Patent Publication Number: US-2009227575-A1

Title: 7H-PYRROLO[2,3-H]QUINAZOLINE COMPOUNDS, THEIR USE AS mTOR KINASE AND PI3 KINASE INHIBITORS, AND THEIR SYNTHESIS

Description:
FIELD OF THE INVENTION 
     The invention relates to 7H-pyrrolo[2,3-h]quinazoline compounds, compositions comprising a 7H-pyrrolo[2,3-h]quinazoline compound, methods of synthesizing these compounds, and methods for treating mTOR-related diseases. The invention also relates to methods for treating PI3K-related diseases. The invention also includes intermediates useful for making the active compounds. 
     BACKGROUND OF THE INVENTION 
     Phosphatidylinositol (hereinafter abbreviated as “PI”) is one of the phospholipids in cell membranes. In recent years it has become clear that PI plays an important role also in intracellular signal transduction. It is well recognized in the art that PI (4,5) bisphosphate (PI(4,5)P2 or PIP2) is degraded into diacylglycerol and inositol (1,4,5) triphosphate by phospholipase C to induce activation of protein kinase C and intracellular calcium mobilization, respectively [M. J. Berridge et al.,  Nature,  312, 315 (1984); Y. Nishizuka,  Science,  225, 1365 (1984)]. 
     In the late 1980s, phosphatidylinositol-3 kinase (“PI3K”) was found to be an enzyme that phosphorylates the 3-position of the inositol ring of phosphatidylinositol [D. Whitman et al.,  Nature,  332, 664 (1988)]. When PI3K was discovered, it was originally considered to be a single enzyme. Recently however, it was clarified that a plurality of PI3K subtypes exists. Three major subtypes of PI3Ks have now been identified on the basis of their in vitro substrate specificity, and these three are designated class I (a &amp; b), class II, and class III [B. Vanhaesebroeck,  Trend in Biol. Sci.,  22, 267(1997)]. 
     The class Ia PI3K subtype has been most extensively investigated to date. Within the class la subtype there are three isoforms (α, β, &amp; δ) that exist as hetero dimers of a catalytic 110-kDa subunit and regulatory subunits of 50-85 kDa. The regulatory subunits contain SH2 domains that bind to phosphorylated tyrosine residues within growth factor receptors or adaptor molecules and thereby localize PI3K to the inner cell membrane. At the inner cell membrane PI3K converts PIP2 to PIP3 (phosphatidylinositol-3,4,5-trisphosphate) that serves to localize the downstream effectors PDK1 and Akt to the inner cell membrane where Akt activation occurs. Activated Akt mediates a diverse array of effects including inhibition of apoptosis, cell cycle progression, response to insulin signaling, and cell proliferation. c Class Ia PI3K subtypes also contain Ras binding domains (RBD) that allow association with activated Ras providing another mechanism for PI3K membrane localization. Activated, oncogenic forms of growth factor receptors, Ras, and even PI3K kinase have been shown to aberrantly elevate signaling in the PI3K/Akt/mTOR pathway resulting in cell transformation. As a central component of the PI3K/Akt/mTOR signaling pathway PI3K (particularly the class Ia α isoform) has become a major therapeutic target in cancer drug discovery. 
     Substrates for class I PI3Ks are PI, PI(4)P and PI(4,5)P2, with PI(4,5)P2 being the most favored. Class I PI3Ks are further divided into two groups, class Ia and class Ib, because of their activation mechanism and associated regulatory subunits. The class Ib PI3K is p110γ that is activated by interaction with G protein-coupled receptors. Interaction between p110γ and G protein-coupled receptors is mediated by regulatory subunits of 110, 87, and 84 kDa. 
     PI and PI(4)P are the known substrates for class II PI3Ks; PI(4,5)P2 is not a substrate for the enzymes of this class. Class II PI3Ks include PI3K C2α, C2β and C2γ isoforms, which contain C2 domains at the C terminus, implying that their activity is regulated by calcium ions. 
     The substrate for class III PI3Ks is PI only. A mechanism for activation of the class III PI3Ks has not been clarified. Because each subtype has its own mechanism for regulating activity, it is likely that activation mechanism(s) depend on stimuli specific to each respective class of PI3K. 
     The compound PI103 (3-(4-(4-morpholinyl)pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-2-yl)phenol) inhibits PI3K α  and PI3K γ  as well as the mTOR enzymes with IC 50  values of 2, 3, and 50-80 nM respectively. I.P. dosing in mice of this compound in human tumor xenograft models of cancer demonstrated activity against a number of human tumor models, including the glioblastoma (PTEN null U87MG), prostate (PC3), breast (MDA-MB-468 and MDA-MB-435) colon carcinoma (HCT 116); and ovarian carcinoma (SKOV3 and IGROV-1); (Raynaud et al, Pharmacologic Characterization of a Potent Inhibitor of Class I Phosphatidylinositide 3-Kinases,  Cancer Res.  2007 67: 5840-5850). 
     The compound ZSTK474 (2-(2-difluoromethylbenzoimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine) inhibits PI3K α  and PI3K γ  but not the mTOR enzymes with an IC 50  values of 16, 4.6 and &gt;10,000 nM respectively (Dexin Kong and Takao Yamori, ZSTK474 is an ATP-competitive inhibitor of class I phosphatidylinositol 3 kinase isoforms,  Cancer Science,  2007, 98:10 1638-1642). Chronic oral administration of ZSTK474 in mouse human xenograft cancer models, completely inhibited growth which originated from a non-small-cell lung cancer (A549), a prostate cancer (PC-3), and a colon cancer (WiDr) at a dose of 400 mg/kg. (Yaguchi et al, Antitumor Activity of ZSTK474, a New Phosphatidylinositol 3-Kinase Inhibitor,  J. Natl. Cancer Inst.  98: 545-556). 
     The compound NVP-BEZ-235 (2-methyl-2-(4-(3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)propanenitrile) inhibits both PI3K α  and PI3K γ  as well as the mTOR enzymes with IC 50  values 4, 5, and “nanomolar”. Testing in human tumor xenograft models of cancer demonstrated activity against human tumor models of prostrate (PC-3) and glioblastoma (U-87) cancer. It entered clinical trials in December of 2006 (Verheijen, J. C. and Zask, A., Phosphatidylinositol 3-kinase (PI3K) inhibitors as anticancer drugs,  Drugs Fut.  2007, 32(6): 537-547). 
     The compound SF-1126 (a prodrug form of LY-294002, which is 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) is “a pan-PI3K inhibitor”. It is active in preclinical mouse cancer models of prostrate, breast, ovarian, lung, multiple myeloma, and brain cancers. It began clinical trials in April, 2007 for the solid tumors endometrial, renal cell, breast, hormone refractory prostate and ovarian cancers. (Verheijen, J. C. and Zask, A., Phosphatidylinositol 3-kinase (PI3K) inhibitors as anticancer drugs,  Drugs Fut.  2007, 32(6): 537-547). 
     Exelixis Inc. (So. San Francisco, Calif.) recently filed INDs for XL-147 (a selective pan-PI3K inhibitor of unknown structure) and XL-765 (a mixed inhibitor of mTOR and PI3K of unknown structure) as anticancer agents. TargeGen&#39;s short-acting mixed inhibitor of PI3Kγ and δ, TG-100115, is in phase I/II trials for treatment of infarct following myocardial ischemia-reperfusion injury. Cerylid&#39;s antithrombotic PI3Kβ inhibitor CBL-1309 (structure unknown) has completed preclinical toxicology studies. 
     According to Verheijen, J. C. and Zask, A., Phosphatidylinositol 3-kinase (PI3K) inhibitors as anticancer drugs,  Drugs Fut.  2007, 32(6): 537-547,
         Although it seems clear that inhibition of the α isoform is essential for the antitumor activity of PI3K inhibitors, it is not clear whether a more selective inhibitor of a particular PI3K isoform may lead to fewer unwanted biological effects. It has recently been reported that non-PI3Kα class I isoforms (PI3Kβ, δ and γ) have the ability to induce oncogenic transformation of cells, suggesting that nonisoform-specific inhibitors may offer enhanced therapeutic potential over specific inhibitors.   Selectivity versus other related kinases is also an important consideration for the development of PI3K inhibitors. While selective inhibitors may be preferred in order to avoid unwanted side effects, there have been reports that inhibition of multiple targets in the PI3K/Akt pathway (e.g., PI3Kα and mTOR [mammalian target of rapamycin]) may lead to greater efficacy. It is possible that lipid kinase inhibitors may parallel protein kinase inhibitors in that nonselective inhibitors may also be brought forward to the clinic.       

     Mammalian Target of Rapamycin, mTOR, is a cell-signaling protein that regulates the response of tumor cells to nutrients and growth factors, as well as controlling tumor blood supply through effects on Vascular Endothelial Growth Factor, VEGF. Inhibitors of mTOR starve cancer cells and shrink tumors by inhibiting the effect of mTOR. All mTOR inhibitors bind to the mTOR kinase. This has at least two important effects. First, mTOR is a downstream mediator of the PI3K/Akt pathway. The PI3K/Akt pathway is thought to be over activated in numerous cancers and may account for the widespread response from various cancers to mTOR inhibitors. The over-activation of the upstream pathway would normally cause mTOR kinase to be over activated as well. However, in the presence of mTOR inhibitors, this process is blocked. The blocking effect prevents mTOR from signaling to downstream pathways that control cell growth. Over-activation of the PI3K/Akt kinase pathway is frequently associated with mutations in the PTEN gene, which is common in many cancers and may help predict what tumors will respond to mTOR inhibitors. The second major effect of mTOR inhibition is anti-angiogenesis, via the lowering of VEGF levels. 
     In lab tests, certain chemotherapy agents were found to be more effective in the presence of mTOR inhibitors. George, J. N., et al., Cancer Research, 61, 1527-1532, 2001. Additional lab results have shown that some rhabdomyosarcoma cells die in the presence of mTOR inhibitors. The complete functions of the mTOR kinase and the effects of mTOR inhibition are not completely understood. 
     There are three mTOR inhibitors, which have progressed into clinical trials. These compounds are Wyeth&#39;s Torisel, also known as 42-(3-hydroxy-2-(hydroxymethyl)-rapamycin 2-methylpropanoate, CCI-779 or Temsirolimus; Novartis&#39; Everolimus, also known as 42-O-(2-hydroxyethyl)-rapamycin, or RAD 001; and Ariad&#39;s AP23573 also known as 42-(dimethylphopsinoyl)-rapamycin. The FDA has approved Torisel for the treatment of advanced renal cell carcinoma. In addition, Torisel is active in a NOS/SCID xenograft mouse model of acute lymphoblastic leukemia [Teachey et al,  Blood,  107(3), 1149-1155, 2006]. Everolimus is in a phase II clinical study for patients with Stage IV Malignant Melanoma. AP23573 has been given orphan drug and fast-track status by the FDA for treatment of soft-tissue and bone sarcomas. 
     The three mTOR inhibitors have non-linear, although reproducible pharmacokinetic profiles. Mean area under the curve (AUC) values for these drugs increase at a less than dose related way. The three compounds are all semi-synthetic derivatives of the natural macrolide antibiotic rapamycin. It would be desirable to find fully synthetic compounds, which inhibit mTOR that are more potent and exhibit improved pharmacokinetic behaviors. 
     The most recently described PI3K family member was identified in human cells and named human or hSMG-1. Yamashita (Genes Dev. 2001 15: 2215-2228) characterized two isoforms of hSMG-1 proteins, p430 and p400, which are expressed in various cell lines of human, monkey, rat, and mouse. Yamashita&#39;s p400 hSMG-1 isoform is a 3529-amino-acid protein of 396,040 Daltons. Brumbaugh (Molecular Cell, Volume 14, Issue 5, 4 Jun. 2004, Pages 585-598) isolated a 3521 amino acid polypeptide with a deduced molecular mass of 395 kDa. Brumbaugh&#39;s hSMG-1 is eight amino acids shorter at the amino terminus than the protein isolated by Yamashita. Both hUpf1 and p53 are physiological targets for hSMG-1 in intact cells. Rapamycin in the presence of purified recombinant FKBP12 does not inhibit the kinase activity of hSMG-1. Wortmannin, the modified steroidal anti-infective agent, and the purine caffeine inhibit the kinase activity of hSMG-1 with IC 50  values of ˜60 nM and 0.3 mM, respectively. However, these are non-specific protein kinase inhibitors. 
     Specific inhibition of hSMG-1 is a potential therapeutic strategy because inhibitors of hSMG-1 cause the accumulation of truncated p53 proteins from a premature translation termination codon (PTC) allele, as well as the increase in the level of mRNA with PTC, opening the possibility of the above strategy by specifically suppressing nonsense-mediated mRNA decay (NMD) through the inhibition of hSMG-1. 
     One-fourth of all mutations in human genetic diseases and cancers are of the type that can target the corresponding mRNA for NMD. Although NMD protects cells against deleterious gain-of-function mutations caused by the dominant negative effects of aberrant truncated proteins, there are some cases in which the truncated protein does not show such an effect, rather, it retains residual activity and can compensate for the normal gene function. Thus, the specific inhibition of NMD may provide a novel therapeutic strategy based on the type of mutation rather than on the gene in which the mutation resides. 
     The inhibitors of SMG-1 can rescue the synthesis of mature proteins through two independent mechanisms (i.e., the inhibition of NMD to increase the mRNA level and the suppression of translational termination that leads to the synthesis of a read-through mature protein product). In this sense, the specific inhibitors of hSMG-1 will be of potential therapeutic importance for all the genetic diseases associated with PTC mutations. 
     As explained above, PI3K inhibitors and mTOR inhibitors are expected to be novel types of medicaments useful against cell proliferation disorders, especially as carcinostatic agents. Thus, it would be advantageous to have new PI3K inhibitors and mTOR inhibitors as potential treatment regimens for mTOR- and PI3K-related diseases. The instant invention is directed to these and other important ends. 
     SUMMARY OF THE INVENTION 
     In one aspect, the invention provides compounds of the Formula I: 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salt thereof, wherein the constituent variables are as defined below. 
     In one aspect, the invention provides compounds of the Formula II: 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salt thereof, wherein the constituent variables are as defined below. 
     In other aspects, the invention provides pharmaceutical compositions comprising compounds or pharmaceutically acceptable salts of compounds of the present formula II. 
     In one aspect, the compounds or pharmaceutically acceptable salts of the compounds of the present formula II are useful as mTOR inhibitors. 
     In one aspect, the compounds or pharmaceutically acceptable salts of the compounds of the present formula II are useful as PI3K inhibitors. 
     In one aspect, the invention provides methods for treating an mTOR-related disorder, comprising administering to a mammal in need thereof, the compounds or pharmaceutically acceptable salts of compounds of the present formula II in an amount effective to treat an mTOR-related disorder. 
     In one aspect, the invention provides methods for treating a PI3K-related disorder, comprising administering to a mammal in need thereof the compounds or pharmaceutically acceptable salts of compounds of the present formula II in an amount effective to treat a PI3K-related disorder. 
     In other aspects, the invention provides further methods of synthesizing the compounds or pharmaceutically acceptable salts of compounds of the present formula II. 
     In other aspects, the invention provides intermediates of Formula III useful in synthesizing compounds of Formula II: 
     
       
         
         
             
             
         
       
     
     wherein the constituent variables are as defined below. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     In one aspect, the invention provides compounds of the Formula I: 
     
       
         
         
             
             
         
       
         
         or pharmaceutically acceptable salt thereof, wherein 
         Ar is phenyl, naphthyl, or nitrogen-containing mono- or bicyclic C 1 -C 9 heteroaryl; 
         R 1  is independently NR 3 R 4 ; NHC(O)NR 3 R 4 ; —NHC(O)OR 5 ; R 5 C(O)NH—; R 5 C(O)—; R 5 S(O) p NH—; CHO; C 1 -C 6 hydroxylalkyl-; C 3 -C 6 hydroxylalkenyl-; (C 6 -C 14 aryl)alkyl optionally substituted by hydroxyl; (C 6 -C 14 aryl)alkyl-O—; (C 1 -C 6 alkoxy)carbonyl; HO 2 C—; R 3 R 4 NC(O)—; N≡C—; carboxyamido(C 1 -C 6 )alkyl-; hydroxyl; halo; C 1 -C 6 alkoxy optionally substituted with from 1 to 3 substituents independently selected from C 1 -C 6 alkoxy, —NH 2 , —NH(C 1 -C 6 alkyl), and —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl); —NH(SO 2 )NH—(C 1 -C 6 alkyl); —NH(SO 2 )N—(C 1 -C 6 alkyl)(C 1 -C 6 alkyl); —O-heterocycle optionally substituted by C 1 -C 6 alkyl; H 2 NC 1 —C 6 alkyleneSO 2 —; (C 1 -C 6 alkyl)NHC 1 -C 6 alkyleneSO 2 — ;  (C 1 -C 6 alkyl)(C 1 -C 6 alkyl)NC 1 -C 6 alkyleneSO 2 —; heterocyclyl(C 1 -C 6 alkyl)SO 2 —; carboxyamido(C 1 -C 6 )alkyl-C(O)—; heterocycle-C(O)—C 1 -C 6 alkylene-C(O)—; R 3 R 4 NSO 2 C 1 -C 6 alkylene-C(O)—; or —SO 2 NR 3 R 4 ; 
         n is 0, 1, 2, 3, 4, or 5; 
         each p is independently 1 or 2; 
         R 3  and R 4  are each independently:
       (a). H;   (b). C 1 -C 6 alkyl optionally substituted with from 1 to 3 substituents independently selected from:
           (i). —NH 2 ,   (ii). —NH(C 1 -C 6 alkyl),   (iii). —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl),   (iv). C 1 -C 6 alkoxy,   (v). C 3 -C 8 cycloalkyl,   (vi). C 3 -C 8 cycloalkenyl,   (vii). halo,   (viii). and C 1 -C 9 heteroaryl;   
           (c). C 1 -C 9 heteroaryl optionally substituted with from 1 to 3 substituents independently selected from:
           (ix). C 1 -C 6 alkyl,   (x). C 1 -C 6 aminoalkyl-,   (xi). C 1 -C 6 hydroxylalkyl-,   (xii). and C 1 -C 9 heterocyclyl-;   
           (d). heterocyclyl(C 1 -C 6 alkyl)-;   (e). (C 1 -C 9 heterocyclyl)-;   (f). (C 1 -C 9 heterocyclyl)-SO 2 —;   (g). C 6 -C 14 aryl optionally substituted with from 1 to 3 substituents independently selected from:
           (xiii). C 1 -C 6 alkyl,   (xiv). C 1 -C 6 alkoxy,   (xv). C 1 -C 6 aminoalkyl-,   (xvi). C 1 -C 6 hydroxylalkyl-,   (xvii). C 1 -C 6 aminoalkyl-NH—,   (xviii). C 1 -C 6 hydroxylalkyl-NH—,   (xix). halo,   (xx). C 1 -C 9 heterocyclyl,   (xxi). (C 1 -C 9 heteroaryl)-O—,   (xxii). —(C 1 -C 9 heterocycle)-O—,   (xxiii). (C 1 -C 9 heterocyclyl)-S—,   (xxiv). (C 1 -C 9 heterocyclyl)-CO—,   (xxv). (C 1 -C 6 alkyl)-NH—C(O)—,   (xxvi). (C 1 -C 6 alkyl)(C 1 -C 6 alkyl)N—C(O)—,   (xxvii). H 2 NNH—C(O)—,   (xxviii). R 5 —C(O)—,   (xxix). (C 1 -C 6 alkyl)-NH—NH—C(O)—,   (xxx). (C 1 -C 6 alkyl)(C 1 -C 6 alkyl)NNH—C(O)—,   (xxxi). (C 1 -C 9 heteroaryl)NH—C(O)—,   (xxxii). (C 6 -C 14 aryl)NH—C(O)—,   (xxxiii). (C 1 -C 6 alkyl)-SO 2 —,   (xxxiv). (C 1 -C 9 heterocyclyl)-SO 2 —,   (xxxv). H 2 NS(O) 2 —,   (xxxvi). (C 1 -C 6 alkyl)NH—SO 2 —,   (xxxvii). (C 1 -C 6 alkyl)(C 1 -C 6 alkyl)N—SO 2 —,   (xxxviii). H 2 NNHS(O) 2 —,   (xxxix). (C 1 -C 6 alkyl)NH—NH—SO 2 —,   (xl). (C 1 -C 6 alkyl)(C 1 -C 6 alkyl)N—NH—SO 2 —,   (xli). (C 1 -C 9 heteroaryl)NH—S(O) 2 —,   (xlii). (C 6 -C 14 aryl)NH—S(O) 2 —,   (xliii). and perfluoro(C 1 -C 6 )alkyl-;   
           (h). or C 3 -C 8 cycloalkyl-;   
     
         or R 3  and R 4 , when taken together with the nitrogen to which they are attached, can form a 3- to 7-membered nitrogen containing heterocycle wherein up to two of the carbon atoms of the heterocycle can be replaced with —N(R 6 )—, —O—, S, S(O), or —S(O) 2 —; 
         R 6  is hydrogen or C 1 -C 6 alkyl; 
         R 5  is C 1 -C 6 alkyl-, C 3 -C 8 cycloalkyl-, C 1 -C 9 heteroaryl, or C 6 -C 14 aryl- optionally substituted with from 1 to 3 substituents independently selected halogens; 
         R 2  is H; C 1 -C 6 alkyl optionally substituted with from 1 to 3 substituents independently selected from —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), C 6 -C 14 aryl, and —C(O)O(C 1 -C 6 alkyl); —S(O) q —(C 1 -C 6 alkyl); —S(O) q —(C 1 -C 9 heteroaryl); —S(O) q —(C 6 -C 14 aryl); or —S(O) q -(4- to 7-membered monocyclic heterocycle group) optionally substituted with from 1 to 3 substituents independently selected from C 1 -C 6 alkyl and (C 6 -C 14 aryl)alkyl-O—C(O)—; 
         q is independently 1 or 2; 
         R 7  is H; C 1 -C 6 alkyl optionally substituted with from 1 to 3 substituents independently selected from —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), and C 1 -C 9 heteroaryl; C 2 -C 10 alkenyl; C 2 -C 10 alkynyl; halo; C 1 -C 9 heteroaryl; C 6 -C 14 aryl optionally substituted with from 1 to 3 substituents independently selected from C 1 -C 6 alkyl, halo, and perfluoro(C 1 -C 6 )alkyl; C 3 -C 8 cycloalkyl; or CHO; 
         R 8  and R 9  are each independently H; C 1 -C 6 alkyl optionally substituted with from 1 to 3 substituents independently selected from —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), and C 1 -C 9 heteroaryl; C 1 -C 9 heteroaryl; C 6 -C 14 aryl optionally substituted with from 1 to 3 substituents independently selected from C 1 -C 6 alkyl, halo, and perfluoro(C 1 -C 6 )alkyl; or C 3 -C 8 cycloalkyl; 
         or R 8  and R 9 , when taken together with the nitrogen to which they are attached, can form a 3- to 7-membered nitrogen containing heterocycle wherein up to two of the carbon atoms of the heterocycle can be replaced with —N(R 13 )—, —O—, S, S(O), or —S(O) 2 ; 
         R 13  is hydrogen or C 1 -C 6 alkyl; 
         R 10  is H; C 1 -C 6 alkyl optionally substituted with from 1 to 3 substituents independently selected from —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), and C 1 -C 9 heteroaryl; C 1 -C 9 heteroaryl; C 6 -C 14 aryl optionally substituted with from 1 to 3 substituents independently selected from C 1 -C 6 alkyl, halo, and perfluoro(C 1 -C 6 )alkyl; or C 3 -C 8 cycloalkyl; 
         R 11  is H; C 1 -C 6 alkyl optionally substituted with from 1 to 3 substituents independently selected from —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), and C 1 -C 9 heteroaryl; C 1 -C 9 heteroaryl; C 6 -C 14 aryl optionally substituted with from 1 to 3 substituents independently selected from C 1 -C 6 alkyl, halo, and perfluoro(C 1 -C 6 )alkyl; or C 3 -C 8 cycloalkyl; 
         R 12  is H; C 1 -C 6 alkyl optionally substituted with from 1 to 3 substituents independently selected from —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), and C 1 -C 9 heteroaryl; C 1 -C 9 heteroaryl; C 6 -C 14 aryl optionally substituted with from 1 to 3 substituents independently selected from C 1 -C 6 alkyl, halo, and perfluoro(C 1 -C 6 )alkyl; or C 3 -C 8 cycloalkyl. 
       
    
     In one aspect, the invention provides compounds of the Formula II: 
     
       
         
         
             
             
         
       
         
         or pharmaceutically acceptable salt thereof, wherein 
         A is —O—, —CH 2 O—, or —S(O) m —; 
         m is 0, 1, or 2; 
         Ar is phenyl, naphthyl, or nitrogen-containing mono- or bicyclic C 1 -C 9 heteroaryl; 
         R 1  is independently NR 3 R 4 ; NHC(O)NR 3 R 4 ; —NHC(O)OR 5 ; R 5 C(O)NH—; R 5 C(O)—; R 5 S(O) p NH—; CHO; C 1 -C 6 hydroxylalkyl-; C 3 -C 6 hydroxylalkenyl-; (C 6 -C 14 aryl)alkyl optionally substituted by hydroxyl; (C 6 -C 14 aryl)alkyl-O—; (C 1 -C 6 alkoxy)carbonyl; HO 2 C—; R 3 R 4 NC(O)—; N≡C—; carboxyamido(C 1 -C 6 alkyl-; hydroxyl; halo; C 1 -C 6 alkoxy optionally substituted with from 1 to 3 substituents independently selected from C 1 -C 6 alkoxy, —NH 2 , —NH(C 1 -C 6 alkyl), and —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl); —NH(SO 2 )NH—(C 1 -C 6 alkyl); —NH(SO 2 )N—(C 1 -C 6 alkyl)(C 1 -C 6 alkyl); —O-heterocycle optionally substituted by C 1 -C 6 alkyl; H 2 NC 1 -C 6 alkyleneSO 2 —; (C 1 -C 6 alkyl)NHC 1 -C 6 alkyleneSO 2 — ;  (C 1 -C 6 alkyl)(C 1 -C 6 alkyl)NC 1 -C 6 alkyleneSO 2 —; heterocyclyl(C 1 -C 6 alkyl)SO 2 —; carboxyamido(C 1 -C 6 )alkyl-C(O)—; heterocycle-C(O)—C 1 -C 6 alkylene-C(O)—; R 3 R 4 NSO 2 C 1 -C 6 alkylene-C(O)—; or —SO 2 NR 3 R 4 ; 
         n is 0, 1, 2, 3, 4, or 5; 
         each p is independently 1 or 2; 
         R 3  and R 4  are each independently:
       (a). H;   (b). C 1 -C 6 alkyl optionally substituted with from 1 to 3 substituents independently selected from:
           (i). —NH 2 ,   (ii). —NH(C 1 -C 6 alkyl),   (iii). —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl),   (iv). C 1 -C 6 alkoxy,   (v). C 3 -C 8 cycloalkyl,   (vi). C 3 -C 8 cycloalkenyl,   (vii). halo,   (viii). and C 1 -C 9 heteroaryl;   
           (c). C 1 -C 9 heteroaryl optionally substituted with from 1 to 3 substituents independently selected from:
           (i). C 1 -C 6 alkyl,   (ii). C 1 -C 6 aminoalkyl-,   (iii). C 1 -C 6 hydroxylalkyl-,   (iv). and C 1 -C 9 heterocyclyl-;   
           (d). heterocyclyl(C 1 -C 6 alkyl)-;   (e). (C 1 -C 9 heterocyclyl)-;   (f). (C 1 -C 9 heterocyclyl)-SO 2 —;   (g). C 6 -C 14 aryl optionally substituted with from 1 to 3 substituents independently selected from:
           (i). C 1 -C 6 alkyl,   (ii). C 1 -C 6 alkoxy,   (iii). C 1 -C 6 aminoalkyl-,   (iv). C 1 -C 6 hydroxylalkyl-,   (v). C 1 -C 6 aminoalkyl-NH—,   (vi). C 1 -C 6 hydroxylalkyl-NH—,   (vii). halo,   (viii). C 1 -C 9 heterocyclyl,   (ix). (C 1 -C 9 heteroaryl)-O—,   (x). —(C 1 -C 9 heterocycle)-O—,   (xi). (C 1 -C 9 heterocyclyl)-S—,   (xii). (C 1 -C 9 heterocyclyl)-CO—,   (xiii). (C 1 -C 6 alkyl)-NH—C(O)—,   (xiv). (C 1 -C 6 alkyl)(C 1 -C 6 alkyl)N—C(O)—,   (xv). H 2 NNH—C(O)—,   (xvi). R 5 —C(O)—,   (xvii). (C 1 -C 6 alkyl)-NH—NH—C(O)—,   (xviii). (C 1 -C 6 alkyl)(C 1 -C 6 alkyl)NNH—C(O)—,   (xix). (C 1 -C 9 heteroaryl)NH—C(O)—,   (xx). (C 6 -C 14 aryl)NH—C(O)—,   (xxi). (C 1 -C 6 alkyl)-SO 2 —,   (xxii). (C 1 -C 9 heterocyclyl)-SO 2 —,   (xxiii). H 2 NS(O) 2 —,   (xxiv). (C 1 -C 6 alkyl)NH—SO 2 —,   (xxv). (C 1 -C 6 alkyl)(C 1 -C 6 alkyl)N—SO 2 —,   (xxvi). H 2 NNHS(O) 2 —,   (xxvii). (C 1 -C 6 alkyl)NH—NH—SO 2 —,   (xxviii). (C 1 -C 6 alkyl)(C 1 -C 6 alkyl)N—NH—SO 2 —,   (xxix). (C 1 -C 9 heteroaryl)NH—S(O) 2 —,   (xxx). (C 6 -C 14 aryl)NH—S(O) 2 —,   (xxxi). and perfluoro(C 1 -C 6 )alkyl-;   
           (h). or C 3 -C 8 cycloalkyl-;   
     
         or R 3  and R 4 , when taken together with the nitrogen to which they are attached, can form a 3- to 7-membered nitrogen containing heterocycle wherein up to two of the carbon atoms of the heterocycle can be replaced with —N(R 6 )—, —O—, S, S(O), or —S(O) 2 —; 
         R 6  is hydrogen or C 1 -C 6 alkyl; 
         R 5  is C 1 -C 6 alkyl-, C 3 -C 8 cycloalkyl-, C 1 -C 9 heteroaryl, or C 6 -C 14 aryl- optionally substituted with from 1 to 3 substituents independently selected halogens; 
         R 2  is H; C 1 -C 6 alkyl optionally substituted with from 1 to 3 substituents independently selected from —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), C 6 -C 14 aryl, and —C(O)O(C 1 -C 6 alkyl); —S(O) q —(C 1 -C 6 alkyl); —S(O) q —(C 1 -C 9 heteroaryl); —S(O) q —(C 6 -C 14 aryl); or —S(O) q —(4- to 7-membered monocyclic heterocycle group) optionally substituted with from 1 to 3 substituents independently selected from C 1 -C 6 alkyl and (C 6 -C 14 aryl)alkyl-O—C(O)—; 
         q is independently 1 or 2; 
         R 7  is H; C 1 -C 6 alkyl optionally substituted with from 1 to 3 substituents independently selected from —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), and C 1 -C 9 heteroaryl; C 2 -C 10 alkenyl; C 2 -C 10 alkynyl; halo; C 1 -C 9 heteroaryl; C 6 -C 14 aryl optionally substituted with from 1 to 3 substituents independently selected from C 1 -C 6 alkyl, halo, and perfluoro(C 1 -C 6 )alkyl; C 3 -C 8 cycloalkyl; or CHO; 
       
    
     In one aspect, R 1  is independently NR 3 R 4 ; NHC(O)NR 3 R 4 ; —NHC(O)OR 5 ; R 5 C(O)NH—; R 5 S(O) p NH—; CHO; C 1 -C 6 hydroxylalkyl-; C 3 -C 6 hydroxylalkenyl-; (C 6 -C 14 aryl)alkyl optionally substituted by hydroxyl; (C 6 -C 14 aryl)alkyl-O—; (C 1 -C 6 alkoxy)carbonyl; HO 2 C—; R 3 R 4 NC(O)—; N≡C—; carboxyamido(C 1 -C 6 )alkyl-; hydroxyl; halo; C 1 -C 6 alkoxy optionally substituted with from 1 to 3 substituents independently selected from C 1 -C 6 alkoxy, —NH 2 , —NH(C 1 -C 6 alkyl), and —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl); —NH(SO 2 )NH—(C 1 -C 6 alkyl); —O-heterocycle optionally substituted by C 1 -C 6 alkyl; H 2 NC 1 -C 6 alkyleneSO 2 —; (C 1 -C 6 alkyl)NHC 1 -C 6 alkyleneSO 2 — ;  (C 1 -C 6 alkyl)(C 1 -C 6 alkyl)NC 1 -C 6 alkyleneSO 2 —; heterocyclyl(C 1 -C 6 alkyl)SO 2 —; carboxyamido(C 1 -C 6 )alkyl-C(O)—; heterocycle-C(O)—C 1 -C 6 alkylene-C(O)—; R 3 R 4 NSO 2 C 1 -C 6 alkylene-C(O)—; or —SO 2 NR 3 R 4 ; 
     In one aspect, R 3  and R 4  are each independently H; C 1 -C 6 alkyl optionally substituted with from 1 to 3 substituents independently selected from —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), and C 1 -C 9 heteroaryl; C 1 -C 9 heteroaryl optionally substituted with from 1 to 3 substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl-, C 1 -C 6 hydroxylalkyl- and C 1 -C 9 heterocyclyl; C 6 -C 14 aryl optionally substituted with from 1 to 3 substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 aminoalkyl-, C 1 -C 6 hydroxylalkyl-, C 1 -C 6 aminoalkyl-NH—, C 1 -C 6 hydroxylalkyl-NH—, halo, C 1 -C 9 heterocyclyl, (C 1 -C 9 heteroaryl)-O—, —(C 1 -C 9 heterocycle)-O—, (C 1 -C 9 heterocyclyl)-S—, (C 1 -C 9 heterocyclyl)-CO—, (C 1 -C 6 alkyl)-NH—C(O)—, (C 1 -C 6 alkyl)(C 1 -C 6 alkyl)N—C(O)—, H 2 NNH—C(O)—, (C 1 -C 6 alkyl)-NH—NH—C(O)—, (C 1 -C 6 alkyl)(C 1 -C 6 alkyl)NNH—C(O)—(C 1 -C 9 heteroaryl)NH—C(O)—, (C 6 -C 14 aryl)NH—C(O)—, (C 1 -C 6 alkyl)-SO 2 —, (C 1 -C 9 heterocyclyl)-SO 2 —, H 2 NS(O) 2 —, (C 1 -C 6 alkyl)NH—SO 2 —, (C 1 -C 6 alkyl)(C 1 -C 6 alkyl)N—SO 2 —, H 2 NNHS(O) 2 —, (C 1 -C 6 alkyl)NH—NH—SO 2 —, (C 1 -C 6 alkyl)(C 1 -C 6 alkyl)N—NH—SO 2 —, (C 1 -C 9 heteroaryl)NH—S(O) 2 —, (C 6 -C 14 aryl)NH—S(O) 2 —, and perfluoro(C 1 -C 6 )alkyl; or C 3 -C 8 cycloalkyl; 
     In one aspect, R 5  is C 1 -C 6 alkyl or C 6 -C 14 aryl; 
     In one aspect, n is 1. 
     In one aspect, A is —O—. 
     In one aspect, R 1  is hydroxyl. 
     In one aspect, R 1  is NH 2 . 
     In one aspect, R 1  is —NHC(O)NR 3 R 4 . 
     In one aspect, R 3  is C 1 -C 6 alkyl, C 1 -C 9 heteroaryl, or C 6 -C 14 aryl. 
     In one aspect, R 3  is methyl or 4-pyridyl. 
     In one aspect, R 3  is methyl. 
     In one aspect, R 3  is propyl. 
     In one aspect, R 3  is phenyl. 
     In one aspect, R 3  is 4-pyridyl. 
     In one aspect, R 2  is C 1 -C 6 alkyl optionally substituted with —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl); —S(O) q —(C 1 -C 6 alkyl); or —S(O) q —(C 6 -C 14 aryl). 
     In one aspect, R 2  is C 1 -C 6 alkyl or S(O) q —(C 1 -C 6 alkyl). 
     In one aspect, R 2  is methyl or —SO 2 —CH 3 . 
     In one aspect, R 2  is methyl. 
     In one aspect, R 2  is —S(O) q —(C 1 -C 6 alkyl); —S(O) q —(C 1 -C 9 heteroaryl); —S(O) q —(C 6 -C 14 aryl); —S(O) q -(4- to 7-membered monocyclic heterocycle group) optionally substituted with from 1 to 3 substituents independently selected from C 1 -C 6 alkyl or (C 6 -C 14 aryl)alkyl-O—C(O)—. 
     In one aspect, R 2  is —SO 2 —CH 3 . 
     In one aspect, R 2  is —SO 2 —C 6 H 5 . 
     In one aspect, R 7  is H. 
     In one aspect, A is —O—, Ar is phenyl, n is 1, R 1  is —NHC(O)NR 3 R 4 , R 3  is 4-pyridyl, R 4  is H, R 2  is methyl, and R 7  is H. 
     In one aspect, A is —O—, Ar is 4-pyrimidinyl, n is 1, R 1  is 4-NH 2 , R 2  is —SO 2 —C 6 H 5 , and R 7  is H. 
     In one aspect, A is —O—, Ar is phenyl, n is 1, R 1  is meta-hydroxyl, R 2  is H, and R 7  is CHO. 
     The following compounds exemplify illustrative compounds of Formula II:
     4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline;   1-methyl-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea;   1-ethyl-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea;   1-[2-(dimethylamino)ethyl]-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea;   1-[3-(dimethylamino)propyl]-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea;   4-methyl-N-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]piperazine-1-carboxamide;   1-(2-furylmethyl)-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea;   1-[3-(1H-imidazol-1-yl)propyl]-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea;   1-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]-3-pyridin-2-ylurea;   1-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]-3-phenylurea;   1-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]-3-pyridin-4-ylurea;   1-(4-isopropylphenyl)-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea;   1-(3-chlorophenyl)-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea;   1-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]-3-[4-(trifluoromethyl)phenyl]urea;   1-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]-3-(pyridin-2-ylmethyl)urea;   N-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]acetamide;   N-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-Myl)phenyl]nicotinamide;   N-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]isonicotinamide;   4-fluoro-N-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]benzamide;   ethyl [4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]carbamate;   N-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]methanesulfonamide;   N-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]benzenesulfonamide;   3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)benzaldehyde;   1-[3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]ethanol;   1-[3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]propan-1-ol;   1-[3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]prop-2-en-1-ol;   1-[3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]but-3-en-1-ol;   3-methyl-1-[3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]butan-1-ol;   [3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl](phenyl)methanol;   (3-{7-[2-(dimethylamino)ethyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl}phenyl)methanol;   2-{2-[3-(benzyloxy)phenyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-7-yl}-N,N-dimethylethanamine;   3-{7-[2-(dimethylamino)ethyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl}phenol;   1-(4-{7-[2-(dimethylamino)ethyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl}phenyl)-3-pyridin-4-ylurea;   5-{7-[2-(dimethylamino)ethyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl}pyrimidin-2-amine;   3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenol;   Methyl 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)benzoate;   3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]methanol;   4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)benzoic acid;   3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)benzamide;   3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)benzonitrile;   3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline;   5-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)pyridin-2-amine;   5-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)pyrimidin-2-amine;   N-[3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)benzyl]acetamide;   2-(1H-indol-4-yl)-7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazoline;   3-(7-benzyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenol;   2-(6-methoxypyridin-3-yl)-7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazoline;   5-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)pyridin-2-ol;   2-(1H-indol-4-yl)-7-methyl-4-morpholin-5-yl-7H-pyrrolo[2,3-h]quinazoline;   2-(2-methoxypyrimidin-5-yl)-7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazoline;   5-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)pyrimidin-2-ol;   2-(3-fluorophenyl)-7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazoline;   4-chloro-3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenol;   1-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]-3-propylurea;   N,N-dimethyl-N′-[3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]sulfamide;   N-cyclopropyl-3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)benzenesulfonamide;   3-(4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]methanol;   -(4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)pyrimidin-2-amine;   3-[7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenol;   tert-butyl [2-(6-aminopyridin-3-yl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-7-yl]acetate;   

     benzyl 4-[(4-morpholin-4-yl-2-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-7H-pyrrolo[2,3-h]quinazolin-7-yl)sulfonyl]piperidine-1-carboxylate;
     1-{4-[4-morpholin-4-yl-7-(piperidin-4-ylsulfonyl)-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenyl}-3-pyridin-4-ylurea;   1-(4-{7-[(1-methylpiperidin-4-yl)sulfonyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl}phenyl)-3-pyridin-4-ylurea;   1-(4-{7-[(1-ethylpiperidin-4-yl)sulfonyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl}phenyl)-3-pyridin-4-ylurea;   1-(4-{7-[(1-isopropylpiperidin-4-yl)sulfonyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl}phenyl)-3-pyridin-4-ylurea;   benzyl 4-{[2-(3-hydroxyphenyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-7-yl]sulfonyl}piperidine-1-carboxylate;   3-[4-morpholin-4-yl-7-(piperidin-4-ylsulfonyl)-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenol;   2-[3-(benzyloxy)phenyl]-4-morpholin-4-yl-7-(phenylsulfonyl)-7H-pyrrolo[2,3-h]quinazoline;   3-[4-morpholin-4-yl-7-(phenylsulfonyl)-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenol;   {3-[4-morpholin-4-yl-7-(phenylsulfonyl)-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenyl}methanol;   5-[4-morpholin-4-yl-7-(phenylsulfonyl)-7H-pyrrolo[2,3-h]quinazolin-2-yl]pyrimidin-2-amine;   2-(1H-indazol-4-yl)-4-morpholin-4-yl-7-(phenylsulfonyl)-7H-pyrrolo[2,3-h]quinazoline;   5-[7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl]pyrimidin-2-amine;   {3-[7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenyl}methanol;   2-[5-(methoxymethoxy)pyridin-3-yl]-7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazoline;   5-[7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl]pyridin-3-ol;   2-[5-(methoxymethoxy)pyridin-3-yl]-7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazoline;   5-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)pyridin-3-ol;   2-(1H-indazol-4-yl)-7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazoline;   2-(1H-indazol-4-yl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazoline;   2-[3-(benzyloxy)phenyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazoline;   2-(3-hydroxyphenyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazoline-9-carbaldehyde;   [3-(7-benzyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]methanol;   1-{4-[7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenyl}-3-phenylurea;   1-{4-[7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenyl}-3-pyridin-3-ylurea;   ethyl {4-[7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenyl}carbamate;   N-{4-[7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenyl}cyclopropanecarboxamide;   N-{4-[7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenyl}butanamide;   1-ethyl-3-{4-[7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenyl}urea;   methyl {4-[7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenyl}carbamate;   N-{4-[7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenyl}propanamide;   N-{4-[7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenyl}acetamide;   ethyl (4-{7-[2-(dimethylamino)ethyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl}phenyl)carbamate;   1-(4-{7-[2-(dimethylamino)ethyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl}phenyl)-3-ethylurea;   1-(4-{7-[2-(dimethylamino)ethyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl}phenyl)-3-phenylurea;   N-(4-{7-[2-(dimethylamino)ethyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl}phenyl)cyclopropanecarboxamide;   N-(4-{7-[2-(dimethylamino)ethyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl}phenyl)butanamide;   methyl (4-{7-[2-(dimethylamino)ethyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl}phenyl)carbamate;   1-(1-methylethyl)-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea;   1-(cyclopropylmethyl)-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea;   1-(2-methoxyethyl)-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea;   1-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]-3-(tetrahydrofuran-2-ylmethyl)urea;   1-(2-cyclohex-1-en-1-ylethyl)-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea;   1-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]-3-(3-pyrrolidin-1-ylpropyl)urea;   1-cyclopentyl-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea;   1-cyclobutyl-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea;   1-cyclopropyl-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea;   1-cyclohexyl-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea;   propyl {4-[7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenyl}carbamate;   1-methyl-3-{4-[7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenyl}urea;   1-(4-{7-[2-(dimethylamino)ethyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl}phenyl)-3-pyridin-3-ylurea;   N-(4-{7-[2-(dimethylamino)ethyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl}phenyl)acetamide;   1-(4-{7-[2-(dimethylamino)ethyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl}phenyl)-3-methylurea;   1-(3-acetylphenyl)-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea;   1-(4-acetylphenyl)-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea;   1-(3,5-dimethylisoxazol-4-yl)-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea;   1-(1,1-dioxidotetrahydrothiophen-3-yl)-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea;   1-(2-fluoroethyl)-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea;   1-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)urea;   1-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]-3-(2-pyridin-4-ylethyl)urea;   1-{4-[7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenyl}-3-propylurea;   1-[3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]-3-pyridin-4-ylurea;   1-[3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]-3-pyridin-3-ylurea;   ethyl [3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]carbamate;   N-[3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]cyclopropanecarboxamide;   N-[3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]butanamide;   1-[3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]-3-propylurea;   1-ethyl-3-[3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea;   N-[3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]propanamide;   methyl 4-({[4-(7-ethyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]carbamoyl}amino)benzoate;   1-[4-(7-ethyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea;   4-({[4-(7-ethyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]carbamoyl}amino)-N-[2-(methylamino)ethyl]benzamide;   N-[2-(dimethylamino)ethyl]-4-({[4-(7-ethyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]carbamoyl}amino)-N-methylbenzamide; and   1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(7-ethyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea   

     The invention also includes pharmaceutical compositions comprising a 7H-pyrrolo[2,3-h]quinazoline compound and a pharmaceutically acceptable carrier. The invention includes a 7H-pyrrolo[2,3-h]quinazoline compound when provided as a pharmaceutically acceptable prodrug, hydrated salt, such as pharmaceutically acceptable salt, or mixtures thereof. 
     Representative “pharmaceutically acceptable salts” include but are not limited to, e.g., water-soluble and water-insoluble salts, such as the acetate, aluminum, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzathine (N,N′-dibenzylethylenediamine), benzenesulfonate, benzoate, bicarbonate, bismuth, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate (camphorsulfonate), carbonate, chloride, choline, citrate, clavulariate, diethanolamine, dihydrochloride, diphosphate, edetate, edisylate (camphorsulfonate), esylate (ethanesulfonate), ethylenediamine, fumarate, gluceptate (glucoheptonate), gluconate, glucuronate, glutamate, hexafluorophosphate, hexylresorcinate, hydrabamine (N,N′-bis(dehydroabietyl)ethylenediamine), hydrobromide, hydrochloride, hydroxynaphthoate, 1-hydroxy-2-naphthoate, 3-hydroxy-2-naphthoate, iodide, isothionate (2-hydroxyethanesulfonate), lactate, lactobionate, laurate, lauryl sulfate, lithium, magnesium, malate, maleate, mandelate, meglumine (1-deoxy-1-(methylamino)-D-glucitol), mesylate, methyl bromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, palmitate, pamoate (4,4′-methylenebis-3-hydroxy-2-naphthoate, or embonate), pantothenate, phosphate, picrate, polygalacturonate, potassium, propionate, p-toluenesulfonate, salicylate, sodium, stearate, subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate, tartrate, teoclate (8-chloro-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione), triethiodide, tromethamine (2-amino-2-(hydroxymethyl)-1,3-propanediol), valerate, and zinc salts. 
     An “effective amount” when used in connection a 7H-pyrrolo[2,3-h]quinazoline compound of this invention is an amount effective for inhibiting mTOR or PI3K in a subject. 
     In another aspect, the invention provides a compound of the Formula III: 
     
       
         
         
             
             
         
       
         
         wherein A is —O—, —CH 2 O—, or S(O) m ; 
         m is 0, 1, or 2; 
         X is halogen; 
         R 2  is H; C 1 -C 6 alkyl optionally substituted with from 1 to 3 substituents independently selected from —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), C 6 -C 14 aryl, and —C(O)O(C 1 -C 6 alkyl); —S(O) q —(C 1 -C 6 alkyl); —S(O) q —(C 1 -C 9 heteroaryl); —S(O) q —(C 6 -C 14 aryl); or —S(O) q -(4- to 7-membered monocyclic heterocycle group) optionally substituted with from 1 to 3 substituents independently selected from C 1 -C 6 alkyl and (C 6 -C 14 aryl)alkyl-O—C(O)—; 
         q is independently 1 or 2; 
         R 7  is H; C 1 -C 6 alkyl optionally substituted with from 1 to 3 substituents independently selected from —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), and C 1 -C 9 heteroaryl; C 2 -C 10 alkenyl; C 2 -C 10 alkynyl; halo; C 1 -C 9 heteroaryl; C 6 -C 14 aryl optionally substituted with from 1 to 3 substituents independently selected from C 1 -C 6 alkyl, halo, and perfluoro(C 1 -C 6 )alkyl; C 3 -C 8 cycloalkyl; or CHO. 
       
    
     In one aspect, A is —O—. 
     In one aspect, X is chlorine. 
     In one aspect, R 2  is —S(O) q —(C 1 -C 6 alkyl); —S(O) q —(C 6 -C 14 aryl); or —S(O) q -(4- to 7-membered monocyclic heterocycle group) substituted with (C 6 -C 14 aryl)alkyl-O—C(O)—. 
     In one aspect, R 2  is —SO 2 CH 3 . 
     In one aspect, R 2  is benzyl 4-sulfonylpiperidine-1-carboxylate. 
     In one aspect, R 2  is —SO 2 C 6 H 5 . 
     In one aspect, R 7  is H. 
     In one aspect, A is —O—, X is Cl, R 2  is benzyl 4-sulfonylpiperidine-1-carboxylate, and R 7  is H. 
     In one aspect, A is —O—, X is Cl, R 2  is —SO 2 C 6 H 5 , and R 7  is H. 
     In one aspect, A is —O—, X is Cl, R 2  is —SO 2 —CH 3 , and R 7  is H. 
     The following compounds exemplify illustrative compounds of Formula III:
     benzyl 4-[(2-chloro-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-7-yl)sulfonyl]piperidine-1-carboxylate;   2-chloro-4-morpholin-4-yl-7-(phenylsulfonyl)-7H-pyrrolo[2,3-h]quinazoline;   2-chloro-7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazoline;   2-chloro-7-(2-(dimethylamino)ethyl)-4-morpholin-4-yl-7H-pyrrolo[2,3h]quinazoline; and   2-chloro-7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazoline.   

     In other aspects, the invention provides a composition comprising a compound of Formula I, a second compound selected from the group consisting of a topoisomerase I inhibitor, procarbazine, dacarbazine, gemcitabine, capecitabine, methotrexate, taxol, taxotere, mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, cisplatin, carboplatin, mitomycin, dacarbazine, procarbizine, etoposide, teniposide, campathecins, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, L-asparaginase, doxorubicin, epirubicin, 5-fluorouracil, docetaxel, paclitaxel, leucovorin, levamisole, irinotecan, estramustine, etoposide, nitrogen mustards, BCNU, carmustine, lomustine, vinblastine, vincristine, vinorelbine, cisplatin, carboplatin, oxaliplatin, imatinib mesylate, Avastin (bevacizumab), hexamethylmelamine, topotecan, tyrosine kinase inhibitors, tyrphostins, herbimycin A, genistein, erbstatin, lavendustin A, hydroxyzine, glatiramer acetate, interferon beta-1a, interferon beta-1b, natalizumab and lavendustin A; and a pharmaceutically acceptable carrier. 
     In other aspects, the second compound is Avastin. 
     In other aspects, the invention provides a method of treating a PI3K-related disorder, comprising administering to a mammal in need thereof a compound of Formula I in an amount effective to treat a PI3K-related disorder. 
     In other aspects, the PI3K-related disorder is selected from restenosis, atherosclerosis, bone disorders, arthritis, diabetic retinopathy, psoriasis, benign prostatic hypertrophy, atherosclerosis, inflammation, angiogenesis, immunological disorders, pancreatitis, kidney disease, and cancer. 
     In other aspects, the PI3K-related disorder is cancer. 
     In other aspects, the cancer is selected from the group consisting of leukemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, and brain cancer. 
     In other aspects, the invention provides a method of treating an mTOR-related disorder, comprising administering to a mammal in need thereof a compound of Formula I in an amount effective to treat an mTOR-related disorder. 
     In other aspects, the mTOR-related disorder is selected from restenosis, atherosclerosis, bone disorders, arthritis, diabetic retinopathy, psoriasis, benign prostatic hypertrophy, atherosclerosis, inflammation, angiogenesis, immunological disorders, pancreatitis, kidney disease, and cancer. 
     In other aspects, the mTOR-related disorder is cancer. 
     In other aspects, the cancer is selected from the group consisting of leukemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, and brain cancer. 
     In other aspects, the invention provides a method of treating a hSMG-1-related disorder, comprising administering to a mammal in need thereof a compound of Formula I in an amount effective to treat a hSMG-1-related disorder. 
     In other aspects, the hSMG-1-related disorder is selected from restenosis, atherosclerosis, bone disorders, arthritis, diabetic retinopathy, psoriasis, benign prostatic hypertrophy, atherosclerosis, inflammation, angiogenesis, immunological disorders, pancreatitis, kidney disease, and cancer. 
     In other aspects, the hSMG-1-related disorder is cancer. 
     In other aspects, the cancer is selected from the group consisting of leukemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, and brain cancer. 
     In other aspects, the invention provides a method of treating advanced renal cell carcinoma, comprising administering to a mammal in need thereof a compound of Formula I in an amount effective to treat advanced renal cell carcinoma. 
     In other aspects, the invention provides a method of treating acute lymphoblastic leukemia, comprising administering to a mammal in need thereof a compound of Formula I in an amount effective to treat acute lymphoblastic leukemia. 
     In other aspects, the invention provides a method of treating acute malignant melanoma, comprising administering to a mammal in need thereof a compound of Formula I in an amount effective to treat malignant melanoma. 
     In other aspects, the invention provides a method of treating soft-tissue or bone sarcoma, comprising administering to a mammal in need thereof a compound of Formula I in an amount effective to treat soft-tissue or bone sarcoma. 
     In other aspects, the invention provides a method of treating a cancer selected from the group consisting of leukemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, and brain cancer comprising administering to a mammal in need thereof a composition comprising a compound of Formula I; a second compound selected from the group consisting of a topoisomerase I inhibitor, procarbazine, dacarbazine, gemcitabine, capecitabine, methotrexate, taxol, taxotere, mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, cisplatin, carboplatin, mitomycin, dacarbazine, procarbizine, etoposide, teniposide, campathecins, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, L-asparaginase, doxorubicin, epirubicin, 5-fluorouracil, docetaxel, paclitaxel, leucovorin, levamisole, irinotecan, estramustine, etoposide, nitrogen mustards, BCNU, carmustine, lomustine, vinblastine, vincristine, vinorelbine, cisplatin, carboplatin, oxaliplatin, imatinib mesylate, Avastin (bevacizumab), hexamethylmelamine, topotecan, tyrosine kinase inhibitors, tyrphostins, herbimycin A, genistein, erbstatin, and lavendustin A; and a pharmaceutically acceptable carrier. in an amount effective to treat the cancer. 
     In other aspects, the invention provides a method of inhibiting mTOR in a subject, comprising administering to a subject in need thereof a compound of Formula I in an amount effective to inhibit mTOR. 
     In other aspects, the invention provides a method of inhibiting PI3K in a subject, comprising administering to a subject in need thereof a compound of Formula I in an amount effective to inhibit PI3K. 
     In other aspects, the invention provides a method of inhibiting hSMG-1 in a subject, comprising administering to a subject in need thereof a compound of Formula I in an amount effective to inhibit hSMG-1. 
     In other aspects, the invention provides a method of inhibiting mTOR, PI3K, and hSMG-1 together in a subject, comprising administering to a subject in need thereof a compound of Formula I in an amount effective to inhibit mTOR, PI3K, and hSMG-1. 
     In another aspect, the invention provides a method of synthesizing compounds of the Formula II comprising: reacting a boronic acid of the formula R n   1 —Ar—B(OH) 2  with the 2-chloro-7H-pyrrolo[2,3-h]quinazoline 24: 
     
       
         
         
             
             
         
       
     
     wherein A, Ar, R 1 , n, R 2 , and R 7 , are as defined in Formula II: 
     
       
         
         
             
             
         
       
     
     to give the 7H-pyrrolo[2,3-h]quinazoline II. 
     In one aspect, the invention provides methods of synthesizing compounds of the Formula II further comprising: (a) reacting the 7H-pyrrolo[2,3-h]quinazoline of Formula 17 with an alkylating or acylating agent R 2 —X to substitute the amino group at position 7 of the 7H-pyrrolo[2,3-h]quinazoline, wherein X is halogen, 
     
       
         
         
             
             
         
       
     
     under conditions effective to alkylate or acylate the nitrogen atom at position 7 of the pyrrole ring thereby producing 23, 
     
       
         
         
             
             
         
       
     
     (b) optionally reacting 23 with a formylating agent under Vilsmeier-Haack conditions to formylate the pyrrole ring, thereby producing the chlorinated intermediate 24, 
     
       
         
         
             
             
         
       
     
     wherein R 7  is CHO, under conditions effective to replace the hydrogen atom at position 9 of the 7H-pyrrolo[2,3-h]quinazoline. Suitable formylating agents include DMF, N-formylpyrrolidine, N-formylpiperidine, di-isopropylformamide, N0-methyl-N-adamantyl formamide, dicyclohexylformamide, the preformed Vilsmeier reagent ((chloromethylene)dimethylammonium chloride) and any other formylating agent known in the art. 
     Definitions 
     The following definitions are used in connection with the 7H-pyrrolo[2,3-h]quinazoline compounds of the present invention unless the context indicates otherwise. In general, the number of carbon atoms present in a given group is designated “C x -C y ”, where x and y are the lower and upper limits, respectively. For example, a group designated as “C 1 -C 6 ” contains from 1 to 6 carbon atoms. 
     Acyl” refers to from 1 to 8 carbon atoms of a straight, branched, or cyclic configuration or a combination thereof, attached to the parent structure through a carbonyl functionality. Such groups may be saturated or unsaturated, aliphatic or aromatic, and carbocyclic or heterocyclic. Examples of a C 1 -C 8 acyl group include acetyl-, benzoyl-, nicotinoyl, propionyl-, isobutyryl-, oxalyl-, and the like. Lower-acyl refers to acyl groups containing one to four carbons. An acyl group can be unsubstituted or substituted with one or more of the following groups: halogen, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —N(C 1 -C 3 alkyl)C(O)(C 1 -C 6 alkyl), —NHC(O)(C 1 -C 6 alkyl), —NHC(O)H, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —CN, hydroxyl, —O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, —C(O)OH, —C(O)O(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 alkyl), C 6 -C 14 aryl ,  C 1 -C 9 heteroaryl, or C 3 -C 8 cycloalkyl. 
     “Alkenyl” refer to a straight or branched chain unsaturated hydrocarbon containing 2-10 carbon atoms, and containing at least one double bond. Examples of a C 2 -C 10 alkenyl group include, but are not limited to, ethylene, propylene, 1-butylene, 2-butylene, isobutylene, sec-butylene, 1-pentene, 2-pentene, isopentene, 1-hexene, 2-hexene, 3-hexene, isohexene, 1-heptene, 2-heptene, 3-heptene, 1-octene, 2-octene, 3-octene, 4-octene, 1-nonene, 2-nonene, 3-nonene, 4-nonene, 1-decene, 2-decene, 3-decene, 4-decene and 5-decene. A C 2 -C 10 alkenyl group can be unsubstituted or substituted with one or more of the following groups: halogen, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —N(C 1 -C 3 alkyl)C(O)(C 1 -C 6 alkyl), —NHC(O)(C 1 -C 6 alkyl), —NHC(O)H, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —CN, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, —C(O)OH, —C(O)O(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 alkyl), C 6 -C 14 aryl ,  C 1 -C 9 heteroaryl, and C 3 -C 8 cycloalkyl. 
     “Alkoxy” refers to the group R—O— where R is an alkyl group, as defined below. Exemplary C 1 -C 6 alkoxy groups include but are not limited to methoxy, ethoxy, n-propoxy, 1-propoxy, n-butoxy and t-butoxy. An alkoxy group can be unsubstituted or substituted with one or more of the following groups: halogen, hydroxyl, C 1 -C 6 alkoxy, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —N(C 1 -C 3 alkyl)C(O)(C 1 -C 6 alkyl), —NHC(O)(C 1 -C 6 alkyl), —NHC(O)H, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —CN, C 1 -C 6 alkoxy, —C(O)OH, —C(O)O(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 alkyl), C 6 -C 14 aryl ,  C 1 -C 9 heteroaryl, C 3 -C 8 cycloalkyl, C 1 -C 6 haloalkyl-, C 1 -C 6 aminoalkyl-, —OC(O)C 1 -C 6 alkyl), carboxyamido(C 1 -C 6 )alkyl-, or —NO 2 . 
     “(Alkoxy)carbonyl-” refers to the group alkyl-O—C(O)—. Exemplary alkoxy groups include but are not limited to (methoxy)carbonyl(acetoxy), (ethoxy)carbonyl(propionoxy), and (t-butoxy)carbonyl (t-butyloxycarbonyl). An (alkoxy)carbonyl- group can be unsubstituted or substituted with one or more of the following groups: halogen, hydroxyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —N(C 1 -C 3 alkyl)C(O)(C 1 -C 6 alkyl), —NHC(O)(C 1 -C 6 alkyl), —NHC(O)H, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —CN, C 1 -C 6 alkoxy, —C(O)OH, —C(O)O(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 alkyl), C 6 -C 14 aryl ,  C 1 -C 9 heteroaryl, C 3 -C 8 cycloalkyl, C 1 -C 6 haloalkyl-, C 1 -C 6 aminoalkyl-, —OC(O)(C 1 -C 6 alkyl), carboxyamido(C 1 -C 6 )alkyl-, or —NO 2 . 
     “Alkyl” refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C I -C I0  indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. In the absence of any numerical designation, “alkyl” is a chain (straight or branched) having 1 to 6 (inclusive) carbon atoms in it. Examples of C 1 -C 6  alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl. An alkyl group can be unsubstituted or substituted with one or more of the following groups: halogen, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —N(C 1 -C 3 alkyl)C(O)(C 1 -C 6 alkyl), —NHC(O)(C 1 -C 6 alkyl), —NHC(O)H, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —CN, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, —C(O)OH, —C(O)O(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 alkyl), C 6 -C 14 aryl, C 1 -C 9 heteroaryl, C 3 -C 8 cycloalkyl, C 1 -C 6 haloalkyl-, C 1 -C 6 aminoalkyl-, —OC(O)(C 1 -C 6 alkyl), carboxyamido(C 1 -C 6 )alkyl-, or —NO 2 . 
     The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like. 
     “(Alkyl)amido-” refers to a —C(O)NH— group in which the nitrogen atom of said group is attached to a alkyl group, as defined above. Representative examples of a (C 1 -C 6 alkyl)amido group include, but are not limited to, —C(O)NHCH 3 , —C(O)NHCH 2 CH 3 , —C(O)NHCH 2 CH 2 CH 3 , —C(O)NHCH 2 CH 2 CH 2 CH 3 , —C(O)NHCH 2 CH 2 CH 2 CH 2 CH 3 , —C(O)NHCH(CH 3 ) 2 , —C(O)NHCH 2 CH(CH 3 ) 2 , —C(O)NHCH(CH 3 )CH 2 CH 3 , —C(O)NH—C(CH 3 ) 3  and —C(O)NHCH 2 C(CH 3 ) 3 . 
     “(Alkyl)amino-” refers to an —NH group, the nitrogen atom of said group being attached to a alkyl group, as defined above. Representative examples of an (C 1 -C 6 alkyl)amino group include, but are not limited to —NHCH 3 , —NHCH 2 CH 3 , —NHCH 2 CH 2 CH 3 , —NHCH 2 CH 2 CH 2 CH 3 , —NHCH(CH 3 ) 2 , —NHCH 2 CH(CH 3 ) 2 , —NHCH(CH 3 )CH 2 CH 3  and —NH—C(CH 3 ) 3 . An (alkyl)amino group can be unsubstituted or substituted with one or more of the following groups: halogen, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —N(C 1 -C 3 alkyl)C(O)(C 1 -C 6 alkyl), —NHC(O)(C 1 -C 6 alkyl), —NHC(O)H, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —CN, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, —C(O)OH, —C(O)O(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 alkyl), C 6 -C 14 aryl ,  C 1 -C 9 heteroaryl, C 3 -C 8 cycloalkyl, C 1 -C 6 haloalkyl-, C 1 -C 6 aminoalkyl-, —OC(O)(C 1 -C 6 alkyl), carboxyamido(C 1 -C 6 )alkyl-, or —NO 2 . 
     “Alkylcarboxy” refers to an alkyl group, defined above, attached to the parent structure through the oxygen atom of a carboxyl (C(O)—O—) functionality. Examples include acetoxy, ethylcarboxy, propylcarboxy, and isopentylcarboxy. 
     “(Alkyl)carboxyamido-” refers to a —NHC(O)— group in which the carbonyl carbon atom of said group is attached to a alkyl group, as defined above. Representative examples of a (C 1 -C 6 alkyl)carboxyamido group include, but are not limited to, —NHC(O)CH 3 , —NHC(O)CH 2 CH 3 , —NHC(O)CH 2 CH 2 CH 3 , —NHC(O)CH 2 CH 2 CH 2 CH 3 , —NHC(O)CH 2 CH 2 CH 2 CH 2 CH 3 , —NHC(O)CH(CH 3 ) 2 , —NHC(O)CH 2 CH(CH 3 ) 2 , —NHC(O)CH(CH 3 )CH 2 CH 3 , —NHC(O)—C(CH 3 ) 3  and —NHC(O)CH 2 C(CH 3 ) 3 . 
     “Alkylene”, “alkenylene”, and “alkynylene” refers to the subsets of alkyl, alkenyl and alkynyl groups, as defined above, including the same residues as alkyl, alkenyl, and alkynyl, but having two points of attachment within a chemical structure. Examples of C 1 -C 6 alkylene include ethylene (—CH 2 CH 2 —), propylene (—CH 2 CH 2 CH 2 —), and dimethylpropylene (—CH 2 C(CH 3 ) 2 CH 2 —). Likewise, examples of C 2 -C 6 alkenylene include ethenylene (—CH═CH— and propenylene (—CH═CH—CH 2 —). Examples of C 2 -C 6 alkynylene include ethynylene (—C≡C—) and propynylene (—C≡C—CH 2 —). 
     “Alkylthio” refers to groups of straight chain or branched chain with 1 to 6 carbon atoms, attached to the parent structure through a sulfur atom. Examples include methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i-butylthio, s-butylthio, t-butylthio, n-pentylthio and n-hexylthio. 
     “Alkynyl” refers to a straight or branched chain unsaturated hydrocarbon containing 2-10 carbon atoms, and containing at least one triple bond. Examples of a C 2 -C 10 alkynyl group include, but are not limited to, acetylene, propyne, 1-butyne, 2-butyne, isobutyne, sec-butyne, 1-pentyne, 2-pentyne, isopentyne, 1-hexyne, 2-hexyne, 3-hexyne, isohexyne, 1-heptyne, 2-heptyne, 3-heptyne, 1-octyne, 2-octyne, 3-octyne, 4-octyne, 1-nonyne, 2-nonyne, 3-nonyne, 4-nonyne, 1-decyne, 2-decyne, 3-decyne, 4-decyne and 5-decyne. An alkynyl group can be unsubstituted or substituted with one or more of the following groups: halogen, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —N(C 1 -C 3 alkyl)C(O)(C 1 -C 6 alkyl), —NHC(O)(C 1 -C 6 alkyl), —NHC(O)H, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —CN, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, —C(O)OH, —C(O)O(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 alkyl), C 6 -C 14 aryl ,  C 1 -C 9 heteroaryl, and C 3 -C 8 cycloalkyl. 
     “Amido(aryl)-” refers to an aryl group, as defined below, wherein one of the aryl group&#39;s hydrogen atoms has been replaced with one or more —C(O)NH 2  groups. Representative examples of an amido(C 6 -C 14 aryl)- group include 2-C(O)NH 2 -phenyl, 3-C(O)NH 2 -phenyl, 4-C(O)NH 2 -phenyl, 1-C(O)NH 2 -naphthyl, and 2-C(O)NH 2 -naphthyl. 
     “Aminoalkyl-” refers to an alkyl group, as defined above, wherein one or more of the alkyl group&#39;s hydrogen atoms has been replaced with —NH 2 . Representative examples of an C 1 -C 6 aminoalkyl- group include, but are not limited to —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 CH 2 NH 2 , —CH 2 CH(NH 2 )CH 3 , —CH 2 CH(NH 2 )CH 2 CH 3 , —CH(NH 2 )CH 2 CH 3  and —C(CH 3 ) 2 (CH 2 NH 2 ), —CH 2 CH 2 CH 2 CH 2 CH 2 NH 2 , and —CH 2 CH 2 CH(NH 2 )CH 2 CH 3 . An aminoalkyl- group can be unsubstituted or substituted with one or two of the following groups C 1 -C 6 alkoxy, C 6 -C 14 aryl, C 1 -C 9 heteroaryl, C 3 -C 8 cycloalkyl, and C 1 -C 6 alkyl. 
     “Aryl” refers to an aromatic hydrocarbon group containing 6-14 carbon ring atoms. “C 6 -C 14 Aryl” refers to a phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, and acenaphthenyl, groups. Examples of an C 6 -C 14 aryl group include, but are not limited to, phenyl, 1-naphthyl, 2-naphthyl, and 3-biphen-1-yl. An aryl group can be unsubstituted or substituted with one or more of the following groups: C 1 -C 6 alkyl, halo, haloalkyl-, hydroxyl, hydroxyl(C 1 -C 6 alkyl)-, —NH 2 , aminoalkyl-, dialkylamino-, —COOH, —C(O)O—(C 1 -C 6 alkyl), —OC(O)(C 1 -C 6 alkyl), N-alkylamido-, —C(O)NH 2 , (C 1 -C 6 alkyl)amido-, or —NO 2 . 
     “(Aryl)alkyl” refers to an alkyl group, as defined above, wherein one or more of the alkyl group&#39;s hydrogen atoms has been replaced with an C 6 -C 14 aryl group as defined above. (C 6 -C 14 Aryl)alkyl moieties include benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl and the like. An (aryl)alkyl group can be unsubstituted or substituted with one or more of the following groups: halogen, —NH 2 , hydroxyl, —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —N(C 1 -C 3 alkyl)C(O)(C 1 -C 6 alkyl), —NHC(O)(C 1 -C 6 alkyl), —NHC(O)H, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —CN, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, —C(O)OH, —C(O)O(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 alkyl), C 6 -C 14 aryl ,  C 1 -C 9 heteroaryl, C 3 -C 8 cycloalkyl, C 1 -C 6 haloalkyl-, C 1 -C 6 aminoalkyl-, —OC(O)(C 1 -C 6 alkyl), carboxyamido(C 1 -C 6 )alkyl-, or —NO 2 . 
     “(Aryl)amino” refers to a radical of formula (C 6 -C 14 aryl)-NH—, wherein “C 6 -C 14 aryl” is as defined above. Examples of (C 6 -C 14 aryl)amino radicals include, but are not limited to, phenylamino(anilido), 1-naphthlamino, 2-naphthlamino and the like. An (C 6 -C 14 aryl)amino group can be unsubstituted or substituted with one or more of the following groups: halogen, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —N(C 1 -C 3 alkyl)C(O)(C 1 -C 6 alkyl), —NHC(O)(C 1 -C 6 alkyl), —NHC(O)H, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —CN, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, —C(O)OH, —C(O)O(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 alkyl), C 6 -C 14 aryl ,  C 1 -C 9 heteroaryl, or C 3 -C 8 cycloalkyl. 
     “(Aryl)oxy” refers to the group Ar—O— where Ar is an C 6 -C 14 aryl group, as defined above. Exemplary (C 6 -C 14 aryl)oxy groups include but are not limited to phenyloxy, α-naphthyloxy, and β-naphthyloxy. A (C 6 -C 14 aryl)oxy group can be unsubstituted or substituted with one or more of the following groups: C 1 -C 6 alkyl, halo, C 1 -C 6 haloalkyl-, hydroxyl, C 1 -C 6 hydroxylalkyl-, —NH 2 , C 1 -C 6 aminoalkyl-, -dialkylamino-, —COOH, —C(O)O—(C 1 -C 6 alkyl), —OC(O)(C 1 -C 6 alkyl), N-alkylamido-, —C(O)NH 2 , (C 1 -C 6 alkyl)amido-, or —NO 2 . 
     “Cycloalkyl” refers to a monocyclic, non-aromatic, saturated hydrocarbon ring containing 3-8 carbon atoms. Representative examples of a C 3 -C 8 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. A cycloalkyl can be unsubstituted or independently substituted with one or more of the following groups: halogen, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —N(C 1 -C 3 alkyl)C(O)(C 1 -C 6 alkyl), —NHC(O)(C 1 -C 6 alkyl), —NHC(O)H, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —CN, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, —C(O)OH, —C(O)O(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 alkyl), C 6 -C 14 aryl ,  C 1 -C 9 heteroaryl, or C 3 -C 8 cycloalkyl, C 1 -C 6 haloalkyl-, C 1 -C 6 aminoalkyl-, —OC(O)(C 1 -C 6 alkyl), carboxyamido(C 1 -C 6 )alkyl-, or —NO 2 . Additionally, each of any two hydrogen atoms on the same carbon atom of the carbocyclic ring can be replaced by an oxygen atom to form an oxo (═O) substituent or the two hydrogen atoms can be replaced by an alkylenedioxy group so that the alkylenedioxy group, when taken together with the carbon atom to which it is attached, form a 5- to 7-membered heterocycle containing two oxygen atoms. 
     “Bicyclic cycloalkyl” refers to a bicyclic, non-aromatic, saturated hydrocarbon ring system containing 6-10 carbon atoms. Representative examples of a C 6 -C 10 bicyclic cycloalkyl include, but are not limited to, cis-1-decalinyl, trans 2-decalinyl, cis-4-perhydroindanyl, and trans-7-perhydroindanyl. A bicyclic cycloalkyl can be unsubstituted or independently substituted with one or more of the following groups: halogen, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —N(C 1 -C 3 alkyl)C(O)(C 1 -C 6 alkyl), —NHC(O)(C 1 -C 6 alkyl), —NHC(O)H, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —CN, hydroxyl, —O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, —C(O)OH, —C(O)O(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 alkyl), C 6 -C 14 aryl ,  C 1 -C 9 heteroaryl, or C 3 -C 8 cycloalkyl, haloalkyl-, aminoalkyl-, —OC(O)(C 1 -C 6 alkyl), carboxyamido(C 1 -C 6 )alkyl-, or —NO 2 . Additionally, each of any two hydrogen atoms on the same carbon atom of the bicyclic cycloalkyl rings can be replaced by an oxygen atom to form an oxo (═O) substituent or the two hydrogen atoms can be replaced by an alkylenedioxy group so that the alkylenedioxy group, when taken together with the carbon atom to which it is attached, form a 5- to 7-membered heterocycle containing two oxygen atoms. 
     “Carboxyamido(alkyl)-” refers to a primary carboxyamide (CONH 2 ), a secondary carboxyamide (CONHR′) or a tertiary carboxyamide (CONR′R″), where R′ and R″ are the same or different substituent groups selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 14 aryl, C 1 -C 9 heteroaryl, or C 3 -C 8 cycloalkyl, attached to the parent compound by an C 1 -C 6 alkylene group as defined above. Exemplary carboxyamido(C 1 -C 6 )alkyl- groups include but are not limited to NH 2 C(O)—CH 2 —, CH 3 NHC(O)—CH 2 CH 2 —, (CH 3 ) 2 NC(O)—CH 2 CH 2 CH 2 —, CH 2 ═CHCH 2 NHC(O)—CH 2 CH 2 CH 2 CH 2 —, HCCCH 2 NHC(O)—CH 2 CH 2 CH 2 CH 2 CH 2 —, C 6 H 5 NHC(O)—CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 —, 3-pyridylNHC(O)—CH 2 CH(CH 3 )CH 2 CH 2 —, and cyclopropyl-CH 2 NHC(O)—CH 2 CH 2 C(CH 3 ) 2 CH 2 —. 
     “Cycloalkenyl” refers to monocyclic, non-aromatic carbocyclic rings containing 3-10 carbon atoms with one or more carbon-to-carbon double bonds within the ring system. The “cycloalkenyl” may be a single ring or may be multi-ring. Multi-ring structures may be bridged or fused ring structures. A C 3 -C 10 cycloalkenyl can be unsubstituted or independently substituted with one or more of the following groups: halogen, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —N(C 1 -C 3 alkyl)C(O)(C 1 -C 6 alkyl), —NHC(O)(C 1 -C 6 alkyl), —NHC(O)H, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —CN, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, —C(O)OH, —C(O)O(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 alkyl), C 6 -C 14 aryl ,  C 1 -C 9 heteroaryl, or C 3 -C 8 cycloalkyl, C 1 -C 6 haloalkyl-, C 1 -C 6 aminoalkyl-, —OC(O)(C 1 -C 6 alkyl), carboxyamido(C 1 -C 6 )alkyl-, or —NO 2  Additionally, each of any two hydrogen atoms on the same carbon atom of the C 3 -C 10 cycloalkenyl rings may be replaced by an oxygen atom to form an oxo (═O) substituent or the two hydrogen atoms may be replaced by an alkylenedioxy group so that the alkylenedioxy group, when taken together with the carbon atom to which it is attached, form a 5- to 7-membered heterocycle containing two oxygen atoms. Examples of C 3 -C 10 cycloalkenyls include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 4,4a-octalin-3-yl, and cyclooctenyl. 
     “Di(alkyl)amino-” refers to a nitrogen atom which has attached to it two alkyl groups, as defined above. Each alkyl group can be independently selected. Representative examples of an di(C 1 -C 6 alkyl)amino- group include, but are not limited to, —N(CH 3 ) 2 , —N(CH 2 CH 3 )(CH 3 ), —N(CH 2 CH 3 ) 2 , —N(CH 2 CH 2 CH 3 ) 2 , —N(CH 2 CH 2 CH 2 CH 3 ) 2 , —N(CH(CH 3 ) 2 ) 2 , —N(CH(CH 3 ) 2 )(CH 3 ), —N(CH 2 CH(CH 3 ) 2 ) 2 , —NH(CH(CH 3 )CH 2 CH 3 ) 2 , —N(C(CH 3 ) 3 ) 2 , —N(C(CH 3 ) 3 )(CH 3 ), and —N(CH 3 )(CH 2 CH 3 ). The two alkyl groups on the nitrogen atom, when taken together with the nitrogen to which they are attached, can form a 3- to 7-membered nitrogen containing heterocycle wherein up to two of the carbon atoms of the heterocycle can be replaced with —N(R)—, —O—, or —S(O) p —. R is hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, C 1 -C 9 heteroaryl, C 1 -C 6 aminoalkyl-, or arylamino. Variable p is 0, 1, or 2. 
     “Halo” or “halogen” is —F, —Cl, —Br or —I. 
     “Haloalkyl-” refers to a alkyl group, as defined above, wherein one or more of the C 1 -C 6 alkyl group&#39;s hydrogen atoms has been replaced with —F, —Cl, —Br, or —I. Each substitution can be independently selected from —F, —Cl, —Br, or —I. Representative examples of an C 1 -C 6 haloalkyl- group include, but are not limited to, —CH 2 F, —CCl 3 , —CF 3 , CH 2 CF 3 , —CH 2 Cl, —CH 2 CH 2 Br, —CH 2 CH 2 I, —CH 2 CH 2 CH 2 F, —CH 2 CH 2 CH 2 Cl, —CH 2 CH 2 CH 2 CH 2 Br, —CH 2 CH 2 CH 2 CH 2 I, —CH 2 CH 2 CH 2 CH 2 CH 2 Br, —CH 2 CH 2 CH 2 CH 2 CH 2 I, —CH 2 CH(Br)CH 3 , —CH 2 CH(Cl)CH 2 CH 3 , —CH(F)CH 2 CH 3  and —C(CH 3 ) 2 (CH 2 Cl). 
     “Heteroaryl-” refers to 5-10-membered mono and bicyclic aromatic groups containing at least one heteroatom selected from oxygen, sulfur and nitrogen. Examples of monocyclic C 1 -C 9 heteroaryl radicals include, but are not limited to, oxazinyl, thiazinyl, diazinyl, triazinyl, tetrazinyl, imidazolyl, tetrazolyl, isoxazolyl, furanyl, furazanyl, oxazolyl, thiazolyl, thiophenyl, pyrazolyl, triazolyl, pyrimidinyl, N-pyridyl, 2-pyridyl, 3-pyridyl and 4-pyridyl. Examples of bicyclic C 1 -C 9 heteroaryl radicals include but are not limited to, benzimidazolyl, indolyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indazolyl, quinolinyl, quinazolinyl, purinyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzodiazolyl, benzotriazolyl, isoindolyl and indazolyl. A heteroaryl group can be unsubstituted or substituted with one or more of the following groups: C 1 -C 6 alkyl, halo, C 1 -C 6 haloalkyl-, hydroxyl, C 1 -C 6 hydroxylalkyl-, —NH 2 , C 1 -C 6 aminoalkyl-, dialkylamino-, —COOH, —C(O)O—(C 1 -C 6 alkyl), —OC(O)(C 1 -C 6 alkyl), N-alkylamido-, —C(O)NH 2 , (C 1 -C 6 alkyl)amido-, or —NO 2 . 
     “(Heteroaryl)oxy-” refers to the group Het-O— where Het is a heteroaryl group, as defined above. Exemplary (C 1 -C 9 heteroaryl)oxy groups include but are not limited to pyridin-2-yloxy, pyridin-3-yloxy, pyrimidin-4-yloxy, and oxazol-5-yloxy. A (heteroaryl)oxy group can be unsubstituted or substituted with one or more of the following groups: C 1 -C 6 alkyl, halo, C 1 -C 6 haloalkyl-, hydroxyl, C 1 -C 6 hydroxylalkyl-, —NH 2 , C 1 -C 6 aminoalkyl-, dialkylamino-, —COOH, —C(O)O—(C 1 -C 6 alkyl), —OC(O)(C 1 -C 6 alkyl), N-alkylamido-, —C(O)NH 2 , (C 1 -C 6 alkyl)amido-, or —NO 2 . 
     The term “heteroatom” refers to a sulfur, nitrogen, or oxygen atom. 
     “Heterocycle” or “heterocyclyl-” refers to 3-10-membered mono and bicyclic groups containing at least one heteroatom selected from oxygen, sulfur and nitrogen. A heterocycle may be saturated or partially saturated. Any sulfur atom contained within a heterocycle ring may be at the sulfide (—S—), sulfoxide (—S(O)—), or sulfonyl (—S(O) 2 —) oxidation state. Exemplary C 1 -C 9 heterocycle groups include but are not limited to aziridine, oxirane, oxirene, thiirane, pyrroline, pyrrolidine, dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, 1,1-dioxidotetrahydrothiophene, dithiolane, piperidine, decahydroquinoline, tetrahydropyran, pyran, thiane, thiine, piperazine, oxazine, thiazine, dithiane, and dioxane. 
     “Heterocyclyl(alkyl)” refers to an alkyl group, as defined above, wherein one or more of the alkyl group&#39;s hydrogen atoms has been replaced with a heterocycle group as defined above. Heterocyclyl(C 1 -C 6 alkyl)- moieties include 4-piperidinylmethyl, 1-piperazinylethyl, 4-morpholinylpropyl, 6-piperazinylhexyl, and the like. A heterocyclyl(alkyl) group can be unsubstituted or substituted with one or more of the following groups: halogen, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —N(C 1 -C 3 alkyl)C(O)(C 1 -C 6 alkyl), —NHC(O)(C 1 -C 6 alkyl), —NHC(O)H, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —CN, hydroxyl, —O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, —C(O)OH, —C(O)O(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 alkyl), 4- to 7-membered monocyclic heterocycle, C 6 -C 14 aryl ,  C 1 -C 9 heteroaryl, or C 3 -C 8 cycloalkyl. 
     “Hydroxylalkyl-” refers to a alkyl group, as defined above, wherein one or more of the C 1 -C 6 alkyl group&#39;s hydrogen atoms has been replaced with hydroxyl groups. Examples of C 1 -C 6 hydroxylalkyl- moieties include, for example, —CH 2 OH, —CH 2 CH 2 OH, —CH 2 CH 2 CH 2 OH, —CH 2 CH(OH)CH 2 OH, —CH 2 CH(OH)CH 3 , —CH(CH 3 )CH 2 OH and higher homologs. 
     “Hydroxylalkenyl-” refers to an alkenyl group, defined above, and substituted on one or more sp 3  carbon atoms with a hydroxyl group. Examples of C 3 -C 6 hydroxylalkenyl- moieties include chemical groups such as —CH═CHCH 2 OH, —CH(CH═CH 2 )OH, —CH 2 CH═CHCH 2 OH, —CH(CH 2 CH═CH 2 )OH, —CH═CHCH 2 CH 2 OH, —CH(CH═CHCH 3 )OH, —CH═CHCH(CH 3 )OH, —CH 2 CH(CH═CH 2 )OH, and higher homologs. 
     The term “monocyclic heterocycle” refers to a monocyclic 3- to 7-membered aromatic, cycloalkyl, or cycloalkenyl in which 1-4 of the ring carbon atoms have been independently replaced with an N, O or S atom. The monocyclic heterocyclic ring can be attached via a nitrogen, sulfur, or carbon atom. Representative examples of a 3- to 7-membered monocyclic heterocycle group include, but are not limited to, piperidinyl, 1,2,5,6-tetrahydropyridinyl, piperazinyl, morpholinyl, pyrrolyl, oxazinyl, thiazinyl, diazinyl, triazinyl, tetrazinyl, imidazolyl, tetrazolyl, pyrrolidinyl, isoxazolyl, furanyl, furazanyl, pyridinyl, oxazolyl, thiazolyl, thiophenyl, pyrazolyl, triazolyl, and pyrimidinyl. A monocyclic heterocycle group can be unsubstituted or substituted with one or more of the following groups: C 1 -C 8 acyl, C 1 -C 6 alkyl, heterocyclyl(C 1 -C 6 alkyl), (C 6 -C 14 aryl)alkyl, halo, halo(C 1 -C 6 alkyl)-, hydroxyl, hydroxyl(C 1 -C 6 alkyl)-, —NH 2 , aminoalkyl-, -dialkylamino-, —COOH, —C(O)O—(C 1 -C 6 alkyl), —OC(O)(C 1 -C 6 alkyl), (C 6 -C 14 )arylalkyl-O—C(O)—, N-alkylamido-, —C(O)NH 2 , (C 1 -C 6 alkyl)amido-, or —NO 2 . 
     “Bicyclic heterocycle” refers to a bicyclic aromatic, bicyclic cycloalkyl, or bicyclic cycloalkenyl in which 1-4 of the ring carbon atoms have been independently replaced with an N, O or S atom. The bicyclic heterocyclic ring can be attached via a nitrogen, sulfur, or carbon atom. Representative examples of a 6- to 10-membered bicyclic heterocycle group include, but are not limited to, benzimidazolyl, indolyl, indolinyl, isoquinolinyl, indazolyl, quinolinyl, tetrahydroquinolinyl, decahydroquinoline, quinazolinyl, purinyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzodiazolyl, benzotriazolyl, isoindolyl and indazolyl. A bicyclic heterocycle group can be unsubstituted or substituted with one or more of the following groups: C 1 -C 8 acyl, C 1 -C 6 alkyl, C 1 -C 6 heterocyclylalkyl, (C 6 -C 14 aryl)alkyl, halo, C 1 -C 6 haloalkyl-, hydroxyl, C 1 -C 6 hydroxylalkyl-, —NH 2 , aminoalkyl-, -dialkylamino-, —COOH, —C(O)O—(C 1 -C 6 alkyl), —OC(O)(C 1 -C 6 alkyl), (C 6 -C 14 aryl)alkyl-O—C(O)—, N-alkylamido-, —C(O)NH 2 , (C 1 -C 6 alkyl)amido-, or —NO 2 . 
     “Nitrogen-containing heteroaryl” refers to 5-10-membered mono and bicyclic aromatic groups containing at least one nitrogen atom and optionally additional heteroatoms selected from oxygen and sulfur. Examples of nitrogen-containing monocyclic C 1 -C 9 heteroaryl radicals include, but are not limited to, oxazinyl, thiazinyl, diazinyl, triazinyl, tetrazinyl, imidazolyl, tetrazolyl, isoxazolyl, furazanyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, pyrimidinyl, N-pyridyl, 2-pyridyl, 3-pyridyl and 4-pyridyl. Examples of nitrogen-containing bicyclic C 1 -C 9 heteroaryl radicals include but are not limited to, benzimidazolyl, indolyl, isoquinolinyl, indazolyl, quinolinyl, quinazolinyl, purinyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzodiazolyl, benzotriazolyl, isoindolyl and indazolyl. A nitrogen-containing C 1 -C 9 heteroaryl group can be unsubstituted or substituted with one or more of the following groups: C 1 -C 6 alkyl, halo, C 1 -C 6 haloalkyl-, hydroxyl, C 1 -C 6 hydroxylalkyl-, —NH 2 , C 1 -C 6 aminoalkyl-, dialkylamino-, —COOH, —C(O)O—(C 1 -C 6 alkyl), —OC(O)(C 1 -C 6 alkyl), N-alkylamido-, —C(O)NH 2 , (C 1 -C 6 alkyl)amido-, or —NO 2 . 
     “Perfluoroalkyl-” refers to alkyl group, defined above, having two or more fluorine atoms. Examples of a C 1 -C 6 perfluoroalkyl-group include CF 3 , CH 2 CF 3 , CF 2 CF 3  and CH(CF 3 ) 2 . 
     The term “optionally substituted” as used herein means that at least one hydrogen atom of the optionally substituted group has been substituted with halogen, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —N(C 1 -C 3 alkyl)C(O)(C 1 -C 6 alkyl), —NHC(O)(C 1 -C 6 alkyl), —NHC(O)H, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —CN, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, —C(O)OH, —C(O)O(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 alkyl), C 6 -C 14 aryl ,  C 1 -C 9 heteroaryl, or C 3 -C 8 cycloalkyl. 
     A “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or gorilla. 
     The 7H-pyrrolo[2,3-h]quinazoline compounds of the present invention exhibit an mTOR inhibitory activity and therefore, can be utilized in order to inhibit abnormal cell growth in which mTOR plays a role. Thus, the 7H-pyrrolo[2,3-h]quinazoline compounds are effective in the treatment of disorders with which abnormal cell growth actions of mTOR are associated, such as restenosis, atherosclerosis, bone disorders, arthritis, diabetic retinopathy, psoriasis, benign prostatic hypertrophy, atherosclerosis, inflammation, angiogenesis, immunological disorders, pancreatitis, kidney disease, cancer, etc. In particular, the 7H-pyrrolo[2,3-h]quinazoline compounds of the present invention possess excellent cancer cell growth inhibiting effects and are effective in treating cancers, preferably all types of solid cancers and malignant lymphomas, and especially, leukemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, brain tumor, advanced renal cell carcinoma, acute lymphoblastic leukemia, malignant melanoma, soft-tissue or bone sarcoma, etc. 
     The compounds of the present invention exhibit a PI3 kinase inhibitory activity and, therefore, can be utilized in order to inhibit abnormal cell growth in which PI3 kinases play a role. Thus, the compounds of the present invention are effective in the treatment of disorders with which abnormal cell growth actions of PI3 kinases are associated, such as restenosis, atherosclerosis, bone disorders, arthritis, diabetic retinopathy, psoriasis, benign prostatic hypertrophy, atherosclerosis, inflammation, angiogenesis, immunological disorders, pancreatitis, kidney disease, cancer, etc. In particular, the compounds of the present invention possess excellent cancer cell growth inhibiting effects and are effective in treating cancers, preferably all types of solid cancers and malignant lymphomas, and especially, leukemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, brain tumor, advanced renal cell carcinoma, acute lymphoblastic leukemia, malignant melanoma, soft-tissue or bone sarcoma, etc. 
     For therapeutic use, the pharmacologically active compounds of Formula I will normally be administered as a pharmaceutical composition comprising as the (or an) essential active ingredient at least one such compound in association with a solid or liquid pharmaceutically acceptable carrier and, optionally, with pharmaceutically acceptable adjutants and excipients employing standard and conventional techniques. 
     The pharmaceutical compositions of this invention include suitable dosage forms for oral, parenteral (including subcutaneous, intramuscular, intradermal and intravenous) bronchial or nasal administration. Thus, if a solid carrier is used, the preparation may be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. The solid carrier may contain conventional excipients such as binding agents, fillers, tableting lubricants, disintegrants, wetting agents and the like. The tablet may, if desired, be film coated by conventional techniques. If a liquid carrier is employed, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile vehicle for injection, an aqueous or non-aqueous liquid suspension, or may be a dry product for reconstitution with water or other suitable vehicle before use. Liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, wetting agents, non-aqueous vehicle (including edible oils), preservatives, as well as flavoring and/or coloring agents. For parenteral administration, a vehicle normally will comprise sterile water, at least in large part, although saline solutions, glucose solutions and like may be utilized. Injectable suspensions also may be used, in which case conventional suspending agents may be employed. Conventional preservatives, buffering agents and the like also may be added to the parenteral dosage forms. Particularly useful is the administration of a compound of Formula I directly in parenteral formulations. The pharmaceutical compositions are prepared by conventional techniques appropriate to the desired preparation containing appropriate amounts of the active ingredient, that is, the compound of Formula I according to the invention. See, for example,  Remington: The Science and Practice of Pharmacy,  20th Edition. Baltimore, Md.: Lippincott Williams &amp; Wilkins, 2000. 
     The dosage of the compounds of Formula I to achieve a therapeutic effect will depend not only on such factors as the age, weight and sex of the patient and mode of administration, but also on the degree of potassium channel activating activity desired and the potency of the particular compound being utilized for the particular disorder of disease concerned. It is also contemplated that the treatment and dosage of the particular compound may be administered in unit dosage form and that one skilled in the art would adjust the unit dosage form accordingly to reflect the relative level of activity. The decision as to the particular dosage to be employed (and the number of times to be administered per day is within the discretion of the physician, and may be varied by titration of the dosage to the particular circumstances of this invention to produce the desired therapeutic effect. 
     A suitable dose of a compound of Formula I or pharmaceutical composition thereof for a mammal, including man, suffering from, or likely to suffer from any condition as described herein is an amount of active ingredient from about 0.01 mg/kg to 10 mg/kg body weight. For parenteral administration, the dose may be in the range of 0.1 mg/kg to 1 mg/kg body weight for intravenous administration. For oral administration, the dose may be in the range about 0.1 mg/kg to 5 mg/kg body weight. The active ingredient will preferably be administered in equal doses from one to four times a day. However, usually a small dosage is administered, and the dosage is gradually increased until the optimal dosage for the host under treatment is determined. 
     However, it will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances including the condition to be treated, the choice of compound of be administered, the chosen route of administration, the age, weight, and response of the individual patient, and the severity of the patient&#39;s symptoms. 
     The amount of the compound of the present invention or a pharmaceutically acceptable salt thereof that is effective for inhibiting mTOR or PI3K in a subject. In addition, in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges. The precise dose to be employed can also depend on the route of administration, the condition, the seriousness of the condition being treated, as well as various physical factors related to the individual being treated, and can be decided according to the judgment of a health-care practitioner. Equivalent dosages may be administered over various time periods including, but not limited to, about every 2 hours, about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours, about every 48 hours, about every 72 hours, about every week, about every two weeks, about every three weeks, about every month, and about every two months. The number and frequency of dosages corresponding to a completed course of therapy will be determined according to the judgment of a health-care practitioner. The effective dosage amounts described herein refer to total amounts administered; that is, if more than one compound of the present invention or a pharmaceutically acceptable salt thereof is administered, the effective dosage amounts correspond to the total amount administered. 
     In one embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is administered concurrently with another therapeutic agent. 
     In one embodiment, a composition comprising an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and an effective amount of another therapeutic agent within the same composition can be administered. 
     Effective amounts of the other therapeutic agents are well known to those skilled in the art. However, it is well within the skilled artisan&#39;s purview to determine the other therapeutic agent&#39;s optimal effective amount range. The compound of the present invention or a pharmaceutically acceptable salt thereof and the other therapeutic agent can act additively or, in one embodiment, synergistically. In one embodiment, of the invention, where another therapeutic agent is administered to an animal, the effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof is less than its effective amount would be where the other therapeutic agent is not administered. In this case, without being bound by theory, it is believed that the compound of the present invention or a pharmaceutically acceptable salt thereof and the other therapeutic agent act synergistically. 
     Methods useful for making the 7H-pyrrolo[2,3-h]quinazoline compounds are set forth in the Examples below and generalized in Schemes 1-6: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Scheme 1 shows an 8-step synthesis of 4-(7-methyl-2-aryl-7H-pyrrolo[2,3-h]quinazolin-4-yl)morpholine 9 from commercially available 1-methyl-4-nitro-1H-indole. The key and ultimate step is a Suzuki Coupling, where the boronic acid is activated by base. The synthesis is applicable to a wide variety of boronic acids. 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Scheme 2 shows a seven-step synthesis of the key intermediate 2-chloro-4-(cyclic amino)-7H-pyrrolo[2,3-h]quinazoline 17 from tert-butyl 4-nitro-1H-indole-1-carboxylate. Reaction of 2,4-dichloro-7H-pyrrolo[2,3-h]quinazoline (16) with a wide variety of secondary amines can be performed. 
     
       
         
         
             
             
         
       
     
     A Suzuki coupling on a variety of 4-(7-(sulfonyl)-2-chloro-7H-pyrrolo[2,3-h]quinazolin-4-yl)amines 18, which were in turn made from key intermediate 17, is shown in Scheme 3. 
     
       
         
         
             
             
         
       
     
     Synthesis of another key intermediate, 7-benzyl-2,4-dichloro-7H-pyrrolo[2,3-h]quinazoline, 22 from 4-amino-1-benzylindole 21 is shown in Scheme 4. 
     
       
         
         
             
             
         
       
     
     Substitution on positions 7 and 9 of the 7H-pyrrolo[2,3-h]quinazoline ring, starting from key intermediate 17 is shown in Scheme 5. 
     
       
         
         
             
             
         
       
     
     A two-step process adding ureido functionality to position 4 of the benzene ring is shown in Scheme 6. 
     One of skill in the art will recognize that Schemes 1-6 can be adapted to produce the other 7H-pyrrolo[2,3-h]quinazoline compounds and pharmaceutically acceptable salts of 7H-pyrrolo[2,3-h]quinazoline compounds according to the present invention. 
     The following abbreviations are used herein and have the indicated definitions: ACN is acetonitrile, AcOH is acetic acid, ATP is adenosine triphosphate, CHAPS is 3[(3-cholamidopropyl)dimethylammonio]-propanesulfonic acid, DEAD is diethyl azodicarboxylate, DIAD is diisopropylazodicarboxylate, DMAP is dimethyl aminopyridine, DMF is N,N-dimethylformamide, DMF-DMA is dimethylformamide dimethyl acetal, DMSO is dimethylsulfoxide. Dowtherm™ is a eutectic mixture of biphenyl (C 12 H 10 ) and diphenyl oxide (C 12 H 10 O). Dowtherm™ is a registered trademark of Dow Corning Corporation. DPBS is Dulbecco&#39;s Phosphate Buffered Saline Formulation, EDTA is ethylenediaminetetraacetic acid, ESI stands for Electrospray Ionization, EtOAc is ethyl acetate, EtOH is ethanol, HEPES is 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, GMF is Glass, Hunig&#39;s Base is diisopropylethylamine, HPLC is high pressure liquid chromatography, LPS is lipopolysaccharide, MeCN is acetonitrile, MeOH is methanol, MS is mass spectrometry, NEt 3  is triethylamine, NMR is nuclear magnetic resonance, PBS is phosphate-buffered saline (pH 7.4), RPMI 1640 is a buffer (Sigma-Aldrich Corp., St. Louis, Mo., USA), SDS is dodecyl sulfate (sodium salt), SRB is Sulforhodamine B, TCA is tricholoroacetic acid, TFA is trifluoroacetic acid, THF is tetrahydrofuran, TLC is thin-layer chromatography, and TRIS is tris(hydroxymethyl)aminomethane. 
     EXAMPLES 
     Methods 
     The following methods outline the synthesis of the 7H-pyrrolo[2,3-h]quinazoline compounds. 
     Experimental for the preparation of intermediate 2-chloro-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazoline) (Procedure). 
     Step 1: Preparation of 1-Boc-4-nitroindole Formula 10 
     To a stirred solution of 4-nitroindole (4.0 g, 24.6 mmol) in CH 2 Cl 2  (50 mL) were added catalytic amount of DMAP (Catalyst) and Boc 2 O (5.9 g, 27.1 mmol) at 0° C., and the resulting reaction mixture was stirred at room temperature for additional 3 h. The mixture was diluted with CH 2 Cl 2 , and washed with water. The organic phase was dried over MgSO 4 . The solvent was removed under reduced pressure to give 1-Boc-4-nitroindole as white solid (6.14 g, 95% yield). MS (ESI) m/z 262.1 
     Step 2: Preparation of 1-Boc-4-aminoindole Formula 11 
     To a stirred solution of 1-Boc-4-nitroindole (6.14 g, 23.4 mmol) in EtOH (100 mL) was added 10% Pd/C (614 mg) under N 2 . The resulting mixture was shaken under hydrogen (H 2 , 50 psi) at room temperature for 8 h. The mixture was filtered through a pad of Celite™, and washed with EtOH. The filtrate was concentrated under reduced pressure to give the product 1-Boc-4-aminoindole as off-white solid (5.23 g, 96% yield). MS (ESI) m/z 233.2 
     Step 3: Preparation of 1-Boc-4-(3-(ethoxycarbonyl)thioueido)-indole Formula 12 
     To a solution of 1-Boc-4-aminoindole (5.23 g, 22.5 mmol) in CH 2 Cl 2  was added ethyl isothiocyanatoformate (2.95 g, 22.5 mmol), and the resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure and triturated with diethyl ether to give the title compound as off-white solid (8.1 g, 99% yield). 
     Step 4: Preparation of 1-Boc-4-((ethoxycarbonylamino)ethylthio)methyleneamino)-indole Formula 13 
     To a stirred solution of 1-Boc-4-(3-(ethoxycarbonyl)thioueido)-indole (3.58 g, 9.85 mmol) in acetone (100 mL) was added K 2 CO 3  (2.72 g, 19.7 mmol), followed by addition of iodoethane (1.69 g, 10.8 mmol) at room temperature. The resulting mixture was vigorously stirred at room temperature overnight. The mixture was filtered and washed with acetone. The filtrate was concentrated under reduced pressure, and the residue was treated with CH 2 Cl 2  and water. The mixture was extracted with CH 2 Cl 2 , and the extracts were washed with water, and dried over MgSO 4 . The solvent was removed under reduced pressure to provide the title compound as yellow syrup (3.68 g, 95% yield). MS (ESI) m/z 392.2. 
     Step 5: Synthesis of 7-Boc-2-(ethylthio)-7H-pyrrolo[2,3h]quinazoline-4-one Formula 14 
     A mixture of 1-Boc-4-((ethoxycarbonylamino)ethylthio)methyleneamino)-indole (3.68 g, 9.4 mmol) and phenyl ether (70 mL) was heated at 200° C. for 5 h under N 2 . The mixture was cooled down to room temperature and diluted with hexanes. The resulting solid was collected by filtration to give the title compound as off-white solid (1.5 g, 46% yield). 
     Step 6: Synthesis of 7H-pyrrolo[2,3h]quinazoline-2,4-dione Formula 15 
     To a solution of 7-Boc-2-(ethylthio)-7H-Pyrrolo[2,3h]quinazoline-4-one (1.5 g, 4.34 mmol) in EtOH (30 mL) was added 6N HCl aqueous solution (30 mL). The resulting mixture was heated at 80° C. overnight, and then cooled down to room temperature, and concentrated under reduced pressure to its half volume. The resulting solid was collected by filtration to give 7H-pyrrolo[2,3h]quinazoline-2,4-dione as off-white solid (780 mg, 89% yield). 
     Step 7: Synthesis of 2,4-dichloro-7H-pyrrolo[2,3h]quinazoline Formula 16 
     A mixture of 7H-pyrrolo[2,3h]quinazoline-2,4-dione (3.0 g, 14.9 mmol) and POCl 3  (60 mL) was heated at 115° C. for 12 h. The mixture was cooled down to room temperature and POCl 3  was distilled off under reduced pressure. The residue was poured onto ice water with stirring. The resulting solid was collected by filtration to give the title compound 2,4-dichloro-7H-pyrrolo[2,3h]quinazoline as off-white solid (2.06 g, 58% yield). MS (ESI) m/z 236.0. 
     Step 8: Synthesis of 2-chloro-4-morpholin-4-yl-7H-pyrrolo[2,3h]quinazoline Formula 17 (A=-O—). 
     To a solution of 2,4-dichloro-7H-pyrrolo[2,3h]quinazoline (474 mg , 2.0 mmol) in CHCl 3  (30 mL) was added morpholine (192 mg, 2.2 mmol), followed by the addition of triethylamine (0.56 mL, 4.0 mmol). The reaction mixture was stirred at room temperature overnight, and quenched with water. Reaction mixture was washed well with water, dried over anhydrous MgSO 4 , and filtered. It was concentrated and the separated solid was taken to next step with out purification. The titled compound was obtained total 466 mg, 81% yield. MS (ESI) m/z 289.3. 
     Preparation of 2-chloro-7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazoline Formula 8 
     Step 1: Preparation of 1-methyl-4-nitro-1H-indole Formula 1 
     A mixture of 4-nitro-1H-indole (3.06 g, 18.9 mmole), potassium carbonate anhydrous (13.5 g, 97.8 mmole) and methyl iodide (3.2 g, 22.5 mmole) was heated at reflux in acetone for 8 hours. At the end, reaction mixture was filtered and acetone was evaporated. It was extracted with chloroform (300 mL) and washed water (300 mL). The organic layer was separated, dried with MgSO 4 , filtered and concentrated. The yellow solid, (2.20 g, 66% yield) of 1-methyl-4-nitro-1H-indole was used without further purification. (M+H) 177 
     Step 2: Preparation of 1-methyl-4-amino-indole Formula 2 
     An ethanol solution of 1-methyl-4-nitro-1H-indol (2.0 g, 11.36 mmole) was hydrogenated over 10% Pd catalyst at 40 psi for 4 hours. Reaction mixture was filtered through a pad of Celite™ and concentrated. The residue was extracted with chloroform and washed with water. The organic layer was dried with magnesium sulfate, filtered and concentrated to give the amine. (M+H) 147. 
     Step 3: Preparation of 1-methyl-4-(3-(ethoxycarbonyl)thioueido)-indole Formula 5 
     To a solution of 1-methyl-4-aminoindole (1.76 g, 13.3 mmol) in CH 2 Cl 2  was added ethyl isothiocyanatoformate (1.75 g, 13.3 mmol), and the resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure and triturated with diethyl ether to give the title compound as off-white solid (3.5 g, 95% yield). (M+H) 278. 
     Step 4: Preparation of 1-methyl-4-((ethoxycarbonylamino)ethylthio)methyleneamino)-indole Formula 4 
     To a stirred solution of 1-methyl-4-(3-(ethoxycarbonyl)thioueido)-indole (3.4 g, 12.3 mmol) in acetone (300 mL) was added K 2 CO 3  (8.4 g, 60.8 mmol), followed by addition of iodoethane (1.98 g, 12.7 mmol) at room temperature. The resulting mixture was vigorously stirred at room temperature overnight. The mixture was filtered and washed with acetone. The filtrate was concentrated under reduced pressure, and the residue was treated with CH 2 Cl 2  and water. The mixture was extracted with CH 2 Cl 2 , and the extracts were washed with water, and dried over MgSO 4 . The solvent was removed under reduced pressure to provide the title compound as yellow syrup (3.56 g, 95% yield). (M+H) 306. 
     Step 5: Synthesis of 7-methyl-2-(ethylthio)-7H-Pyrrolo[2,3h]quinazoline-4-one Formula 7 
     A mixture of 1-methyl-4-((ethoxycarbonylamino)ethylthio)methyleneamino)-indole (3.50 g, 11.36 mmol) and phenyl ether (70 mL) was heated at 200° C. for 5 h under N 2 . The mixture was cooled down to room temperature and diluted with hexanes. The resulting solid was collected by filtration to give the title compound as off-white solid (2.8 g, 92% yield). (M−H) 257 
     Step 6: Synthesis of 7-methyl-pyrrolo[2,3h]quinazoline-2,4-dione Formula 8 
     To a solution of 7-methyl-2-(ethylthio)-7H-pyrrolo[2,3h]quinazoline-4-one (2.6 g, 410 mmol) in EtOH (100 mL) was added 6N HCl aqueous solution (30 mL). The resulting mixture was heated at 80° C. overnight, and then cooled down to room temperature, and concentrated under reduced pressure to its half volume. The resulting solid was basified with NH 4 OH and the separated solid was collected by filtration to give 7-methyl-pyrrolo[2,3h]quinazoline-2,4-dione as off-white solid (1.84 g, 86% yield). 
     Step 7: Synthesis of 2,4-dichloro-7-methyl-7H-pyrrolo[2,3h]quinazoline Formula 9 
     A mixture of 7-methyl-7H-pyrrolo[2,3h]quinazoline-2,4-dione (1.84 g, 8.6 mmol) and POCl 3  (60 mL) was heated at 115° C. for 12 h. The mixture was cooled down to room temperature and POCl 3  was distilled off under reduced pressure. The residue was poured onto ice water with stirring. The resulting solid was collected by filtration to give the title compound 2,4-dichloro-7-methyl-7H-pyrrolo[2,3h]quinazoline as off-white solid (2.0 g, 93% yield). MS (ESI) m/z 252.0. 
     Step 8: Synthesis of 7-methyl-2-chloro-4-morpholin-4-yl-7H-pyrrolo[2,3h]quinazoline Formula 8 
     To a solution of 2,4-dichloro-7-methyl-7H-pyrrolo[2,3h]quinazoline (1.0 g, 3.94 mmol) in CHCl 3  (30 mL) was added morpholine (340 mg, 4.0 mmol), followed by the addition of triethylamine (0.56 mL, 4.0 mmol). The reaction mixture was stirred at room temperature overnight, and quenched with water. Reaction mixture was washed well with water and dried over anhydrous MgSO 4  and filtered. It was concentrated and the separated solid was taken to next step with out purification. The titled compound was obtained as a pale yellow solid. 1.15 g, 96% yield. (M+H) 303. 
     Example 1 
     Preparation of 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline 
     A mixture of 2-chloro-7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazoline (723 mg, 2.4 mmol), 4-aminophenylboronic acid, pinacol ester (786 mg, 3.6 mmol), Pd(PPh 3 ) 4  (138 mg, 5 mol %), dimethoxyethane (DME, 8 mL) and 2M Na 2 CO 3  (4 mL) was heated at 120° C. for 0.5 h in microwave oven. The reaction mixture was cooled to room temperature, and filtered through a pad of Celite™, washed with THF. The filtrate was concentrated under reduced pressure, and the residue was subjected to flash chromatography in silica gel (EtOAc:Hexanes:CH 2 Cl 2 =50:30:20) to give the title compound as yellow solid (705 mg, 82% yield). MS (ESI) m/z 360.4. 
     HRMS: calcd for C 21 H 21 N 5 O+H + , 360.18189; found (ESI-FTMS, [M+H]1+), 360.18254. 
     Example 2 
     Preparation of 1-methyl-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3h]quinazolin-2-yl)phenyl]urea 
     To a solution of 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline (22 mg, 0.06 mmol) in CH 2 Cl 2  (1 mL) were added Et 3 N (25 μL, 0.18 mmol) and triphosgene (35 mg, 0.12 mmol). A methylamine solution in THF (2 M, 0.09 mL, 0.18 mmol) was added to the mixture after 15 min, and the resulting mixture was stirred at room temperature for 6 h. The solvent was removed under reduced pressure, and the residue was subjected to HPLC separation to give the title compound as off-white solid (TFA salt, 21.4 mg, 67% yield). MS (ESI) m/z 417.4. 
     Example 3 
     Preparation of 1-ethyl-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea 
     The title compound was prepared by following the procedure as outlined in Example 2. 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline (22 mg, 0.06 mmol) and ethylamine (2 M in THF, 0.09 mL, 0.18 mmol) gave the title compound as off-white solid (TFA salt, 5.6 mg, 17% yield). MS (ESI) m/z 431.4. 
     Example 4 
     Preparation of 1-[2-(dimethylamino)ethyl]-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea 
     The title compound was prepared by following the procedure of Example 2. 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline (22 mg, 0.06 mmol) and N,N-dimethylethylenediamine (16 mg, 0.18 mmol) gave the title compound as off-white solid (TFA salt, 21.4 mg, 61% yield). MS (ESI) m/z 474.8. 
     Example 5 
     Preparation of 1-[3-(dimethylamino)propyl]-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea 
     The title compound was prepared by following the procedure of Example 2. 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline (22 mg, 0.06 mmol) and 3-(dimethylamino)-1-propylamine (18 mg, 0.18 mmol) gave the title compound as off-white solid (TFA salt, 29.1 mg, 81% yield). MS (ESI) m/z 488.9. 
     Example 6 
     Preparation of 4-methyl-N-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]piperazine-1-carboxamide 
     The title compound was prepared by following the procedure of Example 2. 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline (22 mg, 0.06 mmol) and 1-methylpiperazine (18 mg, 0.18 mmol) gave the title compound as off-white solid (TFA salt, 35.6 mg, 99% yield). MS (ESI) m/z 486.5. 
     Example 7 
     Preparation of 1-(2-furylmethyl)-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea 
     The title compound was prepared by following the procedure of Example 2. 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline (22 mg, 0.06 mmol) and furfurylamine (18 mg, 0.18 mmol) gave the title compound as off-white solid (TFA salt, 24.5 mg, 68% yield). MS (ESI) m/z 483.4. 
     Example 8 
     Preparation of 1-[3-(1H-imidazol-1-yl)propyl]-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea 
     The title compound was prepared by following the procedure of Example 2. 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline (22 mg, 0.06 mmol) and 1-(3-aminopropyl)imidazole (23 mg, 0.18 mmol) gave the title compound as off-white solid (TFA salt, 20.7 mg, 55% yield). MS (ESI) m/z 511.9. 
     Example 9 
     Preparation of 1-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]-3-pyridin-2-ylurea 
     The title compound was prepared by following the procedure of Example 2. 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline (22 mg, 0.06 mmol) and 2-aminopyridine (18 mg, 0.18 mmol) gave the title compound as off-white solid (TFA salt, 12.4 mg, 35% yield). MS (ESI) m/z 480.4. 
     Example 10 
     Preparation of 1-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]-3-phenylurea 
     The title compound was prepared by following the procedure of Example 2. 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline (22 mg, 0.06 mmol) and 2-aminopyridine (18 mg, 0.18 mmol) gave the title compound as off-white solid (TFA salt, 24.3 mg, 67% yield). MS (ESI) m/z 479.5. 
     HRMS: calcd for C 28 H 26 N 6 O 2 +H + , 479.21900; found (ESI-FTMS, [M+H]1+), 479.21743. 
     Example 11 
     Preparation of 1-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]-3-pyridin-4-ylurea 
     The title compound was prepared by following the procedure of Example 2. 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline (22 mg, 0.06 mmol) and 4-aminopyridine (18 mg, 0.18 mmol) gave the title compound as off-white solid (TFA salt, 32.3 mg, 91% yield). MS (ESI) m/z 480.3. 
     HRMS: calcd for C 27 H 25 N 7 O 2 +H + , 480.21425; found (ESI-FTMS, [M+H]1+), 480.21209. 
     Example 12 
     Preparation of 1-(4-isopropylphenyl)-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea 
     The title compound was prepared by following the procedure of Example 2. 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline (22 mg, 0.06 mmol) and 4-isopropylaniline (24 mg, 0.18 mmol) gave the title compound as off-white solid (TFA salt, 5.7 mg, 15% yield). MS (ESI) m/z 521.5. 
     Example 13 
     Preparation of 1-(3-chlorophenyl)-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea 
     The title compound was prepared by following the procedure of Example 2. 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline (22 mg, 0.06 mmol) and 3-chloroaniline (23 mg, 0.18 mmol) gave the title compound as off-white solid (TFA salt, 21.9 mg, 58% yield). MS (ESI) m/z 513.4. 
     Example 14 
     Preparation of 1-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]-3-[4-(trifluoromethyl)phenyl]urea 
     The title compound was prepared by following the procedure of Example 2. 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline (22 mg, 0.06 mmol) and 4-(trifluoromethyl)aniline (29 mg, 0.18 mmol) gave the title compound as off-white solid (TFA salt, 11.1 mg, 28% yield). MS (ESI) m/z 547.5. 
     Example 15 
     Preparation of 1-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]-3-(pyridin-2-ylmethyl)urea 
     The title compound was prepared by following the procedure of Example 2. 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline (22 mg, 0.06 mmol) and 2-(aminomethyl)pyridine (19 mg, 0.18 mmol) gave the title compound as off-white solid (TFA salt, 24.2 mg, 66% yield). MS (ESI) m/z 494.5. 
     Example 16 
     Preparation of N-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]acetamide 
     To a solution of 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline (22 mg, 0.06 mmol) in CH 2 Cl 2  (1 mL) were added Et 3 N (25 uL, 0.18 mmol) and acetyl chloride (10 mg, 0.12 mmol). The resulting mixture was stirred at room temperature for 6 h. The solvent was removed under reduced pressure, and the residue was subjected to HPLC separation to give the title compound as off-white solid (TFA salt, 22 mg, 71% yield). MS (ESI) m/z 402.5. 
     Example 17 
     Preparation of N-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]nicotinamide 
     The title compound was prepared by following the procedure of Example 16. 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline (22 mg, 0.06 mmol) and nicotinoyl chloride hydrochloride (21 mg, 0.12 mmol) gave the title compound as off-white solid (TFA salt, 27.5 mg, 79% yield). MS (ESI) m/z 465.6. 
     Example 18 
     Preparation of N-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]isonicotinamide 
     The title compound was prepared by following the procedure of Example 16. 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline (22 mg, 0.06 mmol) and isonicotinoyl chloride hydrochloride (21 mg, 0.12 mmol) gave the title compound as off-white solid (TFA salt, 25.2 mg, 73% yield). MS (ESI) m/z 465.6. 
     Example 19 
     Preparation of 4-fluoro-N-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]benzamide 
     The title compound was prepared by following the procedure of Example 16. 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline (22 mg, 0.06 mmol) and 4-fluorobenzoyl chloride (19 mg, 0.12 mmol) gave the title compound as off-white solid (TFA salt, 21.3 mg, 60% yield). MS (ESI) m/z 482.5. 
     Example 20 
     Preparation of ethyl [4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]carbamate 
     The title compound was prepared by following the procedure of Example 16. 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline (22 mg, 0.06 mmol) and ethyl chloroformate (11 mg, 0.12 mmol) gave the title compound as off-white solid (TFA salt, 25.8 mg, 79% yield). MS (ESI) m/z 432.4. 
     Example 19 
     N-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]methanesulfonamide 
     To a solution of 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline (22 mg, 0.06 mmol) in CH 2 Cl 2  (1 mL) was added Et 3 N (25 uL, 0.18 mmol) and methanesulfonyl chloride (14 mg, 0.12 mmol). The resulting mixture was stirred at room temperature for 6 h. The solvent was removed under reduced pressure, and the residue was treated with 0.5 ml 5M NaOH and MeOH (2 mL). The mixture was stirred at room temperature for 7 h, and concentrated under reduced pressure. The residue was subjected to HPLC separation to give the title compound as off-white solid (TFA salt, 6.7 mg, 26% yield). MS (ESI) m/z 438.5. 
     Example 22 
     N-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]benzenesulfonamide 
     The title compound was prepared by following the procedure of Example 21. 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline (22 mg, 0.06 mmol) and benzenesulfonyl chloride (21 mg, 0.12 mmol) gave the title compound as off-white solid (TFA salt, 18.2 mg, 61% yield). MS (ESI) m/z 500.5. 
     Example 23 
     Preparation of 3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)benzaldehyde 
     A mixture of 2-chloro-7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazoline (550 mg, 1.8 mmol), 3-formylphenylboronic acid (409 mg, 2.7 mmol), Pd(PPh 3 ) 4  (105 mg, 5 mol %), dimethoxyethane (DME, 4 mL) and 2M Na 2 CO 3  (3 mL) was heated at 120° C. for 0.5 h in microwave oven. The reaction mixture was cooled to room temperature, and filtered through a pad of Celite™, washed with THF. The filtrate was concentrated under reduced pressure, and the residue was subjected to flash chromatography in silica gel (EtOAc:Hexane=50:50) to give the title compound as off-white solid (407 mg, 60% yield). MS (ESI) m/z 373.3. 
     HRMS: calcd for C 22 H 20 N 4 O 2 +H + , 373.16590; found (ESI-FTMS, [M+H]1+), 373.16632. 
     Example 24 
     Preparation of 1-[3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]ethanol 
     To a solution of 3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)benzaldehyde (22 mg, 0.06 mmol) in THF (2 mL) was added methyl magnesium bromide (2M in THF, 0.09 mL, 0.18 mmol) at −78° C. The resulting mixture was stirred at −78° C. for 3 h, and then quenched by addition of 1 mL of saturated ammonium chloride aqueous solution. The mixture was allowed to warm to room temperature, and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO 4 . The solvent was removed under reduced pressure, and the residue was subjected to HPLC to give the title compound as yellow solid (TFA salt, 10 mg, 33% yield). MS (ESI) m/z 389.3. 
     Example 25 
     1-[3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]propan-1-ol 
     The title compound was prepared by following the procedure of Example 24. 3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)benzaldehyde (22 mg, 0.06 mmol) and ethyl magnesium bromide (2M in THF, 0.09 mL, 0.18 mmol) gave the title compound as yellow solid (TFA salt, 18.5 mg, 60% yield). MS (ESI) m/z 403.6. 
     Example 26 
     1-[3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]prop-2-en-1-ol 
     The title compound was prepared by following the procedure of Example 24. 3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)benzaldehyde (22 mg, 0.06 mmol) and vinyl magnesium chloride (2M in THF, 0.09 mL, 0.18 mmol) gave the title compound as yellow solid (TFA salt, 16.6 mg, 54% yield). MS (ESI) m/z 401.4. 
     Example 27 
     1-[3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]but-3-en-1-ol 
     The title compound was prepared by following the procedure of Example 24. 3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)benzaldehyde (22 mg, 0.06 mmol) and allyl magnesium chloride (2M in THF, 0.09 mL, 0.18 mmol) gave the title compound as yellow solid (TFA salt, 10.6 mg, 33% yield). MS (ESI) m/z 415.4. 
     Example 28 
     3-methyl-1-[3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]butan-1-ol 
     The title compound was prepared by following the procedure of Example 24. 3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)benzaldehyde (22 mg, 0.06 mmol) and isobutyl magnesium bromide (2M in THF, 0.09 mL, 0.18 mmol) gave the title compound as yellow solid (TFA salt, 16.8 mg, 51% yield). MS (ESI) m/z 431.4. 
     Example 29 
     [3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl](phenyl)methanol 
     The title compound was prepared by following the procedure of Example 24. 3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)benzaldehyde (22 mg, 0.06 mmol) and phenyl magnesium bromide (2M in THF, 0.09 mL, 0.18 mmol) gave the title compound as yellow solid (TFA salt, 20.4 mg, 60% yield). MS (ESI) m/z 451.4. 
     Example 30 
     (3-{7-[2-(dimethylamino)ethyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl}phenyl)methanol 
     To a solution of 2-chloro-4-morpholin-4-yl-7H-pyrrolo[2,3h]quinazoline (500 mg, 1.7 mmol) in DMF (15 mL) were added Cs 2 CO 3  (1.425 g, 4.4 mmol) and 2-(dimethylamino)ethyl chloride hydrochloride (490 mg, 3.4 mmol). The mixture was heated at 80° C. overnight. The mixture was cooled to room temperature, and water was added, extracted with EtOAc. The combined extracts were washed with brine, and dried over MgSO 4 . The solvent was removed under reduced pressure to give the crude intermediate 2-chloro-7-(2-(dimethylamino)ethyl)-4-morpholin-4-yl-7H-pyrrolo[2,3h]quinazoline (424 mg, 68% yield), which was used in next step without further purification. MS (ESI) m/z 360.4. 
     A mixture of 2-chloro-7-(2-(dimethylamino)ethyl)-4-morpholin-4-yl-7H-pyrrolo[2,3h]quinazoline (62 mg, 0.17 mmol), 3-(hydroxymethyl)phenylboronic acid (39 mg, 0.26 mmol), Pd(PPh 3 ) 4  (10 mg, 5 mol %), dimethoxyethane (DME, 3 mL) and 2M Na 2 CO 3  (0.5 mL) was heated at 130° C. for 0.5 h in microwave oven. The reaction mixture was cooled to room temperature, and filtered through a pad of Celite™, washed with THF. The filtrate was concentrated under reduced pressure, and the residue was subjected to HPLC separation to give the title compound as yellow solid (TFA salt, 72 mg, 78% yield). MS (ESI) m/z 432.4. 
     Example 31 
     2-{2-[3-(benzyloxy)phenyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-7-yl}-N,N-dimethylethanamine 
     The title compound was prepared by following the procedure of Example 30. Suzuki reaction of 2-chloro-7-(2-(dimethylamino)ethyl)-4-morpholin-4-yl-7H-pyrrolo[2,3h]quinazoline (124 mg, 0.34 mmol) and 3-benzyloxyphenylboronic acid (118 mg, 0.52 mmol) gave the title compound as yellow solid (96 mg, 56% yield). MS (ESI) m/z 508.4. 
     Example 32 
     3-{7-[2-(dimethylamino)ethyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl}phenol 
     A mixture of 2-{2-[3-(benzyloxy)phenyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-7-yl}-dimethylethanamine (40 mg, 0.08 mmol) and 10% Pd/C (20 mg) in MeOH (10 mL) was stirred at room temperature under hydrogen (50 psi) overnight. The mixture was filtered through a pad of Celite™ and washed with THF and MeOH, and the filtrate was concentrated under reduced pressure. The residue was subjected to HPLC separation to give the title compound as yellow solid (28 mg, 86% yield). MS (ESI) m/z 418.4. 
     Example 33 
     1-(4-{7-[2-(dimethylamino)ethyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl}phenyl)-3-pyridin-4-ylurea 
     The title compound was prepared by following the procedure of Example 30. Suzuki reaction of 2-chloro-7-(2-(dimethylamino)ethyl)-4-morpholin-4-yl-7H-pyrrolo[2,3h]quinazoline (32 mg, 0.09 mmol) and 1-(pyridine-4-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylurea (61 mg, 0.18 mmol) gave the title compound as yellow solid (21 mg, 44% yield). MS (ESI) m/z 537.5. 
     Example 34 
     5-{7-[2-(dimethylamino)ethyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl}pyrimidin-2-amine 
     The title compound was prepared by following the procedure of Example 30. Suzuki reaction of 2-chloro-7-(2-(dimethylamino)ethyl)-4-morpholin-4-yl-7H-pyrrolo[2,3h]quinazoline (32 mg, 0.09 mmol) and 2-aminopyrimidin-5-ylboronic acid (25 mg, 0.18 mmol) gave the title compound as yellow solid (15 mg, 40% yield). MS (ESI) m/z 419.4. 
     Example 35 
     Preparation of 3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenol 
     A mixture of 7-methyl-2-chloro-4-morpholin-4-yl-7H-pyrrolo[2,3h]quinazoline (200 mg, 0.66 mmol), 3-hydroxyphenylboronic acid (220 mg, 1.7 mmol) Pd(PPh 3 ) 4  (50 mg) and 2M solution of Na 2 CO 3  (3 ml) was heated at reflux in dimethoxyethane (30 ml) for 24 h under nitrogen atmosphere. At the end, reaction mixture was filtered through Celite™, washed well with chloroform and extracted with chloroform. Organic layer was washed with water; dried over anhydrous MgSO 4  and concentrated. The product was purified by SiO 2  column chromatography by eluting it with ethyl acetate: methanol (98:2). Yield: 130 mg, 56%; (M+H) 361.416. 
     Example 36 
     Preparation of Methyl 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)benzoate 
     Starting from a mixture of 7-methyl-2-chloro-4-morpholin-4-yl-7H pyrrolo[2,3h]quinazoline (440 mg, 1.45 mmol), 4-carbethoxymethylphenylboronic acid (650 mg, 3.6 mmol) Pd(PPh 3 ) 4  (50 mg) and 2M solution of Na 2 CO 3  (3 ml) and following the procedure as outlined in Example 35, the titled compound was isolated white solid. Yield: 450 mg, 77%; (M+H) 403. 
     Example 37 
     Preparation of 3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]methanol 
     Starting from a mixture of 7-methyl-2-chloro-4-morpholin-4-yl-7H pyrrolo[2,3h]quinazoline (440 mg, 1.45 mmol), 3-hydroxymethyl phenylboronic acid (550 mg, 3.6 mmol) Pd(PPh 3 ) 4  (50 mg) and 2M solution of Na 2 CO 3  (3 ml) and following the procedure as outlined in Example 35, the titled compound was isolated white solid. Yield: 480 mg, 88%; (M+H) 362.3. 
     Example 38 
     Preparation of 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)benzoic  acid 
     To a stirred solution of MeOH/THF (1:1, 75 ml) methyl 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)benzoate (110 mg, 0.27 mmol), NaOH (21 mg, 0.52 mmol) was added in 2 ml water. The reaction mixture was stirred for 12 h at room temperature and at the end, reaction mixture was concentrated and was neutralized with con. HCl. The separated white solid was filtered and washed with water. The product was crystallized from aqueous MeOH. Yield: 70 mg, 66%; (M−H) 388.2. 
     Example 39 
     Preparation of 3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)benzamide 
     Starting from a mixture of 7-methyl-2-chloro-4-morpholin-4-yl-7H pyrrolo[2,3h]quinazoline (400 mg, 1.32 mmol), 3-carbamoylphenylboronic acid (540 mg, 3.3 mmol) Pd(PPh 3 ) 4  (50 mg) and 2M solution of Na 2 CO 3  (3 ml) and following the procedure as outlined in Example 35, the titled compound was isolated white solid. Yield: 52 mg, 10%; (M+H) 389.3. 
     Example 40 
     Preparation of 3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)benzonitrile 
     Starting from a mixture of 7-methyl-2-chloro-4-morpholin-4-yl-7H pyrrolo[2,3h]quinazoline (400 mg, 1.32 mmol), 3-cyanophenylboronic acid (470 mg, 3.3 mmol) Pd(PPh 3 ) 4  (50 mg) and 2M solution of Na 2 CO 3  (3 ml) and following the procedure as outlined in Example 35, the titled compound was isolated white solid. Yield: 150 mg, 27%; (M+H) 371.3. 
     Example 41 
     Preparation of 3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline 
     Starting from a mixture of 7-methyl-2-chloro-4-morpholin-4-yl-7H pyrrolo[2,3h]quinazoline (300 mg, 1 mmol), 3-aminophenylboronic acid (290 mg, 2.5 mmol) Pd(PPh 3 ) 4  (50 mg) and 2M solution of Na 2 CO 3  (3 ml) and following the procedure as outlined in Example 35, the titled compound was isolated white solid. Yield: 48 mg, 12%; (M+H) 348.3. 
     Example 42 
     Preparation of 5-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)pyridin-2-amine 
     Starting from a mixture of 7-methyl-2-chloro-4-morpholin-4-yl-7H pyrrolo[2,3h]quinazoline (150 mg, 0.5 mmol), 6-aminopyridyl-3-boronic acid (270 mg, 1.23 mmol) Pd(PPh 3 ) 4  (50 mg) and 2M solution of Na 2 CO 3  (3 ml) and following the procedure as outlined in Example 35, the titled compound was isolated white solid. Yield: 48 mg, 12%; (M+H) 361.4. 
     Example 43 
     Preparation of 5-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)pyrimidin-2-amine 
     Starting from a mixture of 7-methyl-2-chloro-4-morpholin-4-yl-7H pyrrolo[2,3h]quinazoline (150 mg, 0.5 mmol), 2-aminopyrimidyl-5-boronic acid (270 mg, 1.94 mmol) Pd(PPh 3 ) 4  (50 mg) and 2M solution of Na 2 CO 3  (3 ml) and following the procedure as outlined in Example 35, the titled compound was isolated white solid. Yield: 15 mg, 9%; (M+H) 362.3. 
     Example 44 
     Preparation of N-[3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)benzyl]acetamide 
     To a stirred solution of N-[3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)benzyl amine (150 mg. 0.4 mmol) in methylene chloride, acetyl chloride (40 mg, 0.52 mmol) was added at 0° C. and slowly brought to room temperature. It was stirred for 2 h and quenched with water. Reaction mixture was washed with saturated NaHCO 3  and dried over anhydrous MgSO 4 . It was filtered and concentrated. The product was purified by silica-gel column chromatography (2:1 Hexane/ethyl acetate) to give a white solid. Yield: 30 mg, 15%; (M+H) 416.5. 
     Example 45 
     Preparation of 2-(1H-indol-4-yl)-7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazoline 
     Starting from a mixture of 7-methyl-2-chloro-4-morpholin-4-yl-7H pyrrolo[2,3h]quinazoline (150 mg, 0.5 mmol), 1H-indolyl-4-boronic acid (200 mg, 1.24 mmol) Pd(PPh 3 ) 4  (50 mg) and 2M solution of Na 2 CO 3  (3 ml) and following the procedure as outlined in Example 35, the titled compound was isolated white solid. Yield: 20 mg, 10%; (M+H) 384.3. 
     Example 46 
     Preparation of 3-(7-benzyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenol 
     Step 1: A mixture of 4-amino-1-benzylindole (4.6 g, 20 mmol) and trichloromethyl isocyanate (3.5 g, 22 mmol) was stirred in anhydrous dioxane for 48 h at room temperature. At the end, reaction mixture was concentrated and the separated sticky mass was dissolved in chloroform and triturated with diethyl ether and stirred at room temperature. The separated product, 7-benzyl-4-chloro-1,7-dihydro-2H-pyrrolo[2,3-h]quinazoline-2-one was filtered and washed with ether. Yield: 3.0 g, 49%; (M+H) 310.7. 
     Step 2: A mixture of 7-benzyl-4-chloro-1,7-dihydro-2H-pyrrolo[2,3-h]quinazoline-2-one (1.0 g, 3.23 mmol) and POCl 3  (80 ml) was heated at 80° C. for 1 h. The reaction mixture was then concentrated to dryness and quenched with ice-cold water. The product was carefully neutralized with NH 4 OH and the separated solid, 7-benzyl-2,4-dichloro-7H-pyrrolo[2,3-h]quinazoline, was filtered, dried and used for further transformation without purification. Yield: 980 mg, 92%; (M+H) 329.2. 
     Step 3: A mixture of 7-benzyl-2,4-dichloro-7H-pyrrolo[2,3-h]quinazoline (1.0 g, 3.1 mmol), morpholine (261 mg, 3.2 mmol) and triethylamine (1 ml) was stirred in chloroform solution at room temperature for 6 h. At the end, reaction mixture was quenched with water; washed well with water and dried over anhydrous MgSO 4 . It was filtered and concentrated. The crude product was purified by SiO 2  column chromatography by eluting it with 1:1 EtOAc:Hexane. Yield: 500 mg, 44%; (M+H) 379.8. 
     Step 4: Starting from a mixture of 7-benzyl-2-chloro-4-morpholin-4-yl-7H pyrrolo[2,3-h]quinazoline (100 mg, 0.26 mmol), 3-hydroxy phenylboronic acid (100 mg, excess) Pd(PPh 3 ) 4  (50 mg) and 2M solution of Na 2 CO 3  (3 ml) and following the procedure as outlined in Example 35, the titled compound was isolated white solid. Yield: 66 mg, 58%; (M+H) 437.5. 
     Example 47 
     Preparation of 2-(6-methoxypyridin-3-yl)-7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazoline 
     Starting from a mixture of 7-methyl-2-chloro-4-morpholin-4-yl-7H pyrrolo[2,3h]quinazoline (400 mg, 1.32 mmol), pyridyl-2-methoxy-5-boronic acid (400 mg, 2.9 mmol) Pd(PPh 3 ) 4  (50 mg) and 2M solution of Na 2 CO 3  (3 ml) and following the procedure as outlined in Example 35, the titled compound was isolated white solid. Yield: 180 mg, 32%; (M+H) 376.1. 
     Example 48 
     Preparation of 5-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)pyridin-2-ol 
     2-(6-methoxypyridin-3-yl)-7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazoline (100 mg. 0.26 mmol) was dissolved in conc. HCl (5 ml) and methanol (10 ml) and heated at reflux for 4 h. At the end reaction mixture was concentrated and neutralized with NH 4 OH. Separated solid was dissolved in chloroform; washed well with water; dried over anhydrous MgSO 4  and concentrated. The product was purified by SiO 2  column chromatography by eluting it with EtOAc:MeOH (95:5). Yield: 81 mg, 84%; (M+H) 362.3. 
     Example 49 
     Preparation of 2-(1H-indol-4-yl)-7-methyl-4-morpholin-5-yl-7H-pyrrolo[2,3-h]quinazoline 
     Starting from a mixture of 7-methyl-2-chloro-4-morpholin-5-yl-7H pyrrolo[2,3h]quinazoline (483 mg, 1.6 mmol), 1H-indolyl-5-boronic acid (400 mg, 2.5 mmol) Pd(PPh 3 ) 4  (50 mg) and 2M solution of Na 2 CO 3  (3 ml) and following the procedure as outlined in Example 35, the titled compound was isolated white solid. Yield: 20 mg, 10%; (M+H) 384.3. 
     Example 50 
     Preparation of 2-(2-methoxypyrimidin-5-yl)-7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazoline 
     Starting from a mixture of 7-methyl-2-chloro-4-morpholin-5-yl-7H pyrrolo[2,3h]quinazoline (500 mg, 1.7 mmol), 2-methoxypyrimidyl-5-boronic acid (560 mg, 4.1 mmol) Pd(PPh 3 ) 4  (50 mg) and 2M solution of Na 2 CO 3  (3 ml) and following the procedure as outlined in Example 35, the titled compound was isolated white solid. Yield: 250 mg, 32%; (M+H) 377.4. 
     Example 51 
     Preparation of 5-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)pyrimidin-2-ol 
     2-(2-methoxypyrimidin-5-yl)-7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazoline (100 mg. 0.26 mmol) was dissolved in conc. HCl (5 ml) and methanol (10 ml) and heated at reflux for 4 h. The reaction mixture was concentrated and neutralized with NH 4 OH. The separated solid was filtered and washed well with water. The product was dried, suspended in diethyl ether, and filtered. It was dried and found to be pure. Yield: 80 mg, 83%; (M+H) 363.3. 
     Example 52 
     Preparation of 2-(3-fluorophenyl)-7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazoline 
     Starting from a mixture of 7-methyl-2-chloro-4-morpholin-4-yl-7H pyrrolo[2,3h]quinazoline (150 mg, 0.5 mmol), 3-flourophenylboronic acid (200 mg, 1.43 mmol) Pd(PPh 3 ) 4  (50 mg) and 2M solution of Na 2 CO 3  (3 ml) and following the procedure as outlined in Example 35, the titled compound was isolated white solid. Yield: 38 mg, 21%; (M+H) 363.4. 
     Example 53 
     Preparation of 4-chloro-3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenol 
     Starting from a mixture of 7-methyl-2-chloro-4-morpholin-4-yl-7H pyrrolo[2,3h]quinazoline (150 mg, 0.5 mmol), 2-chloro-5-hydroxy-phenylboronic acid (200 mg, 1.16 mmol) Pd(PPh 3 ) 4  (50 mg) and 2M solution of Na 2 CO 3  (3 ml) and following the procedure as outlined in Example 35, the titled compound was isolated white solid. Yield: 31 mg, 16%; (M+H) 395.2. 
     Example 54 
     Preparation of 1-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]-3-propylurea 
     Starting from a mixture of 7-methyl-2-chloro-4-morpholin-4-yl-7H pyrrolo[2,3h]quinazoline (500 mg, 1.65 mmol), 4-(3-propylureido)phenylboronic acid, pinacol ester (800 mg, 2.6 mmol) Pd(PPh 3 ) 4  (50 mg) and 2M solution of Na 2 CO 3  (3 ml) and following the procedure as outlined in Example 35, the titled compound was isolated white solid. Yield: 58 mg, 8%; (M+H) 455.4. 
     Example 55 
     Preparation of N,N-dimethyl-N′-[3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]sulfamide 
     Starting from a mixture of 7-methyl-2-chloro-4-morpholin-4-yl-7H pyrrolo[2,3h]quinazoline (400 mg, 1.32 mmol), 3-(N,N-dimethylsulfamoylamino)phenylboronic acid (800 mg, 2.6 mmol) Pd(PPh 3 ) 4  (50 mg) and 2M solution of Na 2 CO 3  (3 ml) and following the procedure as outlined in Example 35, the titled compound was isolated white solid. Yield: 60 mg, 10%; (M+H) 467.3. 
     Example 56 
     Preparation of N-cyclopropyl-3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)benzenesulfonamide 
     Starting from a mixture of 7-methyl-2-chloro-4-morpholin-4-yl-7H pyrrolo[2,3h]quinazoline (530 mg, 1.75 mmol), N-cyclopropyl 3-boronobenzenesulfanamide (800 mg, 3.3 mmol) Pd(PPh 3 ) 4  (50 mg) and 2M solution of Na 2 CO 3  (3 ml) and following the procedure as outlined in Example 35, the titled compound was isolated white solid. Yield: 58 mg, 7%; (M+H) 464.2. 
     Example 57 
     Preparation of 3-(4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]methanol 
     Starting from a mixture of 2-chloro-4-morpholin-4-yl-7H pyrrolo[2,3h]quinazoline (230 mg, 0.79 mmol), 3-hydroxymethyl phenylboronic acid (300 mg, 1.98 mmol) Pd(PPh 3 ) 4  (50 mg) and 2M solution of Na 2 CO 3  (3 ml) and following the procedure as outlined in Example 35, the titled compound was isolated white solid. Yield: 45 mg, 16%; (M+H) 361.3. 
     Example 58 
     Preparation of -(4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)pyrimidin-2-amine 
     Starting from a mixture of 2-chloro-4-morpholin-4-yl-7H pyrrolo[2,3h]quinazoline (150 mg, 0.52 mmol), 2-amino-pyrimidine-5-boronic acid (180 mg, 1.3 mmol) Pd(PPh 3 ) 4  (50 mg) and 2M solution of Na 2 CO 3  (3 ml) and following the procedure as outlined in Example 35, the titled compound was isolated white solid. Yield: 70 mg, 41%; (M+H) 348.3. 
     Example 59 
     Preparation of 3-[7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenol 
     To a stirred solution of 2-chloro-4-morpholin-4-yl-7H pyrrolo[2,3h]quinazoline (1.0 g 3.5 mmol) in THF (50 ml) at −78° C., n-butyl lithium (2 ml, 1.6 M solution, 3.2 mmol) was added and kept at this temperature for 20 minutes. Then methane sulfonyl chloride (399 mg, 3.5 mmol) was added in THF solution (1 ml) and stirred at room temperature for 2 h. At the end, reaction mixture was quenched with saturated NH 4 Cl and extracted with CH 2 Cl 2 . It was washed well with water; dried over anhydrous MgSO 4 ; filtered and concentrated. The crude product obtained was taken to the next step with out purification. 
     Starting from the crude product obtained above (240 mg, 0.65 mmol), 3-hydroxy-phenyl boronic acid (136 mg, 1.0 mmol) Pd(PPh 3 ) 4  (50 mg) and 2M solution of Na 2 CO 3  (3 ml) and following the procedure as outlined in Example 35, the titled compound was isolated white solid. Yield: 56 mg, 20%; (M+H) 425.2. 
     Example 60 
     Preparation of tert-butyl [2-(6-aminopyridin-3-yl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-7-yl]acetate 
     A mixture of 2-chloro-4-morpholin-4-yl-7H pyrrolo[2,3h]quinazoline (1.0 g, 3.5 mmol), 1-bromo-tert.butyl acetate (740 mg, 3.8 mmol) and anhydrous K 2 CO 3  was heated at reflux in acetone for 16 h. At the end, reaction mixture was filtered and concentrated. The residue was extracted with chloroform, washed well with water; dried over anhydrous MgSO 4 ; filtered and concentrated. The crude product, tert-butyl (2-chloro-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-7-yl)acetate (1.15 g, 87%) was taken to next step with out purification. 
     Starting from the crude product obtained above (500 mg, 1.2 mmol), 2-amino-5-pyridylboronic acid (250 mg, 2.5 mmol) Pd(PPh 3 ) 4  (50 mg) and 2M solution of Na 2 CO 3  (3 ml) and following the procedure as outlined in Example 35, the titled compound was isolated white solid. Yield: 60 mg, 10%; (M+H) 461.4. 
     Example 61 
     benzyl 4-[(4-morpholin-4-yl-2-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-7H-pyrrolo[2,3-h]quinazolin-7-yl)sulfonyl]piperidine-1-carboxylate 
     MS (ESI) m/z 747.2; 
     MS (ESI) m/z 374.1; 
     MS (ESI) m/z 394.6; 
     HRMS: calcd for C 39 H 38 N 8 O 6 S+H + , 747.27078; found (ESI-FTMS, [M+H]1+), 747.27211. 
     Example 62 
     1-{4-[4-morpholin-4-yl-7-(piperidin-4-ylsulfonyl)-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenyl}-3-pyridin-4-ylurea 
     MS (ESI) m/z 613.4; 
     MS (ESI) m/z 327.7; 
     MS (ESI) m/z 307.2; 
     HRMS: calcd for C 31 H 32 N 8 O 4 S+H + , 613.23400; found (ESI, [M+H]+Obsd), 613.2333. 
     Example 63 
     1-(4-{7-[(1-methylpiperidin-4-yl)sulfonyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl}phenyl)-3-pyridin-4-ylurea 
     HRMS: calcd for C 32 H 34 N 8 O 4 S+H + , 627.24965; found (ESI, [M+H]+Obsd), 627.2491. 
     Example 64 
     1-(4-{7-[(1-ethylpiperidin-4-yl)sulfonyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl}phenyl)-3-pyridin-4-ylurea 
     MS (ESI) m/z 641.4; 
     MS (ESI) m/z 241.8; 
     MS (ESI) m/z 321.2; 
     HRMS: calcd for C 33 H 36 N 8 O 4 S+H + , 641.26530; found (ESI, [M+H]+Obsd), 641.2645. 
     Example 65 
     1-(4-{7-[(1-isopropylpiperidin-4-yl)sulfonyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl}phenyl)-3-pyridin-4-ylurea 
     MS (ESI) m/z 655.5; 
     MS (ESI) m/z 246.5; 
     MS (ESI) m/z 328.3; 
     HRMS: calcd for C 34 H 38 N 8 O 4 S+H + , 655.28095; found (ESI, [M+H]+Obsd), 655.2802. 
     Example 66 
     benzyl 4-{[2-(3-hydroxyphenyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-7-yl]sulfonyl}piperidine-1-carboxylate 
     MS (ESI) m/z 628.4; 
     HRMS: calcd for C 33 H 33 N 5 O 6 S+H + , 628.22243; found (ESI, [M+H]+Obsd), 628.2220. 
     Example 67 
     3-[4-morpholin-4-yl-7-(piperidin-4-ylsulfonyl)-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenol 
     MS (ESI) m/z 494.3; 
     MS (ESI) m/z 268.2; 
     MS (ESI) m/z 288.7; 
     HRMS: calcd for C 25 H 27 N 5 O 4 S+H + , 494.18565; found (ESI-FTMS, [M+H]1+), 494.18682. 
     Example 68 
     2-[3-(benzyloxy)phenyl]-4-morpholin-4-yl-7-(phenylsulfonyl)-7H-pyrrolo[2,3-h]quinazoline 
     MS (ESI) m/z 577.3. 
     Example 69 
     3-[4-morpholin-4-yl-7-(phenylsulfonyl)-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenol 
     MS (ESI) m/z 487.5 
     HRMS: calcd for C 26 H 22 N 4 O 4 S+H + , 487.14345; found (ESI-FTMS, [M+H]1+), 487.14379. 
     Example 70 
     {3-[4-morpholin-4-yl-7-(phenylsulfonyl)-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenyl}methanol 
     MS (ESI) m/z 501.5 
     HRMS: calcd for C 27 H 24 N 4 O 4 S+H + , 501.15910; found (ESI-FTMS, [M+H]1+), 501.16003. 
     Example 71 
     5-[4-morpholin-4-yl-7-(phenylsulfonyl)-7H-pyrrolo[2,3-h]quinazolin-2-yl]pyrimidin-2-amine 
     MS (ESI) m/z 488.4 
     HRMS: calcd for C 24 H 21 N 7 O 3 S+H + , 488.14993; found (ESI-FTMS, [M+H]1+), 488.151. 
     Example 72 
     2-(1H-indazol-4-yl)-4-morpholin-4-yl-7-(phenylsulfonyl)-7H-pyrrolo[2,3-h]quinazoline 
     MS (ESI) m/z 511.3. 
     Example 73 
     5-[7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl]pyrimidin-2-amine 
     MS (ESI) m/z 426.2 
     HRMS: calcd for C 19 H 19 N 7 O 3 S+H + , 426.13428; found (ESI-FTMS, [M+H]1+), 426.13519. 
     Example 74 
     {3-[7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenyl}methanol 
     MS (ESI) m/z 439.3 
     HRMS: calcd for C 22 H 22 N 4 O 4 S+H + , 439.14345; found (ESI, [M+H]+Obsd), 439.1434. 
     Example 75 
     2-[5-(methoxymethoxy)pyridin-3-yl]-7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazoline 
     MS (ESI) m/z 470.3 
     HRMS: calcd for C 22 H 23 N 5 O 5 S+H + , 470.14927; found (ESI, [M+H]+Obsd), 470.1499. 
     Example 76 
     5-[7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl]pyridin-3-ol 
     MS (ESI) m/z 426.3 
     HRMS: calcd for C 20 H 19 N 5 O 4 S+H + , 426.12305; found (ESI, [M+H]+Obsd), 426.1229. 
     Example 77 
     2-[5-(methoxymethoxy)pyridin-3-yl]-7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazoline 
     MS (ESI) m/z 406.2; 
     HRMS: calcd for C 22 H 23 N 5 O 3 +H + , 406.18737; found (ESI-FTMS, [M+H]1+), 406.18738. 
     Example 78 
     5-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)pyridin-3-ol 
     MS (ESI) m/z 362.2; 
     HRMS: calcd for C 20 H 19 N 5 O 2 +H + , 362.16115; found (ESI-FTMS, [M+H]1+), 362.16209. 
     Example 79 
     2-(1H-indazol-4-yl)-7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazoline 
     MS (ESI) m/z 385.3. 
     Example 80 
     2-(1H-indazol-4-yl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazoline 
     MS (ESI) m/z 371.3. 
     Example 81 
     2-[3-(benzyloxy)phenyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazoline 
     MS (ESI) m/z 437.6. 
     Example 82 
     2-(3-hydroxyphenyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazoline-9-carbaldehyde 
     MS (ESI) m/z 375.3; 
     HRMS: calcd for C 21 H 18 N 4 O 3 +H + , 375.14517; found (ESI, [M+H]+Obsd), 375.1455. 
     Example 83 
     Preparation of [3-(7-benzyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]methanol 
     Starting from a mixture of 7-benzyl-2-chloro-4-morpholin-4-yl-7H pyrrolo[2,3h]quinazoline (70 mg, 0.185 mmol), 3-hydroxymethyl phenylboronic acid (100 mg, excess) Pd(PPh 3 ) 4  (50 mg) and 2M solution of Na 2 CO 3  (3 ml) and following the procedure as outlined in Example 35, the titled compound was isolated white solid. Yield: 50 mg, 60%; (M+H) 451.5. 
     Example 84  
     1-{4-[7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenyl}-3-phenylurea 
     4-(2-Chloro-7-(methylsulfonyl)-7H-pyrrolo[2,3-h]quinazolin-4-yl)morpholine was prepared by following the procedure described for example 59. 
     4-(7-(methylsulfonyl)-4-morpholino-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline was prepared by following the procedure described for example 30. A mixture of 4-(2-chloro-7-(methylsulfonyl)-7H-pyrrolo[2,3-h]quinazolin-4-yl)morpholine (0.17 mmol), 4-aminophenylboronic acid, pinacol ester (0.26 mmol), Pd(PPh 3 ) 4  (10 mg, 5 mol %), dimethoxyethane (DME, 3 mL) and 2M Na 2 CO 3  (0.5 mL) was heated at 130° C. for 0.5 hours in microwave oven. The reaction mixture was cooled to room temperature, and filtered through a pad of Celite™, washed with THF. The filtrate was concentrated under reduced pressure, and the residue was subjected to HPLC separation. 
     To a solution of 4-(7-(methylsulfonyl)-4-morpholino-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline (0.06 mmol) in CH 2 Cl 2  (1 mL) were added Et 3 N (25 μL, 0.18 mmol) and phenylisocyanate (0.1 mmol), and the resulting mixture was stirred at room temperature for 6 hours. The solvent was removed under reduced pressure, and the residue was subjected to HPLC separation to give the title compound. MS (ESI) m/z 
     Example 85  
     1-{4-[7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenyl}-3-pyridin-3-ylurea 
     The title compound was prepared by following the procedure as outlined in Example 2 using 4-(7-(methylsulfonyl)-4-morpholino-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline, triphosgene and 3-aminopyridine. MS (ESI) m/z 
     Example 86  
     ethyl {4-[7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenyl}carbamate 
     The title compound was prepared by following the procedure as outlined in Example 16 using 4-(7-(methylsulfonyl)-4-morpholino-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline and ethyl chloroformate. MS (ESI) m/z 
     Example 87  
     N-{4-[7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenyl}cyclopropanecarboxamide 
     The title compound was prepared by following the procedure as outlined in Example 16 using 4-(7-(methylsulfonyl)-4-morpholino-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline and cyclopropane carbonyl chloride. MS (ESI) m/z 
     Example 88  
     N-{4-[7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenyl}butanamide 
     The title compound was prepared by following the procedure as outlined in Example 16 using 4-(7-(methylsulfonyl)-4-morpholino-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline and butyryl chloride. MS (ESI) m/z 
     Example 89  
     1-ethyl-3-{4-[7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenyl}urea 
     The title compound was prepared by following the procedure as outlined in Example 2 using 4-(7-(methylsulfonyl)-4-morpholino-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline, triphosgene and ethylamine. MS (ESI) m/z 
     Example 90  
     methyl {4-[7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenyl}carbamate 
     The title compound was prepared by following the procedure as outlined in Example 16 using 4-(7-(methylsulfonyl)-4-morpholino-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline and methyl chloroformate. MS (ESI) m/z 
     Example 91  
     N-{4-[7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenyl}propanamide 
     The title compound was prepared by following the procedure as outlined in Example 16 using 4-(7-(methylsulfonyl)-4-morpholino-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline and propionyl chloride. MS (ESI) m/z 
     Example 92  
     N-{4-[7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenyl}acetamide 
     The title compound was prepared by following the procedure as outlined in Example 16 using 4-(7-(methylsulfonyl)-4-morpholino-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline and acetyl chloride. MS (ESI) m/z 
     Example 93  
     ethyl (4-{7-[2-(dimethylamino)ethyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl}phenyl)carbamate 
     4-(7-(2-(dimethylamino)ethyl)-4-morpholino-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline was prepared by following the procedure described for example 30. A mixture of 2-chloro-7-(2-(dimethylamino)ethyl)-4-morpholin-4-yl-7H-pyrrolo[2,3h]quinazoline (62 mg, 0.17 mmol), 4-aminophenylboronic acid, pinacol ester (0.26 mmol), Pd(PPh 3 ) 4  (10 mg, 5 mol %), dimethoxyethane (DME, 3 mL) and 2M Na 2 CO 3  (0.5 mL) was heated at 130° C. for 0.5 hours in microwave oven. The reaction mixture was cooled to room temperature, and filtered through a pad of Celite™, washed with THF. The filtrate was concentrated under reduced pressure, and the residue was subjected to HPLC separation. 
     To a solution of 4-(7-(2-(dimethylamino)ethyl)-4-morpholino-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline (0.06 mmol) in CH 2 Cl 2  (1 mL) were added Et 3 N (25 μL, 0.18 mmol) and ethyl chloroformate (0.1 mmol), and the resulting mixture was stirred at room temperature for 6 hours. The solvent was removed under reduced pressure, and the residue was subjected to HPLC separation to give the title compound. MS (ESI) m/z 
     Example 94  
     1-(4-{7-[2-(dimethylamino)ethyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl}phenyl)-3-ethylurea 
     The title compound was prepared by following the procedure described above for example 84, using 4-(7-(2-(dimethylamino)ethyl)-4-morpholino-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline and ethyl isocyanate. MS (ESI) m/z 
     Example 95  
     1-(4-{7-[2-(dimethylamino)ethyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl}phenyl)-3-phenylurea 
     The title compound was prepared by following the procedure described above for example 84, using 4-(7-(2-(dimethylamino)ethyl)-4-morpholino-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline and phenyl isocyanate. MS (ESI) m/z 
     Example 96  
     N-(4-{7-[2-(dimethylamino)ethyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl}phenyl)cyclopropanecarboxamide 
     The title compound was prepared by following the procedure described above for example 16, using 4-(7-(2-(dimethylamino)ethyl)-4-morpholino-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline and cyclopropane carbonyl chloride. MS (ESI) m/z 
     Example 97  
     N-(4-{7-[2-(dimethylamino)ethyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl}phenyl)butanamide 
     The title compound was prepared by following the procedure described above for example 16, using 4-(7-(2-(dimethylamino)ethyl)-4-morpholino-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline and butyryl chloride. MS (ESI) m/z 
     Example 98  
     methyl (4-{7-[2-(dimethylamino)ethyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl}phenyl)carbamate 
     The title compound was prepared by following the procedure described above for example 2, using 4-(7-(2-(dimethylamino)ethyl)-4-morpholino-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline, triphosgene and methanol. MS (ESI) m/z 
     Example 99  
     1-(1-methylethyl)-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea 
     The title compound was prepared by following the procedure as outlined in Example 2 using 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline, triphosgene and isopropyl amine. MS (ESI) m/z 
     Example 100  
     1-(cyclopropylmethyl)-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea 
     The title compound was prepared by following the procedure as outlined in Example 2 using 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline, triphosgene and (aminomethyl)cyclopropane. MS (ESI) m/z 
     Example 101  
     1-(2-methoxyethyl)-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea 
     The title compound was prepared by following the procedure as outlined in Example 2 using 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline, triphosgene and methoxyethylamine. MS (ESI) m/z 
     Example 102  
     1-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]-3-(tetrahydrofuran-2-ylmethyl)urea 
     The title compound was prepared by following the procedure as outlined in Example 2 using 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline, triphosgene and tetrahydrofurfurylamine. MS (ESI) m/z 
     Example 103  
     1-(2-cyclohex-1-en-1-ylethyl)-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea 
     The title compound was prepared by following the procedure as outlined in Example 2 using 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline, triphosgene and 2-(1-cyclohexenyl)ethylamine. MS (ESI) m/z 
     Example 104  
     1-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]-3-(3-pyrrolidin-1-yl]propyl)urea 
     The title compound was prepared by following the procedure as outlined in Example 2 using 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline, triphosgene and 1-(3-aminopropyl)pyrrolidine. MS (ESI) m/z 
     Example 105  
     1-cyclopentyl-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea 
     The title compound was prepared by following the procedure as outlined in Example 2 using 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline, triphosgene and cyclopentylamine. MS (ESI) m/z 
     Example 106  
     1-cyclobutyl-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea 
     The title compound was prepared by following the procedure as outlined in Example 2 using 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline, triphosgene and cyclobutylamine. MS (ESI) m/z 
     Example 107  
     1-cyclopropyl-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea 
     The title compound was prepared by following the procedure as outlined in Example 2 using 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline, triphosgene and cyclobutylamine. MS (ESI) m/z 
     Example 108  
     1-cyclohexyl-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea 
     The title compound was prepared by following the procedure as outlined in Example 2 using 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline, triphosgene and cyclohexylamine. MS (ESI) m/z 
     Example 109  
     propyl {4-[7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenyl}carbamate 
     The title compound was prepared by following the procedure as outlined in Example 2 using 4-(7-(methylsulfonyl)-4-morpholino-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline, triphosgene and propyl chloroformate. MS (ESI) m/z 
     Example 110  
     1-methyl-3-{4-[7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenyl}urea 
     The title compound was prepared by following the procedure as outlined in Example 2 using 4-(7-(methylsulfonyl)-4-morpholino-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline and triphosgene and methylamine. MS (ESI) m/z 
     Example 111  
     1-(4-{7-[2-(dimethylamino)ethyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl}phenyl)-3-pyridin-3-ylurea 
     The title compound was prepared by following the procedure described above for example 2, using 4-(7-(2-(dimethylamino)ethyl)-4-morpholino-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline, triphosgene and 3-aminopyridine. MS (ESI) m/z 
     Example 112  
     N-(4-{7-[2-(dimethylamino)ethyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl}phenyl)acetamide 
     The title compound was prepared by following the procedure described above for example 16, using 4-(7-(2-(dimethylamino)ethyl)-4-morpholino-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline and acetyl chloride. MS (ESI) m/z 
     Example 113  
     1-(4-{7-[2-(dimethylamino)ethyl]-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl}phenyl)-3-methylurea 
     The title compound was prepared by following the procedure described above for example 2, using 4-(7-(2-(dimethylamino)ethyl)-4-morpholino-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline, triphosgene and methylamine. MS (ESI) m/z 
     Example 114  
     1-(3-acetylphenyl)-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea 
     The title compound was prepared by following the procedure as outlined in Example 2 using 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline, triphosgene and 3′-aminoacetophenone. MS (ESI) m/z 
     Example 115  
     1-(4-acetylphenyl)-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea 
     The title compound was prepared by following the procedure as outlined in Example 2 using 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline, triphosgene and 4′-aminoacetophenone. MS (ESI) m/z 
     Example 116  
     1-(3,5-dimethylisoxazol-4-yl)-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea 
     The title compound was prepared by following the procedure as outlined in Example 2 using 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline, triphosgene and 3,5-dimethylisoxazol-4-ylamine. MS (ESI) m/z 
     Example 117  
     1-(1,1-dioxidotetrahydrothiophen-3-yl)-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea 
     The title compound was prepared by following the procedure as outlined in Example 2 using 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline, triphosgene and 1,1-dioxidotetrahydrothiophen-3-ylamine. MS (ESI) m/z 
     Example 118  
     1-(2-fluoroethyl)-3-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea 
     The title compound was prepared by following the procedure as outlined in Example 2 using 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline, triphosgene and 2-fluoroethylamine. MS (ESI) m/z 
     Example 119  
     1-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)urea 
     The title compound was prepared by following the procedure as outlined in Example 2 using 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline, triphosgene and 2,2,2-trifluoroethylamine. MS (ESI) m/z 
     Example 120  
     1-[4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]-3-(2-pyridin-4-ylethyl)urea 
     The title compound was prepared by following the procedure as outlined in Example 2 using 4-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline, triphosgene and 4-(2-aminoethyl)pyridine. MS (ESI) m/z 
     Example 121  
     1-{4-[7-(methylsulfonyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl]phenyl}-3-propylurea 
     The title compound was prepared by following the procedure as outlined in Example 2 using 4-(7-(methylsulfonyl)-4-morpholino-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline, triphosgene and aminopropane. MS (ESI) m/z 
     Example 122  
     1-[3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]-3-pyridin-4-ylurea 
     3-(7-methyl-4-morpholino-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline was prepared as described in example 1 using 2-chloro-7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazoline and 3-aminophenylboronic acid, pinacol ester. 
     The title compound was prepared by following the procedure as outlined in Example 2 using 3-(7-methyl-4-morpholino-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline, triphosgene and 4-aminopyridine. MS (ESI) m/z 
     Example 123  
     1-[3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]-3-pyridin-3-ylurea 
     The title compound was prepared by following the procedure as outlined in Example 2 using 3-(7-methyl-4-morpholino-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline, triphosgene and 3-aminopyridine. MS (ESI) m/z 
     Example 124  
     ethyl [3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]carbamate 
     The title compound was prepared by following the procedure as outlined in Example 16 using 3-(7-methyl-4-morpholino-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline and ethyl chloroformate. MS (ESI) m/z 
     Example 125  
     N-[3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]cyclopropanecarboxamide 
     The title compound was prepared by following the procedure as outlined in Example 216 using 3-(7-methyl-4-morpholino-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline and cyclopropanecarbonyl chloride. MS (ESI) m/z 
     Example 126  
     N-[3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]butanamide 
     The title compound was prepared by following the procedure as outlined in Example 16 using 3-(7-methyl-4-morpholino-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline and butyryl chloride. MS (ESI) m/z 
     Example 127  
     1-[3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]-3-propylurea 
     The title compound was prepared by following the procedure as outlined in Example 2 using 3-(7-methyl-4-morpholino-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline, triphosgene and aminopropane. MS (ESI) m/z 
     Example 128  
     1-ethyl-3-[3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]urea 
     The title compound was prepared by following the procedure as outlined in Example 2 using 3-(7-methyl-4-morpholino-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline, triphosgene and ethylamine. MS (ESI) m/z 
     Example 129  
     N-[3-(7-methyl-4-morpholin-4-yl-7H-pyrrolo[2,3-h]quinazolin-2-yl)phenyl]propanamide 
     The title compound was prepared by following the procedure as outlined in Example 16 using 3-(7-methyl-4-morpholino-7H-pyrrolo[2,3-h]quinazolin-2-yl)aniline and propyl chloride. MS (ESI) m/z 
     Example 130  
     METHYL 4-({[4-(7-ETHYL-4-MORPHOLIN-4-YL-7H-PYRROLO[2,3-H]QUINAZOLIN-2-YL)PHENYL]CARBAMOYL}AMINO)BENZOATE MS (ESI) m/z 551.2. 
     Example 131  
     1-[4-(7-ETHYL-4-MORPHOLIN-4-YL-7H-PYRROLO[2,3-H]QUINAZOLIN-2-YL)PHENYL]-3-{4-[(4-METHYLPIPERAZIN-1-YL)CARBONYL]PHENYL}UREA MS (ESI) m/z 618.7. 
     Example 132  
     4-({[4-(7-ETHYL-4-MORPHOLIN-4-YL-7H-PYRROLO[2,3-H]QUINAZOLIN-2-YL)PHENYL]CARBAMOYL}AMINO)-N-[2-(METHYLAMINO)ETHYL]BENZAMIDE MS (ESI) m/z 592.7. 
     Example 133  
     N-[2-(DIMETHYLAMINO)ETHYL]-4-({[4-(7-ETHYL-4-MORPHOLIN-4-YL-7H-PYRROLO[2,3-H]QUINAZOLIN-2-YL)PHENYL]CARBAMOYL}AMINO)-N-METHYLBENZAMIDE MS (ESI) m/z 620.7 
     Example 134  
     1-(4-{[4-(DIMETHYLAMINO)PIPERIDIN-1-YL]CARBONYL}PHENYL)-3-[4-(7-ETHYL-4-MORPHOLIN-4-YL-7H-PYRROLO[2,3-H]QUINAZOLIN-2-YL)PHENYL]UREA MS (ESI) m/z 646.7. 
     Biological Evaluation 
     mTOR Kinase Assay Methods 
     Human mTOR assays (See Toral-Barza, et al.  Biochem Biophys. Res. Commun.  Jun. 24, 2005;332(1):304-10) with purified enzyme are performed in 96-well plates by DELFIA format as follows. Enzymes are first diluted in kinase assay buffer (10 mM HEPES (pH 7.4), 50 mM NaCl, 50 mM β-glycerophosphate, 10 mM MnCl 2 , 0.5 mM DTT, 0.25 mM microcystin LR, and 100 mg/mL BSA). To each well, 12 μL of the diluted enzyme is mixed briefly with 0.5 μL test inhibitor or control vehicle dimethylsulfoxide (DMSO). The kinase reaction is initiated by adding 12.5 μL kinase assay buffer containing ATP and His6-S6K to give a final reaction volume of 25 μL containing 800 ng/mL FLAG-TOR, 100 mM ATP and 1.25 mM His6-S6K. The reaction plate is incubated for 2 hours (linear at 1-6 hours) at room temperature with gentle shaking and then terminated by adding 25 μL Stop buffer (20 mM HEPES (pH 7.4), 20 mM EDTA, 20 mM EGTA). The DELFIA detection of the phosphorylated (Thr-389) His6-S6K is performed at room temperature using a monoclonal anti-P(T389)-p70S6K antibody (1A5, Cell Signaling) labeled with Europium-N1-ITC (Eu) (10.4 Eu per antibody, PerkinElmer). The DELFIA Assay buffer and Enhancement solution can be purchased from PerkinElmer. 45 μL of the terminated kinase reaction mixture is transferred to a MaxiSorp plate (Nunc) containing 55 μL PBS. The His6-S6K is allowed to attach for 2 hours after which the wells are aspirated and washed once with PBS. 100 μL of DELFIA Assay buffer with 40 ng/mL Eu-P(T389)-S6K antibody is added. The antibody binding is continued for 1 hour with gentle agitation. The wells are then aspirated and washed 4 times with PBS containing 0.05% Tween-20 (PBST). 100 μL of DELFIA Enhancement solution is added to each well and the plates are read in a PerkinElmer Victor model plate reader. Data obtained is used to calculate enzymatic activity and enzyme inhibition by potential inhibitors. 
     PI3K-Alpha and PI3K-Gamma Fluorescence Polarization Assay Protocols 
     The reaction buffer was 20 mM HEPES, pH 7.5, 2 mM MgCl 2 , 0.05% CHAPS; and 0.01% βME (added fresh). The Stop/Detection Buffer was 100 mM HEPES, pH 7.5, 4 mM EDTA, 0.05% CHAPS; ATP 20 mM in water; PIP2 (diC8, Echelon, Salt Lake City Utah cat #P-4508) 1 mM in water (MW=856.5). The GST-GRP was 1.75 mg/mL or 1.4 mg/mL in 10% glycerol. The Red detector (TAMRA) was 2.5 μM. Nunc 384-well black polypropylene fluorescent plates were used for PI3K assays. 
     The assay is run by placing 5 μL of diluted enzyme per well, then 5 μL of diluted compound (or 9.5 μL enzyme then 0.5 μL compound in DMSO) is added and mixed. Then, 10 μL substrate is added to start the reaction. The samples are incubated 30-60 minutes, then the reaction is stopped by adding 20 μL stop/detector mix. PI3K is diluted with reaction buffer (e.g., 5 μL or 7.5 μL PI3K into 620 μL reaction buffer), and 5 μL of diluted enzyme is used per well. A 5 μL portion of reaction buffer or of drug diluted in buffer (e.g., 4 μL/100 so final DMSO is 1% in reaction) is added to each. Pipetting up and down mixes the samples. Alternatively, the enzyme can be diluted to 1215 μL. In this case 9.8 μL is added per well and 0.2 μL compound is added in DMSO. 
     To prepare 1 mL of substrate solution, 955 μL reaction buffer, 40 μL PIP2, and 2.5 μL ATP are mixed. 10 μL of substrate is added to each well to start the reaction. This results in 20 μM PIP2, and 25 μM ATP per reaction. The stop/detector mix is prepared by mixing 4 μL Red detector and 1.6 μL or 2.0 μL GST-GRP with 1 mL stop buffer, which results in 10 nM probe and 70 nM GST-GRP. 20 μL of the stop/detector mix is added to each well to stop the reaction. The plates are read after 30-90 minutes keeping the red probe solutions dark. For the zero time point, stop/detector mix is added to the enzyme just before adding substrate. For an extra control, stop/detector mix is added to buffer (no enzyme) and substrate or to just buffer (no substrate). Pooled PI3K preparations had a protein concentration of 0.25 mg/mL. The recommended reaction has 0.06 μL per 20 μL (0.015 μg/20 μL) or 0.01125 μg/15 μL or 0.75 μg/mL. 
     Plates are read on machines with filters for TAMRA. The units are mP with no enzyme controls reading app 190-220 mP units. Fully active enzyme reduces fluorescence polarization down to 70-100 mP after 30 minutes. An active compound raises the mP values halfway to control or to 120-150 mP units. Compounds of the invention had IC 50 s against PI3K-alpha ranging from 22 nM to 12,000 nM. 
     In Vitro Cell Culture Growth Assay Methods 
     Cell Lines used are human prostate LNCap and human breast MDA468 tumor cell lines. Cells are plated in 96-well culture plates at approximately 3000 cells per well. One day following plating, various concentrations of PI3K inhibitors in DMSO are added to cells (final DMSO concentration in cell assays is 0.25%). Three days after drug treatment, viable cell densities are determined by cell mediated metabolic conversion of the dye MTS, a well-established indicator of cell proliferation in vitro. Cell growth assays are performed using kits purchased from Promega Corporation (Madison, Wis.), following the protocol provided by the vendor. Measuring absorbance at 490 nm generates MTS assay results. Compound effect on cell proliferation is assessed relative to untreated control cell growth. The drug concentration that conferred 50% inhibition of growth is determined as IC 50  (μM). 
     Several compounds were tested in the above mentioned cell based assay and they found to have IC 50  values in the range of 0.048 μM to 30 μM. 
     hSMG-1 Kinase Assay 
     The human SMG-1 (hSMG-1) kinase assay employs the recombinant hSMG-1 protein prepared from transiently transfected HEK293 cells and a GST-p53 (aa 1-70) fusion substrate protein derived from cellular tumor suppressor gene p53. The routine assay is performed in a 96-well plate format as follows. Enzymes were first diluted in kinase assay buffer (10 mM HEPES, pH 7.4, 50 mM NaCl, 0.2 mM DTT, 50 mM β-glycerophosphate, 0.5 μM microcystin LR, 10 mM MnCl 2 ). To each well, 12 μL of the diluted enzyme were mixed briefly with 0.5 μL test inhibitor or control vehicle dimethylsulfoxide (DMSO). The kinase reaction was initiated by adding 12.5 μL kinase assay buffer containing ATP and GST-p53 to give a final reaction volume of 25 μL containing 400-800 ng/mL FLAG-hSMG-1, 0.5 μg GST-p53, 10 μM ATP. The reaction was carried out at room temperature for 1.0 hour before terminated by addition of 25 μl stop solution. The assay mixture was then transferred to FluoroNunc Plates with MaxiSorp Surface (Nunc #439454). The plates were incubated at room temperature for 2 hr (4° C. for overnight) to achieve efficient binding of substrate protein to the plate. The plates were aspirated, washed with PBS. Phospho-substrate proteins were detected by incubating for 1 hour with 125 ng of europium-labeled anti-mouse secondary antibody (PerkinElmer AD2027) and the primary phospho(S15)-p53 monoclonal antibody (Cell Signal #9286) in 100 μL DELFIA assay buffer (PerkinElmer #1244-111). Plates were then washed and incubated for 0.5 hour with 100 μl of DELFIA enhancement solution (PerkinElmer #1244-105). DELFIA assay results are recorded in a Victor Plate Reader (PerkinElmer). Data obtained were used to calculate enzymatic activity and enzyme inhibition by potential inhibitors. 
     Table 1 shows the results of the described biological assays. 
     
       
         
           
               
               
               
               
               
               
               
             
               
                 TABLE 1 
               
               
                   
               
               
                   
                 TOR 
                 PI3 
                 PI3 
                   
                   
                   
               
               
                   
                 Kinase 
                 Kinase α 
                 Kinase γ 
                 LNCap 
                 MDA468 
                 hSMG1 
               
               
                 Example 
                 IC 50  (μM) 
                 IC 50  (nM) 
                 IC 50  (nM) 
                 IC 50  (μM) 
                 IC 50  (μM) 
                 IC 50  (μM) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 1 
                 0.805 
                 6482 
                 10000 
                   
                   
                   
               
               
                 2 
                 0.066 
                 428 
                 5389 
               
               
                 3 
                 0.035 
                 2109 
                 4038 
               
               
                 4 
                 2.05 
                 728 
                 2835 
               
               
                 5 
                 2.05 
                 2700 
                 10000 
               
               
                 6 
                 2.55 
                 7627 
                 10000 
               
               
                 7 
                 0.56 
                 1690 
                 3502 
               
               
                 8 
                 0.19 
                 431 
                 3035 
               
               
                 9 
                 0.075 
                 2700 
                 5129 
               
               
                 10 
                 0.021 
                 71 
                 247 
               
               
                 11 
                 0.0037 
                 101 
                 437 
               
               
                 12 
                 0.355 
                 2000 
                 1328 
               
               
                 13 
                 0.26 
                 62 
                 234 
               
               
                 14 
                 0.125 
                 239 
                 634 
               
               
                 15 
                 2.15 
                 2523 
                 3312 
               
               
                 16 
                 0.37 
                 3082 
                 &gt;10,000 
               
               
                 17 
                 1.4 
                 &gt;10,000 
                 9853 
               
               
                 18 
                 1.45 
                 4460 
                 5620 
               
               
                 19 
                 1.25 
                 12000 
                 6166 
               
               
                 20 
                 0.39 
                 3314 
                 2094 
               
               
                 21 
                 1.2 
                 7830 
                 &gt;10,000 
               
               
                 22 
                 5.3 
                 8396 
                 6159 
               
               
                 23 
                 0.32 
                 5326 
                 9500 
               
               
                 24 
                 1.65 
                 2347 
                 &gt;10,000 
               
               
                 25 
                 3.05 
                 7550 
                 &gt;10,000 
               
               
                 26 
                 2.1 
                 5422 
                 &gt;10,000 
               
               
                 27 
                 2.8 
                 6586 
                 6656 
               
               
                 28 
                 2.7 
                 2506 
                 4524 
               
               
                 29 
                 3.8 
                 2969 
                 4074 
               
               
                 30 
                 9.15 
                 455 
                 4951 
               
               
                 31 
                 &gt;20 
                 4033 
                 2484 
               
               
                 32 
                 4.55 
                 322 
                 3622 
               
               
                 33 
                 0.015 
                 222 
                 862 
               
               
                 34 
                 1.3 
                 201 
                 3191 
               
               
                 35 
                 0.41 
                 174 
                 2232 
               
               
                 36 
                 1.6 
                 1759 
                 4000 
               
               
                 37 
                 1.2 
                 251 
                 3197 
               
               
                 38 
                 4 
                 12000 
                 9838 
               
               
                 39 
                 1.72 
                 2564 
                 7415 
               
               
                 40 
                 2.3 
                 4278 
                 2766 
               
               
                 41 
                 1.45 
                 &gt;10,000 
                 &gt;10,000 
               
               
                 42 
                 0.63 
                 616 
                 3586 
               
               
                 43 
                 0.247 
                 48 
                 426 
               
               
                 44 
                 4 
                 9364 
                 9500 
               
               
                 45 
                 1.13 
                 2464 
                 2829 
               
               
                 46 
                 0.42 
                 216 
                 209 
               
               
                 47 
                 2.05 
                 &gt;10,000 
                 &gt;10,000 
               
               
                 48 
                 7.55 
                 &gt;10,000 
                 &gt;10,000 
               
               
                 49 
                 0.34 
                 6306 
                 4662 
               
               
                 50 
                 2.35 
                 668 
                 &gt;10,000 
               
               
                 51 
                 &gt;20,000 
                 &gt;10,000 
                 &gt;10,000 
               
               
                 52 
                 1.2 
                 8885 
                 3665 
               
               
                 53 
                 0.91 
                 214 
                 1007 
               
               
                 54 
                 0.021 
                 5659 
                 8400 
               
               
                 55 
                 0.525 
                 4341 
                 6163 
               
               
                 56 
                 0.05 
                 6970 
                 6698 
               
               
                 57 
                 0.235 
                 514 
                 3584 
               
               
                 58 
                 0.155 
                 102 
                 471 
               
               
                 59 
                 2.6 
                 63 
                 560 
               
               
                 60 
                 1.35 
                 775 
                 4894 
               
               
                 61 
                 0.13 
                 384 
                 3491 
               
               
                 62 
                 0.028 
                 114 
                 519 
               
               
                 63 
                 0.067 
                 119 
                 491 
               
               
                 64 
                 0.044 
                 74 
                 313 
               
               
                 65 
                 0.073 
                 48 
                 300 
               
               
                 66 
                 2.25 
                 245 
                 5752 
               
               
                 67 
                 0.67 
                 231 
                 1578 
               
               
                 68 
                 NA 
                 NA 
                 NA 
               
               
                 69 
                 1.11 
                 274 
                 1130 
               
               
                 70 
                 5.8 
                 168 
                 2067 
               
               
                 71 
                 0.545 
                 52 
                 114 
               
               
                 72 
                 3.25 
                 4007 
                 5162 
               
               
                 73 
                 0.063 
                 62 
                 198 
               
               
                 74 
                 0.545 
                 212 
                 1187 
               
               
                 75 
                 16.5 
                 &gt;10,000 
                 &gt;10,000 
               
               
                 76 
                 0.13 
                 65 
                 82 
               
               
                 77 
                 0.525 
                 451 
                 933 
               
               
                 78 
                 0.305 
                 73 
                 390 
               
               
                 79 
                 0.435 
                 1083 
                 6086 
               
               
                 80 
                 2.075 
                 10314 
                 &gt;10,000 
               
               
                 81 
                 NA 
                 NA 
                 NA 
               
               
                 82 
                 0.016 
                 111 
                 147 
               
               
                 83 
                 1.7 
                 123 
                 320 
               
               
                 84 
                   
                   
                   
                   
                   
                 0.475 
               
               
                 85 
                   
                 22 
                 142 
                 0.048 
                 0.070 
                 0.160 
               
               
                 86 
                   
                   
                   
                   
                   
                 15.500 
               
               
                 87 
                   
                   
                   
                   
                   
                 5.600 
               
               
                 88 
                   
                   
                   
                   
                   
                 &gt;20.000 
               
               
                 89 
                   
                   
                   
                 0.690 
                 1.900 
                 0.200 
               
               
                 90 
                   
                   
                   
                   
                   
                 5.600 
               
               
                 91 
                   
                   
                   
                   
                   
                 6.100 
               
               
                 92 
                   
                   
                   
                   
                   
                 5.250 
               
               
                 93 
                   
                   
                   
                   
                   
                 &gt;20.000 
               
               
                 94 
                   
                   
                   
                   
                   
                 2.000 
               
               
                 95 
                 0.050 
                   
                   
                   
                   
                 1.800 
               
               
                 96 
                 5.250 
                   
                   
                   
                   
                 &gt;20.000 
               
               
                 97 
                 6.200 
                   
                   
                   
                   
                 &gt;20.000 
               
               
                 98 
                 2.000 
                   
                   
                   
                   
                 &gt;20.000 
               
               
                 99 
                 0.215 
                   
                   
                   
                   
                 14.500 
               
               
                 100 
                 0.500 
                   
                   
                   
                   
                 16.000 
               
               
                 101 
                 1.800 
                   
                   
                   
                   
                 &gt;20.000 
               
               
                 102 
                 1.500 
                   
                   
                   
                   
                 &gt;17.000 
               
               
                 103 
                 13.750 
                   
                   
                   
                   
                 &gt;20.000 
               
               
                 104 
                 2.400 
                   
                   
                   
                   
                 &gt;20.000 
               
               
                 105 
                 2.050 
                   
                   
                   
                   
                 &gt;20.000 
               
               
                 106 
                 1.500 
                   
                   
                   
                   
                 16.500 
               
               
                 107 
                 0.545 
                   
                   
                   
                   
                 &gt;14.000 
               
               
                 108 
                 7.250 
                   
                   
                   
                   
                 &gt;20.000 
               
               
                 109 
                 2.050 
                   
                   
                   
                   
                 &gt;20.000 
               
               
                 110 
                 0.002 
                 95 
                 1910 
                 0.880 
                 1.700 
                 0.043 
               
               
                 111 
                 0.015 
                 118 
                 860 
                   
                   
                 0.290 
               
               
                 112 
                 2.800 
                   
                   
                   
                   
                 &gt;20.000 
               
               
                 113 
                 0.067 
                 427 
                 3090 
                   
                   
                 0.490 
               
               
                 114 
                 5.550 
                   
                   
                   
                   
                 10.500 
               
               
                 115 
                 0.470 
                   
                   
                   
                   
                 4.250 
               
               
                 116 
                 1.275 
                   
                   
                   
                   
                 &gt;20.000 
               
               
                 117 
                 0.600 
                   
                   
                   
                   
                 &gt;20.000 
               
               
                 118 
                 0.625 
                   
                   
                   
                   
                 15.000 
               
               
                 119 
                 1.260 
                   
                   
                   
                   
                 6.500 
               
               
                 120 
                 0.625 
                   
                   
                   
                   
                 3.300 
               
               
                 121 
                 0.026 
                   
                   
                 2.000 
                 30.000 
                 0.140 
               
               
                 122 
                 1.200 
                   
                   
                   
                   
                 6.500 
               
               
                 123 
                 2.550 
                   
                   
                   
                   
                 5.500 
               
               
                 124 
                 1.900 
                   
                   
                   
                   
                 &gt;20.000 
               
               
                 125 
                 1.300 
                   
                   
                   
                   
                 &gt;20.000 
               
               
                 126 
                 1.900 
                   
                   
                   
                   
                 &gt;20.000 
               
               
                 127 
                 1.500 
                   
                   
                   
                   
                 15.500 
               
               
                 128 
                 1.800 
                   
                   
                   
                   
                 &gt;20.000 
               
               
                 129 
                 1.500 
                   
                   
                   
                   
                 &gt;20.000 
               
               
                   
               
            
           
         
       
     
     While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention. 
     Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein. 
     The compounds within the present invention possess double bonds connecting the indole to the benzofuran or benzothiophene nucleus. These double bonds can exist as geometric isomers, and the invention includes both E and Z isomers of such double bonds. All such stable isomers are contemplated in the present invention.