Anti-inflammatory agents

Abstract

Disclosed are methods of regulating interleukin-6 (IL-6) and/or vascular cell adhesion molecule-1 (VCAM-1) and methods of treating and/or preventing cardiovascular and inflammatory diseases and related disease states, such as, for example, atherosclerosis, asthma, arthritis, cancer, multiple sclerosis, psoriasis, and inflammatory bowel diseases, and autoimmune disease(s) by administering a naturally occurring or synthetic quinazolone derivative. The invention provides novel synthetic quinazolone compounds, as well as pharmaceutical compositions comprising those compounds.

Claims

1. A method of treating or reducing the risk of acquiring asthma, chronic obstructive pulmonary disease (COPD), or a non-cardiovascular inflammatory disease mediated by IL-6 in a subject in need thereof, comprising administering a therapeutically effective amount of a composition consisting essentially of a compound of Formula II: ##STR00073## or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein: P is selected from N and CRa.sub.1; V is selected from N and CRa.sub.4; W is selected from N and CH; U is selected from C═O, C═S, SO.sub.2, S═O, and SR.sub.1; Ra.sub.1 and Ra.sub.4 are independently selected from hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.6 cycloalkyl, and halogen; Ra.sub.3 is selected from hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.6 cycloalkyl, and halogen, wherein the C.sub.1-C.sub.6 alkoxy is optionally ##STR00074## n is 1, 2, or 3; and R.sub.5 is C.sub.1-C.sub.6 alkyl substituted with phenyl or heteroaryl; Ra.sub.2 is selected from hydrogen, C.sub.1-C.sub.6 alkyl optionally substituted with heterocyclyl, C.sub.1-C.sub.6 alkoxy, heterocycle, amino, amide, fluoro, and bromo; Rb.sub.2 and Rb.sub.6 are independently selected from hydrogen, methyl, and fluoride; Rb.sub.3 and Rb.sub.5 are independently selected from hydrogen, C.sub.1-C.sub.6 alkyl optionally substituted with heterocyclyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 alkoxy, halogen, and amino; Rb.sub.2 and Rb.sub.3 and/or Rb.sub.5 and Rb.sub.6 may be connected to form a cycloalkyl, phenyl or heterocycle; and XRd is selected from 2-hydroxyethoxy, 2,3-dihydroxypropoxy, aminocarbonylethoxy, methylaminocarbonylethoxy, (4-methoxyphenyl)aminocarbonylethoxy, benzylaminocarbonylethoxy, 4-hydroxybutoxy, methylcarbonylaminoethoxy, methylcarbonylaminomethyl, (2,2,2-trifluoro-ethylamino)ethoxy, methanesulfonylaminoethoxy, isobutyrylaminoethoxy, methylaminoethoxy, isopropylsulfonylaminoethoxy, methylcarbonylaminoethoxy, dimethylaminoethoxy, N-(2-hydroxyethyl)-N-methylacetamide, formamide-N-2-ethoxy, methylformamide-N-2-ethoxy, dimethylsulfonylaminoethoxy, cyanoaminoethoxy, 3-hydroxypropyl, and 2-hydroxyethyl, provided that at least one of Ra.sub.1, Ra.sub.2, Ra.sub.1, and Ra.sub.4 is not hydrogen; and if —XRd is —OCH.sub.2CH.sub.2OH, then Rb.sub.3 is not pyrrolidine.

2. The method according to claim 1, wherein: U is C═O P is CRa.sub.1; Ra.sub.1 is selected from hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, and halogen; Ra.sub.2 is selected from hydrogen, C.sub.1-C.sub.6 alkyl optionally substituted with heterocyclyl, C.sub.1-C.sub.6 alkoxy, heterocycle, amide, and amino; Ra.sub.4 is selected from hydrogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkyl, and halogen; Ra.sub.3 is selected from hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, and halogen, wherein the C.sub.1-C.sub.6 alkoxy is optionally ##STR00075## n is 1, 2, or 3; and R.sub.5 is C.sub.1-C.sub.6 alkyl substituted with phenyl or heteroaryl; and Rb.sub.3 and Rb.sub.5 are independently selected from hydrogen, C.sub.1-C.sub.6 alkyl optionally substituted with heterocyclyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 alkoxy, halogen, and amino, wherein Rb.sub.2 and Rb.sub.3 and/or Rb.sub.5 and Rb.sub.6 may be connected to form a phenyl ring.

3. The method according to claim 2, wherein Ra.sub.1 is selected from hydrogen, unsubstituted C.sub.1-C.sub.6 alkyl, unsubstituted C.sub.1-C.sub.6 alkoxy, and halogen.

4. The method according to claim 2, wherein Ra.sub.2 is selected from hydrogen, C.sub.1-C.sub.6 alkyl substituted with heterocyclyl, unsubstituted C.sub.1-C.sub.6 alkoxy, amino, and heterocycle.

5. The method according to claim 2, wherein: Ra.sub.3 is selected from hydrogen, methoxy, unsubstituted C.sub.1-C.sub.6 alkyl, halogen, and ##STR00076## n is 1, 2, or 3; and R.sub.5 is C.sub.1-C.sub.6 alkyl substituted with phenyl or heteroaryl.

6. The method according to claim 2, wherein Ra.sub.4 is selected from hydrogen, unsubstituted C.sub.1-C.sub.6 alkoxy, and halogen.

7. The method according to claim 2, wherein Rb.sub.3 and Rb.sub.5 are independently selected from hydrogen, methyl, C.sub.1-C.sub.6 alkyl substituted with heterocyclyl, and unsubstituted C.sub.1-C.sub.6 alkoxy wherein Rb.sub.2 and Rb.sub.3 and/or Rb.sub.5 and Rb.sub.6 may be connected to form a phenyl ring.

8. The method according to claim 7, wherein Rb.sub.3 and Rb.sub.5 are independently selected from hydrogen, methyl, methoxy, and morpholinomethyl, and wherein Rb.sub.2 and Rb.sub.3 and/or Rb.sub.5 and Rb.sub.6 may be connected to form a phenyl ring.

9. A method of treating or reducing the risk of acquiring a non-cardiovascular inflammatory disease mediated by IL-6 in a subject in need thereof, comprising administering a therapeutically effective amount of a composition consisting essentially of a compound selected from: 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one; N-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide; 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-morpholinoquinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethylpyrido[2,3-d]pyrimidin-4(3H)-one; 5,7-difluoro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one; 5,7-dichloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one; 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-diisopropoxy-3H-quinazolin-4-one; 2-[4-(2-hydroxyethoxy)-3,5-dimethyl-phenyl]-6-morpholin-4-ylmethyl-3H-quinazolin-4-one; 2-[4-(2,3-Dihydroxy-propoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one; 2-[4-(2-hydroxy-ethoxy)-3,5-dimethylphenyl]-5,7-dimethoxy-6-morpholin-4-ylmethyl-3H-quinazolin-4-one; 2-[4-(2-hydroxy-ethoxy)-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one; 2-[4-(2-hydroxy-ethoxy)-naphthalen-1-yl]-5,7-dimethoxy-3H-quinazolin-4-one; 7-(2-benzyloxy-ethoxy)-2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5-methoxy-3H-quinazolin-4-one; 7-(2-benzyloxy-ethoxy)-2-(2-hydroxymethyl-benzofuran-5-yl)-5-methoxy-3H-quinazolin-4-one; 2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy]-acetamide; 2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy]-N-methyl-acetamide; 2-[4-(5,7-Dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy]-N-(4-methoxy-phenyl)-acetamide; N-benzyl-2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy]acetamide; 2-[4-(4-hydroxy-butoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one; 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-methoxyquinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5-methoxyquinazolin-4(3H)-one; 7-chloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one; 8-chloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-8-methoxyquinazolin-4(3H)-one; 5-chloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-7-methoxyquinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-((4-methylpiperazin-1-yl)methyl)quinazolin-4(3H)-one; N-{2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-2,6-dimethyl-phenoxy]-ethyl}-acetamide; N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylbenzyl)acetamide; N-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-2,6-dimethyl-benzyl]-acetamide; 2-{3,5-Dimethyl-4-[2-(2,2,2-trifluoro-ethylamino)-ethoxy]-phenyl}-5,7-dimethoxy-3H-quinazolin-4-one; N-{2-[4-(6, 8-Dimethoxy-1-oxo-1,2-dihydro-isoquinolin-3-yl)-2,6-dimethyl-phenoxy]-ethyl}-formamide; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)methanesulfonamide; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methoxybenzamide; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)acetamide; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)isobutyramide; 2-(3,5-dimethyl-4-(2-(methylamino)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)propane-2-sulfonamide; 2-(4-(2-(isopropylamino)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylphenoxy)ethyl)acetamide; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylphenoxy)ethyl)isobutyramide; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylphenoxy)ethyl)methanesulfonamide; 2-(4-(2-(dimethylamino)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2, 6-dimethylphenoxy)ethyl)-N-methylacetamide; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2, 6-dimethylphenoxy)ethyl)formamide; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2, 6-dimethylphenoxy)ethyl)-N-methylformamide; N-(2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)dimethylamino-N-sulfonamide; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2, 6-dimethylphenoxy)ethyl)cyanamide; 2-[4-(3-hydroxy-propyl)-3,5-dimethoxyphenyl]-5,7-dimethoxy-3H-quinazolin-4-one; 2-[4-(3-hydroxy-propyl)-3-methoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one; 2-[2-(2-hydroxyethyl)-1H-indol-6-yl]-5,7-dimethoxy-3H-quinazolin-4-one, and tautomers, stereoisomers, pharmaceutically acceptable salts and hydrates thereof.

10. The method according to claim 1, wherein the therapeutically effective amount of the compound is administered with at least one pharmaceutically acceptable carrier in a pharmaceutically acceptable composition.

11. The method according to claim 1, wherein the disease is selected from cystic fibrosis, post transplantation late and chronic solid organ rejection, systemic lupus erythematosus, ocular inflammation, uveitis, rhinitis, glomerulonephritis, Grave's disease, gastrointestinal allergies, and conjunctivitis.

12. A method for treating a cancer associated with elevated levels of IL-6, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of Formula II: ##STR00077## or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein: P is selected from N and CRa.sub.1; V is selected from N and CRa.sub.4; W is selected from N and CH; U is selected from C═O, C═S, SO.sub.2, S═O, and SR.sub.1; Ra.sub.1 and Ra.sub.4 are independently selected from hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.6 cycloalkyl, and halogen; Ra.sub.3 is selected from hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.6 cycloakyl, and halogen, wherein the C.sub.1-C.sub.6 alkoxy is optionally ##STR00078## n is 1, 2, or 3; and R.sub.5 is C.sub.1-C.sub.6 alkyl substituted with phenyl or heteroaryl; Ra.sub.2 is selected from hydrogen, C.sub.1-C.sub.6 alkyl optionally substituted with heterocyclyl, C.sub.1-C.sub.6 alkoxy, heterocycle, amino, amide, fluoro, and bromo; Rb.sub.2 and Rb.sub.6 are independently selected from hydrogen, methyl, and fluoride; Rb.sub.3 and Rb.sub.5 are independently selected from hydrogen, C.sub.1-C.sub.6 alkyl optionally substituted with heterocyclyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 alkoxy, halogen, and amino; Rb.sub.2 and Rb.sub.3 and/or Rb.sub.5 and Rb.sub.6 may be connected to form a cycloalkyl, phenyl or heterocycle; and XRd is selected from 2-hydroxyethoxy, 2,3-dihydroxypropoxy, aminocarbonylethoxy, methylaminocarbonylethoxy, (4-methoxyphenyl)aminocarbonylethoxy, benzylaminocarbonylethoxy, 4-hydroxybutoxy, methylcarbonylaminoethoxy, methylcarbonylaminomethyl, (2,2,2-trifluoro-ethylamino)ethoxy, methanesulfonylaminoethoxy, isobutyrylaminoethoxy, methylaminoethoxy, isopropylsulfonylaminoethoxy, methylcarbonylaminoethoxy, dimethylaminoethoxy, N-(2-hydroxyethyl)-N-methylacetamide, formamide-N-2-ethoxy, methylformamide-N-2-ethoxy, dimethylsulfonylaminoethoxy, cyanoaminoethoxy, 3-hydroxypropyl, and 2-hydroxyethyl, provided that at least one of Ra.sub.1, Ra.sub.2, Ra.sub.3, and Ra.sub.4 is not hydrogen; and if —XRd is —OCH.sub.2CH.sub.2OH, then Rb.sub.3 is not pyrrolidine.

13. The method according to claim 12, wherein: U is C═O P is CRa.sub.1; Ra.sub.1 is selected from hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, and halogen; Ra.sub.2 is selected from hydrogen, C.sub.1-C.sub.6 alkyl optionally substituted with heterocyclyl, C.sub.1-C.sub.6 alkoxy, heterocycle, amide, and amino; Ra.sub.4 is selected from hydrogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkyl, and halogen; Ra.sub.3 is selected from hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, and halogen, wherein the C.sub.1-C.sub.6 alkoxy is optionally ##STR00079## n is 1, 2, or 3; and R.sub.5 is C.sub.1-C.sub.6 alkyl substituted with phenyl or heteroaryl; and Rb.sub.3 and Rb.sub.5 are independently selected from hydrogen, C.sub.1-C.sub.6 alkyl optionally substituted with heterocyclyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 alkoxy, halogen, and amino, wherein Rb.sub.2 and Rb.sub.3 and/or Rb.sub.5 and Rb.sub.6 may be connected to form a phenyl ring.

14. The method according to claim 13, wherein Ra.sub.1 is selected from hydrogen, unsubstituted C.sub.1-C.sub.6 alkyl, unsubstituted C.sub.1-C.sub.6 alkoxy, and halogen.

15. The method according to claim 13, wherein Ra.sub.2 is selected from hydrogen, C.sub.1-C.sub.6 alkyl substituted with heterocyclyl, unsubstituted C.sub.1-C.sub.6 alkoxy, amino, and heterocycle.

16. The method according to claim 13, wherein: Ra.sub.3 is selected from selected from hydrogen, methoxy, unsubstituted C.sub.1-C.sub.6 alkyl, halogen, and ##STR00080## n is 1, 2, or 3; and R.sub.5 is C.sub.1-C.sub.6 alkyl substituted with phenyl or heteroaryl.

17. The method according to claim 13, wherein Ra.sub.4 is selected from hydrogen, unsubstituted C.sub.1-C.sub.6 alkoxy, and halogen.

18. The method according to claim 13, wherein Rb.sub.3 and Rb.sub.5 are independently selected from hydrogen, methyl, C.sub.1-C.sub.6 alkyl substituted with heterocyclyl, and unsubstituted C.sub.1-C.sub.6 alkoxy wherein Rb.sub.2 and Rb.sub.3 and/or Rb.sub.5 and Rb.sub.6 may be connected to form a phenyl ring.

19. The method according to claim 18, wherein Rb.sub.3 and Rb.sub.5 are independently selected from hydrogen, methyl, methoxy, and morpholinomethyl, and wherein Rb.sub.2 and Rb.sub.3 and/or Rb.sub.5 and Rb.sub.6 may be connected to form a phenyl ring.

20. A method for treating a cancer associated with elevated levels of IL-6, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound selected from: 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one; N-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide; 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-morpholinoquinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethylpyrido[2,3-d]pyrimidin-4(3H)-one; 5,7-difluoro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one; 5,7-dichloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one; 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-diisopropoxy-3H-quinazolin-4-one; 2-[4-(2-hydroxyethoxy)-3,5-dimethyl-phenyl]-6-morpholin-4-ylmethyl-3H-quinazolin-4-one; 2-[4-(2,3-Dihydroxy-propoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one; 2-[4-(2-hydroxy-ethoxy)-3,5-dimethylphenyl]-5,7-dimethoxy-6-morpholin-4-ylmethyl-3H-quinazolin-4-one; 2-[4-(2-hydroxy-ethoxy)-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one; 2-[4-(2-hydroxy-ethoxy)-naphthalen-1-yl]-5,7-dimethoxy-3H-quinazolin-4-one; 7-(2-benzyloxy-ethoxy)-2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5-methoxy-3H-quinazolin-4-one; 7-(2-benzyloxy-ethoxy)-2-(2-hydroxymethyl-benzofuran-5-yl)-5-methoxy-3H-quinazolin-4-one; 2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy]-acetamide; 2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy]-N-methyl-acetamide; 2-[4-(5,7-Dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy]-N-(4-methoxy-phenyl)-acetamide; N-benzyl-2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy]acetamide; 2-[4-(4-hydroxy-butoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one; 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-methoxyquinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5-methoxyquinazolin-4(3H)-one; 7-chloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one; 8-chloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-8-methoxyquinazolin-4(3H)-one; 5-chloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-7-methoxyquinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-((4-methylpiperazin-1-yl)methyl)quinazolin-4(3H)-one; N-{2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-2,6-dimethyl-phenoxy]-ethyl}-acetamide; N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylbenzyl)acetamide; N-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-2,6-dimethyl-benzyl]-acetamide; 2-{3,5-Dimethyl-4-[2-(2,2,2-trifluoro-ethylamino)-ethoxy]-phenyl}-5,7-dimethoxy-3H-quinazolin-4-one; N-{2-[4-(6, 8-Dimethoxy-1-oxo-1,2-dihydro-isoquinolin-3-yl)-2,6-dimethyl-phenoxy]-ethyl}-formamide; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)methanesulfonamide; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methoxybenzamide; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)acetamide; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)isobutyramide; 2-(3,5-dimethyl-4-(2-(methylamino)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)propane-2-sulfonamide; 2-(4-(2-(isopropylamino)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylphenoxy)ethyl)acetamide; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylphenoxy)ethyl)isobutyramide; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylphenoxy)ethyl)methanesulfonamide; 2-(4-(2-(dimethylamino)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-N-methylacetamide; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2, 6-dimethylphenoxy)ethyl)formamide; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2, 6-dimethylphenoxy)ethyl)-N-methylformamide; N-(2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)dimethylamino-N-sulfonamide; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2, 6-dimethylphenoxy)ethyl)cyanamide; 2-[4-(3-hydroxy-propyl)-3,5-dimethoxyphenyl]-5,7-dimethoxy-3H-quinazolin-4-one; 2-[4-(3-hydroxy-propyl)-3-methoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one; and 2-[2-(2-hydroxyethyl)-1H-indol-6-yl]-5,7-dimethoxy-3H-quinazolin-4-one, and tautomers, stereoisomers, pharmaceutically acceptable salts, and hydrates thereof.

21. The method according to claim 12, wherein the therapeutically effective amount of the compound is administered with at least one pharmaceutically acceptable carrier in a pharmaceutically acceptable composition.

22. The method according to claim 12, wherein the cancer is selected from multiple myeloma, lymphoma, leukemia, solid tumors, prostate and bladder cancers, cardiac myxoma, tumor-induced cachexia, cancer-associated depression, cerebral edema secondary to brain tumors, hormone-independent prostate cancer, B cell lymphoma, AIDS-associated lymphoma, and metastatic renal cell carcinoma.

23. A method of treating or reducing the risk of acquiring asthma chronic obstructive pulmonary disease (COPD), or a non-cardiovascular inflammatory disease mediated by IL-6 in a subject in need thereof, comprising administering a therapeutically effective amount of at least one compound of Formula II: ##STR00081## or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein: P is selected from N and CRa.sub.1; V is selected from N and CRa.sub.4; W is selected from N and CH; U is selected from C═O, C═S, SO.sub.2, S═O, and SR.sub.1; Ra.sub.1 and Ra.sub.4 are independently selected from hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.6 cycloalkyl, and halogen; Ra.sub.3 is selected from hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.6 cycloakyl, and halogen, wherein the C.sub.1-C.sub.6 alkoxy is optionally ##STR00082## n is 1, 2, or 3; and R.sub.5 is C.sub.1-C.sub.6 alkyl substituted with phenyl or heteroaryl; Ra.sub.2 is selected from hydrogen, C.sub.1-C.sub.6 alkyl optionally substituted with heterocyclyl, C.sub.1-C.sub.6 alkoxy, heterocycle, amino, amide, fluoro, and bromo; Rb.sub.2 and Rb.sub.6 are independently selected from hydrogen, methyl, and fluoride; Rb.sub.3 and Rb.sub.5 are independently selected from hydrogen, C.sub.1-C.sub.6 alkyl optionally substituted with heterocyclyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 alkoxy, halogen, and amino; Rb.sub.2 and Rb.sub.3 and/or Rb.sub.5 and Rb.sub.6 may be connected to form a cycloalkyl, phenyl or heterocycle; and XRd is selected from 2-hydroxyethoxy, 2,3-dihydroxypropoxy, aminocarbonylethoxy, methylaminocarbonylethoxy, (4-methoxyphenyl)aminocarbonylethoxy, benzylaminocarbonylethoxy, 4-hydroxybutoxy, methylcarbonylaminoethoxy, methylcarbonylaminomethyl, (2,2,2-trifluoro-ethylamino)ethoxy, methanesulfonylaminoethoxy, isobutyrylaminoethoxy, methylaminoethoxy, isopropylsulfonylaminoethoxy, methylcarbonylaminoethoxy, dimethylaminoethoxy, N-(2-hydroxyethyl)-N-methylacetamide, formamide-N-2-ethoxy, methylformamide-N-2-ethoxy, dimethylsulfonylaminoethoxy, cyanoaminoethoxy, 3-hydroxypropyl, and 2-hydroxyethyl, provided that at least one of Ra.sub.1, Ra.sub.2, Ra.sub.3, and Ra.sub.4 is not hydrogen; if —XRd is —OCH.sub.2CH.sub.2OH, then Rb.sub.3 is not pyrrolidine; and wherein the compound is not 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one.

24. The method according to claim 23, wherein: U is C═O P is CRa.sub.1; Ra.sub.1 is selected from hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, and halogen; Ra.sub.2 is selected from hydrogen, C.sub.1-C.sub.6 alkyl optionally substituted with heterocyclyl, C.sub.1-C.sub.6 alkoxy, heterocycle, amide, and amino; Ra.sub.4 is selected from hydrogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkyl, and halogen; Ra.sub.3 is selected from hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, and halogen, wherein the C.sub.1-C.sub.6 alkoxy is optionally ##STR00083## n is 1, 2, or 3; and R.sub.5 is C.sub.1-C.sub.6 alkyl substituted with phenyl or heteroaryl; and Rb.sub.3 and Rb.sub.5 are independently selected from hydrogen, C.sub.1-C.sub.6 alkyl optionally substituted with heterocyclyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 alkoxy, halogen, and amino, wherein Rb.sub.2 and Rb.sub.3 and/or Rb.sub.5 and Rb.sub.6 may be connected to form a phenyl ring.

25. The method according to claim 24, wherein Ra.sub.1 is selected from hydrogen, unsubstituted C.sub.1-C.sub.6 alkyl, unsubstituted C.sub.1-C.sub.6 alkoxy, and halogen.

26. The method according to claim 24, wherein Ra.sub.2 is selected from hydrogen, C.sub.1-C.sub.6 alkyl substituted with heterocyclyl, unsubstituted C.sub.1-C.sub.6 alkoxy, amino, and heterocycle.

27. The method according to claim 24, wherein: Ra.sub.3 is selected from selected from hydrogen, methoxy, unsubstituted C.sub.1-C.sub.6 alkyl, halogen, and ##STR00084## n is 1, 2, or 3; and R.sub.5 is C.sub.1-C.sub.6 alkyl substituted with phenyl or heteroaryl.

28. The method according to claim 24, wherein Ra.sub.4 is selected from hydrogen, unsubstituted C.sub.1-C.sub.6 alkoxy, and halogen.

29. The method according to claim 24, wherein Rb.sub.3 and Rb.sub.5 are independently selected from hydrogen, methyl, C.sub.1-C.sub.6 alkyl substituted with heterocyclyl, and unsubstituted C.sub.1-C.sub.6 alkoxy wherein Rb.sub.2 and Rb.sub.3 and/or Rb.sub.5 and Rb.sub.6 may be connected to form a phenyl ring.

30. The method according to claim 29, wherein Rb.sub.3 and Rb.sub.5 are independently selected from hydrogen, methyl, methoxy, and morpholinomethyl, and wherein Rb.sub.2 and Rb.sub.3 and/or Rb.sub.5 and Rb.sub.6 may be connected to form a phenyl ring.

31. A method of treating or reducing the risk of acquiring a non-cardiovascular inflammatory disease mediated by IL-6 in a subject in need thereof, comprising administering a therapeutically effective amount of at least one compound selected from: 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one; N-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide; 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-morpholinoquinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethylpyrido[2,3-d]pyrimidin-4(3H)-one; 5,7-difluoro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one; 5,7-dichloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one; 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-diisopropoxy-3H-quinazolin-4-one; 2-[4-(2-hydroxyethoxy)-3,5-dimethyl-phenyl]-6-morpholin-4-ylmethyl-3H-quinazolin-4-one; 2-[4-(2,3-Dihydroxy-propoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one; 2-[4-(2-hydroxy-ethoxy)-3,5-dimethylphenyl]-5,7-dimethoxy-6-morpholin-4-ylmethyl-3H-quinazolin-4-one; 2-[4-(2-hydroxy-ethoxy)-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one; 2-[4-(2-hydroxy-ethoxy)-naphthalen-1-yl]-5,7-dimethoxy-3H-quinazolin-4-one; 7-(2-benzyloxy-ethoxy)-2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5-methoxy-3H-quinazolin-4-one; 7-(2-benzyloxy-ethoxy)-2-(2-hydroxymethyl-benzofuran-5-yl)-5-methoxy-3H-quinazolin-4-one; 2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy]-acetamide; 2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy]-N-methyl-acetamide; 2-[4-(5,7-Dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy]-N-(4-methoxy-phenyl)-acetamide; N-benzyl-2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy]acetamide; 2-[4-(4-hydroxy-butoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one; 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-methoxyquinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5-methoxyquinazolin-4(3H)-one; 7-chloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one; 8-chloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-8-methoxyquinazolin-4(3H)-one; 5-chloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-7-methoxyquinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-((4-methylpiperazin-1-yl)methyl)quinazolin-4(3H)-one; N-{2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-2,6-dimethyl-phenoxy]-ethyl}-acetamide; N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylbenzyl)acetamide; N-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-2,6-dimethyl-benzyl]-acetamide; 2-{3,5-Dimethyl-4-[2-(2,2,2-trifluoro-ethylamino)-ethoxy]-phenyl}-5,7-dimethoxy-3H-quinazolin-4-one; N-{2-[4-(6, 8-Dimethoxy-1-oxo-1,2-dihydro-isoquinolin-3-yl)-2,6-dimethyl-phenoxy]-ethyl}-formamide; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)methanesulfonamide; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methoxybenzamide; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)acetamide; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)isobutyramide; 2-(3,5-dimethyl-4-(2-(methylamino)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)propane-2-sulfonamide; 2-(4-(2-(isopropylamino)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylphenoxy)ethyl)acetamide; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylphenoxy)ethyl)isobutyramide; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylphenoxy)ethyl)methanesulfonamide; 2-(4-(2-(dimethylamino)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-N-methylacetamide; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)formamide; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-N-methylformamide; N-(2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)dimethylamino-N-sulfonamide; N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)cyanamide; 2-[4-(3-hydroxy-propyl)-3,5-dimethoxyphenyl]-5,7-dimethoxy-3H-quinazolin-4-one; 2-[4-(3-hydroxy-propyl)-3-methoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one; and 2-[2-(2-hydroxyethyl)-1H-indol-6-yl]-5,7-dimethoxy-3H-quinazolin-4-one, and tautomers, stereoisomers, pharmaceutically acceptable salts and hydrates thereof.

32. The method according to claim 23, wherein the therapeutically effective amount of the compound is administered with at least one pharmaceutically acceptable carrier in a pharmaceutically acceptable composition.

33. The method according to claim 23, wherein the disease is selected from cystic fibrosis, post transplantation late and chronic solid organ rejection, systemic lupus erythematosus, ocular inflammation, uveitis, rhinitis, glomerulonephritis, Grave's disease, gastrointestinal allergies, and conjunctivitis.

34. The method according to claim 1 or 23, wherein the disease is asthma.

35. The method of claim 11 or claim 33, wherein the disease is selected from liver transplant rejection, heart transplant rejection, kidney transplant rejection, proliferative glomerulonephritis, and membranous glomerulonephritis.

36. The method according to claim 12, wherein the cancer is selected from uterine cancer, multiple myeloma, histiocytomas, plasmacytoma, hormone-independent prostate cancer, cancer induced cachexia, B cell lymphoma, and metastatic renal cell carcinoma.

Description

EXAMPLES

(1) The invention is further illustrated by the following non-limiting examples, wherein the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.

(2) AcOH=acetic acid

(3) BINAP=2,2′-bis(diphenylphosphino)-1,1′-binaphthyl

(4) Boc=N-tert-butoxycarbonyl

(5) TBDMS=tert-butyldimethylsilyl

(6) dba=dibenzylidene acetone

(7) DCM=dichloromethane

(8) DMAP=dimethylaminopyridine

(9) DMF=dimethylformamide

(10) DMSO=dimethylsulfoxide

(11) EDCI=1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide

(12) EtOH=ethanol

(13) EtOAc=ethyl acetate

(14) IBX=2-Iodoxybenzoic acid

(15) MeOH=methanol

(16) HOBt=N-hydroxybenzotriazole

(17) THF=tetrahydrofuran

(18) TEA=triethylamine

(19) p-TSA=p-toluenesulfonic acid

(20) TBAF=tetrabutylammonium fluoride

(21) DMA=N,N-dimethylacetamide

(22) DIBAL-H=diisobutylaluminum hydride

(23) TPAP=tetrapropylammonium perruthenate

(24) NMO=N-methylmorpholine N-oxide

(25) DDQ=2,3-dicyano-5,6-dichloro-parabenzoquinone

(26) DME=1,2-dimethoxyethane

(27) TFA=trifluoroacetic acid

(28) DPPF=1,1′-bis(diphenylphosphino)ferrocene

(29) Pd(OAc).sub.2=palladium(II) acetate

(30) Pd(PPh.sub.3).sub.4=tetrakis(triphenylphosphine)palladium(0)

Example 1. Preparation of 5-(2-dimethylamino-ethoxy)-2(4-hydroxy-3,5-dimethylphenyl)-7-methoxy-3H-quinazolin-4-one

(31) ##STR00015##

(32) To a solution of 3,5-dimethyl-4-hydroxybenzaldehyde (10.0 g, 66.6 mmol) in anhydrous DMF (20 mL) was added NaH (4.00 g, 99.9 mmol) in portions and the mixture was stirred for 1 hour at room temperature. Benzyl bromide (9.5 mL, 80 mmol) was added dropwise and stirred for 16 hours at room temperature. Water was added, the mixture was acidified with acetic acid to pH approximately 4-5, and the product was isolated by extraction with ethyl acetate. The solvent was evaporated in vacuo and the residue was purified by column chromatography (silica gel 230-400 mesh; 2-5% ethyl acetate/hexane as eluent) to give 4-benzyloxy-3,5-dimethyl-benzaldehyde as white solid. Yield: 15.2 g (95%).

(33) A mixture of 2-amino-4,6-difluorobenzamide (2.13 g, 12.4 mmol), 4-benzyloxy-3,5-dimethylbenzaldehyde (2.98 g, 12.4 mmol), NaHSO.sub.3 (2.50 g, 13.6 mmol) and p-toluene sulfonic acid (0.236 g, 1.24 mmol) in N,N-dimethylacetamide (20 mL) was stirred at 110-120° C. for 16 hours. The solvent was evaporated in vacuo, water was added and the precipitated solid was filtered off, washed with water and ether to give 2-(4-benzyloxy-3,5-dimethylphenyl)-5,7-difluoro-3H-quinazolin-4-one as a light yellow solid. Yield: 1.99 g (41%).

(34) To a solution of 2-dimethylaminoethanol (180 mg, 2.03 mmol) in DMF (2 mL) was added NaH (61 mg, 1.5 mmol) at 0° C. The reaction mixture was stirred at room temperature for 30 minutes. Then, 2-(4-benzyloxy-3,5-dimethylphenyl)-5,7-difluoro-3H-quinazolin-4-one (200 mg, 0.510 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo to give product 2-(4-benzyloxy-3,5-dimethyl phenyl)-5-(2-dimethylamino-ethoxy)-7-fluoro-3H-quinazolin-4-one. Yield: 220 mg (93%).

(35) To a solution of 2-(4-benzyloxy-3,5-dimethylphenyl)-5-(2-dimethylaminoethoxy)-7-fluoro-3H-quinazolin-4-one (220 mg, 0.470 mmol) in DMF (3 mL) was added 25% (w/w) sodium methoxide in methanol (205 mg, 3.81 mmol). The reaction mixture was heated at 95° C. for 4 hours. The reaction mixture was cooled to the room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over anhydrous Na.sub.2SO.sub.4, and concentrated in vacuo to give crude product, which was purified by column chromatography (silica gel 230-400 mesh; 5% NH.sub.3 in methanol/CH.sub.2Cl.sub.2 as eluent) to give pure product 2-(4-benzyloxy-3,5-dimethylphenyl)-5-(2-dimethylamino-ethoxy)-7-methoxy-3H-quinazolin-4-one. Yield: 110 mg (49%).

(36) To a solution of 2-(4-benzyloxy-3,5-dimethylphenyl)-5-(2-dimethylaminoethoxy)-7-methoxy-3H-quinazolin-4-one (110 mg, 0.23 mmol) in methanol (5 mL) and THF (5 mL) was added Pd/C (50 mg, 10% on charcoal). The reaction mixture was hydrogenated for 2 hours at 50 psi at room temperature. The mixture was filtered through celite and solvent was evaporated in vacuo to give crude product, which was purified by column chromatography (silica gel 230-400 mesh; 5% NH.sub.3 in methanol/CH.sub.2Cl.sub.2 as eluent) to give the title compound as a light brown solid. Yield: 70 mg (78%). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.58 (s, 2H), 6.80 (s, 1H), 6.40 (s, 1H), 4.20 (t, 2H), 3.90 (s, 3H), 2.90 (t, 2H), 2.40 (s, 3H), 2.25 (s, 3H). MS (ES.sup.+) m/z: 384.09 (M+1).

Example 2. Preparation of 2-(4-hydroxy-3,5-dimethyl-phenyl)-7-methoxy-5-(2-methoxy-ethoxy)-3H-quinazolin-4-one

(37) ##STR00016##

(38) To a solution of 2-methoxy-ethanol (2 mL) in anhydrous DMF (2 mL) was added NaH (0.276 g, 6.90 mmol) in portions at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. The compound 2-(4-benzyloxy-3,5-dimethyl-phenyl)-5,7-difluoro-3H-quinazolin-4-one (0.25 g, 0.64 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. Water was added and the mixture was acidified with acetic acid to pH approximately 4-5. The precipitated solid was filtered off and washed with water and dried over anhydrous Na.sub.2SO.sub.4 to give 2-(4-benzyloxy-3,5-dimethyl-phenyl)-7-fluoro-5-(2-methoxy-ethoxy)-3H-quinazolin-4-one as a white solid. Yield: 0.28 g (98%).

(39) To a solution of 2-(4-benzyloxy-3,5-dimethyl-phenyl)-7-fluoro-5-(2-methoxy-ethoxy)-3H-quinazolin-4-one (0.28 g, 0.62 mmol) in anhydrous DMF (3 mL) was added a 25% solution of sodium methoxide in methanol (1.5 mL, 7.0 mmol) and the reaction mixture was heated to 80-90° C. for 6 hours. Water was added and the mixture was acidified with acetic acid, to pH approximately 4-5. The precipitated solid was filtered off and purified by column chromatography (silica gel 230-400 mesh; 20-50% ethyl acetate/CH.sub.2Cl.sub.2 as eluent) to give 2-(4-benzyloxy-3,5-dimethyl-phenyl)-7-methoxy-5-(2-methoxy-ethoxy)-3H-quinazolin-4-one as a white solid. Yield: 0.1 g (35%).

(40) The compound 2-(4-benzyloxy-3,5-dimethyl-phenyl)-7-methoxy-5-(2-methoxy-ethoxy)-3H-quinazolin-4-one (0.1 g, 0.22 mmol) was hydrogenated in THF/methanol (20/20 mL) at room temperature using Pd/C (10 wt %, 0.05 g) for 4 hours. After filtering through celite, the solvent was evaporated in vacuo and the crude material was purified by column chromatography (silica gel 230-400 mesh; 20-50% ethyl acetate/CH.sub.2Cl.sub.2 as eluent) to give the title compound as a white solid. Yield: 0.05 g (61.7%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.81 (s, 2H), 6.70 (s, 1H), 6.51 (s, 1H), 4.19 (t, 2H), 3.87 (s, 3H), 3.70 (t, 2H), 3.40 (s, 3H), 2.21 (s, 6H). MS (ES.sup.+) m/z: 371.11 (M+1).

Example 3. Preparation of 7-(2-amino-ethoxy)-2-(4-hydroxy-3,5-dimethyl-phenyl)-5-methoxy-3H-quinazolin-4-one

(41) ##STR00017##

(42) To a solution of 2-amino-4,6-difluoro-benzamide (0.400 g, 2.32 mmol) and 4-benzyloxy-3,5-dimethylbenzaldehyde (0.560 g, 2.32 mmol) in N,N-dimethylacetamide (5 mL) were added NaHSO.sub.3 (0.450 g, 2.55 mmol) and p-TSA (44 mg, 0.23 mmol) and the reaction mixture was heated at 115-120° C. for 16 hours. The reaction mixture was cooled to room temperature. N,N-Dimethylacetamide was removed under reduced pressure. The residue was diluted with water and the solid was collected and mixed and stirred for 0.5 hours with methanol (20 mL). The solid was filtered to give 2-(4-benzyloxy-3,5-dimethylphenyl)-5,7-difluoro-3H-quinazolin-4-one. Yield: 0.41 g (45%).

(43) A solution of 2-(4-benzyloxy-3,5-dimethyl-phenyl)-5,7-difluoro-3H-quinazolin-4-one (0.39 g, 1.0 mmol) and 25% sodium methoxide in methanol (0.70 g, 3.2 mmol) in DMF (1.5 mL) was stirred at room temperature for 16 hours. Acetic acid (1.0 mL) was added and the mixture was poured into water (20 mL) and stirred for 0.5 hours. The solid was filtered and further rinsed with water (30 mL), and dried to give 2-(4-benzyloxy-3,5-dimethyl-phenyl)-7-fluoro-5-methoxy-3H-quinazolin-4-one. Yield: 0.39 g (92%).

(44) To a solution of 2-(4-benzyloxy-3,5-dimethyl-phenyl)-7-fluoro-5-methoxy-3H-quinazolin-4-one (0.390 g, 0.960 mmol) and 2-dimethylamine-ethanol (0.258 g, 2.89 mmol) in DMF (1.5 mL) was added sodium hydride (0.135 g, 2.97 mmol). The reaction mixture was kept at 80° C. for 16 hours and then poured into water (20 mL). The aqueous layer was adjusted to pH 9.0, and extracted with dichloromethane. The crude product was purified by column chromatography on silica gel (230-400 mesh) using 10% methanol in dichloromethane with 1% triethylamine as eluent to give 7-(2-amino-ethoxy)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-5-methoxy-3H-quinazolin-4-one. Yield: 0.25 g (58%).

(45) To a solution of 7-(2-amino-ethoxy)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-5-methoxy-3H-quinazolin-4-one (0.25 g, 0.56 mmol) in methanol (15 mL) was added 10% palladium charcoal wet (0.17 g) and the reaction mixture was subjected to hydrogenation under hydrogen balloon at room temperature for 16 hours. The catalyst was filtered through celite and methanol was removed. The resulting material was further washed with an ethyl acetate and ether mixture (20 mL/20 mL) to give the title compound. Yield: 0.13 g (75%). .sup.1H NMR (400 Hz, DMSO-d.sub.6): δ 11.70 (s, 1H), 8.98 (s, 1H), 7.83 (s, 2H), 6.78 (s, 1H), 6.48 (s, 1H), 4.25 (t, 2H), 3.82 (s, 3H), 2.81 (t, 2H), 2.35 (s, 6H), 2.24 (s, 6H). MS (ES.sup.+) m/z: 384.14 (M+1).

Example 4. Preparation of 2-(4-hydroxy-3,5-dimethyl-phenyl)-5-methoxy-7-(2-methoxy-ethoxy)-3H-quinazolin-4-one

(46) ##STR00018##

(47) Sodium hydride (0.340 g, 8.62 mmol) was taken in anhydrous DMF (5 mL). Anhydrous 2-methoxy-ethanol (1.64 g, 21.6 mmol) was added dropwise at 0° C. under nitrogen over a period of 15 minutes. Stirring was continued at 0° C. for 5 minutes. The ice-bath was removed and stirring continued at room temperature for 10 minutes. Then, 2-(4-benzyloxy-3,5-dimethyl-phenyl)-7-fluoro-5-methoxy-3H-quinazolin-4-one (0.436 g, 1.08 mmol) was added. The color changed to green and stirring continued at 100° C. for 4 hours (progress of the reaction was monitored by TLC). The reaction mixture was cooled to room temperature, then quenched with glacial acetic acid (2 mL). Water (75 mL) was added. A white precipitate formed, which was filtered, washed with water, and dried under vacuum. Crude compound was purified by column chromatography (silica gel 230-400 mesh; 0-3% methanol in CH.sub.2Cl.sub.2 as eluent) to give 2-(4-benzyloxy-3,5-dimethyl-phenyl)-5-methoxy-7-(2-methoxy-ethoxy)-3H-quinazolin-4-one as a white solid. Yield: 0.09 g (18%).

(48) To a solution of 2-(4-benzyloxy-3,5-dimethyl-phenyl)-5-methoxy-7-(2-methoxy-ethoxy)-3H-quinazolin-4-one (0.083 g, 0.18 mmol) in methanol (15 mL) and THF (5 mL) was added palladium on charcoal (75 mg). The reaction mixture was hydrogenated at 50 psi for 16 hours at room temperature then filtered through celite. The filtrate was concentrated under reduced pressure and the crude compound was purified by preparative HPLC to give the title compound as a white solid. Yield: 0.043 g (45%). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.80 (s, 2H), 7.00 (s, 1H), 6.52 (s, 1H), 4.20 (m, 2H), 3.80 (m, 5H), 3.48 (s, 3H), 2.22 (s, 6H).

Example 5. Preparation of 7-(2-benzyloxy-ethoxy)-2-(4-hydroxy-3,5-dimethyl-phenyl)-5-methoxy-3H-quinazolin-4-one

(49) ##STR00019##

(50) To a suspension of sodium hydride (2.00 g, 50.0 mmol) in anhydrous DMF (30 mL) at 0° C. was added a solution of 4-hydroxy-3,5-dimethyl-benzaldehyde (5.00 g, 33.3 mmol) in anhydrous DMF (20 mL), dropwise over a period of 30 minutes, under nitrogen. Stirring continued at room temperature for 30 minutes and the mixture was cooled to 0° C. Chloromethoxymethane (5.06 mL, 66.6 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours under nitrogen. The reaction mixture was poured into water (200 mL), extracted with ethyl acetate (2×50 mL), dried over anhydrous Na.sub.2SO.sub.4, and concentrated. The crude compound was purified by column chromatography (SiO.sub.2, ethyl acetate/hexanes=1:3) to afford 4-methoxymethoxy-3,5-dimethyl-benzaldehyde as colorless oil. Yield: 5.97 g (92%).

(51) To a solution of 4-methoxymethoxy-3,5-dimethyl-benzaldehyde (4.00 g, 20.6 mmol) and 2-amino-4,6-difluoro-benzamide (3.55 g, 20.6 mmol) in N,N-dimethylacetamide (20 mL) were added sodium hydrogen sulfite (58.5 wt %) (5.45 g, 30.9 mmol) and p-toluenesulfonic acid (0.20 g, 1.0 mmol). The reaction mixture was stirred at 120° C. for 16 hours under nitrogen and cooled to room temperature. The solvent was evaporated under reduced pressure. Methanol (50 mL) and water (200 mL) were added, the separated solid was filtered, washed with water (30 mL), methanol (30 mL), hexanes (100 mL), and dried under vacuum, to afford 5,7-difluoro-2-(4-methoxymethoxy-3,5-dimethyl-phenyl)-3H-quinazolin-4-one as a white solid. Yield: 1.40 g (20%).

(52) To a solution of 5,7-difluoro-2-(4-methoxymethoxy-3,5-dimethyl-phenyl)-3H-quinazolin-4-one (1.40 g, 4.04 mmol) in anhydrous DMF (20 mL) was added a solution of sodium methoxide in methanol (25 wt %, 5.0 mL, 24 mmol). The reaction mixture was stirred at room temperature for 16 hours under nitrogen, diluted with water (100 mL), extracted with ethyl acetate, dried over sodium sulfate, and concentrated on a rotary evaporator to afford 7-fluoro-5-methoxy-2-(4-methoxymethoxy-3,5-dimethyl-phenyl)-3H-quinazolin-4-one as a white solid. Yield: 1.1 g (76%).

(53) To a suspension of sodium hydride (0.176 g, 4.40 mmol) in anhydrous DMF (20 mL) was added benzyloxyethanol (1.02 g, 6.70 mmol) at room temperature under nitrogen. The reaction mixture was stirred 60° C. for 30 minutes to get a clear solution. Then, 7-fluoro-5-methoxy-2-(4-methoxymethoxy-3,5-dimethyl-phenyl)-3H-quinazolin-4-one (0.200 g, 0.559 mmol) was added and the reaction mixture was stirred at 105° C. for 16 hours under nitrogen. The reaction was diluted with water (100 mL), extracted with ethyl acetate (100 mL), and concentrated on a rotary evaporator. The oily residue was subjected to column chromatography (SiO.sub.2, hexanes/ethyl acetate/methanol=6:2:1) to afford a mixture of two components of very similar polarity. The mixture was dissolved in 50% aqueous acetic acid (60 mL) and mixed with concentrated HCl (3 mL). The resulting mixture was stirred at 70° C. for 1 hour and concentrated to dryness on a rotary evaporator. The residue was diluted with saturated sodium bicarbonate aqueous solution (50 mL), extracted with ethyl acetate (150 mL), and concentrated. The residue was purified by column chromatography (SiO.sub.2, hexanes/ethyl acetate/methanol=7:2:1) to afford the title compound as a light yellow solid. Yield: 45 mg (18%). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 9.68 (br s, 1H), 7.69 (s, 2H), 7.40-7.30 (m, 5H), 6.79 (d, 1H), 6.50 (d, 1H), 4.66 (s, 2H), 4.27 (t, 2H), 3.96 (s, 3H), 3.88 (t, 2H), 2.33 (s, 6H). MS (ES.sup.+) m/z: 447.59 (M+1).

Example 6. Preparation of 2-(4-hydroxy-3,5-dimethylphenyl)-5-methoxy-7-[2-(pyridin-3-ylmethoxy)ethoxy]-3H-quinazolin-4-one

(54) ##STR00020##

(55) To a stirred solution of 5,7-difluoro-2-(4-methoxymethoxy-3,5-dimethylphenyl)-3H-quinazolin-4-one (1.04 g, 3.00 mmol) in anhydrous DMF (10 mL) was added a solution of sodium methoxide (25 wt %) in methanol (3.9 mL, 18.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours under nitrogen. Water (100 mL) was added, the white precipitated solid was filtered off, washed with water and dried under vacuum. The solid was further washed with 10% methanol in ether (20 mL), then ether (20 mL), and dried under vacuum. Yield 0.95 g (88%).

(56) Sodium hydride (60% in mineral oil; 1.00 g, 25.0 mmol) was added slowly to ethylene glycol (1.48 g, 239 mmol), cooled to 0° C. under nitrogen. The cooling bath was removed, and the mixture was stirred for a further 15 minutes at room temperature, before 3-(bromomethyl)pyridine hydrobromide (2.53 g, 10.0 mmol) was added. Then, the mixture was stirred at room temperature for 2.5 days. Water was added, the mixture was extracted with EtOAc (5×100 mL), the extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, and concentrated under vacuum. Purification by column chromatography on silica gel, with CH.sub.2Cl.sub.2/MeOH (95:5) as the eluent, gave 2-(pyridin-3-ylmethoxy)-ethanol as a colorless liquid. Yield 0.90 g, 59%.

(57) To a solution of 7-fluoro-5-methoxy-2-(4-methoxymethoxy-3,5-dimethyl-phenyl)-3H-quinazolin-4-one (0.30 g, 0.86 mmol) and 2-(pyridin-3-ylmethoxy)ethanol (0.20 g, 1.3 mmol) in DMF (2.0 mL), was added sodium hydride (60% in mineral oil) (0.30 g, 6.9 mmol). The mixture was stirred at room temperature under nitrogen for 3 h, then in an oil bath at 95° C. for 2.5 days. The mixture was concentrated under vacuum, water (approximately 50 mL) was added, and the mixture extracted with dichloromethane (3×50 mL). The dichloromethane solution was dried over anhydrous Na.sub.2SO.sub.4, concentrated under vacuum, and purified by column chromatography on silica gel, with CH.sub.2Cl.sub.2/MeOH (95:5) as eluent, to give 5-methoxy-2-(4-methoxymethoxy-3,5-dimethylphenyl)-7-[2-(pyridin-3-ylmethoxy)-ethoxy]-3H-quinazolin-4-one. Yield 150 mg (35%).

(58) To a solution of 5-methoxy-2-(4-methoxymethoxy-3,5-dimethylphenyl)-7-[2-(pyridin-3-ylmethoxy)ethoxy]-3H-quinazolin-4-one (0.10 g, 0.20 mmol) in acetic acid (10 mL) and water (10 mL), sulphuric acid (0.5 mL) was added. The solution was stirred in a 75° C. oil bath for 5 hours. The mixture was then concentrated under reduced pressure. The residue was dissolved in methanol, and 2 M Na.sub.2CO.sub.3 was added until the pH reached 8. The mixture was concentrated under reduced pressure. The resulting precipitate was filtered, washed with water, and dried in air. The precipitate was washed further with methanol to give the title compound. Yield: 67 mg (74%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.69 (s, 1H), 8.95 (s, 1H), 8.59 (s, 1H), 8.51 (d, J=3.2 Hz, 1H), 7.84 (s, 2H), 7.79 (dt, J=7.6 and 2.0 Hz, 1H), 7.41-7.38 (m, 1H), 6.72 (d, J=2.0 Hz, 1H), 6.49 (d, J=2.4 Hz, 1H), 4.63 (s, 2H), 4.30 (m, 2H), 3.86 (m, 2H), 3.83 (s, 3H), 2.23 (s, 6H). MS (ES) m/z: 446.52 (M−1).

Example 7. Preparation of 7-(2-dimethylamino-ethoxy)-2-(4-hydroxy-3,5-dimethylphenyl)-3H-quinazolin-4-one

(59) ##STR00021##

(60) To a solution of 2-amino-4-fluoro-benzamide (0.77 g, 5.00 mmol) and 4-benzyloxy-3,5-dimethyl-benzaldehyde (1.20 g, 5.00 mmol) in N,N-dimethyl acetamide (20 mL) were added sodium hydrogen sulfite (58.5 wt %, 1.10 g, 6.00 mmol) and p-toluenesulfonic acid monohydrate (0.19 g, 1.00 mmol). The reaction mixture was stirred at 120° C. for 16 hours under nitrogen, and then cooled to room temperature. Solvent was evaporated under reduced pressure, and water (100 mL) was added. The separated solid was filtered, washed with water (50 mL), and dried under vacuum to give a white solid. Yield: 0.74 g (39%).

(61) Sodium hydride (60% suspension in mineral oil; 0.36 g, 9.00 mmol) was taken in anhydrous DMF (20 mL). Then, 2-dimethylamino-ethanol (1.07 g, 12.0 mmol) was added drop-wise at room temperature under nitrogen. After the addition, the reaction mixture was stirred at room temperature for 20 minutes. Then, 2-(4-benzyloxy-3,5-dimethylphenyl)-7-fluoro-3H-quinazolin-4-one (0.56 g, 1.50 mmol) was added and the reaction mixture was stirred at 80° C. for 16 hours. The reaction mixture was cooled to room temperature. Water (100 mL) was added and the mixture was neutralized to pH approximately 8 with aqueous 2 N HCl. The separated solid was filtered, washed with water, and dried under vacuum. The crude compound was purified by the Simpliflash system (0-5% methanol in CH.sub.2Cl.sub.2 and 7 N ammonia in methanol 5% in CH.sub.2Cl.sub.2 as eluent) to give 2-(4-benzyloxy-3,5-dimethylphenyl)-7-(2-dimethylamino-ethoxy)-3H-quinazolin-4-one as a white solid. Yield: 0.32 g (48%).

(62) 2-(4-Benzyloxy-3,5-dimethylphenyl)-7-(2-dimethylamino-ethoxy)-3H-quinazolin-4-one (0.30 g, 11.2 mmol) was dissolved in a mixture of methanol and THF (1:1, 60 mL). Palladium on carbon (10 wt %, 0.20 g) was added and the reaction mixture was hydrogenated at 45 psi for 6 hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was washed with 10% methanol in ether, then ether, and dried under vacuum to give the title compound as a white solid. Yield: 0.18 g (75%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.98 (br s, 1H), 8.94 (br s, 1H), 7.99 (d, J=8.59 Hz, 1H), 7.86 (s, 2H), 7.13 (s, 1H), 7.01 (d, J=8.98 Hz, 1H), 4.21 (t, J=5.46 Hz, 2H), 2.68 (t, J=5.27 Hz, 2H), 2.24 (s, 12H). MS (ES+) m/z 354.16 (100%).

Example 8. Preparation of 2-(4-hydroxy-3,5-dimethyl-phenyl)-6-(pyridin-4-ylamino)-3H-quinazolin-4-one

(63) ##STR00022##

(64) To a solution of 6-amino-2-(4-hydroxy-3,5-dimethyl-phenyl)-3H-quinazolin-4-one (300 mg, 1.07 mmol) in pyridine (3 mL), were added 4-bromopyridinium hydrochloride (207 mg, 1.07 mmol), Pd.sub.2(dba).sub.3 (19 mg, 0.02 mmol), dppf (18 mg, 0.03 mmol) and NaO-t-Bu (328 mg, 3.41 mmol). The reaction mixture was heated at 140° C. for 1 hour in a microwave oven. Solvent was removed under reduced pressure. The crude compound was purified by the Simpliflash system (5% 7 N ammonia in methanol and dichloromethane as eluent) to give the title compound as a yellow solid. Yield: 58 mg (15%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.13 (s, 1H), 9.16 (s, 1H), 8.92 (s, 1H), 8.25 (br s, 2H), 7.84 (d, J=2.0 Hz, 1H), 7.81 (s, 2H), 7.65 (m, 2H), 6.99 (d, J=5.2 Hz, 2H), 2.22 (s, 6H). MS (ES) m/z: 359.26 (M+1) (100%).

Example 9. Preparation of 2-(4-hydroxy-3,5-dimethyl-phenyl)-6-(pyridin-2-ylamino)-3H-quinazolin-4-one

(65) ##STR00023##

(66) To a solution of 6-amino-2-(4-hydroxy-3,5-dimethyl-phenyl)-3H-quinazolin-4-one (300 mg, 1.07 mmol) in pyridine (3.5 mL), were added 2-bromopyridine (202 mg, 1.28 mmol), Pd.sub.2(dba).sub.3 (20 mg, 0.02 mmol), dppf (18 mg, 0.03 mmol) and NaO-t-Bu (329 mg, 3.42 mmol). The reaction mixture was heated at 125° C. for 1 hour in a microwave oven (100 W). Solvent was removed under reduced pressure. The crude compound was purified by column chromatography (silica gel 230-400 mesh; 3% methanol, 37% ethyl acetate and 60% CH.sub.2Cl.sub.2 as eluent). The compound was further purified by preparative HPLC to give the title compound as a beige-colored solid. Yield: 35 mg (9%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.01 (br s, 1H), 9.40 (s, 1H), 8.87 (br s, 1H), 8.60 (d, J=2.34 Hz, 1H), 8.23 (d, J=3.91 Hz, 1H), 7.97 (dd, J=8.99 and 2.74 Hz, 1H), 7.82 (s, 2H), 7.72-7.44 (m, 2H), 6.87 (d, J=8.60 Hz, 1H), 6.83-6.78 (m, 1H), 2.23 (s, 6H). MS (ES) m/z: 359.01 (M+1) (100%).

Example 10. Preparation of 2-(4-hydroxy-3,5-dimethylphenyl)-6-((4-methylpiperazin-1-yl)methyl)quinazolin-4(3H)-one

(67) ##STR00024##

(68) A solution of 2-amino-5-bromobenzamide (12.0 g, 55.8 mmol) and 4-hydroxy-3,5-dimethylbenzaldehyde (8.4 g, 55.8 mmol) in DMA (200 mL) was treated with NaHSO.sub.3 (7.7 g, 72.5 mmol) and p-TsOH (1.1 g, 5.6 mmol). The reaction was heated at 135° C. for 2.5 hours, at which time, H.sub.2O (10 mL) and CH.sub.2Cl.sub.2 (100 mL) were added and the solids were collected by filtration. The solids were washed with CH.sub.2Cl.sub.2 and dried in vacuo to afford 6-bromo-2-(4-hydroxy-3,5-dimethylphenyl)quinazolin-4(3H)-one (13.1 g, 68%).

(69) A solution of 6-bromo-2-(4-hydroxy-3,5-dimethylphenyl)quinazolin-4(3H)-one (2.0 g, 5.8 mmol) in DMF (20 mL) was treated with vinyltributyltin (2.6 mL, 8.70 mmol), Pd(PPh.sub.3).sub.4 (0.670 g, 0.58 mmol), and LiCl (0.730 g, 17.4 mmol). The reaction was stirred at reflux for 30 minutes, then concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 30% to 100% of 92:7:1 CHCl.sub.3/MeOH/concentrated NH.sub.4OH in CH.sub.2Cl.sub.2, to afford 2-(4-hydroxy-3,5-dimethylphenyl)-6-vinylquinazolin-4(3H)-one (0.780 g, 46%).

(70) To a suspension of 2-(4-hydroxy-3,5-dimethylphenyl)-6-vinylquinazolin-4(3H)-one (0.500 g, 1.70 mmol) in THF (30 mL) and H.sub.2O (10 mL) was added NaIO.sub.4 (1.09 g, 5.10 mmol), followed by OsO.sub.4 (0.2 mL, 0.017 mmol). The reaction was stirred overnight, then concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 92:7:1 to 6:3:1 CHCl.sub.3/MeOH/concentrated NH.sub.4OH to afford 2-(4-hydroxy-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazoline-6-carbaldehyde (0.475 g, 95%).

(71) To a solution of 2-(4-hydroxy-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazoline-6-carbaldehyde (0.115 g, 0.40 mmol) in DCE/CH.sub.2Cl.sub.2 (1:1, 15 mL) was added 1-methylpiperazine (0.13 mL, 1.20 mmol) and NaBH(OAc).sub.3 (0.250 g, 1.20 mmol). The reaction stirred at room temperature overnight. After this time, the mixture was concentrated in vacuo and purified by flash chromatography on silica gel eluting with 92:7:1 CHCl.sub.3/MeOH/concentrated NH.sub.4OH to afford the title compound (0.036 g, 25%) as a white solid: .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 11.63 (br s, 1H), 8.77 (br s, 1H), 8.00 (s, 1H), 7.85 (s, 2H), 7.65-7.69 (m, 2H), 3.57 (s, 2H), 2.15-2.39 (m, 17H); APCI MS m/z 377 [M−H].sup.−.

Example 11. Preparation of N-((2-(4-hydroxy-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)methanesulfonamide

(72) ##STR00025##

(73) To a solution of methyl-5-methyl-2-nitrobenzoate (2.3 g, 11.8 mmol) in CHCl.sub.3 (150 mL) was added NBS (5.3 g, 30.0 mmol) and benzoyl peroxide (0.285 g, 1.2 mmol). The reaction was heated at reflux temperature overnight. Then, the resulting mixture was washed sequentially with H.sub.2O, Na.sub.2CO.sub.3, and brine. The organic layer was then dried (Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 5% to 20% ethyl acetate/heptane, afforded methyl 5-(bromomethyl)-2-nitrobenzoate (1.3 g, 40%).

(74) To a solution of methyl 5-(bromomethyl)-2-nitrobenzoate (1.3 g, 4.7 mmol) in DMF (15 mL) was added potassium phthalimide (1.0 g, 5.2 mmol) and the reaction was stirred at room temperature for 1 hour and concentrated in vacuo. Purification by flash chromatography, eluting with 15% to 70% ethyl acetate/heptane, afforded methyl 5-((1,3-dioxoisoindolin-2-yl)methyl)-2-nitrobenzoate (1.4 g, 88%).

(75) A solution of methyl 5-((1,3-dioxoisoindolin-2-yl)methyl)-2-nitrobenzoate (0.50 g, 1.4 mmol) in EtOH (10 mL) was treated with hydrazine (0.14 mL, 4.4 mol) and the reaction was stirred at room temperature overnight. After this time, the mixture was concentrated in vacuo and purified by flash chromatography on silica gel, eluting with 30% to 100% of 92:7:1 CHCl.sub.3/MeOH/concentrate NH.sub.4OH in CH.sub.2Cl.sub.2, to afford methyl 5-(aminomethyl)-2-nitrobenzoate (0.23 g, 78%).

(76) To a solution of methyl 5-(aminomethyl)-2-nitrobenzoate (0.23 g, 1.1 mmol) in CH.sub.2Cl.sub.2 (5 mL) was added Et.sub.3N (0.31 mL, 2.2 mmol) and methanesulfonyl chloride (0.08 mL, 1.1 mmol). The reaction was stirred for 15 minutes at room temperature, concentrated in vacuo, and purified by flash chromatography on silica gel, eluting with 2% to 20% MeOH/CH.sub.2Cl.sub.2, to afford methyl 5-(methylsulfonamidomethyl)-2-nitrobenzoate (0.18 g, 57%).

(77) A mixture of methyl 5-(methylsulfonamidomethyl)-2-nitrobenzoate (0.18 g, 0.62 mmol) in EtOH (10 mL) was flushed with N.sub.2. Pd/C (0.018 g) was added and the reaction was flushed with H.sub.2 for 2 hours. Then, the resulting mixture was filtered through celite and the filtrate was concentrated. Purification by flash chromatography, eluting with 15% to 60% of 92:7:1 CHCl.sub.3/MeOH/concentrate NH.sub.4OH in CH.sub.2Cl.sub.2, afforded methyl 2-amino-5-(methylsulfonamidomethyl)-benzoate (0.085 g, 53%).

(78) To a solution of methyl 2-amino-5-(methylsulfonamidomethyl)benzoate (0.085 g, 0.33 mmol) in THF (7 mL) and H.sub.2O (3 mL) was added LiOH.H.sub.2O (0.028 g, 0.65 mol). The reaction was stirred at room temperature for 2 hours and then neutralized with 1 N HCl. The resulting aqueous solution was extracted with EtOAc. The organics were washed with brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated, to afford 2-amino-5-(methylsulfonamidomethyl)benzoic acid (0.066 g, 82%).

(79) A solution of 2-amino-5-(methylsulfonamidomethyl)benzoic acid (0.066 g, 0.27 mol) in THF (5 mL) was treated with EDCI (0.062 g, 0.32 mmol), HOBT (0.044 g, 0.32 mol) and NMM (0.035 mL, 0.32 mmol.) The reaction was stirred at room temperature for 1.5 hours. Then, NH.sub.4OH (0.03 mL, 0.35 mmol) in H.sub.2O (0.03 mL) was added. The mixture was stirred at room temperature for 5 hours and then concentrated. Purification by flash chromatography, eluting with 92:7:1 to 7:2.5:0.5 CHCl.sub.3/MeOH/concentrated NH.sub.4OH, afforded 2-amino-5-(methylsulfonamidomethyl)benzamide (0.035 g, 53%).

(80) A mixture of 2-amino-5-(methylsulfonamidomethyl)benzamide (0.035 g, 0.14 mmol), 4-hydroxy-3,5-dimethyl benzaldehyde (0.022 g, 0.14 mmol) and CuCl.sub.2 (0.039 g, 0.28 mmol) in EtOH (5 mL) was refluxed for 3 h, then concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 92/7/1 CHCl.sub.3:MeOH:concentrated NH.sub.4OH, followed by reverse-phase chromatography, eluting with 10% to 50% CH.sub.3CN in H.sub.2O with 0.1% TFA, and finally flash chromatography on silica gel, eluting with 7:2.5:0.5 CHCl.sub.3/MeOH/concentrated NH.sub.4OH, afforded the title compound (0.030 g, 57%) as a white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 8.09 (s, 1H), 7.83-7.90 (m, 2H), 7.65-7.78 (m, 3H), 6.81-7.54 (m, 2H), 4.30 (d, J=6.2 Hz, 2H), 2.91 (s, 3H), 2.24 (s, 6H). ESI MS m/z 374 [M+H].sup.+.

Example 12. Preparation of 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-morpholinoquinazolin-4(3H)-one

(81) ##STR00026##

(82) A mixture of 3,5-dimethoxy-4-hydroxybenzaldehyde (10 g, 66.67 mmol), (2-bromoethoxy)-dimethyl-tert-butylsilane (15 mL, 70 mmol), potassium iodide (1.1 g, 6.67 mmol), and sodium hydride (4 g, 100 mmol) in DMF (150 mL) was heated and stirred at 70° C. for 14 hours. The reaction was then cooled and quenched by adding water (100 mL). The mixture was extracted with EtOAc (3×100 mL) and concentrated on a rotary evaporator. The resulting residue was purified by column (SiO.sub.2, hexanes/EtOAc, 6:1) to yield 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-benzaldehyde (15.4 g, 75%).

(83) A solution of 5-morpholin-4-yl-2-nitro-benzamide (2 g, 7.96 mmol) in MeOH (50 mL) and DMF (150 mL) in a Parr bottle was mixed with Pd/C (0.5 g) and was subjected to hydrogenation (35 psi) at room temperature for 14 hours. The suspension was then passed through a celite pad and the filtrated was concentrated on a rotary evaporator, to provide 2-amino-5-morpholin-4-yl-benzamide (1.69 g, 96%).

(84) A mixture of 2-amino-5-morpholin-4-yl-benzamide (0.2 g, 0.905 mmol), 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-benzaldehyde (0.28 g, 0.905 mol), sodium hydrogensulfite (0.162 g, 0.905 mmol) and p-toluenesulfonic acid (0.224 g, 1.177 mol) in N,N-dimethyl acetamide (10 mL) was stirred at 150° C. for 4 hours. The reaction mixture was cooled to room temperature, diluted with water (50 L), basified with sodium bicarbonate to pH approximately 8-9, extracted with EtOAc (3×100 mL), and concentrated on a rotary evaporator, affording a solid residue. Further purification on a column (SiO.sub.2, DCM/MeOH/EtOAc=6:1:2) yielded 2-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-phenyl}-6-morpholin-4-yl-3H-quinazolin-4-one (66 mg, 14%).

(85) The above compound (66 mg, 0.129 mmol) in THF (10 mL) was mixed with TBAF in THF (2 mL, 2 mmol) and stirred at room temperature for 5 hours. The mixture was then concentrated on a rotary evaporator and subjected to column chromatography (SiO.sub.2, DCM/MeOH/EtOAc=6:1:2) to yield the title compound as a light yellow solid (35 mg, 68%). MP 279.5-281° C.

Example 13. Preparation of 2-(4-(2-(benzyloxy)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one

(86) ##STR00027##

(87) A mixture of dimethyl acetone-1,3-dicarboxylate (200 g 1.148 mol), cyanamide (48.3 g, 1.148 mol), and Ni(acac).sub.2 (14.75 g, 0.0574 mol) in dioxane (200 mL) was heated to reflux in a 1-L flask with a reflux condenser. The reaction mixture was heated at reflux for 16 hours and then cooled to room temperature. The precipitate was filtered off, and the solid was mixed with methanol (200 mL), stirred for 30 minutes, and filtered again to give methyl 2-amino-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate (93 g, 44%).

(88) In a 1-L flask with a reflux condenser was added methyl 2-amino-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate (93.0 g, 0.505 mol) and POCl.sub.3 (425 mL) and the reaction mixture was heated to reflux for 35 minutes. About 300 mL POCl.sub.3 was evaporated under vacuum. The residue was poured into ice and water (400 mL), which was further neutralized with KOH to pH approximately 6-7. The precipitate was filtered off and extracted with ethyl acetate (2×300 mL). The organic solution was concentrated and passed through a column, eluting with hexane:ethyl acetate 4:1, to give methyl 2-amino-4,6-dichloropyridine-3-carboxylate (22.5 g, 20.1%).

(89) In a 500-mL flask with a reflux condenser was added methyl 2-amino-4.6-dichloropyridine-3-carboxylate (22.5 g, 0.101 mol) and 25 wt % sodium methoxide in methanol (88 mL, 0.407 mol), together with methanol (20 mL). The mixture was heated to reflux for 5 hours, then cooled to room temperature. Acetic acid (15 mL) was added to the mixture and pH was adjusted to approximately 7. Methanol was removed and the residue was poured into water (100 mL). The precipitated solid was filtered and further rinsed with water (3×200 mL) to give methyl 2-amino-4,6-dimethoxypyridine-3-carboxylate (18.5 g, 86.4%).

(90) In a 500-mL flask with a reflux condenser was added methyl 2-amino-4,6-dimethoxypyridine-3-carboxylate (18.5 g, 0.0872 mol), potassium hydroxide (19.5 g, 0.349 mol) in water (80 mL) and ethanol (100 mL). The mixture was heated to 80° C. for 16 hours. The solvent was removed and aqueous HCl was used to adjust the pH to 6. The water was removed by freeze drying. The obtained solid was extracted with methanol to yield 2-amino-4,6-dimethoxy-nicotinic acid (17.2 g, 100%).

(91) 2-Amino-4,6-dimethoxy-nicotinic acid (17.2 g, 0.0872 mol) was added to THF (110 mL). 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (21.73 g, 0.113 mol), 1-hydroxybenzotriazole hydrate (12.96 g, 0.0959 mol) and 4-methyl morpholine (9.7 g, 0.0959 mol) were then added to the suspension. After stirring for 10 minutes at room temperature, 50% v/v ammonium hydroxide (18.3 g, 0.262 mol) was added. The reaction mixture was kept at room temperature for 16 hours. THF was removed and the residue was poured into cold water (100 mL). The precipitate was filtered off and washed with cold water to yield 2-amino-4,6-dimethoxy-nicotinamide (10.8 g, 62.3%).

(92) To a solution of 4-hydroxy-3,5-dimethylbenzaldehyde (6.84 g, 0.0455 mol) in anhydrous DMF (15 mL) was added NaH in mineral oil (60%, 2.23 g, 0.0558 mol). (2-Bromo-ethoxymethyl)-benzene (10.0 g, 0.0465 mol) was added and the reaction was kept at 65° C. overnight. The reaction mixture was poured into water and extracted with dichloromethane to yield (4-(2-benzyloxy-ethoxy)-3,5-dimethylbenzaldehyde (10.5 g, 81%), which was used for next step reaction without further purification.

(93) To a solution of 2-amino-4,6-dimethoxy-nicotinamide (2.55 g, 12.9 mmol) and 4-(2-benzyloxy-ethoxy)-3,5-dimethylbenzaldehyde (3.68 g, 12.9 mmol) in N,N-dimethyl acetamide (20 mL), were added NaHSO.sub.3 (2.52 g, 14.2 mmol) and p-TSA (1.98 g, 10.4 mmol). The reaction mixture was heated at 150° C. for 14 hours. The reaction mixture was cooled to room temperature. The solvent was removed under reduced pressure. The residue was diluted with water and the solid was collected and further washed with methanol. The crude product was purified by column chromatography (silica gel 230-400 mesh; 2% methanol in CH.sub.2Cl.sub.2 as eluent) to give the title compound as an off-white solid (0.88 g, 14.7%). MP 204.5-205.9° C.

Example 14. Preparation of 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethylpyrido[2,3-d]pyrimidin-4(3H)-one

(94) ##STR00028##

(95) A mixture of 3,5-dimethoxy-4-hydroxybenzaldehyde (10 g, 67 mmol), (2-bromoethoxy)-dimethyl-tert-butylsilane (15 mL, 70 mmol), potassium iodide (1.1 g, 6.7 mmol), and sodium hydride (4 g, 100 mmol) in DMF (150 mL) was heated and stirred at 70° C. for 14 hours. The reaction was then cooled and quenched by adding water (100 mL). The mixture was extracted with EtOAc (3×100 mL) and concentrated on a rotary evaporator. The resulting residue was purified by column (SiO.sub.2, hexanes/EtOAc=6:1) to yield 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-benzaldehyde (15.4 g, 75%).

(96) A mixture of 2-amino-4,6-dimethyl-nicotinamide (0.25 g, 1.5 mmol), 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-benzaldehyde (0.468 g, 1.5 mmol), sodium hydrogensulfite (0.271 g, 1.51 mmol) and p-toluenesulfonic acid (0.358 g, 1.82 mmol) in N,N-dimethyl acetamide (10 mL) was stirred at 150° C. for 4 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL), basified with sodium bicarbonate, to pH approximately 8-9, extracted with EtOAc (3×100 mL), and concentrated on a rotary evaporator, to afford a solid residue, which was purified by column chromatography (SiO.sub.2, DCM/MeOH/EtOAc=6:1:2) to yield 2-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-phenyl}-5,7-dimethyl-3H-pyrido[2,3-d]pyrimidin-4-one (56 mg, 8%).

(97) To a solution of 2-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-phenyl}-5,7-dimethyl-3H-pyrido[2,3-d]pyrimidin-4-one (107 mg, 0.234 mmol) in THF (10 mL) was added TBAF in THF (3 mL, 3 mmol) and the mixture was stirred at room temperature for 15 hours. The mixture was then concentrated on a rotary evaporator and subjected to column chromatography (SiO.sub.2, DCM/MeOH/EtOAc=6:1:2) to yield 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethyl-3H-pyrido[2,3-d]pyrimidin-4-one (36 mg, 45%).

(98) A solution of 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethyl-3H-pyrido-[2,3-d]pyrimidin-4-one (36 mg, 0.105 mmol) in MeOH (5 mL) and DCM (5 mL) was mixed with HCl in ether (2 mL, 2 mmol) and stirred at room temperature for 30 minutes. The reaction mixture was then concentrated on a rotary evaporator. The resulting solid residue was re-dissolved in minimal volume of MeOH-DCM (1:1) and triturated with hexanes. The solid was collected by filtration and washed with MeOH-DCM (1:20) to yield the title compound as a yellow solid (16.6 mg, 41%).

Example 15. Preparation of 5,7-difluoro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one

(99) ##STR00029##

(100) A mixture of 3,5-dimethoxy-4-hydroxybenzaldehyde (10 g, 66.67 mmol), (2-bromoethoxy)-dimethyl-tert-butylsilane (15 mL, 70 mmol), potassium iodide (1.1 g, 6.67 mmol), and sodium hydride (4.00 g, 100 mmol) in DMF (150 mL) was heated and stirred at 70° C. for 14 hours. The reaction was then cooled and quenched by addition of water (100 mL). The mixture was extracted with EtOAc (3×100 mL) and concentrated on a rotary evaporator. The resulting residue was purified by column (SiO.sub.2, hexanes/EtOAc=6:1) to yield 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-benzaldehyde (15.4 g, 75%).

(101) A solution of 2-amino-4,6-difluorobenzoic acid (0.5 g, 2.9 mmol), EDCI.HCl (0.887 g, 4.62 mmol), HOBt (0.975 g, 7.22 mmol), and triethylamine (1.6 mL, 11.552 mmol) in THF (50 mL) was stirred at room temperature for 1 hour. Ammonium hydroxide (50% aqueous, 10 mL) was then added to the reaction mixture. The resulting mixture was stirred at room temperature for 6 hours. The reaction was quenched by adding water (50 mL), extracted with DCM (3×100 mL), and concentrated on a rotary evaporator to afford 2-amino-4,6-difluorobenzamide (0.25 g, 50%).

(102) A mixture of 2-amino-4,6-difluoro benzamide (0.25 g, 1.45 mmol), 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-benzaldehyde (0.448 g, 1.45 mmol), sodium hydrogensulfite (0.26 g, 1.45 mmol) and p-toluenesulfonic acid (0.276 g, 1.45 mmol) in N,N-dimethyl acetamide (10 mL) was stirred at 155° C. for 14 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL), extracted with EtOAc (3×100 mL), and concentrated on a rotary evaporator, to afford impure product. The residue was re-dissolved in THF (20 mL) and mixed with TBAF in THF (10 mL, 10 mmol). The reaction mixture was stirred at room temperature for 3 hours and concentrated on a rotary evaporator to afford an oily residue. Further purification by column (SiO.sub.2, EtOAc/DCM=3:1) yielded a light yellow solid. This solid was diluted with MeOH (10 mL) to make a slurry. The solid was collected by filtration and washed with MeOH to afford the title compound as a light yellow solid (49 mg, 5% overall yield).

Example 16. Preparation of 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-diisopropoxy-3H-quinazolin-4-one

(103) ##STR00030##

(104) To a solution of 3,5-dihydroxybenzoic acid (10.0 g, 64.9 mmol) in anhydrous ethanol (100 mL) at room temperature was slowly added concentrated sulfuric acid (10 mL). The resulting mixture was stirred at reflux for 36 hours. The reaction was cooled to room temperature, diluted with water (200 mL), extracted with CH.sub.2Cl.sub.2 (3×100 mL), and concentrated on a rotary evaporator, to afford 3,5-dihydroxybenzoic acid ethyl ester as a colorless oil. Yield: 8.2 g (69%).

(105) A solution of 3,5-dihydroxybenzoic acid ethyl ester (6.0 g, 33 mmol) and 2-iodo-propane (9.9 mL, 99 mmol) in DMF (200 mL) was mixed with potassium carbonate (13.7 g, 98.9 mmol) and the mixture was stirred at room temperature for 14 hours. The reaction mixture was then diluted with water (300 mL), and extracted with ethyl acetate (3×100 mL). The residue obtained upon concentration was subjected to column chromatography (SiO.sub.2, hexanes/ethyl acetate=3:1) to afford 3,5-diisopropoxybenzoic acid ethyl ester. Yield: 8.80 g (100%).

(106) A solution of 3,5-diisopropoxybenzoic acid ethyl ester (8.80 g, 33.1 mmol) and lithium hydroxide (3.18 g, 132 mmol) in water (100 mL), methanol (50 mL), and THF (50 mL) was stirred at reflux for 3 hours. It was then cooled to room temperature, diluted with water (200 mL), acidified with 2 N hydrochloric acid, to pH approximately 2, extracted with CH.sub.2Cl.sub.2 (3×100 mL), and concentrated on a rotary evaporator, to afford 3,5-diisopropoxybenzoic acid as a white solid. Yield: 7.60 g (97%).

(107) A solution of 3,5-diisopropoxybenzoic acid (7.60 g, 31.9 mmol), triethylamine (5.3 mL, 38 mmol), and diphenylphosphoryl azide (8.3 mL, 38 mmol) in 1,4-dioxane (120 mL) and tert-butanol (30 mL) was stirred at reflux for 16 hours. The reaction mixture was then cooled to room temperature, diluted with 0.2 N sodium bicarbonate aqueous (200 mL), extracted with CH.sub.2Cl.sub.2 (3×100 mL), and concentrated on a rotary evaporator. The residue obtained was subjected to column chromatography (SiO.sub.2, hexanes/ethyl acetate=3:1) to afford 3,5-diisopropoxyphenyl)-carbamic acid tert-butyl ester as a white solid. Yield: 5.60 g (57%).

(108) A solution of 3,5-diisopropoxyphenyl)-carbamic acid tert-butyl ester (5.60 g, 18.2 mmol) in trifluoroacetic acid (30 mL) was stirred at reflux for 30 minutes and concentrated on a rotary evaporator to dryness to afford 3,5-diisopropoxyphenylamine trifluoroacetic acid salt as an oil. Yield: 5.27 g (90%).

(109) To a round-bottomed flask contained 3,5-diisopropoxyphenylamine trifluoroacetic acid salt (5.27 g, 16.4 mmol) was slowly added oxalyl chloride (20 mL) and the mixture was stirred at reflux for 1 hour. Extra oxalyl chloride was removed by distillation and methanol (100 mL) was added to the residue. It was then stirred at room temperature for 30 minutes and concentrated to dryness on a rotary evaporator to afford 4,6-diisopropoxy-1H-indole-2,3-dione as a semi-solid. Yield: 4.33 g (100%).

(110) A solution of potassium hydroxide (15.3 g, 273 mmol) in water (60 mL) was mixed with 4,6-diisopropoxy-1H-indole-2,3-dione (4.33 g, 16.4 mmol). To this mixture was slowly added hydrogen peroxide. The resulting mixture was stirred at 70° C. for 30 minutes and cooled to 0° C. The mixture was acidified at 0° C. with 2 N hydrochloric acid to pH approximately 4, extracted with CH.sub.2Cl.sub.2 (3×100 mL), and concentrated on a rotary evaporator to afford 2-amino-4,6-diisopropoxy-benzoic acid as a semi-solid. Yield: 2.91 g (70%).

(111) A solution of 2-amino-4,6-diisopropoxybenzoic acid (2.91 g, 11.5 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (3.20 g, 16.7 mmol), HOBt (3.10 g, 23.0 mmol), and triethylamine (4.2 mL, 30 mmol) in THF (200 mL) was stirred at room temperature for 20 minutes. 50% (v/v) ammonia aqueous (20 mL) was then added. The resulting solution was stirred at room temperature for 14 hours, diluted with water (200 mL), extracted with CH.sub.2Cl.sub.2 (3×100 mL), and concentrated on a rotary evaporator. The residue obtained was subjected to column chromatography (SiO.sub.2, ethyl acetate/dichloromethane/methanol=6:2:1) to afford 2-amino-4,6-diisopropoxybenzamide. Yield: 1.2 g (41%).

(112) A solution of 2-amino-4,6-diisopropoxybenzamide (0.30 g, 1.2 mmol), 4-(2-hydroxy-ethoxy)-3,5-dimethylbenzaldehyde (0.28 g, 1.4 mmol), sodium bisulfite (0.25 g, 1.4 mmol), and p-toluenesulfonic acid (20 mg, 0.11 mmol) in dimethyl acetamide (10 mL) was stirred at 150° C. for 12 hours. Extra solvent was evaporated on a rotary evaporator and the residue was diluted with saturated sodium bicarbonate aqueous solution (100 mL) and extracted with CH.sub.2Cl.sub.2 (3×100 mL). The residue obtained upon concentration was subjected to column chromatography (SiO.sub.2, ethyl acetate/dichloromethane/hexanes/methanol=4:4:4:1) to afford the title compound as a light yellow solid. Yield: 35 mg (6.9%). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 9.78 (br s, 1H), 7.66 (s, 2H), 6.78 (d, 1H), 6.42 (d, 1H), 4.72 (m, 1H), 4.63 (m, 1H), 3.97 (t, 3H), 3.92 (t, 2H), 2.33 (s, 6H), 1.45 (d, 3H), 1.41 (d, 3H). MS (ES.sup.+) m/z: 427.13 (M+1).

Example 17. Preparation of 2-[4-(2-hydroxyethoxy)-3,5-dimethyl-phenyl]-6-morpholin-4-ylmethyl-3H-quinazolin-4-one

(113) ##STR00031##

(114) To a solution of 5-methyl-2-nitrobenzoic acid (25.0 g, 138 mmol) in ethanol (200 mL) was slowly added concentrated sulfuric acid (30 mL). The resulting solution was stirred at reflux for 48 hours. The reaction mixture was then poured into icy water (300 mL), extracted with CH.sub.2Cl.sub.2 (3×100 mL), and concentrated on a rotary evaporator, to afford 5-methyl-2-nitrobenzoic acid ethyl ester. Yield: 28.9 g (100%).

(115) A solution of 5-methyl-2-nitrobenzoic acid ethyl ester (28.9 g, 138 mmol), N-bromosuccinimide (24.6 g, 138 mmol), and benzoyl peroxide (7.41 g, 30.6 mmol) in carbon tetrachloride (400 mL) was stirred at 80° C. under irradiation from a medium pressure mercury lamp for 3 hours. The lamp was then removed and the reaction was cooled to 40° C. To this solution was slowly added morpholine (14.6 mL, 168 mmol) and triethylamine (43.0 mL, 306 mmol). The resulting mixture was stirred at 40° C. for 14 hours, diluted with saturated sodium bicarbonate aqueous (300 mL), extracted with CH.sub.2Cl.sub.2 (3×100 mL), and concentrated on a rotary evaporator. The residue was subjected to column chromatography (SiO.sub.2, hexanes/ethyl ether=1:2) to afford 5-morpholin-4-ylmethyl-2-nitrobenzoic acid ethyl ester as an oil. Yield: 20 g (49%).

(116) To a solution of 5-morpholin-4-ylmethyl-2-nitrobenzoic acid ethyl ester (20 g, 68 mmol) in acetic acid (100 mL) was added iron powder (13.0 g, 231 mmol). The resulting suspension was stirred at 60° C. for 3 hours, cooled to room temperature, and diluted with water (200 mL) and CH.sub.2Cl.sub.2 (200 mL). The solid was filtered off, and the filtrate was extracted with CH.sub.2Cl.sub.2 (3×100 mL) and concentrated on a rotary evaporator to remove all solvent. The residue was re-dissolved in CH.sub.2Cl.sub.2 (400 mL), and backwashed with 2 N potassium hydroxide aqueous (2×200 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated, to afford 2-amino-5-morpholin-4-ylmethylbenzoic acid ethyl ester as an oil. Yield: 17.7 g (100%).

(117) A solution of 2-amino-5-morpholin-4-ylmethylbenzoic acid ethyl ester (3.82 g, 15.3 mmol) and lithium hydroxide (0.733 g, 30.6 mmol) in THF (25 mL), methanol (15 mL), and water (10 mL) was stirred at reflux for 2.5 hours. The reaction mixture was then concentrated to dryness on a rotary evaporator and further dried under high vacuum for 24 hours to afford lithium 2-amino-5-morpholin-4-ylmethylbenzoate. Complete conversion was assumed and the solid obtained was used in the next step without further purification.

(118) A solution of lithium 2-amino-5-morpholin-4-ylmethylbenzoate (3.70 g, 15.3 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (5.87 g, 30.6 mmol), HOBt (4.54 g, 33.6 mmol), and 4-methylmorpholine (5.0 mL, 46 mmol) in THF (200 mL) was stirred at room temperature for 40 minutes. 50% (v/v) aqueous ammonia (20 mL) was then added. The resulting solution was stirred at room temperature for 14 hours, diluted with water (200 mL), extracted with CH.sub.2Cl.sub.2 (3×100 mL), and concentrated on a rotary evaporator, to afford 2-amino-5-morpholin-4-ylmethylbenzamide as a light yellow solid. Yield: 1.2 g (33%).

(119) A solution of 2-amino-5-morpholin-4-ylmethylbenzamide (0.60 g, 2.6 mmol), 4-(2-hydroxyethoxy)-3,5-dimethylbenzaldehyde (0.58 g, 3.9 mmol), sodium bisulfite (1.14 g, 6.44 mmol), and p-toluenesulfonic acid (0.88 g, 4.6 mmol) in dimethyl acetamide (10 mL) was stirred at 150° C. for 12 hours. Extra solvent was evaporated on a rotary evaporator and the residue was diluted with saturated sodium bicarbonate aqueous solution (100 mL) and extracted with CH.sub.2Cl.sub.2 (3×100 mL). The residue obtained on concentration was subjected to column chromatography (SiO.sub.2, hexanes/ethyl acetate/dichloromethane/methanol=4:4:8:1) to afford 2-[4-(2-hydroxyethoxy)-3,5-dimethylphenyl]-6-morpholin-4-ylmethyl-3H-quinazolin-4-one as a light yellow solid. Yield: 0.15 g (14%).

(120) A solution of 2-[4-(2-hydroxyethoxy)-3,5-dimethylphenyl]-6-morpholin-4-ylmethyl-3H-quinazolin-4-one (0.15 g, 0.37 mmol) in CH.sub.2Cl.sub.2 (10 mL) was mixed with 1 N HCl in ethyl ether (3 mL, 3 mmol) and was stirred at room temperature for 10 minutes to form a suspension. The solid was filtered, and washed with CH.sub.2Cl.sub.2 to afford the title compound as a light yellow solid. Yield: 52 mg (29%). .sup.1H NMR (400 MHz, CD.sub.3OD): δ 8.49 (s, 1H), 8.13 (d, 1H), 7.93 (d, 1H), 7.77 (s, 2H), 4.58 (s, 2H), 4.05 (m, 2H), 3.98 (t, 2H), 3.91 (t, 2H), 3.80 (m, 2H), 3.41 (m, 2H), 3.30 (m, 2H), 2.44 (s, 6H). MS (ES.sup.+) m/z: 410.05 (M+1).

Example 18. Preparation of 2-[4-(2,3-Dihydroxy-propoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one

(121) ##STR00032##

(122) To a solution of 4-hydroxy-3,5-dimethylbenzaldehyde (1.50 g, 10.0 mmol) in anhydrous DMF (20 mL) were added cesium carbonate (6.52 g, 20.0 mmol) and 4-chloromethyl-2,2-dimethyl-[1,3]dioxolane (1.50 g, 10.0 mmol). The reaction mixture was stirred at 80° C. for 4 days under nitrogen, then cooled to room temperature. Water (100 mL) was added, and the mixture extracted with ethyl acetate (200 mL). The organic phase was separated, washed with 1 N aqueous NaOH solution (100 mL), water (2×100 mL), brine (100 mL), and dried over anhydrous Na.sub.2SO.sub.4. Solvent was removed under reduced pressure, and the crude compound was purified using the Simpliflash system (20% ethyl acetate in hexanes as eluent) to give 4-(2,2-dimethyl-[1,3]dioxolane-4-ylmethoxy)-3,5-dimethyl-benzaldehyde as a yellow oil. Yield: 0.95 g (36%).

(123) To a solution of 2-amino-4,6-dimethoxybenzamide (0.35 g, 1.8 mmol) in N,N-dimethyl acetamide (10 mL) were added 4-(2,2-dimethyl-[1,3]dioxolane-4-ylmethoxy)-3,5-dimethyl-benzaldehyde (0.520 g, 1.98 mmol), sodium hydrogensulfite (58.5 wt %) (0.350 g, 1.98 mmol) and p-toluenesulfonic acid (0.17 g, 0.90 mmol). The reaction mixture was stirred at 120° C. for 16 hours under nitrogen, then cooled to room temperature. Solvent was evaporated under reduced pressure, water (50 mL) was added, the separated solid was filtered, washed with water, then dichloromethane (10 mL), and dried under vacuum to give the title compound as a yellow solid. Yield: 0.34 g (47%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.8 (s, 1H), 7.83 (s, 2H), 6.64 (s, 1H), 6.44 (s, 1H), 4.95 (d, 1H), 4.40 (t, 1H), 3.88 (s, 3H), 3.84-3.66 (m, 6H), 3.46 (t, 2H), 2.28 (s, 6H). MS (ES) m/z: 401.04 (M+1) (100%).

Example 19. Preparation of 2-[4-(2-hydroxy-ethoxy)-3,5-dimethylphenyl]-5,7-dimethoxy-6-morpholin-4-ylmethyl-3H-quinazolin-4-one hydrochloride

(124) ##STR00033##

(125) Bromine (33.7 mL, 657 mmol) and 1,4-dioxane (56.0 mL, 657 mmol) was mixed at room temperature to provide fresh dioxane dibromide, which was then diluted with ethyl ether (900 mL). To a solution of 2,6-dimethoxytoluene (50.0 g, 328 mmol) in ether (450 mL) was added the freshly prepared dioxane dibromide in ether (900 mL) over 30 minutes while stirring at room temperature. After the addition, the mixture was stirred at room temperature for an additional 1.5 hours, and was poured into a beaker containing water (500 mL) and partitioned. The aqueous was discarded and the ethereal layer was washed sequentially with water (2×500 mL), saturated sodium bicarbonate aqueous (2×500 mL), dried over anhydrous sodium sulfate, and concentrated on a rotary evaporator, to afford 3-bromo-2,6-dimethoxytoluene as a colorless oil. Yield: 76 g, (100%).

(126) A cooling well was used to collect 300 mL of ammonia at −78° C., which was then mixed with 0.5 g potassium and 0.5 g ferric nitrate. After the initial blue color discharged, potassium (14.2 g, 364 mmol) was added at −78° C., portion-wise so that the blue color discharged before to each addition. After complete addition of potassium, the solution was stirred at −78° C. for 15 minutes. To this solution was slowly added 3-bromo-2,6-dimethoxytoluene (42.0 g, 182 mmol) in THF (100 mL). The resulting mixture was stirred at −78° C. for 3 hours and then 0° C. for 1 hour. The reaction was quenched by adding water (150 mL) and was extracted with CH.sub.2Cl.sub.2 (3×200 mL) to afford a brown oil as the crude product. The product was further purified by column chromatography (SiO.sub.2, hexanes/ethyl acetate=1:1) to yield 3,5-dimethoxy-4-methylaniline. Yield: 22.1 g (73%).

(127) A solution of 3,5-dimethoxy-4-methylaniline (22.1 g, 132 mmol) in 1,4-dioxane (380 mL) and water (380 mL) was mixed with potassium carbonate (45.6 g, 331 mmol) and (Boc).sub.2O (34.6 g 159 mmol) and stirred at room temperature for 14 hours. The reaction mixture was then extracted with CH.sub.2Cl.sub.2 (3×100 mL) and concentrated on a rotary evaporator. The resulting solid residue was purified by column chromatography (SiO.sub.2, hexanes/ethyl acetate=2:1) to yield a solid. A mixed solvent of CH.sub.2Cl.sub.2-hexanes (20 mL/300 mL) was used to make a slurry and the solid was collected by filtration and washed with hexanes to provide (3,5-dimethoxy-4-methylphenyl)-carbamic acid tert-butyl ester as a light yellow needle-like solid. Yield: 28.6 g (81%).

(128) A solution of (3,5-dimethoxy-4-methylphenyl)-carbamic acid tert-butyl ester (28.6 g, 107 mmol) in carbon tetrachloride (450 mL) was mixed with NBS (19.05 g, 107.1 mmol) and AIBN (1.55 g, 9.37 mmol) and was stirred at 80° C. under irradiation from a medium-pressure mercury lamp for 2 hours. The reaction was then quenched by adding water (150 mL) and extracted with CH.sub.2Cl.sub.2 (3×100 mL), and concentrated on a rotary evaporator to afford a solid residue. Further purification on column (SiO.sub.2, hexanes/ethyl acetate=2:1) yielded (2-bromo-3,5-dimethoxy-4-methylphenyl)-carbamic acid tert-butyl ester. Yield: 34.9 g (94%).

(129) solution of (2-bromo-3,5-dimethoxy-4-methylphenyl)-carbamic acid tert-butyl ester (34.9 g, 101 mmol) in carbon tetrachloride (450 mL) was mixed with N-bromosuccinimide (21.5 g, 121 mmol) and AIBN (1.55 g, 9.37 mmol) and was stirred at 80° C. under irradiation from a medium-pressure mercury lamp for 4 hours. The reaction was then quenched by adding water (150 mL) and extracted with CH.sub.2Cl.sub.2 (3×100 mL), and concentrated on a rotary evaporator to afford a solid residue. Further purification on a column (SiO.sub.2, hexanes/ethyl acetate=2:1) yielded (2-bromo-4-bromomethyl-3,5-dimethoxyphenyl)-carbamic acid tert-butyl ester. Yield: 39.0 g (91%).

(130) A solution of (2-bromo-4-bromomethyl-3,5-dimethoxyphenyl)-carbamic acid tert-butyl ester (39.0 g, 91.8 mmol) in THF (600 mL) was mixed with morpholine (45.0 mL, 515 mmol) and stirred at room temperature for 7 hours. The reaction was diluted with water (300 mL), extracted with CH.sub.2Cl.sub.2 (3×200 mL), and concentrated on a rotary evaporator. The residue was further purified by column (SiO.sub.2, dichloromethane/methanol=20:1) to provide (2-bromo-3,5-dimethoxy-4-morpholin-4-ylmethylphenyl)-carbamic acid tert-butyl ester. Yield: 35 g (88%).

(131) A solution of (2-bromo-3,5-dimethoxy-4-morpholin-4-ylmethylphenyl)-carbamic acid tert-butyl ester (3.0 g, 6.9 mmol) in THF (150 mL) was mixed with sodium hydride (0.333 g, 8.33 mmol) and stirred at room temperature for 1.5 hours. The resulting mixture was then cooled to −78° C. and mixed with nBuLi (3.33 mL, 8.33 mmol). The reaction was stirred for 1.5 hours at −78° C. before addition of tBuLi (8.16 mL, 13.9 mmol). After addition of tBuLi, the reaction was stirred at −78° C. for 1 hour and carbon dioxide gas was then bubbled through for 8 hours, allowing the temperature to rise gradually to room temperature. The reaction was quenched by adding water (0.50 mL, 28 mmol) and concentrated on a rotary evaporator. The solid residue was made into a slurry in a minimal amount of methanol and the solid was filtered off. The filtrate was then concentrated on a rotary evaporator and the solid was made into a slurry again in methanol and filtered. After repeating three times, the filtrate was concentrated to yield impure 6-tert-butoxycarbonylamino-2,4-dimethoxy-3-morpholin-4-ylmethyl-benzoic acid. Crude yield: 1.80 g (40%).

(132) A solution of crude 6-tert-butoxycarbonylamino-2,4-dimethoxy-3-morpholin-4-ylmethyl-benzoic acid (1.80 g, 4.54 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.31 g, 6.82 mmol), HOBt (1.23 g, 9.09 mmol), and triethylamine (3.3 mL, 24 mmol) in THF (50 mL) was stirred at room temperature for 1 hour. 50% (v/v) aqueous ammonia (20 mL) was then added. The resulting solution was stirred at room temperature for 14 hours, diluted with water (100 mL), extracted with CH.sub.2Cl.sub.2 (3×100 mL), and concentrated on a rotary evaporator. The residue was further purified by column chromatography (SiO.sub.2, dichloromethane/methanol/ethyl acetate=2:1:4) to provide (2-carbamoyl-3,5-dimethoxy-4-morpholin-4-ylmethyl-phenyl)-carbamic acid tert-butyl ester. Yield: 0.90 g (50%).

(133) A solution of (2-carbamoyl-3,5-dimethoxy-4-morpholin-4-ylmethylphenyl)-carbamic acid tert-butyl ester (0.90 g, 2.7 mmol) in acetic acid (20 mL) and 12 N HCl aqueous (20 mL) was stirred at 50° C. for 1 hour, and then concentrated to dryness on a rotary evaporator. The residue was mixed with saturated sodium bicarbonate aqueous (40 mL), extracted with CH.sub.2Cl.sub.2 (3×100 mL), and concentrated on a rotary evaporator. The residue was further purified on a column (SiO.sub.2, dichloromethane/methanol/ethyl acetate=3:2:3), to provide 6-amino-2,4-dimethoxy-3-morpholin-4-ylmethylbenzamide. Yield: 0.6 g (89%).

(134) A solution of 6-amino-2,4-dimethoxy-3-morpholin-4-ylmethylbenzamide (0.50 g, 1.7 mmol), 4-(2-hydroxyethoxy)-3,5-dimethylbenzaldehyde (0.50 g, 2.5 mmol), sodium bisulfite (0.90 g, 5.1 mmol), and p-toluenesulfonic acid (0.80 g, 4.2 mmol) in dimethyl acetamide (15 mL) was stirred at 150° C. for 14 hours. Extra solvent was evaporated on a rotary evaporator and the residue was diluted with saturated sodium bicarbonate aqueous solution (100 mL) and extracted with CH.sub.2Cl.sub.2 (3×100 mL). The residue obtained upon concentration was subjected to column chromatography (SiO.sub.2, hexanes/ethyl acetate/dichloromethane/methanol=1:2:5:1) to afford 2-[4-(2-hydroxy-ethoxy)-3,5-dimethylphenyl]-5,7-dimethoxy-6-morpholin-4-ylmethyl-3H-quinazolin-4-one as a light yellow solid. Yield: 0.12 g (15%).

(135) A solution of 2-[4-(2-hydroxy-ethoxy)-3,5-dimethylphenyl]-5,7-dimethoxy-6-morpholin-4-ylmethyl-3H-quinazolin-4-one (0.12 g, 0.26 mmol) in CH.sub.2Cl.sub.2 (10 mL) was mixed with 1 N HCl in ethyl ether (3 mL, 3 mmol) and was stirred at room temperature for 10 minutes to form a suspension. The solid was filtered, and washed with CH.sub.2Cl.sub.2 to afford the title compound as a light yellow solid. Yield: 32 mg (23%). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.62 (s, 2H), 7.08 (s, 1H), 4.00 (m, 4H), 3.96 (s, 3H), 3.87 (s, 3H), 3.80 (br s, 2H), 3.70 (br s, 4H), 2.67 (br s, 4H), 2.40 (s, 6H). MS (ES.sup.+) m/z: 470.17 (M+1).

Example 20. Preparation of 2-[4-(2-hydroxy-ethoxy)-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one

(136) ##STR00034##

(137) To a flask (250 mL) with a magnetic stirrer were added 4-hydroxybenzaldehyde (10.0 g, 81.8 mmol), 2-chloroethanol (26.3 g, 327 mmol), potassium carbonate (22.6 g, 163 mmol), and ethanol (80 mL). The reaction mixture was stirred at 70° C. for 16 hours. Potassium carbonate was filtered and ethanol was removed. The residue was diluted with ethyl acetate (200 mL) and washed with 5% sodium hydroxide (100 mL), water (100 mL), and brine (100 mL). The crude product was purified by column chromatography (silica gel, 230-400 mesh), using hexane/ethyl acetate (1:1) as eluent, to afford 4-(2-hydroxy-ethoxy)-benzaldehyde. Yield: 10.0 g (73%).

(138) To a solution of 2-amino-4,6-dimethoxy-benzamide (0.400 g, 2.00 mmol) and 4-(2-hydroxy-ethoxy)-benzaldehyde (0.340 g, 2.00 mmol) in N,N-dimethylacetamide (8 mL) were added NaHSO.sub.3 (0.390 g, 2.20 mmol) and p-TSA (38 mg, 0.20 mmol). The reaction mixture was stirred at 115-120° C. for 5 hours and cooled to room temperature. The solvent was removed under reduced pressure. The residue was diluted with water (40 mL) and the solid was collected, mixed with methanol (50 mL), and stirred for 30 min. The solid was filtered and rinsed with ether (30 mL) to give the title compound as white solid. Yield: 0.42 g (61%). .sup.1H NMR (400 Hz, DMSO-d.sub.6): δ 11.98 (s, 1H), 8.18 (d, 2H), 7.08 (d, 2H), 6.78 (s, 1H), 6.52 (s, 1H), 4.98 (s, 1H), 4.10 (t, 2H), 3.90 (s, 3H), 3.84 (s, 3H), 3.74 (t, 2H). MS (ES.sup.+) m/z: 343.13 (M+1).

Example 21. Preparation of 2-[4-(2-hydroxy-ethoxy)-naphthalen-1-yl]-5,7-dimethoxy-3H-quinazolin-4-one

(139) ##STR00035##

(140) To a mixture of 4-hydroxy-naphthalene-1-carbaldehyde (1.0 g, 5.8 mmol) and potassium carbonate (2.40 g, 17.4 mmol) in N,N-dimethylformamide (3 mL) under nitrogen was added 2-chloroethanol (0.80 mL, 12 mmol). The reaction mixture was heated at reflux for 20 hours and the solvent was then removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water, 0.2 N aqueous sodium hydroxide, brine, and dried over anhydrous sodium sulfate. The crude oil (1.03 g) was purified by column chromatography (silica gel 230-400 mesh; methylene chloride/EtOAc=3/7), to give 4-(2-hydroxy-ethoxy)-naphthalene-1-carbaldehyde as a colorless oil. Yield: 0.6 g (48%).

(141) To a solution of 2-amino-4,6-dimethoxy-benzamide (0.45 g, 2.3 mmol) in N,N-dimethylacetamide (25 mL) under nitrogen was added 4-(2-hydroxy-ethoxy)-naphthalene-1-carbaldehyde (0.50 g, 2.3 mmol) followed by sodium hydrogensulfite (0.26 g, 2.5 mmol) and p-toluenesulfonic acid (0.22 g, 1.1 mmol). The resulting mixture was heated at 130° C. for 15 hours and the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water, and dried over sodium sulfate. The crude orange solid (0.37 g) was purified by column chromatography (silica gel, 230-400 mesh; 3/7 methylene chloride/EtOAc then 9/1 methylene chloride/MeOH as eluent) and by triturating with methylene chloride and ether to afford the title compound as a light orange solid. Yield: 0.16 g (36%). .sup.1H NMR (400 MHz, CDCl.sub.3+CD.sub.3OD): δ 8.34 (d, 1H), 8.19 (d, 1H), 7.62 (d, 1H), 7.44-7.53 (m, 2H), 6.84 (d, 1H), 6.75 (s, 1H), 6.43 (s, 1H), 4.22-4.24 (m, 2H), 4.01-4.03 (m, 2H), 9.90 (s, 3H), 3.85 (s, 3H). MS (ES.sup.+) m/z: 393.27 (M+1).

Example 22. Preparation of 2-(2-hydroxymethyl-benzofuran-5-yl)-5,7-dimethoxy-3H-quinazolin-4-one

(142) ##STR00036##

(143) To a solution of 4-hydroxy-benzaldehyde (3.66 g, 30.0 mmol) in 50% (v/v) aqueous ammonium hydroxide (250 mL) was quickly added a solution of potassium iodide (24.9 g, 150 mmol) and iodine (7.62 g, 30.0 mmol) in water (60 mL). The dark colored solution was stirred at room temperature for 1 hour and the color changed to yellow. Stirring was continued at room temperature for 16 hours. The color changed to gray. Then, the reaction mixture was filtered through a celite pad. The filtrate was acidified with concentrated HCl to pH approximately 1 and extracted with ethyl acetate (1×300 mL). The organic phase was washed with water (150 mL) and brine (150 mL), dried over anhydrous Na.sub.2SO.sub.4, and concentrated to give 4-hydroxy-3-iodo-benzaldehyde as an off-white solid (1:1 mixture of starting material and product). Yield: 5.34 g (crude).

(144) To a degassed solution of 4-hydroxy-3-iodo-benzaldehyde (5.34 g, 15.0 mmol) in anhydrous DMF (100 mL) were added bis(triphenylphosphine)palladium(II) dichloride (0.53 g, 0.75 mmol), copper (I) iodide (0.14 g, 0.75 mmol), 1,1,3,3-tetramethyl guanidine (8.64 g, 75.0 mmol), and propargyl alcohol (1.18 g, 21.0 mmol). The reaction mixture was stirred at room temperature for 24 hours under nitrogen and then concentrated to dryness under reduced pressure. The residue was diluted with 2 N aqueous HCl (150 mL) and extracted with ethyl acetate (1×200 mL). Organic phase was washed with water (2×100 mL), brine (100 mL), and dried over anhydrous Na.sub.2SO.sub.4. Solvent was evaporated and crude compound was purified using the Simpliflash system (30% ethyl acetate in hexanes as eluent) to give 2-hydroxymethyl-benzofuran-5-carbaldehyde as a pale yellow solid. Yield: 1.36 g (26% for two steps).

(145) To a solution of 2-hydroxymethyl-benzofuran-5-carbaldehyde (0.450 g, 2.55 mmol) and 2-amino-4,6-dimethoxy-benzamide (0.500 g, 2.55 mmol) in N,N-dimethylacetamide (5 mL) were added sodium hydrogen sulfite (58.5 wt %; 0.510 g, 2.80 mmol) and p-toluenesulfonic acid (50 mg, 0.25 mmol). The reaction mixture was stirred at 120° C. for 6 hours under nitrogen and cooled to room temperature. The separated solid was filtered, washed with ether (30 mL), water (30 mL), and ethyl acetate (20 mL), and then dried under vacuum to give the title compound as a yellow solid. Yield: 0.572 g (64%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.07 (br s, 1H), 8.44 (d, J=2.0 Hz, 1H), 8.10 (dd, J=8.8 and 1.6 Hz, 1H), 7.67 (d, J=8.8 Hz, 1H), 6.89 (s, 1H), 6.76 (d, J=2.4 Hz, 1H), 6.54 (d, J=2.4 Hz, 1H), 4.61 (s, 2H), 3.90 (s, 3H), 3.86 (s, 3H). MS (ES.sup.+) m/z: 353.20 (M+1).

Example 23. Preparation of 7-(2-benzyloxy-ethoxy)-2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5-methoxy-3H-quinazolin-4-one

(146) ##STR00037##

(147) To a solution of 4-hydroxy-3,5-dimethyl-benzaldehyde (1.00 g, 6.70 mmol) in DMF (20 mL) was added cesium carbonate (8.70 g, 26.6 mmol) followed by (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (2.9 mL, 13 mmol). The reaction mixture was stirred at room temperature for 16 hours. Water was added and the product was extracted with ethyl acetate. The solvent was evaporated in vacuo to obtain 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-benzaldehyde as a colorless oil. It was contaminated with (2-bromo-ethoxy)-tert-butyl-dimethyl-silane, but was used in the next step without further purification. Yield: 2.5 g (71%).

(148) To a stirred solution of 2-amino-4,6-difluoro-benzamide (0.50 g, 2.9 mmol) and 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-benzaldehyde (1.3 g, 2.9 mmol) in N,N-dimethylacetamide (10 mL) were added sodium hydrogen sulfite (0.60 g, 3.5 mmol) and p-toluenesulfonic acid (0.1 g, 0.6 mmol) and the reaction mixture was stirred at 120° C. for 16 hours. The solvent was evaporated in vacuo, water was added, and the precipitated solid was filtered off to obtain 2-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-phenyl}-5,7-difluoro-3H-quinazolin-4-one as a yellow solid, which was used in the next step without further purification. Yield: 0.490 g (36%).

(149) To a suspension of 2-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-phenyl}-5,7-difluoro-3H-quinazolin-4-one (0.490 g, 1.06 mmol) in DMF (3 mL) was added sodium methoxide in methanol (2.3 mL, 11 mmol) and the reaction mixture was stirred at room temperature for 16 hours. Water was added, the mixture was acidified with acetic acid, to pH approximately 4-5, and the precipitated solid was filtered off to obtain 7-fluoro-2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5-methoxy-3H-quinazolin-4-one as a white solid. Yield: 0.21 g (55%).

(150) To a solution of 7-fluoro-2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5-methoxy-3H-quinazolin-4-one (0.21 g, 0.59 mmol) in THF (12 mL) was added imidazole (80 mg, 1.2 mmol), followed by tert-butyldiphenylsilyl chloride (0.20 mL, 0.65 mmol). The reaction mixture was stirred at room temperature for 16 hours. Saturated NH.sub.4Cl aqueous solution was added and the product was extracted with ethyl acetate. The solvent was evaporated in vacuo and the residue was purified by column chromatography (silica gel; 230-400 mesh; eluting with 5-10% ethyl acetate/CH.sub.2Cl.sub.2) to afford 2-{-4-[2-(tert-butyl-diphenyl-silanyloxy)-ethoxy]-3,5-dimethyl-phenyl}-7-fluoro-5-methoxy-3H-quinazolin-4-one. Yield: 0.36 g (quantitative).

(151) To a solution of 2-benzyloxy-ethanol (3 mL) in dimethyl sulfoxide (3 mL) was added sodium hydride (0.24 g, 6.0 mmol) in portions and the reaction mixture was stirred at room temperature for 45 minutes. To this mixture was added 2-{4-[2-(tert-butyl-diphenyl-silanyloxy)-ethoxy]-3,5-dimethyl-phenyl}-7-fluoro-5-methoxy-3H-quinazolin-4-one (0.36 g, 0.60 mmol) and the reaction mixture was heated at 70° C. for 16 hours. Water was added, and the mixture was acidified with acetic acid, to pH approximately 4-5, and the precipitated solid was filtered off to obtain a crude product, which was purified by preparative HPLC to obtain the title compound as a white solid. Yield: 0.12 g (42%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.83 (s, 1H), 7.89 (s, 2H), 7.37 (m, 5H), 6.75 (s, 1H), 6.53 (s, 1H), 4.91 (s, 1H), 4.58 (s, 2H), 4.30 (s, 2H), 3.84-3.73 (m, 9H), 2.31 (s, 6H). MS (ES.sup.+) m/z: 491.55 (M+1).

Example 24. Preparation of 7-(2-benzyloxy-ethoxy)-2-(2-hydroxymethyl-benzofuran-5-yl)-5-methoxy-3H-quinazolin-4-one

(152) ##STR00038##

(153) To a stirred solution of 2-hydroxymethyl-benzofuran-5-carbaldehyde (2.00 g, 11.4 mmol) in anhydrous CH.sub.2Cl.sub.2 (25 mL) were added N,N-diisopropylethyl amine (5.17 g, 40.0 mmol) and chloromethyl methyl ether (2.76 g, 34.3 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours under nitrogen. Phosphate buffer (pH 7, 100 mL) was added and the mixture was extracted with dichloromethane (100 mL). The organic phase was separated, washed with brine, and dried over anhydrous Na.sub.2SO.sub.4. Removal of solvent gave 2-methoxymethoxymethyl-benzofuran-5-carbaldehyde as an orange oil. Yield 2.41 g (96%).

(154) To a solution of 2-methoxymethoxymethyl-benzofuran-5-carbaldehyde (2.31 g, 10.5 mmol) and 2-amino-4,6-difluoro-benzamide (1.20 g, 7.00 mmol) in N,N-dimethyl acetamide (15 mL) were added sodium hydrogen sulfite (58.5 wt %; 1.54 g, 8.40 mmol) and p-toluenesulfonic acid monohydrate (0.26 g, 1.40 mmol). The reaction mixture was stirred at 120° C. for 4 hours under nitrogen, then cooled to room temperature. Solvent was evaporated under reduced pressure and water (100 mL) was added. The separated solid was filtered, washed with water (50 mL), and dried under vacuum, to give 5,7-difluoro-2-(2-methoxymethoxymethyl-benzofuran-5-yl)-3H-quinazolin-4-one as a white solid. Yield 0.96 g (37%).

(155) To a suspension of 5,7-difluoro-2-(2-methoxymethoxymethyl-benzofuran-5-yl)-3H-quinazolin-4-one (0.95 g, 2.56 mmol) in anhydrous DMF (5 mL) was added a solution of sodium methoxide (25 wt %) in methanol at 0° C. under nitrogen. Then, the reaction mixture was stirred at 0° C. for 6 hours. Water (20 mL) was added, the mixture was acidified to pH approximately 6 with glacial acetic acid. The separated solid was filtered, washed with water (20 mL), and dried under vacuum to give 7-fluoro-5-methoxy-2-(2-methoxymethoxymethyl-benzofuran-5-yl)-3H-quinazolin-4-one as a white solid. Yield 0.94 g (95%).

(156) Sodium hydride (60% suspension in mineral oil; 0.48 g, 12.0 mmol) was taken in anhydrous DMF (5 mL). 2-Benzyloxyethanol (3.65 g, 24.0 mmol) was added dropwise at room temperature under nitrogen. After the addition, the reaction mixture was stirred at room temperature for 30 minutes. Then, 7-fluoro-5-methoxy-2-(2-methoxymethoxymethyl-benzofuran-5-yl)-3H-quinazolin-4-one (0.46 g, 1.2 mmol) was added and the reaction mixture was stirred at 80° C. for 16 hours. The reaction mixture was then cooled to room temperature. Water (50 mL) was added, the mixture was acidified to pH approximately 6 with glacial acetic acid and extracted with CH.sub.2Cl.sub.2 (2×100 mL). The organic phase was washed with brine (100 mL) and then dried over anhydrous Na.sub.2SO.sub.4. Removal of solvent, followed by purification, by the Simpliflash system (0-2% methanol in CH.sub.2Cl.sub.2 as eluent) gave 7-(2-benzyloxy-ethoxy)-5-methoxy-2-(2-methoxymethoxymethyl-benzofuran-5-yl)-3H-quinazolin-4-one as a white solid. Yield 0.28 g (45%).

(157) To a solution of 7-(2-benzyloxy-ethoxy)-5-methoxy-2-(2-methoxymethoxymethyl-benzo-furan-5-yl)-3H-quinazolin-4-one (0.27 g, 0.53 mmol) in 50% aqueous acetic acid (15 mL), conc. H.sub.2SO.sub.4 (0.3 mL) was added. The reaction mixture was stirred at 75° C. for 2 hours, then cooled to room temperature. Water (50 mL) was added, and the mixture was neutralized to pH approximately 7 with 4 N aqueous NaOH solution. The separated solid was filtered, washed with water (20 mL), and dried under vacuum. Crude compound was purified by column chromatography (silica gel 230-400 mesh; 2:20:78 methanol/ethyl acetate/CH.sub.2Cl.sub.2 as eluent) to give the title compound as a white solid. Yield 0.13 g (52%).

(158) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.03 (bs, 1H), 8.43 (s, 1H), 8.09 (dd, J=8.58 and 1.95 Hz, 1H), 7.65 (d, J=8.58 Hz, 1H), 7.37-7.29 (m, 5H), 6.88 (s, 1H), 6.77 (d, J=1.95 Hz, 1H), 6.55 (d, J=1.56 Hz, 1H), 5.51 (s, 1H), 4.60 (t, J=4.68 Hz, 4H), 4.31 (s, 2H), 3.90-3.83 (m, 5H). MS (ES+) m/z 473.48 (100%).

Example 25. Preparation of 2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy]-N-methyl-acetamide

(159) ##STR00039##

(160) To a solution of [4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy]-acetic acid (0.20 g, 0.52 mmol) in anhydrous DMF (8 mL) were added EDCI (0.12 g, 0.62 mmol) and HOBt (0.084 g, 0.62 mmol). Then, a solution of N-methyl amine (2.0 M solution in THF, 1.3 mL, 2.60 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours under nitrogen. Solvent was evaporated under reduced pressure, water (20 mL) was added, and the separated solid was filtered, washed with water (30 mL), ether (20 mL) and dried under vacuum to give the title compound as a white solid. Yield: 0.13 g (63%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ11.86 (br s, 1H), 8.19 (br s, 1H), 7.91 (s, 2H), 6.74 (d, J=1.95 Hz, 1H), 6.52 (d, J=1.95 Hz, 1H), 4.26 (s, 2H), 3.89 (s, 3H), 3.85 (s, 3H), 2.72 (d, J=4.30 Hz, 3H), 2.30 (s, 6H). MS (ES) m/z: 398.53 (M+1) (100%).

Example 26. Preparation of 2-[4-(5,7-Dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy]-N-(4-methoxy-phenyl)-acetamide

(161) ##STR00040##

(162) To a solution of 4-hydroxy-3,5-dimethyl-benzaldehyde (9.00 g, 60.0 mmol) in ethanol (300 mL) were added potassium carbonate (24.9 g, 180 mmol) and methyl bromoacetate (11.4 mL, 120 mmol). The reaction mixture was stirred at 95° C. under nitrogen for 16 hours. The mixture was concentrated to dryness under reduced pressure. Water (150 mL) and 1 N NaOH solution (90 mL) were added to the residue. The mixture was stirred at room temperature for 30 minutes, then washed with ether. Concentrated HCl was added slowly to the aqueous solution until a large amount of white precipitate formed. The solid was filtered, washed with water, and air-dried, to give (4-formyl-2,6-dimethyl-phenoxy)-acetic acid as a white solid. Yield: 11.1 g (89%).

(163) To a solution of (4-formyl-2,6-dimethyl-phenoxy)-acetic acid (3.12 g, 15.0 mmol) and 2-amino-4,6-dimethoxy-benzamide (2.94 g, 15.0 mmol) in N,N-dimethylacetamide (50 mL) were added sodium hydrogen sulfite (58.5 wt %, 3.02 g, 16.5 mmol) and p-toluenesulfonic acid monohydrate (0.285 g, 1.50 mmol). The reaction mixture was stirred at 120° C. for 17 hours under nitrogen and cooled to room temperature. The precipitate was filtered, washed with water, then methanol, and air-dried to give 1.29 g [4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy]-acetic acid. The filtrate was concentrated to dryness and water was added. The suspension was stirred for 30 minutes and filtered. The solid was washed with water, then methanol. After air drying, 3.78 g more [4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy]-acetic acid was obtained. Yield: 5.07 g (88%).

(164) To a mixture of [4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy]-acetic acid (0.400 g, 1.04 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCI; 0.240 g, 1.24 mmol), 1-hydroxybenzotriazole hydrate (HOBt; 0.17 g, 1.24 mmol) in DMF (10 mL) was added 4-methylmorpholine (0.20 mL, 1.8 mmol). After 10 minutes, p-anisidine (0.26 g, 2.08 mmol) was added. The mixture was stirred at room temperature under nitrogen for 2.5 days. The solvent was removed under reduced pressure. Water was added, stirred for 30 minutes. The solid was filtered, washed with water, and dried in air. The crude product was purified by column chromatography (silica gel, 230-400 mesh; 5% MeOH in CH.sub.2Cl.sub.2 as eluent). The product fractions were combined, concentrated to dryness. The solid was dissolved in small amount of dichloromethane, precipitate out by adding ether. The precipitate was filtered, washed with ether, dried under vacuum to afford the title compound as a white solid. Yield: 0.26 g (51%). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 10.30 (br s, 1H), 8.52 (s, 1H), 7.83 (s, 2H), 7.58 (dd, J=6.8 and 2.0 Hz, 2H), 6.93 (dd, J=6.8 and 2.0 Hz, 2H), 6.84 (d, J=2.4 Hz, 1H), 6.48 (d, J=2.0 Hz, 1H), 4.44 (s, 2H), 3.97 (s, 3H), 3.94 (s, 3H), 3.83 (s, 3H), 2.42 (s, 3H). MS (ES.sup.+) m/z: 490.55 (M+1).

Example 27. Preparation of N-benzyl-2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy]acetamide

(165) ##STR00041##

(166) To a mixture of [4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy]acetic acid (0.25 g, 0.65 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCI; 0.137 g, 0.715 mmol), 1-hydroxybenzotriazole hydrate (HOBT; 0.110 g, 0.715 mmol) in DMF (3 mL) was added 4-methylmorpholine (0.08 mL, 0.715 mmol) at room temperature. After 10 minutes, benzylamine (0.142 mL, 1.30 mmol) was added. The mixture was stirred at room temperature under nitrogen for 15 hours. The solvent was removed under reduced pressure. The crude compound was purified by column chromatography (silica gel 230-400 mesh; 3% methanol in dichloromethane as eluent), followed by triturating with an ether-hexane mixture to afford the title compound as a white solid. Yield: 60 mg (39%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.86 (s, 1H), 8.79 (t, J=6.2 Hz, 1H), 7.89 (s, 2H), 7.34-7.21 (m, 5H), 6.72 (d, J=2.0 Hz, 1H), 6.50 (d, J=2.0 Hz, 1H), 4.38 (d, J=6.0 Hz, 2H), 4.33 (s, 2H), 3.87 (s, 3H), 3.82 (s, 3H), 2.30 (s, 6H). MS (ES.sup.+) m/z: 474.49 (M+1).

Example 28. Preparation of 2-[4-(4-hydroxy-butoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one

(167) ##STR00042##

(168) To a solution of 4-hydroxy-3,5-dimethyl benzaldehyde (5.00 g, 33.3 mmol) in DMF (30 mL) were added 4-bromo butan-1-ol (6.11 g, 39.9 mmol) and Cs.sub.2CO.sub.3 (16.24 g, 50.0 mmol). The reaction mixture was stirred at room temperature for 48 hours. Water was added and the products were extracted with ethyl acetate (2×200 mL). The combined organic phase was washed with water (100 mL), brine (100 mL), and dried over anhydrous Na.sub.2SO.sub.4. Solvent was removed and the crude compound was purified using the Simpliflash system (40% ethyl acetate in hexane as eluent) to give 4-(4-hydroxybutoxy)-3,5-dimethyl benzaldehyde as a colorless liquid. Yield: 0.66 g (7%).

(169) To a solution of 2-amino-4,6-dimethoxy-benzamide (0.50 g, 2.53 mmol) and 4-(4-hydroxybutoxy)-3,5-dimethyl benzaldehyde (0.66 g, 2.53 mmol) in N,N-dimethyl acetamide (10 mL), NaHSO.sub.3 (0.50 g, 2.79 mmol) and p-TSA (96 mg, 0.50 mmol) were added and the reaction mixture was heated at 115° C. for 16 hours, then cooled to room temperature. Solvent was removed under reduced pressure. Water (100 mL) was added and the mixture was stirred for 1 hour. The solid separated was filtered and dried. The solid was again washed with diethyl ether to give the title compound as a white solid. Yield: 1.69 g (82%). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 9.10 (s, 1H), 7.66 (s, 2H), 6.83 (d, J=2.4 Hz, 1H), 6.46 (d, J=2.0 Hz, 1H), 3.98 (s, 3H), 3.93 (s, 3H), 3.85 (t, J=6.0 Hz, 2H), 3.78 (m, 2H), 2.36 (s, 6H), 1.94 (m, 2H), 1.85 (m, 2H). MS (ES) m/z: 399.12 (M+1) (100%).

Example 29. Preparation of 7-chloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one

(170) ##STR00043##

(171) Following the method described in Example 33, the title compound was made starting from 2-amino-4-chlorobenzoic acid and isolated as a white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 12.46 (s, 1H), 8.12 (d, J=8.49 Hz, 1H), 7.90 (s, 2H), 7.77 (d, J=2.00 Hz, 1H), 7.52 (dd, J=8.49, 2.00 Hz, 1H), 4.90 (t, J=5.51 Hz, 1H), 3.86 (t, J=4.88 Hz, 2H), 3.76-3.69 (m, 2H), 2.32 (s, 6H). MS (APCI) m/z 345 [C.sub.18H.sub.17ClN.sub.2O.sub.3+H].sup.+.

Example 30. Preparation of 8-chloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one

(172) ##STR00044##

(173) Following the procedure described in Example 33, the title compound was made starting from 2-amino-3-chlorobenzoic acid and isolated as a white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6: δ 12.55 (s, 1H), 8.09 (dd, J=7.88, 1.37 Hz, 1H), 8.00-7.93 (m, 3H), 7.46 (t, J=7.88 Hz, 1H), 4.91 (t, J=5.54 Hz, 1H), 3.86 (t, J=4.90 Hz, 2H), 3.77-3.69 (m, 2H), 2.33 (s, 6H). MS (APCI) m/z 345 [C.sub.18H.sub.17ClN.sub.2O.sub.3+H].sup.+.

Example 31. Preparation of 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-8-methoxyquinazolin-4(3H)-one

(174) ##STR00045##

(175) Following the procedure described in Example 33, the title compound was made starting from 2-amino-3-methoxybenzoic acid and isolated as a white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 12.34 (s, 1H), 7.87 (s, 2H), 7.69 (dd, J=7.63, 1.59 Hz, 1H), 7.45-7.34 (m, 2H), 4.90 (t, J=5.53 Hz, 1H), 3.94 (s, 3H), 3.85 (t, J=4.92 Hz, 2H), 3.77-3.69 (m, 2H), 2.33 (s, 6H). MS (APCI) m/z 341 [C.sub.19H.sub.20N.sub.2O.sub.4+H].sup.+.

Example 32. Preparation of 5-chloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one

(176) ##STR00046##

(177) A mixture of 2-amino-6-chlorobenzoic acid (5.00 g, 29.1 mmol) in acetonitrile (50.0 mL) was stirred at room temperature under nitrogen. Pyridine (4.72 mL, 58.3 mmol) was added, followed by drop-wise addition of triphosgene (2.85 g, 9.60 mmol) in CH.sub.2Cl.sub.2 (20.0 mL). After the addition, the mixture was heated at 55° C. for 2 hours, then cooled to 25° C. and stirred overnight. Water (100 mL) was added to quench, the mixture was filtered, and washed with cold CH.sub.2Cl.sub.2, to provide 5-chloro-1H-benzo[d][1,3]oxazine-2,4-dione (3.54 g, 62%) as a white solid.

(178) A mixture of 5-chloro-1H-benzo[d][1,3]oxazine-2,4-dione (3.50 g, 17.7 mmol) and 2 M NH.sub.3 in EtOH (11.5 mL, 23.0 mmol) and EtOH (10.0 mL) was stirred at room temperature for 2 hours. The volatiles were removed under reduced pressure, the residue was triturated with water (50 mL), and the solid was filtered, to provide 2-amino-6-chlorobenzamide (1.60 g, 49%) as a tan solid.

(179) A mixture of 2-amino-6-chlorobenzamide (0.490 g, 3.00 mmol), 4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylbenzaldehyde (0.925 g, 3.00 mmol), NaHSO.sub.3 (94%, 0.468 g, 4.50 mmol), and p-TsOH.H.sub.2O (0.171 g, 0.900 mmol) in DMA (10.0 mL) was heated at 140° C. for 16 hours. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was diluted with EtOAc (50 mL), washed with water (50 mL), then brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and the solvent was removed under reduced pressure, to provide 2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylphenyl)-5-chloroquinazolin-4(3H)-one as an off-white solid. The crude material was used directly in the next step without characterization.

(180) Following the method described for desilylation using TBAF in Example 33 below, the title compound was made from 2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylphenyl)-5-chloroquinazolin-4(3H)-one in 21% yield and was isolated as a white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 12.32 (s, 1H), 7.90 (s, 2H), 7.82-7.55 (m, 2H), 7.48 (dd, J=7.54, 1.35 Hz, 1H), 4.90 (t, J=5.51 Hz, 1H), 3.86 (t, J=4.90 Hz, 2H), 3.77-3.68 (m, 2H), 2.32 (s, 6H). MS (APCI) m/z 345 [C.sub.18H.sub.17ClN.sub.2O.sub.3+H].sup.+.

Example 33. Preparation of 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-7-methoxyquinazolin-4(3H)-one

(181) ##STR00047##

(182) A mixture of 2-nitro-4-methoxybenzoic acid (1.00 g, 5.10 mmol) in methanol (10.0 mL) was stirred at room temperature under nitrogen. Palladium on carbon (10% wt, 50% wet, 0.559 g, 0.255 mmol) was added. The round-bottomed flask was capped with a new septa and degassed under vacuum. The flask was charged with hydrogen and degassed again. This was repeated twice and a hydrogen-filled balloon was attached to the flask. The mixture was stirred at room temperature for 4 hours. Nitrogen was then bubbled through the mixture to displace any excess hydrogen. The mixture was filtered through celite 521 and the filtrate was concentrated under reduced pressure to provide 2-amino-4-methoxybenzoic acid (0.890 g, >99%) as an off-white solid. The crude material was used directly in the next step without characterization.

(183) A mixture of 2-amino-4-methoxybenzoic acid (0.490 g, 3.00 mmol), EDCI (1.12 g, 5.83 mmol), HOBt (0.788 g, 5.83 mmol), N-methylmorpholine (0.590 g, 5.83 mmol) and 14.8 N NH.sub.4OH (0.781 mL, 10.6 mmol) in THF was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, then the residue was diluted with EtOAc (100 mL), washed with water (2×100 mL), then brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and the solvent was removed under reduced pressure to provide 2-amino-4-methoxybenzamide as a tan solid.

(184) A mixture of 2-amino-4-methoxybenzamide (0.490 g, 3.00 mmol), 4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylbenzaldehyde (0.925 g, 3.00 mmol), NaHSO.sub.3 (94%, 0.468 g, 4.50 mmol), and p-TsOH.H.sub.2O (0.171 g, 0.900 mmol) in benzene (10.0 mL) was heated at 80° C. for 36 hours. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was diluted with EtOAc (50 mL), washed with water (50 mL) then brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and the solvent was removed under reduced pressure to provide 2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylphenyl)-7-methoxyquinazolin-4(3H)-one as a pink solid. The crude material was used directly in the next step without characterization.

(185) A mixture of 2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylphenyl)-7-methoxyquinazolin-4(3H)-one (1.09 g, 2.30 mmol) in 1 M TBAF (11.6 mL, 11.6 mmol) was stirred at room temperature for 3 hours. The mixture was diluted with water (100 mL) and extracted with EtOAc (2×100 mL). The organic layers were combined, washed with saturated aqueous NH.sub.4Cl (2×75 mL), then brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and the solvent was removed under reduced pressure. The residue was purified over silica gel (12 g, EtOAc/hexanes), triturated in ether, and the product was freeze-dried from MeCN/H.sub.2O to yield the title compound (0.0960 g, 12%) as a white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 12.18 (s, 1H), 8.02 (d, J=8.79 Hz, 1H), 7.91 (s, 2H), 7.16 (d, J=2.46 Hz, 1H), 7.07 (dd, J=8.79, 2.46 Hz, 1H), 4.90 (t, J=5.53 Hz, 1H), 3.91 (s, 3H), 3.89-3.82 (m, 2H), 3.77-3.67 (m, 2H), 2.32 (s, 6H), 2.22 (d, J=6.92 Hz, 1H). MS (APCI) m/z 341 [C.sub.19H.sub.20N.sub.2O.sub.4+H].sup.+.

Example 34. Preparation of 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-((4-methylpiperazin-1-yl)methyl)quinazolin-4(3H)-one

(186) ##STR00048##

(187) To a solution of 4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylbenzaldehyde (7.5 g, 24.4 mmol) in DMA (50 mL) was added 2-amino-5-bromobenzamide (5.2 g, 24.4 mmol), NaHSO3 (3.9 g, 36.5 mmol) and p-TsOH (0.46 g, 2.4 mmol), and the reaction was heated at 160° C. After 1 hour, the resulting mixture was cooled to room temperature, diluted with water, and filtered to afford 6-bromo-2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (6.7 g, 55%) as a white solid (6.7 g, 55%).

(188) A mixture of 6-bromo-2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (5.0 g, 9.9 mmol), vinyltributyltin (4.3 mL, 14.9 mmol) and PdCl.sub.2(PPh.sub.3).sub.2 (0.70 g, 1.0 mmol) in CH.sub.3CN (150 mL) was stirred at reflux overnight. Then, additional PdCl.sub.2(PPh.sub.3).sub.2 (0.10 g, 0.14 mmol) and vinyltributyltin (2.0 mL, 6.8 mmol) were added and the reaction continued to reflux overnight. The resulting mixture was cooled to room temperature, filtered through celite, and the filtrate concentrated. The residue was purified by flash chromatography (silica, eluting with 98:2 CH.sub.2Cl.sub.2/MeOH) to afford 2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylphenyl)-6-vinylquinazolin-4(3H)-one (2.0 g, 45%).

(189) To a solution of 2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylphenyl)-6-vinylquinazolin-4(3H)-one (0.63 g, 1.4 mmol) in THF (50 mL) and H.sub.2O (5 mL) was added NaIO.sub.4 (0.90 g, 4.2 mmol) and OsO.sub.4 (0.11 mL, 0.014 mmol), and the reaction was stirred overnight at room temperature. Then, the mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, eluting with 98:2 to 95:5 CH.sub.2Cl.sub.2/MeOH) to afford 2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazoline-6-carbaldehyde (0.52 g, 82%).

(190) A solution of 2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazoline-6-carbaldehyde (0.11 g, 0.24 mmol) in DCE/CH.sub.2Cl.sub.2 (1:1, 15 mL) was treated with 1-methylpiperazine (0.05 mL, 0.48 mmol) and NaBH(OAc).sub.3 (0.103 g, 0.48 mmol) and the reaction mixture was stirred at room temperature overnight. Then, the mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, eluting with 60% of 92:7:1 CHCl.sub.3/MeOH/concentrated NH.sub.4OH in CH.sub.2Cl.sub.2) to afford 2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylphenyl)-6-((4-methylpiperazin-1-yl)methyl)quinazolin-4(3H)-one (0.14 g, 98%).

(191) A solution of 2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylphenyl)-6-((4-methylpiperazin-1-yl)methyl)quinazolin-4(3H)-one (0.087 g, 0.16 mmol) in a 1 M TBAF/THF solution (1.3 mL, 1.3 mmol) was stirred for 2 hours at room temperature. Then, the resulting mixture was concentrated in vacuo and purified by flash chromatography (silica gel, eluting with 70% of 92:7:1 CHCl.sub.3/MeOH/concentrated NH.sub.4OH in CH.sub.2Cl.sub.2) to afford the title compound (0.070 g, 100%): .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 12.31 (s, 1H), 8.02 (s, 1H), 7.89 (s, 2H), 7.56-7.79 (m, 2H), 4.92 (t, J=5.3 Hz, 1H), 3.77-3.93 (m, 2H), 3.64-3.75 (m, 2H), 3.58 (s, 2H), 2.21-2.45 (m, 14H), 2.15 (s, 3H). APCI MS m/z 423 [M+H].sup.+.

Example 35. Preparation of 5,7-Dimethoxy-2-{3-methyl-4-[2-(5-phenyl-4H-[1,2,4]triazol-3-ylamino)-ethoxy]-phenyl}-3H-quinazolin-4-one

(192) ##STR00049##

(193) To a solution of 2-[4-(2-amino-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.37 g, 1.00 mmol) in anhydrous dichloroethane (20 mL) was added benzoyl isothiocyanate (0.18 g 1.10 mmol). The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed and ether (30 mL) was added. The mixture was stirred for 30 minutes and the solid was filtered and dried to give 1-benzoyl-3-{2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-phenoxy]-ethyl}-thiourea as a white solid. Yield: 0.53 g (99%).

(194) To a solution of 1-benzoyl-3-{2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-phenoxy]-ethyl}-thiourea (0.42 g, 0.785 mmol) in chloroform (20 mL) was added hydrazine hydrate (1.30 mL, 26.5 mmol). The reaction mixture was stirred at reflux for 16 hours. After the solvent was removed, the residue was purified by preparative HPLC to afford the title compound as a white solid. Yield: 35 mg (29%). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 12.26 (s, 1H), 11.82 (s, 1H), 7.91 (m, 2H), 7.89 (s, 2H), 7.40 (m, 3H), 6.84 (s, 1H), 6.73 (d, J=2.0 Hz, 1H), 6.51 (d, J=2.0 Hz, 1H), 3.98 (t, J=5.6 Hz, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 3.62 (m, 2H), 2.29 (s, 6H). MS (ES.sup.+) m/z 513.53 (M+1).

Example 36. Preparation of 2-{3,5-Dimethyl-4-[2-(3-methyl-[1,2,4]oxadiazol-5-ylamino)-ethoxy]-phenyl}-5,7-dimethoxy-3H-quinazolin-4-one

(195) ##STR00050##

(196) Acetamide oxime (5.00 g, 67.5 mmol) and trichloroacetic anhydride (49.3 mL, 270 mmol) were stirred at 120-130° C. for 3 hours. The mixture was then distilled under vacuum. The fraction at approximately 50-70° C./approximately 5 mmHg was collected. The collected fraction was added to cold saturated aqueous NaHCO.sub.3 and extracted with ethyl acetate. The organic phase was washed with saturated aqueous NaHCO.sub.3 solution and dried over Na.sub.2SO.sub.4. The solvent was evaporated to give 3-methyl-5-trichloromethyl-[1,2,4]oxadiazole as a colorless liquid. Yield: 7.69 g (52%)

(197) A mixture of 3-methyl-5-trichloromethyl-[1,2,4]oxadiazole (56 mg, 0.28 mmol), 2-[4-(2-amino-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (92 mg, 0.25 mmol), and cesium carbonate (179 mg, 0.55 mmol) in DMF (3 mL) was stirred at room temperature under nitrogen for 3.5 days. Water was added, and the mixture was extracted with MeOH/CH.sub.2Cl.sub.2. The organic phase was washed with brine, dried over anhydrous Na.sub.2SO.sub.4, purified by column chromatography (silica gel; 5% MeOH in CH.sub.2Cl.sub.2 as eluent) to give the title compound as a beige solid. Yield: 75 mg (60%). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 9.68 (s, 1H), 7.71 (s, 2H), 6.82 (d, J=2.4 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 5.80 (t, J=5.6 Hz, 1H), 4.00-3.97 (m, 5H), 3.93 (s, 3H), 3.83 (m, 2H), 2.34 (s, 6H), 2.24 (s, 3H). MS (ES.sup.+) m/z: 452.57 (M+1).

Example 37. Preparation of N-{2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-2,6-dimethyl-phenoxy]-ethyl}-acetamide

(198) ##STR00051##

(199) To a solution of 4-hydroxy-3,5-dimethyl-benzaldehyde (15.0 g, 0.10 mol) in anhydrous DMF (30 mL) was added 60% sodium hydride (4.80 g, 0.12 mol) and the reaction mixture was kept stirring for 20 minutes. 2-(2-Bromoethyl)-isoindole-1,3-dione (25.4 g, 0.10 mol) in anhydrous DMF (30 mL) was added drop-wise. The reaction mixture was heated to 65° C. for 5 hours. Acetic acid (3 mL) was added, DMF was removed, and the residue was poured into water (150 mL), and extracted with dichloromethane (200 mL). The crude compound was purified by column chromatography (silica gel 230-400 mesh; eluting with ethyl acetate and hexane 1:1) to give 4-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethoxy]-3,5-dimethyl-benzaldehyde. Yield: 11.0 g (34%).

(200) To a solution of 2-amino-4,6-dimethoxy-nicotinamide (0.40 g, 2.02 mmol, and 4-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethoxy]-3,5-dimethyl-benzaldehyde (0.65 g, 2.02 mmol) in N,N-dimethylacetamide (30 mL) was added NaHSO.sub.3 (58.5 wt %, 0.40 g, 2.20 mol) and p-TSA (0.12 g, 6.00 mmol). The reaction mixture was heated to 145° C. for 16 hours, and then cooled to room temperature. Solvent was removed under reduced pressure. Aqueous sodium bicarbonate solution (50 mL) was added and the solid separated was filtered and washed with ether (50 mL). Crude compound was purified by column chromatography (silica gel, 230-400 mesh; methanol, ethyl acetate and dichloromethane 5:20:75) to give 2-{2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-2,6-dimethyl-phenoxy]-ethyl}-isoindole-1,3-dione as a light yellow solid. Yield: 0.43 g (43%).

(201) Hydrazine hydrate (0.2 mL, 4.1 mmol) was added to a solution of 2-{2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-2,6-dimethyl-phenoxy]-ethyl}-isoindole-1,3-dione (0.43 g, 0.86 mmol) in ethanol (10 mL). The reaction mixture was heated to 70° C. for 4 hours, solvent was removed, and the residue was purified by column chromatography (silica gel, 230-400 mesh; eluting with 5% 7 N ammonia in methanol and dichloromethane) to give 2-[4-(2-amino-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-pyrido[2,3-d]pyrimidin-4-one as a white solid. Yield: 0.22 g (69%).

(202) To a solution of 2-[4-(2-amino-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-pyrido[2,3-d]pyrimidin-4-one (0.21 g, 0.56 mmol) in pyridine (4 mL) and dichloromethane (10 mL) was added acetyl chloride (51 mg, 0.65 mmol), and the reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, the residue was poured into water (50 mL) and stirred for 30 minutes. The solid separated was filtered and washed with cold water and ether, and then dried under vacuum to give the title compound as a white solid. Yield: 0.19 g (81%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.15 (s, 1H), 7.90 (s, 2H), 6.36 (s, 1H), 3.93 (s, 3H), 3.88 (s, 3H), 3.79 (t, J=5.6 Hz, 3H), 3.42 (q, J=5.6 Hz, 2H), 2.28 (s, 6H), 1.84 (s, 3H). MS (ES) m/z: 411.15 (M−1).

Example 38. Preparation of N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylbenzyl)acetamide

(203) ##STR00052##

(204) 4-Bromo-2,6-dimethylaniline (4.49 g, 22.4 mmol), water (25 mL) and concentrated HCl (8.0 mL) were sonicated and cooled to 0° C. Sodium nitrite (1.67 g, 24.2 mmol) in water (5 mL) was added over 20 minutes. The mixture was stirred at 0° C. for 30 minutes, and solid Na.sub.2CO.sub.3 was added to adjust the pH to approximately 7. The liquid portion was added, in portions, to copper (I) cyanide (2.42 g, 27.0 mmol) and potassium cyanide (3.65 g, 56.1 mmol) in water (25 mL) at 70° C. over a period of 25 minutes and the mixture was heated at 70° C. for 45 minutes. The mixture was cooled and extracted with toluene (2×150 mL). The organic phase was washed with water (100 mL), then brine (100 mL), dried (Na.sub.2SO.sub.4), filtered, and evaporated to afford a brown oil. Purification by column chromatography (silica gel 230-400 mesh; 25% dichloromethane in hexanes as the eluent) gave 4-bromo-2,6-dimethylbenzonitrile as an orange solid. Yield: 2.3 g (49%).

(205) To 4-bromo-2,6-dimethylbenzonitrile (1.84 g, 8.75 mmol) in anhydrous THF (95 mL), at −78° C. under nitrogen, was added n-butyllithium (2.5 M in hexanes; 3.85 mL, 9.63 mmol) dropwise over 10 minutes. The solution was stirred at −78° C. for 1 hour, and anhydrous DMF (1.00 mL, 12.91 mmol) was added dropwise. The mixture was stirred at −78° C. for 1 hour and at 0° C. for 25 minutes. The reaction was quenched with 1 M HCl, to pH approximately 3. The solution was poured into water (370 mL) and extracted with CHCl.sub.3 (7×100 mL). The organic phase was dried over anhydrous Na.sub.2SO.sub.4, filtered, and evaporated, to give 4-formyl-2,6-dimethylbenzonitrile as a yellow-orange solid (1.20 g, 86%).

(206) 4-Formyl-2,6-dimethylbenzonitrile (1.20 g, 7.53 mmol), anhydrous MeOH (80 mL), trimethylorthoformate (18.0 mL, 164.5 mmol), and camphorsulfonic acid (0.050 g, 0.215 mmol) were stirred at room temperature under nitrogen for 23 hours. Triethylamine (7.5 mL) was added and the solution was evaporated to an oil. The oil was diluted with NaHCO.sub.3 (100 mL) and extracted with CHCl.sub.3 (5×75 mL). The organic phase was dried over anhydrous Na.sub.2SO.sub.4, filtered, and evaporated to afford 4-(dimethoxymethyl)-2,6-dimethylbenzonitrile as a golden-red oil. Yield: 1.40 g (90%).

(207) To 4-(dimethoxymethyl)-2,6-dimethylbenzonitrile (0.86 g, 4.18 mmol) in anhydrous THF (40 mL), at 0° C. under nitrogen, was added solid lithium aluminum hydride (0.34 g, 8.94 mmol) in portions over 15 minutes. The mixture was stirred at 0° C. for 30 minutes and at room temperature for 20 hours. The mixture was cooled to 0° C. and quenched with solid Na.sub.2SO.sub.4.10H.sub.2O, stirred for 10 minutes, and then stirred at room temperature for 15 minutes. Solids were removed by filtration and washed with THF (100 mL). The filtrate was evaporated to give (4-(dimethoxymethyl)-2,6-dimethylphenyl)methanamine as a golden-brown semi-solid. Yield: 0.87 g (100%)

(208) To (4-(dimethoxymethyl)-2,6-dimethylphenyl)methanamine (0.87 g, 4.18 mmol), anhydrous CH.sub.2Cl.sub.2 (20 mL), Et.sub.3N (5.84 mL, 41.89 mmol), at 0° C. under nitrogen, was added acetic anhydride (0.44 mL, 4.65 mmol), followed by DMAP (0.018 g, 0.147 mmol). The mixture was stirred at 0° C. for 15 minutes and then at room temperature for 23 hours. The mixture was evaporated to a solid. The solid was stirred with NaHCO.sub.3 (100 mL) and CHCl.sub.3 (50 mL) for 15 minutes. The organic phase was separated and the aqueous phase extracted with CHCl.sub.3 (4×50 mL). The combined organic phase was washed with brine (75 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and evaporated to afford N-(4-(dimethoxymethyl)-2,6-dimethylbenzyl)acetamide as a light orange solid (1.00 g, 95%).

(209) To N-(4-(dimethoxymethyl)-2,6-dimethylbenzyl)acetamide (0.83 g, 3.30 mmol) in CHCl.sub.3 (65 mL), at 0° C. was added trifluoroacetic acid/water (1:1, 10 mL) added dropwise. The solution was stirred at 0° C. for 1.75 hours. The solution was diluted with water (200 mL) and the organic phase separated. The aqueous phase was extracted with CHCl.sub.3 (4×75 mL). The combined organic phase was washed with NaHCO.sub.3 (200 mL). The aqueous phase was back-extracted with CHCl.sub.3 (3×30 mL). The combined organic phase was dried (Na.sub.2SO.sub.4), filtered, and evaporated to give a N-(4-formyl-2,6-dimethylbenzyl)acetamide as a brown solid. Yield: 0.56 g (82%)

(210) 2-Amino-4,6-dimethoxybenzamide (0.334 g, 1.70 mmol), N-(4-formyl-2,6-dimethylbenzyl)acetamide (0.35 g, 1.70 mmol), anhydrous N,N-dimethylacetamide (10 mL), sodium bisulfite (58.5 wt %, 0.343 g, 1.87 mmol) and p-TsOH.H.sub.2O (0.065 g, 0.341 mmol) were heated at 120° C. for 19.5 hours. The solution was evaporated in vacuo and the residue was triturated with water (50 mL). The yellow solid was filtered off and washed with water (50 mL). The product was purified by column chromatography (silica gel, 230-400 mesh; 6% methanol in dichloromethane as the eluent) and triturated with Et.sub.2O (6 mL) to afford the title compound as a white solid. Yield: 0.202 g (31%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.89 (s, 1H), 7.93 (t, J=4.49 Hz, 1H), 7.85 (s, 2H), 6.74 (d, J=1.95 Hz, 1H), 6.51 (d, J=1.95 Hz, 1H), 4.28 (d, J=4.69 Hz, 2H), 3.87 (s, 3H), 3.83 (s, 3H), 2.37 (s, 6H), 1.80 (s, 3H). MS (ES+) m/z: 382.18 (100%), 383.19.

Example 39. Preparation of N-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-2,6-dimethyl-benzyl]-acetamide

(211) ##STR00053##

(212) To a solution of 2-amino-4,6-dimethoxy-nicotinamide (300 mg, 1.52 mmol), N-(4-formyl-2,6-dimethyl-benzyl)-acetamide (342 mg, 1.67 mmol) in N,N-dimethylacetamide (5 mL) were added sodium hydrogen sulfite (58.5 wt %, 300 mg, 1.68 mmol) and p-toluenesulfonic acid monohydrate (60 mg, 0.32 mmol). The reaction mixture was stirred at 150° C. for 17 hours under nitrogen and then cooled to room temperature. The solvent was evaporated under reduced pressure to dryness. Water (50 mL) was added, and extracted with dichloromethane. The organic phase was dried over anhydrous anhydrous sodium sulfate. Solvent was evaporated and the crude compound was purified by column chromatography (silica gel 230-400 mesh; eluting with 5% methanol in dichloromethane) to give the title compound as a white solid. Yield: 78 mg (13%). .sup.1H NMR (400 MHz, CD.sub.3OD): δ 7.79 (s, 2H), 6.40 (s, 1H), 4.46 (s, 2H), 4.05 (s, 3H), 3.98 (s, 3H), 2.46 (s, 6H), 1.95 (s, 3H). MS (ES.sup.+) m/z: 383.13 (M+1).

Example 40. Preparation of 2-{3,5-dimethyl-4-[2-(2,2,2-trifluoro-ethylamino)-ethoxy]-phenyl}-5,7-dimethoxy-3H-quinazolin-4-one

(213) ##STR00054##

(214) A solution of 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (500 mg, 1.15 mmol) and 2,2,2-trifluoro ethyl amine (1.14 g, 11.53 mmol) and TEA (5 mL) in DMF:THF (10:5 ml) was heated at 40° C. for 24 hours. Then, water (100 mL) was added and product was extracted with ethyl acetate (2×250 mL). The combined organic layer was washed with water, then brine, dried over Na.sub.2SO.sub.4, and evaporated, to give crude product. The crude product was purified by the Simpliflash system, using 2% methanol in dichloromethane as eluent, to give the title compound as a white solid. Yield: 81 mg (15%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.44 (s, 1H), 7.69 (s, 2H), 6.83 (d, J=2.4 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 3.91 (s, br, 2H), 3.33 (d, J=4.4 Hz, 2H), 3.14 (d, J=1.2 Hz, 2H), 2.37 (s, 6H). MS (ES) m/z: 450.07 (M−1) (100%).

Example 41. Preparation of N-{2-[4-(6,8-dimethoxy-1-oxo-1,2-dihydro-isoquinolin-3-yl)-2,6-dimethyl-phenoxy]-ethyl}-formamide

(215) ##STR00055##

(216) To a suspension of 3-[4-(2-Hydroxy-ethoxy)-3,5-dimethyl-phenyl]-6,8-dimethoxy-2H-isoquinolin-1-one (0.80 g, 2.16 mmol), isoindole-1,3-dione (0.35 g, 2.38 mmol), and triphenyl phosphine (0.85 g, 3.25 mmol) in THF (30 mL), was added diethyl azodicarboxylate (0.56 g, 3.25 mmol), and the reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated in vacuo and the residue was washed with ether to give 2-{2-[4-(6,8-dimethoxy-1-oxo-1,2-dihydro-isoquinolin-3-yl)-2,6-dimethyl-phenoxy]-ethyl}-isoindole-1,3-dione as an off-white solid. Yield: 1.11 g (crude).

(217) Hydrazine hydrate (0.29 mL, 6.07 mmol) was added to the solution of 2-{2-[4-(6,8-dimethoxy-1-oxo-1,2-dihydro-isoquinolin-3-yl)-2,6-dimethyl-phenoxy]-ethyl}-isoindole-1,3-dione (1.01 g, 2.03 mmol) in ethanol (20 mL). The reaction mixture was heated to 70° C. for 5 hours. The solvent was removed and the residue was purified by the Simpliflash system, using 5% 7 N ammonia in methanol with dichloromethane as eluent, to give 3-[4-(2-amino-ethoxy)-3,5-dimethyl-phenyl]-6,8-dimethoxy-2H-isoquinolin-1-one as a white solid. Yield: 0.59 g (80.2%).

(218) To a solution of 3-[4-(2-amino-ethoxy)-3,5-dimethyl-phenyl]-6,8-dimethoxy-2H-isoquinolin-1-one (0.30 g, 0.8 mmol) in formic acid (20 mL), was heated at reflux for 72 hours. The reaction mixture was cooled to room temperature and solvent was removed under reduced pressure. Water (100 mL) was added to the residue and neutralized with solid NaHCO.sub.3. The product was extracted with dichloromethane (2×200 mL). The combined organic layer was washed with water, then brine, dried over Na.sub.2SO.sub.4, and evaporated to give crude product. The crude product was purified by the Simpliflash system, using 5% 7 N ammonia in methanol with dichloromethane as eluent, to give the title compound as a white solid. Yield: 97 mg (30%). .sup.1H NMR (400 MHz, DMSO): δ 10.70 (s, 1H), 8.31 (br s, 1H), 8.09 (s, 1H), 7.45 (s, 2H), 6.67 (d, J=2.0 Hz, 1H), 6.64 (s, 1H), 6.45 (d, J=2.0 Hz, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 3.77 (m, 2H), 3.48 (m, 3H), 2.25 (s, 6H). MS (ES) m/z: 397.11 (M+1) (100%).

Example 42. Preparation of 2-(3,5-dimethyl-4-(2-(methylamino)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

(219) ##STR00056##

(220) To a mixture of 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (2.00 g, 5.40 mmol) and Et.sub.3N (0.977 mL, 7.02 mmol) in CH.sub.2Cl.sub.2 (27.0 mL) was added slowly MsCl (0.543 mL, 7.02 mmol) at room temperature. After 1 day, additional Et.sub.3N (0.977 mL, 7.02 mmol) and MsCl (0.543 mL, 7.02 mmol) was added and the mixture was stirred for 2 hours, then diluted with EtOAc (300 mL) and washed with 10% aqueous citric acid (3×75 mL), saturated aqueous NaHCO.sub.3 (75 mL), and brine (75 mL). An insoluble white solid was collected by filtration to provide 2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl methanesulfonate (0.890 g, 37%).

(221) A mixture of compound 2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl methanesulfonate (0.200 g, 0.446 mmol) and 33% CH.sub.3NH.sub.2 in EtOH (5.00 mL) was heated at reflux overnight. The solvent was removed under vacuum and the residue was purified on silica gel (12 g, CH.sub.2Cl.sub.2/CH.sub.3OH) and the product freeze-dried from MeCN/H.sub.2O to provide the title compound (0.0968 g, 57%) as a light yellow solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6: δ 7.90 (s, 2H), 6.73 (d, J=2.29 Hz, 1H), 6.52 (d, J=2.29 Hz, 1H), 3.94-3.80 (m, 8H), 2.98 (t, J=5.46 Hz, 2H), 2.45 (s, 3H), 2.33-2.28 (m, 8H). MS (APCI) m/z 384 [C.sub.21H.sub.25N.sub.3O.sub.4+H].sup.+.

Example 43. Preparation of N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)propane-2-sulfonamide

(222) ##STR00057##

(223) A mixture of 3,5-dimethyl-4-hydroxybenzaldehyde (0.600 g, 4.00 mmol), N-(2-bromoethyl)-phthalimide (1.22 g, 4.80 mmol), K.sub.2CO.sub.3 (0.829 g, 6.00 mmol), NaI (3.00 g, 20.0 mmol) in DMF (40.0 mL) was heated at 80° C. for 2.5 hours. The reaction was cooled to room temperature, diluted with EtOAc (200 mL), washed with 1 M NaOH (2×100 mL), 1 M HCl (2×100 mL), brine (75 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was chromatographed on silica gel (40 g, hexanes/EtOAc) to provide the expected ether (0.300 g, 23%) as a yellow solid. A mixture of this ether (0.293 g, 0.907 mmol), 2-amino-4,6-dimethoxybenzamide (0.178 g, 0.907 mmol), NaHSO.sub.3 (94%, 0.100 g, 0.907 mmol), and p-TsOH.H.sub.2O (0.0173 g, 0.0907 mmol) in DMA (11.3 mL) was stirred at reflux for 1.5 hours, then cooled to room temperature. The mixture was diluted with EtOAc (250 mL), washed with saturated aqueous ammonium chloride (3×75 mL), them brine (75 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was chromatographed on silica gel (40 g, CH.sub.2Cl.sub.2/CH.sub.3OH) to provide the expected product (0.075 g, 17%) as a light yellow solid. A mixture of the above compound (0.213 g, 0.426 mmol) and 2 M methylamine in THF (25.0 mL) was stirred at room temperature for 17 hours. The volatiles were removed under vacuum and 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one was isolated (0.036 g, 23%) as a white solid.

(224) A mixture of 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.125 g, 0.338 mmol), 2-propylsulfonyl chloride (0.040 mL, 0.36 mmol), and DBU (0.100 mL, 0.67 mmol) in THF (2.5 mL) was stirred at 60° C. for 18 hours. Then, the mixture was cooled to room temperature and purified by silica gel chromatography, eluting with 92:7:1 CHCl.sub.3/MeOH/concentrated NH.sub.4OH. The mixture 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 desired product. The product was freeze-dried from CH.sub.3CN/H.sub.2O to afford the title compound (0.080 g, 50%) as a white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6: δ 11.85 (s, 1H), 8.09 (s, 2H), 7.33 (t, J=6.0 Hz, 1H), 6.74 (d, J=2.3 Hz, 1H), 6.52 (d, J=2.3 Hz, 1H), 3.89 (s, 3H), 3.82-3.86 (m, 5H), 3.21-3.39 (m, 3H), 2.31 (s, 6H), 1.26 (d, J=6.8 Hz, 6H). APCI MS m/z 476 [M+H].sup.+.

Example 44. Preparation of 2-(4-(2-(isopropylamino)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

(225) ##STR00058##

(226) A solution of 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.200 g, 0.54 mmol) in EtOH (10 mL) and acetone (0.198 mL, 2.71 mmol) was treated with PtO.sub.2 (0.050 g). The reaction mixture was stirred under 1 atmosphere of hydrogen for 48 hours. Then, the mixture was filtered through celite with ethanol washings, concentrated, and purified by silica gel chromatography, to afford the title compound (0.155 g, 70%). The product 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 as a white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6: δ 7.90 (s, 2H), 6.74 (d, J=2.3 Hz, 1H), 6.52 (s, J=2.3 Hz, 1H), 3.83-3.89 (m, 8H), 2.89 (t, J=5.6 Hz, 2H), 2.75-2.84 (m, 1H), 2.30 (s, 6H), 1.01 (d, J=6.2 Hz, 6H); APCI MS m/z 412 [M+H].sup.+.

Example 45. Preparation of N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylphenoxy)ethyl)acetamide

(227) ##STR00059##

(228) 2-(4-(2-Aminoethoxy)-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one was synthesized as described for 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one from 3-methyl-4-hydroxybenzaldehyde (See Example 43).

(229) A suspension of 2-(4-(2-aminoethoxy)-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.12 g, 0.33 mmol) in CH.sub.2Cl.sub.2 (5 mL) was treated with Et.sub.3N (0.05 mL, 0.41 mmol) and acetyl chloride (0.026 mL, 0.37 mmol) and the mixture stirred at room temperature for 3 hours. Then, the mixture was concentrated in vacuo and the residue purified by flash chromatography on silica gel, eluting with 97:3 to 90:10 CH.sub.2Cl.sub.2/MeOH to 92:7:1 CHCl.sub.3/MeOH/concentrated NH.sub.4OH, to afford crude product. Further purification on a reverse-phase C.sub.18 column, eluting with 10% to 90% CH.sub.3CN in H.sub.2O with 0.05% TFA, afforded the title compound (0.080 g, 61%) as a white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 11.65 (s, 1H), 7.93-8.18 (m, 3H), 7.05 (d, J=8.4 Hz, 1H), 6.71 (d, J=2.3 Hz, 1H), 6.50 (d, J=2.3 Hz, 1H), 4.07 (t, J=5.6 Hz, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 3.35-3.52 (m, 2H), 2.23 (s, 3H), 1.83 (s, 3H). APCI MS m/z 398 [M+H].sup.+.

Example 46. Preparation of 2-(4-(2-(dimethylamino)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

(230) ##STR00060##

(231) To a solution of 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.150 g, 0.41 mmol) in MeOH (16 mL) and CH.sub.2Cl.sub.2 (5 mL) was added 37% aqueous formaldehyde (0.300 mL, 4.0 mmol) and the mixture stirred for 1 hour. Then, NaBH.sub.4 (0.078 g, 2.05 mmol) was added and the reaction was stirred for 16 hours at room temperature. Additional 37% aqueous formaldehyde (1.0 mL) was added and stirred for 1 hour, at which time, additional NaBH.sub.4 (0.100 g, 2.63 mmol) was added and stirred for 1 hour. The reaction mixture was concentrated, redissolved in CH.sub.2Cl.sub.2, washed with brine (100 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with 9:1 CH.sub.2Cl.sub.2/MeOH to 92:7:1 CHCl.sub.3/MeOH/concentrated aqueous NH.sub.4OH. The residue 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 as a white solid (0.070 g, 43%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 11.70 (br s, 1H), 7.90 (s, 2H), 6.74 (d, J=2.3 Hz, 1H), 6.52 (d, J=2.3 Hz, 1H), 3.84-3.89 (m, 8H), 2.64 (t, J=5.8 Hz, 2H), 2.30 (s, 6H), 2.24 (s, 6H). APCI MS m/z 398 [M+H].sup.+.

Example 47. Preparation of N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-N-methylacetamide

(232) ##STR00061##

(233) To a solution of 2-(3,5-dimethyl-4-(2-(methylamino)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.110 g, 0.287 mmol) in CH.sub.2Cl.sub.2 (10 mL) was added Et.sub.3N (0.080 mL, 0.574 mmol), followed by acetyl chloride (0.022 mL, 0.315 mmol). The mixture was stirred at room temperature under nitrogen for 10 minutes, concentrated, and purified by silica gel chromatography, eluting with 9:1 CH.sub.2Cl.sub.2/MeOH, followed 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 as a white solid (0.078 g, 64%). .sup.1H NMR (mixture of amide rotamers, 300 MHz, DMSO-d.sub.6: δ 11.85 (s, 1H), 7.90 (d, J=2.7 Hz, 2H), 6.74 (d, J=2.2 Hz, 1H), 6.52 (d, J=2.2 Hz, 1H), 3.84-3.95 (m, 8H), 3.65-3.74 (m, 2H), 3.12 (s, 1.5H), 2.92 (s, 1.5H), 2.27 (d, J=1.1 Hz, 6H), 2.11 (s, 1.5H), 2.03 (s, 1.5H). APCI MS m/z 424 [M−H].sup.−.

Example 48. Preparation of N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)formamide

(234) ##STR00062##

(235) A solution of 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.086 g, 0.23 mmol) in ethanol (10 mL) and methyl formate (0.028 mL, 0.46 mmol) was stirred at room temperature for 5 hours. At this time, an additional portion of methyl formate (5 mL, 80.6 mmol) was added and the mixture heated at reflux for 4 days. The mixture was concentrated and purified by silica gel chromatography, eluting with 92:7:1 CHCl.sub.3/MeOH/concentrated NH.sub.4OH. The product was freeze-dried from CH.sub.3CN/H.sub.2O to yield the title compound (0.065 g, 71%) as a white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6: δ 11.84 (s, 1H), 8.29-8.37 (m, 1H), 8.11 (d, J=1.3 Hz, 1H), 7.90 (s, 2H), 6.74 (d, J=2.3 Hz, 1H), 6.52 (d, J=2.3 Hz, 1H), 3.89 (s, 3H), 3.79-3.84 (m, 5H), 3.47-3.53 (m, 2H), 2.29 (s, 6H). APCI MS m/z 396 [M−H].sup.−.

Example 49. Preparation of N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-N-methylformamide

(236) ##STR00063##

(237) To a solution of 2-(3,5-dimethyl-4-(2-(methylamino)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.080 g, 0.21 mmol) in EtOH (15 mL) was added methyl formate (5 mL). The mixture was heated at reflux for 24 hours, concentrated, and purified by silica gel chromatography, eluting with 9:1 CH.sub.2Cl.sub.2/MeOH, to afford the title compound as a white solid (0.080 g, 93%): .sup.1H NMR (mixture of amide rotamers, 300 MHz, DMSO-d.sub.6: δ 11.85 (s, 1H), 8.12 (d, J=1.9 Hz, 1H), 7.90 (s, 2H), 6.74 (d, J=2.2 Hz, 1H), 6.52 (d, J=2.2 Hz, 1H), 3.88-3.93 (m, 5H), 3.84 (s, 3H), 3.62-3.68 (m, 2H), 3.08 (s, 0.5H), 2.88 (s, 0.5H), 2.25-2.35 (m, 6H); APCI MS m/z 410 [M−H].sup.−.

Example 50. Preparation of N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)dimethylamino-N-sulfonamide

(238) ##STR00064##

(239) A solution of 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.150 g, 0.41 mmol) in CH.sub.2Cl.sub.2 (10 mL) was treated with Et.sub.3N (0.083 g, 0.82 mmol), then dimethylsulfamoylchloride (0.065 g, 0.45 mmol), and the reaction mixture stirred under nitrogen at room temperature for 1 hour. Then, DBU (0.100 mL) was added and stirring continued for 1 hour at room temperature. Then, the reaction mixture was heated at reflux for 18 hours, additional dimethylsulfamoylchloride (0.150 mL) was added, and heating continued at reflux for a further 2 hours. The reaction mixture was cooled and purified by flash chromatography on silica gel, eluting with 100% CH.sub.2Cl.sub.2 to 100% (92:7:1 CHCl.sub.3/MeOH/concentrated NH.sub.4OH). The resulting solid was further purified by reverse-phase HPLC, eluting with 10% to 90% CH.sub.3CN in H.sub.2O with 0.1% TFA. The solids were then triturated with CH.sub.3CN to afford the title compound as a white solid. .sup.1H NMR (300 MHz, CDCl.sub.3) δ 9.20 (s, 1H), 7.69 (s, 2H), 6.82 (d, J=2.3 Hz, 1H), 6.5 (d, J=2.3 Hz, 1H), 4.72-4.80 (m, 1H), 3.93-3.98 (m, 8H), 3.46-3.56 (m, 2H), 2.87 (s, 6H), 2.38 (s, 6H); ESI MS m/z 477 [M+H].sup.+.

Example 51. Preparation of N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)cyanamide

(240) ##STR00065##

(241) To a solution of 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.150 g, 0.41 mmol) in MeOH (15 mL) was added BrCN (0.043 g, 0.41 mmol) and NaHCO.sub.3 (0.044 g, 0.52 mmol). The reaction was stirred at room temperature for 1 hour and then concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 2% to 10% MeOH/CH.sub.2Cl.sub.2, afforded the title compound (0.120 g, 74%) as a white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 11.85 (s, 1H), 7.82-7.92 (m, 2H), 7.03-7.14 (m, 1H), 6.72 (d, J=1.4 Hz, 1H), 6.59 (d, J=1.4 Hz, 1H), 3.81-3.93 (m, 8H), 3.15-3.29 (m, 2H), 2.28 (s, 6H). APCI MS m/z 395 [M+H].sup.+.

Example 52. Preparation of 2-(3,5-dimethyl-4-(2-(5-methylisoxazol-3-ylamino)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

(242) ##STR00066##

(243) To a solution of 5-methylisoxazol-3-amine (1.0 g, 10.2 mmol) in CH.sub.2Cl.sub.2 was added Et.sub.3N (1.03 g, 10.2 mmol) and bromoacetyl chloride (1.60 g, 10.2 mmol). The mixture was stirred at room temperature for 1 hour, washed with water (100 mL), then brine (100 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated, to afford 2-bromo-N-(5-methylisoxazol-3-yl)acetamide as a white solid (1.2 g, 55%).

(244) To a solution of 2-bromo-N-(5-methylisoxazol-3-yl)acetamide (0.223 g, 1.0 mmol) in THF (10 mL) under nitrogen was added 1.0 M BH.sub.3.THF (3.0 mL, 3.0 mmol). The reaction mixture was stirred at room temperature for 18 hours, quenched with 1 M NaOH, extracted with ethyl acetate (2×100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 1:1 ethyl acetate/hexane to 100% ethyl acetate, to afford N-(2-bromoethyl)-5-methylisoxazol-3-amine as a white solid (0.061 g, 30%).

(245) To a solution of 4-hydroxy-3,5-dimethylbenzaldehyde (0.036 g, 0.24 mmol) in DMF (1.5 mL) was added K.sub.2CO.sub.3 (0.050 g, 0.36 mmol) and the mixture stirred at room temperature under nitrogen for 30 minutes. After this time, a solution of N-(2-bromoethyl)-5-methylisoxazol-3-amine (0.060 g, 0.29 mmol) in DMF (1.5 mL) was added and the reaction heated at reflux for 2 hours. The mixture was concentrated and purified by flash chromatography on silica gel, eluting with 1:1 ethyl acetate/heptane to 100% ethyl acetate, to afford 3,5-dimethyl-4-(2-(5-methylisoxazol-3-ylamino)ethoxy)benzaldehyde (0.028 g, 26%).

(246) A mixture of 3,5-dimethyl-4-(2-(5-methylisoxazol-3-ylamino)ethoxy)benzaldehyde (0.121 g, 0.44 mmol), 2-amino-4,6-dimethoxybenzamide (0.087 g, 0.44 mmol), NaHSO.sub.3 (0.050 g, 0.48 mmol), and p-TsOH (0.008 g, 0.044 mmol) in DMA (3 mL) was heated at 155° C. under nitrogen for 9 hours. Then, the reaction mixture was cooled, diluted with ethyl acetate (200 mL), and washed with water (100 mL), brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 100% CH.sub.2Cl.sub.2 to 100% 92:7:1 CHCl.sub.3/MeOH/concentrated NH.sub.4OH, to afford the title compound (0.129 g, 65%). .sup.1H NMR (300 MHz, DMSO-d.sub.6: δ 11.99 (s, 1H), 7.99 (s, 2H), 6.77 (d, J=2.3 Hz, 1H), 6.55 (d, J=2.3 Hz, 1H), 5.29 (s, 1H), 4.70-4.72 (m, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.55-3.61 (m, 4H), 2.22 (s, 6H), 2.21 (s, 3H). APCI MS m/z 451 [M+H].sup.+.

Example 53. Preparation of 2-(3,5-dimethyl-4-(2-(pyrimidin-2-ylamino)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

(247) ##STR00067##

(248) To a solution of 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.145 g, 0.40 mmol) in t-butanol (10 mL) was added Et.sub.3N (0.06 mL, 0.47 mmol) and 2-chloropyrimidine (0.045 g, 0.40 mmol). The reaction was stirred and heated at reflux temperature overnight, then concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 95:5 CH.sub.2Cl.sub.2/MeOH, afforded the title compound (0.038 g, 21%) as a white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 8.29 (d, J=4.7 Hz, 2H), 7.87 (s, 2H), 7.31 (t, J=6.1 Hz, 1H), 6.72 (d, J=2.3 Hz, 1H), 6.58 (t, J=4.7 Hz, 1H), 6.51 (s, 1H), 3.95 (t, J=5.9 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.65-3.71 (m, 2H), 2.25 (s, 6H). ESI MS m/z 448 [M+H].sup.+.

Example 54. Preparation of 2-(4-(2-(isoxazol-3-ylamino)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

(249) ##STR00068##

(250) To a solution of isoxazol-3-amine (2.28 g, 27.1 mmol) in CH.sub.2Cl.sub.2 at 0° C. under nitrogen was added Et.sub.3N (2.74 g, 27.1 mmol), followed by bromoacetyl chloride (4.26 g, 27.1 mmol). The mixture was warmed to room temperature, stirred for 2 hours, washed sequentially with water (200 mL) and brine (200 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated, to afford 2-bromo-N-(isoxazol-3-yl)acetamide as a tan solid (4.5 g, 81%).

(251) To a solution of 2-bromo-N-(isoxazol-3-yl)acetamide (1.0 g, 4.9 mmol) in THF (50 mL) under nitrogen was added 1.0 M BH.sub.3.THF (14.6 mL, 14.6 mmol). The mixture was stirred at room temperature for 3.5 hours and then an additional portion of BH.sub.3.THF (5.0 mL, 5.0 mmol) was added. After an additional 15 hours at room temperature, the reaction was quenched with 1 M NaOH, extracted with ethyl acetate (2×150 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 1:1 ethyl acetate/heptane to 100% ethyl acetate, to afford N-(2-bromoethyl)isoxazol-3-amine (0.133 g, 14%).

(252) To a solution of 4-hydroxy-3,5-dimethylbenzaldehyde (0.471 g, 3.14 mmol) in DMF (20 mL) was added K.sub.2CO.sub.3 (0.650 g, 4.71 mmol). The reaction mixture was stirred at room temperature under nitrogen for 30 minutes. Then, a solution of N-(2-bromoethyl)isoxazol-3-amine (0.600 g, 3.14 mmol) in DMF (10 mL) was added. The mixture was heated at reflux for 3 hours, concentrated, and purified by flash chromatography on silica gel, eluting with 30% ethyl acetate/heptane to 100% ethyl acetate, to afford 4-(2-(isoxazol-3-ylamino)ethoxy)-3,5-dimethylbenzaldehyde as a white solid (0.260 g, 32%).

(253) A mixture of 4-(2-(isoxazol-3-ylamino)ethoxy)-3,5-dimethylbenzaldehyde (0.253 g, 0.97 mmol), 2-amino-4,6-dimethoxybenzamide (0.190 g, 0.97 mmol), NaHSO.sub.3 (0.111 g, 1.07 mmol), and p-TsOH (0.018 g, 0.097 mmol) in DMA (10 mL) was heated at 150° C. under nitrogen for 44 hours. Then, the reaction mixture was concentrated, diluted with ethyl acetate (200 mL), and washed with water (150 mL), then brine (150 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 100% CH.sub.2Cl.sub.2 to 100% 92:7:1 CHCl.sub.3/MeOH/concentrated NH.sub.4OH, to afford the title compound (0.150 g, 35%). .sup.1H NMR (300 MHz, DMSO-d.sub.6: δ 11.82 (s, 1H), 8.39 (d, J=1.7 Hz, 1H), 7.89 (s, 2H), 6.73 (d, J=2.2 Hz, 1H), 6.51 (d, J=2.2 Hz, 1H), 6.44 (t, J=6.1 Hz, 1H), 6.02 (d, J=1.7 Hz, 1H), 3.94 (t, J=5.5 Hz, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 3.46-3.51 (m, 2H), 2.27 (s, 6H). APCI MS m/z 437 [M+H].sup.+.

Example 55. Preparation of 2-(4-(2-(4,6-dimethoxypyrimidin-2-ylamino)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

(254) ##STR00069##

(255) Following the method described for Example 51 above, the title compound was made from 2-chloro-4,6-dimethoxypyrimidine (0.071 g, 0.40 mmol) in 35% yield. .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 11.82 (s, 1H), 7.88 (s, 2H), 7.22 (t, J=6.1 Hz, 1H), 6.72 (d, J=2.3 Hz, 1H), 6.51 (s, 1H), 5.38 (s, 1H), 3.90-4.02 (m, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 3.77 (s, 6H), 3.59-3.72 (m, 2H), 2.27 (s, 6H). APCI MS m/z 506 [M−H].sup.−.

Example 56. Preparation of 2-[4-(3-hydroxy-propyl)-3,5-dimethoxyphenyl]-5,7-dimethoxy-3H-quinazolin-4-one

(256) ##STR00070##

(257) To a stirred solution of 4-hydroxy-3,5-dimethoxylbenzaldehyde (5.87 g, 32.2 mmol) in CH.sub.2Cl.sub.2 (50 mL) and pyridine (8.6 mL) was added trifluoromethanesulfonic anhydride (10.0 g, 35.4 mmol) at 0° C. After the addition was complete, stirring was continued for 16 hours at room temperature. The reaction mixture was diluted with ethyl acetate (150 mL) and washed with water (3×100 mL). The separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product, trifluoromethanesulfonic acid 4-formyl-2,6-dimethoxyphenyl ester, was used in the next step without further purification. Yield: 10.0 g (98.9%).

(258) To a stirred solution of trifluoromethanesulfonic acid 4-formyl-2,6-dimethoxyphenyl ester (8.00 g, 25.4 mmol) in anhydrous DMF (80 mL) under nitrogen at room temperature were sequentially added triethylamine (5.14 g, 50.8 mmol), methyl acrylate (21.9 g, 254.0 mmol), 1,3-bis-(diphenylphosphino)-propane (0.84 g, 2.03 mmol), and palladium acetate (0.40 g, 1.77 mmol). The reaction mixture was stirred at 115° C. for 16 hours. DMF was removed under reduced pressure and the residue was taken in ethyl acetate (200 mL) and washed with 1 N HCl solution (2×50 mL), and saturated sodium bicarbonate solution (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel 230-400 mesh; eluting with hexane/ethyl acetate=3:1) to give 3-(4-formyl-2,6-dimethoxyphenyl)-acrylic acid methyl ester. Yield: 4.0 g (62%).

(259) To a solution of 3-(4-formyl-2,6-dimethoxyphenyl)-acrylic acid methyl ester (5.00 g, 20.0 mmol) in methanol (80 mL), 1.5 N sodium hydroxide (45 mL) was added. The suspension was stirred at room temperature for 16 hours. Methanol was evaporated and acetic acid (4.0 mL) was added. The aqueous layer was extracted with dichloromethane (200 mL) then acidified, to pH 3, with 2 N HCl. The solid was filtered and further washed with cold water (100 mL) to obtain 3-(4-formyl-2,6-dimethoxyphenyl)-acrylic acid as a yellow solid. Yield: 4.20 g (89%).

(260) To a solution of 3-(4-formyl-2,6-dimethoxyphenyl)-acrylic acid (4.20 g, 17.7 mmol) and N,N-diisopropylethylamine (3.5 mL) in ethanol (80 mL) were added Pd/C (400 mg, 10 wt %). The suspension was vigorously stirred under 1 bar of hydrogen pressure for 16 hours. The mixture was filtered through a celite pad and the filtrate was evaporated. The residue was poured into chilled 1 N HCl (200 mL), the solid was filtered, and further washed with cold water (100 mL) to give a mixture of 3-(4-formyl-2,6-dimethoxyphenyl)-propionic acid and 3-(4-hydroxymethyl-2,6-dimethoxyphenyl)-propionic acid as a white solid. Yield: 3.30 g.

(261) To a suspension of LiAlH.sub.4 (1.00 g, 26.3 mmol) in anhydrous THF (40 mL) was added dropwise a solution of a mixture of 3-(4-formyl-2,6-dimethoxyphenyl)-propionic acid and 3-(4-hydroxymethyl-2,6-dimethoxyphenyl)-propionic acid (3.30 g, 13.8 mmol). After the addition was complete, the reaction mixture was stirred at reflux for 2 hours. The suspension was diluted with THF (20 mL) and another portion of LiAlH.sub.4 (0.60 g, 15.8 mmol) was added. The mixture was refluxed for an additional 1 hour. The reaction was cooled to room temperature, carefully quenched with aqueous saturated NH.sub.4Cl solution (8 mL), acidified to pH 1-2 with 2 N HCl, and extracted with ethyl acetate (200 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to provide 3-(4-hydroxymethyl-2,6-dimethoxyphenyl)-propan-1-ol as a colorless crystalline solid. Yield: 3.08 g (98.7%).

(262) To a solution of 3-(4-hydroxymethyl-2,6-dimethoxyphenyl)-propan-1-ol (3.08 g, 13.6 mmol) in ethanol (50 mL) was added activated MnO.sub.2 (4.15 g, 47.6 mmol) and the resulting suspension was stirred at reflux for 16 hours. The reaction mixture was filtered through a celite pad and the filtrate was concentrated. The residue was purified by column chromatography (silica gel 230-400 mesh; eluting with 2:1 hexane and ethyl acetate) to give 4-(3-hydroxy-propyl)-3,5-dimethoxybenzaldehyde. Yield: 1.10 g (36%).

(263) To a solution of 2-amino-4,6-dimethoxy-benzamide (0.35 g, 1.78 mmol) and 4-(3-hydroxy-propyl)-3,5-dimethylbenzaldehyde (0.40 g, 1.78 mmol) in N,N-dimethylacetamide (8 mL) were added NaHSO.sub.3 (0.35 g, 1.96 mmol) and p-TSA (34 mg, 0.18 mmol) and the reaction mixture was heated at 115-120° C. for 5 hours, then cooled to room temperature. N,N-dimethylacetamide was removed under reduced pressure. The residue was diluted with water (50 mL) and the pH was adjusted to 7 by adding sodium bicarbonate solution. The solid was collected and washed with ether and further mixed with methanol (30 mL) and stirred for 1 hour, filtered, and dried under vacuum to give the title compound as a white solid. Yield: 0.25 g (35%). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 11.13 (s, 1H), 7.30 (s, 2H), 6.86 (d, J=2.4 Hz, 1H), 6.47 (d, J=2.4 Hz, 1H), 3.98 (s, 6H), 3.95 (s, 3H), 3.94 (s, 3H), 3.52 (m, 2H), 2.86 (t, J=6.6 Hz 2H), 2.27 (t, J=6.6 Hz, 1H), 1.81 (m, 2H). MS (ES.sup.+) m/z: 401.49 (M+1).

Example 57. Preparation of 2-[4-(3-hydroxy-propyl)-3-methoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one

(264) ##STR00071##

(265) To a stirred solution of 4-hydroxy-3-methoxy-benzaldehyde (5.00 g, 32.8 mmol) in CH.sub.2Cl.sub.2 (50 mL) and pyridine (8 mL) was added trifluoromethanesulfonic anhydride (10.19 g, 36.1 mmol) at 0° C. After addition was complete, stirring was continued for 16 hours at room temperature. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with water (3×100 mL) and brine (100 mL). The separated organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (silica gel 230-400 mesh; 20% ethyl acetate in hexanes as eluent) to give trifluoromethanesulfonic acid 4-formyl-2-methoxy-phenyl ester. Yield: 8.00 g, (85%).

(266) To a stirred solution of trifluoromethanesulfonic acid 4-formyl-2-methoxy-phenyl ester (5.00 g, 17.5 mmol) in anhydrous DMF (75 mL) under nitrogen at room temperature were sequentially added triethylamine (3.50 g, 34.5 mmol), ethyl acrylate (17.50 g, 174.7 mmol), 1,3-bis-(diphenylphosphino)-propane (0.40 g, 0.96 mmol), and palladium (II) acetate (0.20 g, 0.87 mmol). The reaction mixture was stirred at 100° C. for 5 hours. DMF was removed under reduced pressure, and the residue was taken in ethyl acetate (200 mL) and washed with 1 N HCl solution (2×50 mL), and saturated sodium bicarbonate solution (100 mL) and brine (100 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel 230-400 mesh; 20% ethyl acetate in hexanes as eluent) to give 3-(4-formyl-2-methoxy-phenyl)-acrylic acid ethyl ester as a beige solid. Yield: 3.00 g (73%).

(267) To a solution of 3-(4-formyl-2-methoxy-phenyl)-acrylic acid ethyl ester (3.00 g, 13.6 mmol) and N,N-diisopropylethylamine (3.0 mL) in ethanol (100 mL) were added Pd/C (10 wt %, 400 mg). The suspension was hydrogenated under 25 psi pressure for 5 hours. The mixture was filtered through a celite pad and the filtrate was evaporated. The residue was poured into chilled 1 N HCl (200 mL), the solid was filtered, and further washed with cold water (100 mL) to give a 3-(4-hydroxymethyl-2-methoxy-phenyl)-propionic acid ethyl ester as a beige solid. Yield: 2.80 g (93%).

(268) To a suspension of LiAlH.sub.4 (0.51 g, 26.3 mmol) in anhydrous THF (100 mL) was added dropwise a solution of 3-(4-hydroxymethyl-2-methoxyphenyl)-propionic acid ethyl ester (2.5 g, 11.1 mmol) in THF (10 mL). After the addition was complete, the reaction mixture was stirred at reflux for 3 hours. Then, the reaction was cooled to room temperature, carefully quenched with aqueous saturated NH.sub.4Cl solution (8 mL), acidified to pH approximately 1-2 with 2 N HCl, and extracted with ethyl acetate (200 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated, to provide 3-(4-hydroxymethyl-2-methoxy-phenyl)-propan-1-ol as a colorless crystalline solid. Yield: 1.80 g (90%).

(269) To a solution of 3-(4-hydroxymethyl-2-methoxy-phenyl)-propan-1-ol (1.8 g, 9.1 mmol) in ethanol (50 mL) was added activated MnO.sub.2 (2.79 g, 32.0 mmol) and the resulting suspension was stirred at reflux for 16 hours. The reaction mixture was filtered through celite pad and the filtrate was concentrated. The residue was purified by column chromatography (silica gel 230-400 mesh; 2:1 hexane and ethyl acetate as eluent) to give 4-(3-hydroxy-propyl)-3-methoxy-benzaldehyde. Yield: 1.2 g (67%).

(270) To a solution of 2-amino-4,6-dimethoxy-benzamide (0.48 g, 2.44 mmol) and 4-(3-hydroxy-propyl)-3-methoxy-benzaldehyde (0.40 g, 2.05 mmol) in N,N-dimethylacetamide (10 mL) were added NaHSO.sub.3 (58.5 wt %, 0.40 g, 2.25 mmol) and p-toluenesulfonic acid monohydrate (78 mg, 0.41 mmol) and the reaction mixture was heated at 115° C. for 16 hours, then cooled to room temperature. The solvent was removed under reduced pressure. The residue was diluted with water (50 mL) and the pH was adjusted to approximately 7 by adding sodium bicarbonate solution. The solid was filtered and washed with water. The crude compound was purified by column chromatography (silica gel 230-400 mesh; 5% methanol in dichloromethane as eluent) to give the title compound as an off-white solid. Yield: 0.35 g (46%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.02 (s, 1H), 7.75-7.73 (m, 2H), 7.28 (d, J=7.8 Hz, 1H), 6.75 (d, J=2.3 Hz, 1H), 6.53 (d, J=1.9 Hz, 1H), 4.48 (t, J=5.0 Hz, 1H), 3.90 (d, J=4.2 Hz, 6H), 3.85 (s, 3H), 3.44 (q, J=6.6 Hz, 2H), 2.65 (t, J=7.4 Hz 2H), 1.71-1.67 (m, 2H). MS (ES.sup.+) m/z: 371.51 (M+1).

Example 58. Preparation of 2-[2-(2-hydroxyethyl)-1H-indol-6-yl]-5,7-dimethoxy-3H-quinazolin-4-one

(271) ##STR00072##

(272) To a degassed solution of methyl-3-amino-4-iodobenzoate (2.00 g, 7.22 mmol) in a mixture of 5:1 DMF-triethylamine (30 mL) were added PdCl.sub.2(PPh.sub.3).sub.2 (0.25 g, 0.36 mmol) and copper (I) iodide (0.41 g, 2.16 mmol) and the mixture was degassed again. A degassed solution of 2-(3-butynyloxy)tetrahydro-2H-pyran (1.7 mL, 10.83 mmol) in a mixture of 5:1 DMF-triethylamine (12 mL) was added drop-wise at 75° C. over a period of 45 minutes under nitrogen. Soon after the addition, TLC showed completion of the reaction. The reaction mixture was cooled to room temperature, solvent was removed under reduced pressure, and the residue was diluted with water (75 mL) and extracted with ethyl acetate (3×50 mL). The organic phase was washed with water (50 mL), brine (50 mL), and dried over anhydrous MgSO.sub.4. The solvent was evaporated and the crude product was purified by column chromatography (silica gel 230-400 mesh; 2:1 hexanes and ethyl acetate as eluent) to obtain 3-amino-4-[4-(tetrahydropyran-2-yloxy)-but-1-ynyl]benzoic acid methyl ester as a brown solid. Yield: 1.70 g (78%).

(273) To a stirred solution of 3-amino-4-[4-(tetrahydropyran-2-yloxy)-but-1-ynyl]benzoic acid methyl ester (1.68 g, 5.55 mmol) in anhydrous pyridine (5 mL) was added acetyl chloride (0.43 mL, 6.11 mmol) at 0° C. under nitrogen. Stirring was continued at 0° C. After 30 minutes TLC showed completion of the reaction. Pyridine was removed under reduced pressure and the residue was diluted with ethyl acetate (100 mL). The resulting mixture was washed with aq 2 N HCl (20 mL), water (2×15 mL) and brine (20 mL). After drying over anhydrous MgSO.sub.4, solvent was removed to obtain 3-acetylamino-4-[4-(tetrahydropyran-2-yloxy)-but-1-ynyl]benzoic acid methyl ester as a beige solid. Yield: 1.67 g (87%). Crude product was used in the next step without further purification.

(274) A 1.0 M solution of tetrabutylammonium fluoride (9.67 mL, 9.67 mmol) in THF was added to a solution of 3-acetylamino-4-[4-(tetrahydropyran-2-yloxy)-but-1-ynyl]benzoic acid methyl ester (1.67 g, 4.83 mmol) in anhydrous THF (20 mL) at room temperature. The resulting reddish-brown solution was heated at reflux for 2 hours and then allowed to cool to room temperature. The solvent was removed under reduced pressure and the residue was taken in water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic phase was washed with water (25 mL), brine (50 mL), and dried over anhydrous MgSO.sub.4. The solvent was evaporated and the crude product was purified by column chromatography on (silica gel 230-400 mesh; dichloromethane as eluent) to give 2-[2-(tetrahydropyran-2-yloxy)ethyl]-1H-indole-6-carboxylic acid methyl ester as a light brown solid. Yield: 1.27 g (87%).

(275) To a suspension of lithium aluminum hydride (0.32 g, 8.37 mmol) in anhydrous THF (20 mL) was added a solution of 2-[2-(tetrahydropyran-2-yloxy)ethyl]-1H-indole-6-carboxylic acid methyl ester (1.27 g, 4.19 mmol) in anhydrous THF (10 mL) at −30° C. to −20° C. dropwise over a period of 15 minutes under nitrogen. The temperature was allowed to warm to room temperature and stirring continued for 15 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution at 0° C., diluted with ethyl acetate (50 mL), and filtered. The solid was washed with ethyl acetate. The combined organic phase was dried over anhydrous MgSO.sub.4. The solvent was evaporated and the crude product was purified by the Simpliflash system (3:2 ethyl acetate-hexanes as eluent) to give {2-[2-(tetrahydropyran-2-yloxy)ethyl]-1H-indol-6-yl}-methanol as a white solid. Yield: 0.61 g (53%).

(276) IBX (0.62 g, 2.21 mmol) was added to a solution of {2-[2-(tetrahydropyran-2-yloxy)ethyl]-1H-indol-6-yl}-methanol (0.61 g, 2.21 mmol) in DMSO (10 mL). After 30 min, the reaction mixture became a clear solution. Stirring was continued at room temperature for 2 hours and during this time, some solid precipitated. Water (50 mL) was added, the solid was filtered, and washed with ethyl acetate (50 mL). The filtrate was collected and extracted with ethyl acetate (3×20 mL). The organic phase was washed with brine (30 mL) and dried over anhydrous MgSO.sub.4. Removal of solvent gave 2-[2-(tetrahydropyran-2-yloxy)ethyl]-1H-indole-6-carbaldehyde as a light brown solid. Yield: 0.60 g (99%).

(277) To a solution of 2-amino-4,6-dimethoxy-benzamide (0.48 g, 2.42 mmol) and 2-[2-(tetrahydropyran-2-yloxy)ethyl]-1H-indole-6-carbaldehyde (0.60 g, 2.20 mmol) in N,N-dimethylacetamide (20 mL) were added NaHSO.sub.3 (58.5 wt %, 0.60 g, 3.30 mmol) and p-toluenesulfonic acid monohydrate (0.17 g, 0.88 mmol). The reaction mixture was heated at 110° C. for 20 hours and then cooled to room temperature. N,N-dimethylacetamide was removed under reduced pressure. The residue was diluted with saturated sodium carbonate solution (50 mL) and extracted with dichloromethane (4×25 mL). The combined organic phase was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed and the crude product was purified by column chromatography (silica gel 230-400 mesh; 7% methanol in dichloromethane as eluent). Yield: 0.45 g (56%). The compound was further purified by preparative HPLC to give the title compound as an off-white solid. Yield: 123 mg. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.89 (s, 1H), 11.25 (s, 1H), 8.18 (s, 1H), 7.82 (d, J=8.40 Hz, 1H), 7.50 (d, J=8.40 Hz, 1H), 6.73 (d, J=2.4 Hz, 1H), 6.49 (d, J=2.0 Hz, 1H), 6.27 (s, 1H), 4.80 (t, J=5.2 Hz, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.78-3.73 (m, 2H), 2.92 (t, J=7.2 Hz, 2H). MS (ES+) m/z 366.54 (100%, M+1).

Example 59. Quantification of hIL-6 mRNA

(278) 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 invention.

(279) A human leukemic monocytic lymphoma cell line (U937) was plated (3.2×10.sup.5 cells per well) in a 96-well plate in 100 μL RPMI 1640+10% FBS, and differentiated into macrophages with PMA (60 ng/mL) for 3 days prior to the addition of the compound of interest. The cells were pretreated for 1 h with the test compound in DMSO prior to stimulation with lipopolysaccharide from Escherichia coli at 1 μg/mL. The cells were incubated for 3 h before harvest. At the time of harvest, cells were rinsed in 200 μL PBS. Cell lysis solution (70 μL) was added the cells for 10 min, and mRNA was then prepared using the “mRNA Catcher PLUS plate” (Invitrogen), according to the protocol supplied.

(280) The eluted mRNA isolated was then used in a one-step quantitative real-time PCR reaction, using components of the UltraSense kit together with Applied Biosystems primer-probe mixes. 10 μL of template was amplified with 1.75 μL of IL-6 primer-probe, and 1 μL of hCyclophilin primer probe, and the reaction was carried out in multiplex. Real-time PCR data was analyzed, normalizing the Ct values for hIL-6 to hCyclophilin, prior to determining the fold induction of each unknown sample, relative to the control.

(281) In Table 2, an active compound is one that causes a ≧20% inhibition in IL-6 mRNA at a concentration less than or equal to 10 μM.

(282) TABLE-US-00002 TABLE 2 Example Inhibition of IL-6 expression 1 Active 2 Active 3 Active 4 Active 5 Active 6 Active 7 Active 8 Active 9 Active 10 Active 11 Active 12 Active 13 Active 14 Active 15 Active 16 Active 17 Active 18 Active 19 Active 20 Active 21 Active 22 Active 23 Active 24 Active 25 Active 26 Active 27 Active 28 Active 29 Active 30 Active 31 Active 32 Active 33 Active 34 Active 35 Active 36 Active 37 Active 38 Active 39 Active 40 Active 41 Active 42 Active 43 Active 44 Active 45 Active 46 Active 47 Active 48 Active 49 Active 50 Active 51 Active 52 Active 53 Active 54 Active 55 Active 56 Active 57 Active 58 Active

Example 60. Quantification of hVCAM-1 mRNA

(283) In this example, hVCAM-1 mRNA in tissue culture cells was quantitated to measure the transcriptional inhibition of hVCAM when treated with a compound of the invention.

(284) A human umbilical vein endothelial cell line (HUV-EC-C) was plated in a 96-well plate (5.0×10.sup.3 cells/well) in 100 μL EGM complete media and incubated for 24 h prior to the addition of the compound of interest. The cells were pretreated for 1 h with the test compound in DMSO prior to stimulation with tumor necrosis factor-α (10 ng/mL). The cells were incubated for an additional 24 h before harvest. At time of harvest, the cells were rinsed in 200 μL PBS, and cell lysis solution (70 μL) was then added the cells for 10 min. mRNA was then prepared using the “mRNA Catcher PLUS plate” (Invitrogen), according to the protocol supplied.

(285) The eluted mRNA was then used in a one-step quantitative real-time PCR reaction, using components of the UltraSense kit together with Applied Biosystems primer-probe mixes. 10 μL of template was amplified with 1.75 μL of hVCAM-1 primer-probe, and 1 μL of hCyclophilin primer probe, and the reaction was carried out in multiplex. Real-time PCR data was analyzed, normalizing the Ct values for hVCAM-1 to hCyclophilin, prior to determining the fold induction of each unknown sample, relative to the control.

(286) In Table 3, an active compound is one that causes a ≧20% inhibition in VCAM-1 mRNA at a concentration less than or equal to 10 μM.

(287) TABLE-US-00003 TABLE 3 Example Inhibition of VCAM-1 expression 3 Active 4 Active 5 Active 7 Active 9 Active 10 Active 15 Inactive 17 Inactive 18 Active 20 Active 21 Inactive 22 Active 23 Active 25 Active 26 Active 28 Active 29 Active 30 Inactive 31 Active 32 Active 33 Active 34 Active 35 Active 36 Active 37 Inactive 38 Active 39 Active 40 Active 42 Active 44 Active 47 Active 51 Active 58 Active