Triazine compounds as PI3 kinase and mTOR inhibitors

This is a continuation application from U.S. application Ser. No. 14/477,650, filed on Sep. 4, 2015; which is a continuation application from U.S. application Ser. No. 14/259,414, filed on Apr. 23, 2014, and issued on Oct. 14, 2014 as U.S. Pat. No. 8,859,542; which is a continuation application from U.S. application Ser. No. 13/950,584, filed on Jul. 25, 2013, and issued on Jun. 10, 2014 as U.S. Pat. No. 8,478,421; which is a continuation application from U.S. application Ser. No. 13/718,928, filed on Dec. 18, 2012, and issued on Nov. 5, 2013 as U.S. Pat. No. 8,575,159; which is a continuation application from U.S. application Ser. No. 13/490,309, filed on Jun. 6, 2012, and issued on May 21, 2013 as U.S. Pat. No. 8,445,486; which is a continuation application from U.S. application Ser. No. 13/218,571, filed on Aug. 26, 2011, and issued on Jul. 10, 2012 as U.S. Pat. No. 8,217,036; which is a divisional application from U.S. application Ser. No. 12/470,521, filed on May 22, 2009, and issued on October 18, 2011 as U.S. Pat. No. 8,039,469; which claims the benefit of U.S. Provisional application Ser. No. 61/055,661, filed on May 23, 2008; the contents of which are hereby incorporated by reference in their entireties.

This invention relates to 2,4,6-substituted [1,3,5]triazine compounds in which one substituent is an optionally substituted morpholino, tetrahydropyranyl or dihydropyranyl group, which inhibit PI3 kinase and mTOR, to processes for preparing them, to methods of treatment using them and to pharmaceutical compositions containing them.

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)].

Phosphatidylinositol-3 kinase (“PI3K”) is an enzyme that phosphorylates the 3-position of the inositol ring of phosphatidylinositol [D. Whitman et al., Nature, 332, 664 (1988)]. Pluralities of PI3K subtypes exist. 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 & 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 Ia subtype there are three isoforms (α, β, & 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. 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 a 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 P3K.

The compound PI103 (3-(4-(4-morpholinyl)pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-2-yl)phenol) inhibits PI3Ka and PI3Kg 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 PI3Ka and PI3Kg but not the mTOR enzymes with an IC 50 values of 16, 4.6 and >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 PI3Ka and PI3Kg 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. (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 a 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.

There are three mTOR inhibitors, which have progressed into clinical trials. These compounds are Wyeth's Torisel, also known as 42-(3-hydroxy-2-(hydroxymethyl)-rapamycin 2-methylpropanoate, CCI-779 or Temsirolimus; Novartis' Everolimus, also known as 42-O-(2-hydroxyethyl)-rapamycin, or RAD 001; and Ariad'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]. On Mar. 30, 2009, the U.S. Food and Drug Administration (FDA) approved Everolimus (AFINITOR™) for the treatment of patients with advanced renal cell carcinoma. 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.

This invention provides compounds of formula I

wherein:

R 1 is

and R 2 , R 4 , and R 6-9 are defined below, and pharmaceutically acceptable salts and esters thereof. These compounds are useful as inhibitors of mTOR and PI3 kinases.

This invention further provides compositions containing one or more of the aforementioned compounds, which compositions may contain a pharmaceutically acceptable carrier.

The present invention provides methods for making the compounds of the invention, as described below. Methods of using the invention are also provided, for example: a method for inhibiting mTOR, a method for inhibiting a PI3 kinase, and methods for treating various forms of cancer.

In one aspect, the present invention provides compounds of formula I

wherein:

R 1 is

wherein:

R 6 , R 7 , R 8 , R 9 are each independently selected from the group consisting of a hydrogen atom, and a C 1 -C 6 alkyl optionally substituted with C 2 -C 6 alkenyl, C 4 -C 6 alkadienyl, C 2 -C 6 alkynyl or C 4 -C 6 alkadiynyl;

or one of R 6 and R 7 or R 8 and R 9 , together with the carbon atoms to which they are attached form an optionally substituted 5-8 membered saturated or unsaturated ring containing 0, 1 or 2 atoms independently selected from O, NH and S;

the dashed line - - - - - represents an optional second bond;

R 2 is optionally substituted C 6 -C 14 aryl-NH—COR 3 , optionally substituted C 1 -C 9 heteroaryl-NH—COR 3 , —CH═CH—C 6 -C 10 aryl-NH—COR 3 or —CH═CH—C 1 -C 9 heteroaryl-NH—COR 3 ;

R 3 is OR 5 , NR 5 R 5 or NHR 5 ;

R 5 is independently selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, optionally substituted C 6 -C 10 aryl, C 1 -C 6 haloalkyl, optionally substituted C 1 -C 9 heteroaryl, C 1 -C 6 hydroxylalkyl-, C 3 -C 10 saturated or unsaturated mono or bicyclic C 3 -C 10 cycloalkyl optionally substituted with OH, NR 11 R 11 or 3-7 membered C 1 -C 6 heterocyclyl, and 3-10 membered saturated or unsaturated mono or bicyclic C 1 -C 9 heterocyclyl, with the proviso that three-membered cycloalkyl and heterocyclyl rings are saturated;

or two R 5 groups taken together with the nitrogen atom to which they are attached form a 3 to 8 membered ring system optionally substituted with C 1 -C 6 alkyl, which ring system is saturated or unsaturated and has, in addition to said nitrogen atom, 0 to 2 heteroatom ring members selected from O, S, S(O), S(O) 2 and NR 10 ;

R 10 is selected from the group consisting of H, C 1 -C 6 alkyl, —SO 2 (C 1 -C 6 alkyl), —COO(C 1 -C 6 alkyl), —CONH(C 1 -C 6 alkyl), —CON(C 1 -C 6 alkyl) 2 , —CO(C 1 -C 6 alkyl), and —SO 2 NHR 11 ;

R 11 is selected from the group consisting of H, C 1 -C 6 alkyl optionally substituted with OH, NR 11 R 11 or a 3-7 membered C 1 -C 6 heterocyclyl, —CO(C 1 -C 6 alkyl), optionally substituted C 6 -C 10 aryl, and optionally substituted C 1 -C 9 heteroaryl;

R 4 is selected from the group consisting of: a) C 1 -C 6 alkyl optionally substituted with: i) 3-10 membered C 1 -C 9 heterocyclyl optionally substituted with C 1 -C 6 alkyl-, ii) H 2 N—, iii) (C 1 -C 6 alkyl)NH—, iv) (C 1 -C 6 alkyl) 2 N—, v) NH(CH 2 ) a N(C 1 -C 6 alkyl) 2 wherein a is 2, 3 or 4, and vi) CHO, b) C 3 -C 6 alkenyl, c) C 3 -C 6 alkynyl, d) —O—C 1 -C 8 alkyl optionally substituted with —O—C 1 -C 8 alkyl, e) —O—C 3 -C 8 alkenyl, f) —O—C 3 -C 8 alkynyl, g) saturated or unsaturated mono or bicyclic C 3 -C 8 cycloalkyl, and h) saturated or unsaturated mono or bicyclic —O—C 3 -C 12 cycloalkyl, all the above optionally substituted with OH, NR 11 R 11 or a 3-7 membered C 1 -C 6 heterocyclyl optionally substituted with C 1 -C 6 alkyl-, provided that an OH or NR 11 R 11 is not directly bonded to a carbon atom that is double- or triple-bonded to another carbon atom; i) —CH═CH—C 6 -C 10 aryl; j) —CH═CH—C 1 -C 9 heteroaryl; k) optionally substituted C 6 -C 10 aryl; l) optionally substituted 5-10 membered C 1 -C 9 heteroaryl attached to the triazine moiety via a carbon atom; m) 3-10 membered saturated or unsaturated monocyclic C 1 -C 9 heterocyclyl attached to the triazine moiety through a carbon or nitrogen atom and optionally substituted with from 1 to 3 substituents independently selected from: OH, NR 11 R 11 , C 1 -C 6 alkyl, (C 1 -C 6 alkyl)amido-, (C 1 -C 6 alkyl)C(O)—, (C 1 -C 6 alkoxy)carbonyl-, adamantyl, C 1 -C 6 hydroxylalkyl-, (C 1 -C 6 alkyl)amido-; or a 3-7 membered C 1 -C 6 heterocyclyl, with the proviso that 3 membered heterocyclyl is saturated and attached to the triazine moiety through a nitrogen atom, and 5 membered bicyclic heterocyclyl is saturated; n) optionally substituted —O—C 6 -C 10 aryl; o) optionally substituted —O—C 1 -C 9 heteroaryl; p) —O-(3-12 membered saturated or unsaturated mono or bicyclic)C 1 -C 9 heterocyclyl optionally substituted with (C 1 -C 6 alkoxy)carbonyl-, H 2 NS(O) 2 —, or C 1 -C 6 alkyl further optionally substituted with OH, NR 11 R 11 or a 3-7 membered C 1 -C 6 heterocyclyl, with the proviso that three membered heterocyclyl is saturated; q) —NHC 6 -C 10 aryl, r) —NHC 1 -C 9 heteroaryl, s) —NHNH 2 , t) —NHNHC 1 -C 6 alkyl, u) —NHN(C 1 -C 6 alkyl) 2 , v) —NHOH, w) —COOH, x) —COO—C 1 -C 6 alkyl, y) —CONR 12 R 13 , z) —NR 12 R 13 ,

wherein Z is CH 2 , O, S(O) n or NR 10 and n is 0, 1 or 2;

ee) halogen, ff) C 6 -C 14 aryl-S(O) 2 —NH—, gg) R 11 NHC(O)NH—O—, and hh) optionally substituted 5-membered monocyclic C 1 -C 4 heteroaryl attached to the triazine moiety via a nitrogen atom;

R 12 and R 13 are each independently selected from H, optionally mono or disubstituted C 1 -C 8 alkyl, optionally substituted C 3 -C 8 alkenyl, and optionally substituted C 3 -C 8 alkynyl, the optional substituents being selected from C 1 -C 6 alkoxy, OH, NR 11 R 11 , and 3-7 membered C 1 -C 6 heterocyclyl, provided that an OH or NR 11 R 11 is not directly bonded to a carbon atom that is double- or triple-bonded to another carbon atom;

or R 12 and R 13 taken together with the nitrogen atom to which they are attached form a 3 to 8 membered monocyclic ring system optionally substituted with C 1 -C 6 alkyl, which ring system is saturated or unsaturated and has, in addition to said nitrogen atom, 0 to 2 heteroatom ring members selected from O, S(O) n and NR 10 ;

or R 12 and R 13 taken together with the nitrogen atom to which they are attached form

wherein a and b are each independently —CH 2 —, O, S, or NR 10 , and x is 1-3;

C 1 -C 9 heteroaryl refers to a 5-10 membered aromatic ring system having one or more rings and 1, 2, 3 or 4 ring members independently selected from O, NR 10 , and S(O) n ;

C 1 -C 9 heterocyclyl refers to a 3-10 membered ring system having one or more rings and 1, 2, 3 or 4 ring members independently selected from O, NR 10 , and S(O) n ; and

optionally substituted aryl and heteroaryl groups are unsubstituted or are substituted with 1 or 2 moieties selected from the group consisting of: a) C 1 -C 6 alkyl optionally substituted with OH, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , —NH(CH 2 ) w N(C 1 -C 6 alkyl) 2 wherein w is 2, 3 or 4, or 3-10 membered C 1 -C 9 heterocyclyl optionally substituted with from 1 to 3 independently selected C 1 -C 6 alkyl-substituents; b) halogen; c) hydroxy; d) NH 2 ; e) NO 2 ; f) SO 2 NH 2 ; g) COOH; h) COO(C 1 -C 6 alkyl); i) NHCOO(C 1 -C 6 alkyl); j) NH(C 1 -C 6 alkyl); k) N(C 1 -C 6 alkyl) 2 ; l) C(O)NR a R b , wherein R a is H or C 1 -C 6 alkyl, and R b is H, C 1 -C 6 alkyl, (C 6 -C 14 aryl)alkyl-, or (C 1 -C 9 heteroaryl)alkyl-; m) —Y-Q, wherein Y is: i) O, ii) NH, iii) N(C 1 -C 6 alkyl), iv) NHSO 2 , v) SO 2 NH, vi) NHCONH, vii) NHCON(C 1 -C 6 alkyl), viii) S(O) q , q is 0, 1 or 2, ix) —C(O)NH—, x) —NHC(O)— xi) —C(O)N(CH 3 )—, xii) C(O), or xiii) absent, and Q is selected from: i) C 6 -C 10 aryl, optionally substituted with from 1 to 3 substituents independently selected from: A) C 1 -C 6 alkoxy- optionally substituted with 1) H 2 N—, 2) (C 1 -C 6 alkyl)amino-, 3) di(C 1 -C 6 alkyl)amino-, 4) C 1 -C 9 heterocyclyl- optionally substituted by C 1 -C 6 alkyl-, or 5) hydroxyl, B) (C 1 -C 6 alkoxy)carbonyl-, C) (C 1 -C 6 alkoxy)C(O)NH—, D) C 1 -C 6 alkyl- optionally substituted with 1) H 2 N—, 2) (C 1 -C 6 alkyl)amino-, or 3) di(C 1 -C 6 alkyl)amino-, E) (C 1 -C 6 alkyl)amino-, F) di(C 1 -C 6 alkyl)amino-, G) (C 1 -C 6 alkyl)amido- optionally substituted with 1) H 2 N—, 2) (C 1 -C 6 alkyl)amino-, or 3) di(C 1 -C 6 alkyl)amino-, H) (C 1 -C 6 alkyl)carboxyamido-, I) C 1 -C 9 heterocyclyl- optionally substituted by C 1 -C 6 alkyl- or C 1 -C 6 hydroxylalkyl-, J) heterocyclyl(C 1 -C 6 alkyl)- optionally substituted by C 1 -C 6 alkyl-, K) halogen, L) hydroxyl, M) C 1 -C 6 hydroxylalkyl-, N) perfluoro(C 1 -C 6 )alkyl-, O) H 2 N—, P) O 2 N—, Q) H 2 NSO 2 —, R) HO 2 C—, and S) NC—, ii) 5-10 membered C 1 -C 9 heteroaryl, optionally substituted with from 1 to 3 substituents independently selected from: A) C 1 -C 6 alkoxy- optionally substituted with 1) H 2 N—, 2) (C 1 -C 6 alkyl)amino-, 3) di(C 1 -C 6 alkyl)amino-, 4) C 1 -C 9 heterocyclyl- optionally substituted by C 1 -C 6 alkyl-, or 5) hydroxyl, B) (C 1 -C 6 alkoxy)carbonyl-, C) (C 1 -C 6 alkoxy)C(O)NH—, D) C 1 -C 6 alkyl- optionally substituted with 1) H 2 N—, 2) (C 1 -C 6 alkyl)amino-, or 3) di(C 1 -C 6 alkyl)amino-, E) (C 1 -C 6 alkyl)amino-, F) di(C 1 -C 6 alkyl)amino-, G) (C 1 -C 6 alkyl)amido- optionally substituted with 1) H 2 N—, 2) (C 1 -C 6 alkyl)amino-, or 3) di(C 1 -C 6 alkyl)amino-, H) (C 1 -C 6 alkyl)carboxyamido-, I) C 1 -C 9 heterocyclyl- optionally substituted by C 1 -C 6 alkyl- or C 1 -C 6 hydroxylalkyl-, J) heterocyclyl(C 1- C 6 alkyl)- optionally substituted by C 1 -C 6 alkyl-, K) halogen, L) hydroxyl, M) C 1 -C 6 hydroxylalkyl-, N) perfluoro(C 1 -C 6 )alkyl-, O) H 2 N—, P) O 2 N—, Q) H 2 NSO 2 —, R) HO 2 C—, and S) NC—, iii) 3-10 membered C 1 -C 9 heterocyclyl, optionally substituted with from 1 to 3 substituents independently selected from: A) C 1 -C 6 alkyl-, B) heterocyclyl(C 1 -C 6 alkyl)-, C) (C 6 -C 14 aryl)alkyl-, D) C 1 -C 8 acyl-, E) (C 1 -C 6 alkoxy)carbonyl-, F) (C 1 -C 6 alkyl)carboxyl-, G) halogen, H) C 1 -C 6 haloalkyl-, I) hydroxyl, J) C 1 -C 6 hydroxyalkyl-, K) H 2 N—, L) (C 1 -C 6 alkyl)amino-, M) di(C 1 -C 6 alkyl)amino-, N) HO 2 C—, O) (C 1 -C 6 alkoxy)carbonyl-, P) (C 1 -C 6 alkyl)carboxyl-, Q) (C 1 -C 6 alkyl)amido-, R) H 2 NC(O)—, S) (C 1 -C 6 alkyl)carboxyamido-, T) 5-10 membered C 1 -C 9 heteroaryl, U) C 6 -C 14 ary, V) C 3 -C 8 cycloalkyl W) 3-10 membered C 1 -C 9 heterocyclyl, X) NC—; and Y) —NO 2 ; iv) C 3 -C 10 cycloalkyl, v) C 1 -C 6 alkyl, vi) C 2 -C 6 alkenyl, vii) C 2 -C 6 alkynyl, viii) C 1 -C 6 hydroxyalkyl-, ix) (CH 2 ) v O(C 1 -C 6 alkyl), x) (CH 2 ) v NH 2 , Xi) (CH 2 ) v NH(C 1 -C 6 alkyl), xii) (CH 2 ) v N(C 1 -C 6 alkyl) 2 , xiii) O(CH 2 ) v N(C 1 -C 6 alkyl) 2 , xiv) (CH 2 ) v C 6 -C 10 aryl, xv) —CN, xvi) (CH 2 ) v 5-10 membered C 1 -C 9 heteroaryl, xvii) (CH 2 ) v 3-10 membered C 1 -C 9 heterocyclyl, optionally substituted by C 1 -C 6 alkyl-, wherein v is 1, 2, 3 or 4, and xviii) C 1 -C 6 perfluoroalkyl-; and n) C(O)R c wherein R c is: i) H, ii) C 1 -C 6 alkyl, or iii) C 3 -C 6 cycloalkyl,

and pharmaceutically acceptable salts and esters thereof.

In some embodiments of the invention, R 1 and/or R 4 is

In some embodiments, R 1 and/or R 4 is

In some embodiments, one of R 1 or R 4 is

and the other is

In some embodiments, R 2 is optionally substituted C 6 -C 14 aryl-NH—COR 3 ; in others R 2 is optionally substituted phenyl-NH—COR 3 .

In some embodiments, R 3 is NHR 5 or OR 5 . In some embodiments, R 5 is optionally substituted C 6 -C 10 aryl, such as optionally substituted phenyl or C 1 -C 9 heteroaryl. In some embodiments, the optionally substituted C 6 -C 10 aryl or phenyl is substituted with —Y-Q, C(O)NR a R b or C(O)R c .

In some embodiments, R 5 is phenyl substituted with —Y-Q.

The following compounds exemplify illustrative compounds of Formula I:

1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea; 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-3-ylurea; 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-phenylurea; 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-thiophen-2-ylurea; 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-methyl phenyl)urea; 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-fluorophenyl)urea; 1-(2,4-dimethoxyphenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-urea; 1-(4-chlorophenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-methoxyphenyl)urea; (4-chlorophenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; (2,4-difluorophenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-ethylurea; tert-butyl 3-{[4-(4-{[(4-fluorophenyl)carbamoyl]amino}phenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino}azetidine-1-carboxylate; tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(phenylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate; tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(pyridine-3-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate; tert-butyl 3-{[4-(4-{[(4-methylphenyl)carbamoyl]amino}phenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino}azetidine-1-carboxylate; 1-{4-[4-(azetidin-3-ylamino)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-phenylurea; 1-{4-[4-(azetidin-3-ylamino)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea; 1-{4-[4-(azetidin-3-ylamino)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-(4-fluorophenyl)urea; 1-{4-[4-(azetidin-3-ylamino)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-(4-methylphenyl)urea; tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(pyridine-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate; 1-{4-[4-(azetidin-3-ylamino)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea 1-[2-(dimethylamino)ethyl]-3-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea; 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(2-methyl pyridin-4-yl)urea; 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(2-hydroxyethyl)phenyl]urea; 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxymethyl)phenyl]urea; 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-hydroxyphenyl]urea; 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(1-hydroxyethyl)phenyl]urea; 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(trifluoromethyl)phenyl]urea; 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-hydroxyphenyl)urea; 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[5-(trifluoromethyl)pyridin-2-yl]urea; 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}urea; 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[3-(1-hydroxyethyl)phenyl]urea; methyl 4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoate; 1-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; 1-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}-3-phenylurea; 1-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea; 1-[4-(hydroxymethyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}urea; 1-(2-methylpyridin-4-yl)-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}urea; 1-[2-(methylamino)ethyl]-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}urea; 1-(3-acetylphenyl)-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}urea; 1-[4-(dimethylamino)phenyl]-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}urea; 4-[3-{4-(4,6-dimorpholino-1,3,5-triazin-2yl)phenyl}ureido]benzoic acid; N-(2-(dimethylamino)ethyl)-4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; N-(2-(dimethylamino)ethyl)-4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzamide HCl salt; 1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea; 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)-N-methylbenzamide; N-(2-(dimethylamino)ethyl)-4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)-N-methylbenzamide; 1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-morpholinopiperidine-1-carbonyl)phenyl)urea; 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)-N-(quinuclidin-3-yl)benzamide; 1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)urea; 1-(4-(1,4′-bipiperidine-1′-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazine-1-carbonyl)phenyl)urea; 1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(pyridin-2-yl)acetyl)phenyl)urea; 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(1-hydroxyethyl)phenyl]urea; 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(2-methylpyridin-4-yl)urea; 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxymethyl)phenyl]urea; 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(trifluoromethyl)phenyl]urea; 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}urea; 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[5-(trifluoromethyl)pyridin-2-yl]urea; 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[3-(1-hydroxyethyl)phenyl]urea; 1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea; 1-[4-(2-hydroxyethyl)phenyl]-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea; 1-[4-(2-hydroxymethyl)phenyl]-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea; 1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-(2-methylpyridin-4-yl)urea; 1-[4-(1-hydroxyethyl)phenyl]-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea; 1-[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea; methyl 4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}-amino)benzoate; 1-[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea; 4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(1-methylpiperidin-4-yl)benzamide; 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(1-methylpiperidin-4-yl)urea; 1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-(1-methylpiperidin-4-yl)urea; 1-{4-[4-(3,6-Dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea; 1-{4-[4-Morpholin-4-yl-6-(tetrahydro-pyran-4-yl)-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea; 3-({4-Morpholin-4-yl-6-[4-(3-pyridin-4-yl-ureido)-phenyl]-[1,3,5]triazin-2-ylamino}-methyl)-azetidine-1-carboxylic acid tert-butyl ester; 1-(4-{4-[(azetidin-3-ylmethyl)-amino]-6-morpholin-4-yl-[1,3,5]triazin-2-yl}-phenyl)-3-pyridin-4-yl-urea; 1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; 1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea; 1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-phenylurea; 1-[4-(dimethylamino)phenyl]-3-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea; 1-(4-cyanophenyl)-3-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea; 1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-(2-methylpyridin-4-yl)urea; 1-[2-(dimethylamino)ethyl]-3-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea; 1-[4-(4-morpholin-4-yl-6-quinolin-3-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea; 1-[4-(4-azetidin-1-yl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea; methyl 4-({[4-(4-azetidin-1-yl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoate; 1-[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea; 4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(1-methylpiperidin-4-yl)benzamide; 4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(2-piperidin-1-ylethyl)benzamide; 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(morpholin-4-ylcarbonyl)phenyl]urea; 1-[4-(4-methyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea; 4-({[4-(4-methyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoate; 1-{4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea; 4-({[4-(4-methyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(1-methylpiperidin-4-yl)benzamide; N-[2-(dimethylamino)ethyl]-N-methyl-4-({[4-(4-methyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide; 1-[4-(4-methyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea; 1-(4-{[3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; 1-[4-({4-[2-(dimethylamino)ethyl]piperazin-1-yl}carbonyl)phenyl]-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]phenyl}urea; 4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoic acid; N-[2-(dimethylamino)ethyl]-4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-methylbenzamide; 1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea; N-[2-(dimethylamino)ethyl]-4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide; 4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoate; 4-({[4-(4-azetidin-1-yl-6-morpholin-4-yl-1,3,5-triazin-2yl)phenyl]carbamoyl}amino)benzoic acid; mp 204° C.; 1-[4-(4-azetidin-1-yl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea; mp 170° C.; 4-({[4-(4-azetidin-1-yl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-[2-(dimethylamino)ethyl]-N-methylbenzamide; 4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-[2-(dimethylamino)ethyl]-N-methylbenzamide; 1-{4-[4-(1-ethoxyvinyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; 1-{4-[4-(2-methoxyethoxy)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; 1-[4-(4-acetyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea; methyl 4-[({4-[4-(2-methoxyethoxy)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate; 1-{4-[4-(1-hydroxyethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; methyl 4-[({4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate; 4-[({4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoic acid; 1-(4-{4-morpholin-4-yl-6-[2-(pyridin-4-ylamino)ethyl]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea; 4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-[2-(dimethylamino)ethyl]benzamide; 1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea; 1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea; N-[2-(dimethylamino)ethyl]-4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide; 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; 1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxymethyl)phenyl]urea; 4-[({4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-[2-(dimethylamino)ethyl]-N-methylbenzamide; 1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)urea; N-[2-(dimethylamino)ethyl]-4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-methyl benzamide; N-[2-(di methylamino)ethyl]-4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-methyl benzamide; N-[2-(di methylamino)ethyl]-4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide; 4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-methyl-N-[2-(methylamino)ethyl]benzamide; 1-[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea; 1-{4-[(3,3-dimethyl piperazin-1-yl)carbonyl]phenyl}-3-[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; 4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(2-piperidin-1-ylethyl)benzamide; 4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-[4-(4-methylpiperazin-1-yl)phenyl]benzamide; 1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]urea; 4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-[4-(4-methylpiperazin-1-yl)phenyl]benzamide; 1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea; 1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-formylphenyl)urea; 4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(pyridin-2-ylmethyl)benzamide; 1-(4-{4-[2-(1,3-dioxan-2-yl)ethyl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea; 1-(4-{4-[2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea; 4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-{4-[2-(dimethylamino)ethoxy]phenyl}benzamide; 1-{4-[(4-benzylpiperidin-1-yl)carbonyl]phenyl}-3-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; 4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(1-methylpiperidin-4-yl)benzamide; 4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(1-methylpiperidin-4-yl)benzamide; 1-(4-{4-[3-(dimethylamino)propyl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea; 1-[4-(4-{3-[(1-methylethyl)amino]propyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea; 1-{4-[4-morpholin-4-yl-6-(3-pyrrolidin-1-ylpropyl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; 1-(4-{4-[3-(4-methylpiperazin-1-yl)propyl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea; 1-{4-[4-(3-{[2-(dimethylamino)ethyl]amino}propyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; 1-{4-[4-(3-hydroxypropyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; 1-{4-[4-morpholin-4-yl-6-(3-oxopropyl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; 1-{4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)urea; 4-[({4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-[2-(dimethylamino)ethyl]benzamide; 1-[4-(4-methylpiperazin-1-yl)phenyl]-3-[4-(4-morpholin-4-yl-6-propyl-1,3,5-triazin-2-yl)phenyl]urea; 1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; 1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(4-methyl piperazin-1-yl)phenyl]urea; 1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(2-methylpropyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea; 1-{4-[(3,3-dimethylpiperazin-1-yl)carbonyl]phenyl}-3-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; 4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(1-methylazetidin-3-yl)benzamide; methyl 4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate N-[2-(dimethylamino)ethyl]-4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; N-(1-methylazetidin-3-yl)-4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea; 4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-pyridin-4-ylbenzamide; 4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-pyridin-3-ylbenzamide; N-cyclobutyl-4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; 1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-phenylpiperidin-1-yl)carbonyl]phenyl}urea; 4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(pyridin-4-ylmethyl)benzamide; 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-(2-methylpropyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea; 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-(2-methyl propyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea; N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-(2-methylpropyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; 1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea; N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; 1-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-3-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea; 1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; 1-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-3-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; 4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoic acid; 1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea; methyl 4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate; 1-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-3-[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2-yl)phenyl]urea; 1-[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea; 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl]phenyl}urea; 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea; 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea; 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea; 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea; 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea; 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea; 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)urea; (R)-1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea; (R)-1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea; (R)-1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazin-1-yl)phenyl)urea; 1-(4-(4-((R)-3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-((S)-3-methylpiperazin-1-yl)phenyl)urea; 1-(4-(4-((R)-3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-((R)-3-methylpiperazin-1-yl)phenyl)urea; 1-(4-((3R,5S)-3,5-dimethylpiperazin-1-yl)phenyl)-3-(4-(4-((R)-3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; (R)-1-(4-(2-(dimethylamino)ethoxy)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; (R)-1-(4-(4-ethylpiperazin-1-yl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; (R)-1-(4-(4-isopropylpiperazin-1-yl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; (R)-1-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; (R)-1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea; (R)-1-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; (R)-1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea; 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea; 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea; 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea; 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea; 4-(3-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N,N-dimethylbenzamide; 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)urea; 4-({[4-(4-{4-[(methylcarbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide; 1-{4-[4-(3,5-dimethylmorpholin-4-yl)-6-{4-[(methylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea; 3-({[4-(4-{4-[(methylcarbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide; 1-methyl-3-[4-(4-morpholin-4-yl-6-{4-[(pyridin-3-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)phenyl]urea; 1-methyl-3-[4-(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)phenyl]urea; 3-[({4-[4-(3,5-dimethylmorpholin-4-yl)-6-{4-[(methylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; 4-[({4-[4-(3,5-dimethylmorpholin-4-yl)-6-{4-[(methylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; 1-{4-[4-(3,5-dimethylmorpholin-4-yl)-6-{4-[(methylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-methylurea; 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl]phenyl}urea; 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4-morpholin-4-yl-6-[(3S)-tetrahydrofuran-3-yloxy]-1,3,5-triazin-2-yl}phenyl)urea; 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridazin-4-ylurea; 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(oxetan-3-yloxy)-1,3,5-triazin-2-yl]phenyl}urea; 1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; 1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; 1-[4-(4-isopropyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea; 1-{4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-(4-pyrimidin-5-ylphenyl)urea; 1-(4-{4-[(2,2-dimethoxyethyl)amino]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea; 1-{4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-(4-pyridin-4-ylphenyl)urea; 1-(4-iodophenyl)-3-{4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea; 1-{4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)urea; 1-[4-(4-azetidin-1-yl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)urea; 1-{4-[2-(dimethylamino)pyrimidin-5-yl]phenyl}-3-{4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea; tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)oxy]azetidine-1-carboxylate; 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-nitrophenyl)urea; 1-(4-aminophenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; N-[4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]-4-methylpiperazine-1-carboxamide; 4-(dimethylamino)-N-[4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]piperidine-1-carboxamide; 1-[2-(dimethylamino)ethyl]-3-[4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]-1-methylurea; 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-{[(2-piperidin-1-ylethyl)carbamoyl]amino}phenyl)urea; N-[4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]-4-methyl-1,4-diazepane-1-carboxamide; N-[4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]-4-ethylpiperazine-1-carboxamide; 1-{4-[(dimethylcarbamoyl)amino]phenyl}-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; 1-{4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)urea; 4-[({4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-[2-(dimethylamino)ethyl]-N-methylbenzamide; 1-{4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea; 4-[({4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-[2-(dimethylamino)ethyl]benzamide; 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl]phenyl}urea; N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; 4-[({4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-pyrrolidin-1-ylethyl)benzamide; 4-[({4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-piperidin-1-ylethyl)benzamide; 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)urea; N-[2-(di methylamino)ethyl]-N-methyl-4-{[(4-{4-morpholin-4-yl-6-[(3S)-tetrahydrofuran-3-yloxy]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide; 4-{[(4-{4-morpholin-4-yl-6-[(3S)-tetrahydrofuran-3-yloxy]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}-N-(2-piperidin-1-ylethyl)benzamide; 4-{[(4-{4-morpholin-4-yl-6-[(3S)-tetrahydrofuran-3-yloxy]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}-N-(2-pyrrolidin-1-ylethyl)benzamide; 1-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)-3-(4-{4-morpholin-4-yl-6-[(3S)-tetrahydrofuran-3-yloxy]-1,3,5-triazin-2-yl}phenyl)urea; 1-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl]phenyl}urea; N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; 4-[({4-[4-(2-methylpropyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoic acid; 1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea; 4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoic acid; methyl 4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate; 1-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-3-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; 1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; 1-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-3-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea; N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; 1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea; 1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-pyridin-2-ylpiperazin-1-yl)carbonyl]phenyl}urea; 1-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-3-[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2-yl)phenyl]urea; 1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea; 1-[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea; methyl 4-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoate; N-[2-(dimethylamino)ethyl]-N-methyl-4-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide; methyl 4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzoate; 4-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoic acid; N-[2-(dimethylamino)ethyl]-4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2-yl)phenyl]urea; 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2-yl)phenyl]urea; N-[2-(dimethylamino)ethyl]-4-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide; 4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}-N-[2-(dimethylamino)ethyl]benzamide; 1-{4-[(4-isopropylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea; 4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-pyrrolidin-1-ylethyl)benzamide; 4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzoic acid; N-(2-methoxyethyl)-4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; N-(2-methoxyethyl)-4-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide; 4-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(2-pyrrolidin-1-ylethyl)benzamide; 1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-[4-(pyrrolidin-1-ylcarbonyl)phenyl]urea; N-[3-(dimethylamino)propyl]-4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; 1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-[4-(piperidin-1-ylcarbonyl)phenyl]urea; N-[3-(dimethylamino)propyl]-4-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide; 1-{4-[4-morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; 4-[({4-[4-morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoic acid; 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2-yl]phenyl}urea; methyl 4-[({4-[4-morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate; N-(2-methoxyethyl)-4-[({4-[4-morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; 4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}-N-[2-(dimethylamino)ethyl]-N-methylbenzamide; 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea; 1-{4-[4-morpholin-4-yl-6-(1,4-oxazepan-4-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; methyl 4-[({4-[4-morpholin-4-yl-6-(1,4-oxazepan-4-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate; 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2-yl]phenyl}urea; 4-[({4-[4-morpholin-4-yl-6-(1,4-oxazepan-4-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoic acid; N-[3-(dimethylamino)propyl]-4-[({4-[4-morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)-3-[4-(pyrrolidin-1-ylcarbonyl)phenyl]urea; N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6-(1,4-oxazepan-4-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(1,4-oxazepan-4-yl)-1,3,5-triazin-2-yl]phenyl}urea; N-(2-methoxyethyl)-4-[({4-[4-morpholin-4-yl-6-(1,4-oxazepan-4-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; 1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2-yl]phenyl}urea; 1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{3-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea; 3-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoic acid; methyl 3-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate; 1-(3-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-(4-methyl phenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea; N-[2-(dimethylamino)ethyl]-N-methyl-3-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; methyl 3-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoate; methyl 3-({[4-(4-morpholin-4-yl-6-thiophen-2-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoate; N-[2-(dimethylamino)ethyl]-3-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-morpholin-4-yl-6-(1,4-oxazepan-4-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; 3-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoic acid; methyl 3-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoate; 1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{3-[(4-pyridin-2-ylpiperazin-1-yl)carbonyl]phenyl}urea; N-[2-(dimethylamino)ethyl]-3-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-methylbenzamide; 1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{3-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea; 3-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoic acid; methyl 4-({[4-(4-morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoate; 1-[4-(4-morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea; 4-({[4-(4-morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoic acid; methyl 4-({[4-(4-morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoate; 1-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)-3-[4-(4-morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin-2-yl)phenyl]urea; 1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-[4-(4-morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin-2-yl)phenyl]urea; 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-[4-(4-morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin-2-yl)phenyl]urea; 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4-morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin-2-yl)phenyl]urea; 4-({[4-(4-morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoic acid; 1-[4-(4-morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea; N-[2-(dimethylamino)ethyl]-4-({[4-(4-morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide; 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4-morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin-2-yl)phenyl]urea; 1-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)-3-[4-(4-morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin-2-yl)phenyl]urea; N-[2-(dimethylamino)ethyl]-N-methyl-4-({[4-(4-morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide; N-[2-(dimethylamino)ethyl]-N-methyl-4-({[4-(4-morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide; 1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-[4-(4-morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin-2-yl)phenyl]urea; 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-[4-(4-morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin-2-yl)phenyl]urea; N-[2-(dimethylamino)ethyl]-4-({[4-(4-morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide; 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea; N-[3-(dimethylamino)propyl]-4-({[4-(4-morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide; N-(2-methoxyethyl)-4-({[4-(4-morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide; 1-[4-(4-morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(pyrrolidin-1-ylcarbonyl)phenyl]urea; 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)-3-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}urea; 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)-3-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)urea; methyl 4-{[(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzoate; 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)-3-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)urea; 1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea; 1-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea; 4-{[(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzoic acid; 1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea; N-[3-(dimethylamino)propyl]-4-{[(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide; 4-{[(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}-N-(2-pyrrolidin-1-ylethyl)benzamide; 1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea; 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)-3-(4-{[4-(dipropylamino)piperidin-1-yl]carbonyl}phenyl)urea; 1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4-[(3R)-3-methyl morpholin-4-yl]-6-[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)urea; 4-{[(4-{4-[(3R)-3-methyl morpholin-4-yl]-6-[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzoic acid; 1-{4-[(4-butylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)urea; methyl 4-{[(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzoate; 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)-3-{4-[(4-butylpiperazin-1-yl)carbonyl]phenyl}urea; 1-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)-3-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)urea; 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)-3-(4-{[4-(2-methylpropyl)piperazin-1-yl]carbonyl}phenyl)urea; 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)-3-(4-{[4-(1-methylpropyl)piperazin-1-yl]carbonyl}phenyl)urea; 4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}-N-[2-(4-methylpiperazin-1-yl)ethyl]benzamide; N-[2-(di methylamino)ethyl]-4-{[(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide; 4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}-N-(2-pyrrolidin-1-ylethyl)benzamide; 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)-3-{4-[(4-propylpiperidin-1-yl)carbonyl]phenyl}urea; 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)-3-[4-(piperidin-1-ylcarbonyl)phenyl]urea; 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)-3-{4-[(4-propylpiperazin-1-yl)carbonyl]phenyl}urea; 4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}-N-(2-methoxyethyl)benzamide; 1-{4-[4-morpholin-4-yl-6-(4-tricyclo[3.3.1.13,7]dec-1-ylpiperazin-1-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; methyl 4-{[(4-{4-[4-(dimethylcarbamoyl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzoate; N,N-dimethyl-4-(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)piperazine-1-carboxamide; N,N-dimethyl-4-(4-{4-[({4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}carbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)piperazine-1-carboxamide; N,N-dimethyl-4-{4-morpholin-4-yl-6-[4-({[4-(pyridazin-4-ylcarbamoyl)phenyl]carbamoyl}amino)phenyl]-1,3,5-triazin-2-yl}piperazine-1-carboxamide; N,N-dimethyl-4-(4-morpholin-4-yl-6-{4-[({4-[(4-propylpiperidin-1-yl)carbonyl]phenyl}carbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)piperazine-1-carboxamide; 4-{[(4-{4-[4-(dimethylcarbamoyl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzoic acid; 4-(4-{4-[({4-[(2-methoxyethyl)carbamoyl]phenyl}carbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)-N,N-dimethylpiperazine-1-carboxamide; 4-[4-(4-{[(4-{[2-(dimethylamino)ethyl](methyl)carbamoyl}phenyl)carbamoyl]amino}phenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]-N, N-dimethylpiperazine-1-carboxamide; 4-(4-{4-[({4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}carbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)-N,N-dimethylpiperazine-1-carboxamide; 1-(4-{4-[4-(ethylsulfonyl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea; methyl 4-{[(4-{4-[4-(ethylsulfonyl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzoate; 4-{[(4-{4-[4-(ethylsulfonyl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzoic acid; N-[3-(dimethylamino)propyl]-4-{[(4-{4-[4-(ethylsulfonyl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide; N-[2-(dimethylamino)ethyl]-4-{[(4-{4-[4-(ethylsulfonyl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide; 4-{[(4-{4-[4-(1-methylethyl)-1,4-diazepan-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzoic acid; methyl 4-{[(4-{4-[4-(acetylamino)piperidin-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzoate; 1-(4-{4-[4-(1-methylethyl)-1,4-diazepan-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea; N-[1-(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)piperidin-4-yl]acetamide; 4-{[(4-{4-[4-(acetylamino)piperidin-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzoic acid; N-[2-(dimethylamino)ethyl]-4-{[(4-{4-[4-(1-methylethyl)-1,4-diazepan-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide; N-{1-[(4-{[(4-{4-[4-(1-methylethyl)-1,4-diazepan-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}phenyl)carbonyl]piperidin-4-yl}acetamide; 1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4-[4-(1-methylethyl)-1,4-diazepan-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea; 1-(4-{4-[4-(1-methylethyl)-1,4-diazepan-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)urea; 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)-3-(4-{[(3S)-3-methylmorpholin-4-yl]carbonyl}phenyl)urea; 1-{4-[(4-butylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4-[4-(1-methylethyl)-1,4-diazepan-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea; 1-(4-{4-[(4-methylpiperazin-1-yl)amino]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-phenylurea; 1-(4-{4-[(1-methylpiperidin-4-yl)oxy]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea; 1-{4-[4-morpholin-4-yl-6-(piperidin-4-yloxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; ethyl 4-[(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)oxy]piperidine-1-carboxylate; N-ethyl-4-[(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)oxy]piperidine-1-carboxamide; tert-butyl 4-[(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)oxy]piperidine-1-carboxylate; 4-[(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)oxy]piperidine-1-sulfonamide; 1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; 1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea; 1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-phenylurea; 1-[4-(dimethylamino)phenyl]-3-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea; 1-(4-cyanophenyl)-3-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea; 1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-(2-methylpyridin-4-yl)urea; 1-[2-(dimethylamino)ethyl]-3-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea; 1-[4-(4-morpholin-4-yl-6-quinolin-3-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea; 1-{4-[4-(2-methoxyethoxy)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; methyl 4-[({4-[4-(2-methoxyethoxy)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate; 1-(4-{4-morpholin-4-yl-6-[2-(pyridin-4-ylamino)ethyl]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea; N-[2-(dimethylamino)ethyl]-4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-methylbenzamide; N-[2-(dimethylamino)ethyl]-4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide; 4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-methyl-N-[2-(methylamino)ethyl]benzamide; 1-[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea; 1-{4-[(3,3-dimethylpiperazin-1-yl)carbonyl]phenyl}-3-[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; 4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(2-piperidin-1-ylethyl)benzamide; 1-(4-{4-[2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea; 1-(4-{4-[2-(1,3-dioxan-2-yl)ethyl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea; 1-(4-{4-[3-(dimethylamino)propyl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea; 1-[4-(4-{3-[(1-methylethyl)amino]propyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea; 1-{4-[4-morpholin-4-yl-6-(3-pyrrolidin-1-ylpropyl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; 1-(4-{4-[3-(4-methylpiperazin-1-yl)propyl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea; 1-{4-[4-(3-{[2-(dimethylamino)ethyl]amino}propyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; 1-{4-[4-(3-hydroxypropyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; 1-{4-[4-morpholin-4-yl-6-(3-oxopropyl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; N-(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)benzenesulfonamide; N-{4-[4-({[4-(4-methylpiperazin-1-yl)phenyl]carbamoyl}amino)phenyl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}benzenesulfonamide; N-(4-{4-[({4-[2-(dimethylamino)ethoxy]phenyl}carbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)benzenesulfonamide; N-(4-{4-[({4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}carbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)benzenesulfonamide; N-{4-morpholin-4-yl-6-[4-({[4-(piperazin-1-ylcarbonyl)phenyl]carbamoyl}amino)phenyl]-1,3,5-triazin-2-yl}benzenesulfonamide; N-[4-(4-{[(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)carbamoyl]amino}phenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]benzenesulfonamide; N-[2-(dimethylamino)ethyl]-N-methyl-4-{[(4-{4-morpholin-4-yl-6-[(phenylsulfonyl)amino]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide; N-[2-(dimethylamino)ethyl]-4-{[(4-{4-morpholin-4-yl-6-[(phenylsulfonyl)amino]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide; methyl 4-{[(4-{4-morpholin-4-yl-6-[(phenylsulfonyl)amino]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzoate; 4-{[(4-{4-morpholin-4-yl-6-[(phenylsulfonyl)amino]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzoic acid; 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-[4-(6-morpholin-4-yl-4-oxo-4,5-dihydro-1,3,5-triazin-2-yl)phenyl]urea; 1-(4-(2,4-dimethylpiperazine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropyl-2-methylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(4-cyclobutyl-2-methylpiperazine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropyl-3-methylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(3,4-dimethylpiperazine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-cyclobutyl-3-methylpiperazine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-cyclobutylpiperazine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(2,4-dimethylpiperazine-1-carbonyl)phenyl)-3-(4-(4-morpholino-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-isopropyl-2-methylpiperazine-1-carbonyl)phenyl)-3-(4-(4-morpholino-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-cyclobutyl-2-methylpiperazine-1-carbonyl)phenyl)-3-(4-(4-morpholino-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-isopropyl-3-methylpiperazine-1-carbonyl)phenyl)-3-(4-(4-morpholino-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(3,4-dimethylpiperazine-1-carbonyl)phenyl)-3-(4-(4-morpholino-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-cyclobutyl-3-methylpiperazine-1-carbonyl)phenyl)-3-(4-(4-morpholino-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-cyclobutylpiperazine-1-carbonyl)phenyl)-3-(4-(4-morpholino-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(2-methylpiperazine-1-carbonyl)phenyl)-3-(4-(4-morpholino-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(3-methylpiperazine-1-carbonyl)phenyl)-3-(4-(4-morpholino-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4,6-di morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(3-methylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(4,6-di morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-methylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(3,3-dimethylpiperazine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(3,3-di methylpiperazine-1-carbonyl)phenyl)-3-(4-(4-morpholino-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-morpholino-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(3,3,4-trimethylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(3,3,4-trimethylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(2,4-dimethylpiperazine-1-carbonyl)phenyl)-3-(4-(4-morpholino-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-methylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(4-isopropyl-2-methylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-cyclobutyl-2-methylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-isopropyl-3-methylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(3,4-dimethylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-cyclobutyl-3-methylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-cyclobutylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(3,3,4-trimethylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(3,3-dimethylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; N-(2-(dimethylamino)ethyl)-N-methyl-4-(3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; N-(2-(dimethylamino)ethyl)-4-(3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; 1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(2,4-dimethylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(2-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(2,4-dimethylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(2-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-isopropyl-2-methylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(2-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-cyclobutyl-2-methylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(2-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; N-(2-(dimethylamino)ethyl)-N-methyl-4-(3-(4-(4-(2-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; 1-(4-(4-isopropyl-3-methylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(2-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-(2-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(3-methylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(3,4-dimethylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(2-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-cyclobutyl-3-methylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(2-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(3,3-dimethylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(2-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-(2-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(3,3,4-trimethylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(4-cyclobutylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(2-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; N-(2-(dimethylamino)ethyl)-4-(3-(4-(4-(2-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; 1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4-(2-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)-3-(4-(4-(2-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)-3-(4-(4-morpholino-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea; 1-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)-3-(4-(4-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(quinuclidin-4-yl)phenyl)urea; 1-(4-(4-cyclopropylpiperazin-1-yl)phenyl)-3-(4-(4-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)-3-(4-(4-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea; 1-(4-(4-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea; 1-(4-(4-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(4-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(4-cyclopropylpiperazine-1-carbonyl)phenyl)-3-(4-(4-((2R,5S)-2,5-dimethyl pyrrolidin-1-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)-3-(4-(4-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea; 1-(4-(4-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea; 1-(4-(4-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(quinuclidin-4-yl)phenyl)urea; 1-(4-(4-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea; 1-(4-(4-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)urea; 1-(4-(4-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea; 1-(4-(4-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea; 1-(4-(4-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(4-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(4-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea; 1-(4-(4-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(4-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(4-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)urea; 1-(4-(4-morpholino-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea; 1-(4-(4-morpholino-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea; 1-(4-(4-morpholino-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)-3-(pyridazin-4-yl)urea; 1-(4-(4-morpholino-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)-3-(pyrimidin-5-yl)urea; 4-(3-(4-(4-morpholino-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; N-(2-(dimethylamino)ethyl)-4-(3-(4-(4-morpholino-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; N-(2-(dimethylamino)ethyl)-N-methyl-4-(3-(4-(4-morpholino-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; N-(2-(methylamino)ethyl)-4-(3-(4-(4-morpholino-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; N-methyl-N-(2-(methylamino)ethyl)-4-(3-(4-(4-morpholino-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; 1-(4-((R)-3-(di methylamino)pyrrolidine-1-carbonyl)phenyl)-3-(4-(4-morpholino-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-morpholino-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazine-1-carbonyl)phenyl)urea; 1-(4-(4-methylpiperazine-1-carbonyl)phenyl)-3-(4-(4-morpholino-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-ethylpiperazine-1-carbonyl)phenyl)-3-(4-(4-morpholino-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)-3-(4-(4-morpholino-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-((S)-3-methylmorpholino)-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea; 1-(4-(4-((S)-3-methylmorpholino)-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea; 1-(4-(4-((S)-3-methylmorpholino)-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)-3-(pyridazin-4-yl)urea; 1-(4-(4-((S)-3-methylmorpholino)-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)-3-(pyrimidin-5-yl)urea; 4-(3-(4-(4-((S)-3-methylmorpholino)-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; 1-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)-3-(4-(4-((S)-3-methylmorpholino)-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-((S)-3-methylmorpholino)-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazine-1-carbonyl)phenyl)urea; 1-(4-(4-((S)-3-methylmorpholino)-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(4-ethylpiperazine-1-carbonyl)phenyl)-3-(4-(4-((S)-3-methylmorpholino)-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)-3-(4-(4-((S)-3-methylmorpholino)-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea; 1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridazin-4-yl)urea; 1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyrimidin-5-yl)urea; 1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea; 1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-phenylurea; 1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-chlorophenyl)urea; 1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-fluorophenyl)urea; methyl4-(3-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2yl)phenyl)ureido)benzoate; 4-(3-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid; 4-(3-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(dimethylamino)ethyl)benzamide; 4-(3-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(dimethylamino)ethyl)-N-methylbenzamide; 1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)urea; 4-(3-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; 1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazine-1-carbonyl)phenyl)urea; 1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea; 1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4-(4-methyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-(4-methyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazine-1-carbonyl)phenyl)urea; 1-(4-(4-(4-methyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(4-(4-methyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(4-(4-methyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-n-propylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(4-(4-methyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)-3-(4-(4-(4-methyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; N-(2-(dimethylamino)ethyl)-4-(3-(4-(4-(4-methyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; N-(2-(dimethylamino)ethyl)-N-methyl-4-(3-(4-(4-(4-methyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; 1-(4-(4-(4-methyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-phenylurea; 1-(4-chlorophenyl)-3-(4-(4-(4-methyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-fluorophenyl)-3-(4-(4-(4-methyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-(4-methyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea; 1-(4-(4-(4-methyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea; 1-(4-(4-(4-methyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridazin-4-yl)urea; 1-(4-(4-(4-methyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyrimidin-5-yl)urea; 1-(4-(4-(4-ethyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazine-1-carbonyl)phenyl)urea; 1-(4-(4-(4-ethyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(4-(4-ethyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(4-(4-ethyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-n-propylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(4-(4-ethyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)-3-(4-(4-(4-ethyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; N-(2-(dimethylamino)ethyl)-4-(3-(4-(4-(4-ethyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; N-(2-(dimethylamino)ethyl)-N-methyl-4-(3-(4-(4-(4-ethyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; 1-(4-(4-(4-ethyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-phenylurea; 1-(4-chlorophenyl)-3-(4-(4-(4-ethyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-fluorophenyl)-3-(4-(4-(4-ethyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-(4-ethyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea; 1-(4-(4-(4-ethyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea; 1-(4-(4-(4-ethyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridazin-4-yl)urea; 1-(4-(4-(4-ethyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyrimidin-5-yl)urea; 1-(4-(4-(4-propyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazine-1-carbonyl)phenyl)urea; 1-(4-(4-(4-propyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(4-(4-propyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(4-(4-propyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-n-propylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(4-(4-propyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)-3-(4-(4-(4-propyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; N-(2-(dimethylamino)ethyl)-4-(3-(4-(4-(4-propyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; N-(2-(dimethylamino)ethyl)-N-methyl-4-(3-(4-(4-(4-propyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; 1-(4-(4-(4-propyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-phenylurea; 1-(4-chlorophenyl)-3-(4-(4-(4-propyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-fluorophenyl)-3-(4-(4-(4-propyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-(4-propyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea; 1-(4-(4-(4-propyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea; 1-(4-(4-(4-propyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridazin-4-yl)urea; 1-(4-(4-(4-propyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyrimidin-5-yl)urea; 1-(4-(4-(4-isopropyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea; 1-(4-(4-(4-isopropyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea; 1-(4-(4-(4-isopropyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridazin-4-yl)urea; 1-(4-(4-(4-isopropyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyrimidin-5-yl)urea; 1-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea; 1-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea; 1-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridazin-4-yl)urea; 1-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyrimidin-5-yl)urea; 1-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-phenylurea; 1-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-chlorophenyl)urea; 1-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-fluorophenyl)urea; Methyl-4-(3-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoate; 4-(3-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid; 4-(3-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(dimethylamino)ethyl)benzamide; 4-(3-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(dimethylamino)ethyl)-N-methylbenzamide; 1-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)urea; 4-(3-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; 1-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-n-propylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazine-1-carbonyl)phenyl)urea; 1-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea; 1-(4-(4-(di methylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4-(4-isobutyryl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-(4-isobutyryl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazine-1-carbonyl)phenyl)urea; 1-(4-(4-(4-isobutyryl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(4-ethyl piperazine-1-carbonyl)phenyl)-3-(4-(4-(4-isobutyryl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-(4-isobutyryl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(3-(di methylamino)pyrrolidine-1-carbonyl)phenyl)-3-(4-(4-(4-isobutyryl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-(4-isobutyryl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-phenylurea; 1-(4-chlorophenyl)-3-(4-(4-(4-isobutyryl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-fluorophenyl)-3-(4-(4-(4-isobutyryl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-(4-isobutyryl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea; 1-(4-(4-(4-isobutyryl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridazin-4-yl)urea; 1-(4-(4-(4-isobutyryl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea; 1-(4-(4-(4-isobutyryl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyrimidin-5-yl)urea; tert-butyl 4-(4-(4-(3-(4-(methoxycarbonyl)phenyl)ureido)phenyl)-6-morpholino-1,3,5-triazin-2-yl)-1,4-diazepane-1-carboxylate; methyl4-(3-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl) ureido)benzoate; 1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-phenylurea; 1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-chlorophenyl)urea; 1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-fluorophenyl)urea; 1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea; 1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea; 1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridazin-4-yl)urea; 1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyrimidin-5-yl)urea; N-methyl-4-(4-morpholino-6-(4-(3-phenylureido)phenyl)-1,3,5-triazin-2-yl)-1,4-diazepane-1-carboxamide (M+H) 532.2; 4-(4-(4-(3-(4-chlorophenyl)ureido)phenyl)-6-morpholino-1,3,5-triazin-2-yl)-N-methyl-1,4-diazepane-1-carboxamide; 4-(4-(4-(3-(4-fluorophenyl)ureido)phenyl)-6-morpholino-1,3,5-triazin-2-yl)-N-methyl-1,4-diazepane-1-carboxamide; 4-(4-(4-(3-(4-(2-(dimethylamino)ethylcarbamoyl)phenyl)ureido)phenyl)-6-morpholino-1,3,5-triazin-2-yl)-N-methyl-1,4-diazepane-1-carboxamide; 4-(4-(4-(3-(4-((2-(dimethylamino)ethyl)(methyl)carbamoyl)phenyl)ureido)phenyl)-6-morpholino-1,3,5-triazin-2-yl)-N-methyl-1,4-diazepane-1-carboxamide; 4-(4-(4-(3-(4-carbamoylphenyl)ureido)phenyl)-6-morpholino-1,3,5-triazin-2-yl)-N-methyl-1,4-diazepane-1-carboxamide; 4-(4-(4-(3-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)ureido)phenyl)-6-morpholino-1,3,5-triazin-2-yl)-N-methyl-1,4-diazepane-1-carboxamide; N-methyl-4-(4-morpholino-6-(4-(3-(4-(piperazine-1-carbonyl)phenyl)ureido)phenyl)-1,3,5-triazin-2-yl)-1,4-diazepane-1-carboxamide; N-methyl-4-(4-(4-(3-(4-(4-methylpiperazine-1-carbonyl)phenyl)ureido)phenyl)-6-morpholino-1,3,5-triazin-2-yl)-1,4-diazepane-1-carboxamide; 4-(4-(4-(3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)ureido)phenyl)-6-morpholino-1,3,5-triazin-2-yl)-N-methyl-1,4-diazepane-1-carboxamide; 4-(4-(4-(3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)ureido)phenyl)-6-morpholino-1,3,5-triazin-2-yl)-N-methyl-1,4-diazepane-1-carboxamide; 4-(4-(4-(3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)ureido)phenyl)-6-morpholino-1,3,5-triazin-2-yl)-N-methyl-1,4-diazepane-1-carboxamide; 4-(4-(4-(3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)ureido)phenyl)-6-morpholino-1,3,5-triazin-2-yl)-N-isopropyl-1,4-diazepane-1-carboxamide; N-isopropyl-4-(4-(4-(3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)ureido)phenyl)-6-morpholino-1,3,5-triazin-2-yl)-1,4-diazepane-1-carboxamide; 4-(4-(4-(3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)ureido)phenyl)-6-morpholino-1,3,5-triazin-2-yl)-N-isopropyl-1,4-diazepane-1-carboxamide; N-isopropyl-4-(4-(4-(3-(4-(4-methylpiperazine-1-carbonyl)phenyl)ureido)phenyl)-6-morpholino-1,3,5-triazin-2-yl)-1,4-diazepane-1-carboxamide; N-isopropyl-4-(4-morpholino-6-(4-(3-(4-(piperazine-1-carbonyl)phenyl)ureido)phenyl)-1,3,5-triazin-2-yl)-1,4-diazepane-1-carboxamide; N-isopropyl-4-(4-morpholino-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)-1,4-diazepane-1-carboxamide; N-isopropyl-4-(4-morpholino-6-(4-(3-pyridazin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)-1,4-diazepane-1-carboxamide; N-isopropyl-4-(4-morpholino-6-(4-(3-pyrimidin-5-ylureido)phenyl)-1,3,5-triazin-2-yl)-1,4-diazepane-1-carboxamide; N-isopropyl-4-(4-morpholino-6-(4-(3-pyridin-3-ylureido)phenyl)-1,3,5-triazin-2-yl)-1,4-diazepane-1-carboxamide; 1-(4-(4-morpholino-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea; 1-(4-(4-morpholino-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea; 1-(4-(4-morpholino-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridazin-4-yl)urea; 1-(4-(4-morpholino-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyrimidin-5-yl)urea; 1-(4-(4-morpholino-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-phenylurea; 1-(4-chlorophenyl)-3-(4-(4-morpholino-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-fluorophenyl)-3-(4-(4-morpholino-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-(2-methyl-1H-imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-phenylurea; 1-(4-chlorophenyl)-3-(4-(4-(2-methyl-1H-imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-fluorophenyl)-3-(4-(4-(2-methyl-1H-imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-(2-methyl-1H-imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea; 1-(4-(4-(2-methyl-1H-imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridazin-4-yl)urea; 1-(4-(4-(2-methyl-1H-imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyrimidin-5-yl)urea; 1-(4-acetylphenyl)-3-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazin-1-yl)phenyl)urea; 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)acetyl)phenyl)urea; 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-morpholinoacetyl)phenyl)urea; 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxyacetyl)phenyl)urea; 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(methoxymethyl)phenyl)urea; 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-methoxyethyl)phenyl)urea; 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(1-hydroxyethyl)phenyl)urea; 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxypropan-2-yl)phenyl)urea; 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxypropyl)phenyl)urea; 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxy-2-methylpropyl)phenyl)urea; 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea; 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-cyanophenyl)urea; 4-(3-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N-methylbenzamide; 4-(3-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N,N-dimethylbenzamide; 4-(3-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazine-1-carbonyl)pyridin-3-yl)urea; (R)-1-(4-((di methylamino)methyl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; (R)-1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea; (R)-1-(4-acetylphenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; (R)-1-(4-(2-(dimethylamino)acetyl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; (R)-1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-morpholinoacetyl)phenyl)urea; (R)-1-(4-(2-hydroxyacetyl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; (R)-1-(4-(methoxymethyl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; (R)-1-(4-(2-methoxyethyl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(1-hydroxyethyl)phenyl)-3-(4-(4-((R)-3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; (R)-1-(4-(2-hydroxypropan-2-yl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(2-hydroxypropyl)phenyl)-3-(4-(4-((R)-3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; (R)-1-(4-(2-hydroxy-2-methylpropyl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; (R)-1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; (R)-1-(4-cyanophenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; (R)—N-methyl-4-(3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; (R)—N, N-dimethyl-4-(3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; (R)-4-(3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; (R)-1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazine-1-carbonyl)pyridin-3-yl)urea; 1-(4-(4-(3-methyl-1H-pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyrimidin-5-yl)urea; 1-(4-(4-(3-methyl-1H-pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea; 1-(4-(4-(3-methyl-1H-pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea; 1-(4-(4-(3-methyl-1H-pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridazin-4-yl)urea; 1-(4-(4-(3-methyl-1H-pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-phenylurea; 1-(4-chlorophenyl)-3-(4-(4-(3-methyl-1H-pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-fluorophenyl)-3-(4-(4-(3-methyl-1H-pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; methyl 4-(3-(4-(4-(3-methyl-1H-pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoate; 4-(3-(4-(4-(3-methyl-1H-pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid; 4-(3-(4-(4-(3-methyl-1H-pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; 1-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)-3-(4-(4-(3-methyl-1H-pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-(3-methyl-1H-pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazine-1-carbonyl)phenyl)urea; 1-(4-(4-(3-methyl-1H-pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea; 1-(4-(4-ethylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(3-methyl-1H-pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(3-methyl-1H-pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4-(3-methyl-1H-pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; 1-{4-[(4-butylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4-[4-(1-methylethyl)-1,4-diazepan-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea; 1-(4-{4-[4-(1-methylethyl)-1,4-diazepan-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)urea; 1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4-[4-(1-methylethyl)-1,4-diazepan-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea; 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl]phenyl}urea; 1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; 1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; 1-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl]phenyl}urea; N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; 1-{4-[4-(azetidin-3-yloxy)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; N-(1-methylethyl)-3-[(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)oxy]azetidine-1-carboxamide; N-{1-[(4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}phenyl)carbonyl]piperidin-4-yl}acetamide; 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)-3-(4-{[4-(1-methylethyl)-1,4-diazepan-1-yl]carbonyl}phenyl)urea; 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)-3-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-ylcarbonyl)phenyl]urea; 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)-3-{4-[(4-cyanopiperidin-1-yl)carbonyl]phenyl}urea; 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)-3-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)urea; 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)-3-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)urea; 1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-(4-{4-(morpholin-4-yl)-6-[4-(propan-2-yl)-1,4-diazepan-1-yl]-1,3,5-triazin-2-yl}phenyl)urea; 1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-(4-{4-(morpholin-4-yl)-6-[4-(propan-2-yl)-1,4-diazepan-1-yl]-1,3,5-triazin-2-yl}phenyl)urea; 1-{4-[4,6-di(morpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}-3-{4-[(2-methylpiperazin-1-yl)carbonyl]phenyl}urea; 1-(4-{4-(morpholin-4-yl)-6-[4-(propan-2-yl)-1,4-diazepan-1-yl]-1,3,5-triazin-2-yl}phenyl)-3-[4-(piperazin-1-ylcarbonyl)phenyl]urea; 1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-(4-{4-(morpholin-4-yl)-6-[4-(propan-2-yl)-1,4-diazepan-1-yl]-1,3,5-triazin-2-yl}phenyl)urea; 1-{4-[4,6-di(morpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}-3-{4-[(3,3,4-trimethylpiperazin-1-yl)carbonyl]phenyl}urea; 1-{4-[4,6-di(morpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}-3-(4-{[(3R)-3-methylpiperazin-1-yl]carbonyl}phenyl)urea; 1-(4-{[(3R)-3,4-dimethylpiperazin-1-yl]carbonyl}phenyl)-3-{4-[4,6-di(morpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}urea; 1-(4-{[(3R)-4-cyclobutyl-3-methylpiperazin-1-yl]carbonyl}phenyl)-3-{4-[4,6-di(morpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}urea; 1-{4-[4,6-di(morpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}-3-(4-{[(3R)-3-methyl-4-(propan-2-yl)piperazin-1-yl]carbonyl}phenyl)urea; 1-{4-[4,6-di(morpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}-3-(4-{[(3S)-3-methylpiperazin-1-yl]carbonyl}phenyl)urea; N-[2-(dimethylamino)ethyl]-N-methyl-4-{[(4-{4-[(3S)-3-methyl morpholin-4-yl]-6-[4-(propan-2-yl)-1,4-diazepan-1-yl]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide; 1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-[4-(propan-2-yl)-1,4-diazepan-1-yl]-1,3,5-triazin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea; 1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-[4-(propan-2-yl)-1,4-diazepan-1-yl]-1,3,5-triazin-2-yl}phenyl)urea; N-[3-(dimethylamino)propyl]-4-{[(4-{4-(morpholin-4-yl)-6-[4-(propan-2-yl)-1,4-diazepan-1-yl]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide; N-[2-(dimethylamino)ethyl]-N-methyl-4-{[(4-{4-(morpholin-4-yl)-6-[4-(propan-2-yl)-1,4-diazepan-1-yl]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide; 1-[4-(morpholin-4-ylcarbonyl)phenyl]-3-(4-{4-(morpholin-4-yl)-6-[4-(propan-2-yl)-1,4-diazepan-1-yl]-1,3,5-triazin-2-yl}phenyl)urea; N-(2-methoxyethyl)-4-{[(4-{4-(morpholin-4-yl)-6-[4-(propan-2-yl)-1,4-diazepan-1-yl]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide; 1-[4-(1,4-diazepan-1-ylcarbonyl)phenyl]-3-(4-{4-(morpholin-4-yl)-6-[4-(propan-2-yl)-1,4-diazepan-1-yl]-1,3,5-triazin-2-yl}phenyl)urea; 1-(4-{4-(morpholin-4-yl)-6-[4-(propan-2-yl)-1,4-diazepan-1-yl]-1,3,5-triazin-2-yl}phenyl)-3-(4-{[4-(propan-2-yl)-1,4-diazepan-1-yl]carbonyl}phenyl)urea; 1-(4-{[(3S)-4-cyclobutyl-3-methylpiperazin-1-yl]carbonyl}phenyl)-3-{4-[4,6-di(morpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}urea; 1-(4-{[(3S)-3,4-dimethylpiperazin-1-yl]carbonyl}phenyl)-3-{4-[4,6-di(morpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}urea; 1-{4-[4-(morpholin-4-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl]phenyl}-3-{4-[(3,3,4-trimethylpiperazin-1-yl)carbonyl]phenyl}urea; 1-(4-{[(3S)-3,4-dimethylpiperazin-1-yl]carbonyl}phenyl)-3-{4-[4-(morpholin-4-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl]phenyl}urea; 1-(4-{[(3S)-3-methylpiperazin-1-yl]carbonyl}phenyl)-3-{4-[4-(morpholin-4-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl]phenyl}urea; 1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl]phenyl}urea; and 1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl]phenyl}urea.

The invention also includes pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable carrier. The invention includes a compound of formula I when provided as a pharmaceutically acceptable prodrug, hydrated salt, such as pharmaceutically acceptable salt, or mixtures thereof.

In other aspects, the invention provides that the pharmaceutically acceptable carrier suitable for oral administration and the composition comprises an oral dosage form.

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, a MEK 1/2 inhibitor, a HSP90 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, 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, a MEK 1/2 inhibitor, a HSP90 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 I, which are:

said method comprising reacting 2,4,6-trichloro[1,3,5]triazine with

to form the intermediate dichlorotriazine compound.

The method of synthesizing compounds of the Formula I further comprising reacting the intermediate dichlorotriazine compound with

to form the intermediate compound

The method of synthesizing compounds of the Formula I further comprising reacting the intermediate dichlorotriazine compound with

to form the intermediate compound

wherein each R 6 , R 7 , R 8 and R 9 is independently selected and defined according to formula I.

The method of synthesizing compounds of the Formula I wherein the reacting moiety is

Procedures used to synthesize the compounds of the present invention are described in Schemes 1-12 and are illustrated in the examples. Reasonable variations of the described procedures are intended to be within the scope of the present invention:

Compounds of the present inventions were prepared by a multi-step sequence as depicted in Scheme 1. One chlorine atom at a time was selectively replaced at different temperatures. The commercially available cyanuric acid chloride 1 was reacted with morpholine or substituted morpholine derivatives at −10° C. to give the mono morpholine derivative 2. This pivotal intermediate 2 can be reacted with different nucleophiles. In this present invention, intermediates 2 were reacted with different amines and alcohols to give 3 and 5 respectively. The third chlorine atom in intermediates 3 and 5 was replaced with 4-aminoaryl and aminoheteroaryl boronic acid in the presence of (Ph 3 ) 4 P(Pd)/Na 2 CO 3 /DME/Reflux or microwave condition to yield 4 and 8 respectively. The amino group was converted to the urea derivatives by different two procedures depending upon the availability of the starting material. Some of the examples reported here were transformed into the urea derivative by reacting 4 or 8 with an appropriately substituted isocyanate derivative. Many of the urea derivatives reported here were prepared by reacting intermediates 4 or 8 with triphosgene/Et 3 N and an appropriately substituted primary amine derivative. The corresponding carbamate derivatives were prepared by reacting intermediates 4 or 8 with an appropriately substituted chloroformate reagents. The intermediates 2 were also used to prepare derivatives of 6, where in R is a alkyl, alkene, alkyne, aryl or heteroaryl. Reacting 6 with the appropriately substituted alkyl introduced alkyl or cycloalkyl groups in intermediate 6 or cycloalkyl magnesium bromide or the corresponding appropriately substituted organo-zinc reagent. Alkenes can be introduced in compound 6 by a Pd catalyzed appropriately substituted vinyl tin derivatives. Similarly, aryl or heteroaryl substituents can be introduced either by reacting 6 with the corresponding boronic acid (Suzuki coupling) or aryl or heteroaryl magnesium bromide. Alkynes can be introduced by reacting compound 6 with an appropriately substitute alkyne and Pd(0). The alkyne and the alkene introduced can also be functionally converted into other derivatives such as alkyl, alcohol and amine moieties. Detailed procedures are described in the experimental section for each derivative prepared.

Certain compounds of the invention were prepared by the methods outlined in Scheme 2.

Compounds of the invention were also prepared according to the method illustrated in Scheme 3.

The benzene-1,4-diamine intermediates were prepared from 4-fluoronitrobenzene and

the appropriate amine as shown in Scheme 4.

The 4-(alkoxy)aniline intermediates were prepared from 4-fluoronitrobenzene and the appropriate alcohol as shown in Scheme 5.

The thiomorpholine and bis morpholine compounds were prepared from 2,4-dichloro-6-(4-nitrophenyl)-1,3,5-triazine and the appropriate morpholine and thiomorpholine reagents as shown in Scheme 6.

The dihydropyran and tetrahydropyran compounds were prepared from 2,4-dichloro-6-(4-nitrophenyl)-1,3,5-triazine, tributyl(3,6-dihydro-2H-pyran-4-yl)stannane, and the appropriate morpholine as shown in Scheme 7.

The (4-aminophenyl)(piperazin-1-yl)methanone intermediates were prepared from 4-nitrobenzoyl chloride and the appropriate amine as shown in Scheme 8.

The 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-urea compounds were prepared from 2,4-dichloro-6-(4-nitrophenyl)-1,3,5-triazine, (R)-3-methylmorpholine, 3-oxa-8-azabicyclo[3.2.1]octane-hydrochloride, and the appropriate amine as shown in Scheme 9.

The preparation of both the (6S′) and (6R′) isomers of tert-butyl 6-hydroxy-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate from tert-butyl 1H-pyrrole-1-carboxylate is shown in Scheme 10.

The (6S′)-tert-butyl 6-amino-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate and (6R′)-tert-butyl 6-fluoro-6-(alkyl, aryl, or heteroaryl)-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate compounds could be prepared from tert-butyl 6-oxo-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate (Scheme 10) and the appropriate amine or Grignard reagent as shown in Scheme 11.

Compounds of formula I can be prepared from cyanuric chloride as shown in Scheme 12.

The following definitions are used in connection with the 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. 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. Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming from left to right the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent “arylalkyloxycabonyl” refers to the group (C 6 -C 14 aryl)-(C 1 -C 6 alkyl)-O—C(O)—. Terms not defined herein have the meaning commonly attributed to them by those skilled in the art.

“Acyl-” refers to a group having 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, H 2 N—, (C 1 -C 6 alkyl)amino-, di(C 1 -C 6 alkyl)amino-, (C 1 -C 6 alkyl)C(O)N(C 1 -C 3 alkyl)-, (C 1 -C 6 alkyl)carboxyamido-, HC(O)NH—, H 2 NC(O)—, (C 1 -C 6 alkyl)NHC(O)—, di(C 1 -C 6 alkyl)NC(O)—, —CN, hydroxyl, C 1 -C 6 alkoxy-, C 1 -C 6 alkyl-, HO 2 C—, (C 1 -C 6 alkoxy)carbonyl-, (C 1 -C 6 alkyl)C(O)—, C 6 -C 14 aryl-, C 1 -C 9 heteroaryl-, or C 3 -C 8 cycloalkyl-.

“Alkyl” refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms, for example, a C 1 -C 12 alkyl group may have from 1 to 12 (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. Examples of C 1 -C 8 alkyl groups include, but are not limited to, methyl, propyl, pentyl, hexyl, heptyl, 3-methylhex-1-yl, 2,3-dimethylpent-2-yl, 3-ethylpent-1-yl, octyl, 2-methylhept-2-yl, 2,3-dimethylhex-1-yl, and 2,3,3-trimethylpent-1-yl. An alkyl group can be unsubstituted or substituted with one or more groups, including: halogen, —NH 2 , (C 1 -C 6 alkyl)N—, (C 1 -C 6 alkyl)(C 1 -C 6 alkyl)N—, —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), C 1 -C 6 carboxyamidoalkyl-, and —NO 2 .

“Alkadienyl” refer to a straight or branched chain unsaturated hydrocarbon containing at least two double bonds, and either may exist in the E or Z conformation. Examples of a C 4 -C 6 alkadienyl group include, but are not limited to, buta-1,3-dienyl, buta-2,3-dienyl, isoprenyl, penta-1,3-dienyl, and penta-2,4-dien-2-yl.

“Alkadiynyl” refer to a straight or branched chain unsaturated hydrocarbon containing at least two triple bonds. Examples of a C 4 -C 6 alkadiynyl group include, but are not limited to, buta-1,3-diynyl, buta-2,3-diynyl, penta-1,3-diynyl, and penta-2,4-diynyl.

“Alkenyl” refer to a straight or branched chain unsaturated hydrocarbon containing at least one double bond, and may exist in the E or Z conformation. Examples of a C 2 -C 8 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, and 4-octene. Examples of a C 2 -C 6 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, and isohexene. Examples of a C 3 -C 8 alkenyl group include, but are not limited to, 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, and 4-octene. Examples of a C 3 -C 6 alkenyl group include, but are not limited to, prop-2-enyl, but-3-enyl, but-2-enyl, 2-methyallyl, pent-4-enyl, and hex-5-enyl. An alkenyl group can be unsubstituted or substituted with one or more groups, including: halogen, —NH 2 , (C 1 -C 6 alkyl)N—, (C 1 -C 6 alkyl)(C 1 -C 6 alkyl)N—, —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)NH2, —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.

“Alkynyl” refers to a straight or branched chain unsaturated hydrocarbon containing at least one triple bond. Examples of a C 2 -C 6 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, and isohexyne. Examples of a C 3 -C 6 alkynyl group include, but are not limited to, prop-2-ynyl, but-3-ynyl, but-2-ynyl, pent-4-ynyl, and hex-5-ynyl. Examples of a C 3 -C 8 alkynyl group include, but are not limited to, prop-2-ynyl, but-3-ynyl, but-2-ynyl, pent-4-ynyl, hex-5-ynyl, hept-3-ynyl, 2-methylhex-3-ynyl, oct-4-ynyl, and 2-methylhept-3-ynyl. An alkynyl group can be unsubstituted or substituted with one or more groups, including: halogen, —NH 2 , (C 1 -C 6 alkyl)N—, (C 1 -C 6 alkyl)(C 1 -C 6 alkyl)N—, —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)NH2, —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 above. 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-, H 2 N—, (C 1 -C 6 alkyl)amino-, di(C 1 -C 6 alkyl)amino-, (C 1 -C 6 alkyl)C(O)N(C 1 -C 3 alkyl)-, (C 1 -C 6 alkyl)carboxyamido-, HC(O)NH—, H 2 NC(O)—, (C 1 -C 6 alkyl)NHC(O)—, di(C 1 -C 6 alkyl)NC(O)—, NC—, C 1 -C 6 alkoxy-, HO 2 C—, (C 1 -C 6 alkoxy)carbonyl-, (C 1 -C 6 alkyl)C(O)—, C 6 -C 14 aryl-, C 1 -C 9 heteroaryl-, C 3 -C 8 cycloalkyl-, C 1 -C 6 haloalkyl-, amino(C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)carboxyl-, C 1 -C 6 carboxyamidoalkyl-, or O 2 N—.

“(Alkoxy)carbonyl-” refers to the group alkyl-O—C(O)—. Exemplary (C 1 -C 6 alkoxy)carbonyl-groups include but are not limited to methoxy, ethoxy, n-propoxy, 1-propoxy, n-butoxy and t-butoxy. An (alkoxy)carbonyl group can be unsubstituted or substituted with one or more of the following groups: halogen, hydroxyl, H 2 N—, (C 1 -C 6 alkyl)amino-, di(C 1 -C 6 alkyl)amino-, (C 1 -C 6 alkyl)C(O)N(C 1 -C 3 alkyl)-, (C 1 -C 6 alkyl)carboxyamido-, HC(O)NH—, H 2 NC(O)—, (C 1 -C 6 alkyl)NHC(O)—, di(C 1 -C 6 alkyl)NC(O)—, NC—, C 1 -C 6 alkoxy-, HO 2 C—, (C 1 -C 6 alkoxy)carbonyl-, (C 1 -C 6 alkyl)C(O)—, C 6 -C 14 aryl-, C 1 -C 9 heteroaryl-, C 3 -C 8 cycloalkyl-, C 1 -C 6 haloalkyl-, amino(C 1 -C 6 alkyl)-(C 1 -C 6 alkyl)carboxyl-, C 1 -C 6 carboxyamidoalkyl-, or O 2 N—.

“(Alkyl)amido-” refers to a —C(O)NH— group in which the nitrogen atom of said group is attached to a C 1 -C 6 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 CH 3 NH—, CH 3 CH 2 NH—, CH 3 CH 2 CH 2 NH—, CH 3 CH 2 CH 2 CH 2 NH—, (CH 3 ) 2 CHNH—, (CH 3 ) 2 CHCH 2 NH—, CH 3 CH 2 CH(CH 3 )NH— and (CH 3 ) 3 CNH—. An (alkyl)amino group can be unsubstituted or substituted with one or more of the following groups: halogen, H 2 N—, (C 1 -C 6 alkyl)amino-, di(C 1 -C 6 alkyl)amino-, (C 1 -C 6 alkyl)C(O)N(C 1 -C 3 alkyl)-, (C 1 -C 6 alkyl)carboxyamido-, HC(O)NH—, H 2 NC(O)—, (C 1 -C 6 alkyl)NHC(O)—, di(C 1 -C 6 alkyl)NC(O)—, NC—, hydroxyl, C 1 -C 6 alkoxy-, C 1 -C 6 alkyl-, HO 2 C—, (C 1 -C 6 alkoxy)carbonyl-, (C 1 -C 6 alkyl)C(O)—, C 6 -C 14 aryl-, C 1 -C 9 heteroaryl-, C 3 -C 8 cycloalkyl-, C 1 -C 6 haloalkyl-, amino(C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)carboxyl-, C 1 -C 6 carboxyamidoalkyl-, or O 2 N—.

“Aminoalkyl-” refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with —NH 2 ; one or both H of the NH 2 may be replaced by a substituent.

“Alkylcarboxyl-” refers to an alkyl group, defined above that is attached to the parent structure through the oxygen atom of a carboxyl (C(O)—O—) functionality. Examples of (C 1 -C 6 alkyl)carboxyl-include acetoxy, propionoxy, propylcarboxyl, and isopentylcarboxyl.

“(Alkyl)carboxyamido-” refers to a —NHC(O)— group in which the carbonyl carbon atom of said group is attached to a C 1 -C 6 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 alkyl, alkenyl and alkynyl groups, as defined above, having two points of attachment within a chemical structure. Examples of C 1 -C 6 alkylene include ethylene, propylene, and dimethylpropylene. Likewise, examples of C 2 -C 6 alkenylene include ethenylene and propenylene. Examples of C 2 -C 6 alkynylene include ethynylene and propynylene.

Aryl refers to an aromatic hydrocarbon group. Examples of a C 6 -C 14 aryl group include, but are not limited to, phenyl, α-naphthyl, β-naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, and acenanaphthyl. Examples of a C 6 -C 10 aryl group include, but are not limited to, phenyl, α-naphthyl, β-naphthyl, biphenyl, and tetrahydronaphthyl. An aryl group can be unsubstituted or substituted with one or more groups, including: 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's hydrogen atoms has been replaced with an aryl group as defined above. (C 6 -C 14 Aryl)alkyl-moieties include benzyl, benzhydryl, 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, H 2 N—, hydroxyl, (C 1 -C 6 alkyl)amino-, di(C 1 -C 6 alkyl)amino-, (C 1 -C 6 alkyl)C(O)N(C 1 -C 3 alkyl)-, (C 1 -C 6 alkyl)carboxyamido-, HC(O)NH—, H 2 NC(O)—, (C 1 -C 6 alkyl)NHC(O)—, di(C 1 -C 6 alkyl)NC(O)—, NC—, hydroxyl, C 1 -C 6 alkoxy-, C 1 -C 6 alkyl-, HO 2 C—, (C 1 -C 6 alkoxy)carbonyl-, (C 1 -C 6 alkyl)C(O)—, C 6 -C 14 aryl-, C 1 -C 9 heteroaryl-, C 3 -C 8 cycloalkyl-, C 1 -C 6 haloalkyl-, amino(C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)carboxyl-, C 1 -C 6 carboxyamidoalkyl-, or O 2 N—.

“(Aryl)amino” refers to a radical of formula (aryl)-NH—, wherein aryl is as defined above. “(Aryl)oxy” refers to the group Ar—O— where Ar is an aryl group, as defined above.

“Cycloalkyl” refers to a non-aromatic, saturated, monocyclic, bicyclic or polycyclic hydrocarbon ring system. Representative examples of a C 3 -C 12 cycloalkyl include, but are not limited to, cyclopropyl, cyclopentyl, cycloheptyl, cyclooctyl, decahydronaphthalen-1-yl, octahydro-1H-inden-2-yl, decahydro-1H-benzo[7]annulen-2-yl, and dodecahydros-indacen-4-yl. Representative examples of a C 3 -C 10 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decahydronaphthalen-1-yl, and octahydro-1H-inden-2-yl. Representative examples of a C 3 -C 8 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and octahydropentalen-2-yl. A cycloalkyl can be unsubstituted or substituted with one or more groups, including: halogen, —NH 2 , (C 1 -C 6 alkyl)N—, (C 1 -C 6 alkyl)(C 1 -C 6 alkyl)N—, —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), C 1 -C 6 carboxyamidoalkyl-, and —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.

“Cycloalkenyl” refers to a non-aromatic, unsaturated, monocyclic, bicyclic or polycyclic hydrocarbon ring system containing at least one double bond connecting two ring carbon atoms. Representative examples of a C 5 -C 8 cycloalkenyl include, but are not limited to, cyclopentenyl, cyclohexenyl, 4,4a-octalin-3-yl, and cyclooctenyl. A cycloalkenyl can be unsubstituted or substituted with one or more groups, including: halogen, —NH 2 , (C 1 -C 6 alkyl)N—, (C 1 -C 6 alkyl)(C 1 -C 6 alkyl)N—, —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 6 cycloalkyl. 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.

“Di(alkyl)amino-” refers to a nitrogen atom attached to 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(H)—, —N(C 1 -C 6 alkyl)-, —N(C 3 -C 8 cycloalkyl)-, —N(C 6 -C 14 aryl)-, —N(C 1 -C 9 heteroaryl)-, —N(amino(C 1 -C 6 alkyl))-, —N(C 6 -C 14 arylamino)-, —O—, —S—, —S(O)—, or —S(O) 2 —.

“Halo” or “halogen” refers to —F, —Cl, —Br and —I.

“C 1 -C 6 Haloalkyl-” refers to a C 1 -C 6 alkyl group, as defined above, wherein one or more of the C 1 -C 6 alkyl group'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 a monocyclic, bicyclic, or polycyclic aromatic ring system containing at least one ring atom selected from the heteroatoms oxygen, sulfur and nitrogen. Examples of C 1 -C 9 heteroaryl groups include furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1-methyl-1,2,4-triazole, 1H-tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline. Bicyclic C 1 -C 9 heteroaryl groups include those where a phenyl, pyridine, pyrimidine or pyridazine ring is fused to a 5 or 6-membered monocyclic heteroaryl ring having one or two nitrogen atoms in the ring, one nitrogen atom together with either one oxygen or one sulfur atom in the ring, or one O or S ring atom. Examples of monocyclic C 1 -C 4 heteroaryl groups include 2H-tetrazole, 3H-1,2,4-triazole, furan, thiophene, oxazole, thiazole, isoxazole, isothiazole, imidazole, and pyrrole. A heteroaryl group can be unsubstituted or substituted with one or more groups, including: 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 .

“(Heteroaryl)alkyl-” refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with a heteroaryl-group as defined above. Examples of (C 1 -C 9 heteroaryl)alkyl-moieties include 2-pyridylmethyl, 2-thiophenylethyl, 3-pyridylpropyl, 2-quinolinylmethyl, 2-indolylmethyl, and the like. A (heteroaryl)alkyl group can be unsubstituted or substituted with one or more of the following groups: halogen, H 2 N—, hydroxyl, (C 1 -C 6 alkyl)amino-, di(C 1 -C 6 alkyl)amino-, (C 1 -C 6 alkyl)C(O)N(C 1 -C 3 alkyl)-, (C 1 -C 6 alkyl)carboxyamido-, HC(O)NH—, H 2 NC(O)—, (C 1 -C 6 alkyl)NHC(O)—, di(C 1 -C 6 alkyl)NC(O)—, NC—, hydroxyl, C 1 -C 6 alkoxy-, C 1 -C 6 alkyl-, HO 2 C—, (C 1 -C 6 alkoxy)carbonyl-, (C 1 -C 6 alkyl)C(O)—, C 6 -C 14 aryl-, C 1 -C 9 heteroaryl-, C 3 -C 8 cycloalkyl-, C 1 -C 6 haloalkyl-, amino(C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)carboxyl-, C 1 -C 6 carboxyamidoalkyl-, or O 2 N—.

The term “heteroatom” refers to a sulfur, nitrogen, or oxygen atom.

“Heterocycle” or “heterocyclyl” refers to monocyclic, bicyclic and polycyclic groups in which at least one ring atom is a heteroatom. A heterocycle may be saturated or partially saturated. Exemplary C 1 -C 9 heterocyclyl-groups include but are not limited to aziridine, oxirane, oxirene, thiirane, pyrroline, pyrrolidine, dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, dithiolane, piperidine, 1,2,3,6-tetrahydropyridine-1-yl, tetrahydropyran, pyran, thiane, thiine, piperazine, oxazine, 5,6-dihydro-4H-1,3-oxazin-2-yl, 2,5-diazabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.2]octane, 3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 6-oxa-3,8-diazabicyclo[3.2.1]octane, 7-oxa-2,5-diazabicyclo[2.2.2]octane, 2,7-dioxa-5-azabicyclo[2.2.2]octane, 2-oxa-5-azabicyclo[2.2.1]heptane-5-yl, 2-oxa-5-azabicyclo[2.2.2]octane, 3,6-dioxa-8-azabicyclo[3.2.1]octane, 3-oxa-6-azabicyclo[3.1.1]heptane, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 5,7-dioxa-2-azabicyclo[2.2.2]octane, 6,8-dioxa-3-azabicyclo[3.2.1]octane, 6-oxa-3-azabicyclo[3.1.1]heptane, 8-oxa-3-azabicyclo[3.2.1]octan-3-yl, 2-methyl-2,5-diazabicyclo[2.2.1]heptane-5-yl, 1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl, 3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl-, 7-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl, 9-oxa-3-azabicyclo[3.3.1]nonan-3-yl, 3-oxa-9-azabicyclo[3.3.1]nonan-9-yl, 3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl, 4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl, thiazine, dithiane, and dioxane. The contemplated heterocycle rings or ring systems have a minimum of 3 members. Therefore, for example, C 1 heterocyclyl-radicals would include but are not limited to oxaziranyl, diaziridinyl, and diazirinyl, C 2 heterocyclyl-radicals include but are not limited to aziridinyl, oxiranyl, and diazetidinyl, C 9 heterocyclyl-radicals include but are not limited to azecanyl, tetrahydroquinolinyl, and perhydroisoquinolinyl. A heterocyclyl group can be unsubstituted or substituted with one or more groups, including: 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 .

“Heterocyclyl(alkyl)-” refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with a heterocycle group as defined above. Heterocyclyl(C 1 -C 6 alkyl)-moieties include 2-pyridylmethyl, 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, H 2 N—, (C 1 -C 6 alkyl)amino-, di(C 1 -C 6 alkyl)amino-, (C 1 -C 6 alkyl)C(O)N(C 1 -C 3 alkyl)-, (C 1 -C 6 alkyl)carboxyamido-, HC(O)NH—, H 2 NC(O)—, (C 1 -C 6 alkyl)NHC(O)—, di(C 1 -C 6 alkyl)NC(O)—, NC—, hydroxyl, C 1 -C 6 alkoxy-, C 1 -C 6 alkyl-, HO 2 C—, (C 1 -C 6 alkoxy)carbonyl-, (C 1 -C 6 alkyl)C(O)—, 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 alkyl group'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.

“Monocyclic heterocyclyl” refers to monocyclic groups in which at least one ring atom is a heteroatom. A heterocycle may be saturated or partially saturated. Exemplary monocyclic C 1 -C 9 heterocyclyl-groups include but are not limited to aziridine, oxirane, oxirene, thiirane, pyrroline, pyrrolidine, dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, dithiolane, piperidine, 1,2,3,6-tetrahydropyridine-1-yl, tetrahydropyran, pyran, thiane, thiine, piperazine, oxazine, 5,6-dihydro-4H-1,3-oxazin-2-yl, 4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl, thiazine, dithiane, and dioxane. The contemplated heterocycle ring systems have a minimum of 3 members. Therefore, for example, C 1 heterocyclyl-radicals would include but are not limited to oxaziranyl, diaziridinyl, and diazirinyl, C 2 heterocyclyl-radicals include but are not limited to aziridinyl, oxiranyl, and diazetidinyl, C 9 heterocyclyl-radicals include but are not limited to azecanyl. A heterocyclyl group can be unsubstituted or substituted with one or more groups, including: 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 .

“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 .

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 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.

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 with a compound of this invention is an amount effective for inhibiting mTOR or PI3K in a subject.

Some compounds within the present invention possess one or more chiral centers, and the present invention includes each separate enantiomer of such compounds as well as mixtures of the enantiomers. Where multiple chiral centers exist in compounds of the present invention, the invention includes each combination as well as mixtures thereof. All chiral, diastereomeric, and racemic forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials.

The 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 compounds of the present invention 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 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 & 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'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's purview to determine the other therapeutic agent'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 compounds of Formula I are set forth in the Examples below and generalized in Schemes 1-3:

One of skill in the art will recognize that Schemes 1-3 can be adapted to produce the other compounds of Formula I and pharmaceutically acceptable salts of compounds of Formula I 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 diisopropyl azodicarboxylate, 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'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'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, TBSCl is tert-butyldimethylsilyl chloride, TCA is tricholoroacetic acid, TFA is trifluoroacetic acid, THF is tetrahydrofuran, TLC is thin-layer chromatography, and TRIS is tris(hydroxymethyl)aminomethane.

Methods

The following methods outline the synthesis of the compounds of Formula I. The following examples are presented to illustrate certain embodiments of the present invention, but should not be construed as limiting the scope of this invention.

Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea

To a stirred solution of cyanuric chloride (18.4 g, 10 mmol) in acetone (100 ml) and crushed ice (500 g), a mixture of triethylamine (30.0 g, excess) and morpholine (17.4 g, 20 mmol) was added at −10° C. After the addition, reaction mixture was stirred at room temperature and for 1 hour and diluted with 50 ml water. Separated white solid was filtered and washed with water. The white solid was dried and filtered. The crude product was found to be pure and taken to next step without purification. Yield: 25 g, 87%; (M+H) 286.7

A mixture of 2-chloro-4,6-di-morpholin-4-yl-[1,3,5]triazine (1.4 g, 4.9 mmoles), a catalytic amount of tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.061 mmoles), sodium carbonate solution 2 M (3 mL), 4-aminophenylboronic acid pinacol ester (1.6 g, 7.3 mmoles) and DME (100 mL) was refluxed for 24 hours. The solvent was evaporated, and the residue was dissolved in methylene chloride and filtered through Celite™. The filtrate was washed with water (200 mL) and the organic layer was dried with magnesium sulfate. This was filtered and the solvent was evaporated. The residue was purified by Silica gel column chromatography and eluted with Ethyl acetate/hexanes (1:1) to give 1.40 g, (83% yield) of 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline as an amorphous solid. (M+H) 343.

To a mixture of 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.20 g 0.40 mmoles) in methylene chloride (80 mL) at 0° C. was added triphosgene (0.25 mg, 0.84 mmoles) and triethylamine (3 mL). The mixture was stirred for 20 minutes at 0° C. and 4-amino pyridine (0.10 g 0.83 mmoles) was added to the reaction mixture and stirred for another 2 hours at room temperature. The solvent was evaporated and the residue was submitted to the HPLC using acetonitrile/TFA as mobile phase to give 98.2 mg (36% yield) of 1-[4-(4,6-dimophorlin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea. (M+H)=463.3.

Procedure A for Preparation of Ureas Using Aryl Isocyanates:

To a stirred mixture of 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (140 mg, 0.40 mmoles) and a catalytic amount of dimethylaminopyridine (DMAP) in methylene chloride 100 (mL), was added a small excess of aryl isocyanate (0.61 mmoles). The mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated to half of its original volume and the separated precipitate was collected by filtration and washed with methanol (15 ml) and then with diethyl ether. In some cases the crude product obtained was purified by Silica gel column chromatography by eluting it with appropriate solvents, depending upon the polarity of the products.

The following compounds were prepared according to Procedure A:

To a stirred solution of cyanuric chloride (18.4 g, 10 mmol) in acetone (100 ml) and crushed ice (500 g), a mixture of triethylamine (30.0 g, excess) and morpholine (8.7 g, 10 mmol) was added at −10° C. After the addition, reaction mixture was stirred at room temperature and for 1 hour and diluted with 50 ml water. Separated white solid was filtered and washed with water. The white solid was dried and filtered. The crude product was found to be pure and taken to next step with out purification. Yield: 18 g, 76%; (M+H) 236.4

Step 2: Preparation of tert-butyl 3-(4-chloro-6-morpholine-1,3,5-triazin-2-2-ylamino)azetidine-1-carboxylate

To a stirred solution of 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (2.35 g, 10 mmol) in acetone (50 ml) and crushed ice, a mixture of triethylamine and 1-boc-3-(amino)azetidine (1.72 g) was added slowly. The reaction mixture was stirred at room temperature for 6 hours and the separated solid was filtered. The product was dried and taken to next step with out purification. Yield: 3.0 g (81%); (M+H) 373

Step 3: Preparation of tert-butyl-3-4-(4-(4-aminophenyl)-6-morpholine-1,3,5-triazin-2-ylamino)azetidine-1-carboxylate

A mixture of tert-butyl 3-(4-chloro-6-morpholine-1,3,5-triazin-2-2-ylamino)azetidine-1-carboxylate (1.1 g, 3.0 mmoles), tetrakis(triphenylphosphine)palladium (0) in catalytic amount (70 mg, 0061 mmoles), sodium carbonate solution 2 M (3 mL), 4-aminophenylboronic acid pinacol ester (0.97 g, 4.5 mmoles), DME (100 mL) was refluxed for 24 hours. The solvent was evaporated and the residue was dissolved in methylene chloride and filtered though Celite™. The organic layer was washed with water (200 mL) and dried over magnesium sulfate. It was filtered and the solvent was evaporated. The residue was chromatographed on silica gel column using Ethyl acetate/hexanes (1:1) as an eluent, to give 0.86 g, (68% yield) of tert-butyl-3-4-(4-(4-aminophenyl)-6-morpholine-1,3,5-triazin-2-ylamino)azetidine-1-carboxylate. (M+H) 428

Step 4: Preparation of tert-butyl 3-{[4-(4-{[(4-fluorophenyl)carbamoyl]amino}phenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino}azetidine-1-carboxylate

A mixture of tert-butyl 3-{[4-(4-aminophenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino}azetidine-1-carboxylate (100 mg, 0.23 mmol), 4-fluorophenylisocyanate (63 mg, 0.46 mmol) and DMAP (5 mg) was stirred at room temperature for a period of 24 hours. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. White solid; Yield 40 mg (30%); (M+H) 565.6

To a solution of cyanuric chloride (2.5 g, 13.5 mmol) in CH 2 Cl 2 (150 mL) was added dropwise morpholine (1.14 g, 13.5 mmol) at −78° C., followed by addition of Et3N (3.0 mL, 21.5 mmol). The resulting reaction mixture was stirred at −78° C. for 20 min, and then diluted with CH 2 Cl 2 . The organic phase was washed with water and brine, and dried over MgSO 4 . The solvent was removed in vacuum to give the title compound as white crystalline solid (3.027 g, 95% yield). MS(ESI) m/z 235.1.

To a solution of 4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine (2.34 g, 10 mmol) in CH 2 Cl 2 (100 mL) were added 3-oxa-8-azabicyclo[3,2,1]octane hydrochloride (1.645 g, 11 mmol) and Et3N (4.2 mL, 30 mmol). The mixture was stirred at room temperature over night. The reaction mixture was washed with water and brine, and dried over MgSO 4 . The solvent was removed in vacuum to give the title compound as white solid (3.0 g, 96% yield). MS(ESI) m/z 312.1.

Step 3: Synthesis of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline

To a 10 mL vial were added 8-(4-chloro-6-morpholino-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3,2,1]octane (311 mg, 1.0 mmol), 4-aminophenylboronic acid pinacol ester (328 mg, 1.5 mmol), Pd(PPh3)4 (58 mg, 5 mol %), 1,2-dimethoxyethane (DME, 2.5 mL) and 2M Na2CO3 aqueous solution (1.5 mL). The resulting mixture was heated at 130° C. for 30 min in microwave oven. The reaction mixture was cooled to room temperature. The aqueous phase was extracted with EtOAc, and the combined organic phases were dried over (MgSO 4 ). The solvent was removed under reduced pressure and the residue was subjected to HPLC separation to give the title compound as off-white solid (280 mg, 76% yield). MS(ESI) m/z 369.2.

To a stirred solution of dichoromonomorpholino derivative of 1,3,5-triazine (2.0 g, 8.5 mmoles) in methylene chloride 200 mL, was added 3S-3-methylmorpholine (0.85 g, 8.5 mmoles) combined with two equivalents of triethylamine 1.7 mL dropwise manner. After the addition reaction mixture was stirred at room temperature for 3 hours and quenched with water. The aqueous layer was washed well with water; dried over anhydrous MgSO 4 and filtered. The solvent was evaporated and the residue obtained was triturated with diethyl ether/hexane (1:1) and filtered. The solid was used without further purification. (1.0 g, 40% yield). M+H 357.3.

Step 2: Preparation of 4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}aniline

A mixture of 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazine (1.26, 4.2 mmol), sodium carbonate solution (2M, 2 mL), tetrakis palladium triphenylphosphine 70 mg (catalytic amount) and 4-aminophenyl boronic pinacol ester (1.37 g, 6.3 mmoles) in DME (100 mL) was heated to reflux for 24 hours. The solvent was evaporated, the residue was re-dissolved in methylene chloride and filtered through Celite™. The solvent was evaporated and the residue was chromatographed on silica gel eluting with first 26/4 hexanes/ethyl acetate then increased to 1/1 hexanes ethyl acetate to give 1.0 of 4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}aniline (71% yield); M+H 357.2.

Step 3: Preparation of 1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea

Starting from 4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}aniline (0.160, 0.44 mmoles) and 4-aminopyridine (100 mg, 1.06 mmoles) and following the procedure as outlined in example 81, 1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea was isolated by HPLC purification. Yield: 125 mg, 60%; MS (ESI) m/z 477.3.

In a three necked flask under nitrogen equipped was dissolved 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (610 mg, 2.6 mmol), tributyldihydropyranylstanane (1.45 g, 3.89 mmol, 1.5 eq), and (Ph 3 P) 2 PdCl 2 (150 mg, 0.21 mmol, 0.1 eq) in anhydrous dioxan (5 ml). The reaction mixture was heated under stirring to 90° C. for 16 hrs. For purification silica gel (10 g) was added to the mixture and the solvent was removed to let the product adsorbed on the silica gel. The silica gel plug was placed on a column and the mixture was flash chromatographed with hexane:ethyl acetate (10:1) to give after removal solvent the product as off white solid (345 mg=47% yield); MS (ESI) m/z 281.

Step 2: Preparation of 4-[4-(3,6-Dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenylamine

To a microwave processing tube was added dimethoxyethane (4 mL), aqueous Na 2 CO 3 (2 molar)(1 mL, 2 mmol, 2 eq), (Ph 3 P) 4 Pd (101 mg, 0.088 mmol), 4-anilinoboronic acid or ester (581 mg, 2.65 mmol, 1.5 eq) and the 2-chloro-4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-[1,3,5]triazine (500 mg, 1.76 mmol) and the vessel was sealed. The mixture was heated to 140° C. for 60 minutes. The solvents were distilled and the crude compound was purified by silica gel chromatography using CH 2 Cl 2 /ethyl acetate (10:1) and later CH 2 Cl 2 /MeOH/NH3 (20:1:0.1) to give the product as a off-white solid (520 mg, 87% yield); MS (ESI) m/z 340.2

Step 3: Preparation of 1-{4-[4-(3,6-Dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea

To a stirred solution of triphosgene (140 mg, 0.47 mmol) in CH 2 Cl 2 (6 mL) was added 4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenylamine (200 mg, 0.59 mmol) at 25° C. The reaction mixture was stirred for 15 min and 4-aminopyridine (166 mg, 1.77 mmol) and NEt 3 (814 μL, 5.89 mmol) were added and the reaction mixture was stirred for additional 1 hr. The solvents were distilled and the crude mixture was purified by semi-prep-HPLC (TFA-method) to give 1-{4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea (75 mg, 22% yield); MS (ESI) m/z 460

To magnetically stirred ice-water (72 mL) was added a solution of cyanuric chloride (2.2 g, 12 mmol) in acetone (48 mL), followed by piperidone monohydrate hydrochloride (1.8 g, 12 mmol) as a suspension in acetone (20 mL) and water (10 mL). To the mixture was added a suspension of sodium hydrogen carbonate (2.2 g, 24 mmol) in water (25 mL). The mixture was stirred at 0° C. for two hours. The title compound was collected by filtration, washed with water, and dried under vacuum.

MS (ES+) 248.8 (M+H)+

Step 2: Preparation of 1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-yl)piperidin-4-one

To an aqueous solution of 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (66 mL) was added 1-(4,6-dichloro-1,3,5-triazin-2-yl)piperidin-4-one (2.7 g, 11 mmol) as a suspension in acetone (40 mL). To the mixture was added solid sodium carbonate (2.5 g, 24 mmol). The suspension was stirred at 80° C. for two hours and then allowed to cool to room temperature. The title compound was collected by filtration, washed with water, and dried under vacuum; MS (ES+) 324.4 (M+H)+

Step 3: Preparation of 1-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)piperidin-4-one

A suspension of 1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-yl)piperidin-4-one (1.0 g, 3.1 mmol), 4-aminophenylboronic acid, pinacol ester (1.0 g, 4.7 mmol), and tetrakis(triphenylphosphine) palladium (0.20 g, 0.17 mmol) in aqueous 2 M sodium carbonate solution (3 mL) and 1:1 ethanol/toluene (12 mL) was irradiated in the microwave at 120° C. for 1 hour. After cooling, the biphasic mixture was extracted thrice with ethyl acetate. The extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to give the title compound as a golden yellow foam.

MS (ES+)=381.6 (M+H)+

Step 4: Preparation of 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea

A mixture of crude 1-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)piperidin-4-one (approx. 3.1 mmol) and triethylamine (4 mL) in dichloromethane (30 mL) was treated with triphosgene (0.71 g, 2.4 mmol). The mixture was then treated with a solution of 4-aminopyridine (1.8 g, 19 mmol) in tetrahydrofuran (20 mL). The mixture was concentrated to dryness under reduced pressure and the residue purified by HPLC to give the title compound as its TFA salt. MS (ES+) 501.2 (M+H)+

A solution of 2,4-dichloro-6-(4-nitrophenyl)-1,3,5-triazine (1.25 g, 4.61 mmol) and sodium bicarbonate (0.775 g, 9.22 mmol) in acetone (20 mL) and ice water (20 mL) was prepared. To this was added dropwise over 5 minutes (R)-3-methylmorpholine (0.466 g, 4.61 mmol). The resulting tan solution was allowed to stir at 0° C. for 2 hours, then gradually allowed to warm to room temperature over 18 hours. The light brown suspension was filtered and washed with water to provide (R)-4-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-methylmorpholine (1.40 g, 90%) as a light brown solid. HRMS 336.0857 (M+H, calc.), 336.0845 (M+H, obs.).

Step 2: Preparation of 8-(4-((R)-3-methylmorpholino)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane

A solution of (R)-4-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-methylmorpholine (0.94 g, 2.80 mmol) in acetone (10 mL) and ice water (10 mL) was prepared. To this was added dropwise over 10 minutes a suspension of 3-oxa-8-azabicyclo[3.2.1]octane-hydrochloride (0.419 g, 2.80 mmol) and sodium bicarbonate (0.470 g, 5.60 mmol) in acetone (10 mL) and water (10 mL). The resulting tan solution was allowed to stir at 0° C. for 2 hours, then gradually allowed to warm to room temperature over 3 hours. The light brown suspension was filtered and washed with water to provide 8-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.964 g, 83%) as a brown solid. HRMS 413.1931 (M+H, calc.), 413.1936 (M+H, obs.).

Step 3: Preparation of 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)aniline

A solution of 8-(4-((R)-3-methylmorpholino)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.915 g, 2.22 mmol) in ethyl acetate (10 ml), methanol (10 ml), and methylene chloride (5 ml—added due to poor solubility of SM in EA/methanol) was prepared and 10% palladium on carbon (0.270 g, 30% by weight) was added. The flask was purged with hydrogen gas (balloon) and allowed to stir under positive pressure of hydrogen for 16 hours. The suspension was filtered through Celite™, the filter cake was washed with ethyl acetate, and the filtrate was concentrated to provide 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)aniline (0.587 g, 69%) as an off-white solid. (M+H) 383.3.

Step 4: Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea

The method of urea formation using triphosgene and triethylamine in methylene chloride, described in Scheme 1, was utilized using commercially available 4-(4-ethylpiperazin-1-yl)aniline as the amine component. Purification by HPLC (5-95% acetonitrile in water over 20 minutes, 0.05% TFA buffer, Waters Atlantis column) provided 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea (0.0761 g, 95%) as a light yellow solid. (M+H) 614.3.

To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (25.0 g, 114 mmol) and pyridine (4 mL, 57 mmol) in dry dichloromethane (250 mL) phenyl chloroformate (12 mL, 114 mmol) was added drop wise at −10° C. The reaction mixture was stirred at −10° C. for 30 min and then at room temperature for 30 minutes. The reaction mixture was diluted with dichloromethane (100 mL) and washed with water (2×70 mL). The organic layer was dried over anhydrous Na 2 SO 4 and concentrated to get the crude product. Then the crude product was dissolved in diethyl ether (15 mL) and sonicated for 10 min and then pentane (30 mL) was added. the resulting solid was filtered and washed with pentane to give phenyl 4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)phenylcarbamate (26 g, 88% yield).

1 HNMR (300 MHz, CDCl 3 ): δ 7.8 (d, 2H) 7.5 (d, 2H), 7.4 (m, 2H), 7.2 (m, 3H), 7.0 (s, 1H), 1.3 (s, 12H).

A mixture of phenyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (26 g, 76.6 mmol)), 2.0M Methylamine/THF (265 mL, 530 mmol) in 150 mL of THF was stirred at room temperature for 6 hours, then excess solvent was distilled off from the reaction mixture; residue was dissolved into water, extracted with ethyl acetate. The organic layer was dried over anhydrous Na 2 SO 4 , concentrated under reduced pressure. The crude product was purified by silica gel column chromatography by using 5-60% ethyl acetate in pet-ether as an eluent. to give 1-methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea. (20 g, 88% yield) as white solid.

1 HNMR (300 MHz, CDCl 3 ): δ 7.7 (d, 2H), 7.2 (d, 2H), 6.7 (s, 1H), 5.0 (s, 1H), 2.8 (s, 3H), 1.2 (s, 12H).

Morpholine (9.5 mL, 108 mmol)) was added to a solution of cyanuric chloride (20 g, 108 mmol) in chloroform (10 mL) and stirred at −5° C. for 1 hour. Reaction mixture was diluted with water, extracted with dichloromethane. The organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. Crude product was purified by silica gel (100-200 mesh) column chromatography using 5% ethyl acetate in pet-ether as an eluent to give 4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine (10 g, 39% yield).

A mixture of compound 4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine (10 g, 42.7 mmol), Pd (PPh 3 ) 4 (2.46 g, 2.1 mmol), 1-methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea. (11.7 g, 42.4 mmol) and 1N Na 2 CO 3 (168 mL, 168 mmol) in degassed 1,2-dimethoxyethane (400 mL) was heated to 65° C. for 8 hours under N 2 atmosphere. The reaction mixture filtered, diluted with water, extracted with ethyl acetate and washed with water, brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. Crude product was purified by silica gel (100-200 mesh) column chromatography using 20-60% ethyl acetate in pet-ether as an eluent. To give 1-(4-(4-chloro-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea (5.0 g, 34% yield).

1 HNMR (300 MHz, DMSO-d6): δ 9.4 (br, 1H), 8.2 (d, 2H), 7.6 (d, 2H), 6.6 (br, 1H), 4.0 (m, 2H), 3.8 (m, 6H), 2.8 (s, 3H).

The title compound was prepared by following the procedure of Example 462 step 4 using 1-(4-(4-chloro-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. Yield 2 g, 45% yield.

To a solution of 4-aminobenzamide (5.0 g, 36.7 mmol) and pyridine (2.9 g, 36.7 mmol)) in dry CH 2 Cl 2 (100 mL) at −10° C., phenyl chloroformate (6.9 g, 44.1 mmol) was added dropwise, stirred at −10° C. for 30 min and then at room temperature for 30 minutes The reaction mixture was diluted with CH 2 Cl 2 (100 mL) and washed with water (2×70 mL). The organic layer was dried over anhydrous Na 2 SO 4 and concentrated to get the crude product. The crude product was dissolved in diethyl ether (15 mL) and sonicated for 10 minutes and then pentane (30 mL) was added, the resulting solid was filtered and washed with pentane to give phenyl 4-carbamoylphenylcarbamate (7.2 g, 77% yield).

Step 7: Preparation of 4-({[4-(4-{4-[(methylcarbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide

To a solution of 1-(4-(4-(4-aminophenyl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea (0.6 g, 1.5 mmol) and triethylamine (4-5 mL) in dry DMF (10 mL), phenyl 4-carbamoylphenylcarbamate (1.15 g, 4.5 mmol).) was added at room temperature and mixture was heated to 90° C. for 10 hours under nitrogen atmosphere. After cooling to room temperature reaction mixture was quenched with ice water and resulting solid was filtered to get crude product. Crude product was purified by Preparative HPLC to give 4-({[4-(4-{4-[(methylcarbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide (45 mg, 5.3% yield).

Preparation of 1-{4-[4-(3,5-dimethylmorpholin-4-yl)-6-{4-[(methylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea

The title compound was prepared by following the procedure of Example 462 step 3 using cyanuric chloride and 3, 5-dimethylmorpholine. Yield 5 g, 35% yield.

1 HNMR (300 MHz, CDCl 3 ): δ 4.6 (m, 2H), 3.6 (m, 2H), 2.8 (m, 2H), 1.2 (d, 6H).

Step 2: Preparation of 1-(4-(4-chloro-6-(3,5-dimethylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea

The title compound was prepared by following the procedure of example 462 step 4 using 4-(4,6-dichloro-1,3,5-triazin-2-yl)-3,5-dimethylmorpholine and 1-methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea. Yield 1.15 g, 16% yield.

Step 3: Preparation of 1-(4-(4-(4-aminophenyl)-6-(3,5-dimethylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea

The title compound was prepared by following the procedure of example 462 step 4 using 1-(4-(4-chloro-6-(3,5-dimethylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. Yield 2 g, 86% yield.

The title compound was prepared by following the procedure of example 462 step 6 using 3-aminopyridine and phenyl chloroformate. Yield 7 g, 62% yield.

Step 5: Preparation of 1-{4-[4-(3,5-dimethylmorpholin-4-yl)-6-{4-[(methylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea

The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-(3,5-dimethylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl pyridin-3-ylcarbamate. Yield 77 mg, 6% yield.

Preparation of 4-[({4-[4-{4-[(methylcarbamoyl)amino]phenyl}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide

The title compound was prepared by following the procedure of example 462 step 3 using cyanuric chloride and 8-oxa-3-azabicyclo[3.2.1]octane. Yield 10 g, 47% yield.

Step 2: Preparation of 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-yl)phenyl)-3-methylurea

The title compound was prepared by following the procedure of example 462 step 4 using 3-(4,6-dichloro-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane and 1-methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea. Yield 5 g, 29% yield.

Step 3: Preparation of 1-(4-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)phenyl)-3-methylurea

The title compound was prepared by following the procedure of example 462 step 4 using 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-yl)phenyl)-3-methylurea and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. Yield 2.8 g, 49% yield.

Step 4: Preparation of 4-[({4-[4-{4-[(methylcarbamoyl)amino]phenyl}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide

The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl 4-carbamoylphenylcarbamate. Yield 90 mg, 13% yield.

Preparation of 3-[({4-[4-{4-[(methylcarbamoyl)amino]phenyl}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide

The title compound was prepared by following the procedure of example 462 step 6 using 3-aminobenzamide and phenyl chloroformate. Yield 7 g, 74% yield.

Step 2: Preparation of 3-[({4-[4-{4-[(methylcarbamoyl)amino]phenyl}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide

The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl 3-carbamoylphenylcarbamate. Yield 90 mg, 13% yield.

EXAMPLE: 466

Preparation of 3-({[4-(4-{4-[(methylcarbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide

The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl 3-carbamoylphenylcarbamate. Yield 51 mg, 4% yield.

Preparation of 1-methyl-3-[4-(4-morpholin-4-yl-6-{4-[(pyridin-3-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)phenyl]urea

The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl pyridin-3-ylcarbamate. Yield 77 mg, 6% yield.

Preparation of 1-methyl-3-[4-(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)phenyl]urea

The title compound was prepared by following the procedure of example 462 step 6 using 4-aminopyridine and phenyl chloroformate. Yield 6 g, 534% yield.

Step 2: Preparation of 1-methyl-3-[4-(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)phenyl]urea

The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl pyridin-4-ylcarbamate. Yield 75 mg, 3.9% yield.

A solution of morpholine (8.71 g, 100 mmol) in 100 mL of methylene was added dropwise to a mixture of cyanuric chloride (9.22 g, 50.0 mmol) and triethylamine (10.1 g, 100 mmol) in 200 mL of methylene chloride at 0° C. Then the reaction mixture was stirred at 0° C. for 1 hr and slowly warmed up to room temperature. After stirring at room temperature for 1 hr, the reaction mixture was filtered to remove the triethylamine hydrochloride salt. The filtrate was concentrated to give 4,4′-(6-chloro-1,3,5-triazine-2, 4-diyl) dimorpholine (14.2 g, 100 yield) as a white solid. HPLC: Rt=2.43 min; MS 286, 288 [M+H].

A mixture of 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine (1.40 g, 4.90 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.62 g, 11.9 mmol) and tetrakis (triphenylphosphine) palladium (0) (282 mg, 0.240 mmol) in 2M sodium carbonate aqueous solution (10 mL, 20 mmol) and 40 mL of DME was stirred at 80° C. for 2 hr. The reaction mixture was diluted with 300 mL of ethyl acetate and washed with water. The organic layer was concentrated and purified by flash chromatography (ISCO, 120 g silica gel column, eluting with 0-100% EtOAc/Hexane) to give 4-(4,6-dimorpholino-1,3,5-triazin-2-yl)aniline (0.68 g, 40% yield). HPLC: Rt=2.09 min; MS 343 [M+H].

To a mixture of 2, 2-difluoroacetic acid (20 mg, 0.21 mmol), HBTU (76 mg, 0.2 mmol), and DIEA (52 mg, 0.40 mmol) in 2 mL of DMF was added 4-(4,6-dimorpholino-1,3,5-triazin-2-yl) aniline (40 mg, 0.12 mmol). The reaction was stirred at 60° C. 16 hr. Then the reaction mixture was cooled to room temperature and purified by reverse phase chromatography to give N-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-2, 2-difluoroacetamide (23 mg, 46% yield). HPLC: Rt=2.19 min; MS 421 [M+H].

Preparation of N-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-4, 5-dihydro-1H-imidazol-2-amine

A mixture of 4-(4,6-dimorpholino-1,3,5-triazin-2-yl)aniline (40 mg, 0.12 mmol), imidazolidine-2-thione (15 mg, 0.15 mmol0 and mercury(II) chloride (40 mg, 0.15 mmol) in 2 mL of DMF was stirred at 140° C. 16 hr. Then the reaction mixture was cooled to room temperature and filtered through Celite™. The filtration was concentrated and purified by reverse phase chromatography to give N-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-4, 5-dihydro-1H-imidazol-2-amine (9.0 mg, 22% yield). HPLC: Rt=1.74 min; MS 411 [M+H].

Preparation of 2, 4-dimorpholin-4-yl-6-[4-(2H-tetrazol-5-yl)phenyl]-1,3,5-triazine

The title compound was prepared by following the procedure of example 473 step 2 using 4, 4′-(6-chloro-1,3,5-triazine-2, 4-diyl) dimorpholine and 4-cyanophenyl-boronic acid. Yield 86 mg, 50% yield; HPLC: Rt=2.60 min; MS 353 [M+H].

A mixture of 4-(4,6-dimorpholino-1,3,5-triazin-2-yl)benzonitrile (11 mg, 0.031 mmol), sodium azide (5.5 mg, 0.085 mmol) and triethylamine hydrochloride (6.0 mg, 0.043 mmol) in 2 mL of DMF was stirred at 120° C. for 6 hr. Then the reaction mixture was cooled to room temperature and purified by reverse phase chromatography to give 2,4-dimorpholin-4-yl-6-[4-(2H-tetrazol-5-yl)phenyl]-1,3,5-triazine. Yield 12 mg, 97% yield; HPLC: Rt=2.09 min; MS 394 [M−H].

Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-methylurea

A mixture of 2-(4-isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (750 mg, 3.06 mmol), 2.0M Methylamine/THF (2.3 mL, 4.60 mmol) in 50 mL of THF was stirred at room temperature for 6 hr. Then the traction mixture was concentrated to give 1-methyl-3-[4-(4, 4, 5, 5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea. (760 mg, 90% yield). Rt=2.21 min; 277 [M+H].

The title compound was prepared by following the procedure of example 473 step 2 using 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine and 1-Methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea. Yield 13 mg, 11% yield; HPLC: Rt=1.98 min; MS 400 [M+H].

Preparation of 2-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-N-pyridin-3-ylacetamide

A mixture of 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine (285 mg, 1.0 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid. (315 mg, 1.2 mmol) and tetrakis (triphenylphosphine) palladium (0) (58 mg, 0.05 mmol) in 2M sodium carbonate aqueous solution (3 mL, 8 mmol) and 20 mL of DME was stirred at 80° C. for 2 hr. Then the reaction mixture was diluted with 50 mL of ethyl acetate and extracted with 1N NaOH (50 mL, three times)). The combined aqueous layers were neutralized to pH=6. Then the aqueous solution was extracted with ethyl acetate (50 mL, three times). The combined organic layers were washed with saturated sodium carbonate and brine. Then the organic layer was dried over anhydrous sodium sulfate and concentrated to give 2-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl) acetic acid (68 mg, 18% yield). HPLC: Rt=2.04 min; MS 386 [M+H].

The title compound was prepared by following the procedure of example 473 step 3 using 2-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl) acetic acid and 3-aminopyridine. Yield 21 mg, 44% yield; HPLC: Rt=1.91 min; MS 462 [M+H].

Preparation of ((2S,5R)-1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-diyl)dimethanol

A suspension of ((2S,5R)-1-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-diyl)dimethanol (1.3 g, 2.7 mmol), 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (0.51 g, 3.4 mmol) in ethanol (15 mL) was treated with triethylamine (1.35 mL, 10 mmol) and heated with a heat gun briefly to reflux. The reaction mixture was purified by automated flash chromatography (methanol/chloroform) to provide the title compound as a hard peach colored foam. MS (ES + )=443.2 (M+H) +

Preparation of 3-(4-((2S,5R)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidin-1-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

A solution of ((2S,5R)-1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-diyl)dimethanol (1.5 g, 3.4 mmol) in dichloromethane (15 mL) was treated successively with tert-butyl dimethyl chlorosilane (1.3 g, 8.5 mmol) and imidazole (0.69 g, 10 mmol). The resulting suspension was stirred overnight at room temperature and then quenched with water. The aqueous phase was extracted three times with dichloromethane. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude residue (a peach-colored solid) was carried on to the following step without further purification. MS (ES + )=671.4 (M+H) +

Preparation of 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)aniline

A suspension of palladium on charcoal (10%, 100 mg) and crude 3-(4-((2S,5R)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidin-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane (3.4 mmol maximum) in tetrahydrofuran (30 mL) was shaken for 8 hours under 50 psi of hydrogen. The mixture was filtered through a pad of Celite™ diatomaceous earth and concentrated under reduced pressure to provide the title compound as an orange foam. MS (ES + )=642.4 (M+H) +

To a solution of (2R′,3S′,5R′)-tert-butyl 2,5-bis((tert-butyldimethylsilyloxy)methyl)-3-hydroxypyrrolidine-1-carboxylate (2.515 g, 5.3 mmol) in THF (50 mL) were added NaH (60%, 0.423 g, 10.6 mmol). The mixture was stirred at room temperature for 30 minutes, and benzyl bromide (1.085 g, 6.3 mmol) and TBAl (0.195 g, 0.5 mmol) were added. The mixture was stirred at room temperature for 12 hours, and quenched by addition of sat.NH 4 CL solution (20 mL). Concentrated in vacuo, and the residue was taken up in water and EtOAc. The organic layer was separated, and the aqueous phase was extracted with EtOAc. Combined organic phases were washed with water and brine, and dried (MgSO 4 ). The organic solvent was removed in vacuo to give the crude product, which was purified by flash chromatography in silica gel with EtOAc:Hex (10:90) to give (2R′,3S′,5R′)-tert-butyl 3-(benzyloxy)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidine-1-carboxylate (3.0 g, 100%) as colorless oil.

Step 6: Synthesis of (2R′,3S′,5R′)-tert-butyl 3-(benzyloxy)-2,5-bis(hydroxymethyl)pyrrolidine-1-carboxylate (benzyloxy diol)

To a solution of (2R′,3S′,5R′)-tert-butyl 3-(benzyloxy)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidine-1-carboxylate (3.0 g, 5.3 mmol) in THF (50 mL) was added slowly of TBAF solution (1M in THF, 21.8 mL, 21.8 mmol) at 0° C. The resulting mixture was stirred at room temperature for 6, and quenched by addition of sat.NH 4 Cl solution (10 mL). Concentrated in vacuo, and the residue was treated with water and EtOAc. The organic layer was separated, and the aqueous phase was extracted with EtOAc. Combined organic phases were washed with water and brine, and dried (MgSO 4 ). The organic solvent was removed in vacuo to give the crude product, which was purified by flash chromatography in silica gel with EtOAc:Hex:MeOH (50:50:5) to give the title compound (1.15 g, 62.5%).

Step 7: Synthesis of (6S′)-tert-butyl 6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate by cyclization

To a solution of (2R′,3S′,5R′)-tert-butyl 3-(benzyloxy)-2,5-bis(hydroxymethyl)pyrrolidine-1-carboxylate (1.15 g, 3.4 mmol) in THF (50 mL) was added NaH (60%, 0.409 g, 10.2 mmol). The mixture was stirred at room temperature for 30 minutes, and cooled down to 0° C. A solution of p-TsCl (0.65 g, 3.4 mmol) in THF (5 mL) was slowly added to the mixture. The reaction mixture was then stirred at room temperature for 12 hours, and quenched by addition of sat.NH 4 Cl solution (20 mL). Concentrated in vacuo, and the residue was taken up in water and EtOAc. The organic layer was separated, and the aqueous phase was extracted with EtOAc. Combined organic phases were washed with water and brine, and dried (MgSO 4 ). The organic solvent was removed in vacuo to give the crude product, which was purified by flash chromatography in silica gel with EtOAc:Hex (20:80) to give the title compound (716 mg, 66%) as off-white solid.

The compounds in Table I were made by the proceeding methods.

TABLE ! MS (ESI) Example Name m/z 478 1-(4-{[4-(dimethylamino)piperidin-1- 615.5 yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6- (tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2- yl]phenyl}urea 479 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-(4- 589.6 {4-morpholin-4-yl-6-[(3S)-tetrahydrofuran-3-yloxy]- 1,3,5-triazin-2-yl}phenyl)urea 480 1-{4-[4-(5-hydroxy-3-oxa-7-azabicyclo[4.1.1]oct-7-yl)- 505.3 253.2 6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin- 273.8 4-ylurea 481 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3- 464.2 253.1 pyridazin-4-ylurea 482 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4- 575.5 [4-morpholin-4-yl-6-(oxetan-3-yloxy)-1,3,5-triazin-2- yl]phenyl}urea 483 1-{4-[4-morpholin-4-yl-6-(3-oxa-8- 490.6 azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3- pyridazin-4-ylurea 484 1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1- 602.5 yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5- triazin-2-yl)phenyl]urea 485 1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1- 602.6 yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5- triazin-2-yl)phenyl]urea 486 1-[4-(4-isopropyl-6-morpholin-4-yl-1,3,5-triazin-2- 545.1 293.5 yl)phenyl]-3-{4-[(4-methylpiperazin-1- 273 yl)carbonyl]phenyl}urea 487 1-{4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin- 497.3 2-yl]phenyl}-3-(4-pyrimidin-5-ylphenyl)urea 488 1-(4-{4-[(2,2-dimethoxyethyl)amino]-6-morpholin-4- 481.2 241.1 yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea 261.6 489 1-{4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin- 496.3 248.6 2-yl]phenyl}-3-(4-pyridin-4-ylphenyl)urea 269.1 490 1-(4-iodophenyl)-3-{4-[4-(1-methylethyl)-6-morpholin- 545.1 4-yl-1,3,5-triazin-2-yl]phenyl}urea 491 1-{4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin- 573.4 287.2 2-yl]phenyl}-3-(4-{[4-(1-methylethyl)piperazin-1- yl]carbonyl}phenyl)urea 492 1-[4-(4-azetidin-1-yl-6-morpholin-4-yl-1,3,5-triazin-2- 586.6 yl)phenyl]-3-(4-{[4-(1-methylethyl)piperazin-1- yl]carbonyl}phenyl)urea 493 1-{4-[2-(dimethylamino)pyrimidin-5-yl]phenyl}-3-{4-[4- 540.5 (1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2- yl]phenyl}urea 494 tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(pyridin-4- 549.6 ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2- yl)oxy]azetidine-1-carboxylate 495 1-(4-{[4-(dimethylamino)piperidin-1- 616.4 308.7 yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5- triazin-2-yl)phenyl]urea 496 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3- 507.1 (4-nitrophenyl)urea 497 1-(4-aminophenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5- 477.1 259.6 triazin-2-yl)phenyl]urea 498 N-[4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2- 603.2 302.1 yl)phenyl]carbamoyl}amino)phenyl]-4- 322.6 methylpiperazine-1-carboxamide 499 4-(dimethylamino)-N-[4-({[4-(4,6-dimorpholin-4-yl- 631.3 1,3,5-triazin-2- yl)phenyl]carbamoyl}amino)phenyl]piperidine-1- carboxamide 500 1-[2-(dimethylamino)ethyl]-3-[4-({[4-(4,6-dimorpholin- 605.3 4-yl-1,3,5-triazin-2- yl)phenyl]carbamoyl}amino)phenyl]-1-methylurea 501 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3- 631.3 (4-{[(2-piperidin-1- ylethyl)carbamoyl]amino}phenyl)urea 502 N-[4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2- 617.3 yl)phenyl]carbamoyl}amino)phenyl]-4-methyl-1,4- diazepane-1-carboxamide 503 N-[4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2- 617.3 yl)phenyl]carbamoyl}amino)phenyl]-4- ethylpiperazine-1-carboxamide 504 1-{4-[(dimethylcarbamoyl)amino]phenyl}-3-[4-(4,6- 548.3 dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea 505 1-{4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl- 613.4 1,3,5-triazin-2-yl]phenyl}-3-(4-{[4- (dimethylamino)piperidin-1-yl]carbonyl}phenyl)urea 506 4-[({4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4- 587.4 yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-[2- (dimethylamino)ethyl]-N-methylbenzamide 507 1-{4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl- 585.3 1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1- yl)carbonyl]phenyl}urea 508 4-[({4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4- 573.3 yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-[2- (dimethylamino)ethyl]benzamide 509 N-[4-({[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl- 668.4 1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]-2- (4-methylpiperazin-1-yl)acetamide 510 1-(4-{[4-(dimethylamino)piperidin-1- 615.5 yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6- (tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2- yl]phenyl}urea 511 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4- 587.3 [4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5- triazin-2-yl]phenyl}urea 512 N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6- 575.3 (tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 513 4-[({4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)- 601.3 1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2- pyrrolidin-1-ylethyl)benzamide 514 4-[({4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)- 615.3 1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2- piperidin-1-ylethyl)benzamide 515 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3- 616.3 308.6 (4-{[4-(1-methylethyl)piperazin-1- 329.2 yl]carbonyl}phenyl)urea 516 1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1- 627.7 yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa- 8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 517 1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1- 449.4 yl]carbonyl}phenyl)-3-{4-[4-morpholin- 518 4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5- 616.4 triazin-2-yl]phenyl}urea 519 N-[2-(dimethylamino)ethyl]-N-methyl-4-{[(4-{4- 616.4 morpholin-4-yl-6-[(3S)-tetrahydrofuran-3-yloxy]-1,3,5- triazin-2-yl}phenyl)carbamoyl]amino}benzamide 520 4-{[(4-{4-morpholin-4-yl-6-[(3S)-tetrahydrofuran-3- 616.4 yloxy]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}-N- (2-piperidin-1-ylethyl)benzamide 521 4-{[(4-{4-morpholin-4-yl-6-[(3S)-tetrahydrofuran-3- 616.4 yloxy]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}-N- (2-pyrrolidin-1-ylethyl)benzamide 522 1-(4-{[4-(1-methylethyl)piperazin-1- 616.4 yl]carbonyl}phenyl)-3-(4-{4-morpholin-4-yl-6-[(3S)- tetrahydrofuran-3-yloxy]-1,3,5-triazin-2- yl}phenyl)urea 523 1-(4-{[4-(1-methylethyl)piperazin-1- 616.4 yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6- (tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2- yl]phenyl}urea 524 N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4- 616.4 morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5- triazin-2-yl]phenyl}carbamoyl)amino]benzamide 525 4-[({4-[4-(2-methylpropyl)-6-morpholin-4-yl-1,3,5- 477.3 triazin-2-yl]phenyl}carbamoyl)amino]benzoic acid 526 1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 565.4 triazin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1- yl)phenyl]urea 527 4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 511.4 triazin-2-yl]phenyl}carbamoyl)amino]benzoic acid 528 methyl 4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl- 525.4 1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate 529 1-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-3-[4-(4- 531.4 ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea 530 1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 468.3 triazin-2-yl]phenyl}-3-pyridin-4-ylurea 531 1-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-3-{4-[4- 593.4 (4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2- yl]phenyl}urea 532 N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-(4- 595.5 methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 533 1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 593.5 triazin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1- yl)carbonyl]phenyl}urea 534 1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2- 594.5 yl)phenyl]-3-{4-[(4-pyridin-2-ylpiperazin-1- yl)carbonyl]phenyl}urea 535 1-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-3-[4-(4- 579.5 morpholin-4-yl-6-phenyl-1,3,5-triazin-2- yl)phenyl]urea 536 1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2- 531.1 yl)phenyl]-3-{4-[(4-methylpiperazin-1- yl)carbonyl]phenyl}urea 537 1-[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2- 454.1 yl)phenyl]-3-pyridin-4-ylurea 538 methyl 4-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5- 511 triazin-2-yl)phenyl]carbamoyl}amino)benzoate 539 N-[2-(dimethylamino)ethyl]-N-methyl-4-({[4-(4- 581.2 morpholin-4-yl-6-phenyl-1,3,5-triazin-2- yl)phenyl]carbamoyl}amino)benzamide 540 methyl 4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]- 548 1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzoate 541 4-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2- 497 yl)phenyl]carbamoyl}amino)benzoic acid 542 N-[2-(dimethylamino)ethyl]-4-[({4-[4-(4- 581.3 methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 543 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-[4- 579.2 (4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2- yl)phenyl]urea 544 1-(4-{[4-(dimethylamino)piperidin-1- 661.5 yl]carbonyl}phenyl)-3-[4-(4-morpholin-4-yl-6-phenyl- 1,3,5-triazin-2-yl)phenyl]urea 545 N-[2-(dimethylamino)ethyl]-4-({[4-(4-morpholin-4-yl- 567.2 6-phenyl-1,3,5-triazin-2- yl)phenyl]carbamoyl}amino)benzamide 546 4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 604.4 triazin-2-yl}phenyl)carbamoyl]amino}-N-[2- (dimethylamino)ethyl]benzamide 547 1-{4-[(4-isopropylpiperazin-1-yl)carbonyl]phenyl}-3- 621.5 {4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin- 2-yl]phenyl}urea 548 4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 607.5 triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-pyrrolidin- 1-ylethyl)benzamide 549 4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 534.5 triazin-2-yl}phenyl)carbamoyl]amino}benzoic acid 550 N-(2-methoxyethyl)-4-[({4-[4-(4-methylphenyl)-6- 568.2 morpholin-4-yl-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 551 N-(2-methoxyethyl)-4-({[4-(4-morpholin-4-yl-6- 554.2 phenyl-1,3,5-triazin-2- yl)phenyl]carbamoyl}amino)benzamide 552 4-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2- 593.5 yl)phenyl]carbamoyl}amino)-N-(2-pyrrolidin-1- ylethyl)benzamide 553 1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 567.6 triazin-2-yl]phenyl}-3-[4-(pyrrolidin-1- ylcarbonyl)phenyl]urea 554 N-[3-(dimethylamino)propyl]-4-[({4-[4-(4- 595.4 methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 555 1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 578.1 triazin-2-yl]phenyl}-3-[4-(piperidin-1- ylcarbonyl)phenyl]urea 556 N-[3-(dimethylamino)propyl]-4-({[4-(4-morpholin-4-yl- 581.4 291.2 6-phenyl-1,3,5-triazin-2- yl)phenyl]carbamoyl}amino)benzamide 557 1-{4-[4-morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2- 460.2 230.6 yl]phenyl}-3-pyridin-4-ylurea 558 4-[({4-[4-morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2- 503.4 yl]phenyl}carbamoyl)amino]benzoic acid 559 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4- 585.5 [4-morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2- yl]phenyl}urea 560 methyl 4-[({4-[4-morpholin-4-yl-6-(2-thienyl)-1,3,5- 517.2 triazin-2-yl]phenyl}carbamoyl)amino]benzoate 561 N-(2-methoxyethyl)-4-[({4-[4-morpholin-4-yl-6-(2- 560.3 thienyl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 562 N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4- 587.3 294.1 morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 563 N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6- 573.1 (2-thienyl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 564 4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 618.4 309.7 triazin-2-yl}phenyl)carbamoyl]amino}-N-[2- (dimethylamino)ethyl]-N-methylbenzamide 565 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 616.4 329.2 triazin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-1- 308.7 yl)carbonyl]phenyl}urea 566 1-{4-[4-morpholin-4-yl-6-(1,4-oxazepan-4-yl)-1,3,5- 477.2 triazin-2-yl]phenyl}-3-pyridin-4-ylurea 567 methyl 4-[({4-[4-morpholin-4-yl-6-(1,4-oxazepan-4- 534.4 yl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzoate 568 1-(4-{[4-(dimethylamino)piperidin-1- 613.4 307.2 yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(2- thienyl)-1,3,5-triazin-2-yl]phenyl}urea 569 4-[({4-[4-morpholin-4-yl-6-(1,4-oxazepan-4-yl)-1,3,5- 520.3 triazin-2-yl]phenyl}carbamoyl)amino]benzoic acid 570 N-[3-(dimethylamino)propyl]-4-[({4-[4-morpholin-4-yl- 587.3 294.2 6-(2-thienyl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 571 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 587.5 triazin-2-yl}phenyl)-3-[4-(pyrrolidin-1- ylcarbonyl)phenyl]urea 572 N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6- 590.3 295.6 (1,4-oxazepan-4-yl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 573 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4- 602.3 322.2 [4-morpholin-4-yl-6-(1,4-oxazepan-4-yl)-1,3,5-triazin- 301.7 2-yl]phenyl}urea 574 N-(2-methoxyethyl)-4-[({4-[4-morpholin-4-yl-6-(1,4- 577.2 oxazepan-4-yl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 575 1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4- 599.3 300.2 morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2- 320.7 yl]phenyl}urea 576 1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 593.3 317.7 triazin-2-yl]phenyl}-3-{3-[(4-methylpiperazin-1- 521.3 yl)carbonyl]phenyl}urea 577 3-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 511.2 triazin-2-yl]phenyl}carbamoyl)amino]benzoic acid 578 methyl 3-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl- 525.2 1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate 579 1-(3-{[4-(dimethylamino)piperidin-1- 521.3 yl]carbonyl}phenyl)-3-{4-[4-(4-methylphenyl)-6- morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea 580 N-[2-(dimethylamino)ethyl]-N-methyl-3-[({4-[4-(4- 595.3 298.2 methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 581 methyl 3-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin- 463.5 2-yl)phenyl]carbamoyl}amino)benzoate 582 methyl 3-({[4-(4-morpholin-4-yl-6-thiophen-2-yl-1,3,5- 517.2 triazin-2-yl)phenyl]carbamoyl}amino)benzoate 583 N-[2-(dimethylamino)ethyl]-3-[({4-[4-(4- 581.3 291.1 methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 584 N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4- 604.4 302.7 morpholin-4-yl-6-(1,4-oxazepan-4-yl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 585 3-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2- 449.4 yl)phenyl]carbamoyl}amino)benzoic acid 586 methyl 3-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5- 511.4 triazin-2-yl)phenyl]carbamoyl}amino)benzoate 587 1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2- 594.6 yl)phenyl]-3-{3-[(4-pyridin-2-ylpiperazin-1- yl)carbonyl]phenyl}urea 588 N-[2-(dimethylamino)ethyl]-3-({[4-(4-ethyl-6- 533.3 267.1 morpholin-4-yl-1,3,5-triazin-2- yl)phenyl]carbamoyl}amino)-N-methylbenzamide 589 1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2- 531.3 266.1 yl)phenyl]-3-{3-[(4-methylpiperazin-1- 286.7 yl)carbonyl]phenyl}urea 590 3-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2- 497.3 yl)phenyl]carbamoyl}amino)benzoic acid 591 methyl 4-({[4-(4-morpholin-4-yl-6-piperidin-1-yl-1,3,5- 518.3 triazin-2-yl)phenyl]carbamoyl}amino)benzoate 592 1-[4-(4-morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin-2- 461.3 yl)phenyl]-3-pyridin-4-ylurea 593 4-({[4-(4-morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin- 504..3 2-yl)phenyl]carbamoyl}amino)benzoic acid 594 methyl 4-({[4-(4-morpholin-4-yl-6-pyrrolidin-1-yl- 504.5 1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoate 595 1-(4-{[4-(1-methylethyl)piperazin-1- 604.5 yl]carbonyl}phenyl)-3-[4-(4-morpholin-4-yl-6- piperidin-1-yl-1,3,5-triazin-2-yl)phenyl]urea 596 1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-[4-(4- 600.5 morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin-2- yl)phenyl]urea 597 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-[4- 586.5 (4-morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin-2- yl)phenyl]urea 598 1-(4-{[4-(dimethylamino)piperidin-1- 614.5 yl]carbonyl}phenyl)-3-[4-(4-morpholin-4-yl-6- piperidin-1-yl-1,3,5-triazin-2-yl)phenyl]urea 599 4-({[4-(4-morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin- 490.5 2-yl)phenyl]carbamoyl}amino)benzoic acid 600 1-[4-(4-morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin- 447.5 2-yl)phenyl]-3-pyridin-4-ylurea 601 N-[2-(dimethylamino)ethyl]-4-({[4-(4-morpholin-4-yl- 474.6 6-piperidin-1-yl-1,3,5-triazin-2- yl)phenyl]carbamoyl}amino)benzamide 602 1-(4-{[4-(dimethylamino)piperidin-1- 600.4 300.7 yl]carbonyl}phenyl)-3-[4-(4-morpholin-4-yl-6- pyrrolidin-1-yl-1,3,5-triazin-2-yl)phenyl]urea 603 1-(4-{[4-(1-methylethyl)piperazin-1- 600.4 300.7 yl]carbonyl}phenyl)-3-[4-(4-morpholin-4-yl-6- pyrrolidin-1-yl-1,3,5-triazin-2-yl)phenyl]urea 604 N-[2-(dimethylamino)ethyl]-N-methyl-4-({[4-(4- 574.6 morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin-2- yl)phenyl]carbamoyl}amino)benzamide 605 N-[2-(dimethylamino)ethyl]-N-methyl-4-({[4-(4- 588.3 294.6 morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin-2- yl)phenyl]carbamoyl}amino)benzamide 606 1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-[4-(4- 586.3 293.7 morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin-2- 286.7 yl)phenyl]urea 607 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-[4- 572.3 (4-morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin-2- yl)phenyl]urea 608 N-[2-(dimethylamino)ethyl]-4-({[4-(4-morpholin-4-yl- 560.1 280.6 6-pyrrolidin-1-yl-1,3,5-triazin-2- yl)phenyl]carbamoyl}amino)benzamide 609 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 491.2 266.6 triazin-2-yl}phenyl)-3-pyridin-4-ylurea 246.1 610 N-[3-(dimethylamino)propyl]-4-({[4-(4-morpholin-4-yl- 588.3 294.6 6-piperidin-1-yl-1,3,5-triazin-2- yl)phenyl]carbamoyl}amino)benzamide 611 N-(2-methoxyethyl)-4-({[4-(4-morpholin-4-yl-6- 561.4 281.2 piperidin-1-yl-1,3,5-triazin-2- yl)phenyl]carbamoyl}amino)benzamide 612 1-[4-(4-morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin- 543.3 2-yl)phenyl]-3-[4-(pyrrolidin-1-ylcarbonyl)phenyl]urea 613 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 630.6 triazin-2-yl}phenyl)-3-{4-[(4-ethylpiperazin-1- yl)carbonyl]phenyl}urea 614 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 644.7 triazin-2-yl}phenyl)-3-(4-{[4-(1-methylethyl)piperazin- 1-yl]carbonyl}phenyl)urea 615 methyl 4-{[(4-{4-[(3S)-3-methylmorpholin-4-yl]-6- 534.3 morpholin-4-yl-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzoate 616 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 644.6 triazin-2-yl}phenyl)-3-(4-{[4-(dimethylamino)piperidin- 1-yl]carbonyl}phenyl)urea 617 1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4- 602.3 322.2 yl-1,3,5-triazin-2-yl}phenyl)-3-{4-[(4-methylpiperazin- 301.7 1-yl)carbonyl]phenyl}urea 618 1-(4-{[4-(1-methylethyl)piperazin-1- 630.4315.7 yl]carbonyl}phenyl)-3-(4-{4-[(3S)-3-methylmorpholin- 4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea 619 4-{[(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin- 520.2 4-yl-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzoic acid 620 1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4- 616.4 308.7 [(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5- 329.2 triazin-2-yl}phenyl)urea 621 N-[3-(dimethylamino)propyl]-4-{[(4-{4-[(3S)-3- 604.6 methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin- 2-yl}phenyl)carbamoyl]amino}benzamide 622 4-{[(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin- 616.5 4-yl-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}-N-(2- pyrrolidin-1-ylethyl)benzamide 623 1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[(3S)-3- 616.4 308.7 methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)-3-{4- 329.2 [(4-methylpiperazin-1-yl)carbonyl]phenyl}urea 624 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 700.6 350.8 triazin-2-yl}phenyl)-3-(4-{[4-(dipropylamino)piperidin- 1-yl]carbonyl}phenyl)urea 625 1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4- 630.5 315.7 [(3R)-3-methylmorpholin-4-yl]-6-[(3S)-3- methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)urea 626 4-{[(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[(3S)-3- 534.3 methylmorpholin-4-yl]-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzoic acid 627 1-{4-[(4-butylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4- 658.6 [(3R)-3-methylmorpholin-4-yl]-6-[(3S)-3- methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)urea 628 methyl 4-{[(4-{4-[(3R)-3-methylmorpholin-4-yl]-6- 548.2 [(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzoate 629 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 658.5 329.7 triazin-2-yl}phenyl)-3-{4-[(4-butylpiperazin-1- yl)carbonyl]phenyl}urea 630 1-(4-{[4-(1-methylethyl)piperazin-1- 644.5 yl]carbonyl}phenyl)-3-(4-{4-[(3R)-3-methylmorpholin- 4-yl]-6-[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2- yl}phenyl)urea 631 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 658.5 triazin-2-yl}phenyl)-3-(4-{[4-(2- methylpropyl)piperazin-1-yl]carbonyl}phenyl)urea 632 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 658.6 triazin-2-yl}phenyl)-3-(4-{[4-(1- methylpropyl)piperazin-1-yl]carbonyl}phenyl)urea 633 4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 659.6 triazin-2-yl}phenyl)carbamoyl]amino}-N-[2-(4- methylpiperazin-1-yl)ethyl]benzamide 634 N-[2-(dimethylamino)ethyl]-4-{[(4-{4-[(3R)-3- 604.5 methylmorpholin-4-yl]-6-[(3S)-3-methylmorpholin-4- yl]-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzamide 635 4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 626.5 triazin-2-yl}phenyl)carbamoyl]amino}-N-(2-pyrrolidin- 1-ylethyl)benzamide 636 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 643.4 322.2 triazin-2-yl}phenyl)-3-{4-[(4-propylpiperidin-1- yl)carbonyl]phenyl}urea 637 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 601.5 triazin-2-yl}phenyl)-3-[4-(piperidin-1- ylcarbonyl)phenyl]urea 638 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 643.5 triazin-2-yl}phenyl)-3-{4-[(4-propylpiperazin-1- yl)carbonyl]phenyl}urea 639 4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 591.6 triazin-2-yl}phenyl)carbamoyl]amino}-N-(2- methoxyethyl)benzamide 640 1-{4-[4-morpholin-4-yl-6-(4-tricyclo[3.3.1.13,7]dec-1- 596.7 ylpiperazin-1-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4- ylurea 641 methyl 4-{[(4-{4-[4-(dimethylcarbamoyl)piperazin-1- 590.5 yl]-6-morpholin-4-yl-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzoate 642 N,N-dimethyl-4-(4-morpholin-4-yl-6-{4-[(pyridin-4- 533.6 ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2- yl)piperazine-1-carboxamide 643 N,N-dimethyl-4-(4-{4-[({4-[(4-methylpiperazin-1- 658.3 329.7 yl)carbonyl]phenyl}carbamoyl)amino]phenyl}-6- morpholin-4-yl-1,3,5-triazin-2-yl)piperazine-1- carboxamide 644 N,N-dimethyl-4-{4-morpholin-4-yl-6-[4-({[4-(pyridazin- 653.3 4-ylcarbamoyl)phenyl]carbamoyl}amino)phenyl]- 1,3,5-triazin-2-yl}piperazine-1-carboxamide 645 N,N-dimethyl-4-(4-morpholin-4-yl-6-{4-[({4-[(4- 685.6 propylpiperidin-1- yl)carbonyl]phenyl}carbamoyl)amino]phenyl}-1,3,5- triazin-2-yl)piperazine-1-carboxamide 646 4-{[(4-{4-[4-(dimethylcarbamoyl)piperazin-1-yl]-6- 576.2 morpholin-4-yl-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzoic acid 647 4-(4-{4-[({4-[(2- 633.3 317.1 methoxyethyl)carbamoyl]phenyl}carbamoyl)amino]phenyl}- 6-morpholin-4-yl-1,3,5-triazin-2-yl)-N,N- dimethylpiperazine-1-carboxamide 648 4-[4-(4-{[(4-{[2- 660.3 330.7 (dimethylamino)ethyl](methyl)carbamoyl}phenyl)carbamoyl]amino}phenyl)- 6-morpholin-4-yl-1,3,5-triazin- 2-yl]-N,N-dimethylpiperazine-1-carboxamide 649 4-(4-{4-[({4-[(4-ethylpiperazin-1- 672.6 yl)carbonyl]phenyl}carbamoyl)amino]phenyl}-6- morpholin-4-yl-1,3,5-triazin-2-yl)-N,N- dimethylpiperazine-1-carboxamide 650 1-(4-{4-[4-(ethylsulfonyl)piperazin-1-yl]-6-morpholin- 554.2 4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea 651 methyl 4-{[(4-{4-[4-(ethylsulfonyl)piperazin-1-yl]-6- 611.2 morpholin-4-yl-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzoate 652 4-{[(4-{4-[4-(ethylsulfonyl)piperazin-1-yl]-6-morpholin- 597.7 4-yl-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzoic acid 653 N-[3-(dimethylamino)propyl]-4-{[(4-{4-[4- 681.2 341.1 (ethylsulfonyl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5- triazin-2-yl}phenyl)carbamoyl]amino}benzamide 654 N-[2-(dimethylamino)ethyl]-4-{[(4-{4-[4- 667.3 334.2 (ethylsulfonyl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5- triazin-2-yl}phenyl)carbamoyl]amino}benzamide 655 4-{[(4-{4-[4-(1-methylethyl)-1,4-diazepan-1-yl]-6- 561.5 morpholin-4-yl-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzoic acid 656 methyl 4-{[(4-{4-[4-(acetylamino)piperidin-1-yl]-6- 575.4 morpholin-4-yl-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzoate 657 1-(4-{4-[4-(1-methylethyl)-1,4-diazepan-1-yl]-6- 643.6 morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-{4-[(4- methylpiperazin-1-yl)carbonyl]phenyl}urea 658 N-[1-(4-morpholin-4-yl-6-{4-[(pyridin-4- 518.5 ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2- yl)piperidin-4-yl]acetamide 659 4-{[(4-{4-[4-(acetylamino)piperidin-1-yl]-6-morpholin- 561.5 4-yl-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzoic acid 660 N-[2-(dimethylamino)ethyl]-4-{[(4-{4-[4-(1- 631.5 methylethyl)-1,4-diazepan-1-yl]-6-morpholin-4-yl- 1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzamide 661 N-{1-[(4-{[(4-{4-[4-(1-methylethyl)-1,4-diazepan-1-yl]- 685.6 6-morpholin-4-yl-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}phenyl)carbonyl]piperidin- 4-yl}acetamide 662 1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4- 657.4 329.2 [4-(1-methylethyl)-1,4-diazepan-1-yl]-6-morpholin-4- 219.8 yl-1,3,5-triazin-2-yl}phenyl)urea 663 1-(4-{4-[4-(1-methylethyl)-1,4-diazepan-1-yl]-6- 671.4 336.2 morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-(4-{[4-(1- 224.5 methylethyl)piperazin-1-yl]carbonyl}phenyl)urea 664 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 617.5 triazin-2-yl}phenyl)-3-(4-{[(3S)-3-methylmorpholin-4- yl]carbonyl}phenyl)urea 665 1-{4-[(4-butylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4- 685.6 [4-(1-methylethyl)-1,4-diazepan-1-yl]-6-morpholin-4- yl-1,3,5-triazin-2-yl}phenyl)urea 666 N-[4-({[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl- 1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]-2- (4-methylpiperazin-1-yl)acetamide 667 1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1- 533.3 yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin- 2-yl}phenyl)-3-pyridin-4-ylurea 668 1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1- 630.4 yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin- 2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea 669 1-{4-[4-morpholin-4-yl-6-(3-oxa-8- 489.3 azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3- pyridin-4-ylurea 670 4-[({4-[4-morpholin-4-yl-6-(3-oxa-8- 531.2 azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 671 1-{4-[4-morpholin-4-yl-6-(3-oxa-8- 489.5 azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3- pyridin-3-ylurea 672 1-(4-fluorophenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8- 506.5 azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 673 1-[4-(hydroxymethyl)phenyl]-3-{4-[4-morpholin-4-yl- 518.5 6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 674 1-[4-(2-hydroxyethyl)phenyl]-3-{4-[4-morpholin-4-yl- 532.5 6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 675 2-(diethylamino)ethyl 4-[({4-[4-morpholin-4-yl-6-(3- 631.6 oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzoate 676 1-(4-methylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa- 502.5 8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 677 1-(4-cyanophenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8- 513.5 azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 678 1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4- 586.6 morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)- 1,3,5-triazin-2-yl]phenyl}urea 679 1-isopropyl-3-{4-[4-morpholin-4-yl-6-(3-oxa-8- 454.5 azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 680 1-(2-hydroxyethyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8- 456.5 azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 681 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct- 369.2 8-yl)-1,3,5-triazin-2-yl]aniline 682 {3-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct- 384.4 8-yl)-1,3,5-triazin-2-yl]phenyl}methanol 683 3-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct- 370.4 8-yl)-1,3,5-triazin-2-yl]phenol 684 5-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct- 409.4 8-yl)-1,3,5-triazin-2-yl]-1H-benzimidazol-2-amine 685 1-{4-[4-(3-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-6- 502.5 morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3- phenylurea 686 1-(4-{4-[(4-methylpiperazin-1-yl)amino]-6-morpholin- 490.5 4-yl-1,3,5-triazin-2-yl}phenyl)-3-phenylurea 687 1-(4-{4-[(1-methylpiperidin-4-yl)oxy]-6-morpholin-4- 491.5 yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea 688 1-{4-[4-morpholin-4-yl-6-(piperidin-4-yloxy)-1,3,5- 477.5 triazin-2-yl]phenyl}-3-pyridin-4-ylurea 689 ethyl 4-[(4-morpholin-4-yl-6-{4-[(pyridin-4- 549.5 ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2- yl)oxy]piperidine-1-carboxylate 690 N-ethyl-4-[(4-morpholin-4-yl-6-{4-[(pyridin-4- 548.5 ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2- yl)oxy]piperidine-1-carboxamide 691 tert-butyl 4-[(4-morpholin-4-yl-6-{4-[(pyridin-4- 577.3 ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2- yl)oxy]piperidine-1-carboxylate 692 4-[(4-morpholin-4-yl-6-{4-[(pyridin-4- 556.5 ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2- yl)oxy]piperidine-1-sulfonamide 693 methyl 4-[({4-[4-morpholin-4-yl-6-(3-oxa-8- 546.3 azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzoate 694 N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6- 602.4 (3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 695 N,N-dimethyl-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8- 559.2 azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 696 N-methyl-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8- 545.2 azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 697 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4- 614.3 [4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8- yl)-1,3,5-triazin-2-yl]phenyl}urea 698 N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4- 616.4 morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)- 1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 699 N-(2-hydroxyethyl)-4-[({4-[4-morpholin-4-yl-6-(3-oxa- 575.4 8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 700 N-[3-(dimethylamino)propyl]-4-[({4-[4-morpholin-4-yl- 616.4 6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 701 N-methyl-N-[2-(methylamino)ethyl]-4-[({4-[4- 602.4 morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)- 1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 702 N-(2-morpholin-4-ylethyl)-4-[({4-[4-morpholin-4-yl-6- 644.4 (3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 703 1-{4-[(3,5-dimethylpiperazin-1-yl)carbonyl]phenyl}-3- 628.4 {4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct- 8-yl)-1,3,5-triazin-2-yl]phenyl}urea 704 4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin- 399.3 4-yl-1,3,5-triazin-2-yl]aniline 705 1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6- 519.7 morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4- ylurea 706 1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6- 519.2 morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3- ylurea 707 1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6- 518.2 morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3- phenylurea 708 1-[4-(dimethylamino)phenyl]-3-{4-[4-(1,4-dioxa-8- 561.3 azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin- 2-yl]phenyl}urea 709 1-(4-cyanophenyl)-3-{4-[4-(1,4-dioxa-8- 543.2 azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin- 2-yl]phenyl}urea 710 1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6- 533.7 morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-(2- methylpyridin-4-yl)urea 711 1-[2-(dimethylamino)ethyl]-3-{4-[4-(1,4-dioxa-8- 513.7 azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin- 2-yl]phenyl}urea 712 1-[4-(4-morpholin-4-yl-6-quinolin-3-yl-1,3,5-triazin-2- 505.7 yl)phenyl]-3-pyridin-4-ylurea 713 1-(diethylcarbamoyl)-4-[({4-[4-morpholin-4-yl-6-(3- 588.3 oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]pyridinium 714 1-{4-[4-(2-methoxyethoxy)-6-morpholin-4-yl-1,3,5- 452.6 triazin-2-yl]phenyl}-3-pyridin-4-ylurea 715 methyl 4-[({4-[4-(2-methoxyethoxy)-6-morpholin-4-yl- 509.4 1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate 716 4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5- 395.3 triazin-2-yl)aniline 717 1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5- 515.8 triazin-2-yl)phenyl]-3-pyridin-4-ylurea 718 1-(4-{4-morpholin-4-yl-6-[2-(pyridin-4-ylamino)ethyl]- 498.6 1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea 719 1-(4-acetylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8- 530.4 azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 720 N-[2-(dimethylamino)ethyl]-4-({[4-(4-methoxy-6- 535.5 morpholin-4-yl-1,3,5-triazin-2- yl)phenyl]carbamoyl}amino)-N-methylbenzamide 721 N-[2-(dimethylamino)ethyl]-4-({[4-(4-methoxy-6- 521.5 morpholin-4-yl-1,3,5-triazin-2- yl)phenyl]carbamoyl}amino)benzamide 722 4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2- 521.5 yl)phenyl]carbamoyl}amino)-N-methyl-N-[2- (methylamino)ethyl]benzamide 723 1-[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2- 533.5 yl)phenyl]-3-{4-[(4-methylpiperazin-1- yl)carbonyl]phenyl}urea 724 1-{4-[(3,3-dimethylpiperazin-1-yl)carbonyl]phenyl}-3- 547.5 [4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2- yl)phenyl]urea 725 4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2- 561.5 yl)phenyl]carbamoyl}amino)-N-(2-piperidin-1- ylethyl)benzamide 726 1-(4-ethenylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa- 514.3 8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 727 1-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-{4-[4- 601.1 morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)- 1,3,5-triazin-2-yl]phenyl}urea 728 1-(4-{4-[2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6- 508 morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4- ylurea 729 1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4- 575.5 morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)- 1,3,5-triazin-2-yl]phenyl}urea 730 1-(4-{4-[2-(1,3-dioxan-2-yl)ethyl]-6-morpholin-4-yl- 492.9 1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea 731 1-(4-{4-[3-(dimethylamino)propyl]-6-morpholin-4-yl- 463.4 1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea 732 1-[4-(4-{3-[(1-methylethyl)amino]propyl}-6-morpholin- 477.4 4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea 733 1-{4-[4-morpholin-4-yl-6-(3-pyrrolidin-1-ylpropyl)- 489.4 1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea 734 1-(4-{4-[3-(4-methylpiperazin-1-yl)propyl]-6- 518.4 morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4- ylurea 735 1-{4-[4-(3-{[2-(dimethylamino)ethyl]amino}propyl)-6- 506.5 morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4- ylurea 736 1-{4-[4-(3-hydroxypropyl)-6-morpholin-4-yl-1,3,5- 436.3 triazin-2-yl]phenyl}-3-pyridin-4-ylurea 737 1-{4-[4-morpholin-4-yl-6-(3-oxopropyl)-1,3,5-triazin-2- 434.3 yl]phenyl}-3-pyridin-4-ylurea 738 4-[4-(6,8-dioxa-3-azabicyclo[3.2.1]oct-3-yl)-6- 371.3 morpholin-4-yl-1,3,5-triazin-2-yl]aniline 739 tert-butyl 7-[4-(4-aminophenyl)-6-morpholin-4-yl- 484.4 1,3,5-triazin-2-yl]-9-oxa-3,7- diazabicyclo[3.3.1]nonane-3-carboxylate 740 1-{4-[4-(6,8-dioxa-3-azabicyclo[3.2.1]oct-3-yl)-6- 491.3 morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4- ylurea 741 tert-butyl 7-(4-morpholin-4-yl-6-{4-[(pyridin-4- 604.4 ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)-9-oxa- 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate 742 1-{4-[4-morpholin-4-yl-6-(9-oxa-3,7- 504.4 diazabicyclo[3.3.1]non-3-yl)-1,3,5-triazin-2- yl]phenyl}-3-pyridin-4-ylurea 743 1-{4-[4-(7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3- 518.4 yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3- pyridin-4-ylurea 744 1-{4-[4-(7-acetyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3- 546.4 yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3- pyridin-4-ylurea 745 1-(4-{4-[7-(methylsulfonyl)-9-oxa-3,7- 582.5 diazabicyclo[3.3.1]non-3-yl]-6-morpholin-4-yl-1,3,5- triazin-2-yl}phenyl)-3-pyridin-4-ylurea 746 1-(2-chloropyridin-4-yl)-3-{4-[4-morpholin-4-yl-6-(3- 523.3 oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 747 1-(2,3′-bipyridin-4-yl)-3-{4-[4-morpholin-4-yl-6-(3-oxa- 566.4 8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 748 tert-butyl N-[4-morpholin-4-yl-6-(4-nitrophenyl)-1,3,5- 417.2 triazin-2-yl]glycinate 749 1-(6-chloropyridin-3-yl)-3-{4-[4-morpholin-4-yl-6-(3- 523.3 oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 750 N-[4-morpholin-4-yl-6-(4-nitrophenyl)-1,3,5-triazin-2- 361.3 yl]glycine 751 1,3-bis{4-[4-morpholin-4-yl-6-(3-oxa-8- 763.5 azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 752 1-(4-{[4-(dimethylamino)piperidin-1- 642.4 yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa- 8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 753 N-[2-(4-methylpiperazin-1-yl)ethyl]-4-[({4-[4- 657.4 morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)- 1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 754 1-{4-[(4-isopropylpiperazin-1-yl)carbonyl]phenyl}-3- 642.4 {4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct- 8-yl)-1,3,5-triazin-2-yl]phenyl}urea 755 1-{4-[(4-cyclopentylpiperazin-1-yl)carbonyl]phenyl}-3- 668.4 {4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct- 8-yl)-1,3,5-triazin-2-yl]phenyl}urea 756 1-{4-[4-morpholin-4-yl-6-(3-oxa-8- 600.4 azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3- [4-(piperazin-1-ylcarbonyl)phenyl]urea 757 1-{4-[4-morpholin-4-yl-6-(3-oxa-8- 684.4 azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3- {4-[(4-morpholin-4-ylpiperidin-1- yl)carbonyl]phenyl}urea 758 4-[({4-[4-morpholin-4-yl-6-(3-oxa-8- 628.4 azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]-N-(2-pyrrolidin-1- ylethyl)benzamide 759 4-[({4-[4-morpholin-4-yl-6-(3-oxa-8- 642.4 azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]-N-(2-piperidin-1- ylethyl)benzamide 760 1-[4-(1,4′-bipiperidin-1′-ylcarbonyl)phenyl]-3-{4-[4- 682.5 morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)- 1,3,5-triazin-2-yl]phenyl}urea 761 1-{4-[4-morpholin-4-yl-6-(3-oxa-8- 668.5 azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3- {4-[(4-pyrrolidin-1-ylpiperidin-1- yl)carbonyl]phenyl}urea 762 1-{4-[4-morpholin-4-yl-6-(3-oxa-8- 617.3 azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3- [4-(thiomorpholin-4-ylcarbonyl)phenyl]urea 763 1-[4-(morpholin-4-ylcarbonyl)phenyl]-3-{4-[4- 601.4 morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)- 1,3,5-triazin-2-yl]phenyl}urea 764 4-[({4-[4-morpholin-4-yl-6-(3-oxa-8- 532.3 azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzoic acid 765 1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 505.3 morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4- ylurea 766 1-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-3-{4-[4- 587.4 morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)- 1,3,5-triazin-2-yl]phenyl}urea 767 1-(4-{[4-(dimethylamino)piperidin-1- 658.4 yl]carbonyl}phenyl)-3-{4-[4-(3,7-dioxa-9- azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5- triazin-2-yl]phenyl}urea 768 N-[2-(dimethylamino)ethyl]-4-[({4-[4-(3,7-dioxa-9- 632.4 azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5- triazin-2-yl]phenyl}carbamoyl)amino]-N- methylbenzamide 769 1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 630.4 morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4- methylpiperazin-1-yl)carbonyl]phenyl}urea 770 methyl 4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9- 562.3 yl)-6-morpholin-4-yl-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzoate 771 4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 548.3 morpholin-4-yl-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzoic acid 772 1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 616.3 morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-[4- (piperazin-1-ylcarbonyl)phenyl]urea 773 1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 658.3 morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4- isopropylpiperazin-1-yl)carbonyl]phenyl}urea 774 4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 644.3 morpholin-4-yl-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]-N-(2-pyrrolidin-1- ylethyl)benzamide 775 4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 658.4 morpholin-4-yl-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]-N-(2-piperidin-1- ylethyl)benzamide 776 1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 684.4 morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4- pyrrolidin-1-ylpiperidin-1-yl)carbonyl]phenyl}urea 777 1-[4-(1,4′-bipiperidin-1′-ylcarbonyl)phenyl]-3-{4-[4- 698.4 (3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin- 4-yl-1,3,5-triazin-2-yl]phenyl}urea 778 4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 652.4 morpholin-4-yl-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]-N-(2-pyridin-2- ylethyl)benzamide 779 4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 652.4 morpholin-4-yl-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]-N-(2-pyridin-4- ylethyl)benzamide 780 N-[4-(4-aminophenyl)-6-morpholin-4-yl-1,3,5-triazin- 413.2 2-yl]benzenesulfonamide 781 N-(4-morpholin-4-yl-6-{4-[(pyridin-4- 533.4 ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2- yl)benzenesulfonamide 782 N-{4-[4-({[4-(4-methylpiperazin-1- 630.3 yl)phenyl]carbamoyl}amino)phenyl]-6-morpholin-4-yl- 1,3,5-triazin-2-yl}benzenesulfonamide 783 N-(4-{4-[({4-[2- 619.3 (dimethylamino)ethoxy]phenyl}carbamoyl)amino]phenyl}- 6-morpholin-4-yl-1,3,5-triazin-2- yl)benzenesulfonamide 784 N-(4-{4-[({4-[(4-methylpiperazin-1- 658.3 yl)carbonyl]phenyl}carbamoyl)amino]phenyl}-6- morpholin-4-yl-1,3,5-triazin-2-yl)benzenesulfonamide 785 N-{4-morpholin-4-yl-6-[4-({[4-(piperazin-1- 644.4 ylcarbonyl)phenyl]carbamoyl}amino)phenyl]-1,3,5- triazin-2-yl}benzenesulfonamide 786 N-[4-(4-{[(4-{[4-(dimethylamino)piperidin-1- 686.4 yl]carbonyl}phenyl)carbamoyl]amino}phenyl)-6- morpholin-4-yl-1,3,5-triazin-2-yl]benzenesulfonamide 787 N-[2-(dimethylamino)ethyl]-N-methyl-4-{[(4-{4- 660.4 morpholin-4-yl-6-[(phenylsulfonyl)amino]-1,3,5- triazin-2-yl}phenyl)carbamoyl]amino}benzamide 788 N-[2-(dimethylamino)ethyl]-4-{[(4-{4-morpholin-4-yl- 646.4 6-[(phenylsulfonyl)amino]-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzamide 789 methyl 4-{[(4-{4-morpholin-4-yl-6- 590.3 [(phenylsulfonyl)amino]-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzoate 790 4-{[(4-{4-morpholin-4-yl-6-[(phenylsulfonyl)amino]- 576.2 1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzoic acid 791 1-{4-[4-morpholin-4-yl-6-(3-oxa-9- 503.2 azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}- 3-pyridin-4-ylurea 792 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4- 628.5 [4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9- yl)-1,3,5-triazin-2-yl]phenyl}urea 793 1-{4-[4-morpholin-4-yl-6-(3-oxa-9- 614.5 azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}- 3-[4-(piperazin-1-ylcarbonyl)phenyl]urea 794 1-(4-{[4-(dimethylamino)piperidin-1- 656.5 yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa- 9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2- yl]phenyl}urea 795 N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4- 630.4 morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)- 1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 796 N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6- 616.4 (3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 797 N-(2-methoxyethyl)-4-[({4-[4-morpholin-4-yl-6-(3-oxa- 603.4 9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 798 4-[({4-[4-morpholin-4-yl-6-(3-oxa-9- 642.4 azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]-N-(2-pyrrolidin-1- ylethyl)benzamide 799 4-[({4-[4-morpholin-4-yl-6-(3-oxa-9- 656.4 azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]-N-(2-piperidin-1- ylethyl)benzamide 800 1-{4-[4-morpholin-4-yl-6-(3-oxa-9- 682.5 azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}- 3-{4-[(4-pyrrolidin-1-ylpiperidin-1- yl)carbonyl]phenyl}urea 801 N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-[({4-[4- 656.6 morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)- 1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 802 N-methyl-N-[2-(methylamino)ethyl]-4-[({4-[4- 616.5 morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)- 1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 803 1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4- 628.3 morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)- 1,3,5-triazin-2-yl]phenyl}urea 804 1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4- 642.5 morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)- 1,3,5-triazin-2-yl]phenyl}urea 805 1-(4-{[4-(1-methylethyl)piperazin-1- 656.3 yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa- 9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2- yl]phenyl}urea 806 1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 644.5 morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4- ethylpiperazin-1-yl)carbonyl]phenyl}urea 807 1-{4-[4-morpholin-4-yl-6-(2-oxa-5- 489.2 azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}-3- pyridin-4-ylurea 808 1-(1,3-dimethyl-1H-pyrazol-5-yl)-3-{4-[4-morpholin-4- 506.2 yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin- 2-yl]phenyl}urea 809 1-{4-[4-morpholin-4-yl-6-(2-oxa-5- 478.2 azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}-3- (1H-pyrazol-3-yl)urea 810 1-(4-{[4-(dimethylamino)piperidin-1- 642.2 yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(2-oxa- 5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2- yl]phenyl}urea 811 1-(4-{[4-(1-methylethyl)piperazin-1- 642.5 yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(2-oxa- 5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2- yl]phenyl}urea 812 1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4- 628.2 morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)- 1,3,5-triazin-2-yl]phenyl}urea 813 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4- 614.2 [4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5- yl)-1,3,5-triazin-2-yl]phenyl}urea 814 1-{4-[4-morpholin-4-yl-6-(2-oxa-5- 600.3 azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}-3- [4-(piperazin-1-ylcarbonyl)phenyl]urea 815 N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6- 602.5 (2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 816 N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4- 616.3 morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)- 1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 817 2-tert-butoxy-4-morpholin-4-yl-6-(4-nitrophenyl)- 360.1 1,3,5-triazine 818 1-(4-{4-[(6S)-6-hydroxy-3-oxa-8-azabicyclo[3.2.1]oct- 505.2 8-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3- pyridin-4-ylurea 819 1-(4-{4-[6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]oct- 595.2 8-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3- pyridin-4-ylurea 820 1-(4-{4-[(6R)-6-hydroxy-3-oxa-8-azabicyclo[3.2.1]oct- 505.2 8-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3- pyridin-4-ylurea 821 1-(4-{4-[(6R)-6-(benzyloxy)-3-oxa-8- 595.2 azabicyclo[3.2.1]oct-8-yl]-6-morpholin-4-yl-1,3,5- triazin-2-yl}phenyl)-3-pyridin-4-ylurea 822 1-{4-[(1,1-dioxidothiomorpholin-4- 649.1 yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa- 8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 823 1-[4-(4,6-di-3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl- 644.3306 1,3,5-triazin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1- yl)phenyl]urea 824 1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1- 628.5, yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa- 314.8, 356.8 8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 825 1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1- 628.5, yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa- 314.8, 356.8 8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 826 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-[4- 519.1, (6-morpholin-4-yl-4-oxo-4,5-dihydro-1,3,5-triazin-2- 280.5, 260 yl)phenyl]urea 827 1-{4-[(4-butylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4- [4-(1-methylethyl)-1,4-diazepan-1-yl]-6-morpholin-4- yl-1,3,5-triazin-2-yl}phenyl)urea 828 1-(4-{4-[4-(1-methylethyl)-1,4-diazepan-1-yl]-6- 671.4; 336.2; morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-(4-{[4-(1- 224.5; methylethyl)piperazin-1-yl]carbonyl}phenyl)urea 829 1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4- 657.4; 329.2; [4-(1-methylethyl)-1,4-diazepan-1-yl]-6-morpholin-4- 219.8; yl-1,3,5-triazin-2-yl}phenyl)urea 830 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4- 587.6; 314.8; [4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5- 294.3; triazin-2-yl]phenyl}urea 831 1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1- yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5- triazin-2-yl)phenyl]urea 832 1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1- yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5- triazin-2-yl)phenyl]urea 833 1-(4-{[4-(1-methylethyl)piperazin-1- 615.5; 308.3; yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6- 328.8; (tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2- yl]phenyl}urea 834 N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4- 589.5; 295.3; morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5- triazin-2-yl]phenyl}carbamoyl)amino]benzamide 835 1-{4-[4-(azetidin-3-yloxy)-6-morpholin-4-yl-1,3,5- 449.1; 225.1; triazin-2-yl]phenyl}-3-pyridin-4-ylurea 836 N-(1-methylethyl)-3-[(4-morpholin-4-yl-6-{4-[(pyridin- 534.4; 267.7; 4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2- yl)oxy]azetidine-1-carboxamide 837 N-{1-[(4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]- 658.5; 329.8; 1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}phenyl)carbonyl]piperidin- 4-yl}acetamide 838 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 658.8; 329.8; triazin-2-yl}phenyl)-3-(4-{[4-(1-methylethyl)-1,4- diazepan-1-yl]carbonyl}phenyl)urea 839 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 629.7; 315.3; triazin-2-yl}phenyl)-3-[4-(3-oxa-8- azabicyclo[3.2.1]oct-8-ylcarbonyl)phenyl]urea 840 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- triazin-2-yl}phenyl)-3-{4-[(4-cyanopiperidin-1- yl)carbonyl]phenyl}urea 841 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- triazin-2-yl}phenyl)-3-(4-{[(3S)-3- (dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)urea 842 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- triazin-2-yl}phenyl)-3-(4-{[(3R)-3- (dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)urea 843 1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1- 657.6; 329.3; yl]carbonyl}phenyl)-3-(4-{4-(morpholin-4-yl)-6-[4- 233.6; (propan-2-yl)-1,4-diazepan-1-yl]-1,3,5-triazin-2- yl}phenyl)urea 844 1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1- 657.5; 329.3; yl]carbonyl}phenyl)-3-(4-{4-(morpholin-4-yl)-6-[4- (propan-2-yl)-1,4-diazepan-1-yl]-1,3,5-triazin-2- yl}phenyl)urea 845 1-{4-[4,6-di(morpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}- 3-{4-[(2-methylpiperazin-1-yl)carbonyl]phenyl}urea 846 1-(4-{4-(morpholin-4-yl)-6-[4-(propan-2-yl)-1,4- diazepan-1-yl]-1,3,5-triazin-2-yl}phenyl)-3-[4- (piperazin-1-ylcarbonyl)phenyl]urea 847 1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1- yl]carbonyl}phenyl)-3-(4-{4-(morpholin-4-yl)-6-[4- (propan-2-yl)-1,4-diazepan-1-yl]-1,3,5-triazin-2- yl}phenyl)urea 848 1-{4-[4,6-di(morpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}- 616.3; 638.3; 3-{4-[(3,3,4-trimethylpiperazin-1- 654.3; yl)carbonyl]phenyl}urea 849 1-{4-[4,6-di(morpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}- 3-(4-{[(3R)-3-methylpiperazin-1- yl]carbonyl}phenyl)urea 850 1-(4-{[(3R)-3,4-dimethylpiperazin-1- yl]carbonyl}phenyl)-3-{4-[4,6-di(morpholin-4-yl)-1,3,5- triazin-2-yl]phenyl}urea 851 1-(4-{[(3R)-4-cyclobutyl-3-methylpiperazin-1- yl]carbonyl}phenyl)-3-{4-[4,6-di(morpholin-4-yl)-1,3,5- triazin-2-yl]phenyl}urea 852 1-{4-[4,6-di(morpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}- 3-(4-{[(3R)-3-methyl-4-(propan-2-yl)piperazin-1- yl]carbonyl}phenyl)urea 853 1-{4-[4,6-di(morpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}- 3-(4-{[(3S)-3-methylpiperazin-1- yl]carbonyl}phenyl)urea 854 N-[2-(dimethylamino)ethyl]-N-methyl-4-{[(4-{4-[(3S)- 3-methylmorpholin-4-yl]-6-[4-(propan-2-yl)-1,4- diazepan-1-yl]-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzamide 855 1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-[4-(propan-2- yl)-1,4-diazepan-1-yl]-1,3,5-triazin-2-yl}phenyl)-3-{4- [(4-methylpiperazin-1-yl)carbonyl]phenyl}urea 856 1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1- yl]carbonyl}phenyl)-3-(4-{4-[(3S)-3-methylmorpholin- 4-yl]-6-[4-(propan-2-yl)-1,4-diazepan-1-yl]-1,3,5- triazin-2-yl}phenyl)urea 857 N-[3-(dimethylamino)propyl]-4-{[(4-{4-(morpholin-4- yl)-6-[4-(propan-2-yl)-1,4-diazepan-1-yl]-1,3,5-triazin- 2-yl}phenyl)carbamoyl]amino}benzamide 858 N-[2-(dimethylamino)ethyl]-N-methyl-4-{[(4-{4- (morpholin-4-yl)-6-[4-(propan-2-yl)-1,4-diazepan-1- yl]-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzamide 859 1-[4-(morpholin-4-ylcarbonyl)phenyl]-3-(4-{4- (morpholin-4-yl)-6-[4-(propan-2-yl)-1,4-diazepan-1- yl]-1,3,5-triazin-2-yl}phenyl)urea 860 N-(2-methoxyethyl)-4-{[(4-{4-(morpholin-4-yl)-6-[4- (propan-2-yl)-1,4-diazepan-1-yl]-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzamide 861 1-[4-(1,4-diazepan-1-ylcarbonyl)phenyl]-3-(4-{4- 643.4; (morpholin-4-yl)-6-[4-(propan-2-yl)-1,4-diazepan-1- yl]-1,3,5-triazin-2-yl}phenyl)urea 862 1-(4-{4-(morpholin-4-yl)-6-[4-(propan-2-yl)-1,4- diazepan-1-yl]-1,3,5-triazin-2-yl}phenyl)-3-(4-{[4- (propan-2-yl)-1,4-diazepan-1-yl]carbonyl}phenyl)urea 863 1-(4-{[(3S)-4-cyclobutyl-3-methylpiperazin-1- yl]carbonyl}phenyl)-3-{4-[4,6-di(morpholin-4-yl)-1,3,5- triazin-2-yl]phenyl}urea 864 1-(4-{[(3S)-3,4-dimethylpiperazin-1- yl]carbonyl}phenyl)-3-{4-[4,6-di(morpholin-4-yl)-1,3,5- triazin-2-yl]phenyl}urea 865 1-{4-[4-(morpholin-4-yl)-6-(tetrahydro-2H-pyran-4-yl)- 1,3,5-triazin-2-yl]phenyl}-3-{4-[(3,3,4- trimethylpiperazin-1-yl)carbonyl]phenyl}urea 866 1-(4-{[(3S)-3,4-dimethylpiperazin-1- yl]carbonyl}phenyl)-3-{4-[4-(morpholin-4-yl)-6- (tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2- yl]phenyl}urea 867 1-(4-{[(3S)-3-methylpiperazin-1-yl]carbonyl}phenyl)- 3-{4-[4-(morpholin-4-yl)-6-(tetrahydro-2H-pyran-4-yl)- 1,3,5-triazin-2-yl]phenyl}urea 868 1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1- yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6- (tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2- yl]phenyl}urea 869 1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1- yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6- (tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2- yl]phenyl}urea

Biological Evaluation

mTOR Kinase Assay Methods

Human mTOR assays (See Toral-Barza, et al. Biochem Biophys. Res. Commun. 2005 Jun. 24; 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.

In Vitro Cell Culture Growth Assay Methods

Cell Lines used are human breast MDA-MB-361, human prostate PC3-mm2, and human prostate LNCap 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).

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 2 shows the results of the described PI3K-α, PI3K-γ, and mTOR kinase assays.

Table 3 shows the results of the described hSMG-1 kinase assay.

Table 4 shows the results of the described MDA-MB-361, PC3-mm2, and LNCap assays.

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.