Quinazolinones as bromodomain inhibitors

10500209 · 2019-12-10

Assignee

Zenith Epigenetics Ltd. (Calgary, Alberta, CA)

Inventors

Cpc classification

International classification

Abstract

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

Claims

1. A method for inhibiting BET protein function in a mammal, comprising administering a therapeutically effective amount of a compound of Formula I: ##STR00084## or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: W.sub.1 is selected from N and CR.sub.1; W.sub.2 is selected from N and CR.sub.2; W.sub.3 is selected from N and CR.sub.3; W.sub.4 is selected from N and CR.sub.4; X is selected from N and CH; Y is selected from S(O), NH, NHCH.sub.2, NHCH.sub.2CH.sub.2, and NHCH.sub.2CH.sub.2CH.sub.2, wherein if Y is NH, NHCH.sub.2, NHCH.sub.2CH.sub.2, or NHCH.sub.2CH.sub.2CH.sub.2, then the nitrogen is attached to the B ring, and one or more hydrogens may be optionally substituted with alkyl(C.sub.1-C.sub.3), halogen, hydroxyl, or amino; R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, amino, aryloxy, aryl, hydroxyl, and halogen, wherein each alkyl and alkoxy may be optionally substituted with hydroxyl, amino, or halogen, wherein each aryl and aryloxy may be optionally substituted with halogen, alkoxy, or amino, and wherein two adjacent substituents selected from R.sub.1, R.sub.2, R.sub.3, and R.sub.4 may be connected in a 5- or 6-membered ring to form a bicyclic carbocycle or bicyclic heterocycle; R.sub.5 is selected from amino and 5- and 6-membered carbocycles and heterocycles; R.sub.6 is selected from hydrogen, alkoxy, alkyl, halogen, aminoalkyl, and thioalkyl; R.sub.7 is selected from hydrogen, alkyl, alkoxy, thioalkyl, aminoalkyl, and halogen; and wherein said mammal is afflicted with a cancer selected from B-acute lymphocytic leukemia, Burkitt's lymphoma, diffuse large cell lymphoma, multiple myeloma, primary plasma cell leukemia, atypical carcinoid lung cancer, bladder cancer, breast cancer, cervix cancer, colon cancer, gastric cancer, glioblastoma, hepatocellular carcinoma, large cell neuroendocrine carcinoma, medulloblastoma, melanoma, neuroblastoma, esophageal cancer, osteosarcoma, ovarian cancer, prostate cancer, renal carcinoma, retinoblastoma, rhabdomyosarcoma, small cell lung carcinoma, NUT midline carcinoma, B-cell lymphoma, non-small cell lung cancer, head and neck squamous cell carcinoma, chronic lymphocytic leukemia, follicular lymphoma, diffuse large B cell lymphoma with germinal center phenotype, Hodgkin's lymphoma, activated anaplastic large cell lymphoma, primary neuroectodermal tumor, pancreatic cancer, adenoid cystic carcinoma, T-cell prolymphocytic leukemia, malignant glioma, thyroid cancer, Barrett's adenocarcinoma, hepatoma, pro-myelocytic leukemia, and mantle cell lymphoma.

2. The method of claim 1, wherein the compound is a compound of Formula Ia: ##STR00085## or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: X is selected from N and CH; Y is selected from S(O), NH, NHCH.sub.2, NHCH.sub.2CH.sub.2, and NHCH.sub.2CH.sub.2CH.sub.2, wherein if Y is NH, NHCH.sub.2, NHCH.sub.2CH.sub.2, or NHCH.sub.2CH.sub.2CH.sub.2, then the nitrogen is attached to the B ring, and one or more hydrogens may be optionally substituted with alkyl(C.sub.1-C.sub.3), halogen, hydroxyl, or amino; R.sub.1 and R.sub.3 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, amino, aryloxy, aryl, hydroxyl, and halogen, wherein each alkyl and alkoxy may be optionally substituted with hydroxyl, amino, or halogen, wherein each aryl and aryloxy may be optionally substituted with halogen, alkoxy, or amino; R.sub.5 is selected from amino and 5- and 6-membered carbocycles and heterocycles; wherein the 5- and 6-membered carbocycles and heterocycles are selected from: ##STR00086## wherein the 5- and 6-membered carbocycles and heterocycles may be optionally substituted with halogen, amino, amide, alkyl(C.sub.1-C.sub.6), or alkoxy(C.sub.1-C.sub.6); and wherein Ra is selected from hydrogen, methyl, ethyl, propyl, isopropyl, t-butyl, C(O)Me, C(O)Pr, C(O)iPr, benzyl, C(O)CF.sub.3, C(O)-tBu, C(O)NHiPr, C(O)NMe.sub.2, C(O)NHEt, C(O)NH.sub.2, C(O)CH(OH)CH.sub.3, C(O)C(O)OMe, CF.sub.3, CH.sub.2CH.sub.2OH, CH.sub.2CH.sub.2, amino, and CH.sub.2CH.sub.2C(Me).sub.2OH; R.sub.6 is selected from hydrogen, alkoxy, alkyl, halogen, aminoalkyl, and thioalkyl; and R.sub.7 is selected from hydrogen, alkyl, alkoxy, thioalkyl, aminoalkyl, and halogen.

3. The method of claim 2, wherein X is N.

4. The method of claim 2, wherein R.sub.1 and R.sub.3 are each independently an alkoxy group.

5. The method of claim 4, wherein R.sub.1 and R.sub.3 are each independently selected from methoxy, ethoxy, isopropoxy, and propoxy.

6. The method of claim 5, wherein R.sub.1 and R.sub.3 are each methoxy.

7. The method of claim 2, wherein R.sub.1 is methoxy and R.sub.3 is amino.

8. The method of claim 2, wherein Y is selected from NH, NHCH.sub.2, NHCH.sub.2CH.sub.2, and NHCH.sub.2CH.sub.2CH.sub.2, wherein the nitrogen attached to the B ring, and wherein one or more hydrogens may be optionally substituted with F, Me, or Cl.

9. The method of claim 8, wherein Y is NH.

10. The method of claim 2, wherein R.sub.5 is selected from NHRa and 5- and 6-membered carbocycles and heterocycles; wherein the 5- and 6-membered carbocycles and heterocycle are selected from: ##STR00087## wherein the 5- and 6-membered carbocycles and heterocycles may be optionally substituted with halogen, amino, amide, alkyl(C.sub.1-C.sub.6), or alkoxy(C.sub.1-C.sub.6); and wherein Ra is selected from hydrogen, methyl, ethyl, propyl, isopropyl, t-butyl, C(O)Me, C(O)Pr, C(O)iPr, benzyl, C(O)CF.sub.3, C(O)-tBu, C(O)NHiPr, C(O)NMe.sub.2, C(O)NHEt, C(O)NH.sub.2, C(O)CH(OH)CH.sub.3, C(O)C(O)OMe, CF.sub.3, CH.sub.2CH.sub.2OH, CH.sub.2CH.sub.2-amino, and CH.sub.2CH.sub.2C(Me).sub.2OH.

11. The method of claim 2, wherein R.sub.6 is selected from hydrogen, methyl, and methoxy.

12. The method of claim 2, wherein R.sub.6 is selected from groups of Formula II: ##STR00088## wherein: D is selected from O, N, and S; E is independently selected from O and N; R.sub.8 is selected from hydrogen and alkyl, wherein R.sub.8 is present only if D is N; R.sub.9 and R.sub.10 are independently selected from hydrogen, alkyl, and cycloalkyl, wherein only one of R.sub.9 and R.sub.10 is present if E is O; R.sub.9 and R.sub.10 may be connected to form a heterocycle containing one or more heteroatoms; and n is selected from 1, 2, and 3.

13. The method of claim 12, wherein R.sub.6 is selected from: ##STR00089##

14. The method of claim 2, wherein: R.sub.1 and R.sub.3 are each alkoxy; Y is selected from NH, NHCH.sub.2, NHCH.sub.2CH.sub.2, and NHCH.sub.2CH.sub.2CH.sub.2, wherein the nitrogen is attached to the B ring; R.sub.5 is selected from NHRa and 5- and 6-membered carbocycles and heterocycles, wherein the 5- and 6-membered carbocycles and heterocycles are selected from: ##STR00090## wherein Ra is selected from hydrogen, methyl, ethyl, propyl, isopropyl, t-butyl, C(O)Me, C(O)Pr, C(O)iPr, benzyl, C(O)CF.sub.3, C(O)-tBu, C(O)NHiPr, C(O)NMe.sub.2, C(O)NHEt, C(O)NH.sub.2, C(O)CH(OH)CH.sub.3, C(O)C(O)OMe, CF.sub.3, CH.sub.2CH.sub.2OH, CH.sub.2CH.sub.2 amino, and CH.sub.2CH.sub.2C(Me).sub.2OH; and R.sub.6 is selected from hydrogen, methyl, and alkoxy, wherein the alkoxy is optionally substituted with hydroxyl or amino.

15. The method of claim 2, wherein: R.sub.1 is alkoxy; R.sub.3 is amino; Y is selected from NH, NHCH.sub.2, NHCH.sub.2CH.sub.2, and NHCH.sub.2CH.sub.2CH.sub.2, wherein the nitrogen is attached to the B ring; R.sub.5 is selected from NHRa and 5- and 6-membered carbocycles and heterocycles, wherein the 5- and 6-membered carbocycles and heterocycles are selected from: ##STR00091## wherein Ra is selected from hydrogen, methyl, ethyl, propyl, isopropyl, t-butyl, C(O)Me, C(O)Pr, C(O)iPr, benzyl, C(O)CF.sub.3, C(O)-tBu, C(O)NHiPr, C(O)NMe.sub.2, C(O)NHEt, C(O)NH.sub.2, C(O)CH(OH)CH.sub.3, C(O)C(O)OMe, CF.sub.3, CH.sub.2CH.sub.2OH, CH.sub.2CH.sub.2 amino, and CH.sub.2CH.sub.2C(Me).sub.2OH; and R.sub.6 is selected from hydrogen, methyl, and alkoxy, wherein the alkoxy is optionally substituted with hydroxyl or amino.

16. The method of claim 1, wherein the cancer: (a) exhibits overexpression, translocation, amplification, or rearrangement of a myc family oncoprotein; (b) results from aberrant regulation of BET proteins; (c) relies on pTEFb (Cdk9/cyclin T) and BET proteins to regulate oncogenes; (d) is associated with upregulation of BET responsive genes CDK6, Bcl2, TYRO3, MYB and/or hTERT; and/or (e) is associated with a viral infection.

17. The method of claim 16, wherein: (a) the cancer exhibiting overexpression, translocation, amplification, or rearrangement of a myc family oncoprotein is selected from B-acute lymphocytic leukemia, Burkitt's lymphoma, diffuse large cell lymphoma, multiple myeloma, primary plasma cell leukemia, atypical carcinoid lung cancer, bladder cancer, breast cancer, cervix cancer, colon cancer, gastric cancer, glioblastoma, hepatocellular carcinoma, large cell neuroendocrine carcinoma, medulloblastoma, Nodular melanoma, Superficial spreading melanoma, neuroblastoma, esophageal squamous cell carcinoma, osteosarcoma, ovarian cancer, prostate cancer, renal clear cell carcinoma, retinoblastoma, rhabdomyosarcoma, and small cell lung carcinoma; (b) the cancer resulting from aberrant regulation of BET proteins is selected from NUT midline carcinoma, B-cell lymphoma, non-small cell lung cancer, esophageal cancer, head and neck squamous cell carcinoma, and colon cancer; (c) the cancer relying on pTEFb (Cdk9/cyclin T) and BET proteins to regulate oncogenes is selected from chronic lymphocytic leukemia, multiple myeloma, follicular lymphoma, diffuse large B cell lymphoma with germinal center phenotype, Burkitt's lymphoma, Hodgkin's lymphoma, anaplastic large cell lymphoma, neuroblastoma, primary neuroectodermal tumor, rhabdomyosarcoma, prostate cancer, and breast cancer; (d) the cancer associated with upregulation of BET responsive genes CDK6, Bcl2, TYRO3, MYB, and hTERT is selected from pancreatic cancer, breast cancer, colon cancer, glioblastoma, adenoid cystic carcinoma, T-cell prolymphocytic leukemia, malignant glioma, bladder cancer, medulloblastoma, thyroid cancer, melanoma, multiple myeloma, Barrett's adenocarcinoma, hepatoma, prostate cancer, pro-myelocytic leukemia, chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma, small cell lung cancer, and renal carcinoma; and/or (e) the viral infection is selected from Epstein-Barr Virus, hepatitis B virus, hepatitis C virus, Kaposi's sarcoma associated virus, human papilloma virus, Merkel cell polyomavirus, and human cytomegalovirus.

18. The method of claim 1, wherein the compound of Formula I is administered in combination with another anticancer agent.

19. The method of claim 18, wherein the anticancer agent is selected from ABT-737, Azacitidine (Vidaza), AZD1152 (Barasertib), AZD2281 (Olaparib), AZD6244 (Selumetinib), BEZ235, Bleomycin Sulfate, Bortezomib (Velcade), Busulfan (Myleran), Camptothecin, Cisplatin, Cyclophosphamide (Clafen), CYT387, Cytarabine (Ara-C), Dacarbazine, DAPT (GSI-IX), Decitabine, Dexamethasone, Doxorubicin (Adriamycin), Etoposide, Everolimus (RAD001), Flavopiridol (Alvocidib), Ganetespib (STA-9090), Gefitinib (Iressa), Idarubicin, Ifosfamide (Mitoxana), IFNa2a (Roferon A), Melphalan (Alkeran), Methazolastone (temozolomide), Metformin, Mitoxantrone (Novantrone), Paclitaxel, Phenformin, PKC412 (Midostaurin), PLX4032 (Vemurafenib), Pomalidomide (CC-4047), Prednisone (Deltasone), Rapamycin, Revlimid (Lenalidomide), Ruxolitinib (INCB018424), Sorafenib (Nexavar), SU11248 (Sunitinib), SU11274, Vinblastine, Vincristine (Oncovin), Vinorelbine (Navelbine), Vorinostat (SAHA), and WP1130 (Degrasyn).

20. A method for inhibiting BET protein function in a mammal, comprising administering a therapeutically effective amount of a compound selected from: 5,7-Dimethoxy-2-(4-methoxy-2-((1-methylpiperidin-4-yl)amino)phenyl)-quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(4-methoxy-2-(4-methylpiperazine-1-carbonyl)phenyl) quinazolin-4(3H)-one; 2-(2-((1-isopropylpiperidin-4-yl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 5,7-Dimethoxy-2-(4-methoxy-2-((1-methylpyrrolidin-3-yl)amino)phenyl)quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(4-methoxy-2-(methyl(1-methylpiperidin-4-yl)amino)phenyl) quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(4-methoxy-2-(((1-methylpiperidin-4-yl)methyl)amino)phenyl) quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(4-methoxy-2-(((1-methylpyrrolidin-3-yl)methyl)amino)phenyl)-quinazolin-4(3H)-one; 2-(2-((2-(Isopropylamino)ethyl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 5,7-dim ethoxy-2-(4-Methoxy-2-((tetrahydro-2H-pyran-4-yl)amino)-phenyl)quinazolin-4(3H)-one; 2-(2-((1-Isopropylpiperidin-4-yl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 5,7-Dimethoxy-2-(4-methoxy-2-((2-(pyrrolidin-1-yl)ethyl)amino)phenyl)quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(4-methoxy-2-((2-(piperidin-1-yl)ethyl)amino)-phenyl)quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(4-methoxy-2-((3-morpholinopropyl)amino)-phenyl)quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(4-methoxy-2-((2-morpholinoethyl)amino)phenyl)-quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(4-methoxy-2-((3-(pyrrolidin-1-yl)propyl)amino)phenyl)quinazolin-4(3H)-one; 2-(2-(((1-Isopropylpyrrolidin-3-yl)methyl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(2-(((1-Isopropylpyrrolidin-2-yl)methyl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(3-((1-Isopropylpiperidin-4-yl)amino)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(2-((1-Isobutyrylpiperidin-4-yl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(2-((3-(Isopropylamino)propyl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 5,7-Dimethoxy-2-(4-methoxy-2-j(3-(4-methylpiperazin-1-yl)propyl)amino)-phenyl)quinazolin-4(3H)-one; 2-(2-((2-(4-Isopropylpiperazin-1-yl)ethyl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 5,7-Dimethoxy-2-[4-methoxy-2-(1-methylpiperidin-4-ylsulfinyl)phenyl]quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(4-methoxy-2-((2-(piperazin-1-yl)ethyl)amino)phenyl)quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(4-methoxy-2-((2-(4-methylpiperazin-1-yl)ethyl)amino)phenyl)-quinazolin-4(3H)-one; 2-(2-((1-Isopropylpiperidin-4-yl)amino)-5-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(3-((1-Isopropylpiperidin-4-yl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 5,7-Dimethoxy-2-(4-methoxy-2-[3-(piperazin-1-yl)propylamino]phenyl)quinazolin-4(3H)-one; 2-(2-((4,4-Dimethylcyclohexyl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(3-((1-Isopropylpiperidin-4-yl)amino)-5-methoxypyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(2-((trans-4-(2-Hydroxypropan-2-yl)cyclohexyl)amino)-4-m ethoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(3-((1-Isobutyrylpiperidin-4-yl)amino)-5-methoxypyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(4-Chloro-2-((1-isopropylpiperidin-4-yl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(4-Chloro-2-((1-isobutyrylpiperidin-4-yl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(2-((1-Benzylpiperidin-4-yl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(-((1-Isobutyrylpiperidin-4-yl)amino)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(3-((1-Acetylpiperidin-4-yl)amino)pyridine-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; N-(cis-4-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-5-methoxypyridin-3-yl)amino)cyclohexyl)isobutyramide; 2-(2-((1-Acetylpiperidin-4-yl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 5,7-Dimethoxy-2-(5-methoxy-3-((1-methylpiperidin-4-yl)amino)pyridin-2-yl)quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(3-(((1-methylpyrrolidin-3-yl)methyl)amino)pyridin-2-yl)quinazolin-4(3H)-one; 4-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)-N,N-dimethylpiperidine-1-carboxamide; 2-(3-((3-(Isopropylamino)propyl)amino)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 5,7-Dimethoxy-2-(3-((1-methylpiperidin-4-yl)amino)pyridine-2-yl)quinazolin-4(3H)-one; cis-4-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-5-methoxypyridin-3-yl)amino)-N-isopropylcyclohexane-1-carboxamide; 5,7-Dimethoxy-2-(3-((1-(2,2,2-trifluoroacetyl)piperidin-4-yl)amino)pyridin-2-yl)quinazolin-4(3H)-one; 4-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)-N-isopropylpiperidine-1-carboxamide; 5,7-Dimethoxy-2-(3-((1-pivaloylpiperidin-4-yl)amino)pyridin-2-yl)quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(3-((2-morpholinoethyl)amino)pyridine-2-yl)quinazolin-4(3H)-one; 2-(3-((1-Isopropylpiperidin-4-yl)amino)-5-(2-((1-isopropylpiperidin-4-yl)amino)ethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(4-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)piperidin-1-yl)-N,N-dimethyl-2-oxoacetamide; 4-((2-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)-N-ethylpiperidine-1-carboxamide; cis-4-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)-N,N-dimethylcyclohexane-1-carboxamide; 4-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)piperidine-1-carboxamide; Methyl-2-(4-((2-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)piperidin-1-yl)-2-oxoacetate; N-(2-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)ethyl)isobutyramide; N-(3-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)propyl)isobutyramide; 2-(3-((1-Isopropylpiperidin-4-yl)amino)pyridin-2-yl)-5-methoxypyrido[3,4-d]pyrimidin-4(3H)-one; 2-(3-((1-(2-Hydroxy-2-methylpropyl)piperidin-4-yl)amino)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(3-((1-(2-hydroxypropanoyl)piperidin-4-yl)amino)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(3-((1-Isopropylpiperidin-4-yl)amino)pyridin-2-yl)-5-methoxy-7-((4-methoxybenzyl)amino)quinazolin-4(3H)-one; 2-[5-(2-Hydroxyethoxy)-3-(1-isopropylpiperidin-4-ylamino)pyridin-2-yl]-5,7-dimethoxyquinazolin-4(3H)-one; cis-4-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)-N-isopropylcyclohexane-1-carboxamide; 2-[5-(2-Hydroxyethoxy)-3-(1-isobutyroylpiperidin-4-ylamino)pyridin-2-yl]-5,7-dimethoxyquinazolin-4(3H)-one; 7-amino-2-(3-((1-Isopropylpiperidin-4-yl)amino)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one; 2-{3-(1-Isopropylpiperidin-4-ylamino)-5-[2-(pyrrolidin-1-yl)ethoxy]pyridin-2-yl}-5,7-dimethoxyquinazolin-4(3H)-one; 2-{5-[2-(Isopropylamino)ethoxy]-3-(1-isopropylpiperidin-4-ylamino)pyridin-2-yl}-5,7-dimethoxyquinazolin-4(3H)-one; 2-(3-((1-(1-Hydroxy-2-methylpropan-2-yl)piperidin-4-yl)amino)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; and 7-(Ethylamino)-2-(3-((1-isopropylpiperidin-4-yl)amino)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one; and stereoisomers, tautomers, and pharmaceutically acceptable salts thereof; wherein said mammal is afflicted with a cancer selected from B-acute lymphocytic leukemia, Burkitt's lymphoma, diffuse large cell lymphoma, multiple myeloma, primary plasma cell leukemia, atypical carcinoid lung cancer, bladder cancer, breast cancer, cervix cancer, colon cancer, gastric cancer, glioblastoma, hepatocellular carcinoma, large cell neuroendocrine carcinoma, medulloblastoma, melanoma, neuroblastoma, esophageal cancer, osteosarcoma, ovarian cancer, prostate cancer, renal carcinoma, retinoblastoma, rhabdomyosarcoma, small cell lung carcinoma, NUT midline carcinoma, B-cell lymphoma, non-small cell lung cancer, head and neck squamous cell carcinoma, chronic lymphocytic leukemia, follicular lymphoma, diffuse large B cell lymphoma with germinal center phenotype, Hodgkin's lymphoma, activated anaplastic large cell lymphoma, primary neuroectodermal tumor, pancreatic cancer, adenoid cystic carcinoma, T-cell prolymphocytic leukemia, malignant glioma, thyroid cancer, Barrett's adenocarcinoma, hepatoma, pro-myelocytic leukemia, and mantle cell lymphoma.

21. The method of claim 20, wherein the cancer: (a) exhibits overexpression, translocation, amplification, or rearrangement of a myc family oncoprotein; (b) results from aberrant regulation of BET proteins; (c) relies on pTEFb (Cdk9/cyclin T) and BET proteins to regulate oncogenes; (d) is associated with upregulation of BET responsive genes CDK6, Bcl2, TYRO3, MYB and/or hTERT; and/or (e) is associated with a viral infection.

22. The method of claim 21, wherein: (a) the cancer exhibiting overexpression, translocation, amplification, or rearrangement of a myc family oncoprotein is selected from B-acute lymphocytic leukemia, Burkitt's lymphoma, diffuse large cell lymphoma, multiple myeloma, primary plasma cell leukemia, atypical carcinoid lung cancer, bladder cancer, breast cancer, cervix cancer, colon cancer, gastric cancer, glioblastoma, hepatocellular carcinoma, large cell neuroendocrine carcinoma, medulloblastoma, Nodular melanoma, Superficial spreading melanoma, neuroblastoma, esophageal squamous cell carcinoma, osteosarcoma, ovarian cancer, prostate cancer, renal clear cell carcinoma, retinoblastoma, rhabdomyosarcoma, and small cell lung carcinoma; (b) the cancer resulting from aberrant regulation of BET proteins is selected from NUT midline carcinoma, B-cell lymphoma, non-small cell lung cancer, esophageal cancer, head and neck squamous cell carcinoma, and colon cancer; (c) the cancer relying on pTEFb (Cdk9/cyclin T) and BET proteins to regulate oncogenes is selected from chronic lymphocytic leukemia, multiple myeloma, follicular lymphoma, diffuse large B cell lymphoma with germinal center phenotype, Burkitt's lymphoma, Hodgkin's lymphoma, anaplastic large cell lymphoma, neuroblastoma, primary neuroectodermal tumor, rhabdomyosarcoma, prostate cancer, and breast cancer; (d) the cancer associated with upregulation of BET responsive genes CDK6, Bcl2, TYRO3, MYB, and hTERT is selected from pancreatic cancer, breast cancer, colon cancer, glioblastoma, adenoid cystic carcinoma, T-cell prolymphocytic leukemia, malignant glioma, bladder cancer, medulloblastoma, thyroid cancer, melanoma, multiple myeloma, Barrett's adenocarcinoma, hepatoma, prostate cancer, pro-myelocytic leukemia, chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma, small cell lung cancer, and renal carcinoma; and/or (e) the viral infection is selected from Epstein-Barr Virus, hepatitis B virus, hepatitis C virus, Kaposi's sarcoma associated virus, human papilloma virus, Merkel cell polyomavirus, and human cytomegalovirus.

23. The method of claim 20, wherein the compound of Formula I is administered in combination with another anticancer agent.

24. The method of claim 23, wherein the anticancer agent is selected from ABT-737, Azacitidine (Vidaza), AZD1152 (Barasertib), AZD2281 (Olaparib), AZD6244 (Selumetinib), BEZ235, Bleomycin Sulfate, Bortezomib (Velcade), Busulfan (Myleran), Camptothecin, Cisplatin, Cyclophosphamide (Clafen), CYT387, Cytarabine (Ara-C), Dacarbazine, DAPT (GSI-IX), Decitabine, Dexamethasone, Doxorubicin (Adriamycin), Etoposide, Everolimus (RAD001), Flavopiridol (Alvocidib), Ganetespib (STA-9090), Gefitinib (Iressa), Idarubicin, Ifosfamide (Mitoxana), IFNa2a (Roferon A), Melphalan (Alkeran), Methazolastone (temozolomide), Metformin, Mitoxantrone (Novantrone), Paclitaxel, Phenformin, PKC412 (Midostaurin), PLX4032 (Vemurafenib), Pomalidomide (CC-4047), Prednisone (Deltasone), Rapamycin, Revlimid (Lenalidomide), Ruxolitinib (INCB018424), Sorafenib (Nexavar), SU11248 (Sunitinib), SU11274, Vinblastine, Vincristine (Oncovin), Vinorelbine (Navelbine), Vorinostat (SAHA), and WP1130 (Degrasyn).

Description

EXEMPLARY EMBODIMENTS OF THE INVENTION

(1) In certain aspects, the invention is directed to a compound according to Formula I:

(2) ##STR00004##
or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof,
wherein:

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

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

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

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

(7) X is selected from N and CH;

(8) Y is selected from S(O), C(O), NH, NHCH.sub.2, NHCH.sub.2CH.sub.2, and NHCH.sub.2CH.sub.2CH.sub.2, with the nitrogen attached to the B ring, and one or more hydrogens may be optionally substituted with alkyl(C.sub.1-C.sub.3), halogen, hydroxyl, or amino;

(9) R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, amino (such as, e.g., aminoalkyl), aryloxy, aryl, hydroxyl, and halogen;

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

(11) R.sub.5 is selected from amino and 5- and 6-membered carbocycles and heterocycles;

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

(13) R.sub.7 is selected from hydrogen, alkyl, alkoxy, thioalkyl, aminoalkyl, and halogen.

(14) Another aspect of the invention is directed to a compound according to Formula Ia:

(15) ##STR00005##
or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof,
wherein:

(16) X is selected from N and CH;

(17) Y is selected from S(O), C(O), NH, NHCH.sub.2, NHCH.sub.2CH.sub.2, and NHCH.sub.2CH.sub.2CH.sub.2, with the nitrogen attached to the B ring, and one or more hydrogens may be optionally substituted with alkyl(C.sub.1-C.sub.3), halogen, hydroxyl, or amino;

(18) R.sub.1 and R.sub.3 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, amino such as, e.g., aminoalkyl, aryloxy, aryl, hydroxyl, and halogen; R.sub.5 is selected from amino, aminoalkyl, 5- and 6-membered carbocycles and heterocycles optionally substituted with halogen, amino, amide, alkyl(C.sub.1-C.sub.6), or alkoxy(C.sub.1-C.sub.6) for example, the structures

(19) ##STR00006##
where Ra is selected from hydrogen, methyl, ethyl, propyl, isopropyl, t-butyl, C(O)Me, C(O)Pr, C(O)iPr, benzyl, C(O)CF.sub.3, C(O)-tBu, C(O)NHiPr, C(O)NMe.sub.2, C(O)NHEt, C(O)NH.sub.2, C(O)CH(OH)CH.sub.3, C(O)C(O)OMe, CF.sub.3, CH.sub.2CH.sub.2OH, CH.sub.2CH.sub.2 amino, and CH.sub.2CH.sub.2C(Me).sub.2OH;

(20) R.sub.6 is selected from hydrogen, alkoxy, alkyl, halogen, aminoalkyl, and thioalkyl; and R.sub.7 is selected from hydrogen, alkyl, alkoxy, thioalkyl, aminoalkyl, and halogen.

(21) In some embodiments of a compound of Formula I, each of R.sub.1, R.sub.2, R.sub.3, and R.sub.4, if present, are independently selected from hydrogen, alkyl, alkoxy, amino, and halogen.

(22) In some embodiments of a compound of Formula Ia, each of R.sub.1 and R.sub.3 are independently selected from hydrogen, alkyl, alkoxy, amino, and halogen.

(23) In some embodiments of a compound of Formula I, each of R.sub.1, R.sub.2, R.sub.3, and R.sub.4, if present, are independently selected from hydrogen, alkyl, and alkoxy, each of which may be optionally substituted with hydroxyl, amino, or halogen.

(24) In some embodiments of a compound of Formula Ia, each of R.sub.1 and R.sub.3 are independently selected from hydrogen, alkyl, and alkoxy, each of which may be optionally substituted with hydroxyl, amino, or halogen.

(25) In some embodiments of a compound of Formula I, each of R.sub.1, R.sub.2, R.sub.3, and R.sub.4, if present, is independently selected from aryl and aryloxy, each of which may be optionally substituted with halogen, alkoxy, or amino.

(26) In some embodiments of a compound of Formula Ia, each of R.sub.1 and R.sub.3 are independently selected from aryl and aryloxy, each of which may be optionally substituted with halogen, alkoxy, or amino.

(27) In certain embodiments of a compound of Formula I, W.sub.1 is CR.sub.1, W.sub.3 is CR.sub.3, and R.sub.1 and R.sub.3 are each independently an alkoxy group, for example methoxy, ethoxy, isopropoxy, and propoxy.

(28) In certain embodiments of a compound of Formula Ia, R.sub.1 and R.sub.3 are each independently an alkoxy group, for example methoxy, ethoxy, isopropoxy, and propoxy.

(29) In other embodiments of a compound of Formula I, W.sub.1 is CR.sub.1, W.sub.2 is CR.sub.2, W.sub.3 is CR.sub.3, W.sub.4 is CR.sub.4, and R.sub.1 and R.sub.3 are each alkoxy and R.sub.2 and R.sub.4 are each hydrogen.

(30) In other embodiments of a compound of Formula I, W.sub.1 is CR.sub.1, W.sub.2 is CR.sub.2, W.sub.3 is N, W.sub.4 is CR.sub.4, and R.sub.1 and R.sub.3 are each alkoxy and R.sub.2 is hydrogen.

(31) In other embodiments of a compound of Formula I, W.sub.1 is CR.sub.1, W.sub.2 is CR.sub.2, W.sub.3 is CR.sub.3, W.sub.4 is CR.sub.4, and R.sub.1 and R.sub.3 are each methoxy and R.sub.2 and R.sub.4 are each hydrogen.

(32) In other embodiments of a compound of Formula Ia, R.sub.1 and R.sub.3 are each methoxy.

(33) In other embodiments of a compound of Formula I, W.sub.1 is CR.sub.1, W.sub.2 is CR.sub.2, W.sub.3 is CR.sub.3, W.sub.4 is CR.sub.4, R.sub.1 is methoxy, R.sub.3 is amino or aminoalkyl, and R.sub.2 and R.sub.4 are each hydrogen.

(34) In other embodiments of a compound of Formula Ia, R.sub.1 is methoxy and R.sub.3 is amino or aminoalkyl.

(35) In some embodiments of a compound of Formula I or Formula Ia, R.sub.5 is aminoalkyl.

(36) In some embodiments of a compound of Formula I or Formula Ia, Y is selected from NH, NHCH.sub.2, NHCH.sub.2CH.sub.2, and NHCH.sub.2CH.sub.2CH.sub.2, with the nitrogen attached to the B ring, and one or more hydrogens may be optionally substituted with F, Me, OMe, and Cl.

(37) In certain embodiments of a compound of Formula I or Formula Ia, Y is NH.

(38) In certain embodiments of a compound of Formula I or Formula Ia, X is N.

(39) In certain embodiments of a compound of Formula I or Formula Ia, X is CH.

(40) In some embodiments of a compound of Formula I or Formula Ia, R.sub.5 is selected from amino, aminoalkyl, and 5- and 6-membered carbocycles and heterocycles optionally substituted with halogen, amino, urea, ester, carbamate, amide, alkyl(C.sub.1-C.sub.6); alkoxy(C.sub.1-C.sub.6), and aryl.

(41) In some embodiments of a compound of Formula I or Formula Ia, R.sub.5 is selected from NHRa and 5- and 6-membered carbocycles and heterocycles optionally substituted with halogen, amino, urea, ester, carbamate, amide, alkyl(C.sub.1-C.sub.6), alkoxy(C.sub.1-C.sub.6), or aryl, for example, the structures

(42) ##STR00007##
where Ra is selected from hydrogen, alkyl, alkenyl, aryl, C(O)Alkyl(C.sub.1-C.sub.4), C(O)Amino, C(O)Oalkyl(C.sub.1-C.sub.4), and benzyl.

(43) In some embodiments of a compound of Formula I or Formula Ia, R.sub.5 is selected from NHRa and 5- and 6-membered carbocycles and heterocycles optionally substituted with halogen, amino, amide, alkyl(C.sub.1-C.sub.6), or alkoxy(C.sub.1-C.sub.6) for example, the structures

(44) ##STR00008##
where Ra is selected from hydrogen, methyl, ethyl, propyl, isopropyl, t-butyl, C(O)Me, C(O)Pr, C(O)iPr, benzyl, C(O)CF.sub.3, C(O)-tBu, C(O)NHiPr, C(O)NMe.sub.2, C(O)NHEt, C(O)NH.sub.2, C(O)CH(OH)CH.sub.3, C(O)C(O)OMe, CF.sub.3, CH.sub.2CH.sub.2OH, CH.sub.2CH.sub.2 amino, and CH.sub.2CH.sub.2C(Me).sub.2OH.

(45) In some embodiments of a compound of Formula I or Formula Ia, R.sub.6 is selected from hydrogen, alkyl, alkoxy, aminoalkyl, and thioalkyl, each of which may be optionally substituted with halogen, amino, hydroxyl, or alkoxy.

(46) In some embodiments of a compound of Formula I or Formula Ia, R.sub.6 is selected from hydrogen, methyl, methoxy, ethoxy, and alkoxy optionally substituted with a hydroxyl or amino.

(47) In some embodiments of a compound of Formula I or Formula Ia, R.sub.6 is selected from hydrogen, methyl, and methoxy.

(48) In a selected embodiment of a compound of Formula I or Formula Ia, R.sub.6 is selected from groups represented by Formula II:

(49) ##STR00009## wherein: D and E are independently selected from O, N, and S; R.sub.8 is selected from hydrogen and alkyl, and R.sub.8 is present only if D is N; R.sub.9 and R.sub.10 are independently selected from hydrogen, alkyl, and cycloalkyl, and only one of R.sub.9 and R.sub.10 is present if E is O or S; R.sub.9 and R.sub.10 may be connected to form a carbocycle or a heterocycle containing one or more heteroatoms; and n is selected from 1, 2, and 3.

(50) In some embodiments of a compound of Formula I or Formula Ia, D is O and E is N;

(51) n is 1; and

(52) R.sub.9 and R.sub.10 are independently selected from hydrogen, alkyl, and carbocycle.

(53) In certain embodiments of a compound of Formula I or Formula Ia, R.sub.6 is selected from:

(54) ##STR00010##

(55) In some embodiments of a compound of Formula I or Formula Ia, R.sub.7 is selected from hydrogen, methoxy, ethoxy, propoxy, isopropoxy, methyl, ethyl, propyl, isopropyl, and OCF.sub.3.

(56) In some embodiments of a compound of Formula I, W.sub.1 is CR.sub.1; W.sub.2 is CR.sub.2; W.sub.3 is CR.sub.3; W.sub.4 is CR.sub.4; R.sub.1 and R.sub.3 are each alkoxy; R.sub.2 and R.sub.4 are each hydrogen; Y is selected from NH, NHCH.sub.2, NHCH.sub.2CH.sub.2, and NHCH.sub.2CH.sub.2CH.sub.2, with the nitrogen attached to the B ring; R.sub.5 is selected from NHRa and 5- or 6-membered carbocycle or heterocycles selected from

(57) ##STR00011##
where Ra is selected from hydrogen, methyl, ethyl, propyl, isopropyl, t-butyl, C(O)Me, C(O)Pr, C(O)iPr, benzyl, C(O)CF.sub.3, C(O)-tBu, C(O)NHiPr, C(O)NMe.sub.2, C(O)NHEt, C(O)NH.sub.2, C(O)CH(OH)CH.sub.3, C(O)C(O)OMe, CF.sub.3, CH.sub.2CH.sub.2OH, CH.sub.2CH.sub.2 amino, and CH.sub.2CH.sub.2C(Me).sub.2OH; and

(58) R.sub.6 is selected from hydrogen, methyl, methoxy, ethoxy, and alkoxy optionally substituted with a hydroxyl or amino.

(59) In some embodiments of a compound of Formula Ia, R.sub.1 and R.sub.3 are each alkoxy; Y is selected from NH, NHCH.sub.2, NHCH.sub.2CH.sub.2, and NHCH.sub.2CH.sub.2CH.sub.2, with the nitrogen attached to the B ring; R.sub.5 is selected from NHRa and 5- or 6-membered carbocycle or heterocycles selected from

(60) ##STR00012##
where Ra is selected from hydrogen, methyl, ethyl, propyl, isopropyl, t-butyl, C(O)Me, C(O)Pr, C(O)iPr, benzyl, C(O)CF.sub.3, C(O)-tBu, C(O)NHiPr, C(O)NMe.sub.2, C(O)NHEt, C(O)NH.sub.2, C(O)CH(OH)CH.sub.3, C(O)C(O)OMe, CF.sub.3, CH.sub.2CH.sub.2OH, CH.sub.2CH.sub.2 amino, and CH.sub.2CH.sub.2C(Me).sub.2OH; and R.sub.6 is selected from hydrogen, methyl, methoxy, ethoxy, and alkoxy optionally substituted with a hydroxyl or amino.

(61) In some embodiments of a compound of Formula I, W.sub.1 is CR.sub.1; W.sub.2 is CR.sub.2; W.sub.3 is CR.sub.3; W.sub.4 is CR.sub.4; R.sub.1 is alkoxy; R.sub.3 is amino or aminoalkyl; R.sub.2 and R.sub.4 are each hydrogen; Y is selected from NH, NHCH.sub.2, NHCH.sub.2CH.sub.2, and NHCH.sub.2CH.sub.2CH.sub.2, with the nitrogen attached to the B ring; R.sub.5 is selected from NHRa and 5- or 6-membered carbocycle or heterocycles selected from

(62) ##STR00013##
where Ra is selected from hydrogen, methyl, ethyl, propyl, isopropyl, t-butyl, C(O)Me, C(O)Pr, C(O)iPr, benzyl, C(O)CF.sub.3, C(O)-tBu, C(O)NHiPr, C(O)NMe.sub.2, C(O)NHEt, C(O)NH.sub.2, C(O)CH(OH)CH.sub.3, C(O)C(O)OMe, CF.sub.3, CH.sub.2CH.sub.2OH, CH.sub.2CH.sub.2 amino, and CH.sub.2CH.sub.2C(Me).sub.2OH; and R.sub.6 is selected from hydrogen, methyl, methoxy, ethoxy, and alkoxy optionally substituted with a hydroxyl or amino.

(63) In some embodiments of a compound of Formula Ia, R.sub.1 is alkoxy; R.sub.3 is amino or aminoalkyl; Y is selected from NH, NHCH.sub.2, NHCH.sub.2CH.sub.2, and NHCH.sub.2CH.sub.2CH.sub.2, with the nitrogen attached to the B ring; R.sub.5 is selected from NHRa and 5- or 6-membered carbocycle or heterocycles selected from

(64) ##STR00014##
where Ra is selected from hydrogen, methyl, ethyl, propyl, isopropyl, t-butyl, C(O)Me, C(O)Pr, C(O)iPr, benzyl, C(O)CF.sub.3, C(O)-tBu, C(O)NHiPr, C(O)NMe.sub.2, C(O)NHEt, C(O)NH.sub.2, C(O)CH(OH)CH.sub.3, C(O)C(O)OMe, CF.sub.3, CH.sub.2CH.sub.2OH, CH.sub.2CH.sub.2 amino, and CH.sub.2CH.sub.2C(Me).sub.2OH; and

(65) R.sub.6 is selected from hydrogen, methyl, methoxy, ethoxy, and alkoxy optionally substituted with a hydroxyl or amino.

(66) In some embodiments, the compound is selected from: 5,7-Dimethoxy-2-(4-methoxy-2-((1-methylpiperidin-4-yl)amino)phenyl)-quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(4-methoxy-2-(4-methylpiperazine-1-carbonyl)phenyl) quinazolin-4(3H)-one; 2-(2-((1-isopropylpiperidin-4-yl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 5,7-Dimethoxy-2-(4-methoxy-2-((1-methylpyrrolidin-3-yl)amino)phenyl)quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(4-methoxy-2-(methyl(1-methylpiperidin-4-yl)amino)phenyl) quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(4-methoxy-2-(((1-methylpiperidin-4-yl)methyl)amino)phenyl) quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(4-methoxy-2-(((1-methylpyrrolidin-3-yl)methyl)amino)phenyl)-quinazolin-4(3H)-one; 2-(2-((2-(Isopropylamino)ethyl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 5,7-dimethoxy-2-(4-Methoxy-2-((tetrahydro-2H-pyran-4-yl)amino)-phenyl)quinazolin-4(3H)-one; 2-(2-((1-Isopropylpiperidin-4-yl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 5,7-Dimethoxy-2-(4-methoxy-2-((2-(pyrrolidin-1-yl)ethyl)amino)phenyl)quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(4-methoxy-2-((2-(piperidin-1-yl)ethyl)amino)-phenyl)quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(4-methoxy-2-((3-morpholinopropyl)amino)-phenyl)quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(4-methoxy-2-((2-morpholinoethyl)amino)phenyl)-quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(4-methoxy-2-((3-(pyrrolidin-1-yl)propyl)amino)phenyl)quinazolin-4(3H)-one; 2-(2-(((1-Isopropylpyrrolidin-3-yl)methyl)amino)-4-methoxyphenyl)-5,7-dimethoxy quinazolin-4(31H)-one; 2-(2-(((1-Isopropylpyrrolidin-2-yl)methyl)amino)-4-methoxyphenyl)-5,7-dimethoxy quinazolin-4(3H)-one; 2-(3-((1-Isopropylpiperidin-4-yl)amino)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(2-((1-Isobutyrylpiperidin-4-yl)amino)-4-methoxyphenyl)-5,7-dimethoxy quinazolin-4(3H)-one; 2-(2-((3-(Isopropylamino)propyl)amino)-4-methoxyphenyl)-5,7-dimethoxy quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(4-methoxy-2-((3-(methylpiperazin-1-yl)propyl)amino)-phenylquinazolin-4(3H)-one; 2-(2-((2-(4-Isopropylpiperazin-1-yl)ethyl)amino)-4-methoxyphenyl)-5,7-dimethoxy quinazolin-4(3H)-one; 5,7-Dimethoxy-2-[4-methoxy-2-(1-methylpiperidin-4-ylsulfinyl)phenyl]quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(4-methoxy-2-((2-(piperazin-1-yl)ethyl)amino)phenyl)quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(4-methoxy-2-((2-(4-methylpiperazin-1-yl)ethyl)amino)phenyl)-quinazolin-4(3H)-one; 2-(2-((1-Isopropylpiperidin-4-yl)amino)-5-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(3-((1-Isopropylpiperidin-4-yl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 5,7-Dimethoxy-2-(4-methoxy-2-[3-(piperazin-1-yl)propylamino]phenyl)quinazolin-4(3H)-one; 2-(2-((4,4-Dimethylcyclohexyl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(3-((1-Isopropylpiperidin-4-yl)amino)-5-methoxypyridin-2-yl)-5,7-dimethoxy quinazolin-4(3H)-one; 2-(2-((trans-4-(2-Hydroxypropan-2-yl)cyclohexyl)amino)-4-methoxyphenyl)-5,7-dimethoxy quinazolin-4(3H)-one; 2-(3-((1-Isobutyrylpiperidin-4-yl)amino)-5-methoxypyridin-2-yl)-5,7-dimethoxy quinazolin-4(3H)-one; 2-(4-Chloro-2-((1-isopropylpiperidin-4-yl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(4-Chloro-2-((1-isobutyrylpiperidin-4-yl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(2-((1-Benzylpiperidin-4-yl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(-((1-Isobutyrylpiperidin-4-yl)amino)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(3-((1-Acetylpiperidin-4-yl)amino)pyridine-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; N-(cis-4-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-5-methoxypyridin-3-yl)amino)cyclohexyl)isobutyramide; 2-(2-((1-Acetylpiperidin-4-yl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one; 5,7-Dimethoxy-2-(5-methoxy-3-((1-methylpiperidin-4-yl)amino)pyridin-2-yl)quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(3-(((1-methylpyrrolidin-3-yl)methyl)amino)pyridin-2-yl)quinazolin-4(3H)-one; 4-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)-N,N-dimethylpiperidine-1-carboxamide; 2-(3-((3-(Isopropylamino)propyl)amino)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 5,7-Dimethoxy-2-(3-((1-methylpiperidin-4-yl)amino)pyridine-2-yl)quinazolin-4(3H)-one; cis-4-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-5-methoxypyridin-3-yl)amino)-N-isopropylcyclohexane-1-carboxamide; 5,7-Dimethoxy-2-(3-((1-(2,2,2-trifluoroacetyl)piperidin-4-yl)amino)pyridin-2-yl)quinazolin-4(3H)-one; 4-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)-N-isopropylpiperidine-1-carboxamide; 5,7-Dimethoxy-2-(3-((1-pivaloylpiperidin-4-yl)amino)pyridin-2-yl)quinazolin-4(3H)-one; 5,7-Dimethoxy-2-(3-((2-morpholinoethyl)amino)pyridine-2-yl)quinazolin-4(3H)-one; 2-(3-((1-Isopropylpiperidin-4-yl)amino)-5-(2-((1-isopropylpiperidin-4-yl)amino)ethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; 2-(4-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)piperidin-1-yl)-N,N-dimethyl-2-oxoacetamide; 4-((2-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)-N-ethylpiperidine-1-carboxamide; cis-4-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)-N,N-dimethylcyclohexane-1-carboxamide; 4-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)piperidine-1-carboxamide; Methyl-2-(4-((2-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)piperidin-1-yl)-2-oxoacetate; N-(2-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)ethyl)isobutyramide; N-(3-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)propyl)isobutyramide; 2-(3-((1-Isopropylpiperidin-4-yl)amino)pyridin-2-yl)-5-methoxypyrido[3,4-d]pyrimidin-4(3H)-one; 2-(3-((1-(2-Hydroxy-2-methylpropyl)piperidin-4-yl)amino)pyridin-2-yl)-5,7-dimethoxy quinazolin-4(3H)-one; 2-(3-((1-(2-hydroxypropanoyl)piperidin-4-yl)amino)pyridin-2-yl)-5,7-dimethoxy quinazolin-4(3H)-one; 2-(3-((1-Isopropylpiperidin-4-yl)amino)pyridin-2-yl)-5-methoxy-7-((4-methoxybenzyl)amino)quinazolin-4(3H)-one; 2-[5-(2-Hydroxyethoxy)-3-(1-isopropylpiperidin-4-ylamino)pyridin-2-yl]-5,7-dimethoxy quinazolin-4(3H)-one; cis-4-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)-N-isopropylcyclohexane-1-carboxamide; 2-[5-(2-Hydroxyethoxy)-3-(1-isobutyroylpiperidin-4-ylamino)pyridin-2-yl]-5,7-dimethoxy quinazolin-4(3H)-one; 7-amino-2-(3-((1-Isopropylpiperidin-4-yl)amino)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one; 2-{3-(1-Isopropylpiperidin-4-ylamino)-5-[2-(pyrrolidin-1-yl)ethoxy]pyridin-2-yl}-5,7-dimethoxyquinazolin-4(3H)-one; 2-{5-[2-(Isopropylamino)ethoxy]-3-(1-isopropylpiperidin-4-ylamino)pyridin-2-yl}-5,7-dimethoxyquinazolin-4(3H)-one; 2-(3-((1-(1-Hydroxy-2-methylpropan-2-yl)piperidin-4-yl)amino)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; and 7-(Ethylamino)-2-(3-((1-isopropylpiperidin-4-yl)amino)pyridin-2-yl)-5-methoxy quinazolin-4(3H)-one; or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof.

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

(68) In one embodiment, because of potent effects of BET inhibitors in vitro on IL-6 and IL-17 transcription, BET inhibitor compounds of Formula I or Formula Ia may be used as therapeutics for inflammatory disorders in which IL-6 and/or IL-17 have been implicated in disease. The following autoimmune diseases are amenable to therapeutic use of BET inhibition by administration of a compound of Formula I or Formula Ia or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof because of a prominent role of IL-6 and/or IL-17: Acute Disseminated Encephalomyelitis (T. Ishizu et al., CSF cytokine and chemokine profiles in acute disseminated encephalomyelitis, J Neuroimmunol 175(1-2): 52-8 (2006)), Agammaglobulinemia (M. Gonzalez-Serrano, et al., Increased Pro-inflammatory Cytokine Production After Lipopolysaccharide Stimulation in Patients with X-linked Agammaglobulinemia, J Clin Immunol 32(5):967-74 (2012)), Allergic Disease (L. McKinley et al., TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice, J Immunol 181(6):4089-97 (2008)), Ankylosing spondylitis (A. Taylan et al., Evaluation of the T helper 17 axis in ankylosing spondylitis, Rheumatol Int 32(8):2511-5 (2012)), Anti-GBM/Anti-TBM nephritis (Y. Ito et al., Pathogenic significance of interleukin-6 in a patient with antiglomerular basement membrane antibody-induced glomerulonephritis with multinucleated giant cells, Am J Kidney Dis 26(1):72-9 (1995)), Anti-phospholipid syndrome (P. Soltesz et al., Immunological features of primary anti-phospholipid syndrome in connection with endothelial dysfunction, Rheumatology (Oxford) 47(11): 1628-34 (2008)), Autoimmune aplastic anemia (Y. Gu et al., Interleukin (IL)-17 promotes macrophages to produce IL-8, IL-6 and tumour necrosis factor-alpha in aplastic anaemia, Br J Haematol 142(1): 109-14 (2008)), Autoimmune hepatitis (L. Zhao et al., Interleukin-17 contributes to the pathogenesis of autoimmune hepatitis through inducing hepatic interleukin-6 expression, PLoS One 6(4):e18909 (2011)), Autoimmune inner ear disease (B. Gloddek et al., Pharmacological influence on inner ear endothelial cells in relation to the pathogenesis of sensorineural hearing loss, Adv Otorhinolaryngol 59:75-83 (2002)), Autoimmune myocarditis (T. Yamashita et al., IL-6-mediated Th17 differentiation through RORgammat is essential for the initiation of experimental autoimmune myocarditis, Cardiovasc Res 91(4):640-8 (2011)), Autoimmune pancreatitis (J. Ni et al., Involvement of Interleukin-17A in Pancreatic Damage in Rat Experimental Acute Necrotizing Pancreatitis, Inflammation (2012)), Autoimmune retinopathy (S. Hohki et al., Blockade of interleukin-6 signaling suppresses experimental autoimmune uveoretinitis by the inhibition of inflammatory Th17 responses, Exp Eye Res 91(2): 162-70 (2010)), Autoimmune thrombocytopenic purpura (D. Ma et al., Profile of Th17 cytokines (IL-17, TGF-beta, IL-6) and Th1 cytokine (IFN-gamma) in patients with immune thrombocytopenic purpura, Ann Hematol 87(11):899-904 (2008)), Behcet's Disease (T. Yoshimura et al., Involvement of Th117 cells and the effect of anti-IL-6 therapy in autoimmune uveitis, Rheumatology (Oxford) 48(4):347-54 (2009)), Bullous pemphigoid (L. D'Auria et al., Cytokines and bullous pemphigoid, Eur Cytokine Netw 10(2):123-34 (1999)), Castleman's Disease (H. El-Osta and R. Kurzrock, Castleman's disease: from basic mechanisms to molecular therapeutics, Oncologist 16(4):497-511 (2011)), Celiac Disease (A. Lahdenpera et al., Up-regulation of small intestinal interleukin-17 immunity in untreated coeliac disease but not in potential coeliac disease or in type 1 diabetes, Clin Exp Immunol 167(2):226-34 (2012)), Churg-Strauss syndrome (A. Fujioka et al., The analysis of mRNA expression of cytokines from skin lesions in Churg-Strauss syndrome, J Dermatol 25(3):171-7 (1998)), Crohn's Disease (V. Holtta et al., IL-23/IL-17 immunity as a hallmark of Crohn's disease, Inflamm Bowel Dis 14(9):1175-84 (2008)), Cogan's syndrome (M. Shibuya et al., Successful treatment with tocilizumab in a case of Cogan's syndrome complicated with aortitis, Mod Rheumatol (2012)), Dry eye syndrome (C. De Paiva et al., IL-17 disrupts corneal barrier following desiccating stress, Mucosal Immunol 2(3):243-53 (2009)), Essential mixed cryoglobulinemia (A. Antonelli et al., Serum levels of proinflammatory cytokines interleukin-1beta, interleukin-6, and tumor necrosis factor alpha in mixed cryoglobulinemia, Arthritis Rheum 60(12):3841-7 (2009)), Dermatomyositis (G. Chevrel et al., Interleukin-17 increases the effects of IL-1 beta on muscle cells: arguments for the role of T cells in the pathogenesis of myositis, J Neuroimmunol 137(1-2):125-33 (2003)), Devic's Disease (U. Linhares et al., The Ex Vivo Production of IL-6 and IL-21 by CD4(+) T Cells is Directly Associated with Neurological Disability in Neuromyelitis Optica Patients, J Clin Immunol (2012)), Encephalitis (D. Kyburz and M. Corr, Th17 cells generated in the absence of TGF-beta induce experimental allergic encephalitis upon adoptive transfer, Expert Rev Clin Immunol 7(3):283-5 (2011)), Eosinophlic esophagitis (P. Dias and G. Banerjee, The Role of Th17/IL-17 on Eosinophilic Inflammation, J Autoimmun (2012)), Eosinophilic fasciitis (P. Dias and G. Banerjee, J Autoimmun (2012)), Erythema nodosum (I. Kahawita and D. Lockwood, Towards understanding the pathology of erythema nodosum leprosum, Trans R Soc Trop Med Hyg 102(4):329-37 (2008)), Giant cell arteritis (J. Deng et al., Th17 and Th1 T-cell responses in giant cell arteritis, Circulation 121(7):906-15 (2010)), Glomerulonephritis (J. Ooi et al., Review: T helper 17 cells: their role in glomerulonephritis, Nephrology (Carlton) 15(5):513-21 (2010)), Goodpasture's syndrome (Y. Ito et al., Pathogenic significance of interleukin-6 in a patient with antiglomerular basement membrane antibody-induced glomerulonephritis with multinucleated giant cells, Am J Kidney Dis 26(1):72-9 (1995)), Granulomatosis with Polyangiitis (Wegener's) (H. Nakahama et al., Distinct responses of interleukin-6 and other laboratory parameters to treatment in a patient with Wegener's granulomatosis, Intern Med 32(2):189-92 (1993)), Graves' Disease (S. Kim et al., Increased serum interleukin-17 in Graves' ophthalmopathy, Graefes Arch Clin Exp Ophthalmol 250(10):1521-6 (2012)), Guillain-Barre syndrome (M. Lu and J. Zhu, The role of cytokines in Guillain-Barre syndrome, J Neurol 258(4):533-48 (2011)), Hashimoto's thyroiditis (N. Figueroa-Vega et al., Increased circulating pro-inflammatory cytokines and Th17 lymphocytes in Hashimoto's thyroiditis, J Clin Endocrinol Metab 95(2):953-62 (2009)), Hemolytic anemia (L. Xu et al., Critical role of Th17 cells in development of autoimmune hemolytic anemia, Exp Hematol (2012)), Henoch-Schonlein purpura (H. Jen et al., Increased serum interleukin-17 and peripheral Th17 cells in children with acute Henoch-Schonlein purpura, Pediatr Allergy Immunol 22(8):862-8 (2011)), IgA nephropathy (F. Lin et al., Imbalance of regulatory T cells to Th17 cells in IgA nephropathy, Scand J Clin Lab Invest 72(3):221-9 (2012)), Inclusion body myositis (P. Baron et al., Production of IL-6 by human myoblasts stimulated with Abeta: relevance in the pathogenesis of IBM, Neurology 57(9):1561-5 (2001)), Type I diabetes (A. Belkina and G. Denis, Nat Rev Cancer 12(7):465-77 (2012)), Interstitial cystitis (L. Lamale et al., Interleukin-6, histamine, and methylhistamine as diagnostic markers for interstitial cystitis, Urology 68(4):702-6 (2006)), Kawasaki's Disease (S. Jia et al., The T helper type 17/regulatory T cell imbalance in patients with acute Kawasaki disease, Clin Exp Immunol 162(1): 131-7 (2010)), Leukocytoclastic vasculitis (Min, C. K., et al., Cutaneous leucoclastic vasculitis (LV) following bortezomib therapy in a myeloma patient; association with pro-inflammatory cytokines, Eur J Haematol 76(3):265-8 (2006)), Lichen planus (N. Rhodus et al., Proinflammatory cytokine levels in saliva before and after treatment of (erosive) oral lichen planus with dexamethasone, Oral Dis 12(2): 112-6 (2006)), Lupus (SLE) (M. Mok et al., The relation of interleukin 17 (IL-17) and IL-23 to Th1/Th2 cytokines and disease activity in systemic lupus erythematosus, J Rheumatol 37(10):2046-52 (2010)), Microscopic polyangitis (A. Muller Kobold et al., In vitro up-regulation of E-selectin and induction of interleukin-6 in endothelial cells by autoantibodies in Wegener's granulomatosis and microscopic polyangiitis, Clin Exp Rheumatol 17(4):433-40 (1999)), Multiple sclerosis (F. Jadidi-Niaragh and A. Mirshafiey, Th17 cell, the new player of neuroinflammatory process in multiple sclerosis, Scand J Immunol 74(1):1-13 (2011)), Myasthenia gravis (R. Aricha et al., Blocking of IL-6 suppresses experimental autoimmune myasthenia gravis, J Autoimmun 36(2):135-41 (2011)), myositis (G. Chevrel et al., Interleukin-17 increases the effects of IL-1 beta on muscle cells: arguments for the role of T cells in the pathogenesis of myositis, J Neuroimmunol 137(1-2):125-33 (2003)), Optic neuritis (S. Icoz et al., Enhanced IL-6 production in aquaporin-4 antibody positive neuromyelitis optica patients, Int J Neurosci 120(1):71-5 (2010)), Pemphigus (E. Lopez-Robles et al., TNFalpha and IL-6 are mediators in the blistering process of pemphigus, Int J Dermatol 40(3):185-8 (2001)), POEMS syndrome (K. Kallen et al., New developments in IL-6 dependent biology and therapy: where do we stand and what are the options? Expert Opin Investig Drugs 8(9):1327-49 (1999)), Polyarteritis nodosa (T. Kawakami et al., Serum levels of interleukin-6 in patients with cutaneous polyarteritis nodosa, Acta Derm Venereol 92(3):322-3 (2012)), Primary biliary cirrhosis (K. Harada et al., Periductal interleukin-17 production in association with biliary innate immunity contributes to the pathogenesis of cholangiopathy in primary biliary cirrhosis, Clin Exp Immunol 157(2):261-70 (2009)), Psoriasis (S. Fujishima et al., Involvement of IL-17F via the induction of IL-6 in psoriasis, Arch Dermatol Res 302(7):499-505 (2010)), Psoriatic arthritis (S. Raychaudhuri et al., IL-17 receptor and its functional significance in psoriatic arthritis, Mol Cell Biochem 359(1-2):419-29 (2012)), Pyoderma gangrenosum (T. Kawakami et al., Reduction of interleukin-6, interleukin-8, and anti-phosphatidylserine-prothrombin complex antibody by granulocyte and monocyte adsorption apheresis in a patient with pyoderma gangrenosum and ulcerative colitis, Am J Gastroenterol 104(9):2363-4 (2009)), Relapsing polychondritis (M. Kawai et al., Sustained response to tocilizumab, anti-interleukin-6 receptor antibody, in two patients with refractory relapsing polychondritis, Rheumatology (Oxford) 48(3):318-9 (2009)), Rheumatoid arthritis (Z. Ash and P. Emery, The role of tocilizumab in the management of rheumatoid arthritis, Expert Opin Biol Ther, 12(9):1277-89 (2012)), Sarcoidosis (F. Belli et al., Cytokines assay in peripheral blood and bronchoalveolar lavage in the diagnosis and staging of pulmonary granulomatous diseases, Int J Immunopathol Pharmacol 13(2):61-67 (2000)), Scleroderma (T. Radstake et al., The pronounced Th17 profile in systemic sclerosis (SSc) together with intracellular expression of TGFbeta and IFNgamma distinguishes SSc phenotypes, PLoS One, 4(6): e5903 (2009)), Sjogren's syndrome (G. Katsifis et al., Systemic and local interleukin-17 and linked cytokines associated with Sjogren's syndrome immunopathogenesis, Am J Pathol 175(3):1167-77 (2009)), Takayasu's arteritis (Y. Sun et al., MMP-9 and IL-6 are potential biomarkers for disease activity in Takayasu's arteritis, Int J Cardiol 156(2):236-8 (2012)), Transverse myelitis (J. Graber et al., Interleukin-17 in transverse myelitis and multiple sclerosis, J Neuroimmunol 196(1-2): 124-32 (2008)), Ulcerative colitis (J. Mudter and M. Neurath, 11-6 signaling in inflammatory bowel disease: pathophysiological role and clinical relevance, Inflamm Bowel Dis 13(8):1016-23 (2007)), Uveitis (H. Haruta et al., Blockade of interleukin-6 signaling suppresses not only th17 but also interphotoreceptor retinoid binding protein-specific Th1 by promoting regulatory T cells in experimental autoimmune uveoretinitis, Invest Ophthalmol Vis Sci 52(6):3264-71 (2011)), and Vitiligo (D. Bassiouny and O. Shaker, Role of interleukin-17 in the pathogenesis of vitiligo, Clin Exp Dermatol 36(3):292-7 115. (2011)). Thus, the invention includes compounds of Formula I or Formula Ia, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof; pharmaceutical compositions comprising one or more of those compounds; and methods of using those compounds or compositions for treating these diseases.

(69) Acute and chronic (non-autoimmune) inflammatory diseases characterized by increased expression of pro-inflammatory cytokines, including IL-6, MCP-1, and IL-17, would also be amenable to therapeutic BET inhibition. These include, but are not limited to, sinusitis (D. Bradley and S. Kountakis, Role of interleukins and transforming growth factor-beta in chronic rhinosinusitis and nasal polyposis, Laryngoscope 115(4):684-6 (2005)), pneumonitis (Besnard, A. G., et al., Inflammasome-IL-1-Th17 response in allergic lung inflammation J Mol Cell Biol 4(1):3-10 (2012)), osteomyelitis (T. Yoshii et al., Local levels of interleukin-1 beta, -4, -6 and tumor necrosis factor alpha in an experimental model of murine osteomyelitis due to Staphylococcus aureus, Cytokine 19(2):59-65 2002), gastritis (T. Bayraktaroglu et al., Serum levels of tumor necrosis factor-alpha, interleukin-6 and interleukin-8 are not increased in dyspeptic patients with Helicobacter pylori-associated gastritis, Mediators Inflamm 13(1):25-8 (2004)), enteritis (K. Mitsuyama et al., STAT3 activation via interleukin 6 trans-signalling contributes to ileitis in SAMP1/Yit mice, Gut 55(9):1263-9. (2006)), gingivitis (R. Johnson et al., Interleukin-11 and IL-17 and the pathogenesis of periodontal disease, J Periodontol 75(1):37-43 (2004)), appendicitis (S. Latifi et al., Persistent elevation of serum interleukin-6 in intraabdominal sepsis identifies those with prolonged length of stay, J Pediatr Surg 39(10): 1548-52 (2004)), irritable bowel syndrome (M. Ortiz-Lucas et al., Irritable bowel syndrome immune hypothesis. Part two: the role of cytokines, Rev Esp Enferm Dig 102(12):711-7 (2010)), tissue graft rejection (L. Kappel et al., IL-17 contributes to CD4-mediated graft-versus-host disease, Blood 113(4):945-52 (2009)), chronic obstructive pulmonary disease (COPD) (S. Traves and L. Donnelly, Th17 cells in airway diseases, Curr Mol Med 8(5):416-26 (2008)), septic shock (toxic shock syndrome, SIRS, bacterial sepsis, etc) (E. Nicodeme et al., Nature 468(7327):1119-23 (2010)), osteoarthritis (L. Chen et al., IL-17RA aptamer-mediated repression of IL-6 inhibits synovium inflammation in a murine model of osteoarthritis, Osteoarthritis Cartilage 19(6):711-8 (2011)), acute gout (W. Urano et al., The inflammatory process in the mechanism of decreased serum uric acid concentrations during acute gouty arthritis, J Rheumatol 29(9):1950-3 (2002)), acute lung injury (S. Traves and L. Donnelly, Th17 cells in airway diseases, Curr Mol Med 8(5):416-26 (2008)), acute renal failure (E. Simmons et al., Plasma cytokine levels predict mortality in patients with acute renal failure, Kidney Int 65(4):1357-65 (2004)), burns (P. Paquet and G. Pierard, Interleukin-6 and the skin, Int Arch Allergy Immunol 109(4):308-17 (1996)), Herxheimer reaction (G. Kaplanski et al., Jarisch-Herxheimer reaction complicating the treatment of chronic Q fever endocarditis: elevated TNFalpha and IL-6 serum levels, J Infect 37(1):83-4 (1998)), and SIRS associated with viral infections (A. Belkinaand G. Denis, Nat Rev Cancer 12(7):465-77 (2012)). Thus, the invention includes compounds of Formula I or Formula Ia, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof; pharmaceutical compositions comprising one or more of those compounds; and methods of using those compounds or compositions for treating these diseases.

(70) In one embodiment, BET inhibitor compounds of Formula I or Formula Ia, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds may be used for treating rheumatoid arthritis (RA) and multiple sclerosis (MS). Strong proprietary data exist for the utility of BET inhibitors in preclinical models of RA and MS. R. Jahagirdar et al., An Orally Bioavailable Small Molecule RVX-297 Significantly Decreases Disease in a Mouse Model of Multiple Sclerosis, World Congress of Inflammation, Paris, France (2011). Both RA and MS are characterized by a dysregulation of the IL-6 and IL-17 inflammatory pathways (A. Kimura and T. Kishimoto, IL-6: regulator of Treg/Th17 balance, Eur J Immunol 40(7):1830-5 (2010)) and thus would be especially sensitive to BET inhibition. In another embodiment, BET inhibitor compounds of Formula I or Formula Ia may be used for treating sepsis and associated afflictions. BET inhibition has been shown to inhibit development of sepsis, in part, by inhibiting IL-6 expression, in preclinical models in both published (E. Nicodeme et al., Nature 468(7327): 1119-23 (2010)) and proprietary data.

(71) In one embodiment, BET inhibitor compounds of Formula I or Formula Ia, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds may be used to treat cancer. Cancers that have an overexpression, translocation, amplification, or rearrangement c-myc or other myc family oncoproteins (MYCN, L-myc) are particularly sensitive to BET inhibition. J. Delmore et al., Cell 146(6):904-17 (2010); J. Mertz et al., Proc Natl Acad Sci USA 108(40):16669-74 (2011). These cancers include, but are not limited to, B-acute lymphocytic leukemia, Burkitt's lymphoma, Diffuse large cell lymphoma, Multiple myeloma, Primary plasma cell leukemia, Atypical carcinoid lung cancer, Bladder cancer, Breast cancer, Cervix cancer, Colon cancer, Gastric cancer, Glioblastoma, Hepatocellular carcinoma, Large cell neuroendocrine carcinoma, Medulloblastoma, Melanoma, nodular, Melanoma, superficial spreading, Neuroblastoma, esophageal squamous cell carcinoma, Osteosarcoma, Ovarian cancer, Prostate cancer, Renal clear cell carcinoma, Retinoblastoma, Rhabdomyosarcoma, and Small cell lung carcinoma. M. Vita and M. Henriksson, Semin Cancer Biol 16(4):318-30 (2006).

(72) In one embodiment, BET inhibitor compounds of Formula I or Formula Ia, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds may be used to treat cancers that result from an aberrant regulation (overexpression, translocation, etc) of BET proteins. These include, but are not limited to, NUT midline carcinoma (Brd3 or Brd4 translocation to nutlin 1 gene) (C. French Cancer Genet Cytogenet 203(1):16-20 (2010)), B-cell lymphoma (Brd2 overexpression) (R. Greenwald et al., Blood 103(4):1475-84 (2004)), non-small cell lung cancer (BrdT overexpression) (C. Grunwald et al., Expression of multiple epigenetically regulated cancer/germline genes in nonsmall cell lung cancer, Int J Cancer 118(10):2522-8 (2006)), esophageal cancer and head and neck squamous cell carcinoma (BrdT overexpression) (M. Scanlan et al., Expression of cancer-testis antigens in lung cancer: definition of bromodomain testis-specific gene (BRDT) as a new CT gene, CT9, Cancer Lett 150(2):55-64 (2000)), and colon cancer (Brd4) (R. Rodriguez et al., Aberrant epigenetic regulation of bromodomain BRD4 in human colon cancer, J Mol Med (Berl) 90(5):587-95 (2012)).

(73) In one embodiment, because BET inhibitors decrease Brd-dependent recruitment of pTEFb to genes involved in cell proliferation, BET inhibitor compounds of Formula I or Formula Ia, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds may be used to treat cancers that rely on pTEFb (Cdk9/cyclin T) and BET proteins to regulate oncogenes. These cancers include, but are not limited to, chronic lymphocytic leukemia and multiple myeloma (W. Tong et al., Phase I and pharmacologic study of SNS-032, a potent and selective Cdk2, 7, and 9 inhibitor, in patients with advanced chronic lymphocytic leukemia and multiple myeloma, J Clin Oncol 28(18):3015-22 (2010)), follicular lymphoma, diffuse large B cell lymphoma with germinal center phenotype, Burkitt's lymphoma, Hodgkin's lymphoma, follicular lymphomas and activated, anaplastic large cell lymphoma (C. Bellan et al., CDK9/CYCLIN T1 expression during normal lymphoid differentiation and malignant transformation, J Pathol 203(4):946-52 (2004)), neuroblastoma and primary neuroectodermal tumor (G. De Falco et al., Cdk9 regulates neural differentiation and its expression correlates with the differentiation grade of neuroblastoma and PNET tumors, Cancer Biol Ther 4(3):277-81 (2005)), rhabdomyosarcoma (C. Simone and A. Giordano, Abrogation of signal-dependent activation of the cdk9/cyclin T2a complex in human RD rhabdomyosarcoma cells, Cell Death Differ 14(1): 192-5 (2007)), prostate cancer (D. Lee et al., Androgen receptor interacts with the positive elongation factor P-TEFb and enhances the efficiency of transcriptional elongation, J Biol Chem 276(13):9978-84 (2001)), and breast cancer (K. Bartholomeeusen et al., BET bromodomain inhibition activates transcription via a transient release of P-TEFb from 7SK snRNP, J Biol Chem (2012)).

(74) In one embodiment, BET inhibitor compounds of Formula I or Formula Ia, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds may be used to treat cancers in which BET-responsive genes, such as CDK6, Bcl2, TYRO3, MYB, and hTERT are up-regulated. M. Dawson et al., Nature 478(7370):529-33 (2011); J. Delmore et al., Cell 146(6):904-17 (2010). These cancers include, but are not limited to, pancreatic cancer, breast cancer, colon cancer, glioblastoma, adenoid cystic carcinoma, T-cell prolymphocytic leukemia, malignant glioma, bladder cancer, medulloblastoma, thyroid cancer, melanoma, multiple myeloma, Barret's adenocarcinoma, hepatoma, prostate cancer, pro-myelocytic leukemia, chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma, small cell lung cancer, and renal carcinoma. M. Ruden and N. Puri, Novel anticancer therapeutics targeting telomerase, Cancer Treat Rev (2012); P. Kelly and A. Strasser, The role of Bcl-2 and its pro-survival relatives in tumourigenesis and cancer therapy Cell Death Differ 18(9):1414-24 (2011); T. Uchida et al., Antitumor effect of bcl-2 antisense phosphorothioate oligodeoxynucleotides on human renal-cell carcinoma cells in vitro and in mice, Mol Urol 5(2):71-8 (2001).

(75) Published and proprietary data have shown direct effects of BET inhibition on cell proliferation in various cancers. In one embodiment, BET inhibitor compounds of Formula I or Formula Ia, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds may be used to treat cancers for which exist published and, for some, proprietary, in vivo and/or in vitro data showing a direct effect of BET inhibition on cell proliferation. These cancers include NMC (NUT-midline carcinoma), acute myeloid leukemia (AML), acute B lymphoblastic leukemia (B-ALL), Burkitt's Lymphoma, B-cell Lymphoma, Melanoma, mixed lineage leukemia, multiple myeloma, pro-myelocytic leukemia (PML), and non-Hodgkin's lymphoma. P. Filippakopoulos et al., Nature 468(7327):1067-73 (2010); M. Dawson et al., Nature 478(7370):529-33 (2011); Zuber, J., et al., RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia, Nature 478(7370):524-8 (2011); M. Segura, et al, Cancer Research. 72(8):Supplement 1 (2012). The compounds of the invention have a demonstrated BET inhibition effect on cell proliferation in vitro for the following cancers: Neuroblastoma, Medulloblastoma, lung carcinoma (NSCLC, SCLC), and colon carcinoma.

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

(77) In one embodiment, BET inhibitor compounds of Formula I or Formula Ia, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds may be used to treat benign proliferative and fibrotic disorders, including benign soft tissue tumors, bone tumors, brain and spinal tumors, eyelid and orbital tumors, granuloma, lipoma, meningioma, multiple endocrine neoplasia, nasal polyps, pituitary tumors, prolactinoma, pseudotumor cerebri, seborrheic keratoses, stomach polyps, thyroid nodules, cystic neoplasms of the pancreas, hemangiomas, vocal cord nodules, polyps, and cysts, Castleman disease, chronic pilonidal disease, dermatofibroma, pilar cyst, pyogenic granuloma, juvenile polyposis syndrome, idiopathic pulmonary fibrosis, renal fibrosis, post-operative stricture, keloid formation, scleroderma, and cardiac fibrosis. X. Tang et al., Am J Pathology in press (2013).

(78) In one embodiment, because of their ability to up-regulate ApoA-1 transcription and protein expression (O. Mirguet et al., Bioorg Med Chem Lett 22(8):2963-7 (2012); C. Chung et al., J Med Chem 54(11):3827-38 (2011)), BET inhibitor compounds of Formula I or Formula Ia, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds may be used to treat cardiovascular diseases that are generally associated with including dyslipidemia, atherosclerosis, hypercholesterolemia, and metabolic syndrome (A. Belkina and G. Denis, Nat Rev Cancer 12(7):465-77 (2012); G. Denis Discov Med 10(55):489-99 (2010)). In another embodiment, BET inhibitor compounds of Formula I or Formula Ia may be used to treat non-cardiovascular disease characterized by deficits in ApoA-1, including Alzheimer's disease. D. Elliott et al., Clin Lipidol 51(4):555-573 (2010).

(79) In one embodiment, BET inhibitor compounds of Formula I or Formula Ia, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds may be used in patients with insulin resistance and type II diabetes. A. Belkina and G. Denis, Nat Rev Cancer 12(7):465-77 (2012); G. Denis Discov Med 10(55):489-99 (2010); F. Wang et al., Biochem J 425(1):71-83 (2010); G. Denis et al, FEBS Lett 584(15):3260-8 (2010). The anti-inflammatory effects of BET inhibition would have additional value in decreasing inflammation associated with diabetes and metabolic disease. K. Alexandraki et al., Inflammatory process in type 2 diabetes: The role of cytokines, Ann N Y Acad Sci 1084:89-117 (2006).

(80) In one embodiment, because of their ability to down-regulate viral promoters, BET inhibitor compounds of Formula I or Formula Ia, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds may be used as therapeutics for cancers that are associated with viruses including Epstein-Barr Virus (EBV), hepatitis virus (HBV, HCV), Kaposi's sarcoma associated virus (KSHV), human papilloma virus (HPV), Merkel cell polyomavirus, and human cytomegalovirus (CMV). D. Gagnon et al., J Virol 83(9):4127-39 (2009); J. You et al., J Virol 80(18):8909-19 (2006); R. Palermo et al., RNA polymerase II stalling promotes nucleosome occlusion and pTEFb recruitment to drive immortalization by Epstein-Barr virus, PLoS Pathog 7(10):e1002334 (2011); E. Poreba et al., Epigenetic mechanisms in virus-induced tumorigenesis, Clin Epigenetics 2(2):233-47. 2011. In another embodiment, because of their ability to reactivate HIV-1 in models of latent T cell infection and latent monocyte infection, BET inhibitors could be used in combination with anti-retroviral therapeutics for treating HIV. J. Zhu, et al., Cell Rep (2012); C. Banerjee et al., J Leukoc Biol (2012); K. Bartholomeeusen et al., J Biol Chem (2012); Z. Li et al., Nucleic Acids Res (2012.)

(81) In one embodiment, because of the role of epigenetic processes and bromodomain-containing proteins in neurological disorders, BET inhibitor compounds of Formula I or Formula Ia, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds may be used to treat diseases including, but not limited to, Alzheimer's disease, Parkinson's disease, Huntington disease, bipolar disorder, schizophrenia, Rubinstein-Taybi syndrome, and epilepsy. R. Prinjha et al., Trends Pharmacol Sci 33(3):146-53 (2012); S. Muller et al., Bromodomains as therapeutic targets, Expert Rev Mol Med 13:e29 (2011).

(82) In one embodiment, because of the effect of BRDT depletion or inhibition on spermatid development, BET inhibitor compounds of Formula I or Formula Ia, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds may be used as reversible, male contraceptive agents. M. Matzuk et al., Small-Molecule Inhibition of BRDT for Male Contraception, Cell 150(4): p. 673-684 (2012); B. Berkovits et al., The testis-specific double bromodomain-containing protein BRDT forms a complex with multiple spliceosome components and is required for mRNA splicing and 3-UTR truncation in round spermatids, Nucleic Acids Res 40(15):7162-75 (2012).

Pharmaceutical Compositions

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

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

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

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

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

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

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

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

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

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

(93) Data obtained from the cell culture assays or animal studies can be used in formulating a range of dosage for use in humans. Therapeutically effective dosages achieved in one animal model may be converted for use in another animal, including humans, using conversion factors known in the art (see, e.g., Freireich et al., Cancer Chemother. Reports 50(4):219-244 (1966) and Table 1 for Equivalent Surface Area Dosage Factors).

(94) TABLE-US-00001 TABLE 1 Equivalent Surface Area Dosage Factors: To: Mouse Rat Monkey Dog Human From: (20 g) (150 g) (3.5 kg) (8 kg) (60 kg) Mouse 1 1/2 1/4 1/6 1/12 Rat 2 1 1/2 1/4 1/7 Monkey 4 2 1 3/5 1/3 Dog 6 4 3/5 1 1/2 Human 12 7 3 2 1

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

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

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

EXAMPLES

Example 1: 5,7-Dimethoxy-2-(4-methoxy-2-((1-methylpiperidin-4-yl)amino)phenyl)-quinazolin-4(3H)-one

(98) ##STR00015##

(99) To a solution of 2-fluoro-4-methoxybenzaldehyde (5.0 g, 25.3 mmol) and 2-amino-4,6-dimethoxybenzamide (3.9 g, 25.3 mmol) in N,N-dimethylacetamide (100 mL) was added NaHSO.sub.3 (58.5% SO.sub.2 content, 6.8 g, 38.1 mmol) followed by p-toluenesulfonic acid monohydrate (0.97 g, 5.1 mmol). The resulting mixture was heated at 120 C. for 18 h. After that time the reaction was cooled to rt and poured onto ice. The precipitated solids were collected by filtration, washed with water and dried under vacuum to give 2-(2-fluoro-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (4.8 g, 57%) as an off-white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.89 (br s, 1H), 7.71 (t, J=8.6 Hz, 1H), 6.99 (dd, J=12.9, 2.3 Hz, 1H), 6.92 (dd, J=8.8, 2.5 Hz, 1H), 6.72 (d, J=2.3 Hz, 1H), 6.55 (d, J=2.3 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 6H); ESI MS m/z 331 [M+H].sup.+.

(100) To a suspension of 2-(2-fluoro-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (1.0 g, 3 mmol) and 1-methylpiperidin-4-amine (0.38 g, 3.3 mmol) in THF (25 mL) was added lithium bis(trimethylsilyl)amide (1 M in THF, 6 mL, 6 mmol). The reaction mixture was heated at reflux with stirring for 18 h. After that time a second portion of lithium bis(trimethylsilyl)amide (1 M in THF, 6 mL, 6 mmol) was added and reflux with stirring was continued for an additional 18 h. After that time the reaction was cooled to rt, diluted with cold water (25 mL) and concentrated under reduced pressure. The precipitated solids were collected by filtration and dried. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol to 90:10 dichloromethane/methanol) to give 5,7-dimethoxy-2-(4-methoxy-2-((1-methylpiperidin-4-yl)amino)phenyl)quinazolin-4(3H)-one (0.052 g, 4%) as an off-white solid: mp 252-253 C., .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.51 (br s, 1H), 9.50 (d, J=7.4 Hz, 1H), 7.83 (d, J=8.6 Hz, 1H), 6.58 (d, J=1.95 Hz, 1H), 6.51 (d, J=2.3 Hz, 1H), 6.16-6.26 (m, 2H), 3.89 (s, 3H), 3.85 (s, 3H), 3.79 (s, 3H), 3.48-3.61 (m, 1H), 2.55-2.66 (m, 2H), 2.24-2.37 (m, 2H), 2.20 (s, 3H), 1.93-2.02 (m, 2H), 1.52-1.66 (m, 2H); ESI MS m/z 425 [M+H].sup.+.

Example 2: 5,7-Dimethoxy-2-(4-methoxy-2-(4-methylpiperazine-1-carbonyl)phenyl) quinazolin-4(3H)-one

(101) ##STR00016##

(102) POCl.sub.3 (1.02 g, 6.66 mmol) was added to a solution of 2-formyl-5-methoxybenzoic acid (1.0 g, 5.55 mmol) in anhydrous pyridine (20 mL) at 0 C. and stirred for 30 min. After that time 1-methyl piperazine (0.556 g, 5.55 mmol) was added. The reaction was allowed to warm to rt and stir for 16 h. After that time the reaction was concentrated under reduced pressure, diluted with water and made basic with aqueous Na.sub.2CO.sub.3. The mixture was extracted with ethyl acetate (3200 mL). The combined organic layers were washed with saturated NaHCO.sub.3 solution, water, brine, dried over Na.sub.2SO.sub.4 and concentrated to give 4-methoxy-2-(4-methylpiperazine-1-carbonyl) benzaldehyde as yellow solid (1.0 g, 68%): .sup.1H NMR (400 MHz, CDCl.sub.3) 9.86 (s, 1H), 7.82 (d, J=8.6 Hz, 1H), 6.95 (dd, J=8.6, 1.95 Hz, 1H), 6.76 (d, J=2.3 Hz, 1H), 3.66-3.87 (m, 5H), 3.11-3.18 (m, 2H), 2.46 (br s, 2H), 2.16-2.28 (m, 5H).

(103) To a solution of 4-methoxy-2-(4-methylpiperazine-1-carbonyl)benzaldehyde (1.0 g, 3.81 mmol) and 2-amino-4,6-dimethoxybenzamide (0.748 g, 3.81 mmol) in N,N-dimethyl acetamide (40 mL), were added NaHSO.sub.3 (1.03 g, 5.72 mmol) and p-toluenesulfonic acid monohydrate (0.871 g, 4.58 mmol). The reaction was heated at 120 C. for 16 h. After that time the mixture was cooled to rt, concentrated under reduced pressure, diluted with water (100 mL) and made basic with Na.sub.2CO.sub.3. The water was removed by lyophilization and the residue was extracted with 3% methanol in dichloromethane (2250 mL). The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 97:3 dichloromethane/methanol) to give 5,7-dimethoxy-2-(4-methoxy-2-(4-methylpiperazine-1-carbonyl)phenyl)quinazolin-4(3H)-one as light yellow solid (0.140 g, 8%): mp 215 OC dec.; .sup.1H NMR (400 MHz, CDCl.sub.3) 9.84 (br s, 1H), 7.91 (d, J=8.6 Hz, 1H), 7.04 (dd, J=8.8, 2.5 Hz, 1H), 6.86 (d, J=2.3 Hz, 1H), 6.72 (d, J=2.3 Hz, 1H), 6.45 (d, J=1.95 Hz, 1H), 3.96 (s, 3H), 3.90 (s, 3H), 3.88 (s, 3H), 3.80 (br s, 2H), 3.23 (br s, 2H), 2.43 (br s, 2H), 2.19 (s, 3H), 1.67 (br s, 2H); ESI MS m/z 439 [M+H].sup.+.

Example 3: 2-(2-((1-isopropylpiperidin-4-yl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

(104) ##STR00017##

(105) To a suspension of 2-(2-fluoro-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.660 g, 2 mmol) in anhydrous THF (20 mL) was added 1-isopropylpiperidin-4-amine (1.25 mL, 8 mmol) and lithium bis(trimethylsilyl)amide (1 M in THF, 10 mL, 10 mmol). The reaction was heated at reflux with stirring for 48 h. After that time a second portion of lithium bis(trimethylsilyl)amide (1 M in THF, 6 mL, 6 mmol) was added and reflux with stirring was continued for an additional 6 h. After that time the reaction was cooled to rt, diluted with cold water (3 mL) and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 97:3 dichloromethane/methanol then 97:3 dichloromethane/7 N ammonia in methanol) to give 2-(2-((1-isopropylpiperidin-4-yl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.267 g, 30%) as an off-white solid: mp 248-250 C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.49 (br s, 1H), 9.49 (d, J=7.4 Hz, 1H), 7.83 (d, J=8.6 Hz, 1H), 6.53-6.64 (m, 1H), 6.50 (s, 1H), 6.10-6.29 (m, 2H), 3.89 (s, 3H), 3.85 (s, 3H), 3.78 (s, 3H), 3.51 (br s, 1H), 2.63-2.76 (m, 3H), 2.42 (t, J=9.2 Hz, 2H), 1.97 (br s, 2H), 1.47-1.63 (m, 2H), 0.97 (d, J=6.25 Hz, 6H); ESI MS m/z 453 [M+H].sup.+.

Example 4: 5,7-Dimethoxy-2-(4-methoxy-2-((1-methylpyrrolidin-3-yl)amino)phenyl)quinazolin-4(3H)-one

(106) ##STR00018##

(107) To a suspension of 2-(2-fluoro-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.660 g, 2 mmol) in anhydrous THF (25 mL) was added 1-methylpyrrolidine-3-amine dihydrochloride (1.03 g, 6 mmol) and lithium bis(trimethylsilyl)amide (1 M solution in THF, 18 mL, 18 mmol). The reaction was heated at reflux with stirring for 24 h. After that time the reaction was cooled to rt, diluted with cold water (5 mL) and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30 mL), diluted with water (30 mL) and stirred for 1 h. The precipitated solid was collected by filtration, washed with water then hexanes and air dried. The product was triturated (1:1, ethyl acetate/hexanes) to give 5,7-dimethoxy-2-(4-methoxy-2-(1-methylpyrrolidin-3-yl)phenyl)quinazolin-4(3H)-one (0.160 g, 20%) as an off-white solid: mp 214-215 C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.85 (br s, 1H), 7.88 (d, J=9.0 Hz, 1H), 6.53 (d, J=1.95 Hz, 1H), 6.49 (s, 1H), 6.20 (dd, J=8.8, 2.15 Hz, 1H), 6.11 (s, 1H), 4.05 (br s, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.79 (s, 3H), 2.69-2.82 (m, 2H), 2.55 (m, 1H), 2.33-2.41 (m, 2H), 2.32 (s, 3H), 1.59-1.68 (m, 1H); ESI MS m/z 411 [M+H].sup.+.

Example 5: 5,7-Dimethoxy-2-(4-methoxy-2-(methyl(1-methylpiperidin-4-yl)amino)phenyl) quinazolin-4(3H)-one

(108) ##STR00019##

(109) To a suspension of 2-(2-fluoro-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.660 g, 2 mmol) in anhydrous THF (20 mL) was added N,1-dimethylpiperidin-4-amine (0.50 g, 8 mmol) and lithium bis(trimethylsilyl)amide (1 M in THF, 6 mL, 6 mmol). The reaction was heated at reflux with stirring for 3 h. After that time a second portion of lithium bis(trimethylsilyl)amide (1 M in THF, 6 mL, 6 mmol) was added and reflux with stirring was continued for an additional 16 h. After that time the reaction was cooled to rt, diluted with cold water (5 mL) and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 97:3 dichloromethane/methanol then 97:3 dichloromethane/7N ammonia in methanol) to give 5,7-dimethoxy-2-(4-methoxy-2-(methyl(1-methylpiperidin-4-yl)amino)phenyl)quinazolin-4(3H)-one (0.362 g, 41%) as an off-white solid: mp 217-218 C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 13.45 (s, 1H), 8.27 (d, J=9.0 Hz, 1H), 6.97 (d, J=2.3 Hz, 1H), 6.91 (dd, J=9.0, 2.3 Hz, 1H), 6.72 (d, J=1.95 Hz, 1H), 6.50 (d, J=2.3 Hz, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.83 (s, 3H), 2.77-2.84 (m, 1H), 2.65-2.76 (m, 5H), 2.06 (s, 3H), 1.59-1.76 (m, 4H), 1.45-1.59 (m, 2H); ESI MS m/z 439 [M+H].sup.+.

Example 6: 5,7-Dimethoxy-2-(4-methoxy-2-(((1-methylpiperidin-4-yl)methyl)amino)phenyl) quinazolin-4(3H)-one

(110) ##STR00020##

(111) Lithium bis(trimethylsilyl)amide (1 M in THF, 11.2 mL, 11.2 mmol) was slowly added to a stirred suspension of 2-(2-fluoro-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.616 g, 1.86 mmol) and (1-methylpiperidin-4-yl)methanamine (0.956 g, 7.46 mmol) in anhydrous THF (20 mL). After the addition was complete, the reaction was heated to reflux with stirring for 24 h. After that time the reaction was cooled to rt, diluted with saturated aqueous NH.sub.4Cl (15 mL) and concentrated under reduced pressure. The residue was suspended in water (25 mL), then saturated aqueous NaHCO.sub.3 solution was added to adjust pH to about 8.5. The resulting suspension was stirred at rt for 30 min and the precipitated solid was collected by filtration, washed with water and air-dried. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/7N ammonia in methanol to 97:3 dichloromethane/7N ammonia in methanol) to give 5,7-dimethoxy-2-(4-methoxy-2-(((1-methylpiperidin-4-yl)methyl)amino)phenyl)quinazolin-4(3H)-one (0.180 g, 22%) as a light yellow solid: mp 264-265 C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.47 (br s, 1H), 9.63 (br s, 1H), 7.88 (d, J=9.0 Hz, 1H), 6.60 (d, J=1.95 Hz, 1H), 6.48 (d, J=1.95 Hz, 1H), 6.13-6.24 (m, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 3.80 (s, 3H), 3.08-3.14 (m, 2H), 2.80-2.87 (m, 2H), 2.15 (s, 3H), 1.85-1.95 (m, 2H), 1.74-1.81 (m, 2H), 1.65-1.73 (m, 1H), 1.43-1.54 (m, 2H); ESI MS m/z 439 [M+H].sup.+.

Example 7: 5,7-Dimethoxy-2-(4-methoxy-2-(((1-methylpyrrolidin-3-yl)methyl)amino)phenyl)-quinazolin-4(3H)-one

(112) ##STR00021##

(113) A 1 M solution of lithium hexamethyldisilazide in THF (10 mL, 10 mmol) was added in a single portion to a stirred suspension of 2-(2-fluoro-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.826 g, 2.5 mmol) and 1-methyl-3-aminoethylpyrrolidine (0.571 g, 5 mmol) in anhydrous THF (20 mL). The reaction mixture was stirred and heated to reflux for 19 h. After cooling to rt, the reaction mixture was quenched with a saturated aqueous solution of NH.sub.4Cl (15 mL) and concentrated under reduced pressure to a volume of 20 mL. A solution of saturated aqueous NaHCO.sub.3 (350 mL) was added and the mixture was extracted with chloroform (430 mL). The combined extracts were dried over MgSO.sub.4, filtered and concentrated under reduced pressure to give a yellow solid. The product was purified by flash column chromatography (silica gel, 95:5 chloroform/methanol) followed by recrystallized from chloroform/hexanes to give 5,7-dimethoxy-2-(4-methoxy-2-(((1-methylpyrrolidin-3-yl)methyl)amino)phenyl)-quinazolin-4(3H)-one (0.367 g, 35%) as a yellow solid: mp 233-235 C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 9.65 (br s, 1H), 9.23 (br s, 1H), 7.56 (d, J=9.2 Hz, 1H), 6.60 (d, J=2.4 Hz, 1H), 6.41 (d, J=2.4 Hz, 1H), 6.30 (dd, J=9.2, 2.4 Hz, 1H), 6.21 (d, J=2.4 Hz, 1H), 3.98 (s, 3H), 3.91 (s, 3H), 3.85 (s, 3H), 3.23-3.20 (m, 2H), 2.83-2.78 (m, 1H), 2.71-2.55 (m, 3H), 2.48-2.45 (m, 1H), 2.37 (s, 3H), 2.21-2.12 (m, 1H), 1.73-1.65 (m, 1H); ESI MS m/z 425 [M+H].sup.+.

Example 8: 2-(2-((2-(Isopropylamino)ethyl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

(114) ##STR00022##

(115) To a suspension of 2-(2-fluoro-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.660 g, 2 mmol) in anhydrous THF (20 mL) was added N.sup.1-isopropylethane-1,2-diamine (1 mL, 8 mmol) and lithium bis(trimethylsilyl)amide (1 M in THF, 6 mL, 6 mmol). The reaction was heated at reflux with stirring for 16 h. After that time a second portion of lithium bis(trimethylsilyl)amide (1 M in THF, 6 mL, 6 mmol) was added and reflux with stirring was continued for an additional 16 h. After that time the reaction was cooled to rt, diluted with sat. NH.sub.4Cl solution (6 mL) and concentrated under reduced pressure. The residue was treated with water (50 mL) and the resulting precipitate was collected by filtration, washed with water, dried and triturated with ethyl acetate to give 2-(2-((2-(isopropylamino)ethyl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.387 g, 47%) as a yellow solid: mp 262-264 C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.35 (t, J=5.3 Hz, 1H), 7.83 (d, J=9.0 Hz, 1H), 6.89 (s, 1H), 6.44-6.55 (m, 1H), 6.20-6.37 (m, 2H), 3.90 (s, 3H), 3.84 (s, 3H), 3.82 (s, 3H), 3.60 (br s, 2H), 3.23 (br s, 1H), 3.03-3.15 (m, 2H), 1.20 (d, J=6.25 Hz, 6H); ESI MS m/z 413 [M+H].sup.+.

Example 9: 5,7-dimethoxy-2-(4-Methoxy-2-((tetrahydro-2H-pyran-4-yl)amino)-phenyl)quinazolin-4(3H)-one

(116) ##STR00023##

(117) To a suspension of 2-(2-fluoro-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.66 g, 2 mmol) and tetrahydro-2H-pyran-4-amine (0.3 g, 3 mmol) in THF (50 mL) was added lithium bis(trimethylsilyl)amide (1 M in THF, 9 mL, 9 mmol). The reaction was heated at reflux with stirring for 18 h. After that time a second portion of lithium bis(trimethylsilyl)amide (1 M in THF, 9 mL, 9 mmol) was added and reflux with stirring was continued for an additional 18 h. After that time the reaction was cooled to rt, diluted with cold water (25 mL) and concentrated under reduced pressure. The precipitated solids were collected by filtration and dried. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol to 90:10 dichloromethane/methanol) to give 5,7-dimethoxy-2-(4-methoxy-2-((tetrahydro-2H-pyran-4-yl)amino)phenyl)quinazolin-4(3H)-one (0.12 g, 14%) as solid: mp 286-287 C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 9.48 (br s, 1H), 9.36 (d, J=7.0 Hz, 1H), 7.56 (dd, J=9.0, 2.7 Hz, 1H), 6.58 (d, J=1.95 Hz, 1H), 6.42 (d, J=2.3 Hz, 1H), 6.31 (dd, J=8.8, 2.5 Hz, 1H), 6.25 (d, J=2.3 Hz, 1H), 4.05 (dt, J=11.9, 4.0 Hz, 2H), 3.99 (s, 3H), 3.93 (s, 3H), 3.86 (s, 3H), 3.58-3.71 (m, 3H), 2.18-2.07 (m, 2H), 1.75-1.64 (m, 2H); ESI MS m/z 412 [M+H].sup.+.

Example 10: 2-(2-((1-Isopropylpiperidin-4-yl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

(118) ##STR00024##

(119) To a solution of 2-amino-4,6-dimethoxybenzamide (3.160 g, 16.1 mmol) and 2-fluorobenzaldehyde (2.0 g, 16.1 mmol) in N,N-dimethylacetamide (20 mL) was added sodium bisulfite (58.5% SO.sub.2 content, 4.29 g, 24.2 mmol) followed by p-toluenosulfonic acid monohydrate (0.613 g, 3.2 mmol). The resulting mixture was heated at 120 C. for 17 h. After that time the reaction was cooled to rt and concentrated under reduced pressure. The residue was diluted with water (100 mL) and saturated aqueous NaHCO.sub.3 was added to adjust the pH to 8. The resulting suspension was stirred for 30 min at rt and the precipitated dark orange solid was collected by filtration, washed with water and air-dried. The product was triturated with ethyl acetate to give 2-(2-fluorophenyl)-5,7-dimethoxyquinazolin-4(3H)-one (2.40 g, 50%) as an off-white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.09 (br s, 1H), 7.70-7.78 (m, 1H), 7.54-7.65 (m, 1H), 7.30-7.41 (m, 2H), 6.74 (d, J=2.3 Hz, 1H), 6.58 (d, J=2.3 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H); ESI MS m/z 301 [M+H].sup.+.

(120) Lithium bis(trimethylsilyl)amide (1 M in THF, 12 mL, 12 mmol) was slowly added to a stirred suspension of 2-(2-fluorophenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.600 g, 2 mmol) and 1-isopropylpiperidin-4-amine (1.14 g, 8 mmol) in anhydrous THF (20 mL). The reaction was heated to reflux with stirring for 40 h. After that time the reaction mixture was cooled to rt, diluted with saturated aqueous. NH.sub.4Cl (5 mL), and concentrated under reduced pressure. The residue was diluted with water (20 mL) and the resulting suspension was stirred at rt for 30 min. The precipitated solid was collected by filtration, washed with water and air-dried. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/7N ammonia in methanol to 97:3 dichloromethane/7N ammonia in methanol) to give 2-(2-((1-isopropylpiperidin-4-yl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.230 g, 27%) as a yellow solid: mp 267-269 C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 9.53 (br s, 1H), 8.98 (d, J=7.4 Hz, 1H), 7.57 (d, J=8.2 Hz, 1H), 7.3 (m, 1H), 6.80 (d, J=8.6 Hz, 1H), 6.70 (m, 1H), 6.64 (d, J=2.3 Hz, 1H), 6.44 (d, J=2.3 Hz, 1H), 3.98 (s, 3H), 3.93 (s, 3H), 3.45-3.55 (m, 1H), 2.85-2.95 (m, 2H), 2.69-2.84 (m, 1H), 2.31-2.46 (m, 2H), 2.12-2.18 (m, 2H), 1.65-1.75 (m, 2H), 1.09 (d, J=6.2 Hz, 6H); ESI MS m/z 423 [M+H].sup.+.

Example 11: 5,7-Dimethoxy-2-(4-methoxy-2-((2-(pyrrolidin-1-yl)ethyl)amino)phenyl)quinazolin-4(3H)-one

(121) ##STR00025##

(122) Lithium bis(trimethylsilyl)amide (1 M in THF, 6 mL, 6 mmol) was slowly added to a stirred suspension of 2-(2-fluoro-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.660 g, 2 mmol) and 2-(pyrrolidin-1-yl)ethan-1-amine (1.01 mL, 8 mmol) in anhydrous THF (20 mL). The reaction was heated at reflux with stirring for 16 h. After that time a second portion of lithium bis(trimethylsilyl)amide (1 M in THF, 6 mL, 6 mmol) was added and reflux with stirring was continued for an additional 16 h. After that time the reaction was cooled to rt, diluted with sat. NH.sub.4Cl solution (6 mL) and concentrated under reduced pressure. The residue was treated with water (50 mL) and the precipitated solids were collected by filtration and dried. The product was triturated with ethyl acetate to give 5,7-dimethoxy-2-(4-methoxy-2-((2-(pyrrolidin-1-yl)ethyl)amino)phenyl)quinazolin-4(3H)-one (0.640 g, 75%) as a yellow solid: mp 226-228 C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 9.10 (br s, 1H), 7.51 (d, J=8.6 Hz, 1H), 6.67 (d, J=1.95 Hz, 1H), 6.40 (d, J=1.95 Hz, 1H), 6.30 (dd, J=8.8, 2.15 Hz, 1H), 6.23 (d, J=1.95 Hz, 1H), 3.98 (s, 3H), 3.92 (s, 3H), 3.86 (s, 3H), 3.32-3.41 (m, 2H), 2.87 (t, J=6.25 Hz, 2H), 2.63 (br s, 4H), 1.81 (br s, 4H); ESI MS m/z 425 [M+H].sup.+.

Example 12: 5,7-Dimethoxy-2-(4-methoxy-2-((2-(piperidin-1-yl)ethyl)amino)-phenyl)quinazolin-4(3H)-one

(123) ##STR00026##

(124) To a suspension of 2-(2-fluoro-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.50 g, 1.5 mmol) and 2-(piperidin-1-yl)ethan-1-amine (0.39 g, 3 mmol) in THF (50 mL) was added lithium bis(trimethylsilyl)amide (1 M in THF, 4.5 mL, 4.5 mmol). The reaction mixture was heated at reflux with stirring for 18 h. After that time a second portion of lithium bis(trimethylsilyl)amide (1 M in THF, 4.5 mL, 4.5 mmol) was added and reflux with stirring was continued for an additional 18 h. After that time the reaction was cooled to rt, diluted with cold water (25 mL) and concentrated under reduced pressure. The precipitated solids were collected by filtration and dried. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol to 90:10 dichloromethane/methanol) to give 5,7-dimethoxy-2-(4-methoxy-2-((2-(piperidin-1-yl)ethyl)amino)phenyl)quinazolin-4(3H)-one (0.16 g, 24%) as an off-white solid: mp 231-232 C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 9.42 (br s, 1H), 8.87 (t, J=4.5 Hz, 1H), 7.50 (d, J=9.0 Hz, 1H), 6.71 (d, J=2.3 Hz, 1H), 6.41 (d, J=2.3 Hz, 1H), 6.30 (dd, J=8.6, 2.3 Hz, 1H), 6.23 (d, J=2.7 Hz, 1H), 3.98 (s, 3H), 3.92 (s, 3H), 3.85 (s, 3H), 3.28-3.39 (m, 2H), 2.71 (t, J=6.4 Hz, 2H), 2.48 (br s, 4H), 1.58 (quin, J=5.6 Hz, 4H), 1.37-1.48 (m, 2H); ESI MS m/z 439 [M+H].sup.+.

Example 13: 5,7-Dimethoxy-2-(4-methoxy-2-((3-morpholinopropyl)amino)-phenyl)quinazolin-4(3H)-one

(125) ##STR00027##

(126) To a suspension of 2-(2-fluoro-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.50 g, 1.5 mmol) and 3-morpholinopropan-1-amine (0.39 g, 3 mmol) in THF (50 mL) was added lithium bis(trimethylsilyl)amide (1 M in THF, 4.5 mL, 4.5 mmol). The reaction mixture was heated at reflux with stirring for 18 h. After that time a second portion of lithium bis(trimethylsilyl)amide (1 M in THF, 4.5 mL, 4.5 mmol) was added and reflux with stirring was continued for an additional 18 h. After that time the reaction was cooled to rt, diluted with cold water (25 mL) and concentrated under reduced pressure. The precipitated solids were collected by filtration and dried. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol to 90:10 dichloromethane/methanol) to give 5,7-dimethoxy-2-(4-methoxy-2-((3-morpholinopropyl)amino)phenyl)quinazolin-4(3H)-one (0.16 g, 24%) as an off-white solid; mp 234-235 C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 8.99 (br s, 1H), 8.93-8.97 (m, 1H), 7.41 (d, J=9.0 Hz, 1H), 6.61 (d, J=2.3 Hz, 1H), 6.42 (d, J=2.3 Hz, 1H), 6.30 (dd, J=9.0, 2.3 Hz, 1H), 6.25 (d, J=2.3 Hz, 1H), 3.98 (s, 3H), 3.92 (s, 3H), 3.86 (s, 3H), 3.69-3.74 (m, 4H), 3.28-3.35 (m, 2H), 2.54 (t, J=7.4 Hz, 2H), 2.44-2.50 (m, 4H), 1.91-1.98 (m, 2H); ESI MS m/z 455 [M+H].sup.+.

Example 14: 5,7-Dimethoxy-2-(4-methoxy-2-((2-morpholinoethyl)amino)phenyl)-quinazolin-4(3H)-one

(127) ##STR00028##

(128) Lithium bis(trimethylsilyl)amide (1 M in THF, 6 mL, 6 mmol) was slowly added to a stirred suspension of 2-(2-fluoro-4-methoxyphenyl)-5,7-dimethoxyquinazolin-(4(3H)-one (0.660 g, 2 mmol) and 2-(morpholin-4-yl)ethanamine (0.780 g, 6 mmol) in anhydrous THF (25 mL). After the addition was complete, the reaction was heated to reflux with stirring for 3 h. After that time a second portion of lithium bis(trimethylsilyl)amide (1M in THF, 6 mL, 6 mmol) was added. Heating to reflux with stirring was continued for 16 h. After that time the reaction was cooled to rt, diluted with saturated aqueous NH.sub.4Cl (5 mL) and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (20 mL), diluted with water (20 mL) and stirred for 1 h. The precipitated solid was collected by filtration, washed with water then hexanes and air dried. The product was purified by column chromatography (silica gel, 90:10 ethyl acetate/methanol) to give 5,7-dimethoxy-2-(4-methoxy((2-morpholinoethyl)amino)phenylquinazolin-4(3H)-one (0.330 g, 38%) as a yellow solid: mp 239-240 C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 9.18 (br s, 1H), 8.87 (br s, 1H), 7.45 (d, J=9.0 Hz, 1H), 6.72 (d, J=2.3 Hz, 1H), 6.42 (d, J=1.95 Hz, 1H), 6.31 (dd, J=9.0, 2.3 Hz, 1H), 6.23 (d, J=2.3 Hz, 1H), 3.99 (s, 3H), 3.91 (s, 3H), 3.86 (s, 3H), 3.69-3.76 (m, 4H), 3.30-3.38 (m, 2H), 2.76 (t, J=6.2 Hz, 2H), 2.51-2.59 (m, 4H); ESI MS m/z 441 [M+H].sup.+.

Example 15: 5,7-Dimethoxy-2-(4-methoxy-2-((3-(pyrrolidin-1-yl)propyl)amino)phenyl)quinazolin-4(3H)-one

(129) ##STR00029##

(130) Lithium bis(trimethylsilyl)amide (1 M in THF, 12 mL, 12 mmol) was slowly added to a stirred suspension of 2-(2-fluoro-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.661 g, 2 mmol) and 3-(pyrrolidin-1-yl)propan-1-amine (1.030 g, 8 mmol) in anhydrous THF (20 mL). After the addition was complete the reaction was heated to reflux with stirring for 24 h. After that time, the reaction was cooled to rt, diluted with saturated aqueous solution of NH.sub.4Cl (10 mL), and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (20 mL), diluted with water (20 mL) and stirred for 1 h. The precipitated solid was collected by filtration, washed with water then hexanes and air dried. The product was purified by column chromatography (silica gel, 99:1 dichloromethane/7N ammonia in methanol to 97:3 dichloromethane/7N ammonia in methanol) to give 5,7-dimethoxy-2-(4-methoxy-2-((3-(pyrrolidin-1-yl)propyl)amino)phenyl)quinazolin-4(3H)-one (0.220 g, 25%) as a yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3) 9.33 (br s, 1H), 9.04 (br s, 1H), 7.49 (d, J=8.8 Hz, 1H), 6.62 (d, J=2.3 Hz, 1H), 6.41 (d, J=2.3 Hz, 1H), 6.29 (dd, J=8.8, 2.3 Hz, 1H), 6.23 (d, J=2.3 Hz, 1H), 3.98 (s, 3H), 3.92 (s, 3H), 3.85 (s, 3H), 3.31 (t, J=7.0 Hz, 2H), 2.62-2.68 (m, 2H), 2.48-2.56 (m, 4H), 1.99 (quin, J=7.0 Hz, 2H), 1.75-1.80 (m, 4H); ESI MS m/z 439 [M+H].sup.+.

Example 16: 2-(2-(((1-Isopropylpyrrolidin-3-yl)methyl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

(131) ##STR00030##

(132) Lithium bis(trimethylsilyl)amide (1 M in THF, 6 mL, 6 mmol) was slowly added to a stirred suspension of 2-(2-fluoro-4-methoxyphenyl)-5,7-dimethoxyquinazolin-(4(3H)-one (0.660 g, 2 mmol) and (1-isopropylpyrrolidin-3-yl)methanamine (1.14 g, 8 mmol) in anhydrous THF (20 mL). After the addition was complete, the reaction was heated to reflux with stirring for 3 h. After that time a second portion of lithium bis(trimethylsilyl)amide (1M in THF, 6 mL, 6 mmol) was added. Heating to reflux with stirring was continued for 16 h. After that time the reaction was cooled to rt, diluted with saturated aqueous NH.sub.4Cl (6 mL) and concentrated under reduced pressure. The residue was diluted with water (50 mL) and the precipitated solid was collected by filtration, washed with water and dried. The resulting solids were triturated with ethyl acetate, then with 90:10 diethyl ether/methanol and dried under vacuum to give 2-(2-(((1-isopropylpyrrolidin-3-yl)methyl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.347 g, 38%) as a pale orange solid: mp 228-230 C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 9.50 (br s, 1H), 9.21 (br s, 1H), 7.53 (d, J=8.6 Hz, 1H), 6.59 (d, J=1.95 Hz, 1H), 6.40 (d, J=1.95 Hz, 1H), 6.30 (dd, J=8.8, 2.5 Hz, 1H), 6.21 (d, J=2.3 Hz, 1H), 3.98 (s, 3H), 3.90 (s, 3H), 3.86 (s, 3H), 3.16-3.25 (m, 2H), 3.01 (t, J=8.8 Hz, 1H), 2.55-2.80 (m, 3H), 2.30-2.45 (m, 2H), 2.10-2.23 (m, 1H), 1.62-1.74 (m, 1H), 1.12 (d, J=6.2 Hz, 6H); ESI MS m/z 453 [M+H].sup.+.

Example 17: 2-(2-(((1-Isopropylpyrrolidin-2-yl)methyl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

(133) ##STR00031##

(134) Lithium bis(trimethylsilyl)amide (1 M in THF, 12 mL, 12 mmol) was slowly added to a stirred suspension of 2-(2-fluoro-4-methoxyphenyl)-5,7-dimethoxyquinazolin-(4(3H)-one (0.660 g, 2 mmol) and (1-isopropylpyrrolidin-2-yl)methanamine (1.140 g, 8 mmol) in anhydrous THF (20 mL). After the addition was complete, the reaction was heated to reflux with stirring for 24 h. After that time the reaction was cooled to rt, diluted with saturated aqueous NH.sub.4Cl (10 mL) and concentrated under reduced pressure. The residue was diluted with water (20 mL) and the resulting suspension was stirred at rt for 30 min. The precipitated solid was collected by filtration, washed with water and dried. The product was purified by column chromatography (silica gel, 99:1 dichloromethane/7N ammonia in methanol to 97:3 dichloromethane/7N ammonia in methanol) to give 2-(2-(((1-isopropylpyrrolidin-2-yl)methyl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.240 g, 27%) as a yellow solid: mp 207-209 C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 9.33 (br s, 1H), 9.20 (br s, 1H), 7.49 (d, J=8.9 Hz, 1H), 6.67 (d, J=2.3 Hz, 1H), 6.40 (d, J=2.3 Hz, 1H), 6.29 (dd, J=8.9, 2.3 Hz, 1H), 6.22 (d, J=2.3 Hz, 1H), 3.98 (s, 3H), 3.91 (s, 3H), 3.85 (s, 3H), 3.15-3.30 (m, 2H), 2.99-3.12 (m, 3H), 2.53-2.61 (m, 1H), 1.68-1.97 (m, 4H), 1.16 (d, J=6.6 Hz, 3H), 1.02 (d, J=6.25 Hz, 3H); ESI MS m/z 453 [M+H].sup.+.

Example 18: 2-(3-((1-Isopropylpiperidin-4-yl)amino)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one

(135) ##STR00032##

(136) Lithium bis(trimethylsilyl)amide (1 M in THF, 3.2 mL, 3.2 mmol) was added to a stirred suspension of 2-(3-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.322 g, 1.07 mmol) and 1-isopropylpiperidin-4-amine (0.676 mL, 4.28 mmol) in anhydrous THF (10 mL). After the addition was complete, the reaction was heated to reflux with stirring for 1 h. After that time a second portion of lithium bis(trimethylsilyl)amide (1M in THF, 3.2 mL, 3.2 mmol) was added. Heating to reflux with stirring was continued for 2 h. After that time the reaction was cooled to rt, diluted with saturated aqueous NH.sub.4Cl (3 mL) and concentrated under reduced pressure. The residue was diluted with water (30 mL) and the precipitated solid was collected by filtration, washed with water and dried. The product was purified by flash column chromatography (silica gel, 97:3 dichloromethane/methanol then 97:3 dichloromethane/7 N ammonia in methanol) to give 2-(3-((1-isopropylpiperidin-4-yl)amino)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.145 g, 32%) as a yellow solid: mp 170-172 C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 10.92 (br s, 1H), 9.50 (d, J=7.8 Hz, 1H), 7.89 (d, J=4.3 Hz, 1H), 7.23 (dd, J=8.6, 4.3 Hz, 1H), 7.10 (d, J=8.6 Hz, 1H), 6.65 (d, J=2.3 Hz, 1H), 6.45 (d, J=2.3 Hz, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 3.43-3.57 (m, 1H), 2.86-2.98 (m, 2H), 2.78 (sept, J=6.5 Hz, 1H), 2.42 (t, J=10.2 Hz, 2H), 2.09-2.21 (m, 2H), 1.61-1.83 (m, 2H), 1.10 (d, J=6.6 Hz, 6H); ESI MS m/z 424 [M+H].sup.+.

Example 19: 2-(2-((1-Isobutyrylpiperidin-4-yl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

(137) ##STR00033##

(138) Lithium bis(trimethylsilyl)amide (1 M in THF, 12.0 mL, 12.0 mmol) was added to a stirred suspension of 2-(2-fluoro-4-methoxyphenyl)-5,7-dimethoxyquinazolin-(4(3H)-one (0.660 g, 2.0 mmol) and 1-(4-aminopiperidin-1-yl)-2-methylpropan-1-one hydrochloride (1.240 g, 6.0 mmol) in anhydrous THF (20 mL). After the addition was complete, the reaction was heated to reflux with stirring for 3 h. After that time a second portion of lithium bis(trimethylsilyl)amide (1M in THF, 6.0 mL, 6.0 mmol) was added. Heating to reflux with stirring was continued for 16 h. After that time the reaction was cooled to rt, diluted with saturated aqueous NH.sub.4Cl (5.0 mL) and concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with CH.sub.2Cl.sub.2 (230 mL). The combined organics were concentrated under reduced pressure and purified by flash column chromatography (silica gel, 90:10 ethyl acetate/methanol) followed by prep. HPCL to give 2-(2-((1-isobutyrylpiperidin-4-yl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.090 g, 9%) as a yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3) 9.35 (br s, 1H), 9.19 (br s, 1H), 7.50 (d, J=8.6 Hz, 1H), 6.54 (s, 1H), 6.42 (s, 1H), 6.32 (d, J=8.6 Hz, 1H), 6.25 (br s, 1H), 4.27 (br s, 1H), 3.98 (s, 3H), 3.92 (s, 3H), 3.86 (s, 3H), 3.70 (br s, 1H), 3.23-3.43 (m, 2H), 2.84 (sept, J=6.2 Hz 1H), 2.07-2.20 (m, 2H), 1.59-1.71 (m, 2H), 1.14 (d, J=6.2 Hz, 6H); ESI MS m/z 481 [M+H].sup.+.

Example 20: 2-(2-((3-(Isopropylamino)propyl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

(139) ##STR00034##

(140) Lithium bis(trimethylsilyl)amide (1 M in THF, 6 mL, 6 mmol) was added to a stirred suspension of 2-(2-fluoro-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.660 g, 2 mmol) and N-isopropylpropane-1,3-diamine (1.35 mL, 8 mmol) in anhydrous THF (20 mL). After the addition was complete, the reaction was heated to reflux with stirring for 3 h. After that time a second portion of lithium bis(trimethylsilyl)amide (1M in THF, 6 mL, 6 mmol) was added. Heating to reflux with stirring was continued for 16 h. After that time the reaction was cooled to rt, diluted with saturated aqueous NH.sub.4Cl (6 mL) and concentrated under reduced pressure. The residue was diluted with water (50 mL) and the precipitated solid was collected by filtration, washed with water and dried. The product was purified by flash column chromatography (silica gel, 97:3 dichloromethane/methanol then 97:3 dichloromethane/7 N ammonia in methanol) to give 2-(2-((3-(isopropylamino)propyl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.171 g, 20%) as a yellow solid: mp 208-210 C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.83 (d, J=9.8 Hz, 1H), 6.61 (d, J=2.3 Hz, 1H), 6.49 (d, J=2.3 Hz, 1H), 6.16-6.24 (m, 2H), 3.89 (s, 3H), 3.85 (s, 3H), 3.80 (s, 3H), 3.50 (br s, 2H), 3.26 (t, J=6.6 Hz, 2H), 2.64-2.75 (m, 3H), 1.86-1.76 (m, 2H), 0.95 (d, J=5.9 Hz, 6H); ESI MS m/z 427 [M+H].sup.+.

Example 21: 5,7-Dimethoxy-2-(4-methoxy-2-((3-(methylpiperazin-1-yl)propyl)amino)-phenylquinazolin-4(3H)-one

(141) ##STR00035##

(142) Lithium bis(trimethylsilyl)amide (1 M in THF, 6.0 mL, 6.0 mmol) was added to a stirred suspension of 2-(2-fluoro-4-methoxyphenyl)-5,7-dimethoxyquinazolin-(4(3H)-one (0.660 g, 2.0 mmol) and 3-(4-methylpiperazin-1-yl)propan-1-amine (0.942 g, 6.0 mmol) in anhydrous THF (25 mL). After the addition was complete, the reaction was heated to reflux with stirring for 3 h. After that time a second portion of lithium bis(trimethylsilyl)amide (1M in THF, 6.0 mL, 6.0 mmol) was added. Heating to reflux with stirring was continued for 16 h. After that time the reaction was cooled to rt, diluted with saturated aqueous NH.sub.4Cl (5.0 mL) and concentrated under reduced pressure. The residue was diluted with water (30 mL) and ethyl acetate (10 mL) and stirred for 1 h. The precipitated solids were collected by filtration, washed with water, then hexanes and air dried. The material was triturated with ethyl acetate (220 mL) and ether (220 mL) to give 5,7-dimethoxy-2-(4-methoxy-2-((3-(methylpiperazin-1-yl)propyl)amino)phenylquinazolin-4(3H)-one (0.440 g, 47%) as a light yellow solid: mp 220-222 C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 9.00 (br s, 1H), 7.51 (d, J=8.8 Hz, 1H), 6.61 (d, J=2.3 Hz, 1H), 6.41 (d, J=1.9 Hz, 1H), 6.29 (dd, J=8.8, 1.9 Hz, 1H), 6.23 (d, J=2.3 Hz, 1H), 3.98 (s, 3H), 3.92 (s, 3H), 3.85 (s, 3H), 3.29 (t, J=6.5 Hz, 2H), 2.37-2.66 (m, 11H), 2.29 (s, 3H), 1.90-2.00 (m, 2H); ESI MS m/z 468 [M+H].sup.+.

Example 22: 2-(2-((2-(4-Isopropylpiperazin-1-yl)ethyl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

(143) ##STR00036##

(144) Lithium bis(trimethylsilyl)amide (1 M in THF, 4 mL, 4 mmol) was added to a stirred suspension of 2-(2-fluoro-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.660 g, 2 mmol) and 2-(4-isopropylpiperazin-1-yl)ethan-1-amine (1.02 g, 6 mmol) in anhydrous THF (20 mL). After the addition was complete, the reaction was heated to reflux with stirring for 3 h. After that time a second portion of lithium bis(trimethylsilyl)amide (1M in THF, 4 mL, 4 mmol) was added. Heating to reflux with stirring was continued for 16 h. After that time the reaction was cooled to rt, diluted with saturated aqueous NH.sub.4Cl (6 mL) and concentrated under reduced pressure. The residue was diluted with water (50 mL) and the precipitated solid was collected by filtration, washed with water and dried. The solid was triturated with ethyl acetate followed by 90:10 diethyl ether/methanol and dried under vacuum to give 2-(2-((2-(4-isopropylpiperazin-1-yl)ethyl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.776 g, 80%) as an off-white solid: mp 227-228 C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.44 (br s, 1H), 9.29 (t, J=4.3 Hz, 1H), 7.80 (d, J=9.8 Hz, 1H), 6.72 (d, J=2.3 Hz, 1H), 6.51 (d, J=2.3 Hz, 1H), 6.15-6.26 (m, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.80 (s, 3H), 3.33 (br s, 1H), 3.25 (q, J=5.1 Hz, 2H), 2.64 (t, J=5.7 Hz, 2H), 2.52-2.60 (m, 1H), 2.43 (br s, 8H), 0.90 (d, J=6.6 Hz, 6H); ESI MS m/z 482 [M+H].sup.+.

Example 23: 5,7-Dimethoxy-2-[4-methoxy-2-(1-methylpiperidin-4-ylsulfinyl)phenyl]quinazolin-4(3H)-one

(145) ##STR00037##

(146) A mixture of 2-(2-fluoro-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (3.62 g, 11 mmol), 1-methylpiperidine-4-thiol (1.51 g, 11.5 mmol), K.sub.2CO.sub.3 (3.04 g, 22 mmol) and anhydrous DMSO (44 mL) was heated at 90 C. with stirring for 20 h. After that time the reaction was cooled to rt, diluted with CHCl.sub.3 (150 mL) and washed with water (3100 mL) and brine (100 mL), dried (MgSO.sub.4) and concentrated under reduced pressure. The residue was triturated with diethyl ether (330 mL) and dried in vacuum to give 5,7-dimethoxy-2-[4-methoxy-2-(1-methylpiperidin-4-ylthio)phenyl]quinazolin-4(3H)-one (4.59 g, 95%) as an off-white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) 11.40 (br s, 1H), 7.82 (d, J=8.8 Hz, 1H), 6.98 (d, J=2.4 Hz, 1H), 6.87 (dd, J=8.8, 2.4 Hz, 1H), 6.78 (d, J=2.4 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 3.97 (s, 3H), 3.91 (s, 3H), 3.86 (s, 3H), 2.99-2.93 (m, 1H), 2.70-2.67 (m, 2H), 2.21 (s, 3H), 1.91-1.84 (m, 4H), 1.59-1.50 (n, 2H).

(147) A solution of NaIO.sub.4 (0.449 g, 2.1 mmol) in water (7 mL) was added dropwise to a stirred suspension of 5,7-dimethoxy-2-[4-methoxy-2-(1-methylpiperidin-4-ylthio)phenyl]quinazolin-4(3H)-one (0.883 g, 2 mmol) in methanol (20 mL). After the addition was complete the reaction was stirred for 18 h at rt. After that time the reaction was diluted with water (80 mL) and the precipitated solid collected by filtration, washed with water (430 mL) and dried. The product was purified by flash column chromatography (silica gel, 95:5 chloroform/methanol) to give 5,7-dimethoxy-2-[4-methoxy-2-(1-methylpiperidin-4-ylsulfinyl)phenyl]quinazolin-4(3H)-one (0.312 g, 34%) as a white solid: mp 263-265 C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.93 (d, J=8.4 Hz, 1H), 7.74 (d, J=2.8 Hz, 1H), 7.13 (dd, J=8.4, 2.8 Hz, 1H), 6.65 (d, J=2.4 Hz, 1H), 6.49 (d, J=2.4 Hz, 1H), 3.99 (s, 3H), 3.97 (s, 3H), 3.93 (s, 3H), 3.48-3.40 (m, 1H), 3.06-2.93 (m, 2H), 2.24 (s, 3H), 2.21-1.87 (m, 5H), 1.36-1.33 (m, 1H); ESI MS m/z 458 [M+H].sup.+.

Example 24: 5,7-Dimethoxy-2-(4-methoxy-2-((2-(piperazin-1-yl)ethyl)amino)phenyl)quinazolin-4(3H)-one

(148) ##STR00038##

(149) Lithium bis(trimethylsilyl)amide (1 M in THF, 6.0 mL, 6.0 mmol) was added slowly to a stirred suspension of 2-(2-fluoro-4-methoxyphenyl)-5,7-dimethoxyquinazolin-(4(3H)-one (0.660 g, 2.0 mmol) and tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (0.916 g, 4.0 mmol) in anhydrous THF (25 mL). After the addition was complete, the reaction was heated to reflux with stirring for 1 h. After that time a second portion of lithium bis(trimethylsilyl)amide (1 M in THF, 4.0 mL, 4.0 mmol) was added. Heating to reflux with stirring was continued for 16 h. After that time the reaction was cooled to rt, diluted with saturated aqueous NH.sub.4Cl (5.0 mL) and concentrated under reduced pressure. The residue was diluted with water (40 mL) and stirred for 1 h. The precipitated solid was collected by filtration, washed with water and hexanes and air dried. The product was purified by flash column chromatography (silica gel, 99:1 ethyl acetate/methanol) to give tert-butyl 4-(2-((2-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-5-methoxyphenyl)amino)ethyl)piperazine-1-carboxylate (0.440 g, 41%) as an off-white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) 9.06 (br s, 1H), 8.82 (br s, 1H), 7.43 (d, J=9.0 Hz, 1H), 6.68 (d, J=2.0 Hz, 1H), 6.42 (d, J=2.0 Hz, 1H), 6.31 (dd, J=8.8, 2.1 Hz, 1H), 6.22 (d, J=2.3 Hz, 1H), 3.99 (s, 3H), 3.89 (s, 3H), 3.86 (s, 3H), 3.44 (br s, 4H), 3.34 (q, J=5.5 Hz, 2H), 2.76 (t, J=6.1 Hz, 2H), 2.49 (br s, 4H), 1.45 (s, 9H); ESI MS m/z 540 [M+H].sup.+.

(150) Trifluoroacetic acid (5.0 mL) was added dropwise to a suspension of tert-butyl 4-(2-((2-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-5-methoxyphenyl)amino)ethyl)piperazine-1-carboxylate (0.420 g, 0.78 mmol) in CH.sub.2Cl.sub.2 (20 mL). The reaction mixture was stirred at rt for 3 h. After that time the reaction was concentrated under reduced pressure and the residue diluted with ice-cold water (30 mL). The resulting mixture was made basic with solid NaHCO.sub.3 and extracted with CH.sub.2Cl.sub.2 (330 mL). The combined organics were dried and concentrated to give a solid residue that was triturated (320 mL, 50:50 hexanes/diethyl ether) to give 5,7-dimethoxy-2-(4-methoxy-2-((2-(piperazin-1-yl)ethyl)amino)phenyl)quinazolin-4(3H)-one (0.230 g, 67%) as an off-white solid: mp 210-212 C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 8.86-8.94 (m, 1H), 7.48 (d, J=8.6 Hz, 1H), 6.72 (d, J=2.3 Hz, 1H), 6.42 (d, J=2.3 Hz, 1H), 6.31 (dd, J=8.8, 2.1 Hz, 1H), 6.22 (d, J=2.3 Hz, 1H), 3.99 (s, 3H), 3.91 (s, 3H), 3.86 (s, 3H), 3.34 (q, J=5.9 Hz, 2H), 2.84-2.96 (m, 4H), 2.75 (t, J=6.3 Hz, 2H), 2.52 (br s, 4H); ESI MS m/z 440 [M+H].sup.+.

Example 25: 5,7-Dimethoxy-2-(4-methoxy-2-((2-(4-methylpiperazin-1-yl)ethyl)amino)phenyl)-quinazolin-4(3H)-one

(151) ##STR00039##

(152) Lithium bis(trimethylsilyl)amide (1 M in THF, 4 mL, 4 mmol) was added to a stirred suspension of 2-(2-fluoro-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.660 g, 2 mmol) and 2-(4-methylpiperazin-1-yl)ethan-1-amine (0.86 g, 6 mmol) in anhydrous THF (20 mL). After the addition was complete, the reaction was heated to reflux with stirring for 3 h. After that time a second portion of lithium bis(trimethylsilyl)amide (1M in THF, 4 mL, 4 mmol) was added. Heating to reflux with stirring was continued for 16 h.

(153) After that time the reaction was cooled to rt, diluted with saturated aqueous NH.sub.4Cl (6 mL) and concentrated under reduced pressure. The residue was diluted with water (50 mL) and the precipitated solid was collected by filtration, washed with water and dried. The product was purified by flash column chromatography (silica gel, 96:4 dichloromethane/methanol then 96:4 dichloromethane/7 N ammonia in methanol) to give 5,7-dimethoxy-2-(4-methoxy-2-((2-(4-methylpiperazin-1-yl)ethyl)amino)phenyl)quinazolin-4(3H)-one (0.310 g, 34%) as pale yellow solid: mp 230-231 C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.46 (br s, 1H), 9.26 (t, J=4.3 Hz, 1H), 7.79 (d, J=9.4 Hz, 1H), 6.70 (d, J=1.95 Hz, 1H), 6.51 (d, J=1.95 Hz, 1H), 6.14-6.27 (m, 2H), 3.89 (s, 3H), 3.86 (s, 3H), 3.80 (s, 3H), 3.26 (q, J=5.1 Hz, 2H), 2.65 (t, J=5.9 Hz, 2H), 2.47 (br s, 4H), 2.32 (br s, 4H), 2.11 (s, 3H); ESI MS m/z 454 [M+H].sup.+.

Example 26: 2-(2-((1-Isopropylpiperidin-4-yl)amino)-5-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

(154) ##STR00040##

(155) A mixture of 2-bromo-5-methoxybenzaldehyde (5.0 g, 23.3 mmol), propane-1,3-diol (2.13 g, 28.0 mmol) and para-toluenosulfonic acid monohydrate (0.10 g, 0.53 mmol) in anhydrous toluene (110 mL) was heated to reflux for 24 h with azeotropic removal of water using a Dean-Stark apparatus. After that time the reaction was cooled to rt, washed with 5% aqueous Na.sub.2CO.sub.3 solution (50 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 95:5 hexanes/ethyl acetate to 80:20 hexanes/ethyl acetate) to give 2-(2-bromo-5-methoxyphenyl)-1,3-dioxane (5.8 g, 91%) as a thick viscous liquid: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.40 (d, J=8.6 Hz, 1H), 7.24 (d, J=2.7 Hz, 1H), 6.77 (dd, J=8.8, 2.9 Hz, 1H), 5.72 (s, 1H), 4.27 (dd, J=11.3, 4.7 Hz, 2H), 4.03 (t, J=11.3 Hz, 2H), 3.81 (s, 3H), 2.18-2.32 (m, 1H), 1.44-1.48 (m, 1H).

(156) A mixture of 2-(2-bromo-5-methoxyphenyl)-1,3-dioxane (5.1 g, 18.7 mmol), 1-isopropylpiperidin-4-amine (3.45 g, 24.38 mmol), 2,2-bis(diphenylphosphino)-1,1-binaphthyl (0.746 g, 1.2 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.366 g, 0.4 mmol) in anhydrous toluene (50 mL) was purged with nitrogen for 15 min. Sodium-tert-butoxide (3.24 g, 33.7 mmol) was added and the mixture was purged with nitrogen for an additional 5 min. The reaction mixture was heated at 110 C. for 18 h, then cooled to rt, diluted with ethyl acetate (100 mL) and filtered. The reaction was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 90:10 ethyl acetate/methanol) to give N-(2-(1,3-dioxan-2-yl)-4-methoxyphenyl)-1-isopropylpiperidin-4-amine (4.5 g, 73%) as a thick viscous liquid: .sup.1H NMR (400 MHz, CDCl.sub.3) 6.90 (d, J=2.7 Hz, 1H), 6.79 (dd, J=8.6, 2.7 Hz, 1H), 6.66 (d, J=8.6 Hz, 1H), 5.41 (s, 1H), 4.54 (br s, 1H), 4.25 (dd, J=11.1, 4.9 Hz, 2H), 3.91-4.02 (m, 2H), 3.74 (s, 3H), 3.31 (br s, 1H), 2.83 (d, J=11.3 Hz, 2H), 2.74 (dt, J=12.9, 6.4 Hz, 1H), 2.31 (t, J=10.4 Hz, 2H), 2.13-2.26 (m, 1H), 2.09 (br s, 1H), 1.42-1.60 (m, 3H), 1.06 (d, J=6.6 Hz, 6H); ESI MS m/z 335 [M+H].sup.+.

(157) A solution of HCl (2.5 M, 15 mL, 37.5.0 mmol) was slowly added to a vigorously stirred solution of N-(2-(1,3-dioxan-2-yl)-4-methoxyphenyl)-1-isopropylpiperidin-4-amine (1.5 g, 4.5 mmol) in methanol (15 mL) cooled to 0 C. The resulting mixture was allowed to warm to rt and stirred for 2 h. The majority of methanol was removed under reduced pressure and the residue was diluted with water (30 mL). The pH of the aqueous phase was adjusted to approx. 10 using solid Na.sub.2CO.sub.3. The mixture was extracted with ethyl acetate (250 mL). The combined organics were washed with brine, dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure to give 2-((1-isopropylpiperidin-4-yl)amino)-5-methoxybenzaldehyde as a thick viscous gum (0.820 g, 65%): .sup.1H NMR (400 MHz, CDCl.sub.3) 9.78 (s, 1H), 8.14 (d, J=7.0 Hz, 1H), 7.06 (dd, J=9.2, 2.9 Hz, 1H), 7.0 (d, J=3.1 Hz, 1H), 6.69 (d, J=9.4 Hz, 1H), 3.79 (s, 3H), 3.44 (br s, 1H), 2.80-2.89 (m, 2H), 2.75 (br s, 1H), 2.35 (br s, 2H), 2.06 (br s, 2H), 1.62 (d, J=9.4 Hz, 2H), 1.07 (d, J=6.3 Hz, 6H); ESI MS m/z 277 [M+H].sup.+.

(158) A mixture of 2-((1-isopropylpiperidin-4-yl)amino)-5-methoxybenzaldehyde (0.8 g, 2.9 mmol), 2-amino-4,6-dimethoxybenzamide (0.57 g, 2.9 mmol), sodium bisulfite (58.5% SO.sub.2 content, 0.773 g, 4.5 mmol) and para-toluenosulfonic acid monohydrate (0.228 g, 1.2 mmol) in N,N-dimethylacetamide (15 mL) was stirred and heated at 120 C. for 20 h. After that time, the reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was diluted with water (20 mL) and the pH was adjusted to approx. 10 with aqueous Na.sub.2CO.sub.3 solution. The mixture was extracted with CH.sub.2Cl.sub.2 (340 mL) and the combined organics were concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 99:1 ethyl acetate/7N ammonia in methanol to 97:3 ethyl acetate/7N ammonia in methanol) followed by prep. HPLC to give 2-(2-((1-isopropylpiperidin-4-yl)amino)-5-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.043 g, 3%) as a yellow solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.53-8.63 (m, 1H), 8.20 (br s, 1H), 7.34 (br s, 1H), 6.95 (d, J=7.4 Hz, 1H), 6.77 (d, J=9.0 Hz, 1H), 6.60 (s, 1H), 6.53 (s, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.74 (s, 3H), 3.58-3.68 (m, 1H), 3.44 (br s, 1H), 2.73 (br s, 2H), 2.40 (br s, 2H), 1.93 (br s, 2H), 1.52 (br s, 2H), 0.95 (d, J=5.5 Hz, 6H); ESI MS m/z 453 [M+H].sup.+.

Example 27: 2-(3-((1-Isopropylpiperidin-4-yl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

(159) ##STR00041##

(160) A mixture of 3-bromobenzaldehyde (10.0 g, 54.1 mmol), propane-1,3-diol (4.93 g, 64.9 mmol) and para-toluenosulfonic acid monohydrate (0.10 g, 0.53 mmol) in anhydrous toluene (100 mL) was heated to reflux for 24 h with azeotropic removal of water using a Dean-Stark apparatus. After that time the reaction was cooled to rt, washed with 5% aqueous Na.sub.2CO.sub.3 solution (50 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 95:5 hexanes/ethyl acetate to 90:10 hexanes/ethyl acetate) to give 2-(3-bromophenyl)-1,3-dioxane (11.5 g, 87%) as a light brown oil: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.62-7.70 (m, 1H), 7.46 (ddd, J=8.1, 2.05, 1.2 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.15-7.27 (m, 1H), 5.46 (s, 1H), 4.24-4.29 (m, 2H), 3.98 (t of d, J=12.11, 2.74 Hz, 2H), 2.11-2.33 (m, 1H), 1.39-1.51 (m, 1H).

(161) A mixture of 2-(3-bromophenyl)-1,3-dioxane (5.0 g, 20.6 mmol), 1-isopropylpiperidin-4-amine (3) (4.39 g, 30.9 mmol), 2,2-bis(diphenylphosphino)-1,1-binaphthyl (1.28 g, 2.06 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.94 g, 1.03 mmol) in anhydrous toluene (60 mL) was purged with nitrogen for 15 min. Sodium-tert-butoxide (3.95 g, 41.1 mmol) was added and the mixture was purged with nitrogen for an additional 5 min. The reaction mixture was heated at 110 C. for 4 h, then cooled to rt, diluted with ethyl acetate (100 mL) and filtered. The reaction was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 98:2 dichloromethane/methanol to 95:5 dichloromethane/methanol) to give N-(3-(1,3-dioxan-2-yl)phenyl)-1-isopropylpiperidin-4-amine (4.43 g, 71%) as an off-white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.12-7.16 (m, 1H), 6.76 (d, J=7.4 Hz, 1H), 6.72 (d, J=1.95 Hz, 1H), 6.56 (dd, J=7.4, 1.95 Hz, 1H), 5.42 (s, 1H), 4.26 (dd, J=11.1, 4.6 Hz, 2H), 3.96-4.05 (m, 2H), 3.52-3.54 (m, 1H), 3.24-3.37 (m, 1H), 2.82-2.85 (m, 2H), 2.65-2.79 (m, 1H), 2.13-2.34 (m, 3H), 2.03-2.08 (m, 2H), 1.33-1.52 (m, 3H), 1.05 (d, J=6.6 Hz, 6H); ESI MS m/z 305 [M+H].sup.+.

(162) A solution of HCl (2N, 50 mL, 100 mmol) was added slowly to a vigorously stirred solution of N-(3-(1,3-dioxan-2-yl)phenyl)-1-isopropylpiperidin-4-amine (4.43 g, 14.6 mmol) in methanol (50 mL) cooled to 0 C. The resulting mixture was allowed to warm to rt and stirred for 17 h. The majority of methanol was removed under reduced pressure and the residue was diluted with water (30 mL). The pH of the aqueous phase was adjusted to approx. 10 using solid Na.sub.2CO.sub.3. The mixture was extracted with ethyl acetate (2150 mL). The combined organics were washed with brine, dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure. The product was triturated (50:50 diethyl ether/hexanes) to give 3-((1-isopropylpiperidin-4-yl)amino)benzaldehyde (0.90 g, 25%) as an off-white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) 9.92 (s, 1H), 7.30-7.39 (m, 1H), 7.21 (d, J=7.8 Hz, 1H), 7.05 (br s, 1H), 6.85-6.94 (m, 1H), 3.92-4.05 (m, 1H), 3.54-3.68 (m, 1H), 3.39-3.57 (m, 3H), 2.67-2.94 (m, 2H), 2.32-2.49 (m, 1H), 2.13-2.33 (m, 3H), 1.46 (d, J=6.6 Hz, 6H); ESI MS m/z 247 [M+H].sup.+.

(163) A mixture of 3-((1-isopropylpiperidin-4-yl)amino)benzaldehyde (0.450 g, 1.83 mmol), 2-amino-4,6-dimethoxybenzamide (0.287 g, 1.46 mmol), sodium bisulfite (58.5% SO.sub.2 content, 0.487 g, 2.74 mmol) and para-toluenosulfonic acid monohydrate (0.174 g, 0.91 mmol) in N,N-dimethylacetamide (15 mL) was stirred and heated at 120 C. for 17 h. After that time, the reaction mixture was cooled to rt and concentrated under reduced pressure. Water (50 mL) was added and the resulting suspension was stirred for 30 min at rt. The precipitated solid was collected by filtration, washed with water and air-dried. The product was purified by flash column chromatography (silica gel, 99:1 ethyl acetate/7N ammonia in methanol to 97:3 ethyl acetate/7N ammonia in methanol) to give 2-(3-((1-isopropylpiperidin-4-yl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.310 g, 50%) as a white solid: mp 239-341 C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.89 (br s, 1H), 7.24-7.36 (m, 2H), 7.09-7.23 (m, 1H), 6.76 (d, J=7.8 Hz, 1H), 6.70 (d, J=2.3 Hz, 1H), 6.53 (d, J=2.3 Hz, 1H), 5.70 (d, J=8.2 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.26-3.37 (m, 1H), 2.65-2.81 (m, 3H), 2.20-2.29 (m, 2H), 1.75-1.94 (m, 2H), 1.28-1.41 (m, 2H), 0.98 (d, J=6.6 Hz, 6H); ESI MS m/z 423 [M+H].sup.+.

Example 28: 5,7-Dimethoxy-2-(4-methoxy-2-[3-(piperazin-1-yl)propylamino]phenyl)quinazolin-4(3H)-one

(164) ##STR00042##

(165) Lithium bis(trimethylsilyl)amide (1 M in THF, 10.3 mL, 10.3 mmol) was added to a stirred suspension of 2-(2-fluoro-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.679 g, 2.06 mmol) and 1-tert-butoxycarbonyl-4-(3-aminopropyl)piperazine (0.957 g, 3.93 mmol) in anhydrous THF (20 mL). After the addition was complete, the reaction was heated to reflux with stirring for 24 h. After that time the reaction was cooled to rt, diluted with saturated aqueous NH.sub.4Cl (15 mL) and concentrated under reduced pressure. Saturated aqueous NaHCO.sub.3 (50 mL) was added and the mixture was extracted with chloroform (430 mL). The combined organic layers were dried (MgSO.sub.4) and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 98:2 chloroform/methanol) followed by recrystallization from chloroform/hexanes to give 5,7-dimethoxy-2-(4-methoxy-2-[3-(1-tert-butoxycarbonylpiperazin-4-yl)propylamino]phenyl)quinazolin-4(3H)-one (0.253 g, 22%) as a yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3) 9.50 (br s, 1H), 9.04 (br s, 1H), 7.54 (d, J=8.8 Hz, 1H), 6.60 (d, J=2.4 Hz, 1H), 6.41 (d, J=2.4 Hz, 1H), 6.30 (dd, J=8.8, 2.4 Hz, 1H), 6.23 (d, J=2.4 Hz, 1H), 3.98 (s, 3H), 3.92 (s, 3H), 3.86 (s, 3H), 3.44-3.42 (m, 4H), 3.33-3.29 (m, 2H), 2.56-2.53 (m, 2H), 2.41 (br s, 4H), 1.98-1.93 (m, 2H), 1.46 (s, 9H).

(166) A solution of 5,7-dimethoxy-2-(4-methoxy-2-[3-(1-tert-butoxycarbonylpiperazin-4-yl)propylamino]phenyl)quinazolin-4(3H)-one (0.253 g, 0.46 mmol) in chloroform (10 mL) was added dropwise to a solution of HCl (1.0 g, 27.4 mmol) in methanol (18 mL) cooled to 0 C. After the addition was complete, the reaction was allowed to warm to rt and stir for 1 h. After that time the reaction was concentrated under reduced pressure and the residue was triturated with chloroform (430 mL). The product was then neutralized with saturated aqueous NaHCO.sub.3 (20 mL) and extracted with chloroform (320 mL). The combined organic layers were dried (MgSO.sub.4) and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 90:10 chloroform/methanol) to give 5,7-dimethoxy-2-(4-methoxy-2-[3-(piperazin-1-yl)propylamino]phenyl)quinazolin-4(3H)-one (0.091 g, 44%) as a yellow solid: mp 225-228 C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.52 (d, J=9.2 Hz, 1H), 6.61 (d, J=2.0 Hz, 1H), 6.41 (d, J=2.4 Hz, 1H), 6.30 (dd, J=9.2, 2.0 Hz, 1H), 6.23 (d, J=2.0 Hz, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 3.86 (s, 3H), 3.31-3.28 (m, 2H), 2.91-2.88 (m, 4H), 2.55-2.46 (m, 6H), 1.99-1.92 (m, 2H); ESI MS m/z 454 [M+H].sup.+.

Example 29: 2-(2-((4,4-Dimethylcyclohexyl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

(167) ##STR00043##

(168) Lithium bis(trimethylsilyl)amide (1 M in THF, 6.0 mL, 6.0 mmol) was added to a stirred suspension of 2-(2-fluoro-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.661 g, 2 mmol) and 4,4-dimethylcyclohexan-1-amine (0.509 g, 4 mmol) in anhydrous THF (20 mL). After the addition was complete, the reaction was heated to reflux with stirring for 24 h. After that time the reaction was cooled to rt, diluted with saturated aqueous NH.sub.4Cl (5 mL) and concentrated under reduced pressure. The residue was diluted with water (50 mL) and the resulting suspension was stirred at rt for 30 min. The precipitated solid was collected by filtration, washed with water and air-dried. The product was purified by column chromatography (silica gel, 99:1 dichloromethane/methanol to 97:3 dichloromethane/methanol), followed by preparative HPLC to give 2-(2-((4,4-dimethylcyclohexyl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.060 g, 7%) as a light yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3) 9.23 (br s, 1H), 9.15 (br s, 1H), 7.45 (d, J=9.0 Hz, 1H), 6.65 (d, J=2.3 Hz, 1H), 6.41 (d, J=2.3 Hz, 1H), 6.22-6.29 (m, 2H), 3.98 (s, 3H), 3.91 (s, 3H), 3.85 (s, 3H), 3.41-3.50 (m, 1H), 1.88-1.98 (m, 2H), 1.48-1.67 (m, 4H), 1.29-1.39 (m, 2H), 0.99 (s, 3H), 0.98 (s, 3H); ESI MS m/z 438 [M+H].sup.+.

Example 30: 2-(3-((1-Isopropylpiperidin-4-yl)amino)-5-methoxypyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one

(169) ##STR00044##

(170) Lithium bis(trimethylsilyl)amide (1 M in THF, 1.0 mL, 1.0 mmol) was added to a stirred suspension of 2-(3-fluoro-5-methoxypyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.166 g, 0.50 mmol) and 1-isopropylpiperidin-4-amine (0.24 mL, 1.50 mmol) in anhydrous THF (5 mL). After the addition was complete, the reaction was heated to reflux with stirring for 1 h. After that time a second portion of lithium bis(trimethylsilyl)amide (1 M in THF, 1.0 mL, 1.0 mmol) was added and reflux with stirring was continued for an additional 5 h. After that time the reaction was cooled to rt, diluted with saturated aqueous NH.sub.4Cl (1 mL) and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 97:3 dichloromethane/methanol then 97:3 dichloromethane/7N ammonia in methanol) to give 2-(3-((1-isopropylpiperidin-4-yl)amino)-5-methoxypyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.070 g, 31%) as a yellow solid: mp 207-208 C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 10.71 (br s, 1H), 9.58 (d, J=7.8 Hz, 1H), 7.63 (d, J=2.3 Hz, 1H), 6.60 (d, J=2.3 Hz, 1H), 6.49 (d, J=2.3 Hz, 1H), 6.42 (d, J=2.3 Hz, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 3.90 (s, 3H), 3.40-3.52 (m, 1H), 2.86-2.97 (m, 2H), 2.78 (sept, J=6.6 Hz, 1H), 2.43 (t, J=10.55 Hz, 2H), 2.10-2.20 (m, 2H), 1.68-1.83 (m, 2H), 1.10 (d, J=6.6 Hz, 6H); ESI MS m/z 454 [M+H].sup.+.

Example 31: 2-(2-((trans-4-(2-Hydroxypropan-2-yl)cyclohexyl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

(171) ##STR00045##

(172) Lithium bis(trimethylsilyl)amide (1 M in THF, 7.2 mL, 7.2 mmol) was added to a stirred suspension of 2-(2-fluoro-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.400 g, 1.20 mmol) and 2-(trans-4-aminocyclohexyl)propan-2-ol (0.476 g, 3.03 mmol) in anhydrous THF (15 mL). After the addition was complete, the reaction was heated to reflux with stirring for 21 h. After that time the reaction was cooled to rt, diluted with saturated aqueous NH.sub.4Cl (6 mL) and concentrated under reduced pressure. The residue was diluted with water (30 mL) and the resulting suspension was stirred at rt for 30 min. The precipitated solid was collected by filtration, washed with water and air-dried. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol to 97:3 dichloromethane/methanol) followed by recrystallization from chloroform/hexanes to give 2-(2-((trans-4-(2-hydroxypropan-2-yl)cyclohexyl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.115 g, 20%) as a light yellow solid: mp: 253 C. dec.; .sup.1H NMR (400 MHz, CDCl.sub.3) 9.18 (br s, 1H), 9.14 (d, J=7.0 Hz, 1H), 7.46 (d, J=9.0 Hz, 1H), 6.58 (d, J=2.3 Hz, 1H), 6.41 (d, J=2.3 Hz, 1H), 6.22-6.30 (m, 2H), 3.98 (s, 3H), 3.93 (s, 3H), 3.85 (s, 3H), 3.25-3.33 (m, 1H), 2.29-2.37 (m, 2H), 1.93-1.99 (m, 2H), 1.24-1.46 (m, 6H), 1.23 (s, 6H); ESI MS m/z 468 [M+H].sup.+.

Example 32: 2-(3-((1-Isobutyrylpiperidin-4-yl)amino)-5-methoxypyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one

(173) ##STR00046##

(174) Lithium bis(trimethylsilyl)amide (1 M in THF, 2.4 mL, 2.4 mmol) was added to a stirred suspension of 2-(3-fluoro-5-methoxypyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.155 g, 0.468 mmol) and 1-(4-aminopiperidin-1-yl)-2-methylpropan-1-one hydrochloride (0.290 g, 1.40 mmol) in anhydrous THF (5 mL). After the addition was complete, the reaction was heated to reflux with stirring for 1 h. After that time a second portion of lithium bis(trimethylsilyl)amide (1 M in THF, 0.9 mL, 0.9 mmol) was added and reflux with stirring was continued for an additional 5 h. After that time the reaction was cooled to rt, diluted with saturated aqueous NH.sub.4Cl (1 mL) and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, dichloromethane to 98:2 dichloromethane/methanol) followed by trituration with diethyl ether to give 2-(3-((1-isobutyrylpiperidin-4-yl)amino)-5-methoxypyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.061 g, 27%) as a light yellow solid: mp 192-193 C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 10.69 (s, 1H), 9.69 (d, J=7.0 Hz, 1H), 7.66 (d, J=2.3 Hz, 1H), 6.54 (d, J=2.3 Hz, 1H), 6.50 (d, J=2.3 Hz, 1H), 6.43 (d, J=1.95 Hz, 1H), 4.23-4.34 (m, 1H), 3.98 (s, 3H), 3.93 (s, 3H), 3.92 (s, 3H), 3.83-3.91 (m, 1H), 3.67-3.75 (m, 1H), 3.32-3.46 (m, 2H), 2.86 (sept, J=6.6 Hz, 1H), 2.06-2.21 (m, 2H), 1.59-1.79 (m, 2H), 1.16 (d, J=6.6 Hz, 6H); ESI MS m/z 482 [M+H].sup.+.

Example 33: 2-(4-Chloro-2-((1-isopropylpiperidin-4-yl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

(175) ##STR00047##

(176) To a solution of 2-amino-4,6-dimethoxybenzamide (3.30 g, 17.0 mmol) and 4-chloro-2-fluorobenzaldehyde (3.0 g, 18.9 mmol) in N,N-dimethylacetamide (50 mL) was added NaHSO.sub.3 (58.5% SO.sub.2 content, 5.05 g, 28.4 mmol) and para-toluenosulfonic acid monohydrate (0.72 g, 3.8 mmol). The resulting mixture was heated at 120 C. for 17 h. After that time the reaction was cooled to rt, concentrated under reduced pressure, and diluted with water (100 mL). The resulting suspension was stirred for 30 min at rt and the precipitated yellow solids were collected by filtration, washed with water and air-dried. The product was purified by trituration (90:10 diethyl ether/methanol, 100 mL) to give 2-(4-chloro-2-fluorophenyl)-5,7-dimethoxyquinazolin-4(3H)-one (2.36 g, 43%) as an off-white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.15 (s, 1H), 7.77-7.79 (m, 1H), 7.65 (dd, J=10.2, 1.6 Hz, 1H), 7.45 (dd, J=8.2, 1.6 Hz, 1H), 6.75 (d, J=2.15 Hz, 1H), 6.59 (d, J=2.15 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H); ESI MS m/z 335 [M+H].sup.+.

(177) Lithium bis(trimethylsilyl)amide (1 M in THF, 12.0 mL, 12.0 mmol) was added to a stirred suspension of 2-(4-chloro-2-fluorophenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.650 g, 1.94 mmol) and 1-isopropylpiperidin-4-amine (0.854 g, 6.0 mmol) in anhydrous THF (20 mL). After the addition was complete, the reaction was heated to reflux with stirring for 6 h. After that time the reaction was cooled to rt, diluted with saturated aqueous NH.sub.4Cl (10 mL) and concentrated under reduced pressure. The residue was diluted with water (50 mL) and the resulting suspension was stirred at rt for 30 min. The precipitated solid was collected by filtration, washed with water and air-dried. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/7N ammonia in methanol to 97:3 dichloromethane/7N ammonia in methanol) to give 2-(4-chloro-2-((1-isopropylpiperidin-4-yl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.200 g, 22%) as a yellow solid: mp 265 C. dec.; .sup.1H NMR (400 MHz, CDCl.sub.3) 9.99 (br s, 1H), 9.23 (d, J=7.4 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 6.74 (d, J=1.8 Hz, 1H), 6.66 (dd, J=8.6, 1.8 Hz, 1H), 6.62 (d, J=2.15 Hz, 1H), 6.45 (d, J=2.15 Hz, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.41-3.47 (m, 1H), 2.86-2.94 (m, 2H), 2.72-2.81 (m, 1H), 2.35-2.46 (m, 2H), 2.11-2.19 (m, 2H), 1.61-1.75 (m, 2H), 1.08 (d, J=6.6 Hz, 6H); ESI MS m/z 457 and 459 [M+H].sup.+.

Example 34: 2-(4-Chloro-2-((1-isobutyrylpiperidin-4-yl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

(178) ##STR00048##

(179) Lithium bis(trimethylsilyl)amide (1 M in THF, 16.0 mL, 16.0 mmol) was added to a stirred suspension of 2-(4-chloro-2-fluorophenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.660 g, 1.97 mmol) and 1-(4-aminopiperidin-1-yl)-2-methylpropan-1-one hydrochloride (1.22 g, 5.92 mmol) in anhydrous THF (20 mL). After the addition was complete, the reaction was heated to reflux with stirring for 6 h. After that time the reaction was cooled to rt, diluted with saturated aqueous NH.sub.4Cl (10 mL) and concentrated under reduced pressure. The residue was diluted with water (50 mL) and the resulting suspension was stirred at rt for 30 min. The precipitated solid was collected by filtration, washed with water and air-dried. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol to 97:3 dichloromethane/methanol) to give 2-(4-chloro-2-((1-isobutyrylpiperidin-4-yl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.250 g, 26%) as a yellow solid: mp 281-283 C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 10.70 (br s, 1H), 9.33 (d, J=7.0 Hz, 1H), 7.75 (d, J=8.2 Hz, 1H), 6.75 (d, J=1.95 Hz, 1H), 6.72 (dd, J=8.2, 1.95 Hz, 1H), 6.56 (d, J=2.15 Hz, 1H), 6.46 (d, J=2.15 Hz, 1H), 4.28-4.36 (m, 1H), 3.99 (s, 3H), 3.95 (m, 3H), 3.82-3.95 (m, 1H), 3.65-3.77 (m, 1H), 3.22-3.42 (m, 2H), 2.81-2.89 (m, 1H), 2.11-2.19 (m, 2H), 1.54-1.67 (m, 2H), 1.15 (d, J=6.7 Hz, 6H); ESI MS m/z 485 and 487 [M+H].sup.+.

Example 35: 2-(2-((1-Benzylpiperidin-4-yl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

(180) ##STR00049##

(181) Lithium bis(trimethylsilyl)amide (1 M in THF, 18 mL, 18 mmol) was added to a stirred suspension of 2-(2-fluoro-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (2.0 g, 6.0 mmol) and 1-benzylpiperidin-4-amine (2.28 g, 12.0 mmol) in anhydrous THF (100 mL). After the addition was complete, the reaction was heated to reflux with stirring for 72 h. After that time the reaction was cooled to rt, diluted with ice cold water (100 mL) and concentrated under reduced pressure. The resulting solids were collected by filtration, washed with water and dried. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol to 90:10 dichloromethane/methanol) to give 2-(2-((1-benzylpiperidin-4-yl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.9 g, 30%) as a yellow solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.50 (s, 1H), 9.50 (d, J=6.6 Hz, 1H), 7.82 (d, J=9.0 Hz, 1H), 7.27-7.36 (m, 5H), 6.59 (s, 1H), 6.51 (s, 1H), 6.21 (br s, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.78 (s, 3H), 3.52-3.61 (m, 2H), 3.49 (s, 2H), 2.60-2.72 (m, 2H), 2.40 (br s, 2H), 1.93-2.05 (m, 2H), 1.51-1.66 (m, 2H); ESI MS m/z 501 [M+H].sup.+.

Example 36: 2-(-((1-Isobutyrylpiperidin-4-yl)amino)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one

(182) ##STR00050##

(183) Lithium bis(trimethylsilyl)amide (1 M in THF, 8 mL, 8 mmol) was added to a stirred suspension of 2-(3-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.390 g, 1.30 mmol) and 1-(4-aminopiperidin-1-yl)-2-methylpropan-1-one (0.828 g, 4.0 mmol) in anhydrous THF (15 mL). After the addition was complete, the reaction was heated to reflux with stirring for 1 h. After that time a second portion of lithium bis(trimethylsilyl)amide (1 M in THF, 4.0 mL, 4.0 mmol) was added and reflux with stirring was continued for an additional 18 h. After that time the reaction was cooled to rt, diluted with saturated aqueous NH.sub.4Cl (3.0 mL) and concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with dichloromethane (230 mL). The combined organic layers were dried (MgSO.sub.4) and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 90:10 ethyl acetate/methanol) followed by prep. HPLC to give 2-(-((1-isobutyrylpiperidin-4-yl)amino)pyridine-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.095 g, 16%) as a yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3) 10.92 (br s, 1H), 9.61 (d, J=6.6 Hz, 1H), 7.94 (d, J=3.5 Hz, 1H), 7.13 (d, J=8.6 Hz, 1H), 6.59 (d, J=2.0 Hz, 1H), 6.47 (s, 1H), 4.28-4.39 (m, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.88 (br s, 1H), 3.75 (br s, 1H), 3.26-3.45 (m, 2H), 2.86 (sept, 6.6 Hz, 1H), 2.14 (br s, 2H), 1.58-1.77 (m, 2H), 1.16 (d, J=6.6 Hz, 6H); ESI MS m/z 452 [M+H].sup.+.

Example 37: 2-(3-((1-Acetylpiperidin-4-yl)amino)pyridine-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one

(184) ##STR00051##

(185) A mixture of 2-(3-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.150 g, 0.5 mmol), 1-(4-aminopiperidin-1-yl)ethanone (0.142 g, 1.0 mmol) and K.sub.2CO.sub.3 (0.207 g, 1.5 mmol) in DMF (5.0 mL) was heated to 110 C. with stirring for 48 h. After that time the reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was dissolved in CH.sub.2Cl.sub.2 (20 mL), washed with water (10 mL) then brine (10 mL), dried (MgSO.sub.4) and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 90:10 ethyl acetate/methanol) to give 2-(3-((1-acetylpiperidin-4-yl)amino)pyridine-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.020 g, 10%) as a yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3) 10.90 (br s, 1H), 9.59 (d, J=7.0 Hz, 1H), 7.87-7.98 (m, 1H), 7.20-7.32 (m, 1H), 7.11 (d, J=8.6 Hz, 1H), 6.57 (s, 1H), 6.46 (s, 1H), 4.26-4.36 (m, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.68-3.86 (m, 2H), 3.23-3.46 (m, 2H), 2.07-2.20 (m, 5H), 1.58-1.74 (m, 2H); ESI MS m/z 424 [M+H].sup.+.

Example 38: N-(cis-4-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-5-methoxypyridin-3-yl)amino)cyclohexyl)isobutyramide

(186) ##STR00052##

(187) A solution of 5-bromo-2-chloro-3-fluoropyridine (8.90 g, 42.3 mmol) in anhydrous toluene (100 mL) was cooled to 78 C. A solution of n-butyl lithium (2.5 M solution in hexanes, 18.6 mL, 46.5 mmol) was added dropwise over a period of 15 min. After the addition was complete, the reaction was stirred at 78 C. for an additional 5 min. After that time trimethyl borate (5.6 mL, 50.7 mmol) was added dropwise at 78 C. over a period of 5 min. After the addition was complete, the reaction was stirred at 78 C. for an additional 15 min, then allowed to warm to rt and stirred for 16 h. The reaction mixture was cooled to 0 C. and aqueous NaOH solution (8 M, 60 mL) was added, followed by hydrogen peroxide (30 wt %, 40 mL). The mixture was stirred at rt for 2 h, then cooled to 0 C. and saturated aqueous sodium thiosulfate solution was added carefully until clear solution was obtained (about 40 mL). The resulting mixture was neutralized to pH 7 using 1 N HCl and extracted with ethyl acetate (2200 mL). The combined organics were washed with water then brine, dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure to give 6-chloro-5-fluoropyridin-3-ol (5.61 g, 90%) as a brown solid: .sup.1H NMR (DMSO-d.sub.6) 10.79 (s, 1H), 7.86 (d, J=2.5 Hz, 1H), 7.33 (dd, J=10.2, 2.5 Hz, 1H).

(188) A suspension of 6-chloro-5-fluoropyridin-3-ol (5.50 g, 37.2 mmol), methyl iodide (4.64 mL, 74.5 mmol) and potassium carbonate (10.3 g, 74.5 mmol) in acetone (300 mL) was heated to reflux with stirring for 16 h. After that time the reaction was cooled to rt and partitioned between water and ethyl acetate. The organic phase was separated, washed with water and brine, dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure to give 2-chloro-3-fluoro-5-methoxypyridine (5.05 g, 84%) as a brown oil: .sup.1H NMR (CDCl.sub.3) 7.94 (d, J=2.7 Hz, 1H), 7.07 (dd, J=9.4, 2.7 Hz, 1H), 3.88 (s, 3H).

(189) A solution of 2-chloro-3-fluoro-5-methoxypyridine (5.05 g, 31.2 mmol), triethylamine (13.0 mL, 93.6 mmol) and Pd(dppf)Cl.sub.2 (1.14 g, 1.56 mmol) in methanol (150 mL) was purged with carbon monoxide three times and then heated in an autoclave with stirring at 110 C. for 6 h under a carbon monoxide atmosphere (200 psi). After that time, the mixture was cooled to rt, filtered through a pad of Celite and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 50:50 ethyl acetate/hexanes) to give methyl 3-fluoro-5-methoxypicolinate (4.52 g, 78%) as a white solid: .sup.1H NMR (CDCl.sub.3) 8.26 (d, J=2.3 Hz, 1H), 7.01 (dd, J=11.7, 2.3 Hz, 1H), 3.99 (s, 3H), 3.94 (s, 3H); ESI MS m/z 186 [M+H].sup.+.

(190) A solution of 3-fluoro-5-methoxypicolinate (2.00 g, 10.8 mmol) in a mixture of anhydrous toluene (30 mL) and THF (25 mL) was cooled to 78 C. A solution of DIBAL-H (1.0 M in toluene, 32.4 mL, 32.4 mmol) was added dropwise at 70 OC over a period of 30 min and the resulting mixture was stirred at 70 OC for 30 min. The reaction was then allowed to warm to 5 C. over a period of 2 h and stirred at 5 OC for an additional 1 h. The mixture was cooled to 70 C. and isopropanol (10 mL) was carefully added followed by water (10 mL). The mixture was stirred at rt for 16 h and filtered through a pad of Celite. The solids were washed with CH.sub.2Cl.sub.2 and then ethyl acetate. The combined filtrates were concentrated under reduced pressure to give (3-fluoro-5-methoxypyridin-2-yl)methanol (1.68 g, 99%) as an off-white solid: .sup.1H NMR (CDCl.sub.3) 8.11 (s, 1H), 6.98 (dd, J=10.5, 2.3 Hz, 1H), 4.76 (d, J=5.3 Hz, 2H), 3.88 (s, 3H), 3.61 (t, J=5.3 Hz, 1H); ESI MS m/z 158 [M+H].sup.+.

(191) A solution of (3-fluoro-5-methoxypyridin-2-yl)methanol (1.85 g, 11.8 mmol) and IBX (3.30 g, 11.8 mmol) in DMSO (20 mL) was stirred at rt for 2 h. After that time water (100 mL) was added and the precipitated solid was collected by filtration. The solid was washed with ethyl acetate (200 mL) and the filtrate was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to give 3-fluoro-5-methoxypicolinaldehyde (1.66 g, 91%) as a pale yellow solid: .sup.1H NMR (CDCl.sub.3) 10.12 (s, 1H), 8.32 (d, J=1.6 Hz, 1H), 7.01 (dd, J=11.7, 2.3 Hz, 1H), 3.97 (s, 3H).

(192) A solution of 3-fluoro-5-methoxypicolinaldehyde (1.57 g, 10.1 mmol), 2-amino-4,6-dimethoxybenzamide (1.99 g, 10.1 mmol), NaHSO.sub.3 (58.5 wt %, 2.75 g, 15.2 mmol) and p-toluenesulfonic acid monohydrate (0.39 g, 2.02 mmol) in N,N-dimethyl acetamide (30 mL) was stirred at 120 C. for 16 h. After that time the reaction was cooled to rt and concentrated under reduced pressure. Water was added and the precipitated solid was collected by filtration, washed with water, then diethyl ether and dried under reduced pressure. The product was purified by flash column chromatography (silica gel, 97:3 dichloromethane/methanol) followed by trituration (50:50 diethyl ether/ethyl acetate, 50 mL) to give 2-(3-fluoro-5-methoxypyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.51 g, 15%) as a yellow solid: .sup.1H NMR (CDCl.sub.3) 10.42 (br s, 1H), 8.22 (d, J=2.3 Hz, 1H), 7.12 (dd, J=12.1, 2.3 Hz, 1H), 6.85 (d, J=2.3 Hz, 1H), 6.50 (d, J=2.3 Hz, 1H), 3.99 (s, 3H), 3.97 (s, 3H), 3.94 (s, 3H); ESI MS m/z 332 [M+H].sup.+.

(193) Isobutyryl chloride (0.945 g, 8.87 mmol) was added dropwise to a vigorously stirred solution of tert-butyl (cis-4-aminocyclohexyl)carbamate (2.0 g, 9.33 mmol) and N,N-diisopropylethylamine (2.41 g, 18.66 mmol) in anhydrous dichloromethane (20 mL) at 0 C. After the addition was complete, the reaction mixture was allowed to warm to rt, stirred for 17 h and then diluted with ethyl acetate (300 mL). The organic phase was washed with 0.5M citric acid solution (50 mL), followed by saturated NaHCO.sub.3 solution (50 mL) and brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to give tert-butyl (cis-4-isobutyramidocyclohexyl)carbamate (2.5 g, 98%) as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) 5.30-5.45 (m, 1H), 4.48-4.60 (m, 1H), 3.83-3.94 (m, 1H), 3.56-3.69 (m, 1H), 2.23-2.39 (m, 1H), 1.68-1.82 (m, 4H), 1.46-1.62 (m, 4H), 1.45 (s, 9H), 1.15 (d, J=7.0 Hz, 6H); ESI MS m/z 285 [M+H].sup.+.

(194) Concentrated HCl (37%, 3.4 mL, 41 mmol) was added slowly to a stirred mixture of tert-butyl (cis-4-isobutyramidocyclohexyl)carbamate (2.33 g, 8.19 mmol) in methanol (50 mL) at 0 C. The reaction mixture was allowed to warm to rt and stirred for 17 h. After that time the reaction was concentrated under reduced pressure to give N-(cis-4-aminocyclohexyl)isobutyramide hydrochloride (1.83 g, >99%) as a white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.15 (br s, 3H), 7.57 (d, J=5.5 Hz, 1H), 3.63 (br s, 1H), 2.95-3.11 (m, 1H), 2.40-2.50 (m, 1H), 1.59-1.81 (m, 6H), 1.42-1.58 (m, 2H), 0.98 (d, J=6.6 Hz, 6H).

(195) Lithium bis(trimethylsilyl)amide (1 M in THF, 12.1 mL, 12.1 mmol) was added to a stirred suspension of 2-(3-fluoro-5-methoxypyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.402 g, 1.21 mmol) and N-(cis-4-aminocyclohexyl)isobutyramide hydrochloride (0.803 g, 3.64 mmol) in anhydrous THF (20 mL). After the addition was complete, the reaction was heated to reflux with stirring for 5 h. After that time the reaction was cooled to rt, diluted with saturated aqueous NH.sub.4Cl (10 mL) and concentrated under reduced pressure. The residue was diluted with water (50 mL) and the resulting suspension was stirred at rt for 30 min. The precipitated solid was collected by filtration, washed with water and air-dried. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol to 97:3 dichloromethane/methanol) to give N-(cis-4-((2-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-5-methoxypyridin-3-yl)amino)cyclohexyl)isobutyramide (0.160 g, 27%) as a yellow solid: mp 285 C. dec.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.56 (s, 1H), 9.72 (d, J=7.4 Hz, 1H), 7.74 (d, J=7.4 Hz, 1H), 7.64 (d, J=1.95 Hz, 1H), 6.72 (d, J=1.6 Hz, 1H), 6.66 (d, J=1.95 Hz, 1H), 6.55 (d, J=1.6 Hz, 1H), 3.89 (s, 6H), 3.78-3.86 (m, 4H), 3.62-3.74 (m, 1H), 2.28-2.42 (m, 1H), 1.83-1.93 (m, 2H), 1.71-1.81 (m, 4H), 1.51-1.66 (m, 2H), 0.97 (d, J=6.6 Hz, 6H); ESI MS m/z 494 [MH].sup..

Example 39: 2-(2-((1-Acetylpiperidin-4-yl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

(196) ##STR00053##

(197) A mixture of 2-(2-((1-benzylpiperidin-4-yl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (3.9 g, mmol) and Pd/C (6 g, 10% Pd, wet) in THF (25 mL) and ethanol (25 mL) was hydrogenated at rt under hydrogen pressure (50 psi) for 18 h. After that time, the mixture was filtered through celite and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol to 90:10 dichloromethane/methanol) to give 5,7-dimethoxy-2-(4-methoxy-2-(piperidin-4-ylamino)phenyl)quinazolin-4(3H)-one (0.55 g, 17%): .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.57 (br s, 1H), 7.83 (d, J=9.0 Hz, 1H), 6.52 (d, J=9.0 Hz, 2H), 6.16-6.25 (m, 2H), 3.89 (s, 3H), 3.85 (s, 3H), 3.78 (s, 3H), 3.52-3.64 (m, 1H), 3.40-3.45 (m, 1H), 2.91-3.00 (m, 2H), 2.61-2.71 (m, 2H), 1.89-2.00 (m, 2H), 1.35-1.49 (m, 2H).

(198) Acetic anhydride (0.0248 g) was added at 0 C. to a solution of 5,7-dimethoxy-2-(4-methoxy-2-(piperidin-4-ylamino)phenyl)quinazolin-4(3H)-one (0.100 g, 0.24 mmol) and triethylamine (0.243 g, 2.4 mmol) in dichloromethane (25 mL). The reaction was allowed to warm to rt and then stirred for 30 min. After that time the reaction was concentrated under reduced pressure and the product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol to 90:10 dichloromethane/methanol) to give 2-(2-((1-acetylpiperidin-4-yl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.10 g, 92%) as white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.51 (s, 1H), 9.50 (d, J=7.4 Hz, 1H), 7.83 (d, J=8.6 Hz, 1H), 6.47-6.56 (m, 2H), 6.30 (s, 1H), 6.18-6.26 (m, 1H), 3.94-4.06 (m, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.80 (s, 3H), 3.65-3.77 (m, 2H), 3.37-3.45 (m, 1H), 3.09-3.21 (m, 1H), 2.02 (s, 3H), 1.93-1.99 (m, 2H), 1.34-1.47 (m, 1H), 1.48-1.62 (m, 1H); ESI MS m/z 453 [M+H].sup.+.

Example 40: 5,7-Dimethoxy-2-(5-methoxy-3-((1-methylpiperidin-4-yl)amino)pyridin-2-yl)quinazolin-4(3H)-one

(199) ##STR00054##

(200) Lithium bis(trimethylsilyl)amide (1 M in THF, 6.0 mL, 6.0 mmol) was added to a stirred suspension of 2-(3-fluoro-5-methoxypyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.331 g, 1.0 mmol) and 1-methylpiperidin-4-amine (0.343 g, 3.0 mmol) in anhydrous THF (20 mL). After the addition was complete, the reaction was heated to reflux with stirring for 5 h. After that time the reaction was cooled to rt, diluted with saturated aqueous NH.sub.4Cl (10 mL) and concentrated under reduced pressure. The residue was diluted with water (40 mL) and the resulting suspension was stirred at rt for 20 min. The precipitated solid was collected by filtration, washed with water and air-dried. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/7N ammonia in methanol to 98:2 dichloromethane/7N ammonia in methanol) followed by trituration with methanol to give 5,7-dimethoxy-2-(5-methoxy-3-((1-methylpiperidin-4-yl)amino)pyridin-2-yl)quinazolin-4(3H)-one (0.080 g, 19%) as an off-white solid: mp 191-193 C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.55 (s, 1H), 9.55 (d, J=7.0 Hz, 1H), 7.65 (d, J=2.3 Hz, 1H), 6.76 (d, J=2.3 Hz, 1H), 6.66 (d, J=2.15 Hz, 1H), 6.55 (d, J=2.15 Hz, 1H), 3.91 (s, 3H), 3.90 (s, 3H), 3.85 (s, 3H), 3.67-3.77 (m, 1H), 2.55-2.64 (m, 2H), 2.28-2.38 (m, 2H), 2.22 (s, 3H), 1.93-2.03 (m, 2H), 1.59-1.69 (m, 2H); ESI MS m/z 426 [M+H].sup.+.

Example 41: 5,7-Dimethoxy-2-(3-(((1-methylpyrrolidin-3-yl)methyl)amino)pyridin-2-yl)quinazolin-4(3H)-one

(201) ##STR00055##

(202) Lithium bis(trimethylsilyl)amide (1 M in THF, 5.6 mL, 5.6 mmol) was added to a stirred suspension of 2-(3-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.420 g, 1.39 mmol) and (1-methylpyrrolidin-3-yl)methanamine (0.478 g, 4.18 mmol) in anhydrous THF (20 mL). After the addition was complete, the reaction was heated to reflux with stirring for 3 h. After that time the reaction was cooled to rt, diluted with saturated aqueous NH.sub.4Cl (5 mL) and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/7N ammonia in methanol to 97:3 dichloromethane/7N ammonia in methanol) to give 5,7-dimethoxy-2-(3-(((1-methylpyrrolidin-3-yl)methyl)amino)pyridin-2-yl)quinazolin-4(3H)-one (0.160 g, 29%) as a yellow solid: mp 157-159 C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 10.90 (br s, 1H), 9.43 (br s, 1H), 7.89-7.93 (m, 1H), 7.22-7.29 (m, 1H), 7.10 (d, J=7.8 Hz, 1H), 6.65 (d, J=1.95 Hz, 1H), 6.46 (d, J=1.95 Hz, 1H), 3.98 (s, 3H), 3.93 (s, 3H), 3.25-3.30 (m, 2H), 2.76-2.83 (m, 1H), 2.54-2.75 (m, 3H), 2.49 (dd, J=8.8, 5.3 Hz, 1H), 2.39 (s, 3H), 2.12-2.23 (m, 1H), 1.65-1.75 (m, 1H); ESI MS m/z 396 [M+H].sup.+.

Example 42: 4-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)-N,N-dimethylpiperidine-1-carboxamide

(203) ##STR00056##

(204) Lithium bis(trimethylsilyl)amide (1 M in THF, 3.5 mL, 3.5 mmol) was added to a stirred suspension of 2-(3-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.352 g, 1.17 mmol) and 4-amino-N,N-dimethylpiperidine-1-carboxamide (0.500 g, 2.92 mmol) in anhydrous THF (20 mL). After the addition was complete, the reaction was heated to reflux with stirring for 6 h. After that time the reaction was cooled to rt, diluted with saturated aqueous NH.sub.4Cl (5 mL) and concentrated under reduced pressure. The residue was diluted with water (30 mL) and the resulting suspension was stirred at rt for 30 min. The precipitated solid was collected by filtration, washed with water and air-dried. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol to 97:3 dichloromethane/methanol) to give 4-((2-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)-N,N-dimethylpiperidine-1-carboxamide (0.180 g, 34%) as a yellow solid: mp 195-197 C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 10.91 (br s, 1H), 9.59 (d, J=7.4 Hz, 1H), 7.90-7.94 (m, 1H), 7.24-7.27 (m, 1H), 7.12 (d, J=8.2 Hz, 1H), 6.65 (d, J=2.15 Hz, 1H), 6.46 (d, J=2.15 Hz, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 3.61-3.71 (m, 3H), 3.09-3.18 (m, 2H), 2.86 (s, 6H), 2.08-2.17 (m, 2H), 1.65-1.76 (m, 2H); ESI MS m/z 453 [M+H].sup.+.

Example 43: 2-(3-((3-(Isopropylamino)propyl)amino)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one

(205) ##STR00057##

(206) Lithium bis(trimethylsilyl)amide (1 M in THF, 3.6 mL, 3.6 mmol) was added to a stirred suspension of 2-(3-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.361 g, 1.20 mmol) and N.sup.1-isopropylpropane-1,3-diamine (0.50 mL, 3.60 mmol) in anhydrous THF (20 mL). After the addition was complete, the reaction was heated to reflux with stirring for 2 h. After that time a second portion of lithium bis(trimethylsilyl)amide (1 M in THF, 1.2 mL, 1.2 mmol) was added and reflux with stirring was continued for an additional 2 h. After that time the reaction was cooled to rt, diluted with saturated aqueous NH.sub.4Cl (3 mL) and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 97:3 dichloromethane/methanol then 97:3 dichloromethane/7N ammonia in methanol) to give 2-(3-((3-(isopropylamino)propyl)amino)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.229 g, 48%) as a yellow solid: mp 121-122 C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 9.32 (t, J=4.7 Hz, 1H), 7.90 (d, J=3.1 Hz, 1H), 7.21-7.27 (m, 1H), 7.12 (d, J=8.6 Hz, 1H), 6.65 (d, J=2.3 Hz, 1H), 6.45 (d, J=2.3 Hz, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.33-3.42 (m, 2H), 2.78-2.88 (m, 3H), 1.92-2.00 (m, 2H), 1.07 (d, J=6.25 Hz, 6H); ESI MS m/z 398 [M+H].sup.+.

Example 44: 5,7-Dimethoxy-2-(3-((1-methylpiperidin-4-yl)amino)pyridine-2-yl)quinazolin-4(3H)-one

(207) ##STR00058##

(208) Lithium bis(trimethylsilyl)amide (1 M in THF, 4.0 mL, 4.0 mmol) was added to a stirred suspension of 2-(3-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.350 g, 1.16 mmol) and 1-methylpiperidine-4-amine (0.400 g, 3.5 mmol) in anhydrous THF (15 mL). After the addition was complete, the reaction was heated to reflux with stirring for 1 h. After that time a second portion of lithium bis(trimethylsilyl)amide (1 M in THF, 3.0 mL, 3.0 mmol) was added and reflux with stirring was continued for an additional 18 h. After that time the reaction was cooled to rt, diluted with saturated aqueous NH.sub.4Cl (3 mL) and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 97:3 dichloromethane/methanol then 97:3 dichloromethane/7N ammonia in methanol) to give 5,7-dimethoxy-2-(3-((1-methylpiperidin-4-yl)amino)pyridine-2-yl)quinazolin-4(3H)-one (0.100 g, 22%) as a yellow solid: mp 186-188 C.; .sup.1H NMR (CDCl.sub.3) 10.91 (br s, 1H), 9.55 (d, J=7.4 Hz, 1H), 7.89 (d, J=4.3 Hz, 1H), 7.19-7.27 (m, 1H), 7.11 (d, J=8.2 Hz, 1H), 6.65 (s, 1H), 6.46 (s, 1H), 3.98 (s, 3H), 3.93 (s, 3H), 3.53 (br s, 1H), 2.83 (br s, 2H), 2.36 (s, 3H), 2.31 (br s, 2H), 2.08-2.18 (m, 2H), 1.70-1.82 (m, 2H); ESI MS m/z 396 [M+H].sup.+.

Example 45: cis-4-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-5-methoxypyridin-3-yl)amino)-N-isopropylcyclohexane-1-carboxamide

(209) ##STR00059##

(210) 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.10 g, 11.0 mmol) was added to a solution of cis-4[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid (2.43 g, 10 mmol) and hydroxybenzotriazole (1.44 g, 11.0 mmol) in DMF (30 mL) and the reaction was stirred at rt for 20 min. After that time, isopropylamine (4.2 mL, 50 mmol) was added and the reaction mixture was stirred at rt for 18 h. After that time the reaction was concentrated under reduced pressure and the residue dissolved in CHCl.sub.3 (80 mL). The organic phase was washed with aqueous saturated NaHCO.sub.3 (240 mL) then brine (240 mL), dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure to give tert-butyl-cis-(4-(isopropylcarbamoyl)cyclohexyl)carbamate (1.9 g, 67%) as an off-white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) 5.29 (br s, 1H), 4.76 (br s, 1H), 4.08 (dq, J=13.9, 6.7 Hz, 1H), 3.75 (br s, 1H), 2.04-2.14 (m, 1H), 1.72-1.81 (m, 2H), 1.65-1.72 (m, 4H), 1.54-1.65 (m, 2H), 1.44 (s, 9H), 1.14 (d, J=6.3 Hz, 6H).

(211) Conc. HCl (4.0 mL, 40 mmol) was added to a solution of tert-butyl-cis-(4-(isopropylcarbamoyl)cyclohexyl)carbamate (1.9 g, 6.7 mmol) in methanol (30 mL) and the reaction was stirred at rt for 18 h. After that time the reaction was concentrated under reduced pressure to give cis-4-amino-N-isopropylcyclohexane-1-carboxamide hydrochloride (1.4 g, 95%) as an off-white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.10 (br s, 3H), 7.62 (d, J=7.8 Hz, 1H), 3.80 (dq, J=13.6, 6.7 Hz, 1H), 3.09 (br s, 1H), 2.11-2.27 (m, 1H), 1.78-1.92 (m, 2H), 1.58-1.77 (m, 4H), 1.40-1.52 (m, 2H), 1.01 (d, J=6.6 Hz, 6H); ESI MS m/z 185 [M+H].sup.+.

(212) Lithium bis(trimethylsilyl)amide (1 M in THF, 6.0 mL, 6.0 mmol) was added to a stirred suspension of 2-(3-fluoro-5-methoxypyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.400 g, 1.2 mmol) and cis-4-amino-N-isopropylcyclohexanecarboxamide hydrochloride (1.10 g, 5.0 mmol) in anhydrous THF (15 mL). After the addition was complete, the reaction was heated to reflux with stirring for 1 h. After that time a second portion of lithium bis(trimethylsilyl)amide (1 M in THF, 3.3 mL, 3.3 mmol) was added and reflux with stirring was continued for an additional 5 h. After that time the reaction was cooled to rt, diluted with saturated aqueous NH.sub.4Cl (3 mL) and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 97:3 dichloromethane/methanol) then triturated with methanol to give cis-4-((2-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-5-methoxypyridin-3-yl)amino)-N-isopropylcyclohexane-1-carboxamide (0.025 g, 4%) as a light yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3) 10.72 (br s, 1H), 9.82 (d, J=7.8 Hz, 1H), 7.63 (s, 1H), 6.89 (s, 1H), 6.49 (s, 1H), 6.42 (s, 1H), 5.22 (d, J=7.0 Hz, 1H), 3.99-4.12 (m, 1H), 3.96 (s, 6H), 3.90 (s, 3H), 3.84 (br s, 1H), 3.49 (d, J=5.8 Hz, 1H), 2.14-2.24 (m, 1H), 1.92-2.09 (m, 4H), 1.81-1.91 (m, 2H), 1.64-1.78 (m, 2H), 1.08 (d, J=6.6 Hz, 6H); ESI MS m/z 496 [M+H].sup.+.

Example 46: 5,7-Dimethoxy-2-(3-((1-(2,2,2-trifluoroacetyl)piperidin-4-yl)amino)pyridin-2-yl)quinazolin-4(3H)-one

(213) ##STR00060##

(214) A suspension of 2-(3-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (1.0 g, 3.3 mmol), 1-benzylpiperidin-4-amine (1.25 g, 6.6 mmol), lithium bis(trimethylsilyl)amide (13.2 mL, 13.2 mmol,) and THF (25 mL) was heated at 70 C. in a sealed tube for 3 h. After this time, the reaction was cooled to rt, quenched with cold water (100 mL) and concentrated under reduced pressure. The precipitated solid was collected by filtration, washed with water and air-dried. The product was purified by flash column chromatography (silica gel, dichloromethane to 70:30 dichloromethane/methanol) to give 2-(3-((1-benzylpiperidin-4-yl)amino)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.92 g, 60%) as a yellow solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.80 (d, J=1.6 Hz, 1H), 9.34-9.47 (m, 1H), 7.93 (d, J=1.95 Hz, 1H), 7.37-7.43 (m, 2H), 7.29-7.37 (m, 4H), 7.21-7.28 (m, 1H), 6.73 (s, 1H), 6.61 (s, 1H), 3.94 (s, 3H), 3.87 (s, 3H), 3.59-3.73 (m, 1H), 3.51 (s, 2H), 2.61-2.77 (m, 2H), 2.26-2.40 (m, 2H), 1.88-2.08 (m, 2H), 1.56-1.72 (m, 2H); ESI MS m/z 472 [M+H].sup.+.

(215) A mixture of 2-(3-((1-benzylpiperidin-4-yl)amino)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.7 g, 1.5 mmol) and Pd/C (2.1 g, 10% Pd, wet) in THF (20 mL) and ethanol (10 mL) was hydrogenated at rt under hydrogen pressure (50 psi) for 18 h. After that time, the mixture was filtered through celite and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, dichloromethane to 70:30 dichloromethane/methanol) to give 5,7-dimethoxy-2-(3-(piperidin-4-ylamino)pyridin-2-yl)quinazolin-4(3H)-one (0.20 g, 35%) as a yellow solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.43 (d, J=7.4 Hz, 1H), 7.92 (s, 1H), 7.38 (s, 2H), 6.66 (s, 1H), 6.60 (s, 1H), 3.93 (s, 3H), 3.87 (s, 3H), 3.58-3.73 (m, 1H), 3.14-3.26 (m, 1H), 2.90-3.06 (m, 2H), 2.59-2.76 (m, 2H), 1.88-2.06 (m, 2H), 1.39-1.58 (m, 2H); ESI MS m/z 382.1 [M+H].sup.+.

(216) Trifluoroacetic anhydride (0.032 g, 0.15 mmol was added to a solution of 5,7-dimethoxy-2-(3-(piperidin-4-ylamino)pyridin-2-yl)quinazolin-4(3H)-one (0.070 g, 0.18 mmol) and triethylamine (0.182 g, 1.8 mmol) in THF (15 mL) at 0 C. The resulting mixture was allowed to warm to rt and stirred for 30 min. After that time the mixture was concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, dichloromethane to 70:30 dichloromethane/methanol) to give 5,7-dimethoxy-2-(3-((1-(2,2,2-trifluoroacetyl)piperidin-4-yl)amino)pyridin-2-yl)quinazolin-4(3H)-one (0.032 g, 39%) as a light yellow solid: mp 218-219 C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.79 (br s, 1H), 9.40 (d, J=7.4 Hz, 1H), 7.94 (d, J=3.5 Hz, 1H), 7.33-7.54 (m, 2H), 6.70 (s, 1H), 6.57 (s, 1H), 4.04-4.20 (m, 1H), 3.89 (s, 3H), 3.77-3.87 (m, 3H), 3.44-3.57 (m, 2H), 3.08-3.25 (m, 2H), 2.03-2.19 (m, 2H), 1.54-1.75 (m, 2H); ESI MS m/z 478 [M+H].sup.+.

Example 47: 4-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)-N-isopropylpiperidine-1-carboxamide

(217) ##STR00061##

(218) 2-Isocyanatopropane (0.016 g, 0.18 mmol) was added to a solution of 5,7-dimethoxy-2-(3-(piperidin-4-ylamino)pyridin-2-yl)quinazolin-4(3H)-one (0.070 g, 0.18 mmol) and triethylamine (0.182 g, 1.8 mmol) in THF (15 mL) at 0 C. The resulting mixture was allowed to warm to rt and stirred for 30 min. After that time the mixture was concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, dichloromethane to 70:30 dichloromethane/methanol) to give 4-((2-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)-N-isopropylpiperidine-1-carboxamide (0.060 g, 71%) as a light yellow solid: mp 198-199 C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.77 (br s, 1H), 9.39 (d, J=8.2 Hz, 1H), 7.92 (d, J=2.7 Hz, 1H), 7.32-7.50 (m, 2H), 6.64 (s, 1H), 6.57 (s, 1H), 6.21 (d, J=7.4 Hz, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.69-3.80 (m, 4H), 3.00-3.14 (m, 2H), 1.88-2.00 (m, 2H), 1.38-1.55 (m, 2H), 1.03 (d, J=6.3 Hz, 6H); ESI MS m/z 467 [M+H].sup.+.

Example 48: 5,7-Dimethoxy-2-(3-((1-pivaloylpiperidin-4-yl)amino)pyridin-2-yl)quinazolin-4(3H)-one

(219) ##STR00062##

(220) Pivaloyl chloride (0.016 g, 0.13 mmol) was added to a solution of 5,7-dimethoxy-2-(3-(piperidin-4-ylamino)pyridin-2-yl)quinazolin-4(3H)-one (0.050 g, 0.13 mmol) and triethylamine (0.131 g, 1.3 mmol) in THF (15 mL) at 0 C. The reaction was allowed to warm to rt and stirred for 30 min. After that time the mixture was concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, dichloromethane to 70:30 dichloromethane/methanol) to give 5,7-dimethoxy-2-(3-((1-pivaloylpiperidin-4-yl)amino)pyridin-2-yl)quinazolin-4(3H)-one (0.044 g, 72%) as a yellow solid: mp 209-210 C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.77 (br s, 1H), 9.43 (d, J=7.4 Hz, 1H), 7.92 (d, J=1.6 Hz, 1H), 7.35-7.48 (m, 2H), 6.64 (s, 1H), 6.57 (s, 1H), 3.95-4.07 (m, 2H), 3.88 (s, 3H), 3.84-3.87 (m, 1H), 3.84 (s, 3H), 3.24-3.27 (m, 2H), 1.93-2.07 (m, 2H), 1.43-1.56 (m, 2H), 1.19 (s, 9H); ESI MS m/z 466 [M+H].sup.+.

Example 49: 5,7-Dimethoxy-2-(3-((2-morpholinoethyl)amino)pyridine-2-yl)quinazolin-4(3H)-one

(221) ##STR00063##

(222) Lithium bis(trimethylsilyl)amide (1 M in THF, 5.0 mL, 5.0 mmol) was added to a stirred suspension of 2-(3-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.400 g, 1.33 mmol) and 2-(morpholin-4-yl)ethanamine (0.520 g, 4.0 mmol) in anhydrous THF (15 mL). After the addition was complete, the reaction was heated to reflux with stirring for 1 h. After that time a second portion of lithium bis(trimethylsilyl)amide (1 M in THF, 3.0 mL, 3.0 mmol) was added and reflux with stirring was continued for an additional 18 h. After that time the reaction was cooled to rt, diluted with saturated aqueous NH.sub.4Cl (3 mL) and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 97:3 dichloromethane/methanol) followed by recrystallization from chloroform/hexanes to give 5,7-dimethoxy-2-(3-((2-morpholinoethyl)amino)pyridine-2-yl)quinazolin-4(3H)-one (0.110 g, 20%) as a yellow solid: mp 168-170 C.; .sup.1H NMR (CDCl.sub.3) 10.91 (br s, 1H), 9.38 (br s, 1H), 7.93 (d, J=3.5 Hz, 1H), 7.29 (br s, 1H), 7.10 (d, J=8.2 Hz, 1H), 6.75 (s, 1H), 6.44-6.51 (m, 1H), 4.00 (s, 3H), 3.93 (s, 3H), 3.74-3.80 (m, 4H), 3.40 (q, J=5.6 Hz, 2H), 2.80 (t, J=6.0 Hz, 2H), 2.59 (br s, 4H); ESI MS m/z 412 [M+H].sup.+.

Example 50: 2-(3-((1-Isopropylpiperidin-4-yl)amino)-5-(2-((1-isopropylpiperidin-4-yl)amino)ethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one

(223) ##STR00064##

(224) Butyllithium (1.6 M in hexanes, 82 mL, 130 mmol) was added dropwise to a suspension of 3-bromo-6-chloro-5-fluoropyridine (25.0 g, 119 mmol) in anhydrous toluene (280 mL) cooled to 78 C. After the addition was complete the reaction was stirred for 10 min. After that time, trimethyl borate (14.82 g, 143 mmol) was added dropwise while maintaining the temperature at 78 C. After the addition was complete, the reaction was allowed to warm to rt and stirring was continued for 17 h. After that time the reaction was re-cooled to 5 C. and carefully treated with 8N NaOH solution (18 mL) followed by 30% hydrogen peroxide (37.6 g, 1105 mmol). The reaction was warmed to rt and stirred an additional 2 h. After that time the reaction was re-cooled to 10 C. and carefully quenched with sat. Na.sub.2S.sub.2O.sub.3 (60 mL). The organic phase was reserved. The aqueous phase was extracted with ethyl acetate (3150 mL). The combined organics were washed with sat. NaCl (200 mL), dried (MgSO.sub.4), filtered and concentrated under reduced pressure. This product was triturated with hexanes (3100 mL) and dried to give 6-chloro-5-fluoropyridin-3-ol (14.2 g, 80%) as a white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.78 (br s, 1H), 7.86 (d, J=2.4 Hz, 1H), 7.32 (dd, J=10.4, 2.4 Hz, 1H).

(225) A suspension of K.sub.2CO.sub.3 (19.8 g, 143 mmol), 6-chloro-5-fluoropyridin-3-ol (14.1 g, 95 mmol) and 2-tert-butyldimethylsilyloxyethyl bromide (25.1 g, 105 mmol) in anhydrous DMF (120 mL) was stirred at rt for 65 h. After that time the reaction mixture was diluted with ethyl acetate (200 mL), washed with water (4100 mL), dried (MgSO.sub.4) and concentrated under reduced pressure to give 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-chloro-3-fluoropyridine (26.3 g, 90%) as a yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.94 (d, J=2.6 Hz, 1H), 7.11 (dd, J=9.5, 2.6 Hz, 1H), 4.10 (t, J=4.8 Hz, 2H), 3.98 (t, J=4.8 Hz, 2H), 0.90 (s, 9H), 0.09 (s, 6H).

(226) A mixture of 5-[2-(tert-butyldimethylsilyloxy)ethoxy]-2-chloro-3-fluoropyridine (11.6 g, 38 mmol), Pd(dppf)Cl.sub.2 (1.39 g, 1.9 mmol) and triethylamine (11.5 g, 114 mmol) in methanol (200 mL) was placed under a CO atmosphere (200 psi) and heated with stirring at 90 C. for 4 h. After that time the reaction was cooled to rt, filtered through a pad of celite and concentrated under reduced pressure. The product was suspended in diethyl ether (600 mL), filtered through a pad of silica gel and concentrated under reduced pressure to give methyl 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-3-fluoropicolinate (11.6 g, 94%) as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.26 (d, J=2.4 Hz, 1H), 7.07 (dd, J=11.7, 2.4 Hz, 1H), 4.17 (t, J=4.4 Hz, 2H), 4.00 (t, J=4.4 Hz, 2H), 3.99 (s, 3H), 0.89 (s, 9H), 0.09 (s, 6H).

(227) Sodium borohydride (7.57 g, 200 mmol) was added portionwise to a suspension of methyl 5-[2-(tert-butyldimethylsilyloxy)ethoxy]-3-fluoropicolinate (16.47 g, 50 mmol) in ethanol (135 mL) cooled to 10 C. and stirred for 15 h. After that time the reaction was concentrated under reduced pressure and dissolved in ethyl acetate (300 mL). The solution was washed with water (2100 mL), sat. NaHCO.sub.3 (100 mL) and sat. NaCl (100 mL), dried (MgSO.sub.4) and concentrated under reduced pressure to give (5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-3-fluoropyridin-2-yl)methanol (14.91 g, 98%) as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.12 (d, J=2.4 Hz, 1H), 7.02 (dd, J=11.2, 2.4 Hz, 1H), 4.77-4.75 (m, 2H), 4.10 (t, J=4.8 Hz, 2H), 3.98 (t, J=4.8 Hz, 2H), 3.57 (t, J=4.8 Hz, 2H), 0.90 (s, 9H), 0.10 (s, 6H).

(228) 2-Iodoxybenzoic acid (18.0 g, 64 mmol) was added in one portion to a solution of (5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-3-fluoropyridin-2-yl)methanol (14.91 g, 50 mmol) in DMSO (82 mL) and stirred at rt for 18 h. After that time the reaction was diluted with water (500 mL). The precipitated solids were collected by filtration and washed with water (2200 mL) and air-dried. The solids were triturated with diethyl ether (3200 mL) to remove the product. The combined ether extracts were washed with sat. NaHCO.sub.3 (100 mL), sat. NaCl (100 mL), dried (MgSO.sub.4) and concentrated under reduced pressure to give 5-(2-(tert-butyldimethylsilyloxy)ethoxy)-3-fluoropicolinaldehyde (11.36 g, 77%) as a white crystalline solid: .sup.1H NMR (400 MHz, CDCl.sub.3) 10.12 (s, 1H), 8.32 (d, J=2.4 Hz, 1H), 7.07 (dd, J=11.8, 2.4 Hz, 1H), 4.20 (t, J=5.2 Hz, 2H), 4.02 (t, J=5.2 Hz, 2H), 0.90 (s, 9H), 0.09 (s, 6H).

(229) A suspension of 2-amino-4,6-dimethoxybenzamide (7.37 g, 37.9 mmol) and 5-(2-(tert-butyldimethylsilyloxy)ethoxy)-3-fluoropicolinaldehyde (11.36 g, 38 mmol) in nitrobenzene (77 mL) was heated to 137 C. with stirring for 24 h. After that time, the reaction was cooled to rt and diluted with hexanes (600 mL). The dark tar-like precipitate was separated and purified by flash column chromatography (silica gel, 85:15 dichloromethane/ethyl acetate) to give 2-[5-(2-(tert-butyldimethylsilyloxy) ethoxy)-3-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (4.26 g, 24%) as a yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3) 10.43 (s, 1H), 8.22 (d, J=2.4 Hz, 1H), 7.17 (dd, J=12.4, 2.4 Hz, 1H), 6.85 (d, J=2.4 Hz, 1H), 6.49 (d, J=2.4 Hz, 1H), 4.20 (t, J=4.8 Hz, 2H), 4.02 (t, J=4.8 Hz, 2H), 3.99 (s, 3H), 3.94 (s, 3H), 0.91 (s, 9H), 0.11 (s, 6H).

(230) Triethylamine trihydrofluoride (4.33 g, 26.9 mmol) was added in one portion to a suspension of 2-[5-(2-(tert-butyldimethylsilyloxy)ethoxy]-3-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (4.26 g, 8.96 mmol) in anhydrous THF (85 mL) and stirred at rt for 14 h. After that time the reaction was concentrated under reduced pressure and the solid was treated with saturated aqueous solution of NaHCO.sub.3 (100 mL). The precipitated solids were collected by filtration and washed with water (3100 mL), diethyl ether (3100 mL) and dried to give 2-3-fluoro-5-(2-hydroxyethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (3.15 g, 97%) as a yellow solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.37 (s, 1H), 8.29 (s, 1H), 7.63 (d, J=11.5 Hz, 1H), 6.70 (s, 1H), 6.56 (s, 1H), 4.99 (t, J=4.6 Hz, 1H), 4.18 (t, J=4.6 Hz, 2H), 3.87 (s, 3H), 3.83 (s, 3H), 3.74 (q, J=4.6 Hz, 2H).

(231) Phosphorus tribromide (4.72 g, 17.4 mmol) was added in one portion to a suspension of 2-(3-fluoro-5-(2-hydroxyethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (3.15 g, 8.7 mmol) in anhydrous DMF (66 mL) and heated at 60 C. with stirring for 1 h. After that time the reaction was cooled to rt and concentrated under reduced pressure. The solids were dissolved in chloroform (130 mL) and the solution was washed with sat. NaHCO.sub.3 (220 mL), dried (MgSO.sub.4) and concentrated under reduced pressure. The product was triturated with diethyl ether (330 mL) and dried to give 2-(3-fluoro-5-(2-bromoethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (3.41 g, 92%) as a yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3) 10.40 (s, 1H), 8.24 (d, J=2.4 Hz, 1H), 7.15 (dd, J=12.4, 2.4 Hz, 1H), 6.86 (d, J=2.4 Hz, 1H), 6.50 (d, J=2.4 Hz, 1H), 4.44 (t, J=5.6 Hz, 2H), 3.99 (s, 3H), 3.94 (s, 3H), 3.71 (t, J=5.6 Hz, 2H).

(232) 1-Isopropyl-4-aminopiperidine (0.711 g, 5 mmol) was added in one portion to a suspension of 2-(3-fluoro-5-(2-bromoethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.212 g, 0.5 mmol) in anhydrous DMSO (2 mL) and heated at 80 C. with stirring for 17 h. After that time the reaction was cooled to rt, diluted with chloroform (15 mL), washed with sat. NaHCO.sub.3 (20 mL), water (215 mL), dried (MgSO.sub.4) and concentrated under reduced pressure. The product was triturated (diethyl ether, 35 mL) and dried to give 2-(3-((1-isopropylpiperidin-4-yl)amino)-5-(2-((1-isopropylpiperidin-4-yl)amino)ethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.252 g, 83%) as a yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3) 9.57 (d, J=7.2 Hz, 1H), 7.62 (d, J=2.0 Hz, 1H), 6.60 (d, J=2.0 Hz, 1H), 6.50 (d, J=2.0 Hz, 1H), 6.41 (d, J=2.0 Hz, 1H), 4.16 (t, J=4.8 Hz, 2H), 3.97 (s, 3H), 3.93 (s, 3H), 3.44 (br s, 1H), 3.07 (t, J=4.8 Hz, 2H), 2.91-2.70 (m, 6H), 2.54-2.40 (m, 3H), 2.21-2.13 (m, 4H), 1.96-1.93 (m, 2H), 1.78-1.74 (m, 3H), 1.45-1.37 (m, 2H), 1.10 (d, J=6.4 Hz, 6H), 1.04 (d, J=6.4 Hz, 6H); ESI MS m/z 608 [M+H].sup.+.

Example 51: 2-(4-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)piperidin-1-yl)-N,N-dimethyl-2-oxoacetamide

(233) ##STR00065##

(234) N,N-dicyclohexylcarbodiimide (0.081 g, 0.39 mmol) was added at room temperature to a solution of 2-(dimethylamino)-2-oxoacetic acid (0.046 g, 0.39 mmol) in DMF (15 mL), followed by 1-hydroxy-1H-benzotriazole (0.053 g, 0.39 mmol). The reaction was stirred for 1 h and then 5,7-dimethoxy-2-(3-(piperidin-4-ylamino)pyridin-2-yl)quinazolin-4(3H)-one (0.050 g, 0.13 mmol) was added. The reaction was then stirred at rt for 16 h, concentrated under reduced pressure and the product was purified by flash column chromatography (silica gel, dichloromethane to 70:30 dichloromethane/methanol) to give 2-(4-((2-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)piperidin-1-yl)-N,N-dimethyl-2-oxoacetamide (0.015 g, 24%) as yellow solid: mp 261-262 C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.78 (br s, 1H), 9.41 (d, J=7.4 Hz, 1H), 7.95 (br s, 1H), 7.37-7.49 (m, 2H), 6.67 (s, 1H), 6.59 (s, 1H), 4.04-4.14 (m, 1H), 3.90 (s, 3H), 3.84 (s, 3H), 3.43-3.52 (m, 2H), 3.15-3.24 (m, 2H), 2.91 (s, 3H), 2.86 (s, 3H), 2.00-2.12 (m, 2H), 1.48-1.65 (m, 2H); ESI MS m/z 479 [MH].sup..

Example 52: 4-((2-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)-N-ethylpiperidine-1-carboxamide

(235) ##STR00066##

(236) Ethyl isocyanate (0.016 g, 0.18 mmol) was added to an ice-cold solution of 5,7-dimethoxy-2-(3-(piperidin-4-ylamino)pyridin-2-yl)quinazolin-4(3H)-one (0.070 g, 0.18 mmol) and triethylamine (0.182 g, 1.8 mmol) in THF (15 mL). The reaction was allowed to warm to rt and stirred for 30 min. After that time the reaction was concentrated under reduced pressure and the product was purified by flash column chromatography (silica gel, dichloromethane to 70:30 dichloromethane/methanol) to give 4-((2-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)-N-ethylpiperidine-1-carboxamide (0.060 g, 78%) as yellow solid: mp 151-152 C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.80 (br s, 1H), 9.42 (d, J=7.4 Hz, 1H), 7.95 (br s, 1H), 7.38-7.48 (m, 2H), 6.66 (s, 1H), 6.60 (s, 1H), 6.51-6.56 (m, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 3.73-3.82 (m, 3H), 3.00-3.16 (m, 4H), 1.91-2.02 (m, 2H), 1.43-1.57 (m, 2H), 1.01 (t, J=7.2 Hz, 3H); ESI MS m/z 453 [M+H].sup.+.

Example 53: cis-4-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)-N,N-dimethylcyclohexane-1-carboxamide

(237) ##STR00067##

(238) 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.10 g, 11.0 mmol) was added to a solution of cis-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid (2.43 g, 10 mmol) and hydroxybenzotriazole (1.436 g, 11.0 mmol) in DMF (30 mL). The reaction was stirred at rt for 20 min. After that time dimethylamine (2 M solution in THF, 25 mL, 50 mmol) was added and the reaction mixture was stirred at rt for 18 h. After that time the reaction was concentrated under reduced pressure and the residue was dissolved in chloroform (80 mL). The organics were washed with sat. NaHCO.sub.3 (240 mL), sat. NaCl (240 mL), dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure to give tert-butyl-cis-(4-(dimethylcarbamoyl)cyclohexyl)carbamate (2.2 g, 82%) as an off-white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) 4.82 (br s, 1H), 3.81 (br s, 1H), 3.04 (s, 3H), 2.94 (s, 3H), 2.52-2.63 (m, 1H), 1.74-1.86 (m, 2H), 1.64-1.77 (m, 2H), 1.51-1.64 (m, 4H), 1.44 (s, 9H).

(239) Concentrated hydrochloric acid (4.0 mL, 40 mmol) was added to a solution of tert-butyl-cis-(4-(dimethylcarbamoyl)cyclohexyl)carbamate (2.2 g, 6.7 mmol) in methanol (30 mL) and stirred at rt for 18 h. After this time the reaction was concentrated under reduced pressure and stirred to give cis-4-amino-N,N-dimethylcyclohexane-1-carboxamide hydrochloride (1.6 g, 95%) as an off-white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.08 (br s, 3H), 3.18 (br s, 1H), 2.99 (s, 3H), 2.80 (s, 3H), 2.73 (br s, 1H), 1.76-1.87 (m, 2H), 1.71 (dd, J=9.4, 4.3 Hz, 4H), 1.44-1.57 (m, 2H); ESI MS m/z 171 [M+H].sup.+.

(240) Lithium bis(trimethylsilyl)amide (1 M in THF, 8.0 mL, 8.0 mmol) was added to a stirred suspension of 2-(3-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.400 g, 1.33 mmol) and cis-4-amino-N,N-dimethylcyclohexane-1-carboxamide hydrochloride (0.826 g, 4.0 mmol) in anhydrous THF (15 mL). After the addition was complete, the reaction was heated to reflux with stirring for 1 h. After that time a second portion of lithium bis(trimethylsilyl)amide (1 M in THF, 4.0 mL, 4.0 mmol) was added and reflux with stirring was continued for an additional 15 h. After that time the reaction was cooled to rt, diluted with saturated aqueous NH.sub.4Cl (3 mL) and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 97:3 chloroform/methanol) followed by recrystallization from chloroform/hexanes to give cis-4-((2-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)-N,N-dimethylcyclohexane-1-carboxamide (0.075 g, 13%) as a light yellow solid: mp. 276-278 C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 10.93 (br s, 1H), 9.80 (d, J=8.2 Hz, 1H), 7.87 (d, J=3.5 Hz, 1H), 7.22 (dd, J=8.6, 3.9 Hz, 1H), 7.05-7.17 (m, 2H), 6.46 (s, 1H), 4.04 (s, 3H), 3.97 (s, 3H), 3.91 (br s, 1H), 3.08 (s, 3H), 2.92 (s, 3H), 2.60-2.72 (m, 1H), 1.96-2.18 (m, 4H), 1.65-1.83 (m, 4H); ESI MS m/z 452 [M+H].sup.+.

Example 54: 4-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)piperidine-1-carboxamide

(241) ##STR00068##

(242) Trimethylsilyl isocyanate (1.0 mL) was added to a solution of 5,7-dimethoxy-2-(3-(piperidin-4-ylamino)pyridin-2-yl)quinazolin-4(3H)-one (0.050 g, 0.13 mmol) and triethyl amine (1.0 mL) in THF (15 mL) cooled to 0 C. The reaction was allowed to warm to rt and stirred 16 h. After that time the reaction was concentrated under reduced pressure and the product was purified by flash column chromatography (silica gel, dichloromethane to 70:30 dichloromethane/methanol) to give 4-((2-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)piperidine-1-carboxamide (0.025 g, 45%) as yellow solid: mp 265-266 C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.75 (br s, 1H), 9.39 (d, J=7.4 Hz, 1H), 7.92 (br s, 1H), 7.35-7.45 (m, 2H), 6.63 (s, 1H), 6.57 (s, 1H), 5.97 (br s, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 3.67-3.80 (m, 3H), 3.03-3.16 (m, 2H), 1.87-2.01 (m, 2H), 1.40-1.54 (m, 2H); ESI MS m/z 425 [M+H].sup.+.

Example 55: Methyl-2-(4-((2-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)piperidin-1-yl)-2-oxoacetate

(243) ##STR00069##

(244) Methyl-2-chloro-2-oxoacetate (0.022 g, 0.183 mmol) was added to a solution of 5,7-dimethoxy-2-(3-(piperidin-4-ylamino)pyridin-2-yl)quinazolin-4(3H)-one (0.070 g, 0.183 mmol) and triethyl amine (0.182 g, 1.8 mmol) in THF (25 mL) cooled to 0 C. The reaction was allowed to warm to rt and stirred 30 min. After that time the reaction was concentrated under reduced pressure and the product was purified by flash column chromatography (silica gel, dichloromethane to 70:30 dichloromethane/methanol) to give methyl-2-(4-((2-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)piperidin-1-yl)-2-oxoacetate (0.044 g, 72%) as yellow solid: mp 165-166 C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.79 (s, 1H), 9.38 (d, J=7.8 Hz, 1H), 7.94 (dd, J=3.9, 1.1 Hz 1H), 7.37-7.48 (m, 2H), 6.69 (d, J=1.9 Hz, 1H), 6.57 (d, J=1.9 Hz, 1H), 4.01-4.11 (m, 1H), 3.90 (s, 3H), 3.84 (s, 3H), 3.80 (s, 3H), 3.51-3.62 (m, 1H), 3.14-3.25 (m, 2H), 1.99-2.11 (m, 2H), 1.48-1.66 (m, 2H); ESI MS m/z 466 [MH].sup..

Example 56: N-(2-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)ethyl)isobutyramide

(245) ##STR00070##

(246) Lithium bis(trimethylsilyl)amide (1 M in THF, 10.0 mL, 10.0 mmol) was added to a stirred suspension of 2-(3-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.300 g, 0.99 mmol) and N-(2-aminoethyl)isobutyramide hydrochloride (0.498 g, 2.99 mmol in anhydrous THF (20 mL). After the addition was complete, the reaction was heated to reflux with stirring for 17 h. After that time the reaction was cooled to rt, diluted with saturated aqueous NH.sub.4Cl (10 mL) and concentrated under reduced pressure. The residue was diluted with water (30 mL) and the resulting suspension was stirred at rt for 30 min. The precipitated solid was collected by filtration, washed with water and air-dried. The product was purified by flash column chromatography (silica gel, 97:3 dichloromethane/methanol) followed by recrystallization from chloroform/hexanes to give N-(2-((2-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)ethyl)isobutyramide (0.102 g, 25%) as a yellow solid: mp 235-237 C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 10.80 (s, 1H), 9.34 (t, J=5.6 Hz, 1H), 7.84 (dd, J=4.3, 1.2 Hz, 1H), 7.19-7.25 (m, 1H), 7.12-7.18 (m, 1H), 6.70 (d, J=2.3 Hz, 1H), 6.35 (d, J=2.3 Hz, 1H), 6.25 (t, J=5.6 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.61-3.67 (m, 2H), 3.46-3.52 (m, 2H), 2.47 (sept, J=6.7, 1H), 1.17 (d, J=6.7 Hz, 6H); ESI MS m/z 412 [M+H].sup.+.

Example 57: N-(3-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)propyl)isobutyramide

(247) ##STR00071##

(248) Lithium bis(trimethylsilyl)amide (1 M in THF, 9.6 mL, 9.6 mmol) was added to a stirred suspension of 2-(3-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.361 g, 1.20 mmol) and N-(3-aminopropyl)isobutyramide (0.65 g, 3.60 mmol) in anhydrous THF (20 mL). After the addition was complete, the reaction was heated to reflux with stirring for 1 h. After that time a second portion of lithium bis(trimethylsilyl)amide (1 M in THF, 2.4 mL, 2.4 mmol) was added and reflux with stirring was continued for an additional 2 h. After that time the reaction was cooled to rt, diluted with saturated aqueous NH.sub.4Cl (5 mL) and concentrated under reduced pressure. The residue was diluted with water (30 mL) and the resulting suspension was stirred at rt for 30 min. The precipitated solid was collected by filtration, washed with water and air-dried. The product was purified by flash column chromatography (silica gel, dichloromethane to 97:3 dichloromethane/methanol) followed by trituration (90:10 diethyl ether/methanol) to give N-(3-((2-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)propyl)isobutyramide (0.207 g, 40%) as a yellow solid: mp 230-231 C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.76 (s, 1H), 9.38 (t, J=5.7 Hz, 1H), 7.93 (dd, J=4.3, 1.2 Hz, 1H), 7.87 (t, J=5.7 Hz, 1H), 7.41 (dd, J=8.6, 3.9 Hz, 1H), 7.33 (dd, J=8.0, 1.2 Hz, 1H), 7.10 (d, J=2.3 Hz, 1H), 6.57 (d, J=2.3 Hz, 1H), 3.94 (s, 3H), 3.85 (s, 3H), 3.28-3.36 (m, 2H), 3.25 (q, J=6.6 Hz, 2H), 2.37 (sept, J=6.6 Hz, 1H), 1.70-1.80 (m, 2H), 1.02 (d, J=6.6 Hz, 6H); ESI MS m/z 426 [M+H].sup.+.

Example 58: 2-(3-((1-Isopropylpiperidin-4-yl)amino)pyridin-2-yl)-5-methoxypyrido[3,4-d]pyrimidin-4(3H)-one

(249) ##STR00072##

(250) Lithium bis(trimethylsilyl)amide (1 M in THF, 2.0 mL, 2.0 mmol) was added to a suspension of 2-(3-fluoropyridin-2-yl)-5-methoxypyrido[3,4-d]pyrimidin-4(3H)-one (0.103 g, 0.37 mmol) and 1-isopropylpiperidin-4-amine (0.142 g, 1.0 mmol) in anhydrous THF (10 mL). After the addition was complete, the reaction was heated to in a sealed tube at 70 C. for 3 h. After that time the reaction was cooled to rt, diluted with ice-cold water (50 mL) and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol to 90:10 dichloromethane/methanol) to give 2-(3-((1-isopropylpiperidin-4-yl)amino)pyridin-2-yl)-5-methoxypyrido[3,4-d]pyrimidin-4(3H)-one (0.025 g, 17%) as a yellow solid: mp 237-238 C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.32 (br s, 1H), 9.32 (d, J=8.2 Hz, 1H), 8.67 (s, 1H), 8.40 (s, 1H), 7.98 (br s, 1H), 7.45 (d, J=2.3 Hz, 2H), 4.01 (s, 3H), 3.63-3.86 (m, 1H), 2.72-3.17 (m, 5H), 2.01-2.23 (m, 2H), 1.58-1.89 (m, 2H), 1.0 (d, J=7.0 Hz, 6H); ESI MS m/z 395 [M+H].sup.+.

Example 59: 2-(3-((1-(2-Hydroxy-2-methylpropyl)piperidin-4-yl)amino)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one

(251) ##STR00073##

(252) A solution of 5,7-dimethoxy-2-(3-(piperidin-4-ylamino)pyridin-2-yl)quinazolin-4(3H)-one (0.050 g, 0.13 mmol) and 2,2-dimethyloxirane (0.047 g, 0.65 mmol) in ethanol (3 mL) was heated to 140 C. with stirring in a sealed tube for 1.5 h using microwave radiation. After that time the reaction was cooled to rt, concentrated under reduced pressure and the product was purified by flash column chromatography (silica gel, dichloromethane to 70:30 dichloromethane/methanol) to give 2-(3-((1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)amino)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.029 g, 72%) as yellow solid: mp 220-221 C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.79 (s, 1H), 9.41 (d, J=7.8 Hz, 1H), 7.93 (dd, J=3.7, 1.8 Hz, 1H), 7.35-7.42 (m, 2H), 6.72 (d, J=1.95 Hz, 1H), 6.60 (d, J=1.95 Hz, 1H), 4.08 (s, 1H), 3.93 (s, 3H), 3.87 (s, 3H), 3.59-3.69 (m, 1H), 2.76-2.86 (m, 2H), 2.53-2.57 (m, 2H), 2.24 (s, 2H), 1.91-2.01 (m, 2H), 1.56-1.67 (m, 2H), 1.10 (s, 6H); ESI MS m/z 454 [M+H].sup.+.

Example 60: 2-(3-((1-(2-hydroxypropanoyl)piperidin-4-yl)amino)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one

(253) ##STR00074##

(254) N,N-Dicyclohexylcarbodiimide (0.113 g, 0.55 mmol) and 1-hydroxy-1H-benzotriazole (0.074 g, 0.55 mmol) were added to a solution of 2-hydroxypropanoic acid (0.058 g, 0.55 mmol; 85% in water) in DMF (15 mL) at rt. The reaction was stirred for 1 h and then 5,7-dimethoxy-2-(3-(piperidin-4-ylamino)pyridin-2-yl)quinazolin-4(3H)-one (0.070 g, 0.18 mmol) was added. The reaction was stirred 18 h at rt. After that time the reaction was concentrated under reduced pressure and the product was purified by prep. HPLC to give 2-(3-((1-(2-hydroxypropanoyl)piperidin-4-yl)amino)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.010 g, 12%) as yellow solid: mp 290-291 C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.75 (s, 1H), 9.44 (d, J=7.0 Hz, 1H), 7.95-7.97 (m, 1H), 7.40-7.49 (m, 2H), 6.67 (s, 1H), 6.60 (d, 1H), 4.84-4.96 (m, 1H), 4.41-4.54 (m, 1H), 4.00-4.19 (m, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 3.38-3.44 (m, 1H), 3.05-3.26 (m, 2H), 1.96-2.13 (m, 2H), 1.44-1.70 (m, 2H), 1.20 (d, J=6.25 Hz, 3H); ESI MS m/z 452 [MH].sup..

Example 61: 2-(3-((1-Isopropylpiperidin-4-yl)amino)pyridin-2-yl)-5-methoxy-7-((4-methoxybenzyl)amino)quinazolin-4(3H)-one

(255) ##STR00075##

(256) A solution of 3-bromopicolinaldehyde (5.00 g, 27 mmol), ethylene glycol (6.0 mL, 108 mmol) and p-toluenesulfonic acid monohydrate (0.256 g, 1.35 mmol) in anhydrous toluene (120 mL) was heated to reflux for 16 h with azeotropic removal of water using a Dean-Stark apparatus. After that time the reaction was cooled to rt and diluted with ethyl acetate (100 mL). The organic phase was separated, washed with 5% aq. Na.sub.2CO.sub.3 (120 mL), sat. NaCl (100 mL), dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure to give 3-bromo-2-(1,3-dioxolan-2-yl)pyridine (5.36 g, 87%) as a brown oil: .sup.1H NMR (CDCl.sub.3) 8.60 (d, J=3.5 Hz, 1H), 7.86-7.93 (m, 1H), 7.18 (dd, J=8.2, 4.7 Hz, 1H), 6.31 (s, 1H), 4.26-4.34 (m, 2H), 4.08-4.15 (m, 2H).

(257) Tris(dibenzylideneacetone)dipalladium (0.092 g, 0.10 mmol) was added to a de-gassed solution of 3-bromo-2-(1,3-dioxolan-2-yl)pyridine (1.15 g, 5.00 mmol), 1-isopropylpiperidin-4-amine (1.03 mL, 6.50 mmol), sodium-tert-butoxide (0.865 g, 9.00 mmol) and 2,2-bis(diphenylphosphino)-1,1-binaphthyl (0.187 g, 0.30 mmol) in toluene (10 mL). The mixture was de-gassed again and heated at 110 C. with stirring for 3 h under nitrogen. After that time the mixture was cooled to rt, filtered through celite, and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 97:3 dichloromethane/methanol then 97:3 dichloromethane/7N ammonia in methanol) to give 2-(1,3-dioxolan-2-yl)-N-(1-isopropylpiperidin-4-yl)pyridin-3-amine (1.342 g, 92%) as a brown oil: .sup.1H NMR (CDCl.sub.3) 7.89 (dd, J=4.7, 1.2 Hz, 1H), 7.10 (dd, J=8.4, 4.5 Hz, 1H), 6.96 (d, J=7.8 Hz, 1H), 5.79 (s, 1H), 5.10 (d, J=7.8 Hz, 1H), 4.10-4.18 (m, 2H), 4.02-4.10 (m, 2H), 3.24-3.38 (m, 1H), 2.69-2.87 (m, 2H), 2.26-2.38 (m, 2H), 1.99-2.11 (m, 2H), 1.46-1.59 (m, 2H), 1.06 (d, J=6.6 Hz, 6H).

(258) A solution of 2-(1,3-dioxolan-2-yl)-N-(1-isopropylpiperidin-4-yl)pyridin-3-amine (1.32 g, 4.53 mmol) and 2 N aqueous HCl (10 mL) was stirred at rt for 16 h. After that time the reaction was concentrated under reduced pressure and dried to give 3-((1-isopropylpiperidin-4-yl)amino)picolinaldehyde dihydrochloride (4.53 g). The aldehyde was dissolved in N,N-dimethylacetamimde (20 mL) and 2-amino-4,6-difluorobenzamide (0.64 g, 3.70 mmol) was added followed by NaHSO.sub.3 (58.5 wt %, 1.01 g, 5.55 mmol) and p-toluenesulfonic acid monohydrate (0.14 g, 0.74 mmol). The reaction was heated at 130 C. with stirring for 16 h. After that time the mixture was cooled to rt, concentrated under reduced pressure and diluted with water (100 mL). The resulting precipitate was collected by filtration, washed with water and dried. The product was purified by flash column chromatography (silica gel, 97:3 dichloromethane/methanol) to give 5,7-difluoro-2-(3-((1-isopropylpiperidin-4-yl)amino)pyridin-2-yl)quinazolin-4(3H)-one (0.705 g, 48%) as yellow solid: .sup.1H NMR (CDCl.sub.3) 11.16 (br s, 1H), 9.35 (d, J=7.8 Hz, 1H), 7.90 (dd, J=4.3, 1.2 Hz, 1H), 7.23-7.31 (m, 1H), 7.05-7.19 (m, 2H), 6.80-6.93 (m, 1H), 3.47-3.58 (m, 1H), 2.84-2.94 (m, 2H), 2.74-2.84 (m, 1H), 2.35-2.48 (m, 2H), 2.08-2.20 (m, 2H), 1.67-1.79 (m, 2H), 1.09 (d, J=6.6 Hz, 6H); ESI MS m/z 400 [M+H].sup.+.

(259) A solution of sodium methoxide in methanol (25 wt %, 2.3 mL, 10.6 mmol) was added to a suspension of 5,7-difluoro-2-(3-((1-isopropylpiperidin-4-yl)amino)pyridin-2-yl)quinazolin-4(3H)-one (0.703 g, 1.76 mmol) in anhydrous DMF (10 mL). The reaction was stirred at rt for 16 h under nitrogen. After that time 2N HCl was added to quench the reaction and adjust the reaction pH to about 2. The reaction was then made strongly basic with aq.

(260) Na.sub.2CO.sub.3 solution. The resulting precipitate was collected by filtration, washed with water and dried. The product was purified by flash column chromatography (silica gel, 97:3 dichloromethane/methanol) to give 7-fluoro-2-(3-((1-isopropylpiperidin-4-yl)amino)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one (0.765 g, (>99%) as yellow solid: .sup.1H NMR (DMSO-d.sub.6) 10.96 (br s, 1H), 9.28 (d, J=7.4 Hz, 1H), 7.93 (dd, J=3.5, 2.0 Hz, 1H), 7.34-7.44 (m, 2H), 6.94-7.08 (m, 2H), 3.90 (s, 3H), 3.52-3.65 (m, 1H), 2.68-2.79 (m, 3H), 2.33-2.45 (m, 2H), 1.93-2.03 (m, 2H), 1.53-1.67 (m, 2H), 0.99 (d, J=6.3 Hz, 6H); ESI MS m/z 412 [M+H].sup.+.

(261) A suspension of 7-fluoro-2-(3-((1-isopropylpiperidin-4-yl)amino)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one (0.412 g, 1.00 mmol)) and 4-methoxybenzylamine (0.78 mL, 6.00 mmol) in DMSO (5 mL) was heated at 100 C. with stirring for 24 h. After that time the reaction was cooled to rt and diluted with water (50 mL). The resulting precipitate was collected by filtration, washed with water and dried. The product was triturated with diethyl ether and then purified by flash column chromatography (silica gel, 97:3 dichloromethane/methanol then 97:3 dichloromethane/7N ammonia in methanol) to give 2-(3-((1-isopropylpiperidin-4-yl)amino)pyridin-2-yl)-5-methoxy-7-((4-methoxybenzyl)amino)quinazolin-4(3H)-one (0.230 g, 43%) as yellow solid: mp 220-222 C.; .sup.1H NMR (DMSO-d.sub.6) 10.37 (br s, 1H), 9.52 (d, J=7.8 Hz, 1H), 7.84-7.93 (m, 1H), 7.30-7.43 (m, 4H), 7.26 (t, J=5.7 Hz, 1H), 6.87-6.99 (m, 2H), 6.31 (d, J=2.0 Hz, 1H), 6.22-6.29 (m, 1H), 4.32 (d, J=5.7 Hz, 2H), 3.77 (s, 3H), 3.73 (s, 3H), 3.53 (br.s, 1H), 2.68-2.80 (m, 3H), 2.32-2.42 (m, 2H), 1.92-2.03 (m, 2H), 1.43-1.57 (m, 2H), 0.99 (d, J=6.6 Hz, 6H); ESI MS m/z 529 [M+H].sup.+.

Example 62: 2-[5-(2-Hydroxyethoxy)-3-(l-isopropylpiperidin-4-ylamino)pyridin-2-yl]-5,7-dimethoxyquinazolin-4(3H)-one

(262) ##STR00076##

(263) A solution of 2-[5-(2-(tert-butyldimethylsilyloxy)ethoxy]-3-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.476 g, 1.0 mmol) and 1-isopropyl-4-aminopiperidine (0.711 g, 5 mmol) in anhydrous acetonitrile (5 mL) was heated to reflux with stirring for 26 h. After that time the reaction was cooled to rt and concentrated under reduced pressure. The solids were treated with chloroform (25 mL) and the resulting mixture was filtered, washed with sat. NaHCO.sub.3 (15 mL), dried (MgSO.sub.4) and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 95:5 dichloromethane/methanol) followed by recrystallization from chloroform/diethyl ether to give 2-[5-(2-Hydroxyethoxy)-3-(1-isopropylpiperidin-4-ylamino)pyridin-2-yl]-5,7-dimethoxyquinazolin-4(3H)-one (0.292 g, 60%) as a yellow solid: mp 231-233 C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 10.67 (br s, 1H), 9.56 (d, J 7.2 Hz, 1H), 7.62 (d, J=2.4 Hz, 1H), 6.59 (d, J=2.4 Hz, 1H), 6.50 (d, J=2.0 Hz, 1H), 6.42 (d, J=2.0 Hz, 1H), 4.19 (t, J=4.4 Hz, 2H), 4.02 (t, J=4.4 Hz, 2H), 3.97 (s, 3H), 3.93 (s, 3H), 3.40 (br s, 1H), 2.93-2.90 (m, 2H), 2.81-2.77 (m, 1H), 2.44-2.42 (m, 2H), 2.14-2.11 (m, 2H), 1.79-1.74 (m, 2H), 1.10 (d, J=6.4 Hz, 6H); ESI MS m/z 484 [M+H].sup.+.

Example 63: cis-4-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)-N-isopropylcyclohexane-1-carboxamide

(264) ##STR00077##

(265) Lithium bis(trimethylsilyl)amide (1 M in THF, 10.0 mL, 10.0 mmol) was added to a stirred suspension of 2-(3-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.500 g, 1.66 mmol) and cis-4-amino-N-(propan-2-yl)cyclohexanecarboxamide hydrochloride (1.10 g, 5.0 mmol) in anhydrous THF (15 mL). After the addition was complete, the reaction was heated to reflux with stirring for 2 h. After that time a second portion of lithium bis(trimethylsilyl)amide (1 M in THF, 5.0 mL, 5.0 mmol) was added and reflux with stirring was continued for an additional 18 h. After that time the reaction was cooled to rt, diluted with saturated aqueous NH.sub.4Cl (3 mL), concentrated under reduced pressure and the product was purified by flash column chromatography (silica gel, 98:2 dichloromethane/methanol) to give cis-4-((2-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)-N-isopropylcyclohexane-1-carboxamide (0.120 g, 16%) as a light yellow solid: mp 256-257 C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 10.93 (br s, 1H), 9.74 (d, J=8.2 Hz, 1H), 7.89 (d, J=4.3 Hz, 1H), 7.23 (dd, J=8.6, 4.3 Hz, 1H), 7.10 (d, J=8.6 Hz, 1H), 6.95 (d, J=2.3 Hz, 1H), 6.46 (d, J=2.3 Hz, 1H), 5.23 (d, J=7.0 Hz, 1H), 4.00-4.09 (m, 1H), 3.98 (s, 6H), 3.84-3.94 (m, 1H), 2.12-2.24 (m, 1H), 1.93-2.08 (m, 4H), 1.81-1.91 (m, 2H), 1.65-1.79 (m, 2H), 1.09 (d, J=6.6 Hz, 6H); ESI MS m/z 464 [MH].sup..

Example 64: 2-[5-(2-Hydroxyethoxy)-3-(1-isobutyroylpiperidin-4-ylamino)pyridin-2-yl]-5,7-dimethoxyquinazolin-4(3H)-one

(266) ##STR00078##

(267) A mixture of 2-[5-(2-(tert-butyldimethylsilyloxy)ethoxy]-3-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.476 g, 1.0 mmol), 1-isobutyroyl-4-aminopiperidine hydrochloride (1.034 g, 5.0 mmol) and K.sub.2CO.sub.3 (1.11 g, 8.0 mmol) in anhydrous DMSO (10 mL) was heated to 96 C. with stirring for 26 h. After that time the reaction was cooled to rt, diluted with chloroform (100 mL), washed with water (510 mL), dried (MgSO.sub.4) and concentrated under reduced pressure. The oily product was triturated (diethyl ether, (510 mL) to give a solid product that was purified by flash column chromatography (silica gel, 98:2 chloroform/methanol) to give 2-[5-(2-hydroxyethoxy)-3-(1-isobutyroylpiperidin-4-ylamino)pyridin-2-yl]-5,7-dimethoxyquinazolin-4(3H)-one (0.172 g, 34%) as a yellow solid: mp 173-176 C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 10.66 (br s, 1H), 9.65 (d, J 6.8 Hz, 1H), 7.65 (d, J=2.4 Hz, 1H), 6.52 (s, 2H), 6.43 (d, J=2.4 Hz, 1H), 4.13-4.28 (m, 1H), 4.22-4.20 (m, 2H), 4.05-4.03 (m, 2H), 3.98 (s, 3H), 3.93 (s, 3H), 3.90-3.86 (m, 1H), 3.66-3.63 (m, 1H), 3.41-3.28 (m, 2H), 2.88-2.82 (m, 1H), 2.34 (t, J=6.4 Hz, 1H), 2.12 (br s, 2H), 1.72-1.58 (m, 2H), 1.16 (d, J=7.2 Hz, 6H); ESI MS m/z 512 [M+H].sup.+.

Example 65: 7-amino-2-(3-((1-Isopropylpiperidin-4-yl)amino)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one

(268) ##STR00079##

(269) A solution of 2-(3-((1-isopropylpiperidin-4-yl)amino)pyridin-2-yl)-5-methoxy-7-((4-methoxybenzyl)amino)quinazolin-4(3H)-one (0.200 g, 0.37 mmol) and trifluroacetic acid (2 mL) in dichloromethane (18 mL) was stirred at rt for 48 h. After this time the reaction was concentrated under reduced pressure, diluted with water (20 mL) and made basic with sat. Na.sub.2CO.sub.3. The precipitated solids were collected by filtration, washed with water and dried. The product was purified by flash column chromatography (silica gel, 97:3 dichloromethane/methanol then 97:3 dichloromethane/7N ammonia in methanol) to give 7-amino-2-(3-((1-isopropylpiperidin-4-yl)amino)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one (0.023 g, 15%) as yellow solid: .sup.1H NMR (DMSO-d.sub.6) 10.72 (s, 1H), 8.74 (d, J=7.8 Hz, 1H), 7.99 (t, J=2.7 Hz, 1H), 7.44 (d, J=2.7 Hz, 2H), 6.24 (s, 1H), 5.92 (br s, 2H), 4.41 (s, 1H), 3.72 (s, 3H), 3.40-3.52 (m, 1H), 2.62-2.77 (m, 2H), 2.57 (sept, J=6.3 Hz 1H), 2.14-2.29 (m, 2H), 1.91-2.04 (m, 2H), 1.27-1.38 (m, 2H), 0.84 (d, J=6.3 Hz, 6H); ESI MS m/z 409 [M+H].sup.+.

Example 66: 2-{3-(1-Isopropylpiperidin-4-ylamino)-5-[2-(pyrrolidin-1-yl)ethoxy]pyridin-2-yl}-5,7-dimethoxyquinazolin-4(3H)-one

(270) ##STR00080##

(271) Carbon tetrabromide (1.33 g, 4.0 mmol) and triphenylphosphine (1.10 g, 4.2 mmol) were added to a stirred suspension of 2-[5-(2-hydroxyethoxy)-3-(1-isopropylpiperidin-4-ylamino)pyridin-2-yl]-5,7-dimethoxyquinazolin-4(3H)-one (0.967 g, 2.0 mmol) in dichloromethane (60 mL). The reaction was stirred for 2 h at rt. After that time the reaction was concentrated under reduced pressure. The residue was suspended in anhydrous DMSO (10 mL) and pyrrolidine (7.11 g, 100 mmol) was added. The reaction mixture was heated to 80 C. with stirring for 14 h. After that time the reaction was cooled to rt, diluted with chloroform (100 mL), washed with sat. NaHCO.sub.3 (20 mL), water (420 mL), dried (MgSO.sub.4) and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 90:10 chloroform/methanol) followed by trituration (diethyl ether) to give 2-{3-(1-isopropylpiperidin-4-ylamino)-5-[2-(pyrrolidin-1-yl)ethoxy]pyridin-2-yl}-5,7-dimethoxyquinazolin-4(3H)-one (0.520 g, 48%) as a yellow solid: mp 166-169 C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 10.69 (br s, 1H), 9.57 (d, J 7.2 Hz, 1H), 7.64 (d, J=2.4 Hz, 1H), 6.60 (d, J=2.0 Hz, 1H), 6.54 (d, J=2.0 Hz, 1H), 6.41 (d, J=2.4 Hz, 1H), 4.21 (t, J=5.6 Hz, 2H), 3.97 (s, 3H), 3.93 (s, 3H), 3.45 (br s, 1H), 2.97-2.93 (m, 3H), 2.84-2.80 (m, 1H), 2.67 (br s, 4H), 2.46-2.44 (m, 2H), 2.17-2.15 (m, 2H), 1.86-1.77 (m, 6H), 1.12 (d, J=6.4 Hz, 6H); ESI MS m/z 537 [M+H].sup.+.

Example 67: 2-{5-[2-(Isopropylamino)ethoxy]-3-(1-isopropylpiperidin-4-ylamino)pyridin-2-yl}-5,7-dimethoxyquinazolin-4(3H)-one

(272) ##STR00081##

(273) Carbon tetrabromide (1.79 g, 5.4 mmol) and triphenylphosphine (1.49 g, 5.7 mmol) were added to a stirred suspension of 2-[5-(2-hydroxyethoxy)-3-(1-isopropylpiperidin-4-ylamino)pyridin-2-yl]-5,7-dimethoxyquinazolin-4(3H)-one (1.303 g, 2.7 mmol) in dichloromethane (80 mL). The reaction was stirred for 2 h at rt and was then concentrated under reduced pressure. The residue was suspended in anhydrous DMSO (10 mL) and isopropylamine (7.98 g, 135 mmol) was added. The reaction mixture was heated to 60 C. with stirring for 18 h. After that time the reaction was cooled to rt, diluted with chloroform (100 mL), washed with sat. NaHCO.sub.3 (20 mL), water (420 mL), dried (MgSO.sub.4) and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 90:10 chloroform/methanol) followed by recrystallization from chloroform/diethyl ether to give 2-{5-[2-(isopropylamino)ethoxy]-3-(1-isopropylpiperidin-4-ylamino)pyridin-2-yl}-5,7-dimethoxyquinazolin-4(3H)-one (0.742 g, 52%) as a yellow solid: mp 178-181 C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 9.58 (d, J 8.0 Hz, 1H), 7.63 (d, J=1.6 Hz, 1H), 6.60 (d, J=1.6 Hz, 1H), 6.51 (d, J=2.2 Hz, 1H), 6.42 (d, J=2.2 Hz, 1H), 4.17 (t, J=5.2 Hz, 2H), 3.97 (s, 3H), 3.93 (s, 3H), 3.45 (br s, 1H), 3.05 (t, J=5.2 Hz, 2H), 2.94-2.79 (m, 4H), 2.48-2.44 (m, 2H), 2.17-2.13 (m, 2H), 1.80-1.76 (m, 2H), 1.14-1.10 (m, 12H); ESI MS m/z 525 [M+H].sup.+.

Example 68: 2-(3-((1-(1-Hydroxy-2-methylpropan-2-yl)piperidin-4-yl)amino)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one

(274) ##STR00082##

(275) A solution of tert-butyl piperidin-4-ylcarbamate (5.0 g, 25 mmol), ethyl 2-bromo-2-methylpropanoate (7.30 g, 37 mmol) and potassium carbonate (8.60 g, 62 mmol) in anhydrous acetonitrile (80 mL) was heated to reflux for 17 h. After that time the reaction was cooled to rt, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 80:20 hexanes/ethyl acetate to 60:40 hexanes/ethyl acetate) to give ethyl 2-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-2-methylpropanoate (3.20 g, 41%) as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) 4.40 (br s, 1H), 4.18 (q, J=6.8 Hz, 2H), 3.44 (br s, 1H), 2.84-2.92 (m, 2H), 2.27 (td, J=11.5, 2.3 Hz, 2H), 1.87-1.96 (m, 2H), 1.44 (s, 9H), 1.34-1.49 (m, 2H), 1.30 (s, 6H), 1.24-1.29 (m, 3H); ESI MS m/z 315 [M+H].sup.+.

(276) A solution of diisobutylaluminum hydride (1M in toluene, 36 mL, 36 mmol) was slowly added to a vigorously stirred solution of ethyl 2-(4-((tert-butoxycarbonyl)amino) piperidin-1-yl)-2-methylpropanoate (2.80 g, 8.9 mmol) in anhydrous dichloromethane (120 mL) at 78 C. The reaction was stirred at 78 C. for 15 min and then warmed to 0 C. and stirred an additional 45 min. After this time the reaction was quenched by addition of saturated aqueous NH.sub.4Cl (40 mL). The resulting mixture was diluted with ethyl acetate (150 mL) and chloroform (150 mL), dried (MgSO.sub.4), concentrated under reduced pressure and dried in vacuum to give tert-butyl (1-(1-hydroxy-2-methylpropan-2-yl)piperidin-4-yl)carbamate (2.17 g, 89%) as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) 4.46 (br s, 1H), 3.39-3.55 (m, 1H), 3.35 (s, 2H), 2.85-2.97 (m, 2H), 2.22-2.38 (m, 2H), 1.94-2.05 (m, 2H), 1.44 (s, 9H), 1.36-1.51 (m, 2H), 1.05 (s, 6H); ESI MS m/z 273 [M+H].sup.+.

(277) Concentrated HCl (3.3 mL, 39.8 mmol) was added slowly to a stirred solution of tert-butyl (1-(1-hydroxy-2-methylpropan-2-yl)piperidin-4-yl)carbamate (2.17 g, 7.97 mmol) in methanol (50 mL). The reaction mixture was then stirred at rt for 17 h. After that time the reaction was concentrated under reduced pressure, triturated with diethyl ether and dried to give 2-(4-aminopiperidin-1-yl)-2-methylpropan-1-ol dihydrochloride (1.71 g, 87%) as a white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.64 (t, J=9.0 Hz, 1H), 8.49 (br s, 3H), 5.78 (br s, 1H), 3.55 (s, 2H), 3.39-3.55 (m, 2H), 3.19-3.37 (m, 1H); 3.00-3.15 (m, 2H), 1.93-2.20 (m, 4H), 1.27 (s, 6H); ESI MS m/z 173 [M+H].sup.+.

(278) A mixture of 2-(3-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.300 g, 0.99 mmol), 2-(4-aminopiperidin-1-yl)-2-methylpropan-1-ol dihydrochloride (0.624 g, 2.54 mmol) and potassium carbonate (1.38 g, 9.96 mmol) in anhydrous DMF (15 mL) was heated at 100 C. for 40 h. After that time the reaction was cooled to rt and concentrated under reduced pressure. Water (50 mL) was added and the resulting suspension was stirred at rt for 20 min. The precipitated solid was collected by filtration and air-dried. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/7N ammonia in methanol to 97:3 dichloromethane/7N ammonia in methanol) to give 2-(3-((1-(1-hydroxy-2-methylpropan-2-yl)piperidin-4-yl)amino)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.218 g, 48%) as a yellow solid: mp 223-225 C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.78 (s, 1H), 9.37 (d, J=7.0 Hz, 1H), 7.92 (d, J=2.7 Hz, 1H), 7.30-7.44 (m, 2H), 6.71 (d, J=2.15 Hz, 1H), 6.59 (d, J=2.15 Hz, 1H), 4.23 (t, J=4.7 Hz, 1H), 3.93 (s, 3H), 3.86 (s, 3H), 3.60 (br s, 1H), 3.29 (d, J=4.7 Hz, 2H), 2.79-2.90 (m, 2H), 2.46-2.57 (m, 2H), 1.92-2.03 (m, 2H), 1.52-1.66 (m, 2H), 0.97 (s, 6H); ESI MS m/z 454 [M+H].sup.+.

Example 69: 7-(Ethylamino)-2-(3-((1-isopropylpiperidin-4-yl)amino)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one

(279) ##STR00083##

(280) Ethylamine (2.0 M solution in THF, 10 mL, 20.0 mmol) was added to a suspension of 7-fluoro-2-(3-((1-isopropylpiperidin-4-yl)amino)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one (0.284 g, 0.69 mmol) in DMSO (5 mL). The reaction heated under microwave conditions at 100 C. with stirring for 10 h. After that time the reaction was cooled to rt, concentrated under reduced pressure and diluted with water (50 mL). The resulting precipitate was collected by filtration, washed with water and dried. The product was purified by flash column chromatography (silica gel, 97:3 chloroform/methanol then 97:3 chloroform/7N ammonia in methanol) to give 7-(ethylamino)-2-(3-((1-isopropylpiperidin-4-yl)amino)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one (0.106 g, 35%) as yellow solid: mp 219-221 C.; .sup.1H NMR (400 MHz, CDCl.sub.3) 10.73 (s, 1H), 9.62 (d, J=7.4 Hz, 1H), 7.87 (dd, J=3.9, 1.2 Hz, 1H), 7.20 (dd, J=8.6, 4.3 Hz, 1H), 7.08 (d, J=8.2 Hz, 1H), 6.32 (d, J=2.0 Hz, 1H), 6.08 (d, J=2.0 Hz, 1H), 4.10-4.19 (m, 1H), 3.95 (s, 3H), 3.41-3.56 (m, 1H), 3.23-3.36 (m, 2H), 2.85-2.97 (m, 2H), 2.71-2.84 (m, 1H), 2.38-2.47 (m, 2H), 2.07-2.19 (m, 2H), 1.67-1.82 (m, 2H), 1.34 (t, J=7.2 Hz, 3H), 1.10 (d, J=6.6 Hz, 6H); ESI MS m/z 437 [M+H].sup.+.

Example 70: Inhibition of Tetra-Acetylated Histone H4 Binding Individual BET Bromodomains

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

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

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

(284) TABLE-US-00002 TABLE 2 Inhibition of Tetra-acetylated Histone H4 Binding to Brd4 bromodomain 1 (BRD4(1) as Measured by FRET FRET FRET FRET FRET Example activity Example activity Example activity Example activity Number BRD4(1) Number BRD4(1) Number BRD4(1) Number BRD4(1) 1 Active 2 Active 3 Active 4 Active 5 Not 6 Active 7 Active 8 Active 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 Not 34 Active 35 Active 36 Active Active 37 Active 38 Not 39 Active 40 Active 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 59 Active 60 Active 61 Active 62 Active 63 Active 64 Active 65 Active 66 Active 67 Active 68 Active 69 Active

Example 71: Inhibition of c-Myc Expression in Cancer Cell Lines

(285) MV4-11 cells (2.510.sup.4 cells) were plated in 96 well U-bottom plates with test compound or DMSO (0.1%), and incubated for 3 h at 37 C. Cells were then harvested by centrifugation, lysed, and mRNA was isolated using the mRNA catcher plus kit (Invitrogen). Reverse transcription of the mRNA and duplex amplification of the c-myc and cyclophilin cDNAs was performed using the RNA Ultrasense kit (Invitrogen) and a ViiA7 real-time PCR machine (Applied Biosystems). IC.sub.50 values were determined from a dose response curve.

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

(287) TABLE-US-00003 TABLE 3 Inhibition of c-myc Activity in Human AML MV4-11 cells c-myc c-myc c-myc c-myc activity activity activity activity Example (IC50 < 30 Example (IC50 < 30 Example (IC50 < 30 Example (IC50 < 30 Number M) Number M) Number M) Number M) 1 Active 3 Active 7 Active 8 Active 9 Not 13 Not 14 Not 15 Active Active Active Active 16 Active 17 Active 18 Active 19 Active 20 Active 21 Active 22 Active 23 Not Active 26 Active 28 Active 30 Not 31 Not Active Active 32 Active 36 Active 37 Active 39 Active 42 Active 45 Not 46 Active 47 Not Active Active 48 Active 51 Active 52 Active 55 Active 56 Active 57 Active 59 Active 60 Active 61 Active 62 Active 63 Not 64 Active Active 66 Active 67 Active 69 Active

Example 72: Inhibition of Cell Proliferation in Cancer Cell Lines

(288) MV4-11 cells: 96-well plates were seeded with 510.sup.4 cells per well of exponentially growing human AML MV-4-11 (CRL-9591) cells and immediately treated with two-fold dilutions of test compounds, ranging from 30 M to 0.2 M. Triplicate wells were used for each concentration, as well as a media only and three DMSO control wells. The cells and compounds were incubated at 37 C., 5% CO.sub.2 for 72 h before adding 20 L of the CellTiter Aqueous One Solution (Promega) to each well and incubating at 37 C., 5% CO.sub.2 for an additional 3-4 h. The absorbance was taken at 490 nm in a spectrophotometer and the percentage of proliferation relative to DMSO-treated cells was calculated after correction from the blank well. IC.sub.50 were calculated using the GraphPad Prism software.

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

(290) TABLE-US-00004 TABLE 4 Inhibition of Cell Proliferation in Human AML MV-4-11 cells Cell Cell Cell Proliferation Proliferation Proliferation Example activity Example activity Example activity Number (IC50 < 30 M) Number (IC50 < 30 M) Number (IC50 < 30 M) 1 Active 3 Active 7 Active 8 Active 9 Not Active 14 Not Active 15 Active 16 Active 18 Active 19 Active 20 Active 21 Active 22 Active 23 Not Active 26 Not Active 28 Active 30 Active 31 Not Active 32 Active 36 Active 37 Active 39 Active 42 Active 45 Not Active 46 Active 47 Not Active 48 Active 51 Active 52 Not Active 55 Active 56 Active 57 Not Active 59 Active 60 Active 61 Active 62 Active 63 Not Active 64 Active 66 Active 67 Active 69 Active

Example 73: Inhibition of hIL-6 mRNA Transcription

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

(292) A human leukemic monocyte lymphoma cell line (U937) was plated (3.210.sup.4 cells per well) in a 96-well plate in 100 L RPMI-1640 containing 10% FBS and penicillin/streptomycin, and differentiated into macrophages for 3 days in 60 ng/mL PMA (phorbol-13-myristate-12-acetate) at 37 C. in 5% CO.sub.2 prior to the addition of the compound of interest. The cells were pretreated for 1 h with the test compound prior to stimulation with 1 ug/mL lipopolysaccharide from Escherichia coli. The cells were incubated at 37 C. for 3 h before the cells were harvested. At time of harvest, the spent media was removed from the cells and the cells were rinsed in 200 L PBS. Cell lysis solution (70 L) was added the cells in each well and incubated for 5-10 min at room temperature, to allow for complete cell lysis and detachment. mRNA was then prepared using the mRNA Catcher PLUS plate (Invitrogen), according to the protocol supplied. After the last wash, as much wash buffer as possible was aspirated without allowing the wells to dry. Elution buffer (E3, 70 L) was then added to each well. mRNA was then eluted by incubating the mRNA Catcher PLUS plate with Elution Buffer for 5 min at 68 C. and then immediately placing the plate on ice.

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

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

(295) TABLE-US-00005 TABLE 5 Inhibition of hIL-6 mRNA Transcription IL-6 IL-6 IL-6 IL-6 activity activity activity activity Example (IC50 < 30 Example (IC50 < 30 Example (IC50 < 30 Example (IC50 < 30 Number M) Number M) Number M) Number M) 1 Active 3 Active 7 Active 8 Active 14 Not 15 Not 16 Not 18 Active Active Active Active 19 Active 20 Active 21 Not 22 Active Active 23 Not 25 Active 26 Active 28 Active Active 30 Not 31 Active 32 Active 36 Active Active 37 Active 39 Active 45 Active 46 Active 47 Active 48 Active 50 Active 51 Active 52 Active 55 Active 56 Active 57 Active 59 Not 60 Active 62 Not 63 Not Active Active Active 64 Active 66 Not 67 Not 69 Active Active Active

Example 74: Inhibition of IL-17 mRNA Transcription

(296) In this example, hIL-17 mRNA in human peripheral blood mononuclear cells was quantitated to measure the transcriptional inhibition of hIL-17 when treated with a compound of the invention.

(297) Human peripheral blood mononuclear cells were plated (2.010.sup.5 cells per well) in a 96-well plate in 45 L OpTimizer T Cell expansion media containing 20 ng/ml IL-2 and penicillin/streptomycin. The cells were treated with the test compound (45 L at 2x concentration), and then the cells were incubated at 37 C. for 1 h before addition of 10x stock OKT3 antibody at 10 ug/ml in media. Cells were incubated at 37 C. for 6 h before the cells were harvested. At time of harvest, cells were centrifuged (800 rpm, 5 min). Spent media was removed and cell lysis solution (70 L) was added the cells in each well and incubated for 5-10 min at room temperature, to allow for complete cell lysis and detachment. mRNA was then prepared using the mRNA Catcher PLUS plate (Invitrogen), according to the protocol supplied. After the last wash, as much wash buffer as possible was aspirated without allowing the wells to dry. Elution buffer (E3, 70 L) was then added to each well. mRNA was then eluted by incubating the mRNA Catcher PLUS plate with Elution Buffer for 5 min at 68 C. and then immediately placing the plate on ice.

(298) The eluted mRNA isolated was then used in a one-step quantitative RT-PCR reaction, using components of the Ultra Sense Kit together with Applied Biosystems primer-probe mixes. Real-time PCR data was analyzed, normalizing the Ct values for hIL-17 to an internal control, prior to determining the fold induction of each unknown sample, relative to the control.

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

(300) TABLE-US-00006 TABLE 6 Inhibition of hIL-17 mRNA Transcription Example IL-17 activity (IC50 < 30 M) Example 19 Active

Example 75: Inhibition of hVCAM mRNA Transcription

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

(302) Human umbilical vein endothelial cells (HUVECs) are plated in a 96-well plate (4.010.sup.3 cells/well) in 100 L EGM media and incubated for 24 h prior to the addition of the compound of interest. The cells are pretreated for 1 h with the test compound prior to stimulation with tumor necrosis factor-. The cells are incubated for an additional 24 h before the cells are harvested. At time of harvest, the spent media is removed from the HUVECs and rinsed in 200 L PBS. Cell lysis solution (70 L) is then added the cells in each well and incubated for 5-10 min at room temperature, to allow for complete cell lysis and detachment. mRNA is then prepared using the mRNA Catcher PLUS plate (Invitrogen), according to the protocol supplied. After the last wash, as much wash buffer as possible is aspirated without allowing the wells to dry. Elution buffer (E3, 70 L) is then added to each well. mRNA is then eluted by incubating the mRNA Catcher PLUS plate with elution buffer for 5 min at 68 C. and then immediately placing the plate on ice.

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

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

Example 76: Inhibition of hMCP-1 mRNA Transcription

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

(306) Human Peripheral Blood Mononuclear Cells are plated (1.010.sup.5 cells per well) in a 96-well plate in 45 L RPMI-1640 containing 10% FBS and penicillin/streptomycin. The cells are treated with the test compound (45 L at 2x concentration), and then the cells are incubated at 37 C. for 3 h before the cells are harvested. At time of harvest, cells are transferred to V-bottom plates and centrifuged (800 rpm, 5 min). Spent media is removed and cell lysis solution (70 L) is added to the cells in each well and incubated for 5-10 min at room temperature, to allow for complete cell lysis and detachment. mRNA is then prepared using the mRNA Catcher PLUS plate (Invitrogen), according to the protocol supplied. After the last wash, as much wash buffer as possible is aspirated without allowing the wells to dry. Elution buffer (E3, 70 L) is then added to each well. mRNA is then eluted by incubating the mRNA Catcher PLUS plate with Elution Buffer for 5 min at 68 C. and then immediately placing the plate on ice.

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

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

Example 77: Up-Regulation of hApoA-1 mRNA Transcription

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

(310) Huh7 cells (2.510.sup.5 per well) were plated in a 96-well plate using 100 L DMEM per well, (Gibco DMEM supplemented with penicillin/streptomycin and 10% FBS), 24 h before the addition of the compound of interest. After 48 h treatment, the spent media was removed from the Huh-7 cells and placed on ice (for immediate use) or at 80 C. (for future use) with the LDH cytotoxicity assay Kit II from Abcam. The cells remaining in the plate were rinsed with 100 L PBS.

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

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

(313) Compounds with an EC.sub.170 value less than 30 M were deemed to be active.

(314) TABLE-US-00007 TABLE 8 Up-regulation of hApoA-1 mRNA Transcription. ApoA-1 ApoA-1 ApoA-1 ApoA-1 activity activity activity activity Example (EC.sub.170 < 30 Example (EC.sub.170 < 30 Example (EC.sub.170 < 30 Example (EC.sub.170 < 30 Number M) Number M) Number M) Number M) 1 Active 20 Active 25 Active 32 Active 36 Active

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

(315) MV4-11 cells (ATCC) are grown under standard cell culture conditions and (NCr) nu/nu fisol strain of female mice age 6-7 weeks are injected with 510.sup.6 cells/animal in 100 L PBS+100 L Matrigel in the lower left abdominal flank. By approximately day 18 after MV4-11 cells injection, mice are randomized based on tumor volume (LWH)/2) of average 120 mm.sup.3. Mice are dosed orally with compound at 75 mg/kg b.i.d and 120 mg/kg b.i.d in EA006 formulation at 10 mL/kg body weight dose volume. Tumor measurements are taken with electronic micro calipers and body weights measured on alternate days beginning from dosing period. The average tumor volumes, percent Tumor Growth Inhibition (TGI) and % change in body weights are compared relative to Vehicle control animals. The means, statistical analysis and the comparison between groups are calculated using Student's t-test in Excel.

Example 79: Evaluation of Target Engagement

(316) MV4-11 cells (ATCC) are grown under standard cell culture conditions and (NCr) nu/nu fisol strain of female mice age 6-7 weeks were injected with 510.sup.6 cells/animal in 100 L PBS+100 L Matrigel in the lower left abdominal flank. By approximately day 28 after MV4-11 cells injection, mice are randomized based on tumor volume (LWH)/2) of average 500 mm.sup.3. Mice are dosed orally with compound in EA006 formulation at 10 mL/kg body weight dose volume and tumors harvested 6 hrs post dose for Bcl2 and c-myc gene expression analysis as PD biomarkers.

Example 80: In Vivo Efficacy in Mouse Endotoxemia Model Assay

(317) Sub lethal doses of Endotoxin (E. Coli bacterial lipopolysaccharide) are administered to animals to produce a generalized inflammatory response which is monitored by increases in secreted cytokines. Compounds are administered to C57/B16 mice at T=4 hours orally at 75 mg/kg dose to evaluate inhibition in IL-6 and IL-17 and MCP-1 cytokines post 3-h challenge with lipopolysaccharide (LPS) at T=0 hours at 0.5 mg/kg dose intraperitoneally.

Example 81: In Vivo Efficacy in Rat Collagen-Induced Arthritis

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

Example 82: In Vivo Efficacy in Experimental Autoimmune Encephalomyelitis (EAE) Model of MS

(319) Experimental autoimmune encephalomyelitis (EAE) is a T-cell-mediated autoimmune disease of the CNS which shares many clinical and histopathological features with human multiple sclerosis (MS). EAE is the most commonly used animal model of MS. T cells of both Th1 and Th17 lineage have been shown to induce EAE. Cytokines IL-23, IL-6 and IL-17, which are either critical for Th1 and Th17 differentiation or produced by these T cells, play a critical and non-redundant role in EAE development. Therefore, drugs targeting production of these cytokines are likely to have therapeutic potential in treatment of MS.

(320) Compounds of Formula I or Formula Ia are administered to EAE mice to access anti-inflammatory activity. In this model, EAE is induced by MOG.sub.35-55/CFA immunization and pertussis toxin injection in female C57Bl/6 mice.

Example 83: Ex Vivo Effects on T Cell Function from Splenocyte and Lymphocyte Cultures Stimulated with External MOG Stimulation

(321) Mice are immunized with MOG/CFA and simultaneously treated with the compound for 11 days on a b.i.d regimen. Inguinal Lymph node and spleen are harvested and cultures set up with external MOG stimulation for 72 hours. Supernatants from these cultures are analyzed for TH1, Th2 and Th117 cytokines using a Cytometric Bead Array assay.

Example 84: In Vivo Efficacy in Athymic Nude Mouse Strain of Multiple Myeloma Xenograft Model Using MM1.s Cells

(322) MM1.s cells (ATCC) are grown under standard cell culture conditions and (NCr) nu/nu fisol strain of female mice age 6-7 weeks are injected with 1010.sup.6 cells/animal in 100 L PBS+100 L Matrigel in the lower left abdominal flank. By approximately day 21 after MM1.s cells injection, mice are randomized based on tumor volume (LWH)/2) of average 120 mm.sup.3. Mice are dosed orally with compound at 75 mg/kg b.i.d in EA006 formulation at 10 mL/kg body weight dose volume. Tumor measurements are taken with electronic micro calipers and body weights measured on alternate days beginning from dosing period. The average tumor volumes, percent Tumor Growth Inhibition (TGI) and % change in body weights are compared relative to Vehicle control animals. The means, statistical analysis and the comparison between groups are calculated using Student's t-test in Excel.

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

Quinazolinones as bromodomain inhibitors

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