WO2008086158A1

WO2008086158A1 - Benzodihydroquinazoline as pi3 kinase inhibitors

Info

Publication number: WO2008086158A1
Application number: PCT/US2008/050201
Authority: WO
Inventors: Karen A. Evans; David Kendall Jung; Steven D. Knight; Leanna E. Shuster; Robert A. Stavenger; Domingos J. Silva; Thomas H. Faitg; Haifeng Cui; Felix Deanda; Guosen Ye; Robert Hunter; Joanne Philip; Paul Reid
Original assignee: Smithkline Beecham Corporation
Priority date: 2007-01-04
Filing date: 2008-01-04
Publication date: 2008-07-17

Abstract

Invented are novel benzodihydroquinazoline compounds useful for inhibiting the activity/function of PI3 kinases and treating cancer.

Description

BENZODIHYDROQUINAZOLINE AS PI3 KINASE INHIBITORS

Field of the invention

This invention relates to the use of benzodihydroquinazoline for the inhibition of the activity or function of a phosphor-inositide-3'OH kinase (hereinafter PI3K), suitably, PI3Kα, PI3Kδ, PI3Kβ, and/or PI3Kγ kinases. The present invention relates to the use of benzodihydroquinazoline PI3K inhibitors in the treatment of one or more disease states selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection, and lung injuries.

Background of the invention

To date, eight mammalian PI3Ks have been identified, divided into three main classes (I, II, and III) on the basis of sequence homology, structure, binding partners, mode of activation, and substrate preference in vitro.

Cellular processes in which PI3Ks play an essential role include suppression of apoptosis, reorganization of the actin skeleton, cardiac myocyte growth, glycogen synthase stimulation by insulin, TNFα-mediated neutrophil priming and superoxide generation, and leukocyte migration and adhesion to endothelial cells.

It is now well understood that deregulation of onocogenes and tumor- suppressor genes contributes to the formation of malignant tumors, for example, by way of increased cell proliferation or increased cell survival. It is also recognized that signaling pathways mediated by the PI3K family have a central role in a number of cell processes, such as proliferation and survival. Deregulation of these pathways is a causative factor of a wide spectrum of human cancers and other diseases (Katso et al., Annual Rev. Cell Dev. Biol., 2001 , 17: 615-617 and Foster et al., J. Cell Science, 2003, 1 16: 3037-3040).

Class I PI3K is a heterodimer consisting of a p1 10 catalytic subunit and a regulatory subunit. This family is further divided into Class Ia and Class Ib enzymes on the basis of regulatory partners and mechanism of regulation. Class Ia enzymes consist of three distinct catalytic subunits (p1 10a, p110β, and p110δ) that dimerise with five distinct regulatory subunits (p85α, p55α, p50α, p85β, and p55γ), with all catalytic subunits being able to interact with all regulatory subunits to form a variety of heterodimers. There is now considerable evidence indicating that Class Ia PI3K enzymes contribute to tumorigenesis in a wide variety of human cancers, either directly or indirectly (Vivanco and Sawyers, Nature Reviews Cancer, 2002, 2, 489-501 ). For example, the p1 10a subunit is amplified in some tumors such as those of the ovary (Shayesteh, et al., Nature Genetics, 1999, 21 : 99-102) and cervix (Ma et al.,

Oncogene, 2000, 19: 2739-2744). More recently, activating mutations within p110α have been associated with various other tumors such as those of the colorectal region and of the breast and lung (Samuels, et al., Science, 2004, 304, 554). Tumor-related mutations in p85α have also been identified in cancers such as those of the ovary and colon (Philp et al., Cancer Research, 2001 , 61 , 7426-7429). In addition to direct effects, it is believed that activation of Class Ia PI3K contributes to tumorigenic events that occur upstream in signaling pathways, for example by way of ligan-dependent or ligand-independent activation of receptor tyrosine kinases, GPCR systems or integrins (Vara et al., Cancer Treatment Reviews, 2004, 30, 193-204). Examples of such upstream signaling pathways include over- expression of the receptor tyrosine kinase Erb2 in a variety of tumors leading to activation of PI3K-mediated pathways (Harari et al., Oncogene, 2000, 19, 6102- 61 14) and over-expression of the oncogene Ras (Kauffmann-Zeh et al., Nature, 1997, 385, 544-548). Class Ia PI3Ks may also contribute indirectly to tumorigenesis caused by various downstream signaling events. For example, loss of the effect of the PTEN tumor-suppressor phosphatase that catalyses conversion of PI(3,4,5)P3 back to PI(4,5)P2 is associated with a very broad range of tumors via deregulation of PI3K-mediated production of PI(3,4,5)P3 (Simpson and Parsons, Exp. Cell Res., 2001 , 264, 29-41 ). Furthermore, augmentation of the effects of other PI3K-mediated signaling events is believed to contribute to a variety of cancers, for example by activation of AKT (Nicholson and Andeson, Cellular Signaling, 2002, 14, 381-395).

As Class I PI3 kinases are also involved in motility and migration (Sawyer, Expert Opinion Investing, Drugs, 2004, 13, 1-19), PI3K inhibitors should provide therapeutic benefit via inhibition of tumor cell invasion and metastasis.

Laffargue et al. (Immunity 16(3) p. 441-51 (2002)) recently reported that PI3Kγ relays inflammatory signals through various G(i)-coupled receptors.

Accordingly, there is a need for PI3K inhibitors that would be useful for the treatment of such PI3K-meidated diseases and disorders. Summary of the Invention

This invention relates to novel compounds of Formula (I):

wherein:

R¹ is hydrogen or -NHR^1a, where R^1a is hydrogen, optionally substituted Ci-C₄ alkyl, optionally substituted C_3-6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R² is hydrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, -OR^X, or -NR^BR^c, where R^B and R^c are not both hydrogen, wherein R^x is optionally substituted aryl; and R^B and R^c are independently selected from the group: hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or R^B and R^c taken together with the nitrogen atom to which they are bound form a 3-8 membered ring with 1-3 heteroatoms, which 3-8 membered ring is optionally substituted with 1-4 substituents independently selected from optionally substituted d-C₄ alkyl; each of R³ and R⁴ is independently selected from the group: hydrogen, halo, nitro, cyano, optionally substituted CrC₆ alkyl, optionally substituted C₃-C₇ cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, -NR^bR^c, -NH-C(O)NR^bR^c, -NH-C(O )OR^d, -NH-SO₂NR^bR^c, -NH-SO₂R^d, -OR^d, -O(CO)R^d, -C(O)R^d, -C(O)NR^bR^c, -SO₂NR^bR^c, -SO₂R^d, -CO₂R^d; where R^b and R^c are independently selected from the group: hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or R^b and R^c taken together with the nitrogen atom to which they are bound form a 3-8 membered ring with 1-3 heteroatoms; which 3-8 membered ring is optionally substituted with 1-4 substituents independently selected from CrC₄ alkyl, or where R^d is selected from the group: hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl. Detailed Description of the Invention

This invention further relates to compounds of Formula (Ia):

wherein R^1a, R², R³, and R⁴ are as defined above.

This invention also relates to compounds of Formula (Ib):

wherein R², R³, and R⁴ are as defined above.

In another embodiment of the compounds of Formula (I) and/or (Ia), R^1a is hydrogen, optionally substituted C₁-C₄ alkyl, optionally substituted aryl, or optionally substituted heteroaryl;

R² is hydrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, -OR^X, or -NR^BR^C, where R^B and R^c are not both hydrogen, wherein R^x is optionally substituted phenyl or naphthyl; and R^B and R^c are independently selected from the group: hydrogen, optionally substituted CrC₄ alkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or R^B and R^c taken together with the nitrogen atom to which they are bound form a 5-6 membered ring with 1-3 heteroatoms, which 5-6 membered ring is optionally substituted with 1-4 substituents independently selected from optionally substituted Ci-C₄ alkyl; each R³ and R⁴ is independently selected from the group: hydrogen, halo, nitro, cyano, -OR^d, -SO₂NR^bR^c, where R^b and R^c are independently selected from the group: hydrogen, optionally substituted d-C₄ alkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and where R^b and R^c , taken together with the nitrogen atom to which they are attached, form a ring of 5-6 members with 1-3 heteroatoms, which 5- 6 membered ring is optionally substituted with 1-4 substituents independently selected from C₁-C₄ alkyl; where R^d is selected from the group: hydrogen, optionally substituted CrC₆ alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl.

In another embodiment of the compounds of Formula (I), (Ia) and/or (Ib), R² is hydrogen, optionally substituted aryl, optionally substituted heteroaryl, or -NR^BR^c, where R^B and R^c are not both hydrogen, wherein R^x is optionally substituted phenyl or naphthyl; and R^B and R^c are independently selected from the group: hydrogen, optionally substituted Ci-C₄ alkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or R^B and R^c taken together with the nitrogen atom to which they are bound form a 5-6 membered ring with 1-3 heteroatoms, which 5-6 membered ring is optionally substituted with 1-4 substituents independently selected from optionally substituted Ci-C₄ alkyl; each R³ and R⁴ is independently selected from the group: hydrogen, halo, nitro, cyano, -OR^d, -SO₂NR^bR^c, where R^b and R^c are independently selected from the group: hydrogen, optionally substituted Ci-C₄ alkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and where R^b and R^c , taken together with the nitrogen atom to which they are attached, form a ring of 5-6 members with 1-3 heteroatoms, which 5- 6 membered ring is optionally substituted with 1-4 substituents independently selected from Ci-C₄ alkyl; where R^d is selected from the group: hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl.

In another embodiment of the compounds of Formula (I) and (Ia), when R^1a is optionally substituted alkyl, the optional substituents are selected from the group: hydroxy, alkoxy, dialkylamino, alkylamino, amino, aryl, heterocycloalkyl, and cycloalkyl.

In another embodiment of the compounds of Formula (I) and (Ia), when R^1a is optionally substituted aryl, the optional substituents are selected from the group: cyano, alkoxy, hydroxy, nitro, -CH₂-SO₂(Ci-C₄alkyl), -SO₂NH₂, and -SO₂(Ci-C₄alkyl). In yet another embodiment of the compounds of Formula (I) and (Ia), R^1a is optionally substituted heteroaryl, such as 2-pyridyl or 3-pyridyl.

In specific embodiments of the compounds of Formula (I) and (Ia), R^1a is hydrogen, methyl, hydroxypropyl, -(CH₂^-NEt₂, -(CH₂)₂ N-morpholine, -(CH₂)₂-((3-F)phenyl), cyclopentyl, or optionally substituted phenyl.

In other specific embodiments of the compounds of Formula (I) and (Ia), R^1a is hydrogen. In other specific embodiments of the compounds of Formula (I) and (Ia), R^1a is methyl, hydroxypropyl, 3-cyanophenyl, 4-cyanophenyl, 3,4,5- trimethoxyphenyl, pyrid-2-yl, pyrid-3-yl, 4-(4-morpholinylsulfonyl)phenyl, 4- [(methylsulfonyl)methyl]phenyl, or 4-{[(5-methyl-isoxazol-3-yl)amino]sulfonyl} phenyl.

In further embodiment of the compounds of Formula (I) and (Ia), when R^1a is optionally substituted phenyl, the optional substituents are attached in meta or para positions on the benzene ring and are selected from the group: cyano, CrC₄ alkoxy, hydroxy, nitro, -CH₂-SO₂(C_rC₄alkyl), -SO₂NH₂, and -SO₂(Ci-C₄alkyl).

In one embodiment of the compounds of Formula (I), (Ia) and/or (Ib), the optional substituents for any R² group (including the R^x moiety of -OR^X, and the R^B and R^c moieties of -NR^BR^C (including when R^B and R^c taken together form a ring), such as optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkyl, and optionally substituted cycloalkyl), are independently selected from the group: d-C₄ alkyl, Ci-C₄ alkoxy, halo, hydroxy, hydroxy(Ci-C₄)alkyl, carboxy(Ci-C₄)alkyl (or hydroxycarbonyl(Ci-C₄)alkyl-), 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, amino, C₁-C₄ alkylamino, di(C₁-C₄)alkylamino, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylamido (or C₁-C₄ alkylaminocarbonyl), cyano, C₁-C₄ alkylsulfonyl, and C₁-C₄ alkylcarbonyl (or C₁-C₄ acyl).

In another embodiment of the compounds of Formula (I), (Ia) and/or (Ib), R² is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl, the optional substituents are independently selected from the group: C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, hydroxy, hydroxy(CrC₄)alkyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, amino, C₁-C₄ alkylamino, di(C₁-C₄)alkylamino, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylamido, cyano, C₁-C₄ alkylsulfonyl, and C₁-C₄ alkylcarbonyl. In other embodiments of the compounds of Formula (I), (Ia) and/or (Ib), the optionally substituted aryl, heteroaryl, or heterocycloalkyl of R² is selected from optionally substituted phenyl, quinolyl, pyrazolyl, indolyl, pyridyl, thienyl, furanyl, pyrrolyl, indazolyl, quinazolinyl, imidazolyl, pyrrolyl, 1 ,2,3,4-tetrahydroquinolinyl, 3,4-dihydro-2H-1 ,4-benzoxazinyl, and piperazinyl.

In another embodiment of the compounds of Formula (I), (Ia) and/or (Ib), R² is optionally substituted amino having the formula NR^BR^C, wherein R^B is H or C₁-C₆ alkyl; and R^c is selected from the group: H, optionally substituted CrC₆ alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl.

In another embodiment of the compounds of Formula (I), (Ia) and/or (Ib), R² is optionally substituted amino having the formula NR^BR^C, wherein R^B and R^c are joined to form an optionally substituted heterocycloalkyl group selected from: morpholinyl, piperazinyl and pyrrolidinyl,

In the embodiment of the compounds of Formula (I), (Ia) and/or (Ib), when R² group is -NR^BR^C, the optionally substituted R^B and R^c moieties (e.g., optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl, or when R^B and R^c are taken together to form an optionally substituted ring), the optional substituents are independently selected from the group: d-C₄ alkyl, d-C₄ alkoxy, halo, hydroxy, hydroxy(Ci-C₄)alkyl , carboxy(Ci-C₄)alkyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, amino, Ci-C₄alkylamino, di(Ci-C₄)alkylamino, CrC₄ alkylsulfonyl, Ci-C₄ alkylamido (or Ci-C₄ alkylaminocarbonyl), cyano, CrC₄ alkylsulfonyl, and CrC₄ alkylcarbonyl.

In specific embodiments of the compounds of Formula (I), (Ia) and/or (Ib), R² is optionally substituted amino having the formula NR^BR^C, R^B is H or CrC₆ alkyl; and R^c is selected from the group: CrC₆ alkyl, 2-methoxybenzyl, 3-(2-methyl-1 ,3-thiazol-4-yl) phenyl, (2,2-dioxido-1 ,3-dihydro-2-benzothien-5-yl), 3,4,5-tri(methoxy)phenyl, and 3-(methylsulfonyl)phenyl,

3-[(methylsulfonyl)amino]phenyl, 3-chloro-4-fluorophenyl, 4-(1 ,2,4-triazolyl)phenyl, 3-(2-methylthiazole-5-yl)phenyl, 3-(methylsulfonylmethyl)phenyl, 3-(methylsulfonamido)phenyl, 3-methylsufonylphenyl, 4-(methylsulfonamido)phenyl, 4-acetamidophenyl, 4-aminosulfonylphenyl, (N-acetyl-indoline-5-yl)phenyl, 3-(cyclopropylmethanonyl)phenyl, 4-(methylsulfonylmethyl)phenyl, 3-(methylsulfonylethyl)phenyl, benzothiazol-5-yl, benzothiazol-6-yl, phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-cyanophenyl, 4-cyanophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-(2-propyl)oxyphenyl, 4-(2-propyl)oxyphenyl, 4-acetylphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-acetamidophenyl, 4-acetamidophenyl, 4-(methylsulfonyl)phenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-(dimethylamino)phenyl,

3-acetylphenyl, phenylmethyl, phenylethyl, N-(methoxyethyl)-3-methyl-indole-5-yl,

3-carboxamidophenyl, N-methylpiperazin-1-yl-propoyl, benzimidazol-5-yl, morpholine-1-ylethyl, 4-carboxamidophenyl, quinoline-6-yl, indole-6-yl, benzotriazole-5-yl, 3-trifluoromethoxyphenyl, indole-5-yl, 2,4-dimethoxyphenyl, and

2-napthyl.

In another specific embodiment of the compounds of Formula (I), (Ia) and/or

(Ib), R² is optionally substituted amino having the formula NR^BR^C, wherein R^B and

R^c are joined to form an optionally substituted 5-6 membered heterocycloalkyl group selected from: morpholinyl, 4-(diethylaminopropyl)-piperazinyl and pyrrolidinyl.

In further specific embodiments of the compounds of Formula (I), (Ia) and/or

(Ib), when R² is optionally substituted heteroaryl or heterocycloalkyl, the optional substituents are selected from the group: Ci-C₄alkyl, d-C₄ alkoxy, hydroxy-Ci-C₄ alkyl, Ci-C₄ alkylcarbonyl, CrC₄alkyl(C=O)NH-, halo, 5-6 membered heteroaryl

(specifically, thienyl or pyridyl), 5-6 membered heterocycloalkyl, amino,

Ci-C₄alkylamino, and di(C-i-C₄)alkylamino.

In other specific embodiments of the compounds of Formula (I), (Ia) and/or

(Ib), R² is optionally substituted phenyl, quinol-6-yl, pyrazol-4-yl, indol-5-yl, pyrid-3-yl, 5-(thien-2-yl)-thiene-2-yl, thien-2-yl, 5-(hydroxymethyl)-furan-2-yl,

N-methyl-pyrrol-2-yl, 1-H-indazol-3-yl, 2,4-diamino-quinazolin-6-yl,

1 -methyl-imidazol-5-yl, 1 -(pyrid-3-yl)pyrrol-2-yl,

1-methyl-1 ,2,3,4-tetrahydroquinolin-6-yl,

4-methyl-3,4-dihydro-2H-1 ,4-benzoxazin-6-yl, 4-[2-(diethylamino)ethyl]-piperazin-1-yl, 5-methyl-thien-2-yl, 2-bromopyridin-6-yl,

N-methyl-pyrazol-4-yl, 3-aminoindazol-5-yl, quinoline-6-yl, or 5-acetylthien-2-yl.

In further specific embodiments of the compounds of Formula (I), (Ia) and/or

(Ib), R² is optionally substituted phenyl, the optional substituents are selected from the group: d-C₄ alkyl(C=O)NH-, chloro, methoxy, 3-pyridyl, 3,5-dimethyl, d-C₄ alkylsulfonyl, triazolyl, 5-pyrimidinyl, acetamido, (1 ,2,4-triazol-1-yl)methyl, fluoro,

(dimethylaminopropoxy), methylsulfonyl, cyano, hydroxy, and trifluoromethoxy.

In other embodiments of the compounds of Formula (I), (Ia) and/or (Ib), R² is substituted hydroxy having the formula OR^X, where R^x is optionally substituted phenyl, the optional substituents are selected from the group: methoxy and cyano. In other specific embodiments of the compounds of Formula (I) and (Ia), R² is H or R² is phenyl; 3-(fluoro)phenyl; 4-(fluoro)phenyl; 3-(chloro)phenyl; 4-(chloro)phenyl; 3-(cyano)phenyl; 4-(cyano)phenyl; 3-(methoxy)phenyl;

3-(trifluoromethoxyphenyl; 4-(methoxy)phenyl; 3-(hydroxy)phenyl;

4-(hydroxy)phenyl; 3,4,5-(tri-methoxy)phenyl; 2,4-(di-methoxy)phenyl;

3,5-(di-methoxy)phenyl; 3,5-di-methyl-4-hydroxy-phenyl; ; 4-(acetamido)phenyl (or 4-(methylcarbonylamino)phenyl); 3-(methylsulfonyl)phenyl (or

3-(methanesulfonyl)phenyl); 4-(methylsulfonyl)phenyl;

4-(methylsulfonylamino)phenyl (or 4-(methanesulfonylamino)phenyl);

4-[(cyanoethyl)(ethyl)amino]-2-(methyl)-phenyl; 3-(3-pyridinyl)phenyl;

4-(5-pyrimidinyl)phenyl; 4-[2-(ethyloxy)-pyrimidin-4-yl]phenyl; 4-{[3-(dimethylamino)propyl]oxy}phenyl; 4-(1 ,2,4-triazol-1-yl)phenyl; quinolin-6-yl;

1-methyl-1 ,2,3,4-tetrahydro-quinolin-6-yl; 1-methyl-1 ,2,3,4-tetrahydroquinolin-7-yl; morpholin-4-yl; indol-5-yl; 1-methyl-imidazol-5-yl; indazol-3-yl; 3-amino-indazol-5-yl; pyrrolidin-1-yl; (3-pyridinyl)-pyrrol-2-yl; pyridin-3-yl; 3-methyl-pyridin-2-yl;

6-bromo-pyridin-2-yl; 1-methyl-pyrazol-4-yl; 1-methyl-pyrrol-2-yl; 1 ,3-benzodioxol-5-yl; thien-2-yl; 5-bromo-thien-2-yl; 5-methyl-thien-2-yl; thien-3-yl;

5-acetamido-thien-2-yl (or δ-methylcarbonylamino-thien^-yl); 2,2'-bithien-5-yl;

5-(hydroxymethyl)furan-2-yl; 2,4-(di-amino)quinazolin-6-yl; or

4-methyl-3,4-dihydro-2H-1 ,4-benzoxazin-7-yl.

In other specific embodiments of the compounds of Formula (I) and (Ia), R² is -OR^X, where R^x is 3-methoxyphenyl; 3,4,5-trimethoxy-phenyl; 3-(cyano)phenyl; or naphthalen-2-yl.

In other specific embodiments of the compounds of Formula (I) and (Ia), R² is -NR^2CR^2D, where R^2C is H and R^2D is [2-(methyloxy)phenyl]methyl; 2-phenylethyl; phenylmethyl; 2-(4-morpholinyl)ethyl; 3-(4-(methyl)-piperazin-1-yl)prop-1-yl; phenyl; 3-fluorophenyl; 4-fluorophenyl; 3-chlorophenyl; 4-chlorophenyl; 2-methoxyphenyl;

3-methoxyphenyl; 4-methyloxyphenyl; 3-[(1-methylethyl)oxy]-phenyl (or

3-(isopropoxy)phenyl); 4-[(1-methylethyl)oxy]-phenyl (or 4-(isopropoxy)phenyl);

3,4,5-trimethoxyphenyl; 3-(chloro)-4-(fluoro)phenyl; 3-hydroxyphenyl ;

4-hydroxyphenyl ; 3-cyanophenyl; 4-cyanophenyl; 3-(methylsulfonyl)phenyl; 4-(methylsulfonyl)phenyl; 3-[(methylsulfonyl)methyl]phenyl;

3-(methylsulfonylamino)phenyl; 4-(methylsulfonylamino)phenyl;

4-(methylsulfonylaminomethyl)phenyl (or 4-(benzyl-methanesulfonamide);

4-[(methylsulfonyl)methyl]phenyl}; 3-[2-(methylsulfonyl)ethyl]phenyl;

3-(trifluoromethyl)phenyl; 4-(trifluoromethyl)phenyl; 3-(di-methylamino)phenyl; 4-(di-methylamino)phenyl; 3-(acetyl)phenyl (or 3-(methylcarbonyl)phenyl);

4-(acetyl)phenyl (or 4-(methylcarbonyl)phenyl); 3-(amido)phenyl (or 3-(aminocarbonyl)phenyl) ; 4-(amido)phenyl (or 4-(aminocarbonyl)phenyl) ;

3-(acetamido)phenyl (or 3-(methylcarbonylamino)phenyl); 4-(acetamido)phenyl (or

4-(methylcarbonylamino)phenyl); 4-(1 ,2,4-triazol-1 -ylmethyl)phenyl;

4-[3-(diethylamino)propyl]-piperazin-1-yl; (2,2-dioxido-1 ,3-dihydro-2-benzothien-5-yl); 3-(2-methyl-1 ,3-thiazol-4-yl)phenyl;

3-(cyclopropylcarbonyl)phenyl; 1 ,3-benzothiazol-5-yl; 1 ,3-benzothiazol-6-yl;

1 ,2,3-benzotriazol-5-yl; benzimidazol-5-yl; indol-6-yl; indazol-5-yl;

2-methyl-1-[2-(methyloxy)ethyl]-indol-5-yl; or 1-acetyl-2,3-dihydro-indol-5-yl.

In other specific embodiments of the compounds of Formula (I) and (Ia), R² -NR^2CR^2D, where R^2C is methyl; and R^2D is phenyl.

In another embodiment of the compounds of Formula (I), (Ia) and/or (Ib), R³ is hydrogen, methyl, methoxy, nitro, chloro, fluoro, aminosulfonyl (from piperidinylsulfonyl, morpholinylsulfonyl, pyrrolidinesulfonyl, or

N-methylpiperazinylsulfonyl). In another embodiment of the compounds of Formula (I), (Ia) and/or (Ib), R³ is hydrogen, halo, C₁-C₄ BIkOXy, or -SO₂NR^bR^c, where R^b and R^c are independently selected from the group: hydrogen and Ci-C₄ alkyl, or R^b and R^c , taken together with the nitrogen atom to which they are attached, form a 5-6 membered ring containing 0 or 1 additional heteroatoms selected from N and O, which 5-6 membered ring is optionally substituted with 1-4 C₁-C₄ alkyl.substitutents. In specific embodiments of the compounds of Formula (I) and (Ia), R³ is hydrogen, methoxy, fluoro, piperidinylsulfonyl, morpholin-4-ylsulfonyl, pyrrolidin-1 -ylsulfonyl, or

4-(N-methyl)piperazin-1-ylsulfonyl). In specific embodiments of the compounds of

Formula (Ib), R³ is hydrogen. In another embodiment of the compounds of Formula (I), (Ia) and/or (Ib), R⁴ is hydrogen, chloro, bromo, methoxy, nitro, fluoro, amino, methylsulfonylamino,

5-pyrimidinyl, or ethoxy.

In another embodiment of the compounds of Formula (I), (Ia) and/or (Ib), R⁴ is is hydrogen, halo, C₁-C₄ alkoxy, or monocyclic 5-6 membered heteroaryl. In specific embodiments of the compounds of Formula (I) and (Ia), R⁴ is hydrogen, chloro, fluoro, bromo, methoxy, ethoxy, or pyrimidin-5-yl. In another embodiment of the compounds of Formula (Ib), R⁴ is bromo.

The compounds of this invention according to Formula (I), (Ia) and/or (Ib) are suitable for the modulation, notably the inhibition of the activity of PI3K. The compounds of Formula (I), (Ia) and/or (Ib) inhibit PI3 kinase. Suitably, the compounds of Formula (I), (Ia) and/or (Ib), inhibit one or more PI3 kinases selected from: PI3Kα, PI3Kδ, PI3Kβ and PI3Kγ.

Compounds of Formula (I), (Ia) and/or (Ib) are included in the pharmaceutical compositions of the invention.

"Aryl" represents an optionally substituted benzene (phenyl) ring or naphthyl ring. Examples of optional substituents for these groups include, but are not limited to, halogen, aryl, heteroaryl, heterocycloalkylalkyl, hydroxy, alkyl, alkoxy, difluoroalkyl, trifluoroalkyl, amino, alkylamino, dialkylamino, arylamino, heteroarylamino, heterocycloalkylamino, acylamino, sulfonylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, arylaminoalkyl, heteroarylaminoalkyl, cycloalkylaminoalkyl, heteroclylaminoalkyl, hydroxyalkyl, aminocarboxy, carboxy, carboxamido, alkoxycarbonyl, aminoalkoxy, dialkylaminoalkoxy, acylaminoalkoxy, aminosulphonyl, cyano, formyl, nitro, alkylsulfonyl, arylsulfonyl, and heteroarylsulfonyl.

"Heteroaryl" represents a group or moiety comprising an aromatic monovalent monocyclic, bicyclic, or tricyclic radical, containing 5 to 18 ring atoms, including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more of the substituents defined herein. This term also encompasses bicyclic or tricyclic heterocyclic-aryl compounds containing an aryl ring moiety fused to a heterocycloalkyl ring moiety, containing 5 to 16 ring atoms, including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more of the substituents defined herein. Illustrative examples of heteroaryls include, but are not limited to, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl (or furanyl), isothiazolyl, furazanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridyl (or pyridinyl), pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, triazolyl, tetrazolyl, benzo[b]thienyl, naphtho[2,3-b]thianthrenyl, isobenzofuryl, 2,3-dihydrobenzofuryl, chromenyl, chromanyl, xanthenyl, phenoxathienyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthridinyl, quinazolinyl, tetrahydroquinazolinyl, benzothiazolyl, benzimidazolyl, tetrahydroquinolinyl, cinnolinyl, pteridinyl, carbozolyl, beta-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenathiazinyl, 2,2-dioxido-1 ,3-dihydro-2-benzothien-5-yl, dihydro-2H-1 ,4-benzoxazine, benzotriazolyl, and phenoxazinyl. Preferred heteroaryls include: pyrimidinyl, thienyl, pyridyl, pyrrolyl, furanyl, quinazolinyl, triazolyl, imidazolyl, tetrahydroquinolinyl, 2,2-dioxido-1 ,3-dihydro-2-benzothien-5-yl, pyrazolyl, thiazolyl, indolinyl, indolyl, dihydro-2H-1 ,4-benzoxazinyl, isoxazolyl, indazolyl, benzotriazolyl, benzothiazolyl, benzimidazolyl, and quinolinyl.

"Cycloalkyl" represents a saturated hydrocarbon ring having the specified number of member atoms. Cycloalkyl groups are monocyclic ring systems. For example, C3-C6 cycloalkyl refers to a cycloalkyl group having from 3 to 6 member atoms. Cycloalkyl groups may be optionally substituted with one or more substituent as defined herein. Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

"Heterocycloalkyl" represents a saturated or unsaturated ring containing from 1 to 4 heteroatoms as member atoms in the ring. However, heterocycloalkyl rings are not aromatic. Heterocycloalkyl groups containing more than one heteroatom may contain different heteroatoms. Heterocycloalkyl groups may be optionally substituted with one or more substituent as defined herein. Heterocycloalkyl groups are monocyclic ring systems or are fused, spiro, or bridged bicyclic ring systems. Monocyclic heterocycloalkyl rings have from 5 to 7 member atoms. Bicyclic heterocycloalkyl rings have from 7 to 11 member atoms. In certain embodiments, heterocycloalkyl is saturated. In other embodiments, heterocycloalkyl is unsaturated but not aromatic. Heterocycloalkyl includes pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, pyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, azepinyl, 1 ,3-dioxolanyl, 1 ,3-dioxanyl, 1 ,4-dioxanyl, 1 ,3-oxathiolanyl, 1 ,3-oxathianyl, 1 ,3-dithianyl, azetidinyl, azabicylo[3.2.1]octyl, azabicylo[3.3.1]nonyl, azabicylo[4.3.0]nonyl, and oxabicylo[2.2.1]heptyl. Preferred heterocycloalkyls include morpholinyl, piperazinyl, pyrrolidinyl, and piperidinyl. "Heteroatom" means oxygen, nitrogen or sulfur. "Halogen" means a substituent selected from bromide (bromo), iodide (iodo), chloride (chloro) and fluoride (floro). In more specific embodiments, "halogen" means a substituent selected from chloride (chloro) and fluoride (floro). "Alkyl" and derivatives thereof and in all carbon chains as used herein, including alkyl chains defined by the term "-(CH2)_n", "-(CH2)_m " and the like, is meant a saturated hydrocarbon chain having the specified number of member atoms. For example, CrCβ alkyl refers to an alkyl group having from 1 to 6 member atoms. Alkyl groups may be optionally substituted with one or more substituents as defined herein. Alkyl groups may be straight or branched.

Representative branched alkyl groups have one, two, or three branches. Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and t-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl. "Treating" means prophylactic and/or therapeutic therapy.

"Effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

"Co-administering" means either simultaneous administration or any manner of separate sequential administration of a PI3 kinase inhibiting compound, as described herein, and a further active ingredient or ingredients, known to be useful in the treatment of cancer, including chemotherapy and radiation treatment. The term further active ingredient or ingredients, as used herein, includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of treatment for cancer. Suitably, if the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.

As used herein, the term "compounds of the invention" means both the compounds according to Formula (I). (Ia), and/or (Ib) and the pharmaceutically- acceptable salts thereof. The term "a compound of the invention" also appears herein and refers to both a compound according to Formula (I). (Ia), and/or (Ib) and its pharmaceutically-acceptable salts.

The compounds of the invention may exist in solid or liquid form. In the solid state, the compounds of the invention may exist in crystalline or noncrystalline form, or as a mixture thereof. For compounds of the invention that are in crystalline form, the skilled artisan will appreciate that pharmaceutically-acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates." Hydrates include stoichiometric hydrates as well as compositions containing vaiable amounts of water. The invention includes all such solvates, and particularly hydrates.

The skilled artisan will further appreciate that certain compounds of the invention that exist in crystalline form, including the various solvates thereof, may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs." The invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. The skilled artisan will appreciate that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.

Certain compounds described herein may contain one or more chiral atoms, or may otherwise be capable of existing as two enantiomers, or two or more diastereoisomers. Accordingly, the compounds of this invention include mixtures of enantiomers/diastereoisomers as well as purified enantiomers/diastereoisomers or enantiomerically/diastereoisomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds represented by formula I or Il above as well as any wholly or partially equilibrated mixtures thereof. The present invention also covers the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted. Further, an example of a possible tautomer is an oxo substituent in place of a hydroxy substituent. Also, as stated above, it is understood that all tautomers and mixtures of tautomers are included within the scope of the compounds of Formula I or II.

The novel compounds of Formulas I are prepared as shown in General Scheme I below, or by analogous methods. General Scheme

Conditions: a) benzaldehyde, guanidine carbonate, EtOH, μwave, 180 ⁰C; b) Ag₂O, EtOH, μwave, 12O ⁰C.

It has now been found that compounds of the present invention are inhibitors of the Phosphatoinositides 3-kinases (PI3Ks). When the phosphatoinositides 3-kinase (PI3K) enzyme is inhibited by a compound of the present invention, PI3K is unable to exert its enzymatic, biological and/or pharmacological effects. The compounds of the present invention are therefore useful in the treatment of autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection, and lung injuries.

The compounds of Formula (I), (Ia) and/or (Ib) are useful as medicaments in particular for the treatment of autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries. According to one embodiment of the present invention, the compounds of Formula (I), (Ia) and/or (Ib) are inhibitors of one or more phosphatoinositides 3-kinases (PI3Ks), suitably, Phosphatoinositides 3-kinase γ (PI3Kγ), Phosphatoinositides 3-kinase α (PI3Kα), Phosphatoinositides 3-kinase β (PI3Kβ), and/or Phosphatoinositides 3-kinase δ (PI3Kδ).

Compounds according to Formula (I), (Ia) and/or (Ib) are suitable for the modulation, notably the inhibition of the activity of phosphatoinositides 3-kinases (PI3K). Therefore the compounds of the present invention are also useful for the treatment of disorders which are mediated by PI3Ks. Said treatment involves the modulation - notably the inhibition or the down regulation - of the phosphatoinositides 3-kinases. Suitably, the compounds of the present invention are used for the preparation of a medicament for the treatment of a disorder selected from multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosis, glomerulonephritis systemic lupus, inflammatory bowel disease, lung inflammation, thrombosis or brain infection/inflammation, such as meningitis or encephalitis, Alzheimer's disease, Huntington's disease, CNS trauma, stroke or ischemic conditions, heart ischemia, cardiovascular diseases such as athero-sclerosis, heart hypertrophy, cardiac myocyte dysfunction, anaphylaxis, wound healing, aneurysm, venous and venous-like thrombosis, arterial thrombosis, ageing, dementia, peripheral arterial disease, acute coronary syndrome, atrial fibrillation, Crohn's disease, HIV, rhinitis, elevated blood pressure, or vasoconstriction.

Suitably, the compounds of Formula (I), (Ia) and/or (Ib) are useful for the treatment of autoimmune diseases or inflammatory diseases such as multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, lung inflammation, thrombosis or brain infection/inflammation such as meningitis or encephalitis.

Suitably, the compounds of Formula (I), (Ia) and/or (Ib) are useful for the treatment of neurodegenerative diseases including multiple sclerosis, Alzheimer's disease, Huntington's disease, CNS trauma, stroke, or ischemic conditions. Suitably, the compounds of Formula (I), (Ia) and/or (Ib) are useful for the treatment of cardiovascular diseases such as atherosclerosis, heart hypertrophy, cardiac myocyte dysfunction, elevated blood pressure, or vasoconstriction.

Suitably, the compounds of Formula (I), (Ia) and/or (Ib) are useful for the treatment of chronic obstructive pulmonary disease, anaphylactic shock fibrosis, psoriasis, allergic diseases, asthma, stroke, ischemic conditions, ischemia- reperfusion, platelets aggregation/activation, skeletal muscle atrophy/hypertrophy, leukocyte recruitment in cancer tissue, angiogenesis, invasion metastasis, in particular melanoma, Karposi's sarcoma, acute and chronic bacterial and viral infections, sepsis, transplantation rejection, graft rejection, glomerulo sclerosis, glomerulo nephritis, progressive renal fibrosis, endothelial and epithelial injuries in the lung, and lung airway inflammation.

Because the pharmaceutically active compounds of the present invention are active as PI3 kinase inhibitors, particularly the compounds that inhibit PI3Kα, either selectively or in conjunction with one or more of PI3Kδ, PI3Kβ, and/or PI3Kγ, they exhibit therapeutic utility in treating cancer. Suitably, the present invention relates to a method for treating or lessening the severity of a cancer selected from brain (gliomas), glioblastomas, Bannayan- Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma, and thyroid.

Suitably, the present invention relates to a method for treating or lessening the severity of a cancer selected from ovarian, pancreatic, breast, prostate, and leukemia.

When a compound of Formula (I), (Ia) and/or (Ib) is administered for the treatment of cancer, the term "co-administering" and derivatives thereof as used herein is meant either simultaneous administration or any manner of separate sequential administration of a PI3 kinase inhibiting compound, as described herein, and a further active ingredient or ingredients, known to be useful in the treatment of cancer, including chemotherapy and radiation treatment. The term further active ingredient or ingredients, as used herein, includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of treatment for cancer. Preferably, if the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.

Typically, any anti-neoplastic agent that has activity versus a susceptible tumor being treated may be co-administered in the treatment of cancer in the present invention. Examples of such agents can be found in Cancer Principles and Practice f Oncology by VT. Devita and S. Hellman (editors), 6^th edition (February 15, 2001 ), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved. Typical antineoplastic agents useful in the present invention include, but are not limited to, anti- microtubule or antimitotic agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkyl sulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclins, actinomycins and bleomycins; topoisomerase Il inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and anti-folate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; receptor tyrosine kinases; SH2/SH3 domain blockers; inhibitors of Serine/Threonine kinases; MAP kinase cascade blockers; Myo-inositol signaling inhibitors; inhibitors of RAS Oncogene; inhibitors of Phosphotidyl inositol-3 kinases; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; and cell cycle signaling inhibitors.

In one embodiment, the cancer treatment method of the claimed invention includes the co-administration a compound of formula I and/or a pharmaceutically acceptable salt, hydrate, solvate or pro-drug thereof and at least one anti-neoplastic agent, such as one selected from the following group: anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase Il inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, cell cycle signaling inhibitors, nucleoside reverse transcriptase inhibitors such as zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavidine, adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, elvucitabine, and similar agents; non-nucleoside reverse transcriptase inhibitors (including an agent having anti-oxidation activity such as immunocal, oltipraz, etc.) such as nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, capravirine, TMC-278, TMC-125, etravirine, and similar agents; protease inhibitors such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, atazanavir, tipranavir, palinavir, lasinavir, and similar agents; entry inhibitors such as enfuvirtide (T-20), T-1249, PRO-542, PRO-MO, TNX-355, BMS-806, 5-Helix and similar agents;integrase inhibitors such as L-870,180 and similar agents; budding inhibitors such as PA-344 and PA-457, and similar agents; and other CXCR4 and/or CCR5 inhibitors such as vicriviroc (Sch-C), Sch-D, TAK779, maraviroc (UK 427,857), TAK449, as well as those disclosed in WO 02/74769, PCT/US03/39644, PCT/US03/39975, PCT/US03/39619, PCT/US03/39618, PCT/US03/39740, and PCT/US03/39732, and similar agents. Because the pharmaceutically active compounds of the present invention are active as PI3 kinase inhibitors, particularly the compounds that modulate/inhibit PI3Kγ, either selectively or in conjunction with one or more of PI3Kδ, PI3Kβ, and/or PI3Kα, they exhibit therapeutic utility in treating a disease state selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, heart failure, multiorgan failure, kidney diseases, platelet aggregation, sperm motility, transplantation rejection, graft rejection, and lung injuries. When a compound of Formula (I), (Ia) and/or (Ib) is administered for the treatment of a disease state selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, sperm motility, transplantation rejection, graft rejection or lung injuries, the term "coadministering" and derivatives thereof as used herein is meant either simultaneous administration or any manner of separate sequential administration of a PI3 kinase inhibiting compound, as described herein, and a further active ingredient or ingredients, known to be useful in the treatment of autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, sperm motility, transplantation rejection, graft rejection, and/or lung injuries.

In one embodiment, the cardiovascular treatment method of the claimed invention includes the co-administration a compound of formula I and/or a pharmaceutically acceptable salt, hydrate, solvate or pro-drug thereof and at least one cardiovascular agent, such as one selected from the following group: calcium channel blocker, e.g. amlodipine; angiotensin Il receptor antagonist, e.g. eprosartan; angiotensin converting enzye inhitor, e.g. enalapril; renin inhibitor, e.g. aliskiren; Beta2 adrenoreceptor blocker, e.g. metoprolol; mixed alpha/beta blocker, e.g. carvedilol; diuretic, e.g. thiazine; PPAR agonists, e.g. rosiglitazone, HMG-CoA reductase inhibiotors ('statins'), e.g. atorvastatin; fibrates, e.g. fenofibrate; niacin receptor agonists, e.g. niacin; cholesterol absorption inhibotors, e.g. ezitamibe, asprin, purinergin antagonists, e.g. clopidogrel or prasugrel; phosphodiesterase inhibiotors, protease-activated receptor antagonists (PAR1 or PAR4), prostaglandin receptor or synthetic pathway modulators, Gbllb/llla antagonists or antibodies; serotonin receptor reupdate inhibitors, anitcoagulants, e.g. Factor Xa inhibotors, e.g. arixtra; Factor IX inhibotors, direct or indirect thrombin inhibitors, Factor Vila inhibitors, Vit K antagonists, heparins e.g. enoxaparin; and LP-PLA2 inhibitors, e.g. darlapadib.

Representative classes of agents for use in such combinations include, for treating asthma, anti-inflammatory steroids (in particular corticosteroids), anticholinergic agents, topical glucocorticoid agonists, PDE4 inhibitors, IKK2 inhibitors, A2a agonists, Beta₂-adrenoreceptor agonists (including both slow acting and long acting Beta₂-adrenoreceptor agonists), alpha 4 integrin inhibitors, and anti- muscarinics, and, for treating allergies, the foregoing agents, as well as H1 and H1/H3 antagonists. Representative agents for use in combination therapy for treating severe asthma include topically acting p38 inhibitors, and IKK2 inhibitors. The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical composition and thus pharmaceutical compositions comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier represent a further embodiment of the invention. These combinations are of particular interest in respiratory diseases and are conveniently adapted for inhaled or intranasal delivery.

Representative classes of agents for use in such combinations include, for treating rheumatoid arthritis include one or more other therapeutic agents, for example selected from NSAIDS, corticosteroids, COX-2 inhibitors, cytokine inhibitors, anti-TNF agents, inhibitors of oncostatin M, anti-malarials, immunosuppressivess and cytostatics.

Two classes of medication are contemplated for the treatment of RA, these may be classified as "fast acting" and "slow acting" or "second line" drugs (also referred to as Disease Modifying Antirheumatic Drugs or DMARDS). The first line drugs such as typical NSAIDs (e.g. aspirin, ibuprofen, naproxen, etodolac), corticosteroids (e.g. prednisone). Second line drugs include COX-2 inhibitors and anti-TNF agents. Examples of COX-2 inhibitors are celecoxib (Celebrex), etoricoxib and rofecoxib (Vioxx).

Anti-TNF agents include infliximab (Remicade), etanercept (Enbrel) and adalimumab (Humira). Other "biological" treatments include anakinra (Kineret), Rituximab, Lymphostat-B, BAFF/APRIL inhibitors and CTLA-4-lg or mimetics thereof. Other cytokine inhibitors include leflunomide (Arava). Further second line drugs include gold preparations (Auranofin (Ridaura tablets) or Aurothiomalate (Myocrisin injection)), medicines used for malaria: (Hydroxychloroquine (Plaquenil)), medicines that suppress the immune system (Azathioprine (Imuran, Thioprine), methotrexate (Methoblastin, Ledertrexate, Emthexate), cyclosporin (Sandimmun, Neoral)), Cyclophosphamide (Cycloblastin), Cytoxan, Endoxan), D-Penicillamine (D-Penamine), Sulphasalazine (Salazopyrin), nonsteroidal anti inflammatory drugs (including aspirin and ibuprofen). The present invention also provides for so-called "triple" therapy, comprising a compound of formula (I), (Ia) and/or (Ib) or a pharmaceutically acceptable salt thereof together with ₂-adrenoreceptor agonist and an anti-inflammatory corticosteroid. Preferably this combination is for treatment and/or prophylaxis of asthma, COPD or rhinitis, such as, allergic rhinitis. The Beta₂-adrenoreceptor agonist and/or the anti-inflammatory corticosteroid can be described above and/or as described in WO 03/030939 A1. Biological assays

PI3K alpha Leadseeker SPA Assay

Compounds of the present invention were tested according to the following assays and found as inhibitors of PI3 kinases, particularly PI3Kα. The activities (IC₅₀) of exemplified compounds range from about 1 nM to about 10 μM against PI3Kα. Assay principle

SPA imaging beads are microspheres containing scintillant which emit light in the red region of the visible spectrum. As a result, these beads are ideally suited to use with a CCD imager such as the Viewlux. The Leadseeker beads used in this system are polystyrene beads that have been coupled with polyethyleneimine.

When added to the assay mixture, the beads absorb both the substrate (PIP2) and product (PIP3). Adsorbed P³³-PIP3 will cause an increase in signal, measured as ADUs (analog to digital units). This protocol details the use of the PEI-PS Leadseeker beads for assays using His-p1 10/p85 PI3K alpha.

Assay protocol

Solid compounds are typically plated with 0.1 μl of 100% DMSO in all wells (except column 6 and 18) of a 384-well, flat bottom, low volume plate (Greiner 784075). The compounds are serially diluted (3-fold in 100% DMSO) across the plate from column 1 to column 12 and column 13 to column 24 and leave column 6 and 18 containing only DMSO to yield 11 concentraions for each test compound.

The assay buffer contains MOPS (pH 6.5), CHAPS, and DTT. PI3K alpha and PIP2 (L-alpha-D-myo-Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]3-O- phospho linked, D(+)-sn-1 ,2-di-O-octanoylglyceryl, CellSignals # 901 ) are mixed and incubated in the plate with compound for 30min prior to starting the reaction with the addition of P³³-ATP and MgC^ (reagents added using Zoom). Enzyme-free wells (column 18) are typically done to determine the low control. PEI-PS Leadseeker beads in PBS/EDTA/CHAPS are added (by Multidrop) to quench the reaction, and the plates are allowed to incubate for at least one hour (typically overnight) before centrifugation. The signal is determined using a Viewlux detector and is then imported into curve fitting software (Activity Base) for construction of concentration response curves. The percent inhibition of activity was calculated relative to high controls (C1 , 0.1 μl DMSO in column 6, rows A-P)) and low controls (C2, 5 μl of 40 uM PIP2 in buffer in column 18, rows A-P) using, 100^*(1-(U1- C2)/(C1-C2)). The concentration of test compound yielding 50% inhibition was determined using the equation, y = ((Vmax^*x) / (K+x)) + Y2, where "K" was equal to the IC50. The IC50 values were converted to plC50 values, i.e., -log IC50 in Molar concentration.

Celluar assays: DAY 1

• Plate cells before noon o 1OK cells/well in clear flat-bottomed 96-well plates (f.v. 105ul) o Last four wells in last column receive media only o Place in 37degC incubator overnight • Compound plate o Prepare in polypropylene round-bottomed 96-well plates; 8 compounds per plate, 1 1-pt titrations of each (3x serial dilution), DMSO in last column

(0.15% f.c. on cells) o 15ul in first well, 1 OuI DMSO in the rest; take 5ul from first well and mix in next, continue across plate {excluding last column); seal with foil lid and place at 4degC

DAY 2

• Take out Lysis buffer inhibitors (4degC/-20degC) and compound plates (4degC), thaw on bench top; make 1x Tris wash buffer (WB) to fill reservoir on plate washer and top off bench supply (use MiIiQ), turn on centrifuge to allow it to cool

• Block MSD plates o Make 20ml 3% blocking solution/plate (600mg blocker A in 20ml WB), add 150ul/well and incubate at RT for at least 1 hr

• Add compound (while blocking) o Add 30OuI growth media (RPMI w/ Q, 10% FBS) per well (682x dil of compound) to each compound plate o Add 5ul compound dilution into each well {f.v. 11OuI) on duplicate plates o Place in 37degC incubator for 30min

• Make lysates o Prepare MSD Lysis buffer; for 10ml add 20OuI protease inhibitor solution, and 100ul each of Phosphatase inhibitors I & Il (Keep on ice until ready for use) o Remove plates post-incubation, aspirate media with plate washer, wash 1x with cold PBS, and add 8OuI MSD Lysis buffer per well; incubate on shaker at 4degC for ≥30min o Spin cold at 2500rpm for 10min; leave plates in 4degC centrifuge until ready for use

• AKT duplex assay o Wash plates (4x with 200ul/well WB in plate washer); tap plates on paper towel to blot o Add 6OuI of lysates/well, incubate on shaker at RT for 1 hr o During incubation prepare detection Ab (3ml/plate; 2ml WB and 1 ml blocking solution w/ Ab at 1OnM); repeat wash step as above o Add 25ul of Ab/well, incubate on shaker at RT for 1 hr; repeat wash step as above o Add 150ul/well 1x Read Buffer (dilute 4x stock in ddH2O, 20ml/plate), read immediately • Analysis o Observe all the data points at each compound concentration. o The data point from highest inhibitor concentration must be equal or greater than 70% of DMSO control. o IC50 for duplicate runs must be within 2-fold of each other (not flagged in summary template). o Y min must be greater than zero; if both mins are red flagged (>35) then compound is listed as inactive (IC50= > highest dose). If only one min is red flagged, but still <50 then call IC50 as listed. o Any data points equal or greater than 30% off the curve will not be considered.

Cell Growth/Death Assay:

BT474, HCC1954 and T-47D (human breast) were cultured in RPMI-1640 containing 10% fetal bovine serum at 37⁰C in 5% CO₂ incubator. Cells were split into T75 flask (Falcon #353136) two to three days prior to assay set up at density which yields approximately 70-80% confluence at time of harvest for assay. Cells were harvested using 0.25% trypsin-EDTA (Sigma #4049). Cell counts were performed on cell suspension using Trypan Blue exclusion staining. Cells were then plated in 384 well black flat bottom polystyrene (Greiner #781086) in 48 μl of culture media per well at 1 ,000 cells/well. All plates were placed at 5% CO₂, 37⁰C overnight and test compounds were added the following day. One plate was treated with CellTiter-Glo (Promega #G7573) for a day 0 (t=0) measurement and read as described below. The test compounds were prepared in clear bottom polypropylene 384 well plates (Greiner#781280) with consecutive two fold dilutions. 4 μl of these dilutions were added to 105 μl culture media, after mixing the solution, 2 μl of these dilutions were added into each well of the cell plates. The final concentration of DMSO in all wells was 0.15%. Cells were incubated at 37⁰C, 5% CO₂ for 72 hours. Following 72 hours of incubation with compounds each plate was developed and read. CellTiter-Glo reagent was added to assay plates using a volume equivalent to the cell culture volume in the wells. Plates were shaken for approximately two minutes and incubated at room temperature for approximately 30 minutes and chemiluminescent signal was read on the Analyst GT (Molecular Devices) reader. Results were expressed as a percent of the t=0 and plotted against the compound concentration. Cell growth inhibition was determined for each compound by fitting the dose response with a 4 or 6 parameter curve fit using XLfit software and determining the concentration that inhibited 50% of the cell growth (glC50) with the Y min as the t=0 and Y max as the DMSO control. Value from wells with no cells was subtracted from all samples for background correction. Additional references:

The compounds of the present invention can also be tested to determine their inhibitory activity at PI3Kα, PI3Kδ, PI3Kβ and PI3Kγ according to the following references: For all PI3K isoforms:

1. Cloning, expression, purification, and characterization of the human Class Ia phosphoinositide 3-kinase isoforms: Meier, T.I.; Cook, J.A.; Thomas, J. E.; Radding, J.A.; Horn, C; Lingaraj, T.; Smith, M. C. Protein Expr. Purif., 2004, 35(2), 218. 2. Competitive fluorescence polarization assays for the detection of phosphoinositide kinase and phosphatase activity: Drees, B. E.; Weipert, A.; Hudson, H.; Ferguson, C. G.; Chakravarty, L.; Prestwich, G. D. Comb. Chem. High Throughput.Screen., 2003, 6(4), 321. For PI3Kγ: WO 2005/011686 A1 The pharmaceutically active compounds within the scope of this invention are useful as PI3 Kinase inhibitors in mammals, particularly humans, in need thereof.

The present invention therefore provides a method of treating diseases associated with PI3 kinase inhibition, particularly: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries and other conditions requiring PI3 kinase modulation/inhibition, which comprises administering an effective compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate or pro-drug thereof. The compounds of Formula (I) also provide for a method of treating the above indicated disease states because of their ability to act as PI3 inhibitors. The drug may be administered to a patient in need thereof by any conventional route of administration, including, but not limited to, intravenous, intramuscular, oral, subcutaneous, intradermal, and parenteral.

The pharmaceutically active compounds of the present invention are incorporated into convenient dosage forms such as capsules, tablets, or injectable preparations. Solid or liquid pharmaceutical carriers are employed. Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline, and water. Similarly, the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.

The pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to give the desired oral or parenteral products. Doses of the presently invented pharmaceutically active compounds in a pharmaceutical dosage unit as described above will be an efficacious, nontoxic quantity preferably selected from the range of 0.001 - 100 mg/kg of active compound, preferably 0.001 - 50 mg/kg. When treating a human patient in need of a PI3K inhibitor, the selected dose is administered preferably from 1-6 times daily, orally or parenterally. Preferred forms of parenteral administration include topically, rectally, transdermal^, by injection and continuously by infusion. Oral dosage units for human administration preferably contain from 0.05 to 3500 mg of active compound. Oral administration, which uses lower dosages is preferred. Parenteral administration, at high dosages, however, also can be used when safe and convenient for the patient.

Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular PI3 kinase inhibitor in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular patient being treated will result in a need to adjust dosages, including patient age, weight, diet, and time of administration.

The method of this invention of inducing PI3 kinase inhibitory activity in mammals, including humans, comprises administering to a subject in need of such activity an effective PI3 kinase modulating/inhibiting amount of a pharmaceutically active compound of the present invention.

The invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use as a PI3 kinase inhibitor.

The invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use in therapy. The invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use in treating autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries.

The invention also provides for a pharmaceutical composition for use as a PI3 inhibitor which comprises a compound of Formula (I) and a pharmaceutically acceptable carrier.

The invention also provides for a pharmaceutical composition for use in the treatment of autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries, which comprises a compound of Formula (I) and a pharmaceutically acceptable carrier.

No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention.

In addition, the pharmaceutically active compounds of the present invention can be co-administered with further active ingredients, including compounds known to have utility when used in combination with a PI3 kinase inhibitor.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way.

Compositions The compounds of the invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Accordingly, in another embodiment, this invention is directed to pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carries comprised of one or more pharmaceutically-acceptable excipients. Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing

Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press). The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company). The pharmaceutically active compounds of the present invention may be incorporated into convenient dosage forms such as capsules, tablets, or injectable preparations. Solid or liquid pharmaceutical carriers may be employed. Examples of solid carriers include, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose and sodium carboxymethyl cellulose), calcium sulfate, dibasic calcium phosphate, sodium alginate, alginic acid, tragacanth, guar gum, povidone, crospovidone, sodium starch glycolate, croscarmelose, calcium stearate, and combinations thereof. Liquid carriers include syrup, peanut oil, olive oil, saline, and water. Similarly, the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.

The amount of solid carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.

The pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to give the desired oral or parenteral products.

Doses of the presently invented pharmaceutically active compounds in a pharmaceutical dosage unit as described above will be an efficacious, nontoxic quantity preferably selected from the range of 0.001 - 100 mg/kg of active compound, preferably 0.001 - 50 mg/kg. When treating a human patient in need of a PI3K inhibitor, the selected dose is administered preferably from 1-6 times daily, orally or parenterally. Preferred forms of parenteral administration include topically, rectally, transdermal^, by injection, and continuously by infusion. Oral dosage units for human administration preferably contain from 0.05 to 3500 mg of active compound. Oral administration, which uses lower dosages is preferred. Parenteral administration, at high dosages, however, also can be used when safe and convenient for the patient. Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular PI3 kinase inhibitor in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular patient being treated will result in a need to adjust dosages, including patient age, weight, diet, and time of administration.

Additionally, the compounds of the invention may be administered as prodrugs. As used herein, a "prodrug" of a compound of the invention is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of the invention in vivo. Administration of a compound of the invention as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify the duration of action of the compound in vivo; (C) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome or overcome a side effect or other difficulty encountered with the compound. Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleaved in vivo. Such modifications, which include the preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art. For example, where a -COOH or -OH group is present, pharmaceutically acceptable esters can be employed, for example methyl, ethyl, pivaloyloxymethyl, and the like for -COOH, and acetate maleate and the like for -OH. Sustained release or prodrug formulations may be obtained by using those esters known in the art for modifying solubility or hydrolysis characteristics.

The invention also provides for the use of a compound of Formula (I), (Ia) and/or (Ib) in the manufacture of a medicament for use as a PI3 kinase inhibitor. The invention also provides for the use of a compound of Formula (I), (Ia) and/or (Ib) in the manufacture of a medicament for use in therapy.

The invention also provides for the use of a compound of Formula (I), (Ia) and/or (Ib) in the manufacture of a medicament for use in treating autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection, and lung injuries.

The invention also provides for a pharmaceutical composition for use as a PI3 inhibitor which comprises a compound of Formula (I), (Ia) and/or (Ib) and a pharmaceutically acceptable carrier.

The invention also provides for a pharmaceutical composition for use in the treatment of autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries, which comprises a compound of Formula (I), (Ia) and/or (Ib) and a pharmaceutically acceptable carrier. No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention.

Experimental Details

The compounds of the following examples are readily made according to Schemes I - IV or by analogous methods.

Example 1

Method A (Scheme I)

Preparation of 9-(methyloxy)-1-phenyl-5,6-dihydrobenzo[f]quinazolin-3-amine

In a microwave vial was combined 7-methoxy-2-tetralone (1 mmol, 1.0 eq.), ethanol (4ml_), and benzaldehyde (1 mmol, 1.0 eq.). Guanidine carbonate (2mmol, 2.0 eq.) was added and the vial was capped and heated in a microwave at 18O⁰C for 20 minutes. After cooling to ambient temperature, the vial was decapped and silver oxide (1 mmol, 1.0 eq) was added. The vial was recapped and heated in the microwave at 120° C for 10 minutes. The reaction was diluted with ethyl acetate and filtered through a plug of Celite. The filtrate was concentrated to dryness and purified using a Gilson prep system (10 - 90% acetonitrile/water (0.1 % trifluoroacetic acid) over 6 minutes. ¹H NMR (dβ-dmso): δ 7.38(br s, 5H), 7.07(d, 1 H), 6.75(br s, 2H), 6.53(dd, 1 H), 6.08(d, 1 H), 3.20(s, 3H), 2.78(m, 2H), 2.65(m, 2H). MS (ES+) 304 m/e [M+H]⁺

10

Examples prepared by Method A (Scheme I):

* Compound obtained from in-situ deprotection of product derived from 3- OTBDMS benzaldehyde.

5 ** Compound obtained from in-situ de-bromination of product derived from 5-bromo-2- thiophenecarbaldehyde.

H=H=H= Compound obtained starting with 4-cyano-4-fluorobenzaldehyde.

Example 2

Preparation of N-methyl-9-(methyloxy)-1-phenyl-5,6-dihydrobenzo[f]quinazolin-3- amine

In a round-bottomed flask was placed 9-(methyloxy)-1-phenyl-5,6- dihydrobenzo[f]quinazolin-3-amine (50mg, 1eq.) previously prepared as described in Method A. This was dissolved in DMF (3ml_) and treated with 95% sodium hydride (8mg, 2eq.) at room temperature. The mixture was allowed to stir at room temperature for 2 minutes, and then treated with methyl iodide (excess). The reaction was stirred at room temperature for 2 hours and then concentrated to dryness. The residue was taken up in water and extracted with ethyl acetate. The organics were collected, dried over magnesium sulfate then filtered. The filtrate was concentrated to dryness and the residue was purified using thin-layer chromatography. The chromatography plates were eluted with 30% ethyl acetate in hexane. The desired band was collected and washed with ethyl acetate. The washings were filtered and concentrated to dryness to provide N-methyl-9- (methyloxy)-1-phenyl-5,6-dihydrobenzo[f]quinazolin-3-amine (6.5mg). ¹H NMR (CDCI₃): δ 7.5(br m, 2H), 7.36(br m, 3H), 7.06(d, 1 H), 6.57(dd, 1 H), 6.24(d, 1 H), 5.10(br q, 1 H), 3.25(s, 3H), 3.07(d, 3H), 2.84(br m, 4H). MS (ES+) m/e 318 [M+H]⁺.

Scheme Il

Conditions: Method B: a) benzaldehyde, guanidine carbonate, EtOH, μwave, 180 ⁰C; b) Ag₂O, CH3C1.

Method C: a) benzaldehyde, guanidine carbonate, EtOH, μwave, 180 ⁰C; b) Ag₂O, EtOH, μwave, 120 ⁰C. Example 3

Method B (scheme II)

Preparation of 9-(methyloxy)-1-[4-(methyloxy)phenyl]-5,6-dihydro-benzo[f]quin- azolin-3-amine

Method B, Step a:

9-(methyloxy)-1-[4-(methyloxy)phenyl]-1 ,2,5,6-tetrahydrobenzo[f]quinazolin-3-amine trifluoroacetate

In a microwave vial was combined 7-methoxy-2-tetralone (1 mmol, 1.0 eq.), ethanol (4ml_), and 4-methoxybenzaldehyde (1 mmol, 1.0 eq.) Guanidine carbonate (2mmol, 2.0 eq.) was added and the vial was capped and heated in a microwave at 18O⁰C for 20 minutes. The contents were concentrated to dryness and the residue was taken up in ethyl acetate. This solution was treated with water and a saturated sodium bicarbonate solution and the mixture was allowed to stir for 5 minutes. The resulting solids were collected on a filter, washed with ethyl acetate and dissolved in DMSO for purification on the Gilson prep system (10 - 90% acetonitrile/water (0.1% triflouroacetic acid) over 6 minutes. The resulting solids were isolated as the trifluoroacetate salt and used in the next step. ¹H NMR (d₆-dmso): δ 10.40(s, 1 H), 9.05(s, 1 H), 7.45(s, 2H), 7.32(d, 2H), 7.00(d, 1 H), 6.89(d, 2H), 6.57(dd, 1 H), 6.49(d, 1 H), 5.65(s, 1 H), 3.68(s, 3H), 3.58(s, 3H), 2.76(br m, 2H), 2.49(br m, 2H). MS (ES+) m/e 336 [M+H]⁺ . Method B, Step b: 9-(methyloxy)-1-[4-(methyloxy)phenyl]-5,6-dihydrobenzo[f] quinazolin-3-amine

The 9-(methyloxy)-1-[4-(methyloxy)phenyl]-1 ,2,5,6-tetrahydrobenzo[f]quinazolin-3- amine trifluoroacetate (44mg, O.i mmol) (from Method B, step a) was taken up in chloroform (6ml_) containing silver (I) oxide (50mg, 0.2mmol) and stirred at room temperature for three days. The reaction was filtered through a silica gel pad, which was subsequently washed with a 1 :1 methanol/ethyl acetate solution. The filtrate was concentrated and the residue was purified using thin-layer chromatography. The silica gel plates were eluted with ethyl acetate and a bright blue band was collected. After washing the collected band with ethyl acetate and concentrating to dryness 9-(methyloxy)-1-[4-(methyloxy)phenyl]-5,6- dihydrobenzo[f]quinazolin-3-amine was obtained as a white powder (8.5mg). ¹H NMR (de-dmso): δ 7.32(d, 2H), 7.08(d, 1 H), 6.92(d, 2H), 6.69(s, 2H), 6.54(d, 1 H), 6.18(s, 1 H), 3.75(s, 3H), 3.28(s, 3H), 2.76(m, 2H), 2.63(m, 2H). MS (ES+) m/e 334 [M+H]⁺ .

Example 4 Method C: Preparation of 9-(methyloxy)-1 -(3-thienyl)-5,6-dihydrobenzo[f]quinazolin-3-amine

Method C, Step a:

9-(methyloxy)-1-(3-thienyl)-1 ,2,5,6-tetrahydrobenzo[f]quinazolin-3-amine trifluoroacetate

In a microwave vial was combined 7-methoxy-2-tetralone (1 mmol, 1.0 eq.), ethanol (4mL), and 4-methoxybenzaldehyde (1 mmol, 1.0 eq.). Guanidine carbonate (2mmol, 2.0 eq.) was added and the vial was capped and heated in a microwave at 18O⁰C for 20 minutes. The contents were concentrated to dryness and the residue was taken up in ethyl acetate. This solution was treated with water and a saturated sodium bicarbonate solution and the mixture was allowed to stir for 5 minutes. The resulting solids were collected on a filter, washed with ethyl acetate and dissolved in DMSO for purification on the Gilson prep system (10 - 90% acetonitrile/water (0.1% triflouroacetic acid) over 6 minutes. The resulting solids were isolated as the trifluoroacetate salt and used in the next step. ¹H NMR (dβ-dmso): δ 10.25(s, 1 H), 9.05(s, 1 H), 7.50(m, 1 H), 7.43(s, 2H), 7.06(dd, 1 H), 7.02(d, 1 H), 6.61 (dd, 1 H), 6.59(s, 1 H), 5.79(d, 1 H), 3.61 (s, 3H), 2.76(m, 2H), 2.46(m, 2H). MS (ES+) m/e 312 [M+H]⁺ .

Method C, Step b:

9-(methyloxy)-1-(3-thienyl)-5,6-dihydrobenzo[f]quinazolin-3-amine

The 9-(methyloxy)-1 -(3-thienyl)-1 ,2,5,6-tetrahydrobenzo[f]quinazolin-3-amine trifluoroacetate (40mg) from Method C, Step a was placed in a microwave vial with ethanol (3.5ml_) and silver oxide (80mg, 1.0 eq). The vial was capped and heated in the microwave at 120° Celsius for 5-10 minutes. The reaction was diluted with ethyl acetate and filtered through a silica gel pad, which was subsequently washed with a 1 :1 mixture of methanol/ethyl acetate. The filtrate was concentrated and the residue was purified using thin-layer chromatography. The silica gel plates were eluted with ethyl acetate and the desired band was collected. After washing the collected band with ethyl acetate and concentrating to dryness the desired product was obtained as a white crystalline solid (14mg). ¹H NMR (dβ-dmso): δ 7.67(d, 1 H), 7.54(dd, 1 H), 7.10(d, 1 H), 6.98(d, 1 H), 6.73(br s, 2H), 6.59(dd, 1 H), 6.28(d, 1 H), 3.37(s, 3H), 2.77(m, 2H), 2.66(m, 2H). MS (ES+) m/e 310 [M+H]⁺ .

Examples prepared by Method C

Scheme

Conditions: a) benzaldehyde, thiourea, EtOH, reflux; b) MeI, THF, NaOH; c) mCPBA, MeCl₂; d) amine, ethanol, μwave, 160 ⁰C. Example 5

Method D (Scheme III)

Preparation of 3-{[1-(4-chlorophenyl)-5,6-dihydrobenzo[f]quinazolin-3-yl]amino}-1- propanol

Method D, Step a: 1-(4-chlorophenyl)-1 ,4,5,6-tetrahydrobenzo[f]quinazoline-3(2H)-thione

In a round-bottomed flask was combined 2-tetralone (1 eq.), thiourea (2 eq.), 4- chlorobenzaldehyde (1 eq, 2.8g), and ethanol (10OmL). This mixture was treated with concentrated hydrochloric acid (2ml_) and heated to reflux for 14 hours. The reaction was concentrated to one half of its original volume, then allowed to cool to room temperature. The mixture was then stirred vigorously while adding 50 ml. of a 2:1 water to ethanol mixture. The resulting solids were collected on a filter and washed with water. After air-drying an off-white powder was obtained. ¹H NMR (d₆- dmso): δ 10.15(s, 1 H), 9.25(s, 1 H), 7.35(m, 4H), 7.05(d, 1 H), 6.95(m, 2H), 6.88(d, 1 H), 5.44(s, 1 H), 2.77(m, 2H), 2.48(m, 2H). MS (ES+) m/e 327 [M+H]⁺ .

Method D, Step b: 1-(4-chlorophenyl)-3-(methylthio)-5,6-dihydrobenzo[f]quinazoline

The thiopyrimidine (2g) obtained from Method D, Step a was dissolved in THF (5OmL) and treated with a 2.5M NaOH solution (3mL). To this was added methyl iodide (1.2 eq) and the resulting solution was stirred at room temperature for 14 hours. The reaction was diluted with water and diethyl ether. The organics were collected and dried over magnesium sulfate. The drying salts were removed by filtration and concentrated to dryness. The residue was purified by silica gel chromatography to provide the desired thiomethyl derivative. ¹H NMR (CDCI₃): δ 7.52(d, 2H), 7.32(d, 2H), 7.23(d, 1 H), 7.13(dd, 1 H), 6.92(dd, 1 H), 6.88(d, 1 H), 2.60(s, 3H).

Method D, Step c: 1-(4-chlorophenyl)-3-(methylsulfonyl)-5,6-dihydrobenzo[f]quinazoline

The thiomethylpyrimidine (50mg) from Method D, Step b was dissolved in methylene chloride (5ml_) and treated with mCPBA (50mg). The reaction was stirred at room temperature for 5 min. then concentrated to dryness. The residue was taken up in a saturated solution of sodium bicarbonate and stirred for 5 min. The aqueous layer was extracted with ethyl acetate and the organic layer was separated and dried over magnesium sulfate. The drying salts were removed by filtration and the filtrate was concentrated to dryness. The residue was triturated with a diethyl ether/hexanes mixture to provide the desired sulfone as a white powder. ¹H NMR (CDCI₃): δ 7.58(d, 2H), 7.38(d, 2H), 7.32(d, 1 H), 7.26(m, 1 H), 7.02(m, 2H), 3.41 (s, 3H), 3.15(m, 2H), 3.05(m, 2H).

Method D, Step d: 3-{[1-(4-chlorophenyl)-5,6-dihydrobenzo[f]quinazolin-3-yl]amino}-1-propanol

The sulfone (30mg) from Method D, Step c was placed in a microwave tube containing 3-propanolamine (60mg) and ethanol (2ml_). The tube was capped and heated in a microwave reactor at 16O⁰C for 10 min. After cooling, the reaction contents were concentrated to an oil and dissolved in ethyl acetate. The organics were washed with water, then dried over magnesium sulfate. The drying salts were removed by filtration and the filtrate was concentrated to dryness. The residue was purified using thin-layer chromatography. The chromatography plates were eluted with ethyl acetate and the desired band was collected and washed with ethyl acetate. The filtrate was concentrated to provide the desired product as a light yellow powder (15mg). ¹H NMR (CDCI₃): δ 7.47(d, 2H), 7.33(m, 2H), 7.21 (d, 1 H), 7.06(dd, 1 H), 6.89(dd, 1 H), 6.72(d, 1 H), 5.37(t, 1 H), 4.5 (br s, 1 H), 3.65(m, 4H), 2.95(m, 2H), 2.84(m, 2H), 1.76(p, 2H). MS (ES+) m/e 366 [M+H]⁺ .

Examples prepared by Method D

Conditions: a) POCl₃, μwave, 180 ⁰C; b) amine, EtOH, μwave, 160 ⁰C

Example 6

Method E (scheme IV)

9-(methyloxy)-N¹-[3,4,5-tris(methyloxy)phenyl]-5,6-dihydrobenzo[f]quinazoline-1 ,3- diamine

Method E, Step a:

Preparation of 1-chloro-9-(methyloxy)-5,6-dihydrobenzo[f]quinazolin-3-amine

In a microwave vial was placed 3-amino-9-(methyloxy)-6,10b- dihydrobenzo[f]quinazolin-1 (5H)-one (500mg) (US Patent 5,405,851 ). Phosphorus oxychloride (3.5ml_) was added and the tube was heated to 18O⁰C for 10 min. in a microwave reactor. The residue was transferred to a round-bottomed flask and concentrated to an oil. The residue was treated with a saturated sodium bicarbonate solution (15OmL) and heated to reflux for 1 hour. The reaction was cooled and extracted with ethyl acetate. The organics were dried over magnesium sulfate, filtered and the residue was concentrated to an oil. The residue was purified by silica gel chromatography to provide 1-chloro-9-(methyloxy)-5,6- dihydrobenzo[f]quinazolin-3-amine (294mg) as a yellow powder. ¹H NMR (d₆- dmso): δ 7.53(d, 1 H), 7.16-7.20(m, 3H), 6.78 (dd, 1 H), 3.74 (s, 3H), 2.71 (m, 2H), 2.67 (m, 2H). Method E, Step b:

In a microwave tube was combined 1-chloro-9-(methyloxy)-5,6-dihydrobenzo[f]quin- azolin-3-amine (20mg, 1 wt), 3,4,5-trimethoxyaniline (40mg, 2 wt.) and ethanol (3.5ml_). The contents were heated to 16O⁰C for 10 min. in a microwave reactor. The reaction was concentrated to dryness and the residue was taken up in a saturated sodium bicarbonate solution and extracted with ethyl acetate. The organics were dried over magnesium sulfate, filtered and concentrated to dryness. The residue was purified by silica gel chromatography and triturated with diethyl ether to provide 9-(methyloxy)-N¹-[3,4,5-tris(methyloxy)phenyl]-5,6- dihydrobenzo[f]quinazoline-1 ,3-diamine (15mg) as a white powder. ¹H NMR (CDCI₃): δ 7.25(d, 1 H), 7.19(d, 1 H), 7.14(s, 1 H), 6.76(s, 2H), 6.70(dd, 1 H), 4.78 (s, 2H), 3.83 (s, 6H), 3.80(s, 3H), 3.78(s, 3H), 2.75(m, 2H), 2.67(m, 2H). MS (ES+) m/e 409 [M+H]⁺ .

Examples prepared by Method E

(salt)

loxy )-

Scheme V

Conditions: boronic acid, Pd(dppf)₂Cl₂, Dioxane/2 M K₂CO₃, microwave, 120 ⁰C. Example 7

Method F

Preparation of 8-chloro-1-(4-fluorophenyl)-5, 6-dihydrobenzo[f]quinazolin-3-amine trifluoroacetate (salt)

A mixture of 1 ,8-dichloro-5,6-dihydrobenzo[f]quinazolin-3-amine (0.06 g, 0.226 mmol), 4-fluorophenylboronic acid (0.032 g, 0.226mmol) and Pd(dppf)2Cl2-CH2Cl2 (18 mg, 0.023 mmol) in 3 ml of 2:1 Dioxane/2 M K2CO3 was heated to 120 ⁰C by MW for 15 min. The resulting biphase mixture was passed through an SCX column and the eluent was reduced in vacuo. The crude was purified by a Gilson prep system (acetonitrile/water (0.1 % triflouroacetic acid) minutes to afford the title compound, (31 mg, 43%); ¹H NMR (d₆-dmso): 7.52(t, 2H), 7.35(s, 1 H), 7.25(t, 2H), 7.10(br s, 2H), 6.95(d, 1 H), 6.55(d, 1 H), 2.95(m, 2H), 2.75(m, 2H). MS (ES+) 326 m/e [M+H]⁺.

Examples prepared by Method F (scheme 5)

Examples prepared by Method F

Scheme Vl

Preparation of 1-(3-amino-1 H-indazol-5-yl)-8-chloro-5,6-dihydrobenzo[f]quinazolin- 3-amine

A stirred mixture of 1 ,8-dichloro-5,6-dihydrobenzo[f]quinazolin-3-amine (0.05 g, 0.19 mmol), boron ester (0.065 g, 0.19 mmol) and Pd(PPh^ (5 mg, 0.0038 mmol) in 3 ml of 1 :2 IPA/Sat'd NaHCC>3 was heated to 150 ⁰C by MW for 30 min. This procedure was repeated on the same scale and the two reaction mixtures were combined for workup and purification. The biphasic mixture was extracted twice with CH₂CI₂ followed by EtOAc. Both layers contained desired product, so they were combined and concentrated. The crude material was mixed with and 1 ml. of cone. HCI in 5 ml ethanol was heated under reflux for 1.5 hours. The mix was concentrated and the residue was stirred with 5 ml of water and neutralized with ammonium hydroxide and passed through an SCX column. The eluent was purified by silica gel chromatography eluting with 1-10% MeOH in DCM, to afford the title compound, (30 mg, 22%); ¹H NMR (d₆-dmso): 7.95(s, 1 H), 7.32(s, 1 H), 7.15(s, 2H), 6.86(d, 1 H), 6.75(s, 2H), 6.58(d, 1 H), 5.45(s, 2H), 2.90(m, 2H), 2.70(m, 2H). MS (ES+) m/e 363 [M+H]⁺.

Examples prepared by Method F, using Pd(PPh3)4 as catalyst (similar to the preparation of 1-(3-amino-1 H-indazol-5-yl)-8-chloro-5,6-dihydrobenzo[f]quinazolin- 3-amine)

Scheme VII

Conditions: aniline, isopropanol, microwave, 170 ⁰C.

Example 8

Method G (scheme VII)

Preparation of 8-chloro-N¹-phenyl-5,6-dihydrobenzo[f]quinazoline-1 ,3-diamine

In a microwave tube was combined 1 ,8-dichloro-5,6-dihydrobenzo[f]quinazolin-3- amine (40 mg, 0.151 mmol), aniline (27 μl, 0.302 mmol) and isopropanol. The contents were heated to 17O⁰C for 10 min. in a microwave reactor. The residue was purified by a Gilson prep system (acetonitrile/water (0.1 % triflouroacetic acid) over 10 minutes) to afford the title compound, (34 mg, 71%); ¹H NMR (dβ-dmso): 9.75(s, 1 H), 7.92(br s, 2H), 7.79(d, 1 H), 7.64(d, 2H), 7.47(d, 1 H), 7.38(m, 3H), 7.20(t, 1 H), 2.90(m, 2H), 2.77(m, 2H). MS (ES+) 323 m/e [M+H]⁺. Examples prepared by Method G (scheme VII)

Examples prepared by Method G (Scheme VII)

Scheme VIII

Conditions: RNH₂, isopropanol, HCI (cat), microwave, 170 ⁰C.

Example 9

Method H (Scheme VIII)

Preparation of 4-[(3-amino-8-chloro-5,6-dihydrobenzo[f]quinazolin-1 ^■ yl)amino]benzonitrile

In a microwave tube was combined 1 ,8-dichloro-5,6-dihydrobenzo[f]quinazolin-3- amine (30 mg, 0.113 mmol), aniline (27 mg, 0.226 mmol), in isopropanol (2 ml.) and heated to 17O⁰C for 10 min. in a microwave reactor. No reaction had taken place. One drop of cone. HCI was added to the reaction mixture and the resulting mixture was heated to 17O⁰C for 10 min. in a microwave reactor. The crude reaction mixture was purified by a Gilson prep system (acetonitrile/water (0.1% triflouroacetic acid)) to afford the title compound, (8.1 mg, 20%); ¹H NMR (d₆-dmso): 10.00(s, 1 H), 7.92(d, 2H), 7.85(br s, 2H), 7.79(d, 2H), 7.75(d, 1 H), 7.47(s, 1 H), 7.38(d, 1 H), 2.90(m, 2H), 2.77(m, 2H). MS (ES+) 349 m/e [M+H]⁺.

Examples prepared by Method H (scheme VIII)

Scheme IX

Conditions: a) chlorosulfonic acid, 0⁰C to rt; b) DMAP, TEA, amine, CH₂CI₂, rt; c) POCI₃, microwave, 180 ⁰C; d) amine, EtOH, microwave, 160 ⁰C

Preparation of 8-(methyloxy)-9-(4-morpholinylsulfonyl)-N¹-[3,4,5-tris(methyloxy)- phenyl]-5,6-dihydrobenzo[f]quinazoline-1 ,3-diamine

Example 10

Method I (Scheme IX), Steps a and b:

3-amino-8-(methyloxy)-9-(4-morpholinylsulfonyl)-5,6-dihydrobenzo-[f]quinazolin-

1 (2H)-one

To chlorosulfonic acid (20 ml.) was added 3-amino-8-methoxy-5,6-dihydro-2H- benzo[f]quinazolin-1-one (2.15 g, 8.84 mmol) in several portions at 0⁰C. The resulting solution was stirred at room temperature for 14 hours. This solution was treated with water and the mixture was allowed to stir for 10 minutes. The resulting solids were collected on a filter, washed with ethyl acetate and dried in a vacuum oven and used directly in the next step without further purification. The above sulfonyl chloride (1.00 g, 2.93 mmol) was dissolved in CH₂CI₂ (20 ml.) and treated with DMAP (50 mg), triethylamine (1.2 ml_, 8.78 mmol) and morpholine (0.77 ml_, 8.78 mmol) successively. The resulting solution was stirred at room temperature for 10 hours and concentrated in vacuo. The residue was purified by silica gel flash chromatography to provide the desired sulfonamide as a purplish solid. ¹H NMR (DMSO): δ 8.88 (s, 1 H), 7.50 (bs, 2H), 7.15 (s, 1 H), 3.89 (s, 3H), 3.59 (t, 4H), 3.04 (t, 4H), 2.93 (t, 2H), 2.68 (t, 2H). MS (ES+) m/e 393 [M+H]⁺.

Method I (Scheme IX), Step c: 1-chloro-8-(methyloxy)-9-(4-morpholinylsulfonyl)-5,6-dihydrobenzo[f]quinazolin-3- amine

This compound was obtained from 3-amino-8-methoxy-9-(morpholine-4-sulfonyl)- 5,6-dihydro-2H-benzo[f]quinazolin-1-one in a similar manner to Method E, step a. ¹H NMR (DMSO): δ 8.41 (s, 1 H), 7.26(s, 2H), 7.20(s, 1 H), 3.92(s, 3H), 3.60(t, 4H), 3.06(t, 4H), 2.92(t, 2H), 2.75(t, 2H). MS (ES+) m/e 41 1 [M+H]⁺.

Method I (Scheme IX), Step d: 8-(methyloxy)-9-(4-morpholinylsulfonyl)-N¹-[3,4,5-tris(methyloxy)phenyl]-5,6- dihydrobenzo[f]quinazoline-1 ,3-diamine

This compound was obtained from 1-chloro-8-(methyloxy)-9-(4- morpholinylsulfonyl)-5,6-dihydrobenzo[f]quinazolin-3-amine and 3,4,5- trimethyoxyaniline in a similar manner to Method G. ¹H NMR (DMSO): δ 8.76(bs, 1 H), 8.01 (bs, 1 H), 7.31 (s, 1 H), 6.94(bs, 2H), 3.93(s, 3H), 3.75(s, 9H), 3.58(t, 4H), 3.09(t, 4H), 2.95(t, 2H), 2.78(t, 2H). MS (ES+) m/e 558 [M+H]⁺. Examples prepared by Method I (Scheme IX)

Scheme X

Conditions: boronic acid, Pd(dppf)₂CI₂, Dioxane/2 M K₂CO₃, microwave, 120 ⁰C.

Example 11

Method J

Preparation of 8-chloro-9-(morpholine-4-sulfonyl)-1 -phenyl-5,6-dihydro- benzo[f]quinazolin-3-ylamine

This compound was obtained from 3-amino-8-chloro-9-(morpholine-4-sulfonyl)-5,6- dihydro-2H-benzo[f]quinazolin-1-one and benzene boronic acid in a similar manner to Method F. ¹H NMR (MeOD): δ 7.51 (m, 6H), 7.38 (s, 1 H), 3.18 (t, 2H), 2.98 (t, 2H), 2.90 (m, 4H), 6.82 (d, 1 H), 6.74 (s, 1 H), 5.83 (brs, 1 H), 3.86 (s, 3H), 3.70 (m, 4H), 3.26 (m, 4H), 3.12 (m, 4H). MS (ES+) m/e 503 [M+H]⁺.

Examples prepared by Method J (Scheme X)

Scheme Xl

Conditions: NaH, ArOH, Δ

Example 12 Method K

Preparation of 8-chloro-1 -(3-methoxy-phenoxy)-9-(morpholine-4-sulfonyl)-5,6- dihydro-benzo[f]quinazolin-3-ylamine

To a mixture of 3-methoxyphenol (24 uL) and sodium hydride (10 mg, 0.25 mmol) in DMF (2.0 mL) was added 1 ,8-dichloro-9-(4-morpholinylsulfonyl)-5,6- dihydrobenzo[f]quinazolin-3-amine (70 mg, 0.17 mmol). The contents were heated to 120 ⁰C for 20 min in a microwave reactor. The reaction mixture was concentrated and purified using a Gilson prep system (10 - 55% acetonitrile/water (0.1% triflouroacetic acid) the title compound (39 mg, 46%). ¹H NMR (CDCI₃): δ 10.18 (brs, 1 H), 8.79 (s, 1 H), 7.50 (s, 1 H), 7.37 (t, 1 H), 6.91 (d, 1 H), 6.82 (d, 1 H), 6.74 (s, 1 H), 5.83 (brs, 1 H), 3.86 (s, 3H), 3.70 (m, 4H), 3.26 (m, 4H), 3.12 (m, 4H). MS (ES+) m/e 503 [M+H]⁺.

Examples prepared by Method K (Scheme Xl)

Scheme XII

Conditions: a) DMF-dimethylacetal, Δ; b) guanidine carbonate, EtOH, Δ

Example 13

Method L (Scheme XII)

Preparation of 8-chloro-5,6-dihydrobenzo[f]quinazolin-3-amine

Method L (Scheme XII), Step a:

(1 E/Z)-6-chloro-1 -[(dimethylamino)methylidene]-3,4-dihydro-2(1 H)-naphthalenone

A solution of 6-chloro-tetralone (2.0 g, 8.9 mmol) in dimethylformamide dimethylacetal was heated to 90-100 ⁰C for 40 min then allowed to cool to room temperature. The reaction mixture was diluted with EtOAc and purified by silica gel chromatography to give the title compound (1.51 g, 72%)

Method L (Scheme XII), step b: 8-chloro-5,6-dihydrobenzo[f]quinazolin-3-amine

A solution of sodium ethoxide was generated from Na metal (98 mg). To this solution was added guanidine hydrochloride (404 mg) and the mixture was allowed to stir at room temperature for 15 min. The solid NaCI which formed was collected by filtration and washed with dry ethanol. The (1 E/Z)-6-chloro-1- [(dimethylamino)methylidene]-3,4-dihydro-2(1 H)-naphthalenone (500 mg) in dry ethanol was slowly added to the filtrate and the resulting mixture was heated to reflux for 3 hours. The mixture was cooled and concentrated and the residue poured into H₂O and stirred for 1 hour. The resulting solid was filtered and washed with methanol to give the title compound (81 mg). MS (ES+) m/e 232 [M+H]⁺.

Examples prepared by Method L (Scheme XII)

Preparation of 8,9-dichloro-N-phenyl-5,6-dihydrobenzo[f]quinazolin-3-amine

This compound was obtained from (1 E/Z)-6,7-dichloro-1-

[(dimethylamino)methylidene]-3,4-dihydro-2(1 H)-naphthalenone and N- phenylguanidine hydrochloride in a similar manner to Method L. MS (ES+) m/e 342 [M+H]⁺.

Scheme XIII

Conditions: R2Br, Pd₂(dba)₃, CsCO3, xantophos, dioxane, 80 ⁰C Example 14

Method M (Scheme XIII)

3-[(8-chloro-1-phenyl-5,6-dihydrobenzo[f]quinazolin-3-yl)amino]benzonitrile

A mixture of 8-chloro-1-phenyl-5,6-dihydrobenzo[f]quinazolin-3-amine (100 mg, 0.33 mmol), 3-bromobenzonitrile (54 mg, 0.29 mmol), cesium carbonate (150 mg, 0.46 mmol), Pd₂(dba)₃ (3 mg, 1 mol %) and xantphos (4 mg, 1 mol %) in degassed dioxane (1.3 ml) was heated at 80 ⁰C for 5 hours. The reaction was then diluted with dichloromethane and water. The organic was collected via a hydrophobic frit and concentrated to yield a brown oil which was purified by silica SPE (5 g, hexane/ethyl acetate gradient followed by a second column using dichloromethane/hexanes) to give the title compound as a brown solid, 39 mg, 29 %. LCMS: Ref time 3.576 mins, Es⁺ = 409/410.

Examples prepared by Method M (Scheme XIII)

General Scheme XIV

Conditions: R2Br, Pd₂(dba)₃, CsCO3, xantophos, dioxane, 150 ⁰C, microwave

Example 15

Method N (Scheme XIV)

Preparation of 8-chloro-1 -phenyl-N-3-pyridinyl-5,6-dihydrobenzo[f]quinazolin-3- amine trifluoroacetate (salt)

A mixture of the 8-chloro-1-phenyl-5,6-dihydrobenzo[f]quinazolin-3-amine (125 mg, 0.4 mmol), 3-bromopyridine (35 μl, 0.9 eq), cesium carbonate (194 mg, 1.4 eq),

Pd₂(dba)₃ (7.7 mg, 2 mol %) and xantphos (5 mg, 2 mol %) in degassed dioxan (1.6 ml) was heated at 150 ⁰C for 20 minutes in the microwave. The reaction was then diluted by the addition of H₂O (10 ml) and DCM (10 ml). The organic was collected via a hydrophobic frit and concentrated to yield a brown solid, 195 mg which was subsequently purified by SCX (5 g, washed with methanol, eluted with 2M ammonia in methanol). Concentration yielded a yellow solid which was purified by Gilson prep system (10 - 90% acetonitrile/water (0.1% triflouroacetic acid). Concentration yielded the title compound as a yellow solid, 20 mg. MS (ES+) 385 m/e [M+H]⁺ Examples prepared by Method N (Scheme XIV)

Preparation of 8-(methyloxy)-1-(1-pyrrolidinyl)-9-(1-pyrrolidinylsulfonyl)-5,6- dihydrobenzo[f]quinazolin-3-amine

The 1-chloro-8-(methyloxy)-9-(1-pyrrolidinylsulfonyl)-5,6-dihydrobenzo[f]quinazolin- 3-amine (60 mg, 0.15 mmol), which contained less than half an equivalent of pyrrolidine, was combined with 1 ,3-dihydro-2-benzothiophen-5-amine 2,2-dioxide (56 mg, 0.30 mmol) along with isopropanol (2 ml.) in a sealable microwave vial. The suspension was sonicated before being heated to 16O⁰C in a microwave for 15 min. The reaction was cooled to room temperature and concentrated. The crude was purified by acidic HPLC and the title compound was obtained. MS (ES+) 430 m/e [M+H]⁺

Scheme XV

Conditions: ROH, NaH, DMF

Example 16

Method O (Scheme XV)

The phenol was treated with KOtBu in DMF for 10 min, then 8-chloro-1-phenyl-5,6- dihydrobenzo[f]quinazolin-3-amine was added and the reaction mixture stirred at room temperature for 3-5 hours. The pure product was obtained by Gilson preparative HPLC. Examples prepared by Method O

Scheme XVI

Conditions: ArB(OH)₂, (Ph₃)₂PdCI₂, Na₂CO₃, DMF, Δ

Example 17

Method P (Scheme XVI) Preparation of 1-(1 H-indol-5-yl)-8-(5-pyrimidinyl)-5,6-dihydrobenzo[f]quinazolin-3- amine

To a 10 mL microwave vial equipped with a magnetic stir bar was added 8-bromo- 1-(1 H-indol-5-yl)-5,6-dihydrobenzo[f]quinazolin-3-amine (50.0 mgs, 1.0eq) 5- pyrimidinylboronic acid (44.1 mgs, 2.0 eq), and PdCI₂(PPh₃)₂ (7mgs, 0.01eq), in dimethylformamide (3 mLs) and 2N Na₂CO₃ (1 mL). The reaction mixture was heated to 15O⁰C for 10 minutes in a microwave. The reaction mixture was allowed to cool to room temperature and then filtered pad of celite. The filter pad was rinsed with EtOAc. The organics were then gravity filtered through an SCX ion exchange column (previously washed with methanol) and resin was washed with dichloromethane (3x). Wash resin with 2N NH₃/MeOH (3x3ml_s) and filtrate was collected. The solvents were removed in vacuo and the crude material was purified on by preparatory HPLC. (10 to 100% acetonitrile/0.02% aqueous NH₄OH over 14 min). 31 mgs recovered, 62% yield. ¹H NMR (400 MHz, DMSO-D6) δ ppm 2.7 (m, 2 H) 3.0 (m, 2 H) 6.4 (m, 1 H) 6.7 (m, 3 H) 7.1 (dd, J=8.4, 1.5 Hz, 1 H) 7.2 (dd, J=8.4, 2.2 Hz, 1 H) 7.3 (m, 2 H) 7.7 (s, 2 H) 9.1 (s, 2 H) 9.1 (s, 1 H) 1 1.2 (s, 1 H). MS: m/z 391 (M+1 ) ⁺.

Scheme XVII

a) ammonium formate, ethanol, microwave, 160 ⁰C. b) formamide, microwave, 220 ⁰C. c) POCI₃, microwave, 160 ⁰C. d) amine, ethanol, microwave, 16O⁰C

Example 18, Method Q (Scheme XVII)

Preparation of 8-bromo-N-(4-fluorophenyl)-5,6-dihydrobenzo[f]quinazolin-1 -amine

Method Q, Step a: Preparation of ethyl 2-amino-6-bromo-3,4-dihydro-1- naphthalenecarboxylate

A microwave vessel was charged with ethyl 6-bromo-2-oxo-1 , 2,3,4- tetrahydro-1-naphthalenecarboxylate (1g), ammonium formate (1g) and ethanol (3ml_). The contents were heated in a microwave at 16O⁰C for 10min. The reaction was concentrated to dryness and the residue was taken up in water. The aqueous mixture was extracted with ethyl acetate and the organics were dried over magnesium sulfate, then filtered. The filtrate was concentrated and the residue was triturated with methanol. The solids were collected on a filter and washed with methanol to yield ethyl 2-amino-6-bromo-3,4-dihydro-1-naphthalenecarboxylate as a powder (600mg). ¹H NMR (d₆-dmso): δ 8.4(br s, 1 H), 7.5(br s, 1 H), 7.46(d, 1 H), 7.18(d, 1 H), 7.16(dd, 1 H), 4.10(q, 2H), 2.56(m, 2H), 2.32(m, 2H), 1.18(t, 3H).

Method Q, Step b: Preparation of 8-bromo-5,6-dihydrobenzo[f]quinazolin-1-ol

Three microwave vials were charged with ethyl 2-amino-6-bromo-3,4-dihydro-1- naphthalenecarboxylate (300mg each), formamidine acetate (1g each) and 1 M sodium ethoxide (4ml_ each). The reactions were heated in a microwave at 18O⁰C for 10 min. The reactions were combined and concentrated to dryness and the residue was treated with water. The aqueous mixture was extracted with ethyl acetate and the organics were dried over magnesium sulfate then filtered. The residue was purified using silica gel chromatography to provide 8-bromo-5,6- dihydrobenzo[f]quinazolin-1-ol (90mg) as a gray powder. ¹H NMR (d₆-dmso): δ 12.7(br s, 1 H), 8.52(d, 1 H), 8.10(s, 1 H), 7.46(d, 1 H), 7.42(dd, 1 H), 2.85(m, 2H), 2.74(m, 2H).

Method Q, Step c: Preparation of 8-bromo-1-chloro-5,6-dihydrobenzo[f]quinazoline

A microwave vial was charged with 8-bromo-5,6-dihydrobenzo[f]quinazolin-1-ol (90mg) and phosphorus oxychloride (4ml_). The reaction was heated in a microwave at 16O⁰C for 10 min. The reaction was concentrated to dryness and treated with a saturated sodium bicarbonate solution. After stirring for 10 min, the aqueous mixture was extracted with ethyl acetate. The organics were dried over magnesium sulfate and then filtered. The filtrate was concentrated and dissolved in methylene chloride. The resulting solution was loaded onto a silica gel pad and washed with diethyl ether. The eluent was concentrated to dryness to provide 8- bromo-1-chloro-5,6-dihydrobenzo[f]quinazoline (95mg) as a waxy, yellow solid. ¹H NMR (CDCI₃): δ 8.72(s, 1 H), 8.12(d, 1 H), 7.46(dd, 1 H), 7.44(d, 1 H), 2.89(m, 2H), 2.87(m, 2H).

Method Q, Step d: Preparation of 8-bromo-N-(4-fluorophenyl)-5,6- dihydrobenzo[f]quinazolin-1 -amine

A microwave vial was charged with 8-bromo-1-chloro-5,6- dihydrobenzo[f]quinazoline (14mg), 4-fluoro-aniline (50mg) and ethanol (3.5mL). The reaction was heated in a microwave at 16O⁰C for 10 min. The reaction was concentrated to dryness and the residue was dissolved in methylene chloride. The resulting solution was purified by preparative thin-layer silica gel chromatography to provide 8-bromo-N-(4-fluorophenyl)-5,6-dihydrobenzo[f]quinazolin-1 -amine (5.5mg) as a tan powder. ¹H NMR (CDCI₃): δ 8.50(s, 1 H), 7.75(d, 1 H), 7.44-7.53 (m, 4H), 7.14(br s, 1 H), 7.06(m, 2H), 2.87(s, 4H).

Examples prepared by Method Q (Scheme XVII)

Scheme XVIII:

Conditions: a) AICI₃, C₂H₄, CH₂CI₂, -78°C ~ rt; b) Diethylcarbonate, NaH, 80⁰C; c) guanidine-HCI, NaOEt, EtOH, 90⁰C; d) KNO₃, H₂SO₄, 0°C; e) SnCI₂, HCI; f) POCI₃, reflux; g) Pd(dppf)CI₂, ArB(OH)₂, Na₂CO₃, dioxane/H₂O, 10O⁰C; h) RSO₂CI, pyridine, CH₂CI₂, rt.

Example 19

Λ/-[3-amino-8-chloro-1-(4-pyridinyl)-5,6-dihydrobenzo[/]quinazolin-9-yl]-2,4- difluorobenzenesulfonamide

a) 6-chloro-3,4-dihydro-2(1 H)-naphthalenone To a suspension of aluminum trichloride (26.6 g, 200.00 mmol) in dichloromethane (350 ml.) at -78 ⁰C was added a solution of 2-(4-chlorophenyl)acetyl chloride (18.9 g, 100 mmol) in dichloromethane (50 ml.) dropwise over 1 h under nitrogen. After addition, ethylene gas was vigorously bubbled through the solution for 10 min. The reaction mixture was allowed to warm to room temperature gradually and stirred at the temperature for 3.5 h. It was cooled to 0 ⁰C and quenched with 10OmL water. The organic layer was washed with 2M hydrochloric acid, saturated aqueous solution of sodium bicarbonate, dried with MgSO₄, concentrated and purified by column chromatography on silica gel (petroleum ether : ethyl acetate 20:1 ) to afford the product as yellow solid (11.2 g, 62%).

b) Ethyl 6-chloro-2-oxo-1 ,2,3,4-tetrahydro-1-naphthalenecarboxylate

To a mixture of sodium hydride (6.00 g, 150 mmol) in diethyl carbonate (80 ml.) was added a solution of 6-chloro-3,4-dihydro-2(1 H)-naphthalenone (9.00 g, 50.0 mmol) in diethyl carbonate (20 ml.) dropwise at 80 ⁰C. After addition, the mixture was stirred at 90 ⁰C for 1 h. The solvent was removed and the residue was purified by column chromatography on silica gel to give the product as yellow oil (12.1 g,

96%).

c) 3-amino-8-chloro-5,6-dihydrobenzo[/]quinazolin-1 (2H)-one

To a mixture of guanidine hydrochloride (27.0 g, 282.1 mmol) and sodium ethoxide (1 1.4 g, 166.7 mmol) in dry ethanol (200 ml.) was added ethyl 6-chloro-2-oxo- 1 ,2,3,4-tetrahydro-i-naphthalenecarboxylate (28.0 g, 1 11.1 mmol). The resulting mixture was heated to 90 ⁰C for 40 h. TLC (ethyl acetate : methanol 10:1 ) shows the starting material was consumed and desired product had formed. The solvent was removed, and the residue was washed with 30% HCI. The solid was filtered off and washed with ether, and then recrystallized from ether to give the product as yellow solid. [M+H]⁺ = 248.

d) 3-amino-8-chloro-9-nitro-5,6-dihydrobenzo[/]quinazolin-1 (2/-/)-one

To a solution of 3-amino-8-chloro-5,6-dihydrobenzo[/]quinazolin-1 (2/-/)-one (6.0 g, 24.3 mmol) in concentrated sulfuric acid (50 mL) at 0 ⁰C was added KNO₃ (2.45 g, 24.3 mmol) portion-wise over 30 min, making sure that the temperature did not go above 0⁰C. After addition, the resulting mixture was stirred at the same temperature for 1.5 h until it was observed to be complete by LCMS. Then it was poured onto ice and a tan solid formed. The solid was filtered, washed well with water and ether, and dried under vacuum to give the isomers 3-amino-8-chloro-9-nitro-5,6- dihydrobenzo[/]quinazolin-1 (2H)-one and 3-amino-8-chloro-7-nitro-5,6- dihydrobenzo[/]quinazolin-1 (2/-/)-one (6.2 g, 87%). The mixture can be used in the next step without further purification. Further purification by prep-HPLC gave pure 3-amino-8-chloro-9-nitro-5,6-dihydrobenzo[/]quinazolin-1 (2/-/)-one. [M+H]⁺ = 293.

e) 3,9-diamino-8-chloro-5,6-dihydrobenzo[/]quinazolin-1 (2H)-one

To a mixture of 3-amino-8-chloro-9-nitro-5,6-dihydrobenzo[/]quinazolin-1 (2H)-one and 3-amino-8-chloro-7-nitro-5,6-dihydrobenzo[/]quinazolin-1 (2/-/)-one (7.50 g, 25.68 mmol) in concentrated hydrochloric acid (10 ml.) at 0 ⁰C was added tin (II) chloride dihydrate (9.70 g, 51.36 mmol) by portions. After addition, the resulting mixture was stirred at room temperature for 90 min at which point the reaction is complete by LCMS. The reaction was mixture was basicified by sodium bicarbonate. The solvent was removed and the residue was extracted with THF (50 ml. x 4). The combined organic layers were dried and concentrated to give the product as a brown solid (6.1 g, 90%). [M+H]⁺ = 263.

f) 1 ,8-dichloro-5,6-dihydrobenzo[/]quinazoline-3,9-diamine

A mixture of 3,9-diamino-8-chloro-5,6-dihydrobenzo[/]quinazolin-1 (2H)-one (5.24 g, 20.0 mmol) and POCI₃ (30 ml.) was heated at reflux overnight. The excess POCI3 was evaporated and the residue was dissolved in water (20 ml_), then basified with aqueous solution of sodium bicarbonate to pH = 8, a large quantity of precipitate formed, filtered, the solid was washed with water and dried under vacuum to give product as brown solid (2.89 g, 51 %).

g) 8-chloro-1-(4-pyridinyl)-5,6-dihydrobenzo[/]quinazoline-3,9-diamine

A mixture of 1 ,8-dichloro-5,6-dihydrobenzo[/]quinazoline-3,9-diamine (0.84 g, 3.00 mmol), pyridine-4-ylboronic acid (0.37 g, 3.00 mmol), sodium carbonate (0.95 g, 9.00 mmol) and Pd(dppf)CI₂ (60 mg) in dioxane/water (30 mL/10 ml.) was heated at 100 ⁰C under argon overnight. LCMS showed the reaction was complete. The mixture was concentrated and purified by column chromatography on silica gel to give the product as yellow solid (623 mg, 64%). h) /V-[3-amino-8-chloro-1-(4-pyridinyl)-5,6-dihydrobenzo[/]quinazolin-9-yl]-2,4- difluorobenzenesulfonamide

To a solution of 8-chloro-1-(4-pyridinyl)-5,6-dihydrobenzo[/]quinazoline-3,9-diamine (0.1.g, 0.31 mmol) in dichloromethane (5ml_) was added pyridine (73mg, 0.93mmol) and 2,4-difluorobenzene-1-sulfonyl chloride (74mg, 0.37mmol). The resulting mixture was stirred at room temperature overnight. TLC (ethyl acetate: petroleum ether 1 :1 ) showed the reaction was complete. The mixture was concentrated and purified by column chromatography on silica gel to give product as brown solid (42mg, 27%). LC-MS: [M+H]⁺ = 500.1 , Purity = 94.6 %, Rt = 1.81 min. ¹HNMR

(DMSOd₆) δ: 10.20 (s, 1 H), 8.84 (s, 1 H), 7.70 (d, 2H), 7.45-7.54 (m, 2H), 7.34 (s, 1 H), 7.06-7.24 (m, 3H), 6.50 (s, 1 H), 2.86-2.90 (m, 2H), 2.71-2.86 (m, 2H).

Example 20

N-(3-amino-8-chloro-1-pyridin-4-yl-5,6-dihydrobenzo[f]quinazolin-9-yl)-4- cyanobenzenesulfonamide

To a solution of 8-chloro-1-(4-pyridinyl)-5,6-dihydrobenzo[/]quinazoline-3,9-diamine (0.1 g, 0.31 mmol) in dichloromethane (5 mL) was added pyridine (73 mg, 0.93 mmol) and 4-cyanobenzene-1-sulfonyl chloride (74 mg, 0.37 mmol), the resulting mixture was stirred at room temperature overnight. TLC (ethyl acetate: petroleum ether 1 :1 ) showed the reaction was complete. The mixture was concentrated and purified by column chromatography on silica gel to give product as brown solid (35 mg, 23%). LC-MS: [M+H]⁺ = 489.7, Purity = 98.7 %, Rt = 1.78 min. ¹HNMR (DMSO- d₆): δ 8.69 (d, J = 4.5 Hz, 2H), 7.72 (dd, J = 2.1 Hz, 6.9 Hz, 2H), 7.63 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 5.4Hz, 2H), 7.17 (s, 1 H), 6.97 (s, 1 H), 5.24 (s, 2H), 2.83-2.89 (m, 4H). Example 21

N-(3-amino-8-chloro-1-pyridin-4-yl-5,6-dihydrobenzo[f]quinazolin-9-yl)thiophene-2- sulfonamide

To a solution of 8-chloro-1-(4-pyridinyl)-5,6-dihydrobenzo[/]quinazoline-3,9-diamine (0.1 g, 0.31 mmol) in dichloromethane (5 ml.) was added pyridine (73 mg, 0.93 mmol) and thiophene-2-sulfonyl chloride (67 mg, 0.37 mmol). The resulting mixture was stirred at room temperature overnight. TLC (ethyl acetate: petroleum ether 1 :1 ) showed the reaction was complete. The mixture was concentrated and purified by column chromatography on silica gel to give product as brown solid (36 mg, 25%). LC-MS: [M+H]⁺ = 470.7, Purity = 97.6%, Rt = 1.85 min. ¹HNMR (DMSOd₆): δ 9.83 (s, 1 H), 8.58 (d, J = 5.1 Hz, 2H), 7.87 (d, J = 4.5 Hz, 1 H), 7.33-7.30 (m, 3H), 7.18 (d, J = 3.6 Hz, 1 H), 7.08 (t, J = 3.9 Hz, 1 H), 6.97 (s, 2H), 6.56 (s, 1 H), 2.88-2.84 (m, 2H), 2.72-2.70 (m, 2H).

Example 22

N-(3-amino-8-chloro-1-pyridin-4-yl-5,6-dihydrobenzo[f]quinazolin-9- yl)benzenesulfonamide

To a solution of 8-chloro-1-(4-pyridinyl)-5,6-dihydrobenzo[/]quinazoline-3,9-diamine (0.10 g, 0.31 mmol) in dichloromethane (5 mL) was added pyridine (73 mg, 0.93 mmol) and benzenesulfonyl chloride (65 mg, 0.37 mmol). The resulting mixture was stirred at room temperature overnight. TLC (ethyl acetate: petroleum ether 1 :1 ) showed the reaction was complete. The mixture was concentrated and purified by column chromatography on silica gel to give product as brown solid (55 mg, 38%). LC-MS: [M+H]⁺ = 481.7, Purity = 97.2%, Rt = 1.89 min. ¹HNMR (DMSOd₆): δ 9.67 (s, 1 H), 8.60 (dd, J = 1.2 Hz, 4.5 Hz, 2H), 7.60-7.43 (m, 5H), 7.32-7.29 (m, 3H), 6.98 (s, 2H), 6.54 (s, 1 H), 2.86-2.82 (m, 2H), 2.70-2.66 (m, 2H).

Example 23

N-(3-amino-8-chloro-1-pyridin-4-yl-5,6-dihydrobenzo[f]quinazolin-9-yl)-3- cyanobenzenesulfonamide

To a solution of 8-chloro-1-(4-pyridinyl)-5,6-dihydrobenzo[/]quinazoline-3,9-diamine (70 mg, 0.22 mmol) in dichloromethane (10 ml.) was added pyridine (53 mg, 0.66 mmol) and 3-cyanobenzene-1-sulfonyl chloride (49 mg, 0.33 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and purified by column chromatography on silica gel (petroleum ether: ethyl acetate 10:1 to petroleum ether: ethyl acetate 1 :50) to give product as yellow solid (8 mg, 8%). LC-MS: [M+H]⁺ = 489.1 , Purity = 92.1 %, Rt = 1.13 min. ¹HNMR (MeOH- d):δ8.98 (s, 2H) 8.19 (m, 2H), 7.96 (m, 2H), 7.76 (m,2H), 7.28 (s, 1 H), 6.74 (s, 1 H), 2.96 (m, 2H), 2.86(m, 2H).

Example 24

N-(3-amino-8-chloro-1-pyridin-4-yl-5,6-dihydrobenzo[f]quinazolin-9-yl)-3- chlorobenzenesulfonamide

To a solution of 8-chloro-1-(4-pyridinyl)-5,6-dihydrobenzo[/]quinazoline-3,9-diamine (0.1 g, 0.31 mmol) in dichloromethane (5ml_) was added pyridine (73mg, 0.93mmol) and 3-chlorobenzene-1-sulfonyl chloride (65mg, 0.31 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and purified by column chromatography on silica gel to give the product as a brown solid (56mg, 36%). LC-MS: [M+H]⁺ = 500.1 , Purity = 100.0 %, Rt = 1.18 min. 1HNMR (Methanol-d): δ 8.86 (br s, 1 H), 8.00 (br s, 2H), 7.83-7.39 (m, 5H), 7.26 (s, 1 H), 6.74(s, 1 H), 2.97-2.81 (m, 4H).

Example 25

N-(3-amino-8-chloro-1-pyridin-4-yl-5,6-dihydrobenzo[f]quinazolin-9-yl)naphthalene- 2-sulfonamide

To a solution of 8-chloro-1-(4-pyridinyl)-5,6-dihydrobenzo[/]quinazoline-3,9-diamine (70 mg, 0.22 mmol) in dichloromethane (10 ml.) was added pyridine (52 mg, 0.66 mmol) and naphthalene-2-sulfonyl chloride (75 mg, 0.33 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and purified by column chromatography on silica gel to give product as yellow solid (10 mg, 8.8%). LC-MS: [M+H]⁺ = 514.1 , Purity = 68 %,. Rt = 1.80 min. The sample was then taken up into 50OuL of DMSO/ACN/water (1 :10:10) and was repurified by reverse-phase HPLC to afford the product after lyophilization of the pure fractions (5.1 mg) as an off-white powder. [M+H]⁺ = 514.4, Purity = 100 %. ¹ H NMR (MeOH- d4) is consistent with desired structure and purity.

Example 26

N-(3-amino-8-chloro-1-pyridin-4-yl-5,6-dihydrobenzo[f]quinazolin-9-yl)-2-methyl-5- nitrobenzenesulfonamide

To a solution of 8-chloro-1-(4-pyridinyl)-5,6-dihydrobenzo[/]quinazoline-3,9-diamine (6 Omg, 0.19 mmol) in dichloromethane (1 OmL) was added pyridine (45 mg, 0.56 mmol) and 2-methyl-5-nitrobenzene-1-sulfonyl chloride (67mg, 0.28mmol). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and purified by column chromatography on silica gel to give product as yellow solid (15mg, 15%). LC-MS: [M+H]⁺ = 523.1 , Purity = 79 %, Rt = 2.30 min. The sample was taken up into 50OuL of DMSO/ACN/water (1 :10:10) and was repurified by reverse-phease HPLC to afford the product after lyophilization of the pure fractions (5.5 mg) as an off-white powder. [M+H]⁺ = 523.3, Purity = 100 %. ¹ H NMR (MeOH-d4) is consistent with desired structure and purity. Example 27

N-[3-amino-8-chloro-1-(4-fluorophenyl)-5,6-dihydrobenzo[f]quinazolin-9-yl]-2,4- difluorobenzenesulfonamide

a) 8-chloro-1-(4-fluorophenyl)-5,6-dihydrobenzo[f]quinazoline-3,9-diamine

A mixture of 1 ,8-dichloro-5,6-dihydrobenzo[/]quinazoline-3,9-diamine (0.4 g, 1.42 mmol), 4-fluorophenylboronic acid (0.198 g, 1.42 mmol), sodium carbonate (0.45 g, 4.26 mmol) and Pd(dppf)Cl₂ (56 mg) in dioxane/water (20 ml_/6 ml.) was heated at 100 ⁰C under argon overnight. LCMS showed the reaction was complete. The mixture was diluted with water and extracted with dichloromethane (30 ml. x 3). The combined organic layers were concentrated and purified by column chromatography on silica gel to afford the product as a yellow solid (304 mg, 63%).5 b) N-[3-amino-8-chloro-1-(4-fluorophenyl)-5,6-dihydrobenzo[f]quinazolin-9-yl]-2,4- difluorobenzenesulfonamide

To a solution of 8-chloro-1-(4-fluorophenyl)-5,6-dihydrobenzo[/]quinazoline-3,9- diamine (0.10 g, 0.29 mmol) in dichloromethane (5 ml.) was added pyridine (70 mg, 0.87 mmol) and 2,4-difluorobenzene-1-sulfonyl chloride (74 mg, 0.35 mmol). The resulting mixture was stirred at room temperature overnight. TLC (ethyl acetate: petroleum ether 1 :1 ) showed the reaction was complete. The mixture was concentrated and purified by column chromatography on silica gel to give product5 as brown solid (62 mg, 41.4%). LC-MS: [M+1]⁺ = 517.7, Purity = 96.6 %, Rt = 2.23 min. ¹HNMR (DMSOd₆): δ 10.10 (s, 1 H), 7.52-7.45 (m, 5H), 7.40 (s, 1 H), 7.23-7.14 (m, 4H), 6.50 (s, 1 H), 2.85-2.83 (m, 2H), 2.71-2.67 (m, 2H). Example 28

N-[3-amino-8-chloro-1-(4-fluorophenyl)-5,6-dihydrobenzo[f]quinazolin-9- yl]benzenesulfonamide

To a solution of 8-chloro-1-(4-fluorophenyl)-5,6-dihydrobenzo[/]quinazoline-3,9- diamine (0.10 g, 0.29 mmol) in dichloromethane (5 ml.) was added pyridine (70 mg, 0.87 mmol) and benzenesulfonyl chloride (68 mg, 0.35 mmol). The resulting mixture was stirred at room temperature overnight. TLC (ethyl acetate: petroleum ether 1 :1 ) showed the reaction was complete. The mixture was concentrated and purified by column chromatography on silica gel to give product as brown solid (64 mg, 46.0%). LC-MS: [M+H]⁺ = 481.7, Purity = 96.9 %, Rt = 2.19 min. ¹HNMR (DMSO- d₆): 5 9.65 (s, 1 H), 7.52-7.45 (m, 5H), 7.41-7.36 (dd, J = 6.0 Hz, 8.7 Hz, 1 H), 7.28 (s, 1 H), 7.20 (t, J = 9.0Hz, 2H), 6.91 (s, 2H), 6.55 (s, 1 H), 2.85-2.80(m, 2H), 2.69- 2.67 (m, 2H).

Example 29

N-[3-amino-8-chloro-1-(4-fluorophenyl)-5,6-dihydrobenzo[f]quinazolin-9-yl]propane- 2-sulfonamide

To a solution of 8-chloro-1-(4-fluorophenyl)-5,6-dihydrobenzo[/]quinazoline-3,9- diamine (0.32 g, 1.00 mmol) in dichloromethane (8 mL) was added pyridine (240 mg, 3.00 mmol) and propane-2-sulfonyl chloride (210 mg, 1.50 mmol). The resulting mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. The mixture was concentrated and purified by column chromatography on silica gel to give the product as a yellow solid (67 mg, 15%). LC-MS: [M+H]⁺ = 447.7, Purity = 98.5 %, Rt = 2.21 min. ¹HNMR (CDCI₃): δ 8.21 (t, J = 6.9 Hz, 2H), 7.50 (m, 1 H), 7.22-7.06 (m, 4H), 6.11 (s, 1 H), 5.39 (s, 1 H), 3.77 (m, 1 H), 2.81 (s, 4H), 1.61 (d, J = 6.9 Hz, 6H).

Example 30

N-(3-amino-8-chloro-1-phenyl-5,6-dihydrobenzo[f]quinazolin-9-yl)-2,4- difluorobenzenesulfonamide

a) 8-chloro-1 -phenyl-5,6-dihydrobenzo[/]quinazoline-3,9-diamine

A mixture of 1 ,8-dichloro-5,6-dihydrobenzo[/]quinazoline-3,9-diamine (0.56 g, 2.00 mmol), phenylboronic acid (0.24 g, 2.00 mmol), sodium carbonate (0.64 g, 6.00 mmol) and Pd(dppf)CI₂ (50 mg) in dioxane/water (4 mL/1.5 ml.) was heated at 120 ⁰C for 20 min in a microwave reactor. The mixture was diluted with water and extracted with EA (20ml_x3), the combined organic layers were concentrated and purified by column chromatography on silica gel to give product as a white solid (510 mg, 79%).

b) N-(3-amino-8-chloro-1-phenyl-5,6-dihydrobenzo[f]quinazolin-9-yl)-2,4- difluorobenzenesulfonamide

To a solution of 8-chloro-1-phenyl-5,6-dihydrobenzo[/]quinazoline-3,9-diamine (0.12 g, 0.37 mmol) in dichloromethane (10 ml.) was added pyridine (88 mg, 1.12 mmol) and 2,4-difluorobenzene-1-sulfonyl chloride (94.8 mg, 0.44 mmol), the resulting mixture was stirred at room temperature overnight. The mixture was concentrated and purified by column chromatography on silica gel to give product as a white solid (25 mg, 10%). LC-MS [M+H]⁺ = 499.7, Purity = 100.0 %, Rt = 2.09 min. ¹HNMR (MeOH-d): δ 7.58-7.48 (m, 6H), 7.31 (s, 1 H), 7.17-6.98 (m, 2H), 6.81 (s, 1 H), 2.96- 2.92 (m, 4H).

Example 31

N-(3-amino-8-chloro-1-phenyl-5,6-dihydrobenzo[f]quinazolin-9-yl)furan-3- sulfonamide

To a solution of 8-chloro-1-phenyl-5,6-dihydrobenzo[/]quinazoline-3,9-diamine (0.10 g, 0.31 mmol) in dichloromethane (5 ml.) was added pyridine (73 mg, 0.93 mmol) and furan-3-sulfonyl chloride (61 mg, 0.37 mmol). The resulting mixture was stirred at room temperature overnight. TLC (ethyl acetate: petroleum ether 1 :1 ) showed the reaction was complete. The mixture was concentrated and purified by column chromatography on silica gel to give product as brown solid (26 mg, 18.6%). LC- MS: [M+H]⁺ = 453.7, Purity = 98.5%, Rt = 2.10 min. ¹HNMR (DMSOd₆): δ 9.60 (s, 1 H), 7.86 (s, 1 H), 7.77 (s, 1 H), 7.34 (m, 6H), 6.86 (s, 2H), 6.59 (s, 1 H), 6.35 (s, 1 H), 2.86-2.69 (m, 4H)

Example 32

N-(3-amino-8-chloro-1-phenyl-5,6-dihydrobenzo[f]quinazolin-9- yl)benzenesulfonamide

To a solution of 8-chloro-1-phenyl-5,6-dihydrobenzo[/]quinazoline-3,9-diamine (0.10 g, 0.31 mmol) in dichloromethane (5 mL) was added pyridine (73 mg, 0.93 mmol) and furan-3-sulfonyl chloride (65 mg, 0.37 mmol). The resulting mixture was stirred at room temperature overnight. TLC (ethyl acetate: petroleum ether 1 :1 ) showed the reaction was complete. The mixture was concentrated and purified by column chromatography on silica gel to give product as brown solid (56 mg, 39%). LC-MS: [M+H]⁺ = 463.7, Purity = 94.5 %, Rt = 2.16 min. ¹HNMR (DMSOd₆): δ 9.59 (s, 1 H), 7.47-7.33 (m, 1 OH), 7.27 (s, 1 H), 6.86 (s, 2H), 6.57 (s, 1 H), 2.83-2.81 (m, 2H), 2.70- 2.65 (m, 2H).

Example 33

N-(3-amino-8-chloro-1-phenyl-5,6-dihydrobenzo[f]quinazolin-9-yl)propane-2- sulfonamide

To a solution of 8-chloro-1-phenyl-5,6-dihydrobenzo[/]quinazoline-3,9-diamine (0.32 g, 1.00 mmol) in dichloromethane (8 mL) was added pyridine (240 mg, 3.00 mmol) and propane-2-sulfonyl chloride (210 mg, 1.50 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and purified by column chromatography on silica gel to give product as brown solid (71 mg, 17%). LC-MS: [M+H]⁺ = 429.7, Purity = 96.1%, Rt = 3.06 min. ¹HNMR (DMSO-d6): 5 7.50-7.36 (m, 5H), 7.08 (s, 1 H), 6.08 (s, 1 H), 5.27 (s, 2H), 3.80-3.71 (m, 1 H), 2.82 (s, 4H), 1.60 (d, J = 6.9 Hz, 6H).

Example 34

N-(3-amino-8-chloro-1-phenyl-5,6-dihydrobenzo[f]quinazolin-9-yl)-2,4- difluorobenzamide

To a solution of 8-chloro-1-phenyl-5,6-dihydrobenzo[f]quinazoline-3,9-diamine (0.20 g, 0.62 mmol) in dichloromethane (5 ml.) was added pyridine (147 mg, 1.86 mmol) and 2,4-difluoro benzoyl chloride (163 mg, 0.93 mmol) at 0⁰C. The resulting mixture was stirred at room temperature overnight. After 24 h, the mixture was concentrated and purified by column chromatography on silica gel (petroleum ether : ethyl acetate 2:1 ) to give the product (40 mg, 15%). LC-MS: [M+H]⁺ = 463.1 , Purity = 38%. The sample was dissolved in 1 ml. DMSO, filtered, and repurified by reverse- phase HPLC (40-70% ACN/H₂O, 0.1% TFA). HPLC purification (reverse-phase) was performed on an open-access Gilson using Trilution software, with a Phenomenex Luna 5u C18(2) 100A, AXIA. 50x30.00mm 5 micron. A 7.3-minute run (47 mL/min) with UV detection at 254nm was utilized. The desired fractions were concentrated overnight in the EZ2 evaporator to afford 5.2 mg of a yellow solid. LCMS: (100%, M+H=463.1 ). ¹ H NMR (DMSO-d6) is consistent with desired structure and purity.

Example 35

N-[3-amino-8-chloro-1-(1-methyl-1 H-pyrazol-4-yl)-5,6-dihydrobenzo[f]quinazolin-9- yl]-2,4-difluorobenzenesulfonamide

a) 8-chloro-1 -(1 -methyl-1 /-/-pyrazol-4-yl)-5,6-dihydrobenzo[/]quinazoline-3,9- diamine

A mixture of 1 ,8-dichloro-5,6-dihydrobenzo[/]quinazoline-3,9-diamine (0.56 g, 2.00 mmol), 1-methyl-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (0.42 g, 2.00 mmol), sodium carbonate (0.64 g, 6.00 mmol) and Pd(dppf)CI₂ (50 mg) in dioxane/water (20 ml_/6 ml.) was heated at 100 °C under argon overnight. TLC (ethyl acetate: petroleum ether 1 :2) showed the reaction was complete. The mixture was diluted with water and extracted with ethyl acetate (30 ml_x3). The combined organic layers were concentrated and purified by column chromatography on silica gel to give the product as a yellow solid (450 mg, 69%).

b) N-[3-amino-8-chloro-1 -(1 -methyl-1 H-pyrazol-4-yl)-5,6-dihydrobenzo[f]quinazolin- 9-yl]-2,4-difluorobenzenesulfonamide

To a solution of 8-chloro-1-(1 -methyl-1 H-pyrazol-4-yl)-5, 6- dihydrobenzo[/]quinazoline-3,9-diamine (0.163 g, 0.50 mmol) in dichloromethane (10 ml.) was added pyridine (1 19 mg, 1.50 mmol) and 2,4-difluorobenzene-1 - sulfonyl chloride (127 mg, 0.60 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and purified by column chromatography on silica gel to give product as brown solid (124 mg, 49.4%). LC- MS: [M+H]⁺ = 503.7, Purity = 95.3 %, Rt = 1.89 min. ¹HNMR (DMSOd₆): δ 10.24 (s, 1 H), 7.76 (s, 1 H), 7.64-7.56 (m, 2H), 7.51-7.48 (m, 1 H), 7.32 (s, 1 H), 7.20-7.15 (m, 2H), 6.69 (s, 2H), 3.81 (s, 3H), 2.79-2.74 (m, 2H), 2.61-2.56 (t, 2H).

Example 36

N-[3-amino-8-chloro-1-(1-methyl-1 H-pyrazol-4-yl)-5,6-dihydrobenzo[f]quinazolin-9- yl]benzenesulfonamide

To a solution of 8-chloro-1-(1-methyl-1 H-pyrazol-4-yl)-5,6- dihydrobenzo[/]quinazoline-3,9-diamine (0.163 g, 0.50 mmol) in dichloromethane (10 ml.) was added pyridine (119 mg, 1.50 mmol) and benzenesulfonyl chloride (88 mg, 0.50 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and purified by column chromatography on silica gel to give product as a yellow solid (89 mg, 38.2%). LC-MS: [M+H]⁺ = 467.7, Purity = 97.2 %, Rt = 1.84 min. ¹HNMR (DMSOd₆): δ 9.84 (s, 1 H), 7.78 (s, 1 H), 7.63 (s, 1 H), 7.59-7.47 (m, 5H), 7.30 (s, 1 H), 7.15 (s, 1 H), 6.67 (s, 2H), 3.81 (s, 3H), 2.77- 2.73 (m, 2H), 2.59-2.54 (m, 2H).

Example 37

N-(3-amino-8-chloro-1-{4-[(dimethylamino)sulfonyl]phenyl}-5,6- dihydrobenzo[f]quinazolin-9-yl)-2,4-difluorobenzenesulfonamide

a) 4-(3,9-diamino-8-chloro-5,6-dihydrobenzo[/]quinazolin-1-yl)-Λ/,Λ/- dimethylbenzenesulfonamide A mixture of 1 ,8-dichloro-5,6-dihydrobenzo[/]quinazoline-3,9-diamine (0.2 g, 0.71 mmol), 4-(N,N-dimethylsulfamoyl) phenylboronic acid (163 mg, 0.71 mmol), sodium carbonate (0.223 g, 2.1 mmol) and Pd(dppf)CI₂ (26 mg) in dioxane/water (20 ml_/1 ml.) was heated at 100 ⁰C under nitrogen overnight. The mixture was diluted with water and extracted with ethyl acetate (20 ml_x3). The combined organic layers were washed with water (20 ml_x3), dried over Na₂SO₄, filtered and concentrated to give the title compounds as a brown solid (185 mg, 62%).

b) N-(3-amino-8-chloro-1-{4-[(dimethylamino)sulfonyl]phenyl}-5,6- dihydrobenzo[f]quinazolin-9-yl)-2,4-difluorobenzenesulfonamide

To a solution of 4-(3,9-diamino-8-chloro-5,6-dihydrobenzo[/]quinazolin-1-yl)-Λ/,Λ/- dimethylbenzenesulfonamide (185 mg, 0.2 mmol) in dichloromethane (10 ml.) was added pyridine (48 mg, 0.6 mmol) and 2,4-difluorobenzene-1-sulfonyl chloride (64 mg, 0.3 mmol). The resulting mixture was stirred at room temperature overnight, concentrated and purified by column chromatography on silica gel to give product as a yellow solid (30 mg, 24.8%). LC-MS: [M+H]⁺ = 606.1 , Purity = 100.0 %, Rt = 1.57min. ¹HNMR (MeOH-d): 57.88 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.7 Hz, 2H), 7.60-7.53 (m, 1 H), 7.26 (s, 1 H), 7.14-6.98 (m, 2H), 6.86 (s, 1 H), 2.93-2.84 (m, 4H), 2.78 (s, 6H).

Example 38

N-(3-amino-8-chloro-1-{3-[(dimethylamino)sulfonyl]phenyl}-5,6- dihydrobenzo[f]quinazolin-9-yl)-2,4-difluorobenzenesulfonamide

a) 3-(3,9-diamino-8-chloro-5,6-dihydrobenzo[/]quinazolin-1-yl)-Λ/,Λ/- dimethylbenzenesulfonamide A mixture of 1 ,8-dichloro-5,6-dihydrobenzo[/]quinazoline-3,9-diamine (0.2 g, 0.71 mmol), 3-(N,N-dimethylsulfamoyl) phenylboronic acid (163 mg, 0.71 mmol), sodium carbonate (0.223 g, 2.1 mmol) and Pd(dppf)CI₂ (26 mg) in dioxane/water (20 ml_/1 ml.) was heated at 100 ⁰C under argon overnight. The reaction was concentrated to dryness and the residue was extracted with ethyl acetate (20 ml_x3). The combined organic layers were washed with water (20 ml_x3), dried over Na₂SO₄, and concentrated to give the product as a brown solid (200 mg, 66%).

b) N-(3-amino-8-chloro-1-{3-[(dimethylamino)sulfonyl]phenyl}-5,6- dihydrobenzo[f]quinazolin-9-yl)-2,4-difluorobenzenesulfonamide

To a solution of 3-(3,9-diamino-8-chloro-5,6-dihydrobenzo[/]quinazolin-1-yl)-Λ/,Λ/- dimethylbenzenesulfonamide (200 mg, 0.47 mmol) in dichloromethane (10 mL) was added pyridine (11 1 mg, 1.4 mmol) and 2,4-difluorobenzene-1-sulfonyl chloride (148 mg, 0.70 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and purified by column chromatography on silica gel to give product as a yellow solid (35 mg, 12.4%). LC-MS: [M+H]⁺ = 606.1 , Purity = 100.0 %, Rt = 1.57min. ¹HNMR (DMSO-d6): 510.08 (s, 1 H) 7.81 (m, 2H), 7.67-7.44 (m, 5H), 7.29 (s, 1 H), 7.13 (t, J = 9.0 Hz, 1 H), 7.02-6.99 (m, 1 H), 6.59 (s, 1 H), 2.87 (m, 2H), 2.70 (m, 2H ), 2.48 (s, 6H).

Example 39

N-{3-amino-8-chloro-1-[4-(morpholin-4-ylsulfonyl)phenyl]-5,6- dihydrobenzo[f]quinazolin-9-yl}-2,4-difluorobenzenesulfonamide

a) 8-chloro-1-[4-(4-morpholinylsulfonyl)phenyl]-5,6-dihydrobenzo[/]quinazoline-3,9- diamine A mixture of 1 ,8-dichloro-5,6-dihydrobenzo[/]quinazoline-3,9-diamine (0.28 g, 1.00 mmol), 4-(morpholinosulfonyl) phenylboronic acid (0.27 g, 1.00 mmol), sodium carbonate (0.32 g, 3.00 mmol) and Pd(dppf)CI₂ (20 mg) in dioxane/water (15 ml_/5 ml.) was heated at 100 ⁰C under argon overnight. LCMS showed the reaction was complete. The mixture was concentrated and extracted with ethyl acetate (20 ml. x 2). The organic layers were concentrated to afford the crude solid (436 mg, 93%).

b) N-{3-amino-8-chloro-1-[4-(morpholin-4-ylsulfonyl)phenyl]-5,6- dihydrobenzo[f]quinazolin-9-yl}-2,4-difluorobenzenesulfonamide

To a solution of 8-chloro-1-[4-(4-morpholinylsulfonyl)phenyl]-5,6- dihydrobenzo[/]quinazoline-3,9-diamine (0.24 g, 0.50 mmol) in dichloromethane (8 ml.) was added pyridine (1 18 mg, 1.50 mmol) and 2,4-difluorobenzene-1-sulfonyl chloride (159 mg, 0.75 mmol). The resulting mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. The mixture was concentrated and purified by column chromatography on silica gel (ethyl acetate: petroleum ether 20:1 ) to give the product as a yellow solid (93 mg, 29%). LC-MS: [M+H]⁺ = 648.7, Purity = 100.0 %, Rt = 1.58 min. ¹HNMR (DMSOd₆): δ 10.09 (s, 1 H), 7.76 (d, J = 8.4 Hz, 2H), 7.63 (dd, J = 4.2 Hz, 8.7 Hz, 2H), 7.51-7.40 (m, 2H), 7.31 (s, 1 H), 7.19-7.13 (m, 1 H), 6.94 (s, 2H), 6.64 (s, 1 H), 3.56 (br s, 4H), 2.95 (br s, 4H), 2.89-2.85 (m, 2H), 2.72-2.68 (m, 2H).

Example 40

N-{3-amino-8-chloro-1-[3-(morpholin-4-ylsulfonyl)phenyl]-5,6- dihydrobenzo[f]quinazolin-9-yl}-2,4-difluorobenzenesulfonamide

a) 8-chloro-1-[3-(4-morpholinylsulfonyl)phenyl]-5,6-dihydrobenzo[/]quinazoline-3,9- diamine A mixture of 1 ,8-dichloro-5,6-dihydrobenzo[/]quinazoline-3,9-diamine (0.28 g, 1.00 mmol), 4-(morpholinosulfonyl) phenylboronic acid (0.27 g, 1.00 mmol), sodium carbonate (0.32 g, 3.00 mmol) and Pd(dppf)CI₂ (20 mg) in dioxane/water (15 ml_/5 ml.) was heated at 100 ⁰C under nitrogen overnight. LCMS showed the reaction was complete. The mixture was concentrated and extracted with ethyl acetate (20 ml. x 2). The organic layers were concentrated to afford the crude product as a yellow solid (423 mg, 90%).

b) N-{3-amino-8-chloro-1-[3-(morpholin-4-ylsulfonyl)phenyl]-5,6- dihydrobenzo[f]quinazolin-9-yl}-2,4-difluorobenzenesulfonamide

To a solution of ) 8-chloro-1-[3-(4-morpholinylsulfonyl)phenyl]-5,6- dihydrobenzo[/]quinazoline-3,9-diamine (0.24 g, 0.50 mmol) in dichloromethane (8 ml.) was added pyridine (1 18 mg, 1.50 mmol) and 2,4-difluorobenzene-1-sulfonyl chloride (159 mg, 0.75 mmol). The resulting mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. The mixture was concentrated and purified by column chromatography on silica gel (ethyl acetate : petroleum ether 20:1 ) to give the product as a yellow solid (1 15 mg, 35%). LC-MS: [M+H]⁺ = 648.7, Purity = 94.5 %, Rt = 1.58 min. ¹HNMR (DMSOd₆): δ 9.98 (s, 1 H), 7.82-7.80 (m, 2H), 7.69-7.61 (m, 2H), 7.53-7.43 (m, 2H), 7.30 (s, 1 H), 7.15 (t, J = 7.8 Hz, 1 H), 7.01 (s, 2H), 6.63 (s, 1 H), 3.60 (br s, 4H), 2.96-2.87 (m, 6H), 2.76-2.65 (m, 2H).

Example 41

N-{3-amino-8-chloro-1-[3-(methylsulfonyl)phenyl]-5,6-dihydrobenzo[f]quinazolin-9- yl}-2,4-difluorobenzenesulfonamide

a) 8-chloro-1-[3-(methylsulfonyl)phenyl]-5,6-dihydrobenzo[f]quinazoline-3,9-diamine A mixture of 1 ,8-dichloro-5,6-dihydrobenzo[/]quinazoline-3,9-diamine (0.42 g, 1.50 mmol), 3-(methylsulfonyl) phenylboronic acid (0.30 g, 1.50 mmol), sodium carbonate (0.48 g, 4.50 mmol) and Pd(dppf)CI₂ (20 mg) in dioxane/water (15 ml_/5 ml.) was heated at 100 ⁰C under nitrogen overnight. The mixture was concentrated and extracted with ethyl acetate (20 ml_x2). The organic layers were concentrated to afford the crude product as a yellow solid (548 mg, 91%).

b) N-{3-amino-8-chloro-1-[3-(methylsulfonyl)phenyl]-5,6-dihydrobenzo[f]quinazolin- 9-yl}-2,4-difluorobenzenesulfonamide

To a solution of 8-chloro-1-[3-(methylsulfonyl)phenyl]-5,6- dihydrobenzo[/]quinazoline-3,9-diamine (0.40 g, 1.00 mmol) in dichloromethane (8 ml.) was added pyridine (0.24 g, 3.00 mmol) and 2,4-difluorobenzene-1-sulfonyl chloride (0.32 g, 1.50 mmol). The resulting mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. The mixture was concentrated and purified by column chromatography on silica gel to give product as a yellow solid (126 mg, 22%). LC-MS: [M+H]⁺ = 577.7, Purity = 100.0 %, Rt = 1.55 min. ¹HNMR (DMSOd₆): δ 10.12 (s, 1 H), 8.01-7.96 (m, 2H), 7.69-7.63 (m, 2H), 7.49- 7.42 (m, 2H), 7.32 (s, 1 H), 7.17-7.03 (m, 1 H), 6.93 (s, 2H), 6.54 (s, 1 H), 3.16 (s, 3H), 2.89-2.85 (m, 2H), 2.72-2.67 (m, 2H).

Example 42

N-{3-amino-8-chloro-1-[4-(methylsulfonyl)phenyl]-5,6-dihydrobenzo[f]quinazolin-9- yl}-2,4-difluorobenzenesulfonamide

a) 8-chloro-1-[4-(methylsulfonyl)phenyl]-5,6-dihydrobenzo[f]quinazoline-3,9-diamine

A mixture of 1 ,8-dichloro-5,6-dihydrobenzo[/]quinazoline-3,9-diamine (0.15 g, 0.53 mmol), 4-(methylsulfonyl)phenylboronic acid (0.11 g, 0.53 mmol), sodium carbonate (0.17 g, 1.59 mmol) and Pd(dppf)CI₂ (22 mg) in dioxane/water (40 mL/10 mL) was heated at 100 ⁰C under argon overnight. The mixture was concentrated and the water layer was extracted with ethyl acetate (20 ml_x3). The combined organic layers were concentrated to afford the crude product (1 15 mg, 54%).

b) N-{3-amino-8-chloro-1-[4-(methylsulfonyl)phenyl]-5,6-dihydrobenzo[f]quinazolin- 9-yl}-2,4-difluorobenzenesulfonamide

To a solution of 8-chloro-1-[4-(methylsulfonyl)phenyl]-5,6- dihydrobenzo[/]quinazoline-3,9-diamine (0.1 15 g, 0.29 mmol) in dichloromethane (5 ml.) was added pyridine (68.8 mg, 0.87 mmol) and 2,4-difluorobenzene-1-sulfonyl chloride (93.5 mg, 0.44 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and purified by column chromatography on silica gel to give the product (82 mg, 49%). LC-MS: [M+H]⁺ = 577.1 , Purity = 100.0 %, Rt = 1.50min. ¹HNMR (Methanol-d): δ 8.06 (d, J = 8.7 Hz, 2H), 7.74 (d, J = 7.8 Hz, 2H), 7.58 (m, 1 H), 7.26 (s, 1 H), 7.14 (m, 2H), 6.75 (s, 1 H), 3.15 (s, 3H), 2.91 (m, 2H), 2.84 (m, 2H).

Example 43

N-[3-(3-amino-8-chloro-9-{[(2,4-difluorophenyl)sulfonyl]amino}-5,6- dihydrobenzo[f]quinazolin-1-yl)phenyl]acetamide

a) /V-β-^θ-diamino-δ-chloro-S^-dihydrobenzo^quinazolin-i-y^phenyllacetamide

A mixture of 1 ,8-dichloro-5,6-dihydrobenzo[/]quinazoline-3,9-diamine (0.20 g, 0.72 mmol), 3-acetamidophenylboronic acid (0.128 g, 0.72 mmol), sodium carbonate (0.229 g, 2.16 mmol) and Pd(dppf)CI₂ (30 mg) in dioxane/water (20 ml_/5 ml.) was heated at 100 ⁰C overnight. The dioxane was removed in vacuo and the water layer was extracted with ethyl acetate. The combined organic layers were concentrated to afford the crude product (200 mg, 74%). b) N-[3-(3-amino-8-chloro-9-{[(2,4-difluorophenyl)sulfonyl]amino}-5,6- dihydrobenzo[f]quinazolin-1-yl)phenyl]acetamide

To a solution of ) Λ/-[3-(3,9-diamino-8-chloro-5,6-dihydrobenzo[/]quinazolin-1- yl)phenyl]acetamide (0.20 g, 0.53 mmol) in dichloromethane (5 ml.) was added pyridine (125 mg, 1.59 mmol) and 2,4-difluorobenzene-1-sulfonyl chloride (170 mg, 0.80 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and purified by column chromatography on silica gel (petroleum ether : ethyl acetate 2:1 to 100% ethyl acetate) to give the product as a light yellow solid (150 mg, 51%). LC-MS: [M+H]⁺ = 556.1 , Purity = 99.5 %, Rt = 1.45min. ¹HNMR (DMSOd₆): δ 10.05 (s, 1 H), 10.03 (s, 1 H), 7.68-7.62 (m, 2H), 7.48-7.39 (m, 2H), 7.30-7.14 (m, 2H), 7.1 1-7.08 (m, 1 H), 6.90 (m, 3H), 6.58(s, 1 H), 2.83 (m, 2H), 2.68 (m, 2H), 2.00 (s, 3H).

Example 44

N-[4-(3-amino-8-chloro-9-{[(2,4-difluorophenyl)sulfonyl]amino}-5,6- dihydrobenzo[f]quinazolin-1-yl)phenyl]acetamide

a) Λ/-[4-(3,9-diamino-8-chloro-5,6-dihydrobenzo[/]quinazolin-1 -yl)phenyl]acetamide

A mixture of 1 ,8-dichloro-5,6-dihydrobenzo[/]quinazoline-3,9-diamine (0.2 g, 0.71 mol), 4-acetamidophenylboronic acid (0.127 mg, 0.71 mmol), sodium carbonate (0.223 g, 2.1 mmol) and Pd(dppf)CI₂ (26 mg) in dioxane/water (20 ml_/1 ml.) was heated at 100 ⁰C under nitrogen overnight. The mixture was concentrated to dryness and the residue was extracted with ethyl acetate (20 ml_x3). The combined organic layers were washed with water (20 ml_x3), dried over Na₂SO₄, and concentrated to afford the title compound (200 mg, 75%). b) N-[4-(3-amino-8-chloro-9-{[(2,4-difluorophenyl)sulfonyl]amino}-5,6- dihydrobenzo[f]quinazolin-1-yl)phenyl]acetamide

To a solution of Λ/-[4-(3,9-diamino-8-chloro-5,6-dihydrobenzo[/]quinazolin-1- yl)phenyl]acetamide (0.20 g, 0.53 mmol) in dichloromethane (10 ml.) was added pyridine (127 mg, 1.58 mmol) and 2,4-difluorobenzene-1-sulfonyl chloride (170 mg, 0.8 mmol). The resulting mixture was stirred at room temperature overnight. After 2Oh, the mixture was concentrated and purified by column chromatography on silica gel (petroleum ether : ethyl acetate 10:1 to 1 :50) to give product as brown solid (35 mg, 12%). LC-MS: [M+H]⁺ = 556.1 , Purity = 95.1 %, Rt = 1.34min. ¹HNMR (DMSO- d6): δ 10.10 (s, 1 H), 7.58-7.61 (m, 3H), 7.51-7.42 (m, 2H), 7.27-7.35 (m,3H), 7.17- 7.14 (m, 1 H), 6.82 (s, 2H), 6.64 (s, 1 H), 2.81 (m, 2H), 2.64 (m, 2H), 2.07 (s, 3H).

Example 45

N-(3-amino-8-chloro-1-pyridin-3-yl-5,6-dihydrobenzo[f]quinazolin-9-yl)-2,4- difluorobenzenesulfonamide

a) 8-chloro-1-(3-pyridinyl)-5,6-dihydrobenzo[/]quinazoline-3,9-diamine

A mixture of 1 ,8-dichloro-5,6-dihydrobenzo[/]quinazoline-3,9-diamine (0.42 g, 1.50 mmol), pyridin-3-ylboronic acid (0.18 g, 1.50 mmol), sodium carbonate (0.48 g, 4.50 mmol) and Pd(dppf)Cl₂ (20 mg) in dioxane/water (15 ml_/5 ml.) was heated at 100 ⁰C under argon overnight. LCMS showed the reaction was complete. The mixture was concentrated and purified by column chromatography on silica gel (ethyl acetate : petroleum ether 5:1 ) to give the product as yellow solid (350 mg, 72.0%).

b) N-(3-amino-8-chloro-1-pyridin-3-yl-5,6-dihydrobenzo[f]quinazolin-9-yl)-2,4- difluorobenzenesulfonamide To a solution of 8-chloro-1-(3-pyridinyl)-5,6-dihydrobenzo[/]quinazoline-3,9-diamine (0.32 g, 1.00 mmol) in dichloromethane (8 ml.) was added pyridine (0.24 g, 3.00 mmol) and 2,4-difluorobenzene-1-sulfonyl chloride (0.32 g, 1.50 mmol). The resulting mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. The mixture was concentrated and purified by column chromatography on silica gel (ethyl acetate : petroleum ether 10:1 ) to give product as a yellow solid (139 mg, 28%). LC-MS: [M+H]⁺ = 500.1 , Purity = 94.6 %, Rt = 1.81 min. ¹HNMR (DMSOd₆): δ 10.20 (s, 1 H), 8.84 (br s, 2H), 7.69 (s, 2H), 7.45-7.54 (m, 2H), 7.34 (s, 1 H), 7.1 1-7.21 (m, 3H), 6.50 (s, 1 H), 2.86-2.90 (m, 2H), 2.71-2.74 (m, 2H).

Example 46

N-[3-amino-8-chloro-1-(3-fluorophenyl)-5,6-dihydrobenzo[f]quinazolin-9-yl]-2,4- difluorobenzenesulfonamide

a) 8-chloro-1-(3-fluorophenyl)-5,6-dihydrobenzo[/]quinazoline-3,9-diamine

A mixture of 1 ,8-dichloro-5,6-dihydrobenzo[/]quinazoline-3,9-diamine (0.1 g, 0.36 mmol), 3-fluorophenylboronic acid (50 mg, 0.36 mmol), sodium carbonate (0.1 14 g, 1.1 mmol) and Pd(dppf)Cl₂ (17 mg) in dioxane/water (20 mL/1 mL) was heated at 100 ⁰C under nitrogen overnight. The mixture was concentrated to dryness and the residue was extracted with ethyl acetate (20 mLx3). The combined organic layers were washed with water (20 mLx3), dried over Na₂SO₄, and concentrated to afford the crude product (85 mg, 70%).

b) N-[3-amino-8-chloro-1-(3-fluorophenyl)-5,6-dihydrobenzo[f]quinazolin-9-yl]-2,4- difluorobenzenesulfonamide

To a solution of 8-chloro-1-(3-fluorophenyl)-5,6-dihydrobenzo[/]quinazoline-3,9- diamine (85 mg, 0.25 mmol) in dichloromethane (10 mL) was added pyridine (60 mg, 0.75 mmol) and 2,4-difluorobenzene-1-sulfonyl chloride (81 mg, 0.38 mmol). The resulting mixture was stirred at room temperature overnight. After 2Oh, the mixture was concentrated and purified by column chromatography on silica gel to give product as a yellow solid (30 mg, 23%). LC-MS: [M+H]⁺ = 517.1 , Purity = 98.9 %, Rt = 1.90min. ¹HNMR (DMSO-d6): 510.10 (s, 1 H), 7.48 (m, 4H), 7.33 (s, 1 H), 7.15-7.19 (m, 4H), 6.98 (s, 1 H), 6.55 (s, 1 H), 2.87 (m, 2H), 2.70 (m, 2H).

Example 47

3-(3-amino-8-chloro-9-{[(2,4-difluorophenyl)sulfonyl]amino}-5,6- dihydrobenzo[f]quinazolin-1-yl)-N-methylbenzamide

a) 3-(3,9-diamino-8-chloro-5,6-dihydrobenzo[/]quinazolin-1-yl)-Λ/-methylbenzamide

A mixture of 1 ,8-dichloro-5,6-dihydrobenzo[/]quinazoline-3,9-diamine (0.20 g, 0.71 mmol), 3-(methylcarbamoyl)phenyl boronic acid (127 mg, 0.71 mmol), sodium carbonate (0.23 g, 2.13 mmol) and Pd(dppf)CI₂ (29.4 mg) in dioxane/water (40 mL/10 ml.) was heated at 100 ⁰C overnight. The dioxane was removed in vacuo and the water layer was extracted with ethyl acetate (20ml_x3). The combined organic layers were concentrated to give the product (247 mg, 92%).

b) 3-(3-amino-8-chloro-9-{[(2,4-difluorophenyl)sulfonyl]amino}-5,6- dihydrobenzo[f]quinazolin-1-yl)-N-methylbenzamide

To a solution of 3-(3,9-diamino-8-chloro-5,6-dihydrobenzo[/]quinazolin-1-yl)-Λ/- methylbenzamide (0.25 g, 0.65 mmol) in dichloromethane (10 ml.) was added pyridine (152 mg, 1.92 mmol) and 2,4-difluorobenzene-1-sulfonyl chloride (204 mg, 0.96 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and purified by column chromatography on silica gel to give product as a light yellow solid (50 mg, 42%). LC-MS: [M+H]⁺ = 556.1 , Purity = 100 %, Rt = 1.38min. ¹HNMR (CDCI₃): δ 7.95 (s, 1 H), 7.85 (d, J = 7.2 Hz, 1 H), 7.57- 7.34 (m, 3H), 7.18 (s, 1 H), 6.97-6.84 (m, 4H), 6.15 (s, 1 H), 6.14 (s, 2H), 3.00 (d, J = 4.2 Hz, 3H), 2.86 (m, 4H).

Example 48 4-(3-amino-8-chloro-9-{[(2,4-difluorophenyl)sulfonyl]amino}-5,6- dihydrobenzo[f]quinazolin-1-yl)-N-methylbenzamide

a) 4-(3,9-diamino-8-chloro-5,6-dihydrobenzo[/]quinazolin-1-yl)-Λ/-methylbenzamide

A mixture of 1 ,8-dichloro-5,6-dihydrobenzo[/]quinazoline-3,9-diamine (0.2 g, 0.71 mol), 4-(methylcarbamoyl)phenylboronic acid (0.127 g, 0.71 mmol), sodium carbonate (0.223 g, 2.1 mmol) and Pd(dppf)CI₂ (26 mg) in dioxane/water (20 ml_/1 ml.) was heated at 100 ⁰C under nitrogen overnight. The mixture was concentrated to dryness and the residue was extracted with ethyl acetate (20 ml_x3). The combined organic layers were washed with water (20 ml_x3), dried over Na₂SO₄, and concentrated to afford the title compound as a brown solid (210 mg, 75%).

b) 4-(3-amino-8-chloro-9-{[(2,4-difluorophenyl)sulfonyl]amino}-5,6- dihydrobenzo[f]quinazolin-1-yl)-N-methylbenzamide

To a solution of 4-(3,9-diamino-8-chloro-5,6-dihydrobenzo[/]quinazolin-1-yl)-Λ/- methylbenzamide (0.21 g, 0.55 mmol) in dichloromethane (10 ml.) was added pyridine (132 mg, 1.65 mmol) and 2,4-difluorobenzene-1-sulfonyl chloride (176 mg, 0.83 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and purified by column chromatography on silica gel to give product as a yellow solid (35 mg, 11 %). LC-MS: [M+H]⁺ = 556.1 , Purity = 100 %, Rt = 1.37min. ¹HNMR (DMSO-d6): 510.07 (s, 1 H), 8.50 (d, J = 4.8 Hz, 1 H), 7.86 (d, J = 8.4 Hz, 2H), 7.47-7.39 (m, 4H), 7.33 (s, 1 H), 7.15 (t, J = 7.5 Hz, 1 H), 6.92 (s, 2H), 6.50 (s, 1 H), 2.81-2.84 (m, 5H), 2.70-2.73(m, 2H). Example 49

N-[3-amino-8-chloro-1-(4-methoxyphenyl)-5,6-dihydrobenzo[f]quinazolin-9-yl]-2,4- difluorobenzenesulfonamide

a) 8-chloro-1-[4-(methyloxy)phenyl]-5,6-dihydrobenzo[/]quinazoline-3,9-diamine

A mixture of 1 ,8-dichloro-5,6-dihydrobenzo[/]quinazoline-3,9-diamine (0.20 g, 0.72 mmol), 4-methoxyphenylboronic acid (0.11 g, 0.72 mmol), sodium carbonate (0.23 g, 2.16 mmol) and Pd(dppf)CI₂ (30 mg) in dioxane/water (20 ml_/5 ml.) was heated at 100 ° C under nitrogen overnight. The solvent dioxane was removed in vacuo. The water layer was extracted with ethyl acetate, and the combined organic layers were concentrated to give the crude product (220 mg, 87%).

b) N-[3-amino-8-chloro-1-(4-methoxyphenyl)-5,6-dihydrobenzo[f]quinazolin-9-yl]- 2,4-difluorobenzenesulfonamide

To a solution of 8-chloro-1-[4-(methyloxy)phenyl]-5,6-dihydrobenzo[/]quinazoline- 3,9-diamine (0.2Og, 0.57mmol) in dichloromethane (10 ml.) was added pyridine (135 mg, 1.71 mmol) and 2,4-difluorobenzene-1-sulfonyl chloride (182 mg, 0.86 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and purified by column chromatography on silica gel (petroleum ether : ethyl acetate 2:1 to 100% ethyl acetate) to give the final product (103 mg, 34%). LC-MS: [M+H]⁺ = 529.1 , Purity = 100 %, Rt = 1.55min. ¹HNMR (DMSOd₆): δ 10.10 (s, 1 H), 7.51-7.42 (m, 2H), 7.29-7.31 (m, 3H), 7.11 (m, 1 H), 7.04 (m, 1 H), 6.99-6.87 (m, 3H), 6.57 (s, 1 H), 3.79 (s, 3H), 2.84 (m, 2H), 2.67 (m, 2H). Example 50

3-(3-amino-8-chloro-9-{[(2,4-difluorophenyl)sulfonyl]amino}-5,6- dihydrobenzo[f]quinazolin-1-yl)benzamide

a) 3-(3,9-diamino-8-chloro-5,6-dihydrobenzo[/]quinazolin-1-yl)benzamide

A mixture of 1 ,8-dichloro-5,6-dihydrobenzo[/]quinazoline-3,9-diamine (0.42 g, 1.50 mmol), 3-carbamoylphenylboronic acid (0.25 g, 1.50 mmol), sodium carbonate (0.48 g, 4.50 mmol) and Pd(dppf)CI₂ (20 mg) in dioxane/water (15 ml_/5 ml.) was heated at 100 ⁰C under argon overnight. The mixture was concentrated and purified by column chromatography on silica gel (ethyl acetate : petroleum ether 5:1 ) to give product as yellow solid (382 mg, 70%).

b) 3-(3-amino-8-chloro-9-{[(2,4-difluorophenyl)sulfonyl]amino}-5,6- dihydrobenzo[f]quinazolin-1-yl)benzamide

To a solution of 3-(3,9-diamino-8-chloro-5,6-dihydrobenzo[/]quinazolin-1- yl)benzamide (0.37 g, 1.00 mmol) in dichloromethane (8 ml.) was added pyridine (0.24 g, 3.00 mmol) and 2,4-difluorobenzene-1-sulfonyl chloride (0.32 g, 1.50 mmol). The resulting mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. The mixture was concentrated and purified by column chromatography on silica gel (ethyl acetate : petroleum ether 10:1 ) to give the product as a yellow solid (129 mg, 24%). LC-MS: [M+H]⁺ = 542.7, Purity = 100.0 %, Rt = 1.43 min. ¹HNMR (DMSOd₆): δ 10.08 (s, 1 H), 7.90-8.01 (m, 3H), 7.46-7.36 (m, 5H), 7.31 (s, 1 H), 7.17-7.10 (m, 1 H), 6.92 (s, 2H), 6.46 (s, 1 H), 2.87.2.83 (m, 2H), 2.70-2.66 (m, 2H). Example 51

4-(3-amino-8-chloro-9-{[(2,4-difluorophenyl)sulfonyl]amino}-5,6- dihydrobenzo[f]quinazolin-1-yl)benzamide

a) 4-(3,9-diamino-8-chloro-5,6-dihydrobenzo[/]quinazolin-1-yl)benzamide

A mixture of 1 ,8-dichloro-5,6-dihydrobenzo[/]quinazoline-3,9-diamine (0.42 g, 1.50 mmol), 4-carbamoylphenylboronic acid (0.25 g, 1.50 mmol), sodium carbonate (0.48 g, 4.50 mmol) and Pd(dppf)CI₂ (20 mg) in dioxane/water (15 ml_/5 ml.) was heated at 100 ⁰C under argon overnight. LCMS showed the reaction was complete.

The mixture was concentrated and purified by column chromatography on silica gel

(ethyl acetate : petroleum ether 5:1 ) to give product as a yellow solid (396 mg,

72%).

b) 4-(3-amino-8-chloro-9-{[(2,4-difluorophenyl)sulfonyl]amino}-5,6- dihydrobenzo[f]quinazolin-1-yl)benzamide

To a solution of 4-(3,9-diamino-8-chloro-5,6-dihydrobenzo[/]quinazolin-1- yl)benzamide (0.37 g, 1.00 mmol) in dichloromethane (8 ml.) was added pyridine (0.24 g, 3.00 mmol) and 2,4-difluorobenzene-1-sulfonyl chloride (0.32 g, 1.50 mmol). The resulting mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. The mixture was concentrated and purified by column chromatography on silica gel (ethyl acetate: petroleum ether 10:1 ) to give the product as a yellow solid (113 mg, 21 %). LC-MS: [M+H]⁺ = 542.7, Purity = 100.0 %, Rt = 1.43 min. ¹HNMR (DMSOd₆): δ 10.07 (s, 1 H), 8.02 (s, 1 H), 7.89 (d, J = 8.4 Hz, 2H), 7.46-7.36 (m, 5H), 7.31 (s, 1 H), 7.17-7.10 (m, 1 H), 6.93 (s, 2H), 6.46 (s, 1 H), 2.85-2.82 (m, 2H), 2.70-2.65 (m, 2H). Example 52

N-[3-amino-8-chloro-1-(3-methoxyphenyl)-5,6-dihydrobenzo[f]quinazolin-9-yl]-2,4- difluorobenzenesulfonamide

a) 8-chloro-1-[3-(methyloxy)phenyl]-5,6-dihydrobenzo[/]quinazoline-3,9-diamine

A mixture of 1 ,8-dichloro-5,6-dihydrobenzo[/]quinazoline-3,9-diamine (0.20 g, 0.72 mmol), 3-methoxyphenylboronic acid (0.11 g, 0.72 mmol), sodium carbonate (0.23 g, 2.16 mmol) and Pd(dppf)Cl₂ (30 mg) in dioxane/water (20 ml_/5 ml.) was heated at 100 ⁰C overnight. The dioxane was removed in vacuo. The water layer was extracted with ethyl acetate and concentrated to afford the crude product (200 mg, 79%).

b) N-[3-amino-8-chloro-1-(3-methoxyphenyl)-5,6-dihydrobenzo[f]quinazolin-9-yl]- 2,4-difluorobenzenesulfonamide

To a solution of 8-chloro-1-[3-(methyloxy)phenyl]-5,6-dihydrobenzo[/]quinazoline- 3,9-diamine (0.20 g, 0.57 mmol) in dichloromethane (10 ml.) was added pyridine (73 mg, 1.71 mmol) and 2,4-difluorobenzene-1-sulfonyl chloride (78 mg, 0.86 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and purified by column chromatography on silica gel to afford the desired product (142 mg, 47%). LC-MS: [M+H]⁺ = 529.1 , Purity = 100 %, Rt = 1.59min. ¹H NMR (DMSOd₆): δ 10.08 (s, 1 H), 7.47 (m, 2H), 7.29 (m, 2H), 7.17 (m, 1 H), 6.98 (m, 1 H), 6.87 (m, 2H), 6.58 (s, 1 H), 3.70 (s, 3H), 2.85 (m, 2H), 2.70(m, 2H). Biological data

indicates pAKT HCC1954 IC₅₀ (nM) is reported. * indicates HCC1954 growth IC₅₀ (nM) is reported. The following derivatives described can be prepared by the general method J

The following example was prepared according to Scheme XVIIII:

Conditions: a) POCI₃, DMF, 80 ⁰C, 5 minutes; b) arylboronic acid, PdCI₂dppf, aq K₂CO₃, dioxane, 50 ⁰C, 18 hours; c) chlorosulfonic acid, rt; d) NH₃, MeOH, THF, rt, 15 minutes. Example 63 3-amino-8-chloro-1-(4-fluorophenyl)-5,6-dihydrobenzo[f]quinazoline-9-sulfonamide

a) /^-(i ^-dichloro-S^-dihydrobenzo^quinazolin-S-yO-^/V-dimethylimidoformamide

DMF and phosphoric trichloride were added to 3-amino-8-chloro-5,6- dihydrobenzo[f]quinazolin-1 (2H)-one. The reaction was stirred and heated to 80 ⁰C for 5 minutes. The product was confirmed via LCMS. The reaction mixture was quenched with 50 equivalents of a 2.0M aqueous sodium acetate solution, and then the product was extracted 3x with EtOAc and concentrated under vacuum. 550mg of crude material was recovered. 57% via UV-VIS corresponds to product from the LCMS. MS(ES)+ m/e 320.7 [M+H]⁺.

b) 8-chloro-1-(4-fluorophenyl)-5,6-dihydrobenzo[/]quinazolin-3-amine [8-chloro-1-(4-fluorophenyl)-5,6-dihydrobenzo[/]quinazolin-3-yl]formamide Into a 20 ml. scintillation vial, a solution of potassium carbonate (710 mg, 5.14 mmol) in water (0.500 ml) was added to a suspension of PdCI₂(dppf) (125 mg, 0.171 mmol), N'-(1 ,8-dichloro-5,6-dihydrobenzo[f]quinazolin-3-yl)-N,N- dimethylimidoformamide (550mg, 1.712 mmol), and (4-fluorophenyl)boronic acid (252 mg, 1.798 mmol) in 1 ,4-dioxane (2 ml). The reaction was heated at 50 ⁰C for 18 hours. Upon completion, the mixture was concentrated under vacuum and dissolved in 2ml_ of DMSO, then filtered. Purification was performed HPLC (reverse phase) utilizing a 7.3-minute run (47 mL/min, 35% ACN/H₂O, 0.1 %TFA to 75% ACN/H₂O, 0.1% TFA) with UV detection at 254nm. 400mg of a mixture of products was recovered. According to the UV-VIS trace of the LCMS, the ratio of mixtures was 5%: MS(ES)+ m/e 325.9 [M+H]⁺ and 95% : MS(ES)⁺ m/e 353.8 [M+H]⁺.

c) 3-amino-8-chloro-1-(4-fluorophenyl)-5,6-dihydrobenzo[/]quinazoline-9-sulfonyl chloride

Chlorosulfonic acid (6.438 g, 55.3 mmol) was added to 8-chloro-1-(4-fluorophenyl)- 5,6-dihydrobenzo[f]quinazolin-3-amine (400 mg, 1.228 mmol). The reaction mixture stirred for 30 minutes and then was poured slowly over ice. The precipitate of 10Omg (19.2% yield) was collected and carried onto the next step without further purification. MS(ES)+ m/e 423.6 [M+H]⁺.

d) 3-amino-8-chloro-1-(4-fluorophenyl)-5,6-dihydrobenzo[/]quinazoline-9- sulfonamide

To a tetrahydrofuran (THF) (2 ml) solution of 3-amino-8-chloro-1-(4-fluorophenyl)- 5,6-dihydrobenzo[f]quinazoline-9-sulfonyl chloride (100mg, 0.236 mmol), ammonia (42.6 mg, 2.5 mmol) in methanol (1.25 ml) was added and stirred for 15 minutes at room temperature. The reaction mixture was evaporated under vacuum. HPLC (reverse-phase) purification was performed utilizing a 7.3-minute run (47 mL/min, 30% ACN/H₂O, 0.1 %TFA to 80% ACN/H₂O, 0.1 % TFA) with UV detection at 254nm.

35 mg of the title product was isolated (36.7% yield) MS(ES)+ m/e 404.9 [M+H]^{+ 1}H NMR (400 MHz, MeOD) δ ppm 2.65 (s, 2 H) 2.91 - 2.97 (m, 2 H) 3.03 - 3.09 (m, 2 H) 7.22 (ddd, J=8.72, 6.69, 2.02 Hz, 2 H) 7.44 (s, 1 H) 7.52 (s, 1 H) 7.56 (ddd, J=6.88, 5.12, 2.15 Hz, 2 H) Biological Data

Claims

What is claimed is:

1. A compound having formula I:

wherein:

R¹ is hydrogen or -NHR^1a, where R^1a is hydrogen, optionally substituted C₁-C₄ alkyl, optionally substituted C_3-6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

R² is hydrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, -OR^X, or -NR^BR^c, where R^B and R^c are not both hydrogen, wherein R^x is optionally substituted aryl; and R^B and R^c are independently selected from the group: hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or R^B and R^c taken together with the nitrogen atom to which they are bound form a 3-8 membered ring with 1-3 heteroatoms, which 3-8 membered ring is optionally substituted with 1-4 substituents independently selected from optionally substituted Ci-C₄ alkyl; each of R³ and R⁴ is independently selected from the group: hydrogen, halo, nitro, cyano, optionally substituted C₁-C₆ alkyl, optionally substituted C₃-C₇ cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, -NR^bR^c, -NH-C(O)NR^bR^c, -NH-C(O )OR^d, -NH-SO₂NR^bR^c, -NH-SO₂R^d, -OR^d, -O(CO)R^d, -C(O)R^d, -C(O)NR^bR^c, -SO₂NR^bR^c, -SO₂R^d, -CO₂R^d; where R^b and R^c are independently selected from the group: hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or R^b and R^c taken together with the nitrogen atom to which they are bound form a 3-8 membered ring with 1-3 heteroatoms; which 3-8 membered ring is optionally substituted with 1-4 substituents independently selected from d-C₄ alkyl, or where R^d is selected from the group: hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl; and a pharmaceutically-acceptable salt thereof.

2. A compound according to claim 1 , having the formula:

wherein

R^1a is hydrogen, optionally substituted C₁-C₄ alkyl, optionally substituted aryl, or optionally substituted heteroaryl;

R is optionally substituted aryl, optionally substituted heteroaryl, -NR R ,

R^B and R^c are not both hydrogen;

R³ and R⁴ are each independently selected from the group: hydrogen, halo, nitro, cyano, -OR^d, -SO₂NR^bR^c and -NHSO2R^d, where R^b and R^c are independently selected from the group: hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and where R^b and R^c , taken together with the nitrogen atom to which they are attached, form a ring of 3-8 members with 1-3 heteroatoms, which 3-8 membered ring is optionally substituted with 1-4 substituents selected from Ci-C₄ alkyl; where R^d is selected from the group: hydrogen, optionally substituted C₁-C₆ alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl.

3. A compound according to any one of claims 1-2, wherein R^1a is optionally substituted alkyl, the optional substituents are selected from the group: hydroxy, alkoxy, dialkylamino, alkylamino, amino, aryl, heterocycloalkyl, and cycloalkyl.

4. A compound according to any one of claims 1-2, wherein R^1a is optionally substituted phenyl and the optional substituents are selected from the group: cyano, alkoxy, hydroxy, nitro, -CH₂-SO₂(Ci-C₄alkyl), -SO₂NH₂, and -SO₂(d-C₄alkyl). or R^1a is an optionally substituted heteroaryl selected from 2-pyridyl and 3-pyridyl.

5. A compound according to any one of claims 1-2, wherein R is hydrogen.

6. A compound according to any one of claims 1-2, wherein R^1a is methyl, hydroxypropyl, 3-cyanophenyl, 4-cyanophenyl, 3,4,5-trimethoxyphenyl, pyrid-2-yl, pyrid-3-yl, 4-(4-morpholinylsulfonyl)phenyl, 4-[(methylsulfonyl)methyl]phenyl, or 4- {[(5-methyl-isoxazol-3-yl)amino]sulfonyl} phenyl.

7. A compound according to any one of claims 1-6, wherein when R² is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl, the optional substituents are independently selected from the group: CrC₄ alkyl, d-C₄ alkoxy, halo, hydroxy, heteroaryl, heterocycloalkyl, dialkylamino, alkylsulfonyl, alkylamido, cyano, alkylsulfonyl, and alkylacyl.

8. A compound according to any one of claims 1-6, wherein when R² is -NR^BR^C, R^b is H or CrC₆ alkyl; and R^c is selected from optionally substituted CrC₆ alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl, the optional substituents for said optionally substituted R^c groups are each independently selected from the group: C₁-C₄ alkyl, Ci-C₄alkoxy, halo, hydroxy, hydroxy(Ci-C₄)alkyl , carboxy(Ci-C₄)alkyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, amino, Ci-C₄alkylamino, di(Ci-C₄)alkylamino, CrC₄ alkylsulfonyl, CrC₄ alkylamido, cyano, CrC₄ alkylsulfonyl, and C₁-C₄ alkylcarbonyl.

9. A compound according to any one of claims 1-6, wherein R² is optionally substituted amino having the formula NR^bR^c, wherein R^b and R^c are joined to form a heterocycle selected from: morpholinyl, 4-(diethylaminopropyl)-piperazinyl and pyrrolidinyl.

10. A compound according to any one of claims 1-6, wherein R² is H or R² is phenyl; 3-(fluoro)phenyl; 4-(fluoro)phenyl; 3-(chloro)phenyl; 4-(chloro)phenyl; 3-(cyano)phenyl; 4-(cyano)phenyl; 3-(methoxy)phenyl; 3-(trifluoromethoxyphenyl; 4-(methoxy)phenyl; 3-(hydroxy)phenyl; 4-(hydroxy)phenyl; 3,4,5-(tri-methoxy)phenyl; 2,4-(di-methoxy)phenyl; 3,5-(di-methoxy)phenyl; 3,5-di-methyl-4-hydroxy-phenyl; ; 4-(acetamido)phenyl (or 4-(methylcarbonylamino)phenyl); 3-(methylsulfonyl)phenyl (or 3-(methanesulfonyl)phenyl); 4-(methylsulfonyl)phenyl; 4-(methylsulfonylamino)phenyl (or 4-(methanesulfonylamino)phenyl); 4-[(cyanoethyl)(ethyl)amino]-2-(methyl)-phenyl; 3-(3-pyridinyl)phenyl; 4-(5-pyrimidinyl)phenyl; 4-[2-(ethyloxy)-pyrimidin-4-yl]phenyl; 4-{[3-(dimethylamino)propyl]oxy}phenyl; 4-(1 ,2,4-triazol-1 -yl)phenyl; quinolin-6-yl; 1-methyl-1 ,2,3,4-tetrahydro-quinolin-6-yl; 1-methyl-1 ,2,3,4-tetrahydroquinolin-7-yl; morpholin-4-yl; indol-5-yl; 1-methyl-imidazol-5-yl; indazol-3-yl; 3-amino-indazol-5-yl; pyrrolidin-1-yl; (3-pyridinyl)-pyrrol-2-yl; pyridin-3-yl; 3-methyl-pyridin-2-yl; 6-bromo-pyridin-2-yl; 1-methyl-pyrazol-4-yl; 1-methyl-pyrrol-2-yl; 1 ,3-benzodioxol-5-yl; thien-2-yl; 5-bromo-thien-2-yl; 5-methyl-thien-2-yl; thien-3-yl; 5-acetamido-thien-2-yl (or δ-methylcarbonylamino-thien^-yl); 2,2'-bithien-5-yl; 5-(hydroxymethyl)furan-2-yl; 2,4-(di-amino)quinazolin-6-yl; or 4-methyl-3,4-dihydro-2H-1 ,4-benzoxazin-7-yl.

11. A compound according to any one of claims 1-6, wherein R² is -OR^X, where R^x is 3-methoxyphenyl; 3,4,5-trimethoxy-phenyl; 3-(cyano)phenyl; or naphthalen-2-yl.

12. A compound according to any one of claims 1-6, wherein R² is -NR^2CR^2D, where R^2C is H and R^2D is [2-(methyloxy)phenyl]methyl; 2-phenylethyl; phenylmethyl; 2-(4-morpholinyl)ethyl; 3-(4-(methyl)-piperazin-1-yl)prop-1-yl; phenyl; 3-fluorophenyl; 4-fluorophenyl; 3-chlorophenyl; 4-chlorophenyl; 2-methoxyphenyl; 3-methoxyphenyl; 4-methyloxyphenyl; 3-[(1-methylethyl)oxy]-phenyl (or 3-(isopropoxy)phenyl); 4-[(1-methylethyl)oxy]-phenyl (or 4-(isopropoxy)phenyl); 3,4,5-trimethoxyphenyl; 3-(chloro)-4-(fluoro)phenyl; 3-hydroxyphenyl ; 4-hydroxyphenyl ; 3-cyanophenyl; 4-cyanophenyl; 3-(methylsulfonyl)phenyl; 4-(methylsulfonyl)phenyl; 3-[(methylsulfonyl)methyl]phenyl; 3-(methylsulfonylamino)phenyl; 4-(methylsulfonylamino)phenyl; 4-(methylsulfonylaminomethyl)phenyl (or 4-(benzyl-methanesulfonamide); 4-[(methylsulfonyl)methyl]phenyl}; 3-[2-(methylsulfonyl)ethyl]phenyl; 3-(trifluoromethyl)phenyl; 4-(trifluoromethyl)phenyl; 3-(di-methylamino)phenyl; 4-(di-methylamino)phenyl; 3-(acetyl)phenyl (or 3-(methylcarbonyl)phenyl); 4-(acetyl)phenyl (or 4-(methylcarbonyl)phenyl); 3-(amido)phenyl (or 3-(aminocarbonyl)phenyl) ; 4-(amido)phenyl (or 4-(aminocarbonyl)phenyl) ; 3-(acetamido)phenyl (or 3-(methylcarbonylamino)phenyl); 4-(acetamido)phenyl (or 4-(methylcarbonylamino)phenyl); 4-(1 ,2,4-triazol-1 -ylmethyl)phenyl; 4-[3-(diethylamino)propyl]-piperazin-1-yl;

(2,2-dioxido-1 ,3-dihydro-2-benzothien-5-yl); 3-(2-methyl-1 ,3-thiazol-4-yl)phenyl; 3-(cyclopropylcarbonyl)phenyl; 1 ,3-benzothiazol-5-yl; 1 ,3-benzothiazol-6-yl; 1 ,2,3-benzotriazol-5-yl; benzimidazol-5-yl; indol-6-yl; indazol-5-yl; 2-methyl-1-[2-(methyloxy)ethyl]-indol-5-yl; or 1-acetyl-2,3-dihydro-indol-5-yl.

13. A compound according to any one of claims 1-6, wherein R² is -NR^2CR^2D, where R^2C is methyl; and R^2D is phenyl.

14. A compound according to any one of claims 1-13, wherein R³ is hydrogen, halo, Ci-C₄ alkoxy, or -SO₂NR^bR^c, where R^b and R^c are independently selected from the group: hydrogen and C₁-C₄ alkyl, or R^b and R^c , taken together with the nitrogen atom to which they are attached, form a 5-6 membered ring containing 0 or 1 additional heteroatoms selected from N and O, which 5-6 membered ring is optionally substituted with 1-4 CrC₄ alkyl. substitutents.

15. A compound according to any one of claims 1 -13, wherein R³ is hydrogen, methoxy, fluoro, piperidinylsulfonyl, morpholin-4-ylsulfonyl, pyrrolidin-1 -ylsulfonyl, or 4-(N-methyl)piperazin-1-ylsulfonyl).

16. A compound according to any one of claims 1-13, wherein R³ is -NH-SO₂R⁰¹, where R^d is selected from the group: hydrogen, optionally substituted CrC₆ alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl.

17. A compound according to any one of claims 1-16, wherein R⁴ is is hydrogen, halo, CrC₄ alkoxy, or monocyclic 5-6 membered heteroaryl.

18. A compound according to any one of claims 1-16, wherein R⁴ is hydrogen, chloro, fluoro, bromo, methoxy, ethoxy, or pyrimidin-5-yl.

19. A compound according to claim 1 , having the formula:

wherein

R² is optionally substituted aryl, optionally substituted heteroaryl, -NR^BR^C, where R^B and R^c are not both hydrogen; each R³ and R⁴ is independently selected from the group: hydrogen, halo, nitro, cyano, -OR^d, -SO₂NR^bR^c, where R^b and R^c are independently selected from the group: hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and where R^b and R^c , taken together with the nitrogen atom to which they are attached, form a ring of 3-8 members containing 1-3 heteroatoms, which 3-8 membered ring is optionally substituted with 1-4 substituents selected from d-C₄ alkyl; where R^d is selected from the group: hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl.

20. A compound according to claim 18, wherein R³ is hydrogen and R⁴ is bromo.

21. A method of inhibitiing the activity or function of a phosphor-inositide-3'OH kinase in the treatment of one or more disease states selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection, and lung injuries, comprising administering to a subject in need thereof a compound according to any one of claims 1-19.

22. A method of treating cancer which comprises administering an effective amount of a compound according to any one of claims 1-19 or a pharmaceutically acceptable salt thereof to a mammal in need thereof.

23. A method of claim 22 wherein the cancer is selected from the group consisting of: brain (gliomas), glioblastomas, leukemias, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma, renal, ovarian, pancreatic, prostate, sarcoma, osteosarcoma, giant cell tumor of bone and thyroid cancer.

24. A method of claim 22 wherein the cancer is selected from the group consisting of: ovarian, pancreatic, breast, prostate, renal and leukemia.