86-7.74 (m, 3H), 7.60 (dd, J=7.8, 1.2 Hz, 1H), 6.80 (d, J=2.3 Hz, 1H), 6.57 (d, J=2.3 Hz, 1H), 4.18 (t, J=5.4 Hz, 2H), 3.92 (s, 3H), 3.84 (s, 3H), 3.20 (s, 3H), 2.81 (br s, 2H), 2.67 (br s, 1H), 0.86 (d, J=6.2 Hz, 6H); ESI MS m/z 539 [M+H].sup.+.

Example 33: 2-(5-(2-(Isopropylamino)ethoxy)-6-(3-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one

(326) ##STR00057##

(327) To a suspension of 2-(5-(2-hydroxyethoxy)-6-(3-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.498 g, 0.10 mmol) in DMF (15 mL) was added PBr.sub.3 (0.19 mL, 2.00 mmol). The reaction mixture was stirred at 60° C. for 2 h under nitrogen. After that time the reaction was cooled to rt, concentrated under reduced pressure and diluted with water (100 mL). The precipitated solids were collected by filtration, washed with water and dried under vacuum to give 2-(5-(2-bromoethoxy)-6-(3-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.568 g, >99%) as an off-white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.45 (s, 1H), 8.73-8.79 (m, 1H), 8.63 (d, J=8.21 Hz, 1H), 8.40 (d, J=8.60 Hz, 1H), 8.01 (d, J=8.60 Hz, 1H), 7.88 (d, J=8.99 Hz, 1H), 7.80 (t, J=7.82 Hz, 1H), 6.81 (d, J=2.34 Hz, 1H), 6.58 (d, J=2.34 Hz, 1H), 4.55-4.63 (m, 2H), 3.83-3.94 (m, 8H), 3.32 (s, 3H); ESI MS m/z 560 and 562 [M+H].sup.+.

(328) To a suspension of 2-(5-(2-bromoethoxy)-6-(3-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.200 g, 0.36 mmol) in DMSO (3 mL) was added isopropyl amine (2 mL) in a sealed glass tube. The reaction mixture was stirred at 60° C. for 3 h. After that time the reaction was cooled to rt, concentrated under reduced pressure and diluted with Na.sub.2CO.sub.3 solution (60 mL). The precipitated solids were collected by filtration, washed with water, then diethyl ether and dried under vacuum to give 2-(5-(2-(isopropylamino)ethoxy)-6-(3-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.176 g, 91%) as an off-white solid: mp 222-223° C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.70 (s, 1H), 8.63 (d, J=7.82 Hz, 1H), 8.38 (d, J=8.60 Hz, 1H), 7.99 (d, J=7.82 Hz, 1H), 7.84 (d, J=8.99 Hz, 1H), 7.77 (t, J=7.82 Hz, 1H), 6.78 (d, J=1.95 Hz, 1H), 6.55 (d, J=2.34 Hz, 1H), 4.22 (t, J=5.28 Hz, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 3.28 (s, 3H), 2.91 (t, J=5.28 Hz, 2H), 2.74 (quin, J=6.25 Hz, 1H), 0.95 (d, J=6.25 Hz, 6H); ESI MS m/z 539 [M+H].sup.+.

Example 34: 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2-hydroxyethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one

(329) ##STR00058##

(330) To a degassed solution of 6-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)picolinaldehyde (2.50 g, 6.94 mmol) and (4-(ethylsulfonyl)phenyl)boronic acid (1.48 g, 6.94 mmol) in toluene (30 mL) and ethanol (30 mL), was added Na.sub.2CO.sub.3 (2.20 g, 20.83 mmol) in water (12 mL). The reaction mixture was degassed again and Pd(PPh.sub.3).sub.4 (0.401 g, 0.347 mmol) was added. The reaction mixture was heated at 90° C. for 16 h. After that time the reaction was cooled to rt and diluted with ethyl acetate (250 mL). The organic layer was separated and washed with water, brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 80:20 hexanes/ethyl acetate) to give 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(4-(ethylsulfonyl)phenyl)picolinaldehyde (2.34 g, 75%) as white solid: .sup.1H NMR (400 MHz, CDCl.sub.3-d) δ 10.07 (s, 1H), 8.27 (d, J=7.42 Hz, 2H), 7.96-8.05 (m, 2H), 7.51 (d, J=8.59 Hz, 1H), 7.24 (d, J=7.42 Hz, 1H), 4.20-4.30 (m, 2H), 4.00 (t, J=4.68 Hz, 2H), 3.16 (q, J=7.42 Hz, 2H), 1.32 (t, J=7.42 Hz, 3H), 0.87 (s, 9H), 0.05 (s, 6H).

(331) To a solution of 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(4-(ethylsulfonyl)phenyl)picolinaldehyde (2.34 g, 5.21 mmol) and 2-amino-4,6-dimethoxybenzamide (1.02 g, 5.21 mmol) in N,N-dimethylacetamide (20 mL), were added NaHSO.sub.3 (1.38 g, 7.81 mmol) and p-toluenesulfonic acid monohydrate (0.198 g, 1.04 mmol). The reaction mixture was heated at 120° C. for 24 h. After that time the reaction was cooled to rt and concentrated under reduced pressure. The residue was diluted with (200 mL) was added and neutralized with NaHCO.sub.3. The precipitated solids were collected by filtration, washed with water and dried to give 2-(5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(4-(ethylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (3.08 g, 94%) as an off-white solid: .sup.1H NMR (400 MHz, CDCL.sub.3-d) δ 10.44 (br s, 1H), 8.53 (d, J=8.40 Hz, 1H), 8.20 (d, J=8.00 Hz, 2H), 8.02 (d, J=8.00 Hz, 2H), 7.56 (d, J=8.40 Hz, 1H), 6.84 (s, 1H), 6.50 (s, 1H), 4.25 (t, J=4.49 Hz, 2H), 3.97-4.02 (s, 5H), 3.96 (s, 3H), 3.20 (q, J=7.68 Hz, 2H), 1.35 (t, J=7.42 Hz, 3H), 0.88 (s, 9H), 0.05 (s, 6H).

(332) To a solution of 2-(5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(4-(ethylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (3.08 g, 4.93 mmol) in THF (30 mL), was added a 1 M solution of TBAF in THF (9.85 mL, 9.85 mmol). The reaction mixture was stirred at rt for 1 h. After that time the reaction concentrated under reduced pressure and the residue diluted with water (150 mL) and stirred at rt for 1 h. The precipitated solids were collected by filtration, washed with water and dried. The product was purified by flash column chromatography (silica gel, 98:2 dichloromethane/methanol) to give 2-(6-(4-(ethylsulfonyl)phenyl)-5-(2-hydroxyethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (1.15 g, 43% over two steps) as a white solid: mp 282-284° C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.38 (s, 1H), 8.55 (d, J=8.40 Hz, 2H), 8.41 (d, J=8.40 Hz, 1H), 7.98 (d, J=8.40 Hz, 2H), 7.89 (d, J=9.37 Hz, 1H), 6.81 (s, 1H), 6.58 (s, 1H), 5.04 (t, J=5.27 Hz, 1H), 4.28 (t, J=4.29 Hz, 2H), 3.92 (s, 3H), 3.87 (s, 3H), 3.84-3.77 (m, 2H), 3.43-3.36 (m, 2H), 1.16 (t, J=7.22 Hz, 3H); ESI MS m/z 512 [M+H].sup.+.

Example 35: 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2-(isopropylamino)ethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one

(333) ##STR00059##

(334) To a suspension of 2-(6-(4-(ethylsulfonyl)phenyl)-5-(2-hydroxyethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.250 g, 0.49 mmol) in DMF (5 mL), was added PBr.sub.3 (0.264 g, 0.97 mmol). The reaction mixture was stirred at 60° C. for 1 h. After that time the reaction was cooled to rt and concentrated under reduced pressure. The residue was diluted with saturated NaHCO.sub.3 solution and the precipitated solids were collected by filtration and washed with water and dried. The product was purified by flash column chromatography (silica gel, 98:2 dichloromethane/methanol) to give 2-(5-(2-bromoethoxy)-6-(4-(ethylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.245 g, 87%) as a white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.42 (s, 1H), 8.56 (d, J=8.80 Hz, 1H), 8.22 (d, J=8.80 Hz, 2H), 8.06 (d, J=8.40 Hz, 2H), 7.49 (d, J=9.20 Hz, 1H), 6.84 (d, J=1.60 Hz, 1H), 6.50 (d, J=1.60 Hz, 1H), 4.48 (t, J=5.20 Hz, 2H), 3.99 (s, 3H), 3.95 (s, 3H), 3.69 (t, J=5.20 Hz, 2H), 3.22 (q, J=7.20 Hz, 2H), 1.35 (t, J=7.20 Hz, 2H).

(335) To a suspension of 2-(5-(2-bromoethoxy)-6-(4-(ethylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.245 g, 0.43 mmol) in THF (5 mL) and DMSO (1 mL) was added isopropylamine (2 mL). The reaction mixture was stirred at 60° C. for 16 h. After that time the reaction was cooled to rt and concentrated under reduced pressure. The residue was diluted with water (100 mL) and neutralized with NaHCO.sub.3 solution. The precipitated solids were collected by filtration and washed with water and dried to give 2-(6-(4-(ethylsulfonyl)phenyl)-5-(2-(isopropylamino)ethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.202 g, 86%) as an off-white solid: mp 195-197° C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.51 (d, J=8.0 Hz, 2H), 8.40 (d, J=8.40 Hz, 1H), 7.96 (m, J=8.20 Hz, 2H), 7.85 (d, J=8.59 Hz, 1H), 6.79 (s, 1H), 6.56 (s, 1H), 4.23 (t, J=5.2, 2H), 3.90 (s, 3H), 3.84 (s, 3H), 3.30-3.39 (m, 2H), 2.91 (t, J=5.27 Hz, 2H), 2.67-2.81 (m, 1H), 1.13 (t, J=7.02 Hz, 3H), 0.96 (d, J=6.24 Hz, 6H); ESI MS m/z 553 [M+H].sup.+.

Example 36: 2-(5-(2-Hydroxyethoxy)-6-(3-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one methanesulfonate

(336) ##STR00060##

(337) A mixture of 6-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)picolinaldehyde (0.95 g, 2.63 mmol), (3-(methylsulfonyl)phenyl)boronic acid (0.52 g, 2.63 mmol) and Na.sub.2CO.sub.3 (0.83 g, 7.89 mmol) was degassed under nitrogen. Toluene (20 mL), ethanol (20 mL) and water (5 mL) were added and the mixture was degassed again. Pd(PPh.sub.3).sub.4 (0.152 g, 0.13 mmol) was added and the mixture was degassed once more. The reaction was stirred at 90° C. for 16 h under nitrogen. After that time the reaction was cooled to rt, concentrated under reduced pressure and diluted with water (100 mL). The mixture was extracted with ethyl acetate (2×150 mL). The combined organic phase was washed with water, brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 70:30 hexanes/ethyl acetate) to give 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(3-(methylsulfonyl)phenyl)picolinaldehyde (0.945 g, 82%) as a pale yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3): δ 10.07 (s, 1H), 8.64 (t, J=1.56 Hz, 1H), 8.38 (dt, J=7.82, 1.37 Hz, 1H), 7.97-8.04 (m, 2H), 7.66 (t, J=8.21 Hz, 1H), 7.51 (d, J=8.60 Hz, 1H), 4.23-4.28 (m, 2H), 3.99-4.04 (m, 2H), 3.11 (s, 3H), 0.85 (s, 9H), 0.02 (s, 6H).

(338) To a solution of 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(3-(methylsulfonyl)phenyl)-picolinaldehyde (0.93 g, 2.13 mmol) and 2-amino-4,6-dimethoxybenzamide (0.46 g, 2.34 mmol) in N,N-dimethylacetamide (20 ml) was added NaHSO.sub.3 (58.5 wt %, 0.58 g, 3.19 mmol) and p-toluenesulfonic acid monohydrate (81 mg, 0.42 mmol). The reaction mixture was stirred at 120° C. for 18 h. After that time the reaction was cooled to rt, concentrated under reduced pressure and diluted with water (100 mL). The precipitated solids were collected by filtration, washed with water and dried under vacuum. The resulting solid was washed with diethyl ether and dried to give 2-(5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(3-(methylsulfonyl)-phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (1.21 g, 93%) as an off-white solid.

(339) To a solution of 2-(5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(3-(methylsulfonyl)-phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (1.20 g, 1.96 mmol) in THF (20 mL) was added a solution of tetrabutylammoniumfluoride in THF (1M solution, 6.0 mL, 6.00 mmol). The reaction was stirred at rt for 1 h. After that time the reaction was concentrated under reduced pressure, diluted with water (100 mL) and stirred at rt for 1 h. The precipitated solids were collected by filtration, washed with water and dried under vacuum. The resulting solid was then washed with ethyl acetate and again dried under vacuum to give 2-(5-(2-hydroxyethoxy)-6-(3-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.97 g, 99%) as an off-white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.44 (s, 1H), 8.76 (s, 1H), 8.64 (d, J=7.82 Hz, 1H), 8.40 (d, J=8.60 Hz, 1H), 7.99 (d, J=7.82 Hz, 1H), 7.88 (d, J=8.60 Hz, 1H), 7.79 (t, J=7.82 Hz, 1H), 6.81 (d, J=2.34 Hz, 1H), 6.58 (d, J=2.34 Hz, 1H), 5.00 (t, J=5.28 Hz, 1H), 4.27 (t, J=4.88 Hz, 2H), 3.92 (s, 3H), 3.87 (s, 3H), 3.80 (q, J=5.08 Hz, 2H), 3.32 (s, 3H). ESI MS m/z 498 [M+H].sup.+.

(340) To a suspension of 2-(5-(2-hydroxyethoxy)-6-(3-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.075 g, 0.15 mmol) in dichloromethane (5 mL) and methanol (5 mL) was added a solution of 0.1 M methane sulfonic acid in dichloromethane (1.6 mL, 0.16 mmol). The reaction mixture was stirred at rt for 2 h under nitrogen. After that time the reaction was concentrated under reduced pressure, washed with diethyl ether and dried under vacuum to give 2-(5-(2-hydroxyethoxy)-6-(3-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one methanesulfonate (0.085 g, 95%) as a pale green solid: mp 218-220° C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.75 (s, 1H), 8.63 (d, J=8.21 Hz, 1H), 8.41 (d, J=8.60 Hz, 1H), 8.00 (d, J=7.82 Hz, 1H), 7.89 (d, J=8.60 Hz, 1H), 7.79 (t, J=7.82 Hz, 1H), 6.84 (d, J=1.95 Hz, 1H), 6.60 (d, J=1.95 Hz, 1H), 4.28 (t, J=4.69 Hz, 2H), 3.92 (s, 3H), 3.87 (s, 3H), 3.80 (t, J=4.69 Hz, 2H), 3.32 (s, 3H), 2.36 (s, 3H); ESI MS m/z 498 [M+H].sup.+.

Example 37: 2-(5-(2-Hydroxyethoxy)-6-(3-(methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one

(341) ##STR00061##

(342) A mixture of 6-bromo-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-pyridine-2-carbaldehyde (0.58 g, 1.61 mmol), 3-methylsulfinylphenylboronic acid (0.296 g, 1.61 mmol) and 2M Na.sub.2CO.sub.3 solution (0.34 g, 1.61 mL, 3.22 mmol) in toluene (6 mL) and ethanol (3 mL) was purged with nitrogen for 15 min. Pd(PPh.sub.3).sub.4 (0.093 g, 0.08 mmol) was then added and the reaction was heated at 100° C. for 20 h. After that time the reaction mixture was cooled to room temperature, diluted with brine, and extracted twice with EtOAc. The combined organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 80:20 hexanes/ethyl acetate to 50:50 hexanes/ethyl acetate) to give 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(3-(methylsulfinyl)phenyl)picolinaldehyde (0.58 g, 86%) as a yellow oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.07 (s, 1H), 8.27 (s, 1H), 8.21 (d, J=7.82 Hz, 1H), 8.00 (d, J=8.60 Hz, 1H), 7.77 (d, J=7.82 Hz, 1H), 7.61-7.68 (m, 1H), 7.45-7.52 (m, 1H), 4.21-4.29 (m, 2H), 3.97-4.04 (m, 2H), 2.78 (s, 3H), 0.85 (s, 9H), 0.03 (s, 6H).

(343) To a solution of 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(3-(methylsulfinyl)phenyl)picolinaldehyde (0.58 g, 1.38 mmol) in N,N-dimethylacetamide (10 mL) was added 2-amino-4,6-dimethoxybenzamide (0.27 g, 1.38 mmol) followed by NaHSO.sub.3 (0.17 g, 1.66 mmol) and p-toluenesulfonic acid monohydrate (0.13 g, 0.69 mmol). The resulting mixture was heated at 120° C. for 18 h. After that time the reaction was cooled to rt, concentrated under reduced pressure and diluted with water. The pH was adjusted to 8 with 1M Na.sub.2CO.sub.3 solution and the precipitated solids were collected by filtration, washed with water and triturated with diethyl ether. The product was purified by flash column chromatography (99:1 dichloromethane/methanol to 95:5 dichloromethane/methanol) to give 2-(5-(2-hydroxyethoxy)-6-(3-(methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.206 g, 31%) as a light yellow solid: mp 272-273° C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.34 (br s, 1H), 8.52 (s, 1H), 8.45 (d, J=7.81 Hz, 1H), 8.35-8.42 (m, 1H), 7.86 (d, J=7.81 Hz, 1H), 7.76-7.82 (m, 1H), 7.67-7.76 (m, 1H), 6.81 (s, 1H), 6.58 (s, 1H), 4.91-5.06 (m, 1H), 4.18-4.32 (m, 2H), 3.92 (s, 3H), 3.87 (s, 3H), 3.71-3.83 (m, 2H), 2.84 (s, 3H); ESI MS m/z 482 [M+1].sup.+.

Example 38: 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one

(344) ##STR00062##

(345) To a degassed solution of 6-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)picolinaldehyde (0.700 g, 1.94 mmol) and 4,4,5,5-tetramethyl-2-(4-(methylsulfinyl)phenyl)-1,3,2-dioxaborolane (0.517 g, 1.94 mmol) in toluene (20 mL) and ethanol (20 mL), was added Na.sub.2CO.sub.3 (0.618 g, 5.83 mmol) in water (10 mL). The reaction mixture was degassed again and Pd(PPh.sub.3).sub.4 (0.112 g, 0.097 mmol) was added. The reaction mixture was heated at 90° C. for 16 h. After that time the reaction was cooled to rt and diluted with ethyl acetate (250 mL). The organic layer was separated and washed with water, brine, dried over Na.sub.2SO.sub.4 and concentrated under reduce pressure. The product was purified by flash column chromatography (silica gel, 70:30 hexanes/ethyl acetate) to give 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(4-(methylsulfinyl)phenyl)picolinaldehyde (0.542 g, 66%) as white solid: .sup.1H NMR (400 MHz, CDCl.sub.3-d) δ 10.07 (s, 1H), 8.19-8.25 (m, 2H), 8.00 (d, J=8.59 Hz, 1H), 7.71-7.78 (m, 2H), 7.48 (d, J=8.59 Hz, 1H), 4.25 (t, J=4.68 Hz, 2H), 4.12 (q, J=7.02 Hz, 2H), 2.77 (s, 3H), 0.87 (s, 9H), 0.04 (s, 6H).

(346) To a solution of 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(4-(methylsulfinyl)phenyl)picolinaldehyde (0.542 g, 1.29 mmol) and 2-amino-4,6-dimethoxybenzamide (0.253 g, 1.29 mmol) in N,N-dimethylacetamide (15 mL) was added NaHSO.sub.3 (0.344 g, 1.94 mmol) and p-toluenesulfonic acid monohydrate (0.049 g, 0.25 mmol). The reaction mixture was heated at 120° C. for 16 h. After that time the reaction was cooled to rt and concentrated under reduced pressure. The residue was diluted with water (100 mL) and neutralized with solid NaHCO.sub.3. The precipitated solids were collected by filtration, washed with water and dried to give 2-(5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.718 g, 93%) as an off-white solid: .sup.1H NMR (400 MHz, CDCl.sub.3-d) δ 10.48 (s, 1H), 8.51 (d, J=8.59 Hz, 1H), 8.18 (d, J=7.02 Hz, 2H) 7.78 (d, J=8.0 Hz, 2H), 7.54 (d, J=8.98 Hz, 1H), 6.84 (s, 1H), 6.49 (s, 1H), 4.25 (t, J=4.10 Hz, 2H), 3.98-4.04 (m, 5H), 3.96 (s, 3H), 2.82 (s, 3H), 0.88 (s, 9H), 0.05 (s, 6H).

(347) To a solution of 2-(5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.718 g, 1.20 mmol) in THF (20 mL), was added a 1 M solution of TBAF in THF (2.41 mL, 2.41 mmol). The reaction mixture was stirred at rt for 1 h. After that time the reaction was concentrated under reduced pressure. The residue was diluted with water (100 mL) and stirred for 1 h at rt. The precipitated solids were collected by filtration, washed with water and dried. The product was purified by flash column chromatography (silica gel, 96:4 dichloromethane/methanol) to give 2-(5-(2-hydroxyethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.430 g, 78% over two steps) as an off-white solid: mp 281-282° C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.24 (s, 1H), 8.44 (d, J=7.42 Hz, 2H), 8.33-8.40 (d, J=7.81 Hz, 1H), 7.84 (d, J=7.81 Hz, 1H), 7.77 (d, J=7.42 Hz, 2H), 6.79 (s, 1H), 6.56 (s, 1H), 4.99 (t, J=5.27 Hz, 1H), 4.25 (t, J=4.29 Hz, 2H), 3.90 (s, 3H), 3.84 (s, 3H), 3.74-3.81 (m, 2H), 2.80 (s, 3H); ESI MS m/z 482 [M+H].sup.+.

Example 39: 2-(5-(2-Hydroxyethoxy)-6-(2-methyl-4-(methylsulfonyl)phenyl)pyridin-2-yl)-5-dimethoxyquinazolin-4(3H)-one

(348) ##STR00063##

(349) A solution of 1-bromo-2-methyl-4-methylsulfanylbenzene (2.5 g, 11.51 mmol) in methanol (58 mL) and water (5.8 mL) was cooled to 0° C. Oxone (7.07 g, 11.51 mmo) was added as a solid and the reaction was allowed to warm to rt and stirred 18 h. After that time saturated Na.sub.2SO.sub.3 solution was added and the mixture was extracted with methylene chloride (3×100 mL). The combined organic phase was washed with water, brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to give 1-bromo-4-methanesulfonyl-2-methylbenzene (2.38 g, 83%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.81 (d, J=1.95 Hz, 1H), 7.75 (d, J=8.21 Hz, 1H), 7.62 (dd, J=8.01, 2.15 Hz, 1H), 3.05 (s, 3H), 2.50 (s, 3H).

(350) To a solution of 1-bromo-4-methanesulfonyl-2-methylbenzene (2.38 g, 9.55 mmol) in N,N-dimethylformamide (48 mL) under nitrogen was added pinacol diborane (3.64 g, 14.33 mmol), potassium acetate (4.68 g, 47.75 mmol) and Pd(dppf).sub.2Cl.sub.2 (0.69 g, 0.95 mmol). The reaction was heated at 80° C. for 22 h. After that time the reaction was cooled to rt, concentrated under reduced pressure and re-dissolved in ethyl acetate. A solution of 2M HCl was added and the precipitated solids were removed by filtration. The filtrate was extracted with ethyl acetate (2×100 mL). The combined organic phase was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 90:10 Hexanes/ethyl acetate) to give 4,4,5,5-tetramethyl-2-(2-methyl-4-(methylsulfonyl)phenyl)-1,3,2-dioxaborolane (1.92 g, 68%) as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.94 (d, J=8.21 Hz, 1H), 7.69-7.74 (m, 2H), 3.03 (s, 3H), 2.62 (s, 3H), 1.36 (s, 12H).

(351) A mixture of 6-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)picolinaldehyde (1.21 g, 3.37 mmol), 2-(4-methanesulfonyl-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1.0 g, 3.37 mmol) and 2M Na.sub.2CO.sub.3 solution (6.74 mL, 13.48 mmol) in toluene (12 mL) and ethanol (6 mL) was degassed with nitrogen. Pd(PPh.sub.3).sub.4 (0.39 g, 0.337 mmol) was added and the reaction heated at 100° C. for 22 h. After that time the reaction was cooled to rt, diluted with brine and extracted with ethyl acetate (2×100 mL). The combined organic phase was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 90:10 hexanes/ethyl acetate to 70:30 hexanes/ethyl acetate) to give 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(2-methyl-4-(methylsulfonyl)phenyl)picolinaldehyde (1.42 g, 77%) as an orange oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.10 (s, 1H), 8.14 (d, J=8.60 Hz, 1H), 7.91-8.00 (m, 2H), 7.63 (d, J=7.82 Hz, 1H), 7.59 (d, J=8.60 Hz, 1H), 4.23-4.28 (m, 2H), 3.92-3.98 (m, 2H), 3.16 (s, 3H), 2.38 (s, 3H), 0.89 (s, 9H), 0.00 (s, 6H).

(352) To a solution of 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(2-methyl-4-(methylsulfonyl)phenyl)picolinaldehyde (1.42 g, 3.15 mmol) in N,N-dimethylacetamide (20 mL) was added 2-amino-4,6-dimethoxybenzamide (0.62 g, 3.15 mmol) followed by NaHSO.sub.3 (0.49 g, 4.74 mmol) and p-toluenesulfonic acid monohydrate (0.30 g, 1.57 mmol). The resulting mixture was heated at 120° C. for 18 h. After that time the reaction was cooled to rt, concentrated under reduced pressure and diluted with water. The pH was adjusted to 8 with 1M Na.sub.2CO.sub.3 and the precipitated solids were collected, washed with water and triturated with diethyl ether. The product was purified by flash column chromatography (98:2 dichloromethane/methanol to 95:5 dichloromethane/methanol) to give 2-(5-(2-hydroxyethoxy)-6-(2-methyl-4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.835 g, 52%) as a tan solid: mp 341° C. dec.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.92 (s, 1H), 8.43 (d, J=8.60 Hz, 1H), 7.81-7.93 (m, 3H), 7.70-7.79 (m, 1H), 6.81 (d, J=2.34 Hz, 1H), 6.57 (d, J=2.34 Hz, 1H), 4.88 (t, J=5.08 Hz, 1H), 4.21 (t, J=4.88 Hz, 2H), 3.92 (s, 3H), 3.85 (s, 3H), 3.67 (q, J=5.08 Hz, 2H), 3.29 (s, 3H), 2.29 (s, 3H); ESI MS m/z 517 [M+H].

Example 40: 2-(5-(2-(Isopropylamino)ethoxy)-6-(3-(methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one

(353) ##STR00064##

(354) PBr.sub.3 (0.060 mL, 0.63 mmol) was added dropwise to a solution of 2-(5-(2-hydroxyethoxy)-6-(3-(methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.152 g, 0.31 mmol) in N,N-dimethylformamide (4 mL) under nitrogen. The reaction was heated at 60° C. for 4 h. After that time the reaction was cooled to rt and diluted with water. The pH was adjusted to 8 with 1M Na.sub.2CO.sub.3 and the reaction mixture was extracted three times with dichloromethane. The combined organic phase was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The product was purified by flash column chromatography (98:2 dichloromethane/methanol to 95:5 dichloromethane/methanol) to give 2-(5-(2-bromoethoxy)-6-(3-(methylthio)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.104 g, 62%) as a yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.47 (d, J=8.60 Hz, 1H), 7.94 (s, 1H), 7.81 (d, J=7.03 Hz, 1H), 7.41-7.51 (m, 2H), 7.34-7.40 (m, 1H), 6.84 (d, J=2.34 Hz, 1H), 6.49 (d, J=2.34 Hz, 1H), 4.46 (t, J=5.86 Hz, 2H), 3.98 (s, 3H), 3.96 (s, 3H), 3.71 (t, I=5.67 Hz, 2H), 2.58 (s, 3H).

(355) To a solution of 2-(5-(2-bromoethoxy)-6-(3-(methylthio)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.104 g, 0.197 mmol) in chloroform (4 mL) and DMSO (2 mL) was added isopropylamine (0.33 mL, 3.93 mmol). The reaction was heated at 50° C. in a sealed tube for 18 h. After that time the reaction was cooled to rt, concentrated under reduced pressure and diluted with water. The pH was adjusted to 8 with 2M Na.sub.2CO.sub.3 and the precipitated solids were collected by filtration, washed with water and dried under high vacuum to give 2-(5-(2-(isopropylamino)ethoxy)-6-(3-(methylthio)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.080 g, 80%) as a light yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.47 (d, J=8.60 Hz, 1H), 7.80 (s, 1H), 7.68 (d, J=7.42 Hz, 1H), 7.40-7.48 (m, 2H), 7.26-7.37 (m, 1H), 6.82 (d, J=2.34 Hz, 1H), 6.48 (d, J=2.34 Hz, 1H), 4.23-4.29 (m, 2H), 3.99 (s, 3H), 3.95 (s, 3H), 3.04-3.11 (m, 2H), 2.84-2.94 (m, 1H), 2.55 (s, 3H), 1.10 (d, J=6.25 Hz, 6H).

(356) A solution of 2-(5-(2-(isopropylamino)ethoxy)-6-(3-(methylthio)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.04 g, 0.23 mmol) in acetone (0.8 mL), water (0.8 mL) and methanol (0.3 mL) was cooled to 0° C. Oxone (0.024 g, 0.039 mmol) was added as a solid and the reaction was stirred at 0° C. for 1 h. After that time the reaction was warmed to rt and diluted with water. The pH was adjusted to 8 with 2M Na.sub.2CO.sub.3 and the reaction mixture was extracted three times with dichloromethane. The combined organic phase was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The product was purified by flash column chromatography (98:2 dichloromethane/methanol to 94:6 dichloromethane/methanol) followed by precipitation from ethyl acetate/hexanes to give 2-(5-(2-(isopropylamino)ethoxy)-6-(3-(methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.03 g, 53%) as a light yellow solid: mp 156-157° C.; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.52 (d, J=8.99 Hz, 1H), 8.31 (s, 1H), 8.10-8.15 (m, 1H), 7.67-7.77 (m, 2H), 7.50 (d, J=8.60 Hz, 1H), 6.84 (d, J=2.34 Hz, 1H), 6.49 (d, J=2.34 Hz, 1H), 4.22-4.29 (m, 2H), 3.99 (s, 3H), 3.95 (s, 3H), 3.07 (t, J=5.08 Hz, 2H), 2.83-2.90 (m, 1H), 2.81 (s, 3H), 1.07 (d, J=5.86 Hz, 6H); ESI MS m/z: 523 [M+1].sup.+.

Example 41: 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one

(357) ##STR00065##

(358) To a suspension of 2-(5-(2-hydroxyethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.150 g, 0.31 mmol) in DMF (5 mL), was added PBr.sub.3 (0.168 g, 0.62 mmol). The reaction mixture was stirred at 60° C. for 1 h. The reaction mixture was cooled to rt. The reaction was concentrated under reduced pressure and saturated NaHCO.sub.3 solution was added. The precipitated solids were collected by filtration, washed with water and dried. The product was purified by flash column chromatography (silica gel, 98:2 dichloromethane/methanol) to give 2-(5-(2-bromoethoxy)-6-(4-(methylthio)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.070 g, 42%) as a white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.13 (br s, 1H), 8.31 (d, J=8.98 Hz, 1H), 8.23 (d, J=8.59 Hz, 2H), 7.78 (d, J=8.98 Hz, 1H), 7.35 (d, J=7.02 Hz, 2H), 6.79 (s, 1H), 6.56 (s, 1H), 4.55 (m, 2H), 3.87-3.94 (m, 5H), 3.85 (s, 3H), 2.53 (s, 3H).

(359) To a suspension of 2-(5-(2-bromoethoxy)-6-(4-(methylthio)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.112 g, 0.21 mmol) in CHCl.sub.3 (2 mL) and DMSO (1 mL) was added isopropyl amine (1 mL). The reaction mixture was stirred at 60° C. for 16 h. After that time the reaction was cooled to rt and concentrated under reduced pressure. Water (100 ml) was added and the precipitated solids were collected by filtration, washed with water and dried to give 2-(5-(2-(isopropyl amino)ethoxy)-6-(4-(methylthio)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.110 g, >99%) as an off-white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.39 (d, J=8.60 Hz, 1H), 8.24 (d, J=8.60 Hz, 2H), 7.84 (d, J=8.99 Hz, 1H), 7.42 (d, J=8.60 Hz, 2H), 6.85 (s, 1H), 6.63 (s, 1H), 4.27 (t, J=5.47 Hz, 2H), 3.97 (s, 3H), 3.92 (s, 3H), 2.98 (t, J=5.47 Hz, 2H), 2.74-2.87 (m, 1H), 2.60 (s, 3H), 1.04 (d, J=5.86 Hz, 6H).

(360) To a suspension of 2-(5-(2-(isopropylamino)ethoxy)-6-(4-(methylthio)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.110 g, 0.217 mmol) in acetone (3 mL), water (3 mL) and methanol (1 mL), was added oxone (0.066 g, 0.108 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h. After that time the reaction was diluted with water (950 mL) and neutralized with Na.sub.2CO.sub.3 solution. The precipitated solids were collected by filtration, washed with water and dried to give a solid. The product was purified by flash column chromatography (silica gel, 95:5 dichloromethane/methanol) to give 2-(5-(2-(isopropylamino)ethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.087 g, 79% over two steps) as an off-white solid: mp 93-95° C.; .sup.1H NMR (400 MHz, CDCl.sub.3-d) δ 8.39 (d, J=8.40 Hz, 2H), 8.35 (d, J=8.40 Hz, 1H), 7.80 (d, J=8.80 Hz, 1H), 7.77 (d, J=8.40 Hz, 2H), 6.78 (s, 1H), 6.55 (s, 1H), 4.22 (t, J=5.20 Hz, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 2.90 (t, J=5.60 Hz, 2H), 2.9 (s, 3H), 2.77-2.70 (m, 1H), 0.96 (d, J=6.0 Hz, 6H). Exchangeable protons are not visible. ESI MS m/z 523 [M+H].sup.+.

Example 42: 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one

(361) ##STR00066##

(362) To a suspension of 2-(5-(2-bromoethoxy)-6-(4-(ethylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.135 g, 0.235 mmol) in DMSO (1.5 mL) was added pyrrolidine (0.050 g, 0.705 mmol). The reaction was stirred at 40° C. for 3 h. After that time the reaction was cooled to rt, diluted with water (50 mL) and the precipitated solids were collected by filtration, washed with water and dried under vacuum.

(363) The product (0.140 g) was dissolved in a mixture of dichloromethane (10 mL) and methanol (1 mL), and HCl (1N in ether, 2 mL) was added. The mixture was stirred at rt for 1 h. After that time the reaction was concentrated under reduced pressure and the residue was suspended in aqueous 1N HCl (15 mL). The resulting mixture was stirred for 30 min and then lyophilized to give 2-(6-(4-(ethylsulfonyl)phenyl)-5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one hydrochloride (0.124 g, 88% over two steps) as a yellow solid: mp 235-236° C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.37 (br. s., 1H), 8.39-8.49 (m, 3H), 7.98 (d, J=8.21 Hz, 2H), 7.92 (d, J=8.59 Hz, 1H), 6.84 (d, J=1.56 Hz, 1H), 6.587 (d, J=1.56 Hz, 1H), 4.55-4.64 (m, 2H), 3.89 (s, 3H), 3.85 (s, 3H), 3.61-2.68 (m, 2H), 3.30-3.48 (m, 4H), 3.92-3.03 (m, 2H), 1.73-1.95 (m, 4H), 1.13 (t, J=7.42 Hz, 3H); ESI MS m/z 565 [M+H].sup.+.

Example 43: 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2-morpholinoethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one

(364) ##STR00067##

(365) To a suspension of 2-(5-(2-bromoethoxy)-6-(4-(ethylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.135 g, 0.235 mmol) in DMSO (1.5 mL) was added morpholine (0.062 g, 0.705 mmol). The reaction mixture was stirred at 40° C. for 3 h. After that time the reaction was cooled to rt, diluted with water (50 mL) and the precipitated solids were collected by filtration, washed with water and dried under vacuum. The product (0.137 g) was dissolved in a mixture of dichloromethane (10 mL) and methanol (1 mL), and HCl (1N in ether, 2 mL) was added. The resulting mixture was stirred at rt for 1 h. After that time the reaction was concentrated under reduced pressure to give 2-(6-(4-(ethylsulfonyl)phenyl)-5-(2-morpholinoethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one hydrochloride (0.116 g, 73% over two steps) as a yellow solid: mp 245° C. dec. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.62 (br s, 1H), 8.37-8.50 (m, 3H), 8.00 (d, J=8.60 Hz, 2H), 7.92 (d, J=8.99 Hz, 1H), 6.83 (d, J=2.34 Hz, 1H), 6.58 (d, J=2.34 Hz, 1H), 4.68 (t, J=4.69 Hz, 2H), 3.65-4.00 (m, 10H), 3.62 (br s, 2H), 3.26-3.45 (m, 4H), 3.06-3.17 (m, 2H), 1.13 (t, J=7.42 Hz, 3H); ESI MS m/z 581 [M+H].sup.+.

Example 44: 2-(6-(2-(Isopropylamino)ethoxy)-4′-(methylsulfonyl)-[1,1′-biphenyl]-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one

(366) ##STR00068##

(367) A mixture of 3-bromo-4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)benzaldehyde (0.81 g, 2.27 mmol), 4,4,5,5-tetramethyl-2-(4-(methylsulfonyl)phenyl)-1,3,2-dioxaborolane (0.64 g, 2.27 mmol) and Na.sub.2CO.sub.3 (0.72 g, 6.81 mmol) was degassed under nitrogen. Then toluene (20 mL), ethanol (20 mL) and water (5 mL) was added. The reaction mixture was degassed again and Pd(PPh.sub.3).sub.4 (0.130 g, 0.11 mmol) was added and degassed. The reaction mixture was stirred at 90° C. for 16 h under nitrogen. After that time the reaction was cooled to rt, concentrated under reduced pressure, diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic phase was washed with water, brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 70:30 hexanes/ethyl acetate) to give 6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4′-(methylsulfonyl)-[1,1′-biphenyl]-3-carbaldehyde (0.936 g, 94%) as an off-white solid: .sup.1H NMR (400 MHz, CDCl.sub.3): δ 9.96 (s, 1H), 8.00 (d, J=8.21 Hz, 2H), 7.93 (dd, J=8.40, 2.15 Hz, 1H), 7.89 (d, J=1.95 Hz, 1H), 7.79 (d, J=8.60 Hz, 2H), 7.17 (d, J=8.60 Hz, 1H), 4.21 (t, J=4.30 Hz, 2H), 3.94 (t, J=4.88 Hz, 2H), 3.12 (s, 3H), 0.86 (s, 9H), 0.00 (s, 6H).

(368) To a solution of 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(4-(methylsulfonyl)phenyl)picolinaldehyde (0.92 g, 2.11 mmol) and 2-amino-4,6-dimethoxybenzamide (0.46 g, 2.32 mmol) in N,N-dimethyacetamide (20 ml) was added NaHSO.sub.3 (58.5 wt %, 0.58 g, 3.16 mmol) and p-toluenesulfonic acid monohydrate (81 mg, 0.42 mmol). The reaction mixture was stirred at 120° C. for 18 h. After that time the reaction was cooled to rt, concentrated under reduced pressure, diluted with water (100 mL) and the precipitated solids were collected by filtration, washed with water and dried. The product was washed with diethyl ether and dried to give 2-(6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4′-(methylsulfonyl)-[1,1′-biphenyl]-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one (1.26 g, 98%) as a light yellow solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.15 (br s, 1H), 8.23-8.36 (m, 2H), 7.92-8.14 (m, 4H), 7.38 (d, J=8.59 Hz, 1H), 6.79 (s, 1H), 6.57 (s, 1H), 4.22-4.29 (m, 2H), 3.92-3.98 (m, 5H), 3.90 (s, 3H), 3.31 (s, 3H), 0.86 (s, 9H), 0.01 (s, 6H).

(369) To a solution of 2-(6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4′-(methylsulfonyl)-[1,1′-biphenyl]-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one (1.24 g, 2.03 mmol) in THF (20 mL) was added a solution of tetrabutylammoniumfluoride in THF (1M solution, 4.1 mL, 4.06 mmol). The reaction mixture was stirred at rt for 1 h. After that time the reaction was diluted with water (100 mL) and stirred for 3 h at rt. The precipitated solids were collected by filtration, washed with water and dried, then washed with methanol and dried under vacuum to give 2-(6-(2-hydroxyethoxy)-4′-(methylsulfonyl)-[1,1′-biphenyl]-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.785 g, 78%) as a light green solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.09 (s, 1H), 8.17-8.29 (m, 2H), 7.98 (s, 4H), 7.31 (d, J=8.99 Hz, 1H), 6.72 (d, J=2.34 Hz, 1H), 6.50 (d, J=1.95 Hz, 1H), 4.89 (t, J=5.28 Hz, 1H), 4.17 (t, J=4.69 Hz, 2H), 3.86 (s, 3H), 3.83 (s, 3H), 3.71 (q, J=5.08 Hz, 2H), 3.27 (s, 3H); ESI MS m/z 497 [M+H].sup.+.

(370) To a suspension of 2-(6-(2-hydroxyethoxy)-4′-(methylsulfonyl)-[1,1′-biphenyl]-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.596 g, 0.120 mmol) in DMF (15 mL) was added PBr.sub.3 (0.22 mL, 2.40 mmol). The reaction mixture was stirred at 60° C. for 3 h under nitrogen. After that time the reaction was cooled to rt, concentrated under reduced pressure, diluted with saturated NaHCO.sub.3 solution (30 mL) and the precipitated solids were collected by filtration, washed with water and dried, then washed with methanol and dried under vacuum to give 2-(6-(2-bromoethoxy)-4′-(methylsulfonyl)-[1,1′-biphenyl]-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.657 g, 98%) as a yellow-green solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.10 (br s, 1H), 8.22-8.27 (m, 2H), 7.96-8.05 (m, 4H), 7.32 (d, J=9.38 Hz, 1H), 6.73 (d, J=2.34 Hz, 1H), 6.50 (d, J=2.34 Hz, 1H), 4.46-4.53 (m, 2H), 3.87 (s, 3H), 3.79-3.85 (m, 5H), 3.27 (s, 3H); ESI MS m/z 559 and 561 [M+H].sup.+.

(371) To a suspension of 2-(6-(2-bromoethoxy)-4′-(methylsulfonyl)-[1,1′-biphenyl]-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.280 g, 0.50 mmol) in DMSO (2 mL) was added isopropyl amine (2 mL) in a sealed glass tube. The reaction mixture was stirred at 60° C. for 3 h. After that time the reaction was cooled to rt, concentrated under reduced pressure, diluted with water (50 mL) and the precipitated solids were collected by filtration, washed with water, then diethyl ether and dried under vacuum. The product was purified by prep. HPLC (aqueous 0.2% formic acid/acetonitrile) to give 2-(6-(2-(isopropylamino)ethoxy)-4′-(methylsulfonyl)-[1,1′-biphenyl]-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.100 g, 37%) as a white solid. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.53 (br s, 1H), 8.10-8.19 (m, 2H), 8.05 (d, J=8.60 Hz, 2H), 7.90 (d, J=8.60 Hz, 2H), 7.36 (d, J=8.60 Hz, 1H), 6.81 (d, J=2.34 Hz, 1H), 6.59 (d, J=2.34 Hz, 1H), 4.39 (t, J=4.88 Hz, 2H), 3.93 (s, 6H), 3.35 (t, J=4.88 Hz, 2H), 3.14-3.22 (m, 4H), 1.17 (d, J=6.64 Hz, 6H); ESI MS m/z 538 [M+H].sup.+.

Example 45: 2-(5-(2-(Isopropylamino)ethoxy)-6-(2-methyl-4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one

(372) ##STR00069##

(373) To a solution of 2-(5-(2-hydroxyethoxy)-6-(2-methyl-4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.2 g, 0.39 mmol) in N,N-dimethylformamide (5 mL) was added dropwise PBr.sub.3 (0.21 mL, 0.78 mmol). The resulting mixture was heated at 60° C. for 2 h. After that time the reaction was cooled to rt, diluted with water and 1 M Na.sub.2CO.sub.3 solution added to adjust the pH to 8. The aqueous phase was extracted with dichloromethane and the combined extracts were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 98:2 dichloromethane/methanol to 94:6 dichloromethane/methanol) to give 2-[5-(2-bromo-ethoxy)-6-(4-methanesulfonyl-2-methyl-phenyl)-pyridin-2-yl]-5,7-dimethoxy-3H-quinazolin-4-one (0.14 g, 62%) as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3 δ 8.57 (d, J=8.59 Hz, 1H), 7.85-7.94 (m, 2H), 7.57 (d, J=8.20 Hz, 1H), 7.51 (d, J=8.59 Hz, 1H), 6.85 (d, J=2.34 Hz, 1H), 6.50 (d, J=2.34 Hz, 1H), 4.42 (t, J=5.85 Hz, 2H), 3.98 (s, 3H), 3.97 (s, 3H), 3.56 (t, J=5.85 Hz, 2H), 3.16 (s, 3H), 2.32 (s, 3H).

(374) To a solution of 2-[5-(2-bromo-ethoxy)-6-(4-methanesulfonyl-2-methyl-phenyl)-pyridin-2-yl]-5,7-dimethoxy-3H-quinazolin-4-one (0.14 g, 0.24 mmol) in DMSO (4 mL) was added isopropylamine (0.42 mL, 4.87 mmol). The reaction was heated at 50° C. in a sealed tube for 18 h. After that time the reaction was cooled to rt, concentrated under reduced pressure. The residue was dissolved in dichloromethane and the organic phase was washed with water. The aqueous layer was further extracted with dichloromethane and the combined extracts were dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The product was purified by trituration with diethyl ether to give 2-(5-(2-(isopropylamino)ethoxy)-6-(2-methyl-4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.102 g, 76%) as a tan solid: mp 202-203° C.; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.55 (d, J=8.60 Hz, 1H), 7.91-7.94 (m, 1H), 7.86-7.91 (m, 1H), 7.47-7.58 (m, 2H), 6.83 (d, J=2.34 Hz, 1H), 6.48 (d, J=2.34 Hz, 1H), 4.19-4.26 (m, 2H), 3.98 (s, 3H), 3.95 (s, 3H), 3.15 (s, 3H), 2.91-2.97 (m, 2H), 2.70-2.79 (m, 1H), 2.28 (s, 3H), 1.00 (d, J=6.25 Hz, 6H); ESI MS m/z 553 [M+H].sup.+.

Example 46: 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)-2-(trifluoromethyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one

(375) ##STR00070##

(376) A solution of {6-bromo-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-pyridin-2-yl}-methanol (0.49 g, 1.35 mmol), 4-(methylsulfonyl)-2-(trifluoromethyl)phenylboronic acid (0.40 g, 1.49 mmol) and 2.0 M Na.sub.2CO.sub.3 solution (0.57 g, 2.70 mL, 5.40 mmol) in toluene (4 mL) and EtOH (2 mL) was purged with nitrogen for 15 min. Pd(PPh.sub.3).sub.2Cl.sub.2 (0.047 g, 0.067 mmol) was then added and the reaction was heated at 100° C. for 20 h. After that time the reaction was cooled to rt, diluted with brine and extracted with ethyl acetate. The combined organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, dichloromethane to 98:2 dichloromethane/methanol) to give [5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-6-(4-methanesulfonyl-2-trifluoromethyl-phenyl)-pyridin-2-yl]-methanol (0.413 g, 60%) as a yellow oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.46 (d, J=1.95 Hz, 1H), 8.27 (dd, J=8.21, 1.95 Hz, 1H), 7.80 (d, J=8.21 Hz, 1H), 7.50-7.54 (m, 1H), 7.42-7.46 (m, 1H), 4.85 (d, J=5.47 Hz, 2H), 4.12-4.18 (m, 3H), 3.92 (t, J=4.88 Hz, 2H), 3.24 (s, 3H), 0.91 (m, 9H), 0.02 (m, 6H); .sup.19F NMR (376 MHz, CDCl.sub.3) δ −59.51.

(377) To a solution of [5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-6-(4-methanesulfonyl-2-trifluoromethyl-phenyl)-pyridin-2-yl]-methanol (0.71 g, 1.40 mmol) in DMSO (2 mL) was added 2-iodoxybenzoic acid (0.41 g, 1.47 mmol). The reaction was stirred at rt for 2 h. After that time the reaction was diluted with water and the precipitated solids were removed by filtration. The precipitate was washed with ethyl acetate and the filtrate was dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 60:40 ethyl acetate/hexanes) to give 5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-6-(4-methanesulfonyl-2-trifluoromethyl-phenyl)-pyridine-2-carbaldehyde (0.50 g, 71%) as a colorless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.98 (s, 1H), 8.37 (s, 1H), 8.22 (d, J=8.59 Hz, 1H), 8.09 (d, J=8.59 Hz, 1H), 7.70 (d, J=8.20 Hz, 1H), 7.52 (d, J=8.59 Hz, 1H), 4.00-4.24 (m, 2H), 3.84 (t, J=4.29 Hz, 2H), 3.14 (s, 3H), 0.79 (s, 9H), −0.11 (s, 6H); .sup.19F NMR (376 MHz, CDCl.sub.3) δ −59.73.

(378) To a solution of 2-amino-4,6-dimethoxy-benzamide (0.195 g, 0.99 mmol) in N,N-dimethylacetamide (7 mL) was added 5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-6-(4-methanesulfonyl-2-trifluoromethyl-phenyl)-pyridine-2-carbaldehyde (0.50 g 0.99 mmol) followed by NaHSO.sub.3 (0.15 g, 1.48 mmol) and p-toluenesulfonic acid monohydrate (0.094 g, 0.49 mmol). The reaction was heated at 120° C. for 22 h. After that time the reaction was concentrated under reduced pressure, diluted with water and the pH adjusted to 8 with 1 M Na.sub.2CO.sub.3. The precipitated solids were collected by filtration, washed with water and triturated in diethyl ether. The product was purified by flash column chromatography (silica gel, 98:2 dichloromethane/methanol to 95:25 dichloromethane/methanol) to give 2-[5-(2-hydroxy-ethoxy)-6-(4-methanesulfonyl-2-trifluoromethyl-phenyl)-pyridin-2-yl]-5,7-dimethoxy-3H-quinazolin-4-one (0.15 g, 27%) as a white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.68 (s, 1H), 8.44 (d, J=8.99 Hz, 1H), 8.35 (s, 1H), 8.32 (d, J=8.21 Hz, 1H), 7.99 (d, J=7.82 Hz, 1H), 7.92 (d, J=8.99 Hz, 1H), 6.80 (d, J=1.95 Hz, 1H), 6.56 (d, J=1.95 Hz, 1H), 4.85 (t, J=5.28 Hz, 1H), 4.18 (t, J=4.88 Hz, 2H), 3.90 (s, 3H), 3.82 (s, 3H), 3.61 (q, J=4.69 Hz, 2H), 3.42 (s, 4H); .sup.19F NMR (376 MHz, DMSO-d.sub.6) δ ppm −57.81; ESI MS m/z 566 [M+1].sup.+.

(379) To a solution of 2-[5-(2-hydroxy-ethoxy)-6-(4-methanesulfonyl-2-trifluoromethyl-phenyl)-pyridin-2-yl]-5,7-dimethoxy-3H-quinazolin-4-one (0.15 g, 0.26 mmol) in N,N-dimethylformamide (3 mL) was added dropwise PBr.sub.3 (37.4 μL, 0.397 mmol). The resulting mixture was heated at 60° C. for 3 h. After that time the reaction was cooled to rt and the pH was adjusted to 8 with 1M Na.sub.2CO.sub.3 solution. The reaction mixture was extracted with methylene chloride (3×25 mL) and the combined organic phase was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol) to give 2-[5-(2-bromo-ethoxy)-6-(4-methanesulfonyl-2-trifluoromethyl-phenyl)-pyridin-2-yl]-5,7-dimethoxy-3H-quinazolin-4-one (0.107 g, 64%) as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.34 (s, 1H), 8.59 (d, J=8.99 Hz, 1H), 8.41 (s, 1H), 8.26 (dd, J=8.01, 1.76 Hz, 1H), 7.74 (d, J=7.82 Hz, 1H), 7.49 (d, J=8.99 Hz, 1H), 6.84 (d, J=2.34 Hz, 1H), 6.49 (d, J=2.34 Hz, 1H), 4.40 (t, J=6.06 Hz, 1H), 3.98 (s, 3H), 3.96 (s, 3H), 3.52 (t, J=6.06 Hz, 2H), 3.21 (s, 3H); .sup.19F NMR (376 MHz, CDCl.sub.3) δ −59.34.

(380) To a solution of 2-[5-(2-bromo-ethoxy)-6-(4-methanesulfonyl-2-trifluoromethyl-phenyl)-pyridin-2-yl]-5,7-dimethoxy-3H-quinazolin-4-one (0.107 g, 0.17 mmol) in chloroform (3 mL) and DMSO (1 mL) was added isopropylamine (0.29 mL, 3.40 mmol). The reaction was heated at 50° C. in a sealed tube for 24 h. After that time the reaction was cooled to rt, concentrated under reduced pressure, diluted with water and the precipitated solids collected by filtration, washed with water and dried under vacuum to give 2-(5-(2-(isopropylamino)ethoxy)-6-(4-(methylsulfonyl)-2-(trifluoromethyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.085 g, 82%) as a white solid: mp 199-201° C.; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.56 (d, J=8.99 Hz, 1H), 8.41 (d, J=1.56 Hz, 1H), 8.22-8.31 (m, 1H), 7.71 (d, J=8.21 Hz, 1H), 7.51 (d, J=8.99 Hz, 1H), 6.83 (d, J=2.34 Hz, 1H), 6.48 (d, J=2.34 Hz, 1H), 4.20-4.27 (m, 2H), 3.97 (s, 3H), 3.95 (s, 3H), 3.21 (s, 3H), 2.93-2.98 (m, 2H), 2.71-2.82 (m, 1H), 1.00 (d, J=6.25 Hz, 6H); .sup.19F NMR (376 MHz, CDCl.sub.3) δ −59.51; ESI MS m/z 607 [M+1].sup.+.

Example 47: 5,7-Dimethoxy-2-(4′-(methylsulfinyl)-[1,1′-biphenyl]-3-yl)quinazolin-4(3H)-one

(381) ##STR00071##

(382) To a solution of 3-bromobenzaldehyde (0.790 g, 4.27 mmol) and (4-(methylsulfinyl)phenyl)boronic acid (0.940 g, 5.12 mmol) in toluene (20 mL), EtOH (20 mL) and water (5 mL), was added Na.sub.2CO.sub.3 (1.36 g, 12.8 mmol). The resulting mixture was purged with nitrogen for 15 min and then Pd(PPh.sub.3).sub.4 was added in one portion. The reaction was heated at 90° C. for 17 h. After that time the reaction was cooled to rt, concentrated under reduced pressure, diluted with ethyl acetate (25 mL) and washed with water and brine. The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 95:5 hexanes/ethyl acetate to 75:25 hexanes/ethyl acetate) to give 4′-(methylsulfinyl)-[1,1′-biphenyl]-3-carbaldehyde (0.690 g, 66%) as a yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.12 (s, 1H), 8.11-8.16 (m, 1H), 7.87-7.96 (m, 2H), 7.75-7.83 (m, 4H), 7.63-7.70 (m, 1H), 2.80 (s, 3H).

(383) To a solution of 2-amino-4,6-dimethoxybenzamide (0.329 g, 1.68 mmol) and 4′-(methylsulfinyl)-[1,1′-biphenyl]-3-carbaldehyde (0.410 g, 1.68 mmol) in N,N-dimethylacetamide (15 mL) was added NaHSO.sub.3 (58.5% SO.sub.2 content, 0.447 g, 2.52 mmol) and p-toluenesulfonic acid monohydrate (0.638 g, 0.34 mmol). The reaction was heated at 120° C. for 17 h. After that time the reaction was cooled to rt, concentrated under reduced pressure, diluted with water (50 mL) and the resulting suspension was stirred vigorously for 30 min. The precipitated solids were collected by filtration, washed with water and air-dried. The product was purified by trituration (50:50 methanol/ethyl acetate, 20 mL) to afford 5,7-dimethoxy-2-(4′-(methylsulfinyl)-[1,1′-biphenyl]-3-yl)quinazolin-4(3H)-one (0.250 g, 35%) as an off-white solid: mp>300° C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.24 (br s, 1H), 8.48 (s, 1H), 8.21 (d, J=7.42 Hz, 1H), 8.04 (d, J=8.21 Hz, 2H), 7.93 (d, J=7.82 Hz, 1H), 7.81 (d, J=8.21 Hz, 2H), 7.64 (dd, J=7.42, 7.82 Hz, 1H), 6.78 (d, J=1.95 Hz, 1H), 6.54 (d, J=1.95 Hz, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 2.79 (s, 3H); ESI MS m/z 421 [M+H].sup.+.

Example 48: 5,7-Dimethoxy-2-(4-(4-(methylsulfinyl)phenyl)thiophen-2-yl)quinazolin-4(3H)-one

(384) ##STR00072##

(385) To a solution of 4-bromothiophene-2-carbaldehyde (0.60 g, 3.14 mmol) and (4-(methylsulfinyl)phenyl)boronic acid (0.69 g, 3.77 mmol) in DME (5.5 mL) was added Na.sub.2CO.sub.3 (0.87 g, 8.16 mmol) in water (4.1 mL) and Pd(Ph.sub.3P).sub.4 (0.18 g, 0.157 mmol) at rt under N.sub.2. The reaction mixture was heated at 80° C. for 7 h. After that time the reaction was concentrated under reduced pressure and diluted with ethyl acetate (100 mL). The mixture was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. The product was purified by flash column chromatography (silica gel, 95:5 dichloromethane/methanol) to give 4-(4-(methylsulfinyl)phenyl)thiophene-2-carbaldehyde (0.60 g, 77%) as a light yellow solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.97 (s, 1H), 8.56 (d, J=13.27 Hz, 2H), 7.96 (d, J=8.20 Hz, 2H), 7.74 (d, J=8.20 Hz, 2H), 2.76 (s, 3H). ESI MS m/z 251 [M+H].sup.+.

(386) To a solution of 2-amino-4,6-dimethoxybenzamide (0.46 g, 2.32 mmol) and 4-(4-(methylsulfinyl)phenyl)thiophene-2-carbaldehyde (0.58 g, 2.32 mmol) in N,N-dimethylacetamide (28 mL) was added NaHSO.sub.3 (0.62 g, 3.48 mmol) and p-toluenesulfonic acid monohydrate (0.088 g, 0.463 mmol) at rt. The reaction mixture was heated at 120° C. for 15.5 h. After that time the reaction was cooled to rt and concentrated under reduced pressure. The residue was diluted with water (5 mL) and the resulting precipitate collected by filtration, washed with water and dried. The product was purified by flash column chromatography (silica gel, 90:10 dichloromethane/methanol) to give 5,7-dimethoxy-2-(4-(4-(methylsulfinyl)phenyl)thiophen-2-yl)quinazolin-4(3H)-one (0.053 g, 5%) as a light yellow solid: mp>300° C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.16 (s, 1H), 8.80 (s, 1H), 8.33 (s, 1H), 7.93 (d, J=8.59 Hz, 2H), 7.79 (d, J=8.59 Hz, 2H), 6.68 (d, J=2.34 Hz, 1H), 6.54 (d, J=2.34 Hz, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 2.80 (s, 3H). ESI MS m/z: 427 [M+H].sup.+.

Example 49: 5,7-Dimethoxy-2-(6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one

(387) ##STR00073##

(388) A mixture of 6-bromopicolinaldehyde (0.60 g, 3.22 mmol), (4-(methylsulfinyl)phenyl)boronic acid (0.712 g, 3.87 mmol), and Na.sub.2CO.sub.3 (1.36 g, 12.88 mmol) in toluene (10 mL), ethanol (5 mL) and water (6 mL) was degassed. Pd(PPh.sub.3).sub.4 (0.37 g, 0.32 mmol) was added and the resulting mixture was heated at 100° C. for 18 h. After that time the reaction was cooled to rt, diluted with brine and extracted with ethyl acetate. The organic phase was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 67:33 dichloromethane/ethyl acetate) to give 6-(4-(methylsulfinyl)phenyl)picolinaldehyde (0.53 g, 67%) as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 10.18 (s, 1H), 8.27 (d, J=8.8 Hz, 2H), 8.03-7.96 (m, 3H), 7.80 (d, J=8.4 Hz, 2H), 2.79 (s, 3H); ESI MS m/z 246 [M+H].sup.+.

(389) To a solution of 2-amino-4,6-dimethoxy-benzamide (0.392 g, 2.0 mmol) in N,N-dimethylacetamide (20 mL) was added 6-(4-(methylsulfinyl)phenyl)picolinaldehyde (0.490 g, 2.0 mmol) followed by NaHSO.sub.3 (0.312 g, 3.0 mmol) and p-toluenesulfonic acid monohydrate (0.380 g, 2.0 mmol). The reaction was heated at 120° C. for 18 h. After that time the reaction was cooled to rt, concentrated under reduced pressure and diluted with water. The pH was adjusted to 8 with 1.0 M Na.sub.2CO.sub.3 and the precipitated solids were collected by filtration, washed with water and dried under vacuum. The product was purified by flash column chromatography (silica gel, 98:2 dichloromethane/methanol) to give 5,7-dimethoxy-2-(6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one (0.20 g, 24%) as a white solid: mp 281-282° C.; .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 10.58 (br s, 1H), 8.55 (d, J=8.0 Hz, 1H), 8.24 (d, J=8.0 Hz, 2H), 8.01 (m, 2H), 7.83 (d, J=8.0 Hz, 2H), 6.87 (d, J=2.4 Hz, 1H), 6.52 (d, J=2.4 Hz, 1H), 4.01 (s, 3H), 3.96 (s, 3H), 2.82 (s, 3H); ESI MS m/z 422 [M+H].sup.+.

Example 50: 5,7-Dimethoxy-2-(5-methoxy-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one

(390) ##STR00074##

(391) To a solution of 2-bromo-6-(hydroxymethyl)pyridin-3-ol (9.0 g, 44.1 mmol) in acetone (200 mL) was added solid K.sub.2CO.sub.3 (9.14 g, 66.2 mmol) and iodomethane (8.14 g, 57.3 mmol) at rt. The reaction mixture was stirred at reflux for 4.5 h. After this time the reaction was cooled to rt, concentrated under reduce pressure and diluted with dichloromethane (200 mL). The mixture was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to give (6-bromo-5-methoxypyridin-2-yl)methanol (9.28 g, 96.5%) as a solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.49-7.57 (m, 1H), 7.39-7.46 (m, 1H), 5.45 (t, J=5.86 Hz, 1H), 4.46 (d, J=5.86 Hz, 2H), 3.87 (s, 3H).

(392) To a solution of (6-bromo-5-methoxypyridin-2-yl)methanol (9.28 g, 42.6 mmol) in dichloromethane (200 mL) was added MnO.sub.2 (18.5 g, 213 mmol) at rt. The reaction mixture was stirred 7 h. After that time the reaction mixture was filtered and concentrated under reduced pressure. The product was purified by recrystallization to give 6-bromo-5-methoxypicolinaldehyde (4.03 g, 44%) as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3): δ 9.95 (s, 1H), 7.97 (d, J=8.2 Hz, 1H), 7.22-7.30 (m, 1H), 4.03 (s, 3H).

(393) To a solution of 6-bromo-5-methoxypicolinaldehyde (4.03 g, 18.65 mmol) and (4-(methylsulfinyl)phenyl)boronic acid (4.12 g, 22.28 mmol) in toluene (72 mL) and ethanol (36 mL) was added a solution of Na.sub.2CO.sub.3 (7.91 g, 74.62 mmol) in water (36 mL) and Pd(PPh.sub.3).sub.4 (2.156 g, 1.86 mmol) at rt under nitrogen. The reaction mixture was stirred at 90° C. for 18 h. After that time the reaction was cooled to rt and extracted with ethyl acetate (100 mL). The organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 95:5 dichloromethane/methanol) to give 5-methoxy-6-(4-(methylsulfinyl)phenyl)picolinaldehyde (4.55 g, 89%) as a solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.96 (s, 1H), 8.11 (d, J=8.59 Hz, 2H), 8.02 (d, J=8.59 Hz, 1H), 7.76-7.84 (m, 3H), 3.99 (s, 3H), 2.81 (s, 3H).

(394) To a solution of 2-amino-4,6-dimethoxybenzamide (3.24 g, 16.5 mmol) and 5-methoxy-6-(4-(methylsulfinyl)phenyl)picolinaldehyde (4.55 g, 16.5 mmol) in N,N-dimethylacetamide (200 mL) was added NaHSO.sub.3 (4.41 g, 24.8 mmol) and p-toluenesulfonic acid monohydrate (0.63 g, 3.31 mmol) at rt. The reaction mixture was heated at 120° C. for 19 h. After that time the reaction was cooled to rt, concentrated under reduced pressure and diluted with water (100 mL). The precipitated solids were washed with water and dried. The product was purified by flash column chromatography (silica gel, 93:7 chloroform/methanol) to give 5,7-dimethoxy-2-(5-methoxy-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one (2.425 g, 32.6%) as a solid: mp 266-267° C.; .sup.1H NMR (400 MHz, CDCl.sub.3-d) δ 10.47 (s, 1H), 8.53 (d, J=8.99 Hz, 1H), 8.13 (d, J=8.60 Hz, 2H), 7.79 (d, J=8.60 Hz, 2H), 7.50 (d, J=8.99 Hz, 1H), 6.83 (d, J=2.34 Hz, 1H), 6.49 (d, J=1.95 Hz, 1H), 4.00 (s, 3H), 3.99 (s, 3H), 3.95 (s, 3H), 2.82 (s, 3H); ESI MS m/z 452 [M+H].sup.+.

Example 51: 5,7-Dimethoxy-2-(3-(5-(methylsulfinyl)thiophen-2-yl)phenyl)quinazolin-4(3H)-one

(395) ##STR00075##

(396) To a solution of 2-(methylthio)thiophene (2.50 g, 19.20 mmol) in DMF (15 mL) was added solid NBS (3.62 g, 20.5 mmol) at 0° C. The reaction mixture was stirred at rt for 1.5 h. After that time the reaction was concentrated under reduced pressure and diluted with ethyl acetate (100 mL). The organic phase was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to give 2-bromo-5-(methylthio)thiophene (3.22 g, 80%) as an oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.12 (d, J=3.9 Hz, 1H), 6.99 (d, J=3.9 Hz, 1H), 2.46 (s, 3H).

(397) To a solution of 2-bromo-5-(methylthio)thiophene (3.1 g, 14.8 mmol) in dichloromethane (100 mL), was added m-CPBA (3.65 g, 16.3 mmol) at −5° C. The reaction mixture was stirred at −5° C. for 0.5 h. After that time the reaction was filtered. The filtrate was washed with saturated NaHCO.sub.3, brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The product was purified by recrystallization (hexanes/ethyl acetate) to give 2-bromo-5-(methylsulfinyl)thiophene (2.65 g, 79.8%) as a white solid: .sup.1H NMR (400 MHz, DMSO-d) δ 7.44 (d, J=3.97 Hz, 1H), 7.35 (d, J=3.9 Hz, 1H), 2.93 (s, 3H).ESI MS m/z 226 [M+H].sup.+.

(398) To a solution of 2-bromo-5-(methylsulfinyl)thiophene (1.3 g, 5.77 mmol) and bis(pinacolato)diboron (1.61 g, 6.35 mmol) in DMF (20 mL) was added potassium acetate (1.7 g, 17.32 mmol) and PdCl.sub.2(dppf) (0.21 g, 0.298 mmol) at rt under nitrogen. The reaction mixture was stirred at 80° C. for 6 h. After that time the reaction mixture was cooled to 0° C. and THF (5.4 mL), water (5.4 mL), 3-bromobenzaldehyde (0.28 g, 6.93 mmol), cesium carbonate (4.7 g, 14.4 mmol) and PdCl.sub.2(dppf) (0.21 g, 0.298 mmol) were added. The reaction mixture was then stirred at 50° C. for 2 h. After that time the reaction mixture was cooled to rt and diluted with ethyl acetate (150 mL), washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, ethyl acetate) to give 3-(5-(methylsulfinyl)thiophen-2-yl)benzaldehyde (0.34 g, 24%) as an oil: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.06 (s, 1H), 8.22 (s, 1H), 8.06 (d, J=7.82 Hz, 1H), 7.90 (d, J=7.82 Hz, 1H), 7.65-7.77 (m, 2H), 7.63 (d, J=3.91 Hz, 1H), 2.96 (s, 3H); ESI MS m/z 251 [M+H].sup.+.

(399) To a solution of 2-amino-4,6-dimethoxybenzamide (0.266 g, 1.36 mmol) and 3-(5-(methylsulfinyl)thiophen-2-yl)benzaldehyde (0.34 g, 1.36 mmol) in N,N-dimethylacetamide (17 mL) was added NaHSO.sub.3 (0.36 g, 2.03 mmol) and p-toluenesulfonic acid monohydrate (0.052 g, 0.271 mmol) at rt. The reaction mixture was heated at 120° C. for 12.5 h. After that time the reaction was cooled to rt, concentrated under reduced pressure and diluted with water (20 mL). The precipitated solids were collected by filtration, washed with water and dried. The product was purified by flash column chromatography (silica gel, 95:5 chloroform/methanol) to give 5,7-dimethoxy-2-(3-(5-(methylsulfinyl)thiophen-2-yl)phenyl)quinazolin-4(3H)-one (0.060 g, 10%) as a light yellow solid: mp 289-290° C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.19 (br s, 1H), 8.48 (s, 1H), 8.18 (d, J=7.81 Hz, 1H), 7.90 (d, J=8.20 Hz, 1H), 7.72 (d, J=3.90 Hz, 1H), 7.55-7.64 (m, 2H), 6.77 (d, J=2.34 Hz, 1H), 6.54 (d, J=1.95 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 2.96 (s, 3H); ESI MS m/z 427 [M+H].sup.+.

Example 52: 5,7-Dimethoxy-2-(7-(4-(methylsulfinyl)phenyl)-1H-indol-5-yl)quinazolin-4(3H)-one

(400) ##STR00076##

(401) To a solution of methyl 7-bromo-1H-indole-5-carboxylate (0.70 g, 2.76 mmol) in toluene (25 mL) was added DIBAL-H (1M in toluene, 11.0 mL, 11.0 mmol) dropwise at −78° C. After stirring at the same temperature for 1 h, the reaction mixture was allowed to warm to rt and stir an additional 2 h. After that time 1N HCl (15 mL) was slowly added. The reaction was extracted with ethyl acetate (2×100 mL) and the combined organic phase was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to give (7-bromo-1H-indol-5-yl)methanol (0.66 g, 52%) as a sticky colorless solid: .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 8.35 (br s, 1H), 7.57 (s, 1H), 7.41 (s, 1H), 7.30-7.27 (m, 1H), 6.63-6.61 (m, 1H), 4.75 (s, 2H).

(402) To a solution of (7-bromo-1H-indol-5-yl)methanol (0.66 g, 2.76 mmol) in 1,2-dichloroethane (50 mL) under nitrogen was added 2-iodoxybenzoic acid (1.16 g, 4.14 mmol) at rt. The reaction mixture was stirred at 60° C. for 4 h. After that time the reaction was cooled to rt and filtered. The solids were washed with dichloromethane and the combined filtrate was concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, dichloromethane) to give 7-bromo-1H-indole-5-carbaldehyde (0.47 g, 76% over two steps) as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3): δ 9.98 (s, 1H), 8.63 (br s, 1H), 8.12 (s, 1H), 7.95 (d, J=1.2 Hz, 1H), 7.38 (t, J=2.8 Hz, 1H), 6.81 (dd, J=2.8, 2.2 Hz, 1H).

(403) A mixture of 7-bromo-1H-indole-5-carbaldehyde (0.45 g, 2.0 mmol), (4-(methylsulfinyl)phenyl)boronic acid (0.44 g, 2.4 mmol), and Na.sub.2CO.sub.3 (0.85 g, 8.0 mmol) in toluene (8 mL), ethanol (4 mL) and water (4 mL) was degassed. Pd(PPh.sub.3).sub.4 (0.23 g, 0.2 mmol) was added and the resulting mixture was heated at 90° C. for 18 h. After that time the reaction was cooled to rt, concentrated under reduced pressure and diluted with ethanol (50 mL). The reaction was filtered and the solids washed with ethanol (20 mL). The combined filtrate was concentrated under reduced pressure and the product purified by flash column chromatography (silica gel, 97:3 dichloromethane/methanol) to give 7-(4-(methylsulfinyl)phenyl)-1H-indole-5-carbaldehyde (0.36 g, 64%) as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3): δ 10.09 (s, 1H), 9.12 (br s, 1H), 8.22 (s, 1H), 7.84-7.76 (m, 5H), 7.38 (dd, J=3.2, 2.4 Hz, 1H), 6.82 (dd, J=3.2, 3.2 Hz, 1H), 2.79 (s, 3H).

(404) To a solution of 2-amino-4,6-dimethoxy-benzamide (0.235 g, 1.2 mmol) in N,N-dimethylacetamide (20 mL) was added 7-(4-(methylsulfinyl)phenyl)-1H-indole-5-carbaldehyde (0.340 g, 1.2 mmol) followed by NaHSO.sub.3 (0.187 g, 1.8 mmol) and p-toluenesulfonic acid monohydrate (0.228 g, 1.2 mmol). The resulting mixture was heated at 120° C. for 20 h. After that time the reaction was cooled to rt, concentrated under reduced pressure and diluted with water and saturated Na.sub.2CO.sub.3. The precipitated solids were collected by filtration, washed with water and dried under vacuum. The product was purified by flash column chromatography (silica gel, 95:5 dichloromethane/methanol) followed by trituration with ethyl acetate and methanol to give 5,7-dimethoxy-2-(7-(4-(methylsulfinyl)phenyl)-1H-indol-5-yl)quinazolin-4(3H)-one (0.231 g, 42%) as a white solid: mp 316° C. (dec.); .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.10 (br s, 1H), 11.47 (br s, 1H), 8.54 (s, 1H), 8.06 (s, 1H), 7.99 (d, J=8.4 Hz, 2H), 7.88 (d, J=8.0 Hz, 2H), 7.47 (dd, J=2.8, 2.4 Hz, 1H), 6.77 (d, J=2.4 Hz, 1H), 6.72-6.69 (m, 1H), 6.51 (d, J=2.0 Hz, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 2.85 (s, 3H); ESI MS m/z 460 [M+H].sup.+.

Example 53: tert-Butyl (2-((6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(4-(methylsulfinyl)phenyl)pyridin-3-yl)oxy)ethyl)(isopropyl)carbamate

(405) ##STR00077##

(406) A mixture of 6-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)picolinaldehyde (14.68 g, 40.74 mmol), (4-(methylthio)phenyl)boronic acid (6.84 g, 40.74 mmol) and Na.sub.2CO.sub.3 (12.95 g, 122.2 mmol) was degassed under nitrogen. Then toluene (300 mL), ethanol (300 mL) and water (60 mL) was added. The reaction mixture was degassed again and Pd(PPh.sub.3).sub.4 (2.35 g, 2.03 mmol) was added and degassed. The reaction mixture was stirred at 90° C. for 16 h under nitrogen. After that time the reaction was cooled to rt, concentrated under reduced pressure, diluted with water (400 mL) and extracted with ethyl acetate (2×300 mL). The organic phase was washed with water, brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 90:10 hexanes/ethyl acetate) to give 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(4-(methylthio)phenyl)-picolinaldehyde (13.18 g, 80%) as light yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3): δ 10.00 (s, 1H), 7.92-7.99 (m, 2H), 7.87 (d, J=8.59 Hz, 1H), 7.35 (d, J=8.59 Hz, 1H), 7.24-7.30 (m, 2H), 4.12-4.18 (m, 2H), 3.94 (t, J=4.88 Hz, 2H), 2.48 (s, 3H), 0.83 (s, 9H), 0.00 (s, 6H).

(407) To a solution of 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(4-(methylthio)phenyl)-picolinaldehyde (13.10 g, 32.46 mmol) and 2-amino-4,6-dimethoxybenzamide (6.68 g, 34.08 mmol) in N,N-dimethylacetamide (150 ml) was added NaHSO.sub.3 (8.90 g, 48.69 mmol) and p-toluenesulfonic acid monohydrate (6.17 g, 32.46 mmol). The reaction mixture was stirred at 120° C. for 14 h. After that time the reaction was cooled to rt, concentrated under reduced pressure, diluted with saturated Na.sub.2CO.sub.3 (150 mL) and the precipitated solids were collected by filtration, washed with water and dried under vacuum. The product was washed with diethyl ether and dried to give 2-(5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(4-(methylthio)phenyl)-pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (17.38 g, 92%) as light yellow solid: ESI MS m/z 580 [M+H].sup.+.

(408) To a solution of 2-(5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(4-(methylthio)phenyl)-pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (17.37 g, 29.96 mmol) in THF (250 mL) was added a solution of tetrabutylammoniumfluoride in THF (1M solution, 36.0 mL, 36.0 mmol). The reaction mixture was stirred at rt for 30 min. After that time the reaction was concentrated under reduced pressure, diluted with water (300 mL) and the precipitated solids were collected by filtration, washed with water and dried. The product was purified by flash column chromatography (silica gel, 97:3 dichloromethane/methanol) to give 2-(5-(2-hydroxyethoxy)-6-(4-(methylthio)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (7.96 g, 57% over two steps) as white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.08 (br s, 1H), 8.31 (d, J=8.99 Hz, 1H), 8.22 (d, J=8.60 Hz, 2H), 7.78 (d, J=8.60 Hz, 1H), 7.36 (d, J=8.21 Hz, 2H), 6.79 (s, 1H), 6.56 (s, 1H), 4.99 (t, J=5.08 Hz, 1H), 4.23 (t, J=4.30 Hz, 2H), 3.91 (s, 3H), 3.86 (s, 3H), 3.80-3.78 (m, 2H), 2.55 (s, 3H).

(409) To a suspension of 2-(5-(2-hydroxyethoxy)-6-(4-(methylthio)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (4.00 g, 8.60 mmol) in DMF (100 mL) was added PBr.sub.3 (4.65 g, 17.20 mmol). The reaction was stirred at 60° C. for 1 h under nitrogen. After that time the reaction was cooled to rt, concentrated under reduced pressure, diluted with saturated Na.sub.2CO.sub.3 solution (100 mL) and stirred for 1 h. The precipitated solids were collected by filtration, washed with water and dried under vacuum to give 2-(5-(2-bromoethoxy)-6-(4-(methylthio)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (5.10 g) as a yellow solid.

(410) To a suspension of 2-(5-(2-bromoethoxy)-6-(4-(methylthio)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (5.10 g, 9.65 mmol) in DMSO (30 mL) was added isopropyl amine (15 mL) in a sealed glass tube. The reaction was stirred at 60° C. for 4 h. After that time the reaction was cooled to rt, concentrated under reduced pressure and diluted with saturated Na.sub.2CO.sub.3 solution (200 mL). The precipitated solids were collected by filtration, washed with water, then diethyl ether and dried under vacuum. The product was purified by flash column chromatography (silica gel, 96:4 dichloromethane/methanol followed by 96:4 dichloromethane/7N NH.sub.3 in methanol) to give 2-(5-(2-(isopropylamino)ethoxy)-6-(4-(methylthio)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (4.25 g, 87%) as a light yellow solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.31 (d, J=8.60 Hz, 1H), 8.18 (d, J=8.21 Hz, 2H), 7.76 (d, J=8.99 Hz, 1H), 7.36 (d, J=8.60 Hz, 2H), 6.79 (d, J=2.34 Hz, 1H), 6.56 (d, J=2.34 Hz, 1H), 4.20 (t, J=5.67 Hz, 2H), 3.91 (s, 3H), 3.86 (s, 3H), 2.92 (t, J=5.47 Hz, 2H), 2.75 (quin, J=6.15 Hz, 1H), 2.55 (s, 3H), 0.98 (d, J=6.25 Hz, 6H); ESI MS m/z 507 [M+H].sup.+.

(411) To a solution of 2-(5-(2-(isopropylamino)ethoxy)-6-(4-(methylthio)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (3.63 g, 7.16 mmol) in anhydrous dichloromethane (200 mL) was added di-tert-butyl dicarbonate (2.34 g, 10.74 mmol) and triethylamine (2.0 mL, 14.32 mmol). The reaction mixture was stirred at rt for 16 h. After that time the reaction was diluted with water (150 mL) and the organic phase separated. The organics were washed with brine, dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 98:2 dichloromethane/methanol) to give tert-butyl(2-((6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(4-(methylthio)phenyl)pyridin-3-yl)oxy)ethyl)(isopropyl)carba mate (3.50 g, 80%) as an off-white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.50 (s, 1H), 8.45 (d, J=8.60 Hz, 1H), 7.90 (d, J=8.60 Hz, 2H), 7.52 (br s, 1H), 7.37 (d, J=8.60 Hz, 2H), 6.83 (d, J=2.34 Hz, 1H), 6.48 (d, J=1.95 Hz, 1H), 4.22 (br s, 2H), 3.99 (s, 3H), 3.95 (s, 3H), 3.53 (br s, 2H), 2.57 (s, 3H), 1.48 (s, 9H), 1.01-1.15 (m, 6H); ESI MS m/z 607 [M+H].sup.+.

(412) A solution of tert-butyl(2-((6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(4-(methylthio)phenyl)pyridin-3-yl)oxy)ethyl)(isopropyl)carbamate (3.40 g, 5.60 mmol) in anhydrous dichloromethane (200 mL) was cooled to −10° C. m-Chloroperbenzoic acid (1.16 g, 6.74 mmol) was added as a solid in small portions over a period of 15 minutes. After the addition was complete, the reaction was stirred at −5° C. for 1 h. After that time the reaction was warmed to rt and quenched with aq. Saturated NaHCO.sub.3 solution (100 mL). The organic phase was separated, washed with water, dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 98:2 dichloromethane/methanol) to give tert-butyl(2-((6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(4-(methylsulfinyl)phenyl)pyridin-3-yl)oxy)ethyl)(isopropyl)carbamate (2.50 g, 72%) as a white solid: mp 114-116° C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.28 (s, 1H), 8.37 (d, J=8.60 Hz, 1H), 8.34 (d, J=8.21 Hz, 2H), 7.88 (d, J=8.99 Hz, 1H), 7.79 (d, J=8.21 Hz, 2H), 6.80 (d, J=2.34 Hz, 1H), 6.57 (d, J=1.95 Hz, 1H), 4.26 (br s, 2H), 3.91 (s, 3H), 3.86 (s, 3H), 3.52 (br s, 2H), 2.82 (s, 3H), 1.37 (br s, 9H), 1.03 (d, J=6.64 Hz, 6H); ESI MS m/z 623 [M+H].sup.+.

Example 54: 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-methoxypyridin-2-yl)-N,N,3-trimethylbenzamide

(413) ##STR00078##

(414) A mixture of 4-bromo-N,N,3-trimethylbenzamide (0.529 g, 2.18 mmol), bis(pinacolato)diboron (0.610 g, 2.40 mmol) and potassium acetate (0.643 g, 6.55 mmol) in dry DMSO (10 mL) was purged with nitrogen for 15 min. Pd(dppf)Cl.sub.2 was added and the reaction mixture was heated at 80° C. for 17 h. After that time the reaction mixture was cooled to rt, diluted with ethyl acetate (50 mL) and filtered through a plug of silica gel. The filtrate was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give N,N,3-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.77 (d, J=7.62 Hz, 1H), 7.20 (s, 1H), 7.17 (d, J=7.62 Hz, 1H), 3.10 (s, 3H), 2.94 (s, 3H), 2.54 (s, 3H), 1.36 (s, 12H).

(415) A mixture of N,N,3-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.7 g, 2.18 mmol), 2-(6-bromo-5-methoxypyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.285 g, 0.73 mmol) and sodium carbonate (0.308 g, 2.91 mmol) in toluene (20 mL), EtOH (15 mL) and water (5 mL) was purged with nitrogen for 15 min. Pd(PPh.sub.3).sub.4 (0.042 g, 0.04 mmol) was then added and the reaction mixture was heated at 90° C. for 17 h. After that time the reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was diluted with water (20 mL) and the resulting suspension was stirred for 10 min. The precipitated solids were collected by filtration, air-dried and then purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol to 95:5 dichloromethane/methanol) to give 4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-methoxypyridin-2-yl)-N,N,3-trimethylbenzamide (0.220 g, 64%) as an off-white solid: mp 248-251° C.; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.56 (s, 1H), 8.52 (d, J=8.60 Hz, 1H), 7.44 (d, J=8.60 Hz, 1H), 7.37 (s, 1H), 7.29-7.34 (m, 2H), 6.84 (d, J=2.34 Hz, 1H), 6.48 (d, J=2.34 Hz, 1H), 3.98 (s, 3H), 3.96 (s, 3H), 3.88 (s, 3H), 3.16 (s, 3H), 3.11 (s, 3H), 2.18 (s, 3H); ESI MS m/z 475 [M+H].sup.+.

Example 55: 5,7-Dimethoxy-2-(6-(4-(methylsulfinyl)phenyl)-5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-2-yl)quinazolin-4(3H)-one

(416) ##STR00079##

(417) A suspension of 2-[5-(2-hydroxyethoxy)-6-(4-methanesulfinyl-phenyl)pyridin-2-yl]-5,7-dimethoxy-3H-quinazolin-4-one (9.6 g, 19.9 mmol) and triethyl amine (5.2 g, 51.8 mmol) in dichloromethane (800 mL) was cooled to 5° C. with stirring. Methanesulfonyl chloride (2.7 g, 23.9 mmol) was added drop wise and the reaction mixture was allowed to warm to rt and stirred for 2 h. After that time the reaction mixture was washed with water (3×200 mL) and dried over MgSO.sub.4. The resultant mixture was filtered and concentrated under reduced pressure to give 2-[5-(2-hydroxyethoxy)-6-(4-methanesulfinyl-phenyl)pyridin-2-yl]-5,7-dimethoxy-3H-quinazolin-4-one (10.0 g, 89%) as a yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 10.44 (br s, 1H), 8.53 (d, J=8.8 Hz, 1H), 8.14 (d, J=8.4 Hz, 2H), 7.79 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.8 Hz, 1H), 6.83 (d, J=2.4 Hz, 1H), 6.49 (d, J=2.4 Hz, 1H), 4.61-4.59 (m, 2H), 4.43-4.41 (m, 2H), 3.99 (s, 3H), 3.95 (s, 3H), 2.98 (s, 3H), 2.82 (s, 3H).

(418) A mixture of 2-[5-(2-methanesulfonyloxyethoxy)-6-(4-methanesulfinylphenyl)pyridin-2-yl]-5,7-dimethoxy-3H-quinazolin-4-one (3.85 g, 6.9 mmol), pyrrolidine (2.45 g, 34.4 mmol), sodium iodide (1.03 g, 6.9 mmol) and DMSO (28 mL) was heated to 61° C. with stirring for 4 h. After that time the reaction mixture was cooled to rt, diluted with chloroform (180 mL), washed with saturated NaHCO.sub.3 (70 mL), water (3×70 mL) and dried over MgSO.sub.4. The resultant mixture was filtered and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 95:5 chloroform/methanol) to give 5,7-dimethoxy-2-(6-(4-(methylsulfinyl)phenyl)-5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-2-yl)quinazolin-4(3H)-one (0.61 g, 16%) as a yellow solid: mp 103-105° C.; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.47 (br s, 1H), 8.51 (d, J=8.4 Hz, 1H), 8.17 (d, J=8.0 Hz, 2H), 7.77 (d, J=8.0 Hz, 2H), 7.50 (d, J=8.4 Hz, 1H), 6.83 (d, J=2.4 Hz, 1H), 6.48 (d, J=2.4 Hz, 1H), 4.30 (t, J=6.4 Hz, 2H), 3.99 (s, 3H), 3.95 (s, 3H), 2.98 (t, J=6.4 Hz, 2H), 2.82 (s, 3H), 2.64-2.60 (br m, 4H), 1.82-1.79 (m, 4H); ESI MS m/z 535 [M+1].sup.+.

Example 56: 3-Chloro-4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-methoxypyridin-2-yl)-N,N-dimethylbenzamide

(419) ##STR00080##

(420) Thionyl chloride (15 mL) was added to 4-borono-3-chlorobenzoic acid (1.5 g, 7.48 mmol) and the resulting mixture was refluxed for 22 h. After that time the reaction was cooled to rt and concentrated under reduced pressure. The residue was treated with aqueous dimethylamine (40 wt %, 10 mL) and the resulting mixture was refluxed for 40 min. After this time the reaction was cooled to rt and acidified to pH 2 with conc. HCl. The mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to give (2-chloro-4-(dimethylcarbamoyl)phenyl)boronic acid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.88-7.93 (m, 1H), 7.45-7.48 (m, 1H), 7.34-7.40 (m, 1H), 2.98 (s, 3H), 2.89 (s, 3H).

(421) To a solution of 2-(6-bromo-5-methoxypyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.25 g, 0.637 mmol) and (2-chloro-4-(dimethylcarbamoyl)phenyl)boronic acid (0.362 g, 1.594 mmol) in toluene (6 mL) and ethanol (3 mL) was added a solution of Na.sub.2CO.sub.3 (0.405 g, 3.820 mmol) in water (3 mL) and Pd(PPh.sub.3).sub.4 (0.147 g, 0.127 mmol) at rt under nitrogen. The reaction mixture was stirred at 90° C. for 21 h. After that time the reaction was cooled to rt and extracted with ethyl acetate (50 mL). The organic phase was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 95:5 dichloromethane/methanol) to give 3-chloro-4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-methoxypyridin-2-yl)-N,N-dimethylbenzamide (0.031 g, 9.8%) as a solid: mp 271-272° C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.96 (s, 1H), 8.47 (d, J=9.0 Hz, 1H), 7.86 (d, J=9.0 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.60 (d, J=1.6 Hz, 1H), 7.50 (dd, J=7.8, 1.6 Hz, 1H), 6.82 (d, J=1.95 Hz, 1H), 6.58 (d, J=1.95 Hz, 1H), 3.92 (s, 6H), 3.85 (s, 3H), 3.02 (s, 3H), 2.99 (s, 3H); ESI MS m/z 495 [M+H].sup.+.

Example 57: 5-Methoxy-2-(5-methoxy-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one

(422) ##STR00081##

(423) A mixture of 6-bromo-5-methoxypicolinaldehyde (0.648 g, 3.0 mmol), (4-(methylsulfinyl)phenyl)boronic acid (0.662 g, 3.6 mmol) and Na.sub.2CO.sub.3 (1.27 g, 12 mmol) in toluene (12 mL), ethanol (6 mL) and water (6 mL) was degassed. Pd(PPh.sub.3).sub.4 (0.347 g, 0.3 mmol) was added and the resulting mixture was heated at 95° C. for 18 h under nitrogen. After that time the reaction was cooled to rt, diluted with brine and extracted with ethyl acetate. The organic phase was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 98:2 dichloromethane/methanol) to give 5-methoxy-6-(4-(methylsulfinyl)phenyl)picolinaldehyde (0.830 g, >99%) as a white foam: .sup.1H NMR (400 MHz, CDCl.sub.3): δ 10.07 (br s, 1H), 8.16 (d, J=8.0 Hz, 2H), 8.03 (d, J=8.4 Hz, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 1H), 4.00 (s, 3H), 2.78 (s, 3H).

(424) To a solution of 2-amino-6-methoxybenzoic acid (9.0 g, 53.8 mmol) in THF (270 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (23.7 g, 123.7 mmol) and hydroxybenzotriazole (23.9 g, 156.0 mmol). The mixture was stirred at rt for 30 min, then N-methylmorpholine (18.2 g, 180.3 mmol) and NH.sub.4OH (50 vol % in H.sub.2O, 36 mL) were added. The reaction mixture was then stirred for 18 h at rt. After that time the reaction was concentrated under reduced pressure and diluted with ethyl acetate (600 mL). The organic phase was washed with brine (2×100 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to give 2-amino-6-methoxybenzamide (8.80 g, 98%) as a light yellow solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.55 (br s, 1H), 7.29 (br s, 1H), 7.01 (t, J=8.4 Hz, 1H), 6.36 (br s, 2H), 6.30 (dd, J=8.4, 0.8 Hz, 1H), 6.17 (dd, J=8.0, 1.2 Hz, 1H), 3.76 (s, 3H).

(425) To a solution of 5-methoxy-6-(4-(methylsulfinyl)phenyl)picolinaldehyde (0.83 g, 3.0 mmol) in N,N-dimethylacetamide (30 mL) was added 2-amino-6-methoxybenzamide (0.50 g, 3.0 mmol) followed by NaHSO.sub.3 (0.47 g, 4.5 mmol) and p-toluenesulfonic acid monohydrate (0.57 g, 3.0 mmol). The reaction was heated at 120° C. for 20 h. After that time the reaction was cooled to rt, concentrated under reduced pressure and diluted with water (10 mL) and saturated Na.sub.2CO.sub.3 (2 mL). The precipitated solids were collected by filtration, washed with water and dried under vacuum. The product was purified by flash column chromatography (silica gel, 98:2 dichloromethane/methanol) followed by trituration with methanol to give 5-methoxy-2-(5-methoxy-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one (0.758 g, 60%) as a white solid: mp 308-310° C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.36 (br s, 1H), 8.40 (d, J=8.4 Hz, 1H), 8.30 (d, J=8.8 Hz, 2H), 7.84-7.76 (m, 3H), 7.72 (t, J=8.4 Hz, 1H), 7.29 (d, J=7.6 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 3.97 (s, 3H), 3.88 (s, 3H), 2.80 (s, 3H); ESI MS m/z 422 [M+H].sup.+.

Example 58: 5,7-Dimethoxy-2-(5-methoxy-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one

(426) ##STR00082##

(427) A mixture of (4-(methylsulfonyl)phenyl)boronic acid (0.0.275 g, 1.38 mmol), 2-(6-bromo-5-methoxypyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.270 g, 0.69 mmol) and sodium carbonate (0.217 g, 2.0.5 mmol) in toluene (20 mL), EtOH (10 mL) and water (5 mL) was purged with nitrogen for 15 min. Pd(PPh.sub.3).sub.4 (0.040 g, 0.03 mmol) was then added and the reaction mixture was heated at 90° C. for 17 h. After that time the reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was diluted with water (20 mL) and the resulting suspension was stirred for 10 min. The precipitated solids were collected by filtration, air-dried and then purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol to 95:5 dichloromethane/methanol) to give 5,7-dimethoxy-2-(5-methoxy-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one (0.226 g, 70%) as a white solid: mp 279-281° C.; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.41 (s, 1H), 8.56 (d, J=8.78 Hz, 1H), 8.16 (d, J=8.58, 2H), 8.08 (d, J=8.58, 2H), 7.52 (d, J=8.78 Hz, 1H), 6.83 (d, J=2.34 Hz, 1H), 6.49 (d, J=2.34 Hz, 1H), 4.01 (s, 3H), 3.99 (s, 3H), 3.95 (s, 3H), 3.14 (s, 3H); ESI MS m/z 468 [M+H].sup.+.

Example 59: 2-Chloro-5′-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2′-methoxy-N,N-dimethyl-[1,1′-biphenyl]-4-carboxamide

(428) ##STR00083##

(429) A mixture of (2-chloro-4-(dimethylcarbamoyl)phenyl)boronic acid (0.89 g, 1.56 mmol), 3-bromo-4-methoxybenzaldehyde (0.269 g, 1.25 mmol) and sodium carbonate (1.24 g, 11.7 mmol) in toluene (20 mL), EtOH (15 mL) and water (5 mL) was purged with nitrogen for 15 min. Pd(PPh.sub.3).sub.4 (0.226 g, 0.13 mmol) was then added and the reaction mixture was heated at 90° C. for 17 h. After that time the reaction mixture was cooled to rt and diluted with ethyl acetate (30 mL). The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 70:30 hexanes/ethyl acetate to 30:70 hexanes/ethyl acetate) to give 2-chloro-5′-formyl-2′-methoxy-N,N-dimethyl-[1,1′-biphenyl]-4-carboxamide (0.090 g, 23%) as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.93 (s, 1H), 7.95 (dd, J=8.60, 1.95 Hz, 1H), 7.74 (d, J=1.95 Hz, 1H), 7.54 (s, 1H), 7.29-7.41 (m, 2H), 7.11 (d, J=8.60 Hz, 1H), 3.88 (s, 3H), 3.14 (s, 3H), 3.07 (s, 3H); ESI MS m/z 318 [M+H].sup.+.

(430) To a solution of 2-amino-4,6-dimethoxybenzamide (0.056 g, 0.28 mmol) and 2-chloro-5′-formyl-2′-methoxy-N,N-dimethyl-[1,1′-biphenyl]-4-carboxamide (0.090 g, 0.28 mmol) in N,N-dimethylacetamide (10 mL) was added NaHSO.sub.3 (58.5% SO.sub.2 content, 0.076 g, 0.42 mmol) and p-toluenosulfonic acid monohydrate (0.011 g, 0.06 mmol). The reaction was heated at 120° C. for 17 h. After that time the reaction was cooled to rt and concentrated under reduced pressure. The residue was diluted with water (30 mL) and the resulting suspension was stirred for 10 min. The precipitated solids were collected by filtration, air-dried and then purified by flash column chromatography (silica gel, 97:3 dichloromethane/methanol to 93:7 dichloromethane/methanol) to give 2-chloro-5′-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2′-methoxy-N,N-dimethyl-[1,1′-biphenyl]-4-carboxamide (0.055 g, 40%) as an off-white solid: mp>300° C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.03 (s, 1H), 8.31 (dd, J=8.79, 2.15 Hz, 1H), 8.10 (d, J=2.34 Hz, 1H), 7.59 (s, 1H), 7.41-7.50 (m, 2H), 7.28 (d, J=8.99 Hz, 1H), 6.73 (d, J=1.95 Hz, 1H), 6.51 (d, J=1.95 Hz, 1H), 3.87 (s, 3H), 3.83-3.86 (m, 6H), 3.02 (s, 3H), 2.98 (s, 3H); ESI MS m/z 494 [M+H].sup.+.

Example 60: 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)-7-methoxyquinazolin-4(3H)-one

(431) ##STR00084##

(432) To a solution of 2-amino-4-methoxybenzoic acid (5.0 g, 29.91 mmol) in THF (150 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (13.2 g, 68.79 mmol) and hydroxybenzotriazole (13.3 g, 86.74 mmol). The mixture was stirred at rt for 30 min, then N-methylmorpholine (10.1 g, 100.2 mmol) and NH.sub.4OH (50 vol % in H.sub.2O, 20 mL) were added. The reaction mixture was then stirred for 18 h at rt. After that time the reaction was concentrated under reduced pressure and diluted with ethyl acetate (600 mL). The organic phase was washed with brine (2×100 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to give 2-amino-4-methoxybenzamide (4.25 g, 91%) as a light beige solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.54 (br s, 1H), 7.46 (d, J=8.8 Hz, 1H), 6.82 (br s, 1H), 6.73 (br s, 2H), 6.16 (d, J=2.4 Hz, 1H), 6.04 (dd, J=8.8, 2.4 Hz, 1H), 3.68 (s, 3H).

(433) A mixture of 6-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)picolinaldehyde (2.0 g, 5.55 mmol), (4-(methylsulfinyl)phenyl)boronic acid (1.22 g, 6.66 mmol), and Na.sub.2CO.sub.3 (2.35 g, 22.2 mmol) in toluene (20 mL), ethanol (10 mL) and water (10 mL) was degassed. Pd(PPh.sub.3).sub.4 (0.64 g, 0.555 mmol) was added and the resulting mixture was heated at 95° C. for 18 h. After that time the reaction was cooled to rt, diluted with brine and extracted with ethyl acetate. The organic phase was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 40:60 hexanes/ethyl acetate) to give 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(4-(methylsulfinyl)phenyl)-picolinaldehyde (1.67 g, 72%) as a thick yellow oil: .sup.1H NMR (400 MHz, CDCl.sub.3): δ 10.06 (br s, 1H), 8.22 (d, J=6.8 Hz, 2H), 7.99 (d, J=8.4 Hz, 1H), 7.74 (d, J=6.8 Hz, 2H), 7.48 (d, J=8.8 Hz, 1H), 4.25 (dd, J=4.0, 5.2 Hz, 2H), 4.00 (dd, J=4.8, 4.4 Hz, 2H), 2.77 (s, 3H), 0.87 (s, 9H), 0.04 (s, 6H).

(434) To a solution of 2-amino-4-methoxybenzamide (0.34 g, 1.98 mmol) in N,N-dimethylacetamide (20 mL) was added 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(4-(methylsulfinyl)phenyl)-picolinaldehyde (0.83 g, 1.98 mmol) followed by NaHSO.sub.4 (0.31 g, 2.97 mmol) and p-toluenesulfonic acid monohydrate (0.38 g, 1.98 mmol). The reaction was heated at 120° C. for 20 h. After that time the reaction was cooled to rt, concentrated under reduced pressure and diluted with water (10 mL) and saturated Na.sub.2CO.sub.3 (2 mL). The precipitated solids were collected by filtration, washed with water and dried under vacuum. The product was purified by flash column chromatography (silica gel, 98:2 dichloromethane/methanol to 95:5 dichloromethane/methanol) to give 2-(5-(2-hydroxyethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)-7-methoxyquinazolin-4(3H)-one (0.52 g, 58%) as a white solid: mp 266-267° C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.75 (br s, 1H), 8.49 (d, J=8.0 Hz, 2H), 8.42 (d, J=8.8 Hz, 1H), 8.08 (d, J=8.8 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.80 (dd, J=6.8, 2.0 Hz, 2H), 7.23 (d, J=2.4 Hz, 1H), 7.12 (dd, J=8.4, 2.0 Hz, 1H), 5.04 (dd, J=5.2, 4.8 Hz, 1H), 4.28 (dd, J=5.2, 4.4 Hz, 2H), 3.94 (s, 3H), 3.83-3.79 (m, 2H), 2.83 (s, 3H); ESI MS m/z 452 [M+1].sup.+.

Example 61: 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one

(435) ##STR00085##

(436) To a solution of 2-aminobenzamide (0.27 g, 1.98 mmol) in N,N-dimethylacetamide (20 min) was added 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(4-(methylsulfinyl)phenyl)-picolinaldehyde (0.83 g, 1.98 mmol) followed by NaHSO.sub.3 (0.31 g, 2.97 mmol) and p-toluenesulfonic acid monohydrate (0.38 g, 1.98 mmol). The reaction was heated at 120° C. for 20 h. After that time the reaction was cooled to rt, concentrated under reduced pressure and diluted with water (10 mL) and saturated Na.sub.2CO.sub.3(2 mL). The precipitated solids were collected by filtration, washed with water and dried under vacuum. The product was purified by flash column chromatography (silica gel, 98:2 dichloromethane/methanol to 95:5 dichloromethane/methanol) to give 2-(5-(2-hydroxyethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one (0.52 g, 63%) as a white solid: mp 261-262° C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.93 (br s, 1H), 8.50 (d, J=8.0 Hz, 2H), 8.42 (d, J=8.4 Hz, 1H), 8.18 (d, J=7.2 Hz, 1H), 7.89-7.79 (m, 2H), 7.83 (m, 5H), 7.54 (dd, J=8.4, 7.6 Hz, 1H), 5.04 (dd, J=5.2, 4.8 Hz, 1H), 4.28 (dd, J=4.8, 4.4 Hz, 2H), 3.84-3.78 (m, 2H), 2.83 (s, 3H); ESI MS m/z 422 [M+1].sup.+.

Example 62: 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one

(437) ##STR00086##

(438) To a solution of 2-bromo-6-(hydroxyl methyl)pyridin-3-ol (10.20 g, 50.0 mmol) in anhydrous DMF (150 mL) was added K.sub.2CO.sub.3 (10.36 g, 75.0 mmol). The reaction mixture was stirred for 10 min at rt, then (2-bromoethoxy)(tert-butyl)dimethylsilane (11.8 mL, 55.0 mmol) was added. The reaction mixture was stirred at 60° C. for 20 h under nitrogen. After that time the reaction was cooled to rt, concentrated under reduced pressure, diluted with water (100 mL) and extracted with ethyl acetate (200 mL). The organic phase was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 70:30 hexanes/ethyl acetate) to give (6-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-2-yl)methanol (9.40 g, 52%) as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.17-7.29 (m, 2H), 4.69 (d, J=5.86 Hz, 2H), 4.14 (t, J=4.69 Hz, 2H), 4.03 (t, J=5.08 Hz, 2H), 2.76 (t, J=5.67 Hz, 1H), 0.90 (s, 9H), 0.11 (s, 6H).

(439) To a solution of (6-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-2-yl)methanol (5.07 g, 14.0 mmol) in DMSO (30 mL) was added 2-iodoxybenzoic acid (4.31 g, 15.4 mmol). The reaction mixture was stirred at rt for 3 h. After that time the reaction was diluted with water (100 mL) and the precipitated solids were removed by filtration and washed with ethyl acetate (250 mL). The organic layer was washed with water, brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to give 6-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)picolinaldehyde (4.50 g, 89%) as a yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3): δ 9.83 (s, 1H), 7.82 (d, J=8.60 Hz, 1H), 7.24 (d, J=8.21 Hz, 1H), 4.13-4.18 (m, 2H), 3.94-3.99 (m, 2H), 0.79 (s, 9H), 0.01 (s, 6H).

(440) A mixture of 6-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)picolinaldehyde (2.30 g, 6.38 mmol), (4-(methylsulfonyl)phenyl)boronic acid (1.27 g, 6.38 mmol) and Na.sub.2CO.sub.3 (2.02 g, 19.14 mmol) was degassed under nitrogen. Then toluene (60 mL), ethanol (60 mL) and water (10 mL) was added. The reaction mixture was degassed again and Pd(PPh.sub.3).sub.4 (0.37 g, 0.32 mmol) was added and degassed. The reaction mixture was stirred at 90° C. for 16 h under nitrogen. After that time the reaction was cooled to rt, concentrated under reduced pressure, diluted with water (100 mL) and extracted with ethyl acetate (2×150 mL). The organic phase was washed with water, brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 70:30 hexanes/ethyl acetate to 60:40 hexanes/ethyl acetate) to give 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(4-(methylsulfonyl)phenyl)picolinaldehyde (1.63 g, 59%) as light yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3): δ 10.06 (s, 1H), 8.27 (d, J=8.60 Hz, 2H), 8.03 (dd, J=8.60, 3.52 Hz, 3H), 7.51 (d, J=8.60 Hz, 1H), 4.26 (t, J=4.23 Hz, 2H), 4.00 (t, J=4.49 Hz, 2H), 3.10 (s, 3H), 0.87 (s, 9H), 0.05 (s, 6H).

(441) To a solution of 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(4-(methylsulfonyl)phenyl)-picolinaldehyde (0.54 g, 1.50 mmol) and 2-amino-6-methoxybenzamide (0.274 g, 1.65 mmol) in N,N-dimethylacetamide (15 ml) was added NaHSO.sub.3 (58.5 wt %, 0.41 g, 2.25 mmol) and p-toluenesulfonic acid monohydrate (0.057 g, 0.30 mmol). The reaction mixture was stirred at 120° C. for 14 h. After that time the reaction was cooled to rt, concentrated under reduced pressure, diluted with water (100 mL) and the precipitated solids were collected by filtration, washed with water and dried under vacuum. The product was washed with diethyl ether and dried to give 2-(5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(4-(methylsulfonyl)-phenyl)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one (0.41 g) as a brown solid: ESI MS m/z 582 [M+H].sup.+.

(442) To a solution of 2-(5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(4-(methylsulfonyl)-phenyl)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one (0.407 g, crude, 0.70 mmol) in THF (20 mL) was added a solution of tetrabutylammoniumfluoride in THF (1M solution, 1.5 mL, 1.50 mmol). The reaction was stirred at rt for 1 h. After that time the reaction was concentrated under reduced pressure, diluted with water (100 mL) and stirred at rt for 1 h. The precipitated solids were collected by filtration, washed with water and dried. The product was purified by flash column chromatography (silica gel, 98:2 dichloromethane/methanol to 97:3 dichloromethane/methanol) to give 2-(5-(2-hydroxyethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one (0.231 g, 33% for two steps) as a light yellow solid: mp>300° C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.52 (s, 1H), 8.54 (d, J=8.60 Hz, 2H), 8.42 (d, J=8.99 Hz, 1H), 8.03 (d, J=8.60 Hz, 2H), 7.88 (d, J=8.99 Hz, 1H), 7.74 (t, J=8.21 Hz, 1H), 7.31 (d, J=7.82 Hz, 1H), 7.05 (d, J=8.21 Hz, 1H), 5.04 (t, J=5.28 Hz, 1H), 4.28 (t, J=4.49 Hz, 2H), 3.90 (s, 3H), 3.80 (q, J=5.08 Hz, 2H), 3.30 (s, 3H). ESI MS m/z 468 [M+H].sup.+.

Example 63: 1-(2-((6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(4-(methylsulfonyl)phenyl)pyridin-3-yl)oxy)ethyl)pyrrolidine 1-oxide

(443) ##STR00087##

(444) A solution of 2-[5-(2-pyrrolidin-1-ylethoxy)-6-(4-methanesulfinylphenyl)pyridin-2-yl]-5,7-dimethoxy-3H-quinazolin-4-one (0.403 g, 0.75 mmol) in dichloromethane (10 mL) was cooled to 0° C. 3-Chloroperbenzoic acid (≦77% purity, 0.253 g, 1.13 mmol) was added portion wise. After the addition was complete the reaction mixture was allowed to warm to rt and stirred for 16 h. After this time the reaction mixture was extracted with saturated NaHCO.sub.3 (13 ml). The aqueous extract was lyophilized to give a solid that was suspended in isopropanol/chloroform (20:80, 100 mL), stirred for 16 h and filtered. The filtrate was concentrated under reduced pressure. The product was purified by preparative HPLC [column PrepXBridge (30×100 mm, 5 μm), 0.1% NH.sub.4OH/acetonitrile] to give 1-(2-((6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(4-(methylsulfonyl)phenyl)pyridin-3-yl)oxy)ethyl)pyrrolidine 1-oxide (0.129 g, 30%) as a pale yellow solid: mp 167-170° C.; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.58 (d, J=8.4 Hz, 1H), 8.07 (d, J=8.8 Hz, 2H), 8.00 (d, J=8.8 Hz, 2H), 7.68 (d, J=8.4 Hz, 1H), 6.85 (d, J=2.0 Hz, 1H), 6.50 (d, J=2.0 Hz, 1H), 4.88 (t, J=4.4 Hz, 2H), 3.99 (s, 3H), 3.96 (s, 3H), 3.68 (t, J=4.4 Hz, 2H), 3.40-3.35 (m, 2H), 3.21-3.16 (m, 2H), 3.16 (s, 3H), 2.46-2.44 (m, 2H), 1.96-1.92 (m, 2H); ESI MS m/z 567 [M+1].sup.+.

Example 64: 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one

(445) ##STR00088##

(446) To a suspension of 2-(5-(2-hydroxyethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one (0.200 g, 0.43 mmol) in DMF (10 mL) was added PBr.sub.3 (0.232 g, 0.86 mmol). The reaction was stirred at 60° C. for 2 h under nitrogen. After that time the reaction was cooled to rt, concentrated under reduced pressure, diluted with saturated NaHCO.sub.3 solution (20 mL). The precipitated solids were collected by filtration, washed with water and dried to give 2-(5-(2-bromoethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one (0.242 g, >99%) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.56 (s, 1H), 8.56 (d, J=8.60 Hz, 2H), 8.43 (d, J=8.60 Hz, 1H), 8.04 (d, J=8.60 Hz, 2H), 7.89 (d, J=8.99 Hz, 1H), 7.74 (t, J=8.21 Hz, 1H), 7.32 (d, J=7.42 Hz, 1H), 7.06 (d, J=7.82 Hz, 1H), 4.61 (t, J=5.28 Hz, 2H), 3.87-3.95 (m, 5H), 3.31 (s, 3H); ESI MS m/z 530 and 532 [M+H].sup.+.

(447) To a suspension of 2-(5-(2-bromoethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one (0.230 g, 0.43 mmol) in DMSO (3 mL) was added isopropylamine (2 mL) in a sealed glass tube. The reaction was stirred at 60° C. for 4 h. After that time the reaction was cooled to rt, concentrated under reduced pressure, diluted with Na.sub.2CO.sub.3 solution (30 mL) and the precipitated solids were collected by filtration, washed with water and diethyl ether and dried under vacuum to give 2-(5-(2-(isopropylamino)ethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one (0.150 g, 68%) as an off-white solid: mp 222-223° C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.52 (d, J=8.60 Hz, 2H), 8.42 (d, J=8.99 Hz, 1H), 8.02 (d, J=8.60 Hz, 2H), 7.87 (d, J=8.99 Hz, 1H), 7.74 (t, J=8.21 Hz, 1H), 7.31 (d, J=7.82 Hz, 1H), 7.05 (d, J=8.21 Hz, 1H), 4.26 (t, J=5.47 Hz, 2H), 3.90 (s, 3H), 3.29 (s, 3H), 2.94 (t, J=5.47 Hz, 2H), 2.76 (quin, J=6.15 Hz, 1H), 0.99 (d, J=5.86 Hz, 6H); ESI MS m/z 509 [M+H].sup.+.

Example 65: 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one

(448) ##STR00089##

(449) A suspension of 2-(5-(2-hydroxyethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one (0.46 g, 1.09 mmol) and triethylamine (0.29 g, 2.83 mmol) in dichloromethane (40 mL) was cooled to 0° C. with stirring. Methanesulfonyl chloride (0.15 g, 1.31 mmol) was added drop wise and the reaction mixture was allowed to warm to rt and stirred for 2 h. After that time the reaction was diluted with methylene chloride (100 mL), washed with water (2×50 mL) and dried over Na.sub.2SO.sub.4. The reaction was filtered and concentrated under reduced pressure to give 2-((2-(4-(methylsulfinyl)phenyl)-6-(4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)oxy)ethyl methanesulfonate (0.54 g, >99%) as a light yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3): δ 11.79 (br s, 1H), 8.60 (d, J=8.4 Hz, 1H), 8.35 (d, J=8.0 Hz, 1H), 8.16-8.14 (m, 2H), 7.84-7.79 (m, 4H), 7.54-7.50 (m, 2H), 4.62-4.60 (m, 2H), 4.46-4.43 (m, 2H), 2.98 (s, 3H), 2.82 (s, 3H).

(450) To a solution of 2-((2-(4-(methylsulfinyl)phenyl)-6-(4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)oxy)ethyl methanesulfonate (0.54 mmol, 1.09 mmol) in DMSO (4 mL) was added isopropyl amine (3.22 g, 54.5 mmol) and sodium iodide (0.16 g, 1.09 mmol). The reaction was heated at 60° C. in a sealed tube for 4 h. After that time the reaction was cooled to rt, concentrated under reduced pressure and diluted with dichloromethane (100 mL). The mixture was washed with saturated NaHCO.sub.3 (10 mL), water (10 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 90:10:0.1 dichloromethane/methanol/ammonium hydroxide) to give 2-(5-(2-(isopropylamino)ethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one (0.38 g, 76%) as a white foam: .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.57 (d, J=8.8 Hz, 1H), 8.34 (d, J=8.0 Hz, 1H), 8.14 (d, J=8.8 Hz, 2H), 7.83-7.78 (m, 4H), 7.54-7.49 (m, 2H), 4.26 (t, J=5.2 Hz, 2H), 3.06 (t, J=5.2 Hz, 2H), 2.78-2.82 (m, 1H), 2.82 (s, 3H), 1.06 (d, J=6.4 Hz, 6H); ESI MS m/z 463 [M+1].sup.+.

Example 66: 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)-7-methoxyquinazolin-4(3H)-one

(451) ##STR00090##

(452) A suspension of 2-(5-(2-hydroxyethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)-7-methoxyquinazolin-4(3H)-one (0.49 g, 1.09 mmol) and triethylamine (0.28 g, 2.83 mmol) in dichloromethane (40 mL) was cooled to 0° C. with stirring. Methanesulfonyl chloride (0.15 g, 1.31 mmol) was added drop wise and the reaction mixture was allowed to warm to rt and stirred for 2 h. After that time the reaction was diluted with methylene chloride (100 mL), washed with water (2×50 mL) and dried over Na.sub.2SO.sub.4. The reaction was filtered and concentrated under reduced pressure to give 2-((6-(7-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(4-(methylsulfinyl)phenyl)pyridin-3-yl)oxy)ethyl methanesulfonate (0.58 g, >99%) as a light yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3): δ 10.69 (br s, 1H), 8.58 (d, J=8.8 Hz, 1H), 8.24 (d, J=9.2 Hz, 1H), 8.14 (d, J=8.8 Hz, 2H), 7.80 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.8 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 7.09 (dd, J=8.8, 2.4 Hz, 1H), 4.62-4.60 (m, 2H), 4.45-4.43 (m, 2H), 3.97 (s, 3H), 2.99 (s, 3H), 2.82 (s, 3H).

(453) To a solution of 2-((6-(7-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(4-(methylsulfinyl)phenyl)pyridin-3-yl)oxy)ethyl methanesulfonate (0.58 g, 1.09 mmol) in DMSO (4 mL) was added isopropyl amine (3.22 g, 54.5 mmol) and sodium iodide (0.16 g, 1.09 mmol). The reaction was heated at 60° C. in a sealed tube for 4 h. After that time the reaction was cooled to rt, concentrated under reduced pressure and diluted with dichloromethane (100 mL). The mixture was washed with saturated NaHCO.sub.3 (10 mL), water (10 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 90:10:0.1 dichloromethane/methanol/ammonium hydroxide) to give 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin-2-yl)-7-methoxyquinazolin-4(3H)-one (0.416 g, 77%) as a white foam: .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.54 (d, J=8.8 Hz, 1H), 8.24 (d, J=8.8 Hz, 1H), 8.14 (d, J=8.4 Hz, 2H), 7.78 (d, J=8.0 Hz, 2H), 7.52 (d, J=8.8 Hz, 1H), 7.20 (d, J=1.6 Hz, 1H), 7.07 (dd, J=9.2, 1.6 Hz, 1H), 4.26 (t, J=5.0 Hz, 2H), 3.97 (s, 3H), 3.06 (t, J=5.0 Hz, 2H), 2.82-2.78 (m, 1H), 2.82 (s, 3H), 1.06 (d, J=6.4 Hz, 6H); ESI MS m/z 493 [M+1].sup.+.

Example 67: 2-(5-(2-Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-7-methoxyquinazolin-4(3H)-one

(454) ##STR00091##

(455) To a suspension of 2-(5-(2-hydroxyethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-7-methoxyquinazolin-4(3H)-one (0.304 g, 0.65 mmol) in DMF (15 mL) was added PBr.sub.3 (0.352 g, 1.30 mmol). The reaction mixture was stirred at 60° C. for 2 h under nitrogen. After that time the reaction was cooled to rt, concentrated under reduced pressure, diluted with saturated NaHCO.sub.3 solution (20 mL). The precipitated solids were collected by filtration, washed with water and dried under vacuum to give 2-(5-(2-bromoethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-7-methoxyquinazolin-4(3H)-one (0.320 g, 93%) as an off-white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.82 (br s, 1H), 8.58 (d, J=8.60 Hz, 2H), 8.45 (d, J=8.60 Hz, 1H), 8.08 (d, J=8.99 Hz, 1H), 8.04 (d, J=8.60 Hz, 2H), 7.90 (d, J=8.60 Hz, 1H), 7.23 (d, J=2.34 Hz, 1H), 7.12 (dd, J=8.79, 2.54 Hz, 1H), 4.61 (t, J=5.08 Hz, 2H), 3.88-3.97 (m, 5H), 3.31 (s, 3H); ESI MS m/z 528 and 530 [M+H].sup.+.

(456) To a suspension of 2-(5-(2-bromoethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-7-methoxyquinazolin-4(3H)-one (0.306 g, 0.57 mmol) in DMSO (3 mL) was added isopropylamine (2 mL) in a sealed glass tube. The reaction mixture was stirred at 60° C. for 4 h. After that time the reaction was cooled to rt, concentrated under reduced pressure, diluted with Na.sub.2CO.sub.3 solution (30 mL) and the precipitated solids were collected by filtration, washed with water and diethyl ether and dried under vacuum. The product was purified by flash column chromatography (silica gel, 97:3 dichloromethane/methanol followed by 97:3 dichloromethane/7N NH.sub.3 in methanol) to give 2-(5-(2-(isopropylamino)ethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-7-methoxyquinazolin-4(3H)-one (0.203 g, 70%) as a white solid: mp 204-205° C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.55 (d, J=8.60 Hz, 2H), 8.45 (d, J=8.60 Hz, 1H), 8.08 (d, J=8.60 Hz, 1H), 8.02 (d, J=8.21 Hz, 2H), 7.89 (d, J=8.99 Hz, 1H), 7.23 (d, J=1.95 Hz, 1H), 7.12 (dd, J=8.79, 2.54 Hz, 1H), 4.26 (t, J=5.47 Hz, 2H), 3.94 (s, 3H), 3.29 (s, 3H), 2.94 (t, J=5.47 Hz, 2H), 2.76 (quin, J=6.25 Hz, 1H), 0.99 (d, J=6.25 Hz, 6H); ESI MS m/z 509 [M+H].sup.+.

Example 68: 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one

(457) ##STR00092##

(458) To a suspension of 2-(5-(2-hydroxyethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one (0.436 g, 1.00 mmol) in DMF (15 mL) was added PBr.sub.3 (0.540 g, 2.00 mmol). The reaction was stirred at 60° C. for 2 h under nitrogen. After that time the reaction was cooled to rt, concentrated under reduced pressure, diluted with saturated NaHCO.sub.3 solution (20 mL). The precipitated solids were collected by filtration, washed with water and dried under vacuum to give 2-(5-(2-bromoethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one (0.423 g, 84%) as a yellow solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.59 (d, J=8.21 Hz, 2H), 8.48 (d, J=8.60 Hz, 1H), 8.20 (d, J=7.82 Hz, 1H), 8.04 (d, J=8.60 Hz, 2H), 7.85-7.94 (m, 2H), 7.79-7.84 (m, 1H), 7.57 (t, J=7.23 Hz, 1H), 4.62 (t, J=5.08 Hz, 2H), 3.93 (t, J=5.08 Hz, 2H), 3.32 (s, 3H); ESI MS m/z 500 and 502 [M+H].sup.+.

(459) To a suspension of 2-(5-(2-bromoethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one (0.410 g, 0.82 mmol) in DMSO (3 mL) was added isopropyl amine (2 mL) in a sealed glass tube. The reaction mixture was stirred at 60° C. for 4 h. After that time the reaction was cooled to rt, concentrated under reduced pressure, diluted with Na.sub.2CO.sub.3 solution (30 mL) and the precipitated solids were collected by filtration, washed with water and diethyl ether and dried under vacuum. The product was purified by flash column chromatography (silica gel, 97:3 dichloromethane/methanol followed by 97:3 dichloromethane/7N NH.sub.3 in methanol) to give 2-(5-(2-(isopropylamino)ethoxy)-6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one (0.317 g, 81%) as off-white solid: mp 188-189° C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.56 (d, J=8.60 Hz, 2H), 8.47 (d, J=8.60 Hz, 1H), 8.20 (d, J=7.03 Hz, 1H), 8.03 (d, J=8.60 Hz, 2H), 7.84-7.92 (m, 2H), 7.77-7.83 (m, 1H), 7.56 (t, J=7.42 Hz, 1H), 4.26 (t, J=5.47 Hz, 2H), 3.30 (s, 3H), 2.94 (t, J=5.67 Hz, 2H), 2.76 (dt, J=12.21, 6.20 Hz, 1H), 0.99 (d, J=6.25 Hz, 6H); ESI MS m/z 479 [M+H].sup.+.

Example 69: Inhibition of Tetra-Acetylated Histone H4 Binding Individual BET Bromodomains

(460) Proteins were cloned and overexpressed with a N-terminal 6×His tag, then purified by nickel affinity followed by size exclusion chromatography. Briefly, E. coli BL21(DE3) cells were transformed with a recombinant expression vector encoding N-terminally Nickel affinity tagged bromodomains from Brd2, Brd3, Brd4. Cell cultures were incubated at 37° C. with shaking to the appropriate density and induced overnight with IPTG. The supernatant of lysed cells was loaded onto Ni-IDA column for purification. Eluted protein was pooled, concentrated and further purified by size exclusion chromatography. Fractions representing monomeric protein were pooled, concentrated, aliquoted, and frozen at −80° C. for use in subsequent experiments.

(461) Binding of tetra-acetylated histone H4 and BET bromodomains was confirmed by a Time Resolved Fluorescence Resonance Energy Transfer (TR-FRET) method. N-terminally His-tagged bromodomains (200 nM) and biotinylated tetra-acetylated histone H4 peptide (25-50 nM, Millipore) were incubated in the presence of Europium Cryptate-labeled streptavidin (Cisbio Cat. #610SAKLB) and XL665-labeled monoclonal anti-His antibody (Cisbio Cat. #61HISXLB) in a white 96 well microtiter plate (Greiner). For inhibition assays, serially diluted test compound was added to these reactions in a 0.2% final concentration of DMSO. Final buffer concentrations were 30 mM HEPES pH 7.4, 30 mM NaCl, 0.3 mM CHAPS, 20 mM phosphate pH 7.0, 320 mM KF, 0.08% BSA). After 2 hours incubation at room temperature, the fluorescence by FRET was measured at 665 and 620 nm by a SynergyH4 plate reader (Biotek). Illustrative results with the first bromodomain of Brd4 are shown below (Table 1). The binding inhibitory activity was shown by a decrease in 665 nm fluorescence relative to 620 nm. IC.sub.50 values were determined from a dose response curve.

(462) Compounds with an IC.sub.50 value less than 30 μM were deemed to be active.

(463) TABLE-US-00002 TABLE 1 Inhibition of Binding of Tetra-acetylated Histone H4 and Brd4 bromodomain 1 as Measured by FRET FRET activity Name (IC.sub.50 < 30 μM) Example 3: 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2- Active hydroxyethoxy)pyridin-2-yl)-N,N,3-trimethylbenzamide. Example 4: 4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2- Active (isopropylamino)ethoxy)pyridin-2-yl)-N,N,3-trimethylbenzamide Example 5: 3-Chloro-4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Active yl)-3-(2-hydroxyethoxy)pyridin-2-yl)-N,N-dimethylbenzamide Example 6: 3-Chloro-4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Active yl)-3-(2-(isopropylamino)ethoxy)pyridin-2-yl)-N,N-dimethylbenzamide Example 7: (S)-7-Fluoro-5-((1-methylpyrrolidin-3-yl)oxy)-2-(6-(4- Not Active (methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one Example 8: 4-(6-(6,8-Dimethoxy-1-oxo-1,2-dihydroisoquinolin-3- Not Active yl)pyridin-2-yl)-N,N-dimethylbenzamide Example 9: 6,8-Dimethoxy-3-(6-(4-(methylsulfonyl)phenyl)pyridin-2- Not Active yl)isoquinolin-1(2H)-one Example 10: 6,8-dimethoxy-3-(6-(4-(methylsulfinyl)phenyl)pyridin-2- Not Active yl)isoquinolin-1(2H)-one Example 11: 2-(6-(2-(Dimethylamino)ethoxy)-4′-(methylsulfinyl)biphenyl- Active 3-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 13: 5,7-Dimethoxy-2-(6-(1-methylazetidin-3-yloxy)-4′- Active (methylsulfinyl)biphenyl-3-yl)quinazolin-4(3H)-one Example 14: 2-(6-(Azetidin-3-yloxy)-4′-(methylsulfinyl)-[1,1′-biphenyl]-3- Active yl)-7-fluoro-5-methoxyquinazolin-4(3H)-one Example 15: 7-Fluoro-5-methoxy-2-(6-((1-methylazetidin-3-yl)oxy)-4′- Active (methylsulfinyl)-[1,1′-biphenyl]-3-yl)quinazolin-4(3H)-one Example 16: 2-(6-(2-Hydroxyethoxy)-4′-(methylsulfinyl)biphenyl-3-yl)- Active 5,7-dimethoxyquinazolin-4(3H)-one Example 17: 2-(6-(2-(Isopropylamino)ethoxy)-4′- Active (methylsulfinyl)biphenyl-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 18: 2′-(Azetidin-3-yloxy)-5′-(5,7-dimethoxy-4-oxo-3,4- Active dihydroquinazolin-2-yl)-[1,1′-biphenyl]-4-carbonitrile Example 19: 5′-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2′-((1- Active methylazetidin-3-yl)oxy)-[1,1′-biphenyl]-4-carbonitrile Example 20: 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Active yl)pyridin-2-yl)-N,N-dimethylbenzamide Example 21: 2-(5-(2-Hydroxyethoxy)-6-phenylpyridin-2-yl)-5,7- Active dimethoxyquinazolin-4(3H)-one Example 22: 2-(5-(2-(Isopropylamino)ethoxy)-6-phenylpyridin-2-yl)-5,7- Active dimethoxyquinazolin-4(3H)-one Example 23: 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3- Active (2-hydroxyethoxy)pyridin-2-yl)-N,N-dimethylbenzamide. Example 24: 2-(5-(2-Hydroxyethoxy)-6-(4- Active (methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 26: 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2- Active (isopropylamino)ethoxy)pyridin-2-yl)-N,N-dimethylbenzamide Example 27: 2-(5-(2-(Isopropylamino)ethoxy)-6-(4- Active (methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 28: 2-(6-(4-Acetylphenyl)-5-(2-hydroxyethoxy)pyridin-2-yl)-5,7- Active dimethoxyquinazolin-4(3H)-one Example 29: 5,7-Dimethoxy-2-(6-(4-(methylsulfonyl)phenyl)-5-(2- Active (pyrrolidin-1-yl)ethoxy)pyridin-2-yl)quinazolin-4(3H)-one hydrochloride Example 30: 2-(5-(2-Hydroxyethoxy)-6-(2-(methylsulfonyl)phenyl)pyridin- Active 2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 31: 5,7-Dimethoxy-2-(6-(4-(methylsulfonyl)phenyl)-5-(2- Active morpholinoethoxy)pyridin-2-yl)quinazolin-4(3H)-one hydrochloride Example 32: 2-(5-(2-(Isopropylamino)ethoxy)-6-(2- Active (methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 33: 2-(5-(2-(Isopropylamino)ethoxy)-6-(3- Active (methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 34: 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2-hydroxyethoxy)pyridin- Active 2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 35: 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2- Active (isopropylamino)ethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 36: 2-(5-(2-Hydroxyethoxy)-6-(3- Not Active (methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one methanesulfonate Example 37: 2-(5-(2-Hydroxyethoxy)-6-(3-(methylsulfinyl)phenyl)pyridin- Active 2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 38: 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin- Active 2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 39: 2-(5-(2-Hydroxyethoxy)-6-(2-methyl-4- Active (methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 40: 2-(5-(2-(Isopropylamino)ethoxy)-6-(3- Active (methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 41: 2-(5-(2-(Isopropylamino)ethoxy)-6-(4- Active (methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 42: 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2-(pyrrolidin-1- Active yl)ethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 43: 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2- Active morpholinoethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 44: 2-(6-(2-(Isopropylamino)ethoxy)-4′-(methylsulfonyl)-[1,1′- Active biphenyl]-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 45: 2-(5-(2-(Isopropylamino)ethoxy)-6-(2-methyl-4- Active (methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 46: 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)-2- Active (trifluoromethyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 47: 5,7-Dimethoxy-2-(4′-(methylsulfinyl)-[1,1′-biphenyl]-3- Not Active yl)quinazolin-4(3H)-one Example 48: 5,7-Dimethoxy-2-(4-(4-(methylsulfinyl)phenyl)thiophen-2- Not Active yl)quinazolin-4(3H)-one Example 49: 5,7-Dimethoxy-2-(6-(4-(methylsulfinyl)phenyl)pyridin-2- Active yl)quinazolin-4(3H)-one Example 50: 5,7-Dimethoxy-2-(5-methoxy-6-(4- Active (methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one Example 51: 5,7-Dimethoxy-2-(3-(5-(methylsulfinyl)thiophen-2- Active yl)phenyl)quinazolin-4(3H)-one Example 52: 5,7-Dimethoxy-2-(7-(4-(methylsulfinyl)phenyl)-1H-indol-5- Active yl)quinazolin-4(3H)-one Example 53: tert-Butyl (2-((6-(5,7-dimethoxy-4-oxo-3,4- Active dihydroquinazolin-2-yl)-2-(4-(methylsulfinyl)phenyl)pyridin-3- yl)oxy)ethyl)(isopropyl)carbamate Example 54: 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3- Active methoxypyridin-2-yl)-N,N,3-trimethylbenzamide Example 55: 5,7-Dimethoxy-2-(6-(4-(methylsulfinyl)phenyl)-5-(2- Active (pyrrolidin-1-yl)ethoxy)pyridin-2-yl)quinazolin-4(3H)-one Example 56: 3-Chloro-4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin- Not Active 2-yl)-3-methoxypyridin-2-yl)-N,N-dimethylbenzamide Example 57: 5-Methoxy-2-(5-methoxy-6-(4- Active (methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one Example 58: 5,7-Dimethoxy-2-(5-methoxy-6-(4- Active (methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one Example 59: 2-Chloro-5′-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Active yl)-2′-methoxy-N,N-dimethyl-[1,1′-biphenyl]-4-carboxamide Example 60: 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin- Active 2-yl)-7-methoxyquinazolin-4(3H)-one Example 61: 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin- Active 2-yl)quinazolin-4(3H)-one Example 62: 2-(5-(2-Hydroxyethoxy)-6-(4- Active (methylsulfonyl)phenyl)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one Example 63: 1-(2-((6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)- Active 2-(4-(methylsulfonyl)phenyl)pyridin-3-yl)oxy)ethyl)pyrrolidine 1-oxide Example 64: 2-(5-(2-(Isopropylamino)ethoxy)-6-(4- Active (methylsulfonyl)phenyl)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one Example 65: 2-(5-(2-(Isopropylamino)ethoxy)-6-(4- Active (methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one Example 66: 2-(5-(2-(Isopropylamino)ethoxy)-6-(4- Active (methylsulfinyl)phenyl)pyridin-2-yl)-7-methoxyquinazolin-4(3H)-one Example 67: 2-(5-(2-lisopropylamino)ethoxy)-6-(4- Active (methylsulfonyl)phenyl)pyridin-2-yl)-7-methoxyquinazolin-4(3H)-one Example 68: 2-(5-(2-(Isopropylamino)ethoxy)-6-(4- Active (methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one

Example 70: Inhibition of c-myc Expression in Cancer Cell Lines

(464) MV4-11 cells (2.5×10.sup.4 cells) were plated in 96 well U-bottom plates with test compound or DMSO (0.1%), and incubated for 3 hours at 37° C. Cells were then harvested by centrifugation, lysed, and mRNA was isolated using the mRNA catcher plus kit (Invitrogen). Reverse transcription of the mRNA and duplex amplification of the c-myc and cyclophilin cDNAs was performed using the RNA Ultrasense kit (Invitrogen) and a ViiA7 real-time PCR machine (Applied Biosystems). IC.sub.50 values were determined from a dose response curve.

(465) Compounds with an IC.sub.50 value less than 30 μM were deemed to be active.

(466) TABLE-US-00003 TABLE 2 Inhibition of c-myc Activity in Human AML MV4-11 cells c-myc activity Name (IC.sub.50 < 30 μM) Example 3: 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2- Not Active hydroxyethoxy)pyridin-2-yl)-N,N,3-trimethylbenzamide. Example 4: 4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2- Active (isopropylamino)ethoxy)pyridin-2-yl)-N,N,3-trimethylbenzamide Example 5: 3-Chloro-4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Active yl)-3-(2-hydroxyethoxy)pyridin-2-yl)-N,N-dimethylbenzamide Example 6: 3-Chloro-4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Active yl)-3-(2-(isopropylamino)ethoxy)pyridin-2-yl)-N,N-dimethylbenzamide Example 8: 4-(6-(6,8-Dimethoxy-1-oxo-1,2-dihydroisoquinolin-3- Not Active yl)pyridin-2-yl)-N,N-dimethylbenzamide Example 11: 2-(6-(2-(Dimethylamino)ethoxy)-4′-(methylsulfinyl)biphenyl- Active 3-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 12: 2-(6-(Azetidin-3-yloxy)-4′-(methylsulfinyl)biphenyl-3-yl)-5,7- Not Active dimethoxyquinazolin-4(3H)-one Example 13: 5,7-Dimethoxy-2-(6-(1-methylazetidin-3-yloxy)-4′- Active (methylsulfinyl)biphenyl-3-yl)quinazolin-4(3H)-one Example 14: 2-(6-(Azetidin-3-yloxy)-4′-(methylsulfinyl)-[1,1′-biphenyl]-3- Not Active yl)-7-fluoro-5-methoxyquinazolin-4(3H)-one Example 15: 7-Fluoro-5-methoxy-2-(6-((1-methylazetidin-3-yl)oxy)-4′- Active (methylsulfinyl)-[1,1′-biphenyl]-3-yl)quinazolin-4(3H)-one Example 16: 2-(6-(2-Hydroxyethoxy)-4′-(methylsulfinyl)biphenyl-3-yl)- Not Active 5,7-dimethoxyquinazolin-4(3H)-one Example 17: 2-(6-(2-(Isopropylamino)ethoxy)-4′- Active (methylsulfinyl)biphenyl-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 18: 2′-(Azetidin-3-yloxy)-5′-(5,7-dimethoxy-4-oxo-3,4- Active dihydroquinazolin-2-yl)-[1,1′-biphenyl]-4-carbonitrile Example 19: 5′-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2′-((1- Active methylazetidin-3-yl)oxy)-[1,1′-biphenyl]-4-carbonitrile Example 20: 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Active yl)pyridin-2-yl)-N,N-dimethylbenzamide Example 22: 2-(5-(2-(Isopropylamino)ethoxy)-6-phenylpyridin-2-yl)-5,7- Active dimethoxyquinazolin-4(3H)-one Example 23: 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3- Active (2-hydroxyethoxy)pyridin-2-yl)-N,N-dimethylbenzamide Example 24: 2-(5-(2-Hydroxyethoxy)-6-(4- Not Active (methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 26: 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2- Active (isopropylamino)ethoxy)pyridin-2-yl)-N,N-dimethylbenzamide Example 27: 2-(5-(2-(Isopropylamino)ethoxy)-6-(4- Active (methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 29: 5,7-Dimethoxy-2-(6-(4-(methylsulfonyl)phenyl)-5-(2- Active (pyrrolidin-1-yl)ethoxy)pyridin-2-yl)quinazolin-4(3H)-one hydrochloride Example 31: 5,7-Dimethoxy-2-(6-(4-(methylsulfonyl)phenyl)-5-(2- Active morpholinoethoxy)pyridin-2-yl)quinazolin-4(3H)-one hydrochloride Example 34: 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2-hydroxyethoxy)pyridin- Active 2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 35: 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2- Active (isopropylamino)ethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 36: 2-(5-(2-Hydroxyethoxy)-6-(3- Not Active (methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one methanesulfonate Example 37: 2-(5-(2-Hydroxyethoxy)-6-(3-(methylsulfinyl)phenyl)pyridin- Active 2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 38: 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin- Active 2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 39: 2-(5-(2-Hydroxyethoxy)-6-(2-methyl-4- Active (methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 40: 2-(5-(2-(Isopropylamino)ethoxy)-6-(3- Active (methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 41: 2-(5-(2-(Isopropylamino)ethoxy)-6-(4- Active (methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 42: 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2-(pyrrolidin-1- Active yl)ethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 43: 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2- Active morpholinoethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 44: 2-(6-(2-(Isopropylamino)ethoxy)-4′-(methylsulfonyl)-[1,1′- Active biphenyl]-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 45: 2-(5-(2-(Isopropylamino)ethoxy)-6-(2-methyl-4- Active (methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 46: 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)-2- Active (trifluoromethyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 48: 5,7-Dimethoxy-2-(4-(4-(methylsulfinyl)phenyl)thiophen-2- Not Active yl)quinazolin-4(3H)-one Example 49: 5,7-Dimethoxy-2-(6-(4-(methylsulfinyl)phenyl)pyridin-2- Not Active yl)quinazolin-4(3H)-one Example 50: 5,7-Dimethoxy-2-(5-methoxy-6-(4- Active (methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one Example 51: 5,7-Dimethoxy-2-(3-(5-(methylsulfinyl)thiophen-2- Not Active yl)phenyl)quinazolin-4(3H)-one Example 52: 5,7-Dimethoxy-2-(7-(4-(methylsulfinyl)phenyl)-1H-indol-5- Not Active yl)quinazolin-4(3H)-one Example 53: tert-Butyl (2-((6-(5,7-dimethoxy-4-oxo-3,4- Not Active dihydroquinazolin-2-yl)-2-(4-(methylsulfinyl)phenyl)pyridin-3- yl)oxy)ethyl)(isopropyl)carbamate Example 54: 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3- Not Active methoxypyridin-2-yl)-N,N,3-trimethylbenzamide Example 55: 5,7-Dimethoxy-2-(6-(4-(methylsulfinyl)phenyl)-5-(2- Not Active (pyrrolidin-1-yl)ethoxy)pyridin-2-yl)quinazolin-4(3H)-one Example 56: 3-Chloro-4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin- Not Active 2-yl)-3-methoxypyridin-2-yl)-N,N-dimethylbenzamide Example 57: 5-Methoxy-2-(5-methoxy-6-(4- Not Active (methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one Example 58: 5,7-Dimethoxy-2-(5-methoxy-6-(4- Not Active (methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one Example 59: 2-Chloro-5′-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Active yl)-2′-methoxy-N,N-dimethyl-[1,1′-biphenyl]-4-carboxamide Example 60: 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin- Not Active 2-yl)-7-methoxyquinazolin-4(3H)-one Example 63: 1-(2-((6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)- Not Active 2-(4-(methylsulfonyl)phenyl)pyridin-3-yl)oxy)ethyl)pyrrolidine 1-oxide Example 64: 2-(5-(2-(Isopropylamino)ethoxy)-6-(4- Active (methylsulfonyl)phenyl)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one Example 67: 2-(5-(2-lisopropylamino)ethoxy)-6-(4- Active (methylsulfonyl)phenyl)pyridin-2-yl)-7-methoxyquinazolin-4(3H)-one

Example 71: Inhibition of Cell Proliferation in Cancer Cell Lines

(467) MV4-11 cells: 96-well plates were seeded with 5×10.sup.4 cells per well of exponentially growing human AML MV-4-11 (CRL-9591) cells and immediately treated with two-fold dilutions of test compounds, ranging from 30 μM to 0.2 μM. Triplicate wells were used for each concentration, as well as a media only and three DMSO control wells. The cells and compounds were incubated at 37° C., 5% CO.sub.2 for 72 hours before adding 20 μL of the CellTiter Aqueous One Solution (Promega) to each well and incubating at 37° C., 5% CO.sub.2 for an additional 3-4 hours. The absorbance was taken at 490 nm in a spectrophotometer and the percentage of proliferation relative to DMSO-treated cells was calculated after correction from the blank well. IC.sub.50 were calculated using the GraphPad Prism software.

(468) Compounds with an IC.sub.50 value less than 30 μM were deemed to be active.

(469) TABLE-US-00004 TABLE 3 Inhibition of Cell Proliferation in Human AML MV-4-11 cells cell proliferation activity Name (IC.sub.50 < 30 μM) Example 3: 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2- Not Active hydroxyethoxy)pyridin-2-yl)-N,N,3-trimethylbenzamide. Example 4: 4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2- Active (isopropylamino)ethoxy)pyridin-2-yl)-N,N,3-trimethylbenzamide Example 5: 3-Chloro-4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Active yl)-3-(2-hydroxyethoxy)pyridin-2-yl)-N,N-dimethylbenzamide Example 6: 3-Chloro-4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Active yl)-3-(2-(isopropylamino)ethoxy)pyridin-2-yl)-N,N-dimethylbenzamide Example 8: 4-(6-(6,8-Dimethoxy-1-oxo-1,2-dihydroisoquinolin-3- Active yl)pyridin-2-yl)-N,N-dimethylbenzamide Example 11: 2-(6-(2-(Dimethylamino)ethoxy)-4′-(methylsulfinyl)biphenyl- Active 3-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 12: 2-(6-(Azetidin-3-yloxy)-4′-(methylsulfinyl)biphenyl-3-yl)-5,7- Not Active dimethoxyquinazolin-4(3H)-one Example 13: 5,7-Dimethoxy-2-(6-(1-methylazetidin-3-yloxy)-4′- Active (methylsulfinyl)biphenyl-3-yl)quinazolin-4(3H)-one Example 14: 2-(6-(Azetidin-3-yloxy)-4′-(methylsulfinyl)-[1,1′-biphenyl]-3- Not Active yl)-7-fluoro-5-methoxyquinazolin-4(3H)-one Example 15: 7-Fluoro-5-methoxy-2-(6-((1-methylazetidin-3-yl)oxy)-4′- Not Active (methylsulfinyl)-[1,1′-biphenyl]-3-yl)quinazolin-4(3H)-one Example 16: 2-(6-(2-Hydroxyethoxy)-4′-(methylsulfinyl)biphenyl-3-yl)- Not Active 5,7-dimethoxyquinazolin-4(3H)-one Example 17: 2-(6-(2-(Isopropylamino)ethoxy)-4′- Active (methylsulfinyl)biphenyl-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 18: 2′-(Azetidin-3-yloxy)-5′-(5,7-dimethoxy-4-oxo-3,4- Not Active dihydroquinazolin-2-yl)-[1,1′-biphenyl]-4-carbonitrile Example 19: 5′-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2′-((1- Not Active methylazetidin-3-yl)oxy)-[1,1′-biphenyl]-4-carbonitrile Example 20: 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Not Active yl)pyridin-2-yl)-N,N-dimethylbenzamide Example 22: 2-(5-(2-(Isopropylamino)ethoxy)-6-phenylpyridin-2-yl)-5,7- Active dimethoxyquinazolin-4(3H)-one Example 23: 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3- Not Active (2-hydroxyethoxy)pyridin-2-yl)-N,N-dimethylbenzamide Example 24: 2-(5-(2-Hydroxyethoxy)-6-(4- Not Active (methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 26: 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2- Active (isopropylamino)ethoxy)pyridin-2-yl)-N,N-dimethylbenzamide Example 27: 2-(5-(2-(Isopropylamino)ethoxy)-6-(4- Active (methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 29: 5,7-Dimethoxy-2-(6-(4-(methylsulfonyl)phenyl)-5-(2- Active (pyrrolidin-1-yl)ethoxy)pyridin-2-yl)quinazolin-4(3H)-one hydrochloride Example 31: 5,7-Dimethoxy-2-(6-(4-(methylsulfonyl)phenyl)-5-(2- Not Active morpholinoethoxy)pyridin-2-yl)quinazolin-4(3H)-one hydrochloride Example 34: 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2-hydroxyethoxy)pyridin- Active 2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 35: 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2- Active (isopropylamino)ethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 36: 2-(5-(2-Hydroxyethoxy)-6-(3- Not Active (methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one methanesulfonate Example 37: 2-(5-(2-Hydroxyethoxy)-6-(3-(methylsulfinyl)phenyl)pyridin- Not Active 2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 38: 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin- Active 2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 39: 2-(5-(2-Hydroxyethoxy)-6-(2-methyl-4- Active (methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 40: 2-(5-(2-(Isopropylamino)ethoxy)-6-(3- Active (methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 41: 2-(5-(2-(Isopropylamino)ethoxy)-6-(4- Active (methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 42: 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2-(pyrrolidin-1- Active yl)ethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 43: 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2- Active morpholinoethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 44: 2-(6-(2-(Isopropylamino)ethoxy)-4′-(methylsulfonyl)-[1,1′- Active biphenyl]-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 45: 2-(5-(2-(Isopropylamino)ethoxy)-6-(2-methyl-4- Active (methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 46: 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)-2- Active (trifluoromethyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 48: 5,7-Dimethoxy-2-(4-(4-(methylsulfinyl)phenyl)thiophen-2- Not Active yl)quinazolin-4(3H)-one Example 49: 5,7-Dimethoxy-2-(6-(4-(methylsulfinyl)phenyl)pyridin-2- Active yl)quinazolin-4(3H)-one Example 50: 5,7-Dimethoxy-2-(5-methoxy-6-(4- Active (methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one Example 51: 5,7-Dimethoxy-2-(3-(5-(methylsulfinyl)thiophen-2- Not Active yl)phenyl)quinazolin-4(3H)-one Example 52: 5,7-Dimethoxy-2-(7-(4-(methylsulfinyl)phenyl)-1H-indol-5- Not Active yl)quinazolin-4(3H)-one Example 53: tert-Butyl (2-((6-(5,7-dimethoxy-4-oxo-3,4- Not Active dihydroquinazolin-2-yl)-2-(4-(methylsulfinyl)phenyl)pyridin-3- yl)oxy)ethyl)(isopropyl)carbamate Example 54: 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3- Not Active methoxypyridin-2-yl)-N,N,3-trimethylbenzamide Example 55: 5,7-Dimethoxy-2-(6-(4-(methylsulfinyl)phenyl)-5-(2- Active (pyrrolidin-1-yl)ethoxy)pyridin-2-yl)quinazolin-4(3H)-one Example 56: 3-Chloro-4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin- Not Active 2-yl)-3-methoxypyridin-2-yl)-N,N-dimethylbenzamide Example 57: 5-Methoxy-2-(5-methoxy-6-(4- Not Active (methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one Example 58: 5,7-Dimethoxy-2-(5-methoxy-6-(4- Not Active (methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one Example 59: 2-Chloro-5′-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Not Active yl)-2′-methoxy-N,N-dimethyl-[1,1′-biphenyl]-4-carboxamide Example 60: 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin- Not Active 2-yl)-7-methoxyquinazolin-4(3H)-one Example 63: 1-(2-((6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)- Not Active 2-(4-(methylsulfonyl)phenyl)pyridin-3-yl)oxy)ethyl)pyrrolidine 1-oxide Example 64: 2-(5-(2-(Isopropylamino)ethoxy)-6-(4- Active (methylsulfonyl)phenyl)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one Example 67: 2-(5-(2-lisopropylamino)ethoxy)-6-(4- Active (methylsulfonyl)phenyl)pyridin-2-yl)-7-methoxyquinazolin-4(3H)-one

Example 72: Inhibition of hIL-6 mRNA Transcription

(470) In this example, hIL-6 mRNA in tissue culture cells was quantitated to measure the transcriptional inhibition of hIL-6 when treated with a compound of the present disclosure.

(471) A human leukemic monocyte lymphoma cell line (U937) was plated (3.2×10.sup.4 cells per well) in a 96-well plate in 100 μL RPMI-1640 containing 10% FBS and penicillin/streptomycin, and differentiated into macrophages for 3 days in 60 ng/mL PMA (phorbol-13-myristate-12-acetate) at 37° C. in 5% CO.sub.2 prior to the addition of the compound of interest. The cells were pretreated for 1 h with the test compound prior to stimulation with 11 g/mL lipopolysaccharide from Escherichia coli. The cells were incubated at 37° C. for 3 h before the cells were harvested. At time of harvest, the spent media was removed from the cells and the cells were rinsed in 200 μL PBS. Cell lysis solution (70 μL) was added the cells in each well and incubated for 5-10 min at room temperature, to allow for complete cell lysis and detachment. mRNA was then prepared using the “mRNA Catcher PLUS plate” (Invitrogen), according to the protocol supplied. After the last wash, as much wash buffer as possible was aspirated without allowing the wells to dry. Elution buffer (E3, 70 μL) was then added to each well. mRNA was then eluted by incubating the mRNA Catcher PLUS plate with Elution Buffer for 5 min at 68° C. and then immediately placing the plate on ice.

(472) The eluted mRNA isolated was then used in a one-step quantitative real-time PCR reaction, using components of the Ultra Sense Kit together with Applied Biosystems primer-probe mixes. Real-time PCR data was analyzed, normalizing the Ct values for hIL-6 to an internal control, prior to determining the fold induction of each unknown sample, relative to the control.

(473) Compounds with an IC.sub.50 value less than 30 μM are deemed to be active.

(474) TABLE-US-00005 TABLE 4 Inhibition of hIL-6 mRNA Transcrption. IL-6 activity Name (IC.sub.50 < 30 μM) Example 3: 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2- Active hydroxyethoxy)pyridin-2-yl)-N,N,3-trimethylbenzamide. Example 4: 4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2- Active (isopropylamino)ethoxy)pyridin-2-yl)-N,N,3-trimethylbenzamide Example 5: 3-Chloro-4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Active yl)-3-(2-hydroxyethoxy)pyridin-2-yl)-N,N-dimethylbenzamide Example 6: 3-Chloro-4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Active yl)-3-(2-(isopropylamino)ethoxy)pyridin-2-yl)-N,N-dimethylbenzamide Example 7: (S)-7-Fluoro-5-((1-methylpyrrolidin-3-yl)oxy)-2-(6-(4- Not Active (methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one Example 8: 4-(6-(6,8-Dimethoxy-1-oxo-1,2-dihydroisoquinolin-3- Active yl)pyridin-2-yl)-N,N-dimethylbenzamide Example 9: 6,8-Dimethoxy-3-(6-(4-(methylsulfonyl)phenyl)pyridin-2- Not Active yl)isoquinolin-1(2H)-one Example 10: 6,8-dimethoxy-3-(6-(4-(methylsulfinyl)phenyl)pyridin-2- Active yl)isoquinolin-1(2H)-one Example 11: 2-(6-(2-(Dimethylamino)ethoxy)-4′-(methylsulfinyl)biphenyl- Active 3-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 12: 2-(6-(Azetidin-3-yloxy)-4′-(methylsulfinyl)biphenyl-3-yl)-5,7- Not Active dimethoxyquinazolin-4(3H)-one Example 13: 5,7-Dimethoxy-2-(6-(1-methylazetidin-3-yloxy)-4′- Active (methylsulfinyl)biphenyl-3-yl)quinazolin-4(3H)-one Example 14: 2-(6-(Azetidin-3-yloxy)-4′-(methylsulfinyl)-[1,1′-biphenyl]-3- Not Active yl)-7-fluoro-5-methoxyquinazolin-4(3H)-one Example 15: 7-Fluoro-5-methoxy-2-(6-((1-methylazetidin-3-yl)oxy)-4′- Active (methylsulfinyl)-[1,1′-biphenyl]-3-yl)quinazolin-4(3H)-one Example 16: 2-(6-(2-Hydroxyethoxy)-4′-(methylsulfinyl)biphenyl-3-yl)- Active 5,7-dimethoxyquinazolin-4(3H)-one Example 17: 2-(6-(2-(Isopropylamino)ethoxy)-4′- Active (methylsulfinyl)biphenyl-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 18: 2′-(Azetidin-3-yloxy)-5′-(5,7-dimethoxy-4-oxo-3,4- Active dihydroquinazolin-2-yl)-[1,1′-biphenyl]-4-carbonitrile Example 19: 5′-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2′-((1- Active methylazetidin-3-yl)oxy)-[1,1′-biphenyl]-4-carbonitrile Example 20: 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Active yl)pyridin-2-yl)-N,N-dimethylbenzamide Example 21: 2-(5-(2-Hydroxyethoxy)-6-phenylpyridin-2-yl)-5,7- Active dimethoxyquinazolin-4(3H)-one Example 22: 2-(5-(2-(Isopropylamino)ethoxy)-6-phenylpyridin-2-yl)-5,7- Active dimethoxyquinazolin-4(3H)-one Example 23: 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3- Active (2-hydroxyethoxy)pyridin-2-yl)-N,N-dimethylbenzamide Example 24: 2-(5-(2-Hydroxyethoxy)-6-(4- Active (methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 26: 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2- Active (isopropylamino)ethoxy)pyridin-2-yl)-N,N-dimethylbenzamide Example 27: 2-(5-(2-(Isopropylamino)ethoxy)-6-(4- Active (methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 28: 2-(6-(4-Acetylphenyl)-5-(2-hydroxyethoxy)pyridin-2-yl)-5,7- Active dimethoxyquinazolin-4(3H)-one Example 29: 5,7-Dimethoxy-2-(6-(4-(methylsulfonyl)phenyl)-5-(2- Active (pyrrolidin-1-yl)ethoxy)pyridin-2-yl)quinazolin-4(3H)-one hydrochloride Example 31: 5,7-Dimethoxy-2-(6-(4-(methylsulfonyl)phenyl)-5-(2- Active morpholinoethoxy)pyridin-2-yl)quinazolin-4(3H)-one hydrochloride Example 32: 2-(5-(2-(Isopropylamino)ethoxy)-6-(2- Not Active (methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 33: 2-(5-(2-(Isopropylamino)ethoxy)-6-(3- Not Active (methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 34: 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2-hydroxyethoxy)pyridin- Active 2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 35: 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2- Not Active (isopropylamino)ethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 36: 2-(5-(2-Hydroxyethoxy)-6-(3- Not Active (methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one methanesulfonate Example 37: 2-(5-(2-Hydroxyethoxy)-6-(3-(methylsulfinyl)phenyl)pyridin- Active 2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 38: 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin- Active 2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 39: 2-(5-(2-Hydroxyethoxy)-6-(2-methyl-4- Active (methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 40: 2-(5-(2-(Isopropylamino)ethoxy)-6-(3- Active (methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 41: 2-(5-(2-(Isopropylamino)ethoxy)-6-(4- Active (methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 42: 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2-(pyrrolidin-1- Active yl)ethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 43: 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2- Active morpholinoethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 44: 2-(6-(2-(Isopropylamino)ethoxy)-4′-(methylsulfonyl)-[1,1′- Active biphenyl]-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 45: 2-(5-(2-(Isopropylamino)ethoxy)-6-(2-methyl-4- Active (methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 46: 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)-2- Active (trifluoromethyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 47: 5,7-Dimethoxy-2-(4′-(methylsulfinyl)-[1,1′-biphenyl]-3- Not Active yl)quinazolin-4(3H)-one Example 48: 5,7-Dimethoxy-2-(4-(4-(methylsulfinyl)phenyl)thiophen-2- Active yl)quinazolin-4(3H)-one Example 49: 5,7-Dimethoxy-2-(6-(4-(methylsulfinyl)phenyl)pyridin-2- Active yl)quinazolin-4(3H)-one Example 50: 5,7-Dimethoxy-2-(5-methoxy-6-(4- Active (methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one Example 51: 5,7-Dimethoxy-2-(3-(5-(methylsulfinyl)thiophen-2- Active yl)phenyl)quinazolin-4(3H)-one Example 52: 5,7-Dimethoxy-2-(7-(4-(methylsulfinyl)phenyl)-1H-indol-5- Active yl)quinazolin-4(3H)-one Example 53: tert-Butyl (2-((6-(5,7-dimethoxy-4-oxo-3,4- Not Active dihydroquinazolin-2-yl)-2-(4-(methylsulfinyl)phenyl)pyridin-3- yl)oxy)ethyl)(isopropyl)carbamate Example 54: 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3- Active methoxypyridin-2-yl)-N,N,3-trimethylbenzamide Example 55: 5,7-Dimethoxy-2-(6-(4-(methylsulfinyl)phenyl)-5-(2- Active (pyrrolidin-1-yl)ethoxy)pyridin-2-yl)quinazolin-4(3H)-one Example 56: 3-Chloro-4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin- Active 2-yl)-3-methoxypyridin-2-yl)-N,N-dimethylbenzamide Example 57: 5-Methoxy-2-(5-methoxy-6-(4- Active (methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one Example 58: 5,7-Dimethoxy-2-(5-methoxy-6-(4- Active (methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one Example 59: 2-Chloro-5′-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Active yl)-2′-methoxy-N,N-dimethyl-[1,1′-biphenyl]-4-carboxamide Example 60: 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin- Not Active 2-yl)-7-methoxyquinazolin-4(3H)-one Example 62: 2-(5-(2-Hydroxyethoxy)-6-(4- Active (methylsulfonyl)phenyl)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one Example 63: 1-(2-((6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)- Active 2-(4-(methylsulfonyl)phenyl)pyridin-3-yl)oxy)ethyl)pyrrolidine 1-oxide Example 64: 2-(5-(2-(Isopropylamino)ethoxy)-6-(4- Active (methylsulfonyl)phenyl)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one Example 65: 2-(5-(2-(Isopropylamino)ethoxy)-6-(4- Active (methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one Example 67: 2-(5-(2-lisopropylamino)ethoxy)-6-(4- Not Active (methylsulfonyl)phenyl)pyridin-2-yl)-7-methoxyquinazolin-4(3H)-one

Example 73: Inhibition of hVCAM mRNA Transcription

(475) In this example, hVCAMmRNA in tissue culture cells is quantitated to measure the transcriptional inhibition of hVCAM when treated with a compound of the present disclosure.

(476) Human umbilical vein endothelial cells (HUVECs) are plated in a 96-well plate (4.0×10.sup.3 cells/well) in 100 μL EGM media and incubated for 24 h prior to the addition of the compound of interest. The cells are pretreated for 1 h with the test compound prior to stimulation with tumor necrosis factor-α. The cells are incubated for an additional 24 h before the cells are harvested. At time of harvest, the spent media is removed from the HUVECs and rinsed in 200 μL PBS. Cell lysis solution (70 μL) is then added to the cells in each well and incubated for ˜5-10 min at room temperature, to allow for complete cell lysis and detachment. mRNA is then prepared using the “mRNA Catcher PLUS plate” (Invitrogen), according to the protocol supplied. After the last wash, as much wash buffer as possible is aspirated without allowing the wells to dry. Elution buffer (E3, 70 μL) is then added to each well. mRNA is then eluted by incubating the mRNA Catcher PLUS plate with elution buffer for 5 min at 68° C. and then immediately placing the plate on ice.

(477) The eluted mRNA so isolated is then used in a one-step quantitative real-time PCR reaction, using components of the Ultra Sense Kit together with Applied Biosystems primer-probe mixes. Real-time PCR data is analyzed, normalizing the Ct values for hVCAM to an internal control, prior to determining the fold induction of each unknown sample, relative to the control.

(478) Compounds with an IC.sub.50 value less than 30 μM are deemed to be active.

Example 74: Inhibition of hMCP-1 mRNA Transcrption

(479) In this example, hMCP-1 mRNA in human peripheral blood mononuclear cells was quantitated to measure the transcriptional inhibition of hMCP-1 when treated with a compound of the present disclosure.

(480) Human Peripheral Blood Mononuclear Cells were plated (1.0×10.sup.5 cells per well) in a 96-well plate in 45 μL RPMI-1640 containing 10% FBS and penicillin/streptomycin. The cells were treated with the test compound (45 μL at 2× concentration), and then the cells were incubated at 37° C. for 3 h before the cells were harvested. At time of harvest, cells were transferred to V-bottom plates and centrifuged at 800 rpm for 5 minutes. Spent media was removed and cell lysis solution (70 μL) was added the cells in each well and incubated for 5-10 min at room temperature, to allow for complete cell lysis and detachment. mRNA was then prepared using the “mRNA Catcher PLUS plate” (Invitrogen), according to the protocol supplied. After the last wash, as much wash buffer as possible was aspirated without allowing the wells to dry. Elution buffer (E3, 70 μL) was then added to each well. mRNA was then eluted by incubating the mRNA Catcher PLUS plate with Elution Buffer for 5 min at 68° C. and then immediately placing the plate on ice.

(481) The eluted mRNA isolated was then used in a one-step quantitative real-time PCR reaction, using components of the Ultra Sense Kit together with Applied Biosystems primer-probe mixes. Real-time PCR data was analyzed, normalizing the Ct values for hMCP-1 to an internal control, prior to determining the fold induction of each unknown sample, relative to the control.

(482) Compounds with an IC.sub.50 value less than 30 μM were deemed to be active.

(483) TABLE-US-00006 TABLE 5 Inhibition of hMCP-1 mRNA Transcrption MCP-1 Activity Name (IC.sub.50 < 30 μM) Example 41: 2-(5-(2-(Isopropylamino)ethoxy)-6- Active (4-(methylsulfinyl)phenyl)pyridin-2-yl)-5,7- dimethoxyquinazolin-4(3H)-one

Example 75: Up-Regulation of hApoA-1 mRNA Transcription

(484) In this example, ApoA-I mRNA in tissue culture cells was quantitated to measure the transcriptional up-regulation of ApoA-I when treated with a compound of the present disclosure.

(485) Huh7 cells (2.5×10.sup.5 per well) were plated in a 96-well plate using 100 μL DMEM per well, (Gibco DMEM supplemented with penicillin/streptomycin and 10% FBS), 24 h before the addition of the compound of interest. After 48 hrs treatment, the spent media was removed from the Huh-7 cells and placed on ice (for immediate use) or at −80° C. (for future use) with the “LDH cytotoxicity assay Kit II” from Abcam. The cells remaining in the plate were rinsed with 100 μL PBS.

(486) Then 85 μL of cell lysis solution was added to each well and incubated for 5-10 minutes at room temperature, to allow for complete cell lysis and detachment. mRNA was then prepared using the “mRNA Catcher PLUS plate” from Life Technologies, according to the protocol supplied. After the last wash, as much wash buffer as possible was aspirated without allowing the wells to dry. Elution Buffer (E3, 80 μL) was then added to each well. mRNA was then eluted by incubating the mRNA Catcher PLUS plate with Elution Buffer for 5 minutes at 68° C., and then 1 minute at 4° C. Catcher plates with mRNA eluted were kept on ice for use or stored at −80° C.

(487) The eluted mRNA isolated was then used in a one-step real-time PCR reaction, using components of the Ultra Sense Kit together with Life Technologies primer-probe mixes. Real-time PCR data was analyzed, using the Ct values, to determine the fold induction of each unknown sample, relative to the control (that is, relative to the control for each independent DMSO concentration).

(488) Compounds with an EC.sub.170 value less than 30 μM are deemed to be active.

(489) TABLE-US-00007 TABLE 6 Up-regulation of hApoA-1 mRNA transcription. ApoA-1 Activity Name (EC.sub.170 < 30 μM) Example 3: 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2- Active hydroxyethoxy)pyridin-2-yl)-N,N,3-trimethylbenzamide. Example 4: 4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2- Active (isopropylamino)ethoxy)pyridin-2-yl)-N,N,3-trimethylbenzamide Example 5: 3-Chloro-4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Active yl)-3-(2-hydroxyethoxy)pyridin-2-yl)-N,N-dimethylbenzamide Example 6: 3-Chloro-4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Active yl)-3-(2-(isopropylamino)ethoxy)pyridin-2-yl)-N,N-dimethylbenzamide Example 15: 7-Fluoro-5-methoxy-2-(6-((1-methylazetidin-3-yl)oxy)-4′- Active (methylsulfinyl)-[1,1′-biphenyl]-3-yl)quinazolin-4(3H)-one Example 17: 2-(6-(2-(Isopropylamino)ethoxy)-4′- Active (methylsulfinyl)biphenyl-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 18: 2′-(Azetidin-3-yloxy)-5′-(5,7-dimethoxy-4-oxo-3,4- Active dihydroquinazolin-2-yl)-[1,1′-biphenyl]-4-carbonitrile Example 19: 5′-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2′-((1- Active methylazetidin-3-yl)oxy)-[1,1′-biphenyl]-4-carbonitrile Example 20: 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Active yl)pyridin-2-yl)-N,N-dimethylbenzamide Example 23: 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3- Active (2-hydroxyethoxy)pyridin-2-yl)-N,N-dimethylbenzamide Example 24: 2-(5-(2-Hydroxyethoxy)-6-(4- Active (methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 26: 4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(2- Active (isopropylamino)ethoxy)pyridin-2-yl)-N,N-dimethylbenzamide Example 27: 2-(5-(2-(Isopropylamino)ethoxy)-6-(4- Active (methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 29: 5,7-Dimethoxy-2-(6-(4-(methylsulfonyl)phenyl)-5-(2- Active (pyrrolidin-1-yl)ethoxy)pyridin-2-yl)quinazolin-4(3H)-one hydrochloride Example 37: 2-(5-(2-Hydroxyethoxy)-6-(3-(methylsulfinyl)phenyl)pyridin- Active 2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 38: 2-(5-(2-Hydroxyethoxy)-6-(4-(methylsulfinyl)phenyl)pyridin- Active 2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 39: 2-(5-(2-Hydroxyethoxy)-6-(2-methyl-4- Active (methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 40: 2-(5-(2-(Isopropylamino)ethoxy)-6-(3- Active (methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 41: 2-(5-(2-(Isopropylamino)ethoxy)-6-(4- Active (methylsulfinyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 42: 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2-(pyrrolidin-1- Not Active yl)ethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 43: 2-(6-(4-(Ethylsulfonyl)phenyl)-5-(2- Active morpholinoethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 44: 2-(6-(2-(Isopropylamino)ethoxy)-4′-(methylsulfonyl)-[1,1′- Active biphenyl]-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 45: 2-(5-(2-(Isopropylamino)ethoxy)-6-(2-methyl-4- Active (methylsulfonyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 46: 2-(5-(2-(Isopropylamino)ethoxy)-6-(4-(methylsulfonyl)-2- Active (trifluoromethyl)phenyl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Example 49: 5,7-Dimethoxy-2-(6-(4-(methylsulfinyl)phenyl)pyridin-2- Active yl)quinazolin-4(3H)-one Example 50: 5,7-Dimethoxy-2-(5-methoxy-6-(4- Active (methylsulfinyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one Example 53: tert-Butyl (2-((6-(5,7-dimethoxy-4-oxo-3,4- Active dihydroquinazolin-2-yl)-2-(4-(methylsulfinyl)phenyl)pyridin-3- yl)oxy)ethyl)(isopropyl)carbamate Example 55: 5,7-Dimethoxy-2-(6-(4-(methylsulfinyl)phenyl)-5-(2- Active (pyrrolidin-1-yl)ethoxy)pyridin-2-yl)quinazolin-4(3H)-one Example 59: 2-Chloro-5′-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Active yl)-2′-methoxy-N,N-dimethyl-[1,1′-biphenyl]-4-carboxamide Example 67: 2-(5-(2-lisopropylamino)ethoxy)-6-(4- Active (methylsulfonyl)phenyl)pyridin-2-yl)-7-methoxyquinazolin-4(3H)-one

Examples 76: In Vivo Efficacy in Mouse Endotoxemia Model Assay

(490) Sub lethal doses of Endotoxin (E. coli bacterial lipopolysaccharide) were administered to animals to produce a generalized inflammatory response which was monitored by increases in secreted cytokines. Compounds were administered to C57/B16 mice orally at 75 mg/kg dose to evaluate inhibition in IL-6 and IL-17 cytokines post 4 hour challenge with Lipopolysaccharide (LPS) at 0.5 mg/kg dose intraperitoneally.

(491) TABLE-US-00008 TABLE 7 In Vivo Mouse Efficacy in Endotoxemia Model Assay. In vivo In vivo Activity Activity Name (IL-6) (IL-17) Example 27: 2-(5-(2-(Isopropylamino)ethoxy)-6- Active Not (4-(methylsulfonyl)phenyl)pyridin-2-yl)-5,7- Active dimethoxyquinazolin-4(3H)-one

Example 77: In Vivo Efficacy in Rat Collagen Induced Arthritis

(492) Rat collagen-induced arthritis is an experimental model of polyarthritis that has been widely used for preclinical testing of numerous anti-arthritic agents. Following administration of collagen, this model establishes a measurable polyarticular inflammation, marked cartilage destruction in association with pannus formation and mild to moderate bone resorption and periosteal bone proliferation. In this model, collagen was administered to female Lewis strain of rats on Day 1 and 7 of study and dosed with compounds from Day 11 to Day 17. Compounds were evaluated to assess the potential to inhibit the inflammation (including paw swelling), cartilage destruction and bone resorption in arthritic rats, using a model in which the treatment is administered after the disease has been established.

(493) TABLE-US-00009 TABLE 8 In Vivo Efficacy in Rat Collagen Induced Arthritis. In vivo Name Activity Example 41: 2-(5-(2-(Isopropylamino)ethoxy)-6- Active (4-(methylsulfinyl)phenyl)pyridin-2-yl)-5,7- dimethoxyquinazolin-4(3H)-one Example 50: 5,7-Dimethoxy-2-(5-methoxy-6- Active (4-(methylsulfinyl)phenyl)pyridin-2- yl)quinazolin-4(3H)-one

Example 78: In Vivo Efficacy in Athymic Nude Mouse Strain of an Acute Myeloid Leukemia Xenograft Model Using MV4-11 Cells

(494) MV4-11 cells (ATCC) are grown under standard cell culture conditions and (NCr) nu/nu fisol strain of female mice age 6-7 weeks are injected 5 e.sup.6 cells/animal in 100 μl PBS+100 μl Matrigel in lower left abdominal flank. Approximately by day 18 after MV4-11 cells injection, mice are randomized based on tumor volume (L×W×H)/2) of average ˜120 mm.sup.3. Mice are dosed orally with the test compound at 75 mg/kg b.i.d and 120 mg/kg b.i.d in EA006 formulation at 10 ml/kg body weight dose volume. Tumor measurements are taken with electronic micro caliper and body weights measured on alternate days beginning from dosing period. The average tumor volumes, percent Tumor Growth Inhibition (TGI) and % change in body weights are compared relative to Vehicle control animals. The means, statistical analysis and the comparison between groups are calculated using student's t-test in Excel.

(495) Other embodiments of the present disclosure will be apparent to those skilled in the art from consideration of the specification and practice of the present disclosure disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the present disclosure being indicated by the following claims.