# Patent

## Title
Triazine compounds as PI3 kinase and mTOR inhibitors

## Abstract

Compounds of formula I




wherein:

    R1 is






    and R2, R4, and R6-9 are defined herein, and pharmaceutically acceptable salts and esters thereof. These compounds inhibit PI3 kinase and mTOR, and may be used to treat diseases mediated by PI3 kinase and mTOR, such as a variety of cancers. Methods for making and using the compounds of this invention are disclosed. Various compositions containing the compounds of this invention are also disclosed.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This is a continuation application from U.S. application Ser. No. 13/950,584, filed on Jul. 25, 2013; 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 Oct. 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.


FIELD OF THE INVENTION
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.
BACKGROUND OF THE INVENTION
Phosphatidylinositol (hereinafter abbreviated as “PI”) is one of the phospholipids in cell membranes. In recent years it has become clear that PI plays an important role also in intracellular signal transduction. It is well recognized in the art that PI (4,5) bisphosphate (PI(4,5)P2 or PIP2) is degraded into diacylglycerol and inositol (1,4,5) triphosphate by phospholipase C to induce activation of protein kinase C and intracellular calcium mobilization, respectively [M. J. Berridge et al., Nature, 312, 315 (1984); Y. Nishizuka, Science, 225, 1365 (1984)].
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 1 (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 PIPS (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 1 PI3Ks are PI, PI(4)P and PI(4,5)P2, with PI(4,5)P2 being the most favored. Class 1 PI3Ks are further divided into two groups, class Ia and class Ib, because of their activation mechanism and associated regulatory subunits. The class Ib PI3K is p110γ that is activated by interaction with G protein-coupled receptors. Interaction between p110γ and G protein-coupled receptors is mediated by regulatory subunits of 110, 87, and 84 kDa.
PI and PI(4)P are the known substrates for class II PI3Ks; PI(4,5)P2 is not a substrate for the enzymes of this class. Class II PI3Ks include PI3K C2α, C2β and C2γ isoforms, which contain C2 domains at the C terminus, implying that their activity is regulated by calcium ions.
The substrate for class III PI3Ks is PI only. A mechanism for activation of the class III PI3Ks has not been clarified. Because each subtype has its own mechanism for regulating activity, it is likely that activation mechanism(s) depend on stimuli specific to each respective class of PI3K.
The compound PI103 (3-(4-(4-morpholinyl)pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-2-yl)phenol) inhibits PI3Ka and P13 Kg as well as the mTOR enzymes with IC50 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 P13 Kg but not the mTOR enzymes with an IC50 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 IC50 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 α isoform is essential for the antitumor activity of PI3K inhibitors, it is not clear whether a more selective inhibitor of a particular PI3K isoform may lead to fewer unwanted biological effects. It has recently been reported that non-PI3Kα class I isoforms (PI3Kβ, δ and γ) have the ability to induce oncogenic transformation of cells, suggesting that nonisoform-specific inhibitors may offer enhanced therapeutic potential over specific inhibitors.
Selectivity versus other related kinases is also an important consideration for the development of PI3K inhibitors. While selective inhibitors may be preferred in order to avoid unwanted side effects, there have been reports that inhibition of multiple targets in the PI3K/Akt pathway (e.g., PI3Kα and mTOR [mammalian target of rapamycin]) may lead to greater efficacy. It is possible that lipid kinase inhibitors may parallel protein kinase inhibitors in that nonselective inhibitors may also be brought forward to the clinic.
Mammalian Target of Rapamycin, mTOR, is a cell-signaling protein that regulates the response of tumor cells to nutrients and growth factors, as well as controlling tumor blood supply through effects on Vascular Endothelial Growth Factor, VEGF. Inhibitors of mTOR starve cancer cells and shrink tumors by inhibiting the effect of mTOR. All mTOR inhibitors bind to the mTOR kinase. This has at least two important effects. First, mTOR is a downstream mediator of the PI3K/Akt pathway. The PI3K/Akt pathway is thought to be over activated in numerous cancers and may account for the widespread response from various cancers to mTOR inhibitors. The over-activation of the upstream pathway would normally cause mTOR kinase to be over activated as well. However, in the presence of mTOR inhibitors, this process is blocked. The blocking effect prevents mTOR from signaling to downstream pathways that control cell growth. Over-activation of the PI3K/Akt kinase pathway is frequently associated with mutations in the PTEN gene, which is common in many cancers and may help predict what tumors will respond to mTOR inhibitors. The second major effect of mTOR inhibition is anti-angiogenesis, via the lowering of VEGF levels.
In lab tests, certain chemotherapy agents were found to be more effective in the presence of mTOR inhibitors. George, J. N., et al., Cancer Research, 61, 1527-1532, 2001. Additional lab results have shown that some rhabdomyosarcoma cells die in the presence of mTOR inhibitors.
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 (AFINITORTM) 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.
SUMMARY OF THE INVENTION
This invention provides compounds of formula I




wherein:
R1 is




or





and R2, R4, and R6-9 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.


DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the present invention provides compounds of formula I




wherein:
R1 is




or





wherein:
R6, R7, R8, R9 are each independently selected from the group consisting of a hydrogen atom, and a C1-C6alkyl optionally substituted with C2-C6alkenyl, C4-C6alkadienyl, C2-C6alkynyl or C4-C6alkadiynyl;
or one of R6 and R7 or R8 and R9, 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;
R2 is optionally substituted C6-C14aryl-NH—COR3, optionally substituted C1-C9heteroaryl-NH—COR3, —CH═CH—C6-C10aryl-NH—COR3 or —CH═CH—C1-C9heteroaryl-NH—COR3;
R3 is OR5, NR5R5 or NHR5;
R5 is independently selected from the group consisting of C1-C6alkyl, C3-C6alkenyl, C3-C6alkynyl, optionally substituted C6-C10aryl, C1-C6haloalkyl, optionally substituted C1-C9heteroaryl, C1-C6hydroxylalkyl-, C3-C10saturated or unsaturated mono or bicyclic C3-C10cycloalkyl optionally substituted with OH, NR11R11 or 3-7 membered C1-C6heterocyclyl, and 3-10 membered saturated or unsaturated mono or bicyclic C1-C9heterocyclyl, with the proviso that three-membered cycloalkyl and heterocyclyl rings are saturated;
or two R5 groups taken together with the nitrogen atom to which they are attached form a 3 to 8 membered ring system optionally substituted with C1-C6alkyl, 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 NR10;
R10 is selected from the group consisting of H, C1-C6alkyl, —SO2(C1-C6alkyl), —COO(C1-C6alkyl), —CONH(C1-C6alkyl), —CON(C1-C6alkyl)2, —CO(C1-C6alkyl), and —SO2NHR11;
R11 is selected from the group consisting of H, C1-C6alkyl optionally substituted with OH, NR11R11 or a 3-7 membered C1-C6heterocyclyl, —CO(C1-C6alkyl), optionally substituted C6-C10aryl, and optionally substituted C1-C9heteroaryl;
R4 is selected from the group consisting of: a) C1-C6alkyl optionally substituted with: i) 3-10 membered C1-C9heterocyclyl optionally substituted with C1-C6alkyl-, ii) H2N—, iii) (C1-C6alkyl)NH—, iv) (C1-C6alkyl)2N—, v) NH(CH2)aN(C1-C6alkyl)2 wherein a is 2, 3 or 4, and vi) CHO, b) C3-C6alkenyl, c) C3-C6alkynyl, d) —O—C1-C8alkyl optionally substituted with —O—C1-C8alkyl, e) —O—C3-C8alkenyl, f) —O—C3-C8alkynyl, g) saturated or unsaturated mono or bicyclic C3-C8cycloalkyl, and h) saturated or unsaturated mono or bicyclic —O—C3-C12cycloalkyl, all the above optionally substituted with OH, NR11R11 or a 3-7 membered C1-C6heterocyclyl optionally substituted with C1-C6alkyl-, provided that an OH or NR11R11 is not directly bonded to a carbon atom that is double- or triple-bonded to another carbon atom; i) —CH═CH—C6-C10aryl; j) —CH═CH—C1-C9heteroaryl; k) optionally substituted C6-C10aryl; l) optionally substituted 5-10 membered C1-C9heteroaryl attached to the triazine moiety via a carbon atom; m) 3-10 membered saturated or unsaturated monocyclic C1-C9heterocyclyl attached to the triazine moiety through a carbon or nitrogen atom and optionally substituted with from 1 to 3 substituents independently selected from: OH, NR11R11, C1-C6alkyl, (C1-C6alkyl)amido-, (C1-C6alkyl)C(O)—, (C1-C6alkoxy)carbonyl-, adamantyl, C1-C6hydroxylalkyl-, (C1-C6alkyl)amido-; or a 3-7 membered C1-C6heterocyclyl, 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—C6-C10aryl; o) optionally substituted —O—C1-C9heteroaryl; p) —O-(3-12 membered saturated or unsaturated mono or bicyclic)C1-C9heterocyclyl optionally substituted with (C1-C6alkoxy)carbonyl-, H2NS(O)2—, or C1-C6alkyl further optionally substituted with OH, NR11R11 or a 3-7 membered C1-C6heterocyclyl, with the proviso that three membered heterocyclyl is saturated; q) —NHC6-C10aryl, r) —NHC1-C9heteroaryl, s) —NHNH2, t) —NHNHC1-C6alkyl, u) —NHN(C1-C6alkyl)2, v) —NHOH, w) —COOH, x) —COO—C1-C6alkyl, y) —CONR12R13, z) —NR12R13,
















wherein Z is CH2, O, S(O), or NR10 and n is 0, 1 or 2;

ee) halogen, ff) C8-C14aryl-S(O)2—NH—, gg) R11NHC(O)NH—O—, and hh) optionally substituted 5-membered monocyclic C1-C4heteroaryl attached to the triazine moiety via a nitrogen atom;

R12 and R13 are each independently selected from H, optionally mono or disubstituted C1-C8alkyl, optionally substituted C3-C8alkenyl, and optionally substituted C3-C8alkynyl, the optional substituents being selected from C1-C6alkoxy, OH, NR11R11, and 3-7 membered C1-C6heterocyclyl, provided that an OH or NR11R11 is not directly bonded to a carbon atom that is double- or triple-bonded to another carbon atom;
or R12 and R13 taken together with the nitrogen atom to which they are attached form a 3 to 8 membered monocyclic ring system optionally substituted with C1-C8alkyl, 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 NR10;
or R12 and R13 taken together with the nitrogen atom to which they are attached form
















or





wherein a and b are each independently —CH2—, O, S, or NR10, and x is 1-3;
C1-C9heteroaryl 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, NR10, and S(O)n;
C1-C9heterocyclyl 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, NR10, 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) C1-C8alkyl optionally substituted with OH, NH2, NH(C1-C8alkyl), N(C1-C8alkyl)2, —NH(CH2)wN(C1-C8alkyl)2 wherein w is 2, 3 or 4, or 3-10 membered C1-C9heterocyclyl optionally substituted with from 1 to 3 independently selected C1-C6alkyl- substituents; b) halogen; c) hydroxy; d) NH2; e) NO2; f) SO2NH2; g) COOH; h) COO(C1-C6alkyl); i) NHCOO(C1-C6alkyl); j) NH(C1-C6alkyl); k) N(C1-C6alkyl)2; l) C(O)NRaRb, wherein Ra is H or C1-C6alkyl, and Rb is H, C1-C6alkyl, (C6-C14aryl)alkyl-, or (C1-C9heteroaryl)alkyl-; m) —Y-Q, wherein Y is: i) O, ii) NH, iii) N(C1-C8alkyl), iv) NHSO2, v) SO2NH, vi) NHCONH, vii) NHCON(C1-C6alkyl), viii) S(O)q, q is 0, 1 or 2, ix) —C(O)NH—, x) —NHC(O)— xi) —C(O)N(CH3)—, xii) C(O), or xiii) absent, and Q is selected from: i) C6-C10aryl, optionally substituted with from 1 to 3 substituents independently selected from: A) C1-C6alkoxy- optionally substituted with 1) H2N—, 2) (C1-C6alkyl)amino-, 3) di(C1-C6alkyl)amino-, 4) C1-C9heterocyclyl- optionally substituted by C1-C6alkyl-, or 5) hydroxyl, B) (C1-C6alkoxy)carbonyl-, C) (C1-C6alkoxy)C(O)NH—, D) C1-C6alkyl- optionally substituted with 1) H2N—, 2) (C1-C6alkyl)amino-, or 3) di(C1-C6alkyl)amino-, E) (C1-C6alkyl)amino-, F) di(C1-C6alkyl)amino-, G) (C1-C6alkyl)amido- optionally substituted with 1) H2N—, 2) (C1-C6alkyl)amino-, or 3) di(C1-C6alkyl)amino-, H) (C1-C6alkyl)carboxyamido-, I) C1-C9heterocyclyl-optionally substituted by C1-C6alkyl- or C1-C6hydroxylalkyl-, J) heterocyclyl(C1-C6alkyl)- optionally substituted by C1-C6alkyl-, K) halogen, L) hydroxyl, M) C1-C6hydroxylalkyl-, N) perfluoro(C1-C6)alkyl-, O) H2N—, P) O2N—, Q) H2NSO2—, R) HO2C—, and S) NC—, ii) 5-10 membered C1-C9heteroaryl, optionally substituted with from 1 to 3 substituents independently selected from: A) C1-C6alkoxy-optionally substituted with 1) H2N—, 2) (C1-C6alkyl)amino-, 3) di(C1-C6alkyl)amino-, 4) C1-C9heterocyclyl- optionally substituted by C1-C6alkyl-, or 5) hydroxyl, B) (C1-C6alkoxy)carbonyl-, C) (C1-C6alkoxy)C(O)NH—, D) C1-C6alkyl- optionally substituted with 1) H2N—, 2) (C1-C6alkyl)amino-, or 3) di(C1-C6alkyl)amino-, E) (C1-C6alkyl)amino-, F) di(C1-C6alkyl)amino-, G) (C1-C6alkyl)amido-optionally substituted with 1) H2N—, 2) (C1-C6alkyl)amino-, or 3) di(C1-C6alkyl)amino-, H) (C1-C6alkyl)carboxyamido-, I) C1-C9heterocyclyl- optionally substituted by C1-C6alkyl- or C1-C6hydroxylalkyl-, J) heterocyclyl(C1-C6alkyl)- optionally substituted by C1-C6alkyl-, K) halogen, L) hydroxyl, M) C1-C6hydroxylalkyl-, N) perfluoro(C1-C6)alkyl-, O) H2N—, P) O2N—, Q) H2NSO2—, R) HO2C—, and S) NC—, iii) 3-10 membered C1-C9heterocyclyl, optionally substituted with from 1 to 3 substituents independently selected from: A) C1-C6alkyl-, B) heterocyclyl(C1-C6alkyl)-, C) (C6-C14aryl)alkyl-, D) C1-C8acyl-, E) (C1-C6alkoxy)carbonyl-, F) (C1-C6alkyl)carboxyl-, G) halogen, H) C1-C6haloalkyl-, I) hydroxyl, J) C1-C6hydroxyalkyl-, K) H2N—, L) (C1-C6alkyl)amino-, M) di(C1-C6alkyl)amino-, N) HO2C—, O) (C1-C6alkoxy)carbonyl-, P) (C1-C6alkyl)carboxyl-, Q) (C1-C6alkyl)amido-, R) H2NC(O)—, S) (C1-C6alkyl)carboxyamido-, T) 5-10 membered C1-C9heteroaryl, U) C6-C14ary, V) C3-C8cycloalkyl W) 3-10 membered C1-C9heterocyclyl, X) NC—; and Y) —NO2; iv) C3-C10cycloalkyl, v) C1-C6alkyl, vi) C2-C6alkenyl, vii) C2-C6alkynyl, viii) C1-C6hydroxyalkyl-, ix) (CH2)vO(C1-C6alkyl), x) (CH2)vNH2, xi) (CH2)vNH(C1-C6alkyl), xii) (CH2)vN(C1-C6alkyl)2, xiii) O(CH2)vN(C1-C6alkyl)2, xiv) (CH2)vC6-C10aryl, xv) —CN, xvi) (CH2)v 5-10 membered C1-C9heteroaryl, xvii) (CH2), 3-10 membered C1-C9heterocyclyl, optionally substituted by C1-C6alkyl-, wherein v is 1, 2, 3 or 4, and xviii) C1-C6 perfluoroalkyl-; and n) C(O)Rc wherein Rc is: i) H, ii) C1-C6alkyl, or iii) C3-C6cycloalkyl,
and pharmaceutically acceptable salts and esters thereof.
In some embodiments of the invention, R1 and/or R4 is




In some embodiments, R1 and/or R4 is




or





In some embodiments, one of R1 or R4 is




and the other is




or





In some embodiments, R2 is optionally substituted C6-C14aryl-NH—CORS; in others R2 is optionally substituted phenyl-NH—COR3.
In some embodiments, R3 is NHR5 or OR5. In some embodiments, R5 is optionally substituted C6-C10aryl, such as optionally substituted phenyl or C1-C9heteroaryl. In some embodiments, the optionally substituted C6-C10aryl or phenyl is substituted with —Y-Q, C(O)NRaRb or C(O)Rc.
In some embodiments, R5 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-methylphenyl)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-methylpyridin-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-2-yl)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-methyl morpholin-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-methyl morpholin-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-2-yl)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-methylbenzamide;
    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;
    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-methylpiperazin-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-methylpropyl)-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-(dimethylamino)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-methylphenyl)-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-methylmorpholin-4-yl]-6-[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)urea;
    4-{[(4-{4-[(3R)-3-methylmorpholin-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-(dimethylamino)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-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(3-methylpiperazine-1-carbonyl)phenyl)urea;
    1-(4-(4,6-dimorpholino-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-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-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)u rea;
    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-dimethylpyrrolidin-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)pipendin-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-(dimethylamino)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;
    methyl-4-(3-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)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-Aphenyl)urea;
    1-(4-fluorophenyl)-3-(4-(4-(4-methyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-Aphenyl)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-A-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-A-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-A-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-A-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-A-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-(dimethylamino)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-ethylpiperazine-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-(dimethylamino)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;
    methyl-4-(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-((dimethylamino)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)u rea;
    (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-ypurea;
    1-(4-(4-(3-methyl-1H-pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-ypurea;
    1-(4-(4-(3-methyl-1H-pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-ypurea;
    1-(4-(4-(3-methyl-1H-pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridazin-4-ypurea;
    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-methylmorpholin-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 P 13K-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 P 13K-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 R6, R7, R8 and R9 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 (Ph3)4P(Pd)/Na2CO3/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/Et3N 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.




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.
DEFINITIONS
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 “Cx-Cy”, where x and y are the lower and upper limits, respectively. For example, a group designated as “C1-C6” 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 (C6-C14aryl)-(C1-C6alkyl)-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 C1-C8acyl- 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, H2N—, (C1-C6alkyl)amino-, di(C1-C6alkyl)amino-, (C1-C6alkyl)C(O)N(C1-C3alkyl)-, (C1-C6alkyl)carboxyamido-, HC(O)NH—, H2NC(O)—, (C1-C6alkyl)NHC(O)—, di(C1-C6alkyl)NC(O)—, —CN, hydroxyl, C1-C6alkoxy-, C1-C6alkyl-, HO2C—, (C1-C6alkoxy)carbonyl-, (C1-C6alkyl)C(O)—, C6-C14aryl-, C1-C9heteroaryl-, or C3-C8cycloalkyl-.
“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 C1-C12alkyl group may have from 1 to 12 (inclusive) carbon atoms in it. Examples of C1-C6alkyl 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 C1-C8alkyl 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, —NH2, (C1-C6alkyl)N—, (C1-C6alkyl)(C1-C6alkyl)N—, —N(C1-C3alkyl)C(O)(C1-C6alkyl), —NHC(O)(C1-C6alkyl), —NHC(O)H, —C(O)NH2, —C(O)NH(C1-C6alkyl), —C(O)N(C1-C6alkyl)(C1-C6alkyl), —CN, hydroxyl, C1-C6alkoxy, C1-C6alkyl, —C(O)OH, —C(O)O(C1-C6alkyl), —C(O)(C1-C6alkyl), C6-C14aryl, C1-C9heteroaryl, C3-C8cycloalkyl, C1-C6haloalkyl-, C1-C6-aminoalkyl-, —OC(O)(C1-C6alkyl), C1-C6-carboxyamidoalkyl-, and —NO2.
“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 C4-C6alkadienyl 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 C4-C6alkadiynyl 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 C2-C8alkenyl 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 C2-C6alkenyl 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 C3-C8alkenyl 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 C3-C6alkenyl 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, —NH2, (C1-C6alkyl)N—, (C1-C6alkyl)(C1-C6alkyl)N—, —N(C1-C3alkyl)C(O)(C1-C6alkyl), —NHC(O)(C1-C6alkyl), —NHC(O)H, —C(O)NH2, —C(O)NH(C1-C6alkyl), —C(O)N(C1-C6alkyl)(C1-C6alkyl), —CN, hydroxyl, C1-C6alkoxy, C1-C6alkyl, —C(O)OH, —C(O)O(C1-C6alkyl), —C(O)(C1-C6alkyl), C6-C14aryl, C1-C9heteroaryl, and C3-C8cycloalkyl.
“Alkynyl” refers to a straight or branched chain unsaturated hydrocarbon containing at least one triple bond. Examples of a C2-C6alkynyl 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 C3-C6alkynyl 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 C3-C8alkynyl 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, —NH2, (C1-C6alkyl)N—, (C1-C6alkyl)(C1-C6alkyl)N—, —N(C1-C3alkyl)C(O)(C1-C6alkyl), —NHC(O)(C1-C6alkyl), —NHC(O)H, —C(O)NH2, —C(O)NH(C1-C6alkyl), —C(O)N(C1-C6alkyl)(C1-C6alkyl), —CN, hydroxyl, C1-C6alkoxy, C1-C6alkyl, —C(O)OH, —C(O)O(C1-C6alkyl), —C(O)(C1-C6alkyl), O6—C14aryl, O1—C9heteroaryl, and C3-C8cycloalkyl.
“Alkoxy-” refers to the group R—O— where R is an alkyl group, as defined above. Exemplary C1-C6alkoxy- 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, C1-C6alkoxy-, H2N—, (C1-C6alkyl)amino-, di(C1-C6alkyl)amino-, (C1-C6alkyl)C(O)N(C1-C3alkyl)-, (C1-C6alkyl)carboxyamido-, HC(O)NH—, H2NC(O)—, (C1-C6alkyl)NHC(O)—, di(C1-C6alkyl)NC(O)—, NC—, C1-C6alkoxy-, HO2C—, (C1-C6alkoxy)carbonyl-, (C1-C6alkyl)C(O)—, C6-C14aryl-, C1-C9heteroaryl-, C3-C8cycloalkyl-, C1-C6haloalkyl-, amino(C1-C6alkyl)-, (C1-C6alkyl)carboxyl-, C1-C6-carboxyamidoalkyl-, or O2N—.
“(Alkoxy)carbonyl-” refers to the group alkyl-O—C(O)—. Exemplary (C1-C6alkoxy)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, H2N—, (C1-C6alkyl)amino-, di(C1-C6alkyl)amino-, (C1-C6alkyl)C(O)N(C1-C3alkyl)-, (C1-C6alkyl)carboxyamido-, HC(O)NH—, H2NC(O)—, (C1-C6alkyl)NHC(O)—, di(C1-C6alkyl)NC(O)—, NC—, C1-C6alkoxy-, HO2C—, (C1-C6alkoxy)carbonyl-, (C1-C6alkyl)C(O)—, C6-C14aryl-, C1-C9heteroaryl-, C3-C8cycloalkyl-, C1-C6haloalkyl-, amino(C1-C6alkyl)-, (C1-C6alkyl)carboxyl-, C1-C6-carboxyamidoalkyl-, or O2N—.
“(Alkyl)amido-” refers to a —C(O)NH— group in which the nitrogen atom of said group is attached to a C1-C6alkyl group, as defined above. Representative examples of a (C1-C6alkyl)amido- group include, but are not limited to, —C(O)NHCH3, —C(O)NHCH2CH3, —C(O)NHCH2CH2CH3, —C(O)NHCH2CH2CH2CH3, —C(O)NHCH2CH2CH2CH2CH3, —C(O)NHCH(CH3)2, —C(O)NHCH2CH(CH3)2, —C(O)NHCH(CH3)CH2CH3, —C(O)NH—C(CH3)3 and —C(O)NHCH2C(CH3)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 (C1-C6alkyl)amino- group include, but are not limited to CH3NH—, CH3CH2NH—, CH3CH2CH2NH—, CH3CH2CH2CH2NH—, (CH3)2CHNH—, (CH3)2CHCH2NH—, CH3CH2CH(CH3)NH— and (CH3)3CNH—. An (alkyl)amino group can be unsubstituted or substituted with one or more of the following groups: halogen, H2N—, (C1-C6alkyl)amino-, di(C1-C6alkyl)amino-, (C1-C6alkyl)C(O)N(C1-C3alkyp-, (C1-C6alkyl)carboxyamido-, HC(O)NH—, H2NC(O)—, (C1-C6alkyl)NHC(O)—, di(C1-C6alkyl)NC(O)—, NC—, hydroxyl, C1-C6alkoxy-, C1-C6alkyl-, HO2C—, (C1-C6alkoxy)carbonyl-, (C1-C6alkyl)C(O)—, C6-C14aryl-, C1-C9heteroaryl-, C3-C8cycloalkyl-, C1-C6haloalkyl-, amino(C1-C6alkyl)-, (C1-C6alkyl)carboxyl-, C1-C6-carboxyamidoalkyl-, or O2N—.
“Aminoalkyl-” refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with —NH2; one or both H of the NH2 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 (C1-C6alkyl)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 C1-C6alkyl group, as defined above. Representative examples of a (C1-C6alkyl)carboxyamido- group include, but are not limited to, —NHC(O)CH3, —NHC(O)CH2CH3, —NHC(O)CH2CH2CH3, —NHC(O)CH2CH2CH2CH3, —NHC(O)CH2CH2CH2CH2CH3, —NHC(O)CH(CH3)2, —NHC(O)CH2CH(CH3)2, —NHC(O)CH(CH3)CH2CH3, —NHC(O)—C(CH3)3 and —NHC(O)CH2C(CH3)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 C1-C6alkylene include ethylene, propylene, and dimethylpropylene. Likewise, examples of C2-C6alkenylene include ethenylene and propenylene. Examples of C2-C6alkynylene include ethynylene and propynylene.
Aryl refers to an aromatic hydrocarbon group. Examples of a C6-C14aryl group include, but are not limited to, phenyl, α-naphthyl, β-naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, and acenanaphthyl. Examples of a C6-C10aryl 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: C1-C6alkyl, halo, haloalkyl-, hydroxyl, hydroxyl(C1-C6alkyl)-, —NH2, aminoalkyl-, dialkylamino-, —COOH, —C(O)O—(C1-C6alkyl), —OC(O)(C1-C6alkyl), N-alkylamido-, —C(O)NH2, (C1-C6alkyl)amido-, or —NO2.
“(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. (C6-C14Aryl)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, H2N—, hydroxyl, (C1-C6alkyl)amino-, di(C1-C6alkyl)amino-, (C1-C6alkyl)C(O)N(C1-C3alkyl)-, (C1-C6alkyl)carboxyamido-, HC(O)NH—, H2NC(O)—, (C1-C6alkyl)NHC(O)—, di(C1-C6alkyl)NC(O)—, NC—, hydroxyl, C1-C6alkoxy-, C1-C6alkyl-, HO2C—, (C1-C6alkoxy)carbonyl-, (C1-C6alkyl)C(O)—, C6-C14aryl-, C1-C9heteroaryl-, C3-C8cycloalkyl-, C1-C6haloalkyl-, amino(C1-C6alkyl)-, (C1-C6alkyl)carboxyl-, C1-C6-carboxyamidoalkyl-, or O2N—.
“(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 C3-C12cycloalkyl include, but are not limited to, cyclopropyl, cyclopentyl, cycloheptyl, cyclooctyl, decahydronaphthalen-1-yl, octahydro-1 H-inden-2-yl, decahydro-1H-benzo[7]annulen-2-yl, and dodecahydros-indacen-4-yl. Representative examples of a C3-C10cycloalkyl 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 C3-C8cycloalkyl 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, —NH2, (C1-C6alkyl)N—, (C1-C6alkyl)(C1-C6alkyl)N—, —N(C1-C3alkyl)C(O)(C1-C6alkyl), —NHC(O)(C1-C6alkyl), —NHC(O)H, —C(O)NH2, —C(O)NH(C1-C6alkyl), —C(O)N(C1-C6alkyl)(C1-C6alkyl), —CN, hydroxyl, C1-C6alkoxy, C1-C6alkyl, —C(O)OH, —C(O)O(C1-C6alkyl), —C(O)(C1-C6alkyl), C6-C14aryl, O1− C9heteroaryl, C3-C8cycloalkyl, C1-C6haloalkyl-, C1-C6-aminoalkyl-, —OC(O)(C1-C6alkyl), C1-C6-carboxyamidoalkyl-, and —NO2. 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 C5-C8cycloalkenyl 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, —NH2, (C1-C6alkyl)N—, (C1-C6alkyl)(C1-C6alkyl)N—, —N(C1-C3alkyl)C(O)(C1-C6alkyl), —NHC(O)(C1-C6alkyl), —NHC(O)H, —C(O)NH2, —C(O)NH(C1-C6alkyl), —C(O)N(C1-C6alkyl)(C1-C6alkyl), —CN, hydroxyl, C1-C6alkoxy, C1-C6alkyl, —C(O)OH, —C(O)O(C1-C6alkyl), —C(O)(C1-C6alkyl), C6-C14aryl, C1-C9heteroaryl, and C3-C8cycloalkyl. 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(C1-C6alkyl)amino- group include, but are not limited to, —N(CH3)2, —N(CH2CH3)(CH3), —N(CH2CH3)2, —N(CH2CH2CH3)2, —N(CH2CH2CH2CH3)2, —N(CH(CH3)2)2, —N(CH(CH3)2)(CH3), —N(CH2CH(CH3)2)2, —NH(CH(CH3)CH2CH3)2, —N(C(CH3)3)2, —N(C(CH3)3)(CH3), and —N(CH3)(CH2CH3). 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(C1-C6alkyl)-, —N(C3-C8cycloalkyl)-, —N(C6-C14aryl)-, —N(C1-C9heteroaryl)-, —N(amino(C1-C6alkyl))-, —N(C6-C14arylamino)-, —O—, —S—, —S(O)—, or —S(O)2—.
“Halo” or “halogen” refers to —F, —Cl, —Br and —I.
“C1-C6Haloalkyl-” refers to a C1-C6alkyl group, as defined above, wherein one or more of the C1-C6alkyl 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 C1-C6haloalkyl- group include, but are not limited to, —CH2F, —CCl3, —CF3, CH2CF3, —CH2Cl, —CH2CH2Br, —CH2CH2I, —CH2CH2CH2F, —CH2CH2CH2Cl, —CH2CH2CH2CH2Br, —CH2CH2CH2CH2I, —CH2CH2CH2CH2CH2Br, —CH2CH2CH2CH2CH2I, —CH2OH(Br)CH3, —CH2CH(Cl)CH2CH3, —CH(F)CH2CH3 and —C(CH3)2(CH2Cl).
“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 C1-C9heteroaryl 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 C1-C9hetroaryl 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 C1-C4heteroaryl 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: C1-C6alkyl, halo, haloalkyl-, hydroxyl, hydroxyl(C1-C6alkyl)-, —NH2, aminoalkyl-, dialkylamino-, —COOH, —C(O)O—(C1-C6alkyl), —OC(O)(C1-C6alkyl), N-alkylamido-, —C(O)NH2, (C1-C6alkyl)amido-, or —NO2.
“(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 (C1-C9heteroaryl)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, H2N—, hydroxyl, (C1-C6alkyl)amino-, di(C1-C6alkyl)amino-, (C1-C6alkyl)C(O)N(C1-C3alkyl)-, (C1-C6alkyl)carboxyamido-, HC(O)NH—, H2NC(O)—, (C1-C6alkyl)NHC(O)—, di(C1-C6alkyl)NC(O)—, NC—, hydroxyl, O1—C6alkoxy-, C1-C6alkyl-, HO2C—, (C1-C6alkoxy)carbonyl-, (C1-C6alkyl)C(O)—, C6-C14aryl-, O1—C9heteroaryl-, C3-C8cycloalkyl-, C1-C6haloalkyl-, amino(C1-C6alkyl)-, (C1-C6alkyl)carboxyl-, C1-C6-carboxyamidoalkyl-, or O2N—.
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 C1-C9heterocyclyl- 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, C1heterocyclyl- radicals would include but are not limited to oxaziranyl, diaziridinyl, and diazirinyl, C2heterocyclyl- radicals include but are not limited to aziridinyl, oxiranyl, and diazetidinyl, C9heterocyclyl- 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: C1-C6alkyl, halo, haloalkyl-, hydroxyl, hydroxyl(C1-C6alkyl)-, —NH2, aminoalkyl-, dialkylamino-, —COOH, —C(O)O—(C1-C6alkyl), —OC(O)(C1-C6alkyl), N-alkylamido-, —C(O)NH2, (C1-C6alkyl)amido-, or —NO2.
“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(C1-C6alkyl)- 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, H2N—, (C1-C6alkyl)amino-, di(C1-C6alkyl)amino-, (C1-C6alkyl)C(O)N(C1-C3alkyl)-, (C1-C6alkyl)carboxyamido-, HC(O)NH—, H2NC(O)—, (C1-C6alkyl)NHC(O)—, di(C1-C6alkyl)NC(O)—, NC—, hydroxyl, C1-C6alkoxy-, C1-C6alkyl-, HO2C—, (C1-C6alkoxy)carbonyl-, (C1-C6alkyl)C(O)—, 4- to 7-membered monocyclic heterocycle, C6-C14aryl-, C1-C9heteroaryl-, or C3-C8cycloalkyl-.
“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 C1-C6hydroxylalkyl-moieties include, for example, —CH2OH, —CH2CH2OH, —CH2CH2CH2OH, —CH2CH(OH)CH2OH, —CH2CH(OH)CH3, —CH(CH3)CH2OH 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 C1-C9heterocyclyl- 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, C1heterocyclyl- radicals would include but are not limited to oxaziranyl, diaziridinyl, and diazirinyl, C2heterocyclyl- radicals include but are not limited to aziridinyl, oxiranyl, and diazetidinyl, C9heterocyclyl- radicals include but are not limited to azecanyl. A heterocyclyl group can be unsubstituted or substituted with one or more groups, including: C1-C6alkyl, halo, haloalkyl-, hydroxyl, hydroxyl(C1-C6alkyl)-, —NH2, aminoalkyl-, dialkylamino-, —COOH, —C(O)O—(C1-C6alkyl), —OC(O)(C1-C6alkyl), N-alkylamido-, —C(O)NH2, (C1-C6alkyl)amido-, or —NO2.
“Perfluoroalkyl-” refers to alkyl group, defined above, having two or more fluorine atoms. Examples of a C1-C6 perfluoroalkyl- group include CF3, CH2CF3, CF2CF3 and CH(CF3)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, —NH2, —NH(C1-C6alkyl), —N(C1-C6alkyl)(C1-C6alkyl), —N(C1-C3alkyl)C(O)(C1-C6alkyl), —NHC(O)(C1-C6alkyl), —NHC(O)H, —C(O)NH2, —C(O)NH(C1-C6alkyl), —C(O)N(C1-C6alkyl)(C1-C6alkyl), —CN, hydroxyl, C1-C6alkoxy, C1-C6alkyl, —C(O)OH, —C(O)O(C1-C6alkyl), —C(O)(C1-C6alkyl), C6-C14aryl, C1-C9heteroaryl, or C3-C8cycloalkyl.
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:
Scheme 1:
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. DowthermTM is a eutectic mixture of biphenyl (C12H10) and diphenyl oxide (C12H10O). DowthermTM 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, NEt3 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.
Example 1
Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea
Step 1: Preparation of 2-chloro-4,6-di-morpholin-4-yl-[1,3,5]triazine
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
Step 2: Preparation of 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline
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 CeliteTM. 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.
Step 3: Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea
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:
Example 2
Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-3-ylurea
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.08 g 0.23 mmoles) and 3-pyridyl isocyanate (30 mg, 0.25 mmoles) the title compound was isolated as a white solid. The product was purified by Silica gel column chromatography by eluting it with 10% MeOH: ethyl acetate. Yield; 60 mg (56%); (M+H)=463.5.
Example 3
Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-phenylurea
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (140 mg, 0.40 mmoles) and phenyl isocyanate (72 mg, 0.61 mmoles), the title compound was isolated as a white solid. The product was purified by Silica gel column chromatography by eluting it with ethyl acetate. Yield: 0.128 g (68%) (M+H)=462.3
Example 4
Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-thiophen-2-ylurea
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (60 mg, 0.17 mmoles) and 2-thienyl isocyanate (18 mg, 0.14 mmoles), the title compound was isolated as a grey solid after Silica gel column chromatography by eluting with 5% ethyl acetate: methanol. Yield: 12 mg (14%); (M+H)=470.
Example 5
Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-methylphenyl)urea
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140 g 0.40 mmoles) and 4-methylphenyl isocyanate (74 mg, 0.56 mmoles), the title compound was isolated as a white solid. Yield; 65 mg (33%) (M+H)=476.4
Example 6
Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-fluorophenyl)urea
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140 g 0.40 mmoles) and 4-fluorophenyl isocyanate (83 mg, 0.61 mmole), 65 mg (33% yield) of the title product was isolated as white solid. (M+H)=480.3
Example 7
Preparation of 1-(2,4-dimethoxyphenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-urea
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140 g 0.40 mmoles) and 2,4-dimethoxyphenyl isocyanate (131 mg, 0.73 mmoles), the title compound was isolated as a white solid. Yield; 76 mg (36%); (M+H)=522.4
Example 8
Preparation of 1-(4-chlorophenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-urea
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140 g 0.40 mmoles) and 4-chlorophenyl isocyanate (94 mg, 0.61 mmoles), the title compound was isolated as a white solid. Yield; 60 mg (30%); (M+H)=496.3
Example 9
Preparation 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-methoxyphenyl)urea
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140 g 0.40 mmoles) and 4-methoxyphenyl isocyanate (91 mg, 0.63 mmoles) the title compound was isolated as a white solid. Yield; 48 mg (24%); (M+H)=492.3
Example 10
Preparation of (4-chlorophenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140 g 0.40 mmoles) and 4-chlorophenyl isocyanate (94 mg, 0.61 mmoles) the title compound was isolated as a white solid. Yield; 60 mg (30%); (M+H)=496.3
Example 11
Preparation of (2,4-difluorophenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.105 g 0.30 mmoles) and 2,4-difluorophenyl isocyanate (71 mg, 0.45 mmoles) the title compound was isolated as a white solid. Yield; 40 mg (27%); (M+H)=498.6
Example 12
Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-ethylurea
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.130 g 0.38 mmoles) and ethyl isocyanate (260 mg, 10 fold excess) the title compound was isolated as a white solid. Yield; 38 mg (25%); (M+H)=414.4
Example 13
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
Step 1: Preparation of 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine
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 CeliteTM. 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
Example 14
Preparation of tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(phenylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate
The titled compound was prepared by starting from tert-butyl 3-{[4-(4-aminophenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino}azetidine-1-carboxylate (140 mg, 0.32 mmol) phenylisocyanate (58 mg, 0.49 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 H PLC, using ACN/water and TFA. White solid; Yield 40 mg (31%); (M+H) 547.6
Example 15
Preparation of tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(pyridine-3-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate
The titled compound was prepared by starting from tert-butyl 3-{[4-(4-aminophenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino}azetidine-1-carboxylate (140 mg, 0.32 mmol) 3-pyridylisocyanate (70 mg, 0.58 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 H PLC, using ACN/water and TFA. White solid; Yield 40 mg (23%); (M+H) 548.7.
Example 16
Preparation of tert-butyl 3-{[4-(4-{[(4-methylphenyl)carbamoyl]amino}phenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino}azetidine-1-carboxylate
The titled compound was prepared by starting from tert-butyl 3-{[4-(4-aminophenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino}azetidine-1-carboxylate (130 mg, 0.27 mmol) 4-tolyl isocyanate (40 mg, 0.30 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 H PLC, using ACN/water and TFA. White solid; Yield 85 mg (47%); (M+H) 561.6.
Example 17
Preparation of 1-{4-[4-(azetidin-3-ylamino)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-phenylurea
To a stirred solution of tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(phenylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate
30 mg (0.055 mmoles) in DCM, (20 ml) TFA (1.5 ml) was added at room temperature and stirred for 24 hours. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. Yield: 20 (83%); (M+H) 447.
Example 18
Preparation of 1-{4-[4-(azetidin-3-ylamino)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea
To a stirred solution of tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(pyridin-3-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate
30 mg (0.055 mmoles) in DCM, (20 ml) TFA (1.5 ml) was added at room temperature and stirred for 24 hours. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. Yield: 21 (83%); (M+H) 448.5.
Example 19
Preparation of 1-{4-[4-(azetidin-3-ylamino)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-(4-fluorophenyl)urea
To a stirred solution of tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(4-fluoro-phenylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate
30 mg (0.053 mmoles) in DCM, (20 ml) TFA (1.5 ml) was added at room temperature and stirred for 24 hours. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. Yield: 20 (83%); (M+H) 465.5.
Example 20
Preparation of 1-{4-[4-(azetidin-3-ylamino)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-(4-methylphenyl)urea
To a stirred solution of tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(4-methyl-phenylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate
130 mg (0.23 mmoles) in DCM, (20 ml) TFA (1.5 ml) was added at room temperature and stirred for 24 hours. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. Yield: 40 (37%); (M+H) 461.5.
Example 21
Preparation of tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(pyridine-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate
To a stirred solution of tert-butyl 3-{[4-(4-aminophenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino}azetidine-1-carboxylate (200 mg, 0.47 mmol) in DCM (100 ml) at 0° C., triphosgene (300 mg) and triethylamine (3 ml) was added slowly. The reaction mixture was stirred for 15 minutes and 4-aminopyridine (200 mg. 2.1 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours and concentrated. It was quenched with cold water and the separated solid was filtered and washed with water. It was dried and purified by Gilson HPLC. Yield 100 mg (40%); (M+H) 548.6
Example 22
Preparation of 1-{4-[4-(azetidin-3-ylamino)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
To a stirred solution of tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(pyridine-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate
40 mg (0.073 mmoles) in DCM, (20 ml) TFA (1.5 ml) was added at room temperature and stirred for 24 hours. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. Yield: 26 (81%); (M+H) 448.5.
Example 23
Preparation of 1-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-phenylurea
Step 1: Preparation of 3-(4-chloro-6-morpholin-4-yl-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane
To a stirred acetone/crushed ice suspension of 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (1.5 g, 6.5 mmol), 8-oxa-3-azabicyclo[3.2.1]octane (980 mg, 6.5 mmol) and triethylamine (3 ml) was added and stirred at room temperature for 6 hours. At the end, the separated solid was filtered and washed with water. The crude product was found to be pure enough for further transformations. Yield: 2.0 g (99%); mp. 118; (M+H) 313.1
Step 2: Preparation of 4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]aniline
A mixture of 3-(4-chloro-6-morpholin-4-yl-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane (2.0 g, 6.4 mmol), tetrakis(triphenylphosphine)palladium (0) in catalytic amount (100 mg), sodium carbonate solution 2 M (5 mL), 4-aminophenylboronic acid pinacol ester (1.5 g, 6.43 mmoles), DME (200 mL) was refluxed for 24 hours. The solvent was evaporated and the residue was dissolved in methylene chloride and filtered though CeliteTM. 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 1.4 g, (59% yield) of the titled product. mp. 154; (M+H) 369.4.
Step 3: Preparation of 1-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-phenylurea
The titled compound was prepared by starting from 4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]aniline (120 mg, 0.32 mmol) phenylisocyanate (80 mg, 0.67 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 H PLC, using ACN/water and TFA. White solid; mp: 242; Yield 35 mg (28%); (M+H) 488.56
Example 24
Preparation of 1-(4-fluorophenyl)-3-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea
The titled compound was prepared by starting from 4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]aniline (100 mg, 0.27 mmol)-4-fluoro phenylisocyanate (50 mg, 0.36 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; mp: 248; Yield 86 mg (86%); (M+H) 506.4
Example 25
Preparation of 1-(4-methylphenyl)-3-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea
The titled compound was prepared by starting from 4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]aniline (100 mg, 0.27 mmol)-4-tolylisocyanate (60 mg, 0.45 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; mp: 228; Yield 80 mg (80%); (M+H) 502.4
Following the procedure as outlined in example 25, compounds described in examples 26 to 32 were prepared.
Example 26
1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-methylurea (M+H) 452.53
Example 27
2-hydroxyethyl[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]carbamate (M+H) 483.54
Example 28
1-[4-(4,6-di-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 (M+H) 612.8
Example 29
1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-ethylurea (M+H) 466.56
Example 30
1-cyclopropyl-3-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]urea (M+H) 478.55
Example 31
1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea (M+H) 515
Example 32
1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxymethyl)phenyl]urea (M+H) 544.6
Example 33
Preparation of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline
Step 1: Synthesis of 4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine
To a solution of cyanuric chloride (2.5 g, 13.5 mmol) in CH2Cl2 (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 CH2Cl2. The organic phase was washed with water and brine, and dried over MgSO4. 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.
Step 2: Synthesis of 8-(4-chloro-6-morpholino-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3,2,1]octane
To a solution of 4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine (2.34 g, 10 mmol) in CH2Cl2 (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 MgSO4. 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 (MgSO4). 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.
Example 34
Preparation of 1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
To a solution of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) in CHCl3 (1 mL) were added Et3N (25 mL, 0.18 mmol) and triphosgene (18 mg, 0.06 mmol). The mixture was stirred at room temperature for 15 min and 4-aminopyridine (17 mg, 0.18 mmol) was added. The mixture was stirred at room temperature overnight. The solvent was removed, and the residue was subjected to HPLC separation to give the title compound as off-white solid (1TFA salt, 8.8 mg, 24% yield). MS (ESI) m/z 489.2.
Example 35
Preparation of 4-[({4-[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
Following the procedure described in example 34, reaction of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and 4-aminobenzamide (25 mg, 0.18 mmol) gave the title compound as off-white solid (10.6 mg, 33% yield). MS (ESI) m/z 531.2.
Example 36
Preparation of 1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea
Following the procedure described in example 34, reaction of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and 3-aminopyridine (17 mg, 0.18 mmol) gave the title compound as off-white solid (1TFA salt, 14.8 mg, 41% yield). MS (ESI) m/z 489.5.
Example 37
Preparation of 1-(4-fluorophenyl)-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
Following the procedure described in example 34, reaction of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and 4-fluoroaniline (20 mg, 0.18 mmol) gave the title compound as off-white solid (14.8 mg, 49% yield). MS (ESI) m/z 506.5.
Example 38
Preparation of 1-[4-(hydroxymethyl)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
Following the procedure described in example 34, reaction of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and 4-aminobenzyl alcohol (22 mg, 0.18 mmol) gave the title compound as off-white solid (9.6 mg, 31% yield). MS (ESI) m/z 518.5.
Example 39
Preparation of 1-[4-(2-hydroxyethyl)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
Following the procedure described in example 34, reaction of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and 4-aminophenethyl alcohol (24 mg, 0.18 mmol) gave the title compound as off-white solid (10.6 mg, 33% yield). MS (ESI) m/z 532.5.
Example 40
Preparation of 2-(diethylamino)ethyl 4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate
Following the procedure described in example 34, reaction of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and procaine hydrochloride (50 mg, 0.18 mmol) gave the title compound as off-white solid (1TFA salt, 14.6 mg, 33% yield). MS (ESI) m/z 613.6.
Example 41
Preparation of 1-(4-methylphenyl)-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
Following the procedure described in example 34, reaction of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and p-toluidine (20 mg, 0.18 mmol) gave the title compound as off-white solid (9.2 mg, 31% yield). MS (ESI) m/z 502.5.
Example 42
Preparation of 1-(4-cyanophenyl)-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
Following the procedure described in example 34, reaction of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and 4-aminobezonitrile (21 mg, 0.18 mmol) gave the title compound as off-white solid (14.3 mg, 46% yield). MS (ESI) m/z 513.5.
Example 43
Preparation of 1-[4-(4-methylpiperazin-1-yl)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
Following the procedure described in example 34, reaction of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and 4-(4-methylpiperazin-1-yl)aniline (54 mg, 0.18 mmol) gave the title compound as off-white solid (2TFA salt, 3.2 mg, 7% yield). MS (ESI) m/z 586.6.
Example 44
Preparation of 1-isopropyl-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
Following the procedure described in example 34, reaction of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and isopropylamine (11 mg, 0.18 mmol) gave the title compound as off-white solid (13.6 mg, 50% yield). MS (ESI) m/z 454.5.
Example 45
Preparation of 1-(2-hydroxyethyl)-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
Following the procedure described in example 34, reaction of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and ethanolamine (11 mg, 0.18 mmol) gave the title compound as off-white solid (14.4 mg, 53% yield). MS (ESI) m/z 456.5.
Example 46
Preparation of 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, MS (ES+) 513.62 (M+H)+
Example 47
Preparation of 1-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea, MS (ESI) m/z 489.3
Example 48
Preparation of 1-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea, mp 258° C.; MS (ESI) m/z 489.3
Following the procedure as outlined in example 1, step 3 the following compounds were prepared.
Example 49
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(2-methylpyridin-4-yl)urea MS (ESI) m/z 477.3
Example 50
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(2-hydroxyethyl)phenyl]urea MS (ESI) m/z 506.4
Example 51
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxymethyl)phenyl]urea
Example 52
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(1-hydroxyethyl)phenyl]urea MS (ESI) m/z 506.4
Example 53
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(trifluoromethyl)phenyl]urea MS (ESI) m/z 530.2
Example 54
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-hydroxyphenyl)urea MS (ESI) m/z 478.2
Example 55
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[5-(trifluoromethyl)pyridin-2-yl]urea MS (ESI) m/z 530.5
Example 56
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 MS (ESI) m/z 621.54
Example 57
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[3-(1-hydroxyethyl)phenyl]urea MS (ESI) m/z 506.3
Example 58
methyl 4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoate MS (ESI) m/z 520.3
Example 59
Preparation of 1-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
Step 1: To a stirred solution of NaH (50% 460 mg) in dry THF tetrahydro-2H-pyran-4-ol (1.02 g, 10 mmol) was slowly added at room temperature. The reaction mixture was stirred at room temperature for 30 min and 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (2.35 g, 10 mmol) in THF (50 ml) was slowly added. The reaction mixture was stirred at room temperature for 48 hours and slowly quenched with ice-cold water. It was extracted with CHCl3; washed well with water and dried over anhydrous MgSO4. It was filtered and concentrated and 2-chloro-4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazine was purified by silica gel column chromatography by eluting it with 40% ethyl acetate:hexane. Yield: 1.5 g, 50%; White solid; mp 91° C.; MS (ESI) m/z 301.52
Step 2: 4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]aniline was prepared by the procedure as described in example 1, step 2. Starting from 2-chloro-4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazine (1.5 g, 4.9 mmol) 980 mg (56% yield) of the product was isolated after purification using Silica gel column chromatography by eluting it with ethyl acetate. Mp. 188° C.; MS (ESI) m/z 358.2.
Step 3: 1-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea was prepared by the procedure as described in example 1, step 3. Starting from 4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]aniline (212 mg. 0.59 mmol) 190 mg (Yield, 67%) of the final product was isolated as a white solid. mp 238° C.; MS (ESI) m/z 478.3.
Example 60
Preparation of 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-phenylurea was prepared by reacting the 4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]aniline and the corresponding phenylisocyanate. Product was purified by Gilson, HPLC. MS (ESI) m/z 476.5.
Example 61
Preparation of 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-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea was prepared by reacting the 4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]aniline and the corresponding 3-pyridylisocyanate. Product was purified by Gilson, HPLC. MS (ESI) m/z 477.53.
Example 62
Preparation of 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-[4-(hydroxymethyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}urea was prepared by the triphosgene procedure as described in example 1, step 3. Product was purified by Gilson, HPLC. MS (ESI) m/z 506.6.
Example 63
Preparation of 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-methylpyridin-4-yl)-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}urea was prepared by the triphosgene procedure as described in example 1, step 3. Product was purified by Gilson, HPLC. MS (ESI) m/z 491.5.
Example 64
Preparation of 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-[2-(methylamino)ethyl]-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}urea was prepared by the triphosgene procedure as described in example 1, step 3. Product was purified by Gilson, HPLC. MS (ESI) m/z 457.54.
Example 65
Preparation of 1-(3-acetylphenyl)-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 was prepared by reacting the 4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]aniline and the corresponding 3-acetylisocyanate. Product was purified by Gilson, HPLC. MS (ESI) m/z 518.58.
Example 66
Preparation of 1-[4-(dimethylamino)phenyl]-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 was prepared by reacting the 4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]aniline and the corresponding 4-(N,N-dimethyl amino)phenylisocyanate. Product was purified by Gilson, HPLC. MS (ESI) m/z 519.61.
Example 67
Preparation of 4-[3-{4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl}ureido]benzoic acid
To a stirred mixture of methyl 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoate (1.4 g, 2.69 mmol), THF (10 mL), MeOH (5 mL) and H2O (2.5 mL) was added LiOH.H2O (339 mg, 8.07 mmol) then heated under reflux for 8 hrs. Concentrated and added H2O (5 mL) then acidified with 2N HCl. The solid was filtered washed with H2O and dried to give the product as a tan solid (1.3 g, 96% yield); MS (ESI) m/z=506.3
Example 68
Preparation of N-(2-(dimethylamino)ethyl)-4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzamide
To a stirred solution of 4-[3-{4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl}ureido]benzoic acid (150 mg; 0.297 mmol), Hunig's base (303 μL, 1.782 mmol), HBTU (563 mg, 1.485 mmol) in 2 mL of NMP was stirred for 1 hr. at room temperature and added N′,N′-dimethylethane-1,2-diamine (130 μL, 1.188 mmol) then stirred overnight. Added CH2Cl2 (40 mL) and washed with sat. NaHCO3 and H2O. Concentrated and purified by silica gel chromatography CH2Cl2:MeOH:7N NH3 in MeOH (10:1:0.22) to give the product as a white solid (98 mg, 57% yield); MS (ESI) m/z=576.4.
Example 68
Preparation N-(2-(dimethylamino)ethyl)-4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzamide as an HCl salt
To the N-(2-(dimethylamino)ethyl)-4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzamide (72 mg, 0.125 mmol) and MeOH (1 mL) was added 4N HCl in dioxane (1 mL) and stirred for 3 hrs. The solid was filtered and washed with ether to give the product as a white solid (73 mg, yield=95%); MS (ESI) m/z=576.4.
Example 69
Preparation of 1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea hydrochloride
To a stirred solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (150 mg; 0.297 mmol), Hunig's base (303 μL, 1.782 mmol), HBTU (563 mg, 1.485 mmol) in 2 mL of NMP was reacted according to example 68 with 1-methylpiperazine (1324, 1.188 mmol) to give 1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea as a white solid (95 mg, 54% yield); MS (ESI) m/z=588.4.
To a 1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea (70 mg, 0.119 mmol) and MeOH (1 mL) was added 4N HCl in Dioxane (1 mL), stirred for 3 hrs. The solid was filtered and washed with ether to give the product as a white solid (74 mg, yield=100%).
Example 70
Preparation of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)-N-methylbenzamide
To the stirred solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (150 mg; 0.297 mmol), Hunig's base (303 μL, 1.782 mmol), HBTU (563 mg, 1.485 mmol) in 2 mL of NMP was reacted according to example 68 with methylamine (594 μL, 2M solution. in THF) to give the product as a white solid (118 mg, 77% yield); MS (ESI) m/z=519.3.
Example 71
Preparation of N-(2-(dimethylamino)ethyl)-4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)-N-methylbenzamide hydrochloride
To the stirred solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (150 mg; 0.297 mmol), Hunig's base (303 μL, 1.782 mmol), HBTU (563 mg, 1.485 mmol) in 2 mL of NMP was reacted according to example 68 with N1,N1,N2-trimethylethane-1,2-diamine (154 μL, 1.188 mmol) to give N-(2-(dimethylamino)ethyl)-4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)-N-methylbenzamide as a white solid (88 mg, 50% yield); MS (ESI) m/z=590.2.
To the N-(2-(dimethylamino)ethyl)-4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)-N-methylbenzamide (55 mg, 0.127 mmol) and MeOH (1 mL) was added 4N HCl in Dioxane (1 mL) and stirred for 3 hrs. The solid was filtered and washed with ether to give the product as a white solid (70 mg, yield=88%).
Example 72
Preparation of 1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-morpholinopiperidine-1-carbonyl)phenyl)urea
To the stirred solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 1 mL of NMP was reacted according to example 68 with 4-(piperidin-4-yl)morpholine (67 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product (40.1 mg, 62% yield); MS (ESI) m/z=658.7
Example 73
Preparation of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)-N-(quinuclidin-3-yl)benzamide
To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to according to example 68 with quinuclidin-3-amine (79 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product (24.3 mg, 40% yield); MS (ESI) m/z=614.7
Example 74
Preparation of 1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)urea
To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to example 68 with 4-[1-pyrrolidinyl]piperidine (61 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product as a white solid (37 mg, 58% yield); MS (ESI) m/z=642.7
Example 75
Preparation of 1-(4-(1,4′-bipiperidine-1′-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea
To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to example 68 with 1,4′-bipiperidine (67 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product as a white solid (39 mg, 60% yield); MS (ESI) m/z=656.8.
Example 76
Preparation of 1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea
To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to example 68 with N,N-dimethylpiperidin-4-amine (51 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product (30.6 mg, 52% yield); MS (ESI) m/z=616.7
Example 77
Preparation of 1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazine-1-carbonyl)phenyl)urea
To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to example 68 with piperazine (34 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product (17.2 mg, 30% yield); MS (ESI) m/z=573.6
Example 78
Preparation of 1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(pyridin-2-yl)acetyl)phenyl)urea
To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to example 68 with pyridin-2-ylmethanamine (43 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product (9 mg, 15% yield); MS (ESI) m/z=596.6.
Preparation of 3-(4,6-dichloro-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane
To a solution of cyanuric chloride (2.00 g, 10.85 mmoles) in acetone (20 mL) and water (10 mL) at 0° C. was added a solution of 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (1.46 g, 9.76 mmoles) in saturated aqueous NaHCO3 (25 mL) and acetone (25 mL) via addition funnel over 15 minutes. The reaction was stirred at 0° C. for 2 hours, then filtered to collect a white precipitate. The precipitate was washed with water (25 mL) and dried. The crude product was purified by column chromatography (30:70 ethyl acetate in hexanes) to provide 3-(4,6-dichloro-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane (1.55 g) as a white solid.
Procedure to prepare 3-(4-chloro-6-(substituted amino)-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane
To a solution of 3-(4,6-dichloro-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane (0.085 g, 0.33 mmoles) and Na2CO3 (0.041 g, 0.39 mmoles) in acetone (1 mL) and water (1 mL) was added the desired amine (0.36 mmoles). The solution was heated to 55° C. and stirred for 2 hours then concentrated to provide crude amino-triazine, which was used directly without purification. Following this procedure, the following compounds were prepared.

    3-(4-chloro-6-(piperidin-1-yl)-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane; (310.3, M+H)
    3-(4-chloro-6-(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane (296.3, M+H)
    t-butyl 2-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-ylamino)ethylcarbamate (385.3, M+H)
    2-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-ylamino)ethanol (286.3, M+H)
    4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-N-phenyl-1,3,5-triazin-2-amine (318.3, M+H)
    4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-N-cyclohexyl-1,3,5-triazin-2-amine (324.3, M+H)
    t-butyl 3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-ylamino)azetidine-1-carboxylate (397.3, M+H)


Method to prepare 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(substituted amino)-1,3,5-triazin-2-yl)aniline
A suspension of bis-amino triazine chloride (0.33 mmoles) in toluene (2 mL), ethanol (2 mL), and 2M aqueous Na2CO3 (0.700 mL) in a microwave vial was sparged with N2 for 5 minutes. Pd(PPh3)4 (0.021 mgs, 0.018 mmoles) and 4-aminophenylboronic acid pinacol ester (0.094 mgs, 0.43 mmoles) were added and the vial was sealed and heated to 110° C. for 1 hour. The mixture was cooled and filtered through CeliteTM. The filter cake was washed with ethyl acetate and the filtrate was washed with brine, dried, and concentrated. The crude material was purified by HPLC (Waters system, 5-70% CH3CN in H2O w/0.05% NH4OH) to provide the aryl-substituted triazine compounds. Following this procedure, the following compounds were prepared.

    4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperidin-1-yl)-1,3,5-triazin-2-yl)aniline (367.4, M+H)
    4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)aniline (353.3, M+H)
    2-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-ylamino)ethanol; (343.3, M+H)
    4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-phenyl-1,3,5-triazin-2-amine; (375.3, M+H)
    4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-cyclohexyl-1,3,5-triazin-2-amine; (381.4, M+H)
    t-butyl 3-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-ylamino)azetidine-1-carboxylate; (454.4, M+H).


Procedure to prepare 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(substituted amino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
A solution of triphosgene (0.034 mgs, 0.114 mmoles) in CH2Cl2 (1 mL) was prepared. A solution of the desired triazine aniline derivative (0.23 mmoles) in CH2Cl2 (1 mL) and triethylamine (0.095 mL, 0.68 mmoles) was added and the reaction was allowed to stir at room temperature for 15 minutes. A solution of 4-aminopyridine (0.043 mgs, 0.46 mmoles) in THF (1 mL) was then added and the solution was stirred at room temperature for 3 hours, then concentrated and purified by HPLC (Waters system, 5-70% CH3CN in H2O w/0.05% NH4OH) to provide the 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(substituted amino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea derivatives. The following compounds were prepared by this procedure:
Example 79
Preparation of 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea; 487.2, M+H
Example 80
Preparation of 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea; 474.2, M+H
Example 81
Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(1-hydroxyethyl)phenyl]urea
To a stirred mixture of 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140, 0.40 mmoles) in methylene chloride at 0° C. was added triphosgene (0.25, 0.84 mmoles) and Et3N (3 mL). The reaction mixture was stirred for 20 minutes at 0° C. Then 1-(4-aminophenyl)ethanol (0.10 g, 0.73 mmoles) was added to the mixture. The reaction mixture was stirred for about 16 hours at room temperature. The solvent was removed. The residue was dissolved in DMSO and place at HPLC using acetonitrile buffer TFA to give 48 mg (24%) of [4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(1-hydroxyethyl)phenyl]urea. M+H 506.4.
Example 82
Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(2-methylpyridin-4-yl)urea
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140, 0.40 mmoles) and 2-methyl-4-aminopyridine (80 mg, 0.73 mmol) and following the procedure as outlined in Example 81, 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(2-methylpyridin-4-yl)urea was isolated by HPLC purification. Yield: 60 mg, 27%; MS (ESI) m/z=477.3.
Example 83
Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxymethyl)phenyl]urea
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140, 0.40 mmoles) and 4-aminophenylmethanol (100 mg, 0.81 mmol) and following the procedure described in example 81, 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxymethyl)-phenyl]urea was isolated by HPLC purification. Yield: 58 mg, 26%; MS (ESI) m/z=492.3.
Example 84
Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-hydroxyphenyl]urea
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140, 0.40 mmoles) and 4-aminophenol (89 mg, 0.81 mmol) and following the procedure as outlined in Example 81, 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-hydroxyphenyl]urea was isolated by HPLC purification. Yield: 62 mg, 16%; MS (ESI) m/z=478.2.
Example 85
Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(trifluoromethyl)phenyl]urea
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140, 0.40 mmoles) and 4-trifluoromethylaniline (100 mg, 0.62 mmol) and following the procedure as outlined in example 81, 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(trifluoromethyl)phenyl]urea was isolated by HPLC purification. Yield: 25 mg, 13%; MS (ESI) m/z=430.2.
Example 86
Preparation of 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
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140, 0.40 mmoles) and 4-trifluoromethylaniline (140 mg, 0.40 mmol) and following the procedure as outlined in example 81, 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 was isolated by HPLC purification. Yield: 40 mg, 16%; MS (ESI) m/z=628.3.
Example 87
Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[5-(trifluoromethyl)pyridin-2-yl]urea
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.160, 0.47 mmoles) and 2-amino-5-trifluorophenylpyridine (100 mg, 0.61 mmol) and following the procedure as outlined in example 81, 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[5-(trifluoromethyl)pyridin-2-yl]urea was isolated by HPLC purification. Yield: 10 mg, 4.1%; MS (ESI) m/z=531.3.
Example 88
Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[3-(1-hydroxyethyl)phenyl]urea
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.160, 0.47 mmoles) and 1-(3-aminophenyl)ethanol (100 mg, 0.73 mmoles) and following the procedure as outlined in example 81, 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[3-(1-hydroxyethyl)phenyl]urea was isolated by HPLC purification. Yield: 10 mg, 4.1%; MS (ESI) m/z=531.3.
Example 89
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
Step 1: Preparation of 2-chloro-4-[(35)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazine
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 MgSO4 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-[(35)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}aniline
A mixture of 2-chloro-4-[(35)-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 CeliteTM. 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-[(35)-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-[(35)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
Starting from 4-{4-[(35)-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-[(35)-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.
Example 90
Preparation of 1-[4-(2-hydroxyethyl)phenyl]-3-(4-{4-[(35)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea
Starting from 4-{4-[(35)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}aniline (0.160, 0.44 mmoles) and 4-(1-hydroxyethyl)aniline (137 mg, 1 mmole) and following the procedure described in example 81, 1-[4-(2-hydroxyethyl)phenyl]-3-(4-{4-[(35)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea was isolated by HPLC purification. Yield: 125 mg, 60%; MS (ESI) m/z 519.6
Example 91
Preparation of 1-[4-(2-hydroxymethyll)phenyl]-3-(4-{4-[(35)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea
Starting from 4-{4-[(35)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}aniline (0.160, 0.44 mmoles) and 4-aminophenylmethanol (0.10 g, 0.81 mmoles) and following the procedure as outlined in example 81, 1-[4-(2-hydroxymethyll)phenyl]-3-(4-{4-[(35)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea was isolated by HPLC purification. Yield: 55 mg, 16%; MS (ESI) m/z 506.3.
Example 92
Preparation of 1-(4-{4-[(35)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-(2-methylpyridin-4-yl)urea
Starting from 4-{4-[(35)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}aniline (0.160, 0.44 mmoles) and 2-methyl-4-aminopyridine (0.10 g, 0.92 mmoles) and following the procedure as outlined in example 81, 1-(4-{4-[(35)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-(2-methylpyridin-4-yl)urea was isolated by HPLC purification. Yield: 75 mg, 36%; MS (ESI) m/z 491.3.
Example 93
Preparation of 1-[4-(1-hydroxyethyl)phenyl]-3-(4-{4-[(35)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea
Starting from 4-{4-[(35)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}aniline (0.160, 0.44 mmoles) and 1-(4-aminophenyl)ethanol (126 mg, 0.92 mmoles) and following the procedure as outlined in example 81, 1-[4-(1-hydroxyethyl)phenyl]-3-(4-{4-[(35)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea was isolated by HPLC purification. MS (ESI) m/z 519.6.
Example 94
Preparation of 1-[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea
Step 1: To a stirred solution of isopropanol (250 mg, 4.1 mmol) in dry THF (50 ml) at −78° C., n-butyllithium (2.6 ml, 1.6 mol solution) was slowly added. The reaction mixture was stirred for 30 minutes and a solution of 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (1.00 g, 4.25 mmol) in THF was added to the solution. The reaction mixture was stirred at room temperature for 24 hours and quenched with water and extracted with DCM. The crude product obtained was taken to next step without purification.
Step 2: A mixture of (crude) 4-(chloro-6-isopropoxyl-1,2,3-triazin-2-yl)morpholine of (2.91 g, 11.27 mmol) 4-amino-phenylboronic acid pinacol ester (3.59 g, 16.4 mmoles), tetrakis palladium triphenylphosphine (120 mg catalytic amount) and sodium carbonate solution (2M, 2 mL) was refluxed in DME (100 mL) for 24 hours. The solvent was removed and the residue was re-dissolved in methylene chloride and filtered through CeliteTM. The solvent was evaporated and the residue was chromatographed on silica gel eluting with first 26:4 hexane:ethyl acetate then increased to 1/1 hexanes ethyl acetate to give 0.65 g (yield 18%) of 4-(4-isopropoxy-6-morpholino-1,3,5-triazin-2-yl)aniline. M+H 316.3.
Step 3: Starting from 4-(4-isopropoxy-6-morpholino-1,3,5-triazin-2-yl)aniline (0.140, 0.44 mmoles) and 4-aminopyridine (100 mg, 1.06 mmoles) and following the procedure as outlined in example 81, 1-[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea was isolated by HPLC purification. Yield: 15 mg, 7.8%; MS (ESI) m/z=436.3.
Example 95
Preparation of methyl 4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoate
A mixture of 4-(4-isopropoxy-6-morpholino-1,3,5-triazin-2-yl)aniline (1.3 g, 4.1 mmol), triethylamine (2 ml) and 4-carbomethoxy-phenylisocyanate (1451 mg, 8.2 mmol) was stirred for 48 hours and quenched with water and washed well. The organic layer was dried and filtered. It was concentrated and purified by column chromatography by eluting it initially with 10% ethyl acetate:hexane and latter with 40% ethyl acetate:hexane. White solid; 600 mg, 30%; MS (ESI) m/z 492.5.
Example 96
Preparation of 1-[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea
Starting from methyl 4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoic acid (160 mg, 0.33 mmol) and 4-methylpiperazine following the procedure as outlined in Experimental 71, 80 mg (44% Yield) of the titled compound was isolated as white solid. MS (ESI) m/z 281.2.
Example 97
Preparation of 4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(1-methylpiperidin-4-yl)benzamide
Starting from methyl 4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoic acid (200 mg, 0.42 mmol) and 4-amino-1-methylpiperidine following the procedure as outlined in Experimental 71, 65 mg (27% Yield) of the titled compound was isolated as white solid. MS (ESI) m/z 574.68.
Example 98
Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(1-methylpiperidin-4-yl)urea
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (140 mg 0.40 mmoles) and 4-amino-1-methylpiperidine (70 mg, 0.62 mmol) and following the procedure as outlined in example 1, step 3, 20 mg (10% Yield) of the final compound was isolated as a solid. MS (ESI) m/z=483.4
Example 99
Preparation of 1-(4-{4-[(35)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-(1-methylpiperidin-4-yl)urea
Starting from 4-{4-[(35)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}aniline (0.140, 0.39 mmoles) and 4-amino-1-methylpiperidine (70 mg, 0.62 mmol) and following the procedure as outlined in example 81, the titled product was prepared and purified by HPLC. Yield: 120 mg, 40%; 497.4.
Example 100
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
Step 1: Preparation of 2-Chloro-4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-[1,3,5]triazine
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 (Ph3P)2PdCl2 (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 Na2CO3 (2 molar)(1 mL, 2 mmol, 2 eq), (Ph3P)4Pd (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 CH2Cl2/ethyl acetate (10:1) and later CH2Cl2/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 CH2Cl2 (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 NEt3 (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
Example 101
Preparation of 1-{4-[4-Morpholin-4-yl-6-(tetrahydro-pyran-4-yl)-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-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 (130 mg, 0.28 mmol) and Pd—C (10%, wet) (113 mg) were suspended in methanol/THF/CH2Cl2 (4:1:1) (30 mL) and hydrogenated (at 1 atm pressure) for 3 h. After completion, the catalyst was removed by filtration over CeliteTM and the solvents were removed in vacuo to obtain the crude product, which was purified by semi-prep-HPLC (TFA-method), to give (32 mg=20% yield) of 1-{4-[4-Morpholin-4-yl-6-(tetrahydro-pyran-4-yl)-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea; MS (ESI) m/z 462.
Example 102
Preparation of 1-{4-[4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea
Step 1: Preparation of 3-(4-Chloro-6-morpholin-4-yl-[1,3,5]triazin-2-yloxy)-8-methyl-8-aza-bicyclo[3.2.1]octane
In a three neck flask equipped with stirring bar under N2 atmosphere tropine (1 g, 4.24 mmol) was suspended in (anhydrous) THF (15 mL). The mixture was cooled to −78° C. and BuLi (2M in THF) (5.53 ml, 1.2 eq) was added dropwise and the mixture was allowed to warm to 25° C. over 30 minutes. To the reaction mixture 2,4,-dichloro-6-morpholin-4-yl-[1,3,5]triazine (996 mg, 4,24, mmole) was added and allowed to stir overnight. For work up, ether (100 mL) was added. The organic layer was washed with water (20 mL) and brine (20 mL) and dried over MgSO4. filtered and the solvents were removed to obtain a colorless oil. Further purification by flash-chromatography using CH2Cl2/MeOH/NH3 (15:1:0.1) gave the product as white solid (600 mg, 42% yield); MS (ESI) m/z 340
Step 2: Preparation of 4-[4-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenylamine
To a microwave processing tube was added dimethoxyethane (4 mL), aqueous Na2CO3 (2 molar)(1 mL, 2 mmol, 2 eq), (Ph3P)4Pd (85 mg, 0.074 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (482 mg, 2.21 mmol, 1.5 eq) and the 3-(4-chloro-6-morpholin-4-yl-[1,3,5]triazin-2-yloxy)-8-methyl-8-aza-bicyclo[3.2.1]octane (500 mg, 1.47 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 CH2Cl2/ethyl acetate (10:1) and later with CH2Cl2/MeOH/NH3 (10:1:0.1) to give the product as an off-white solid (300 mg, 51% yield); MS (ESI) m/z 369.
Step 3: Preparation of 1-{4-[4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea
To a stirred solution of triphosgene (60 mg, 0.20 mmol) in CH2Cl2 (3 mL) was added 4-[4-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenylamine (100 mg, 0.25 mmol) at 25° C. The reaction mixture was stirred for 15 min and 4-aminopyridine (70 mg, 0.75 mmol) and NEt3 (3464, 2.5 mmol) were added and the reaction mixture was stirred for additional 1 hr. The solvents were removed and the crude mixture was purified by semi-prep-HPLC(NH3-method) to give 1-{4-[4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea (28 mg, 22% yield); MS (ESI) m/z 517.
Example 103
Preparation of 4-(3-{4-[4-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-ureido)-benzamide
To a stirred solution of triphosgene (120 mg, 0.40 mmol) in CH2Cl2 (3 mL) was added 4-[4-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenylamine (200 mg, 0.5 mmol) at 25° C. The reaction mixture was stirred for 15 min and 4-aminobenzamide (204 mg, 1.5 mmol) and NEt3 (692 μL, 5 mmol) were added and the reaction mixture was stirred for additional 1 hr. The solvents were removed and the crude mixture was purified by semi-prep-HPLC (NH3-method) to give 4-(3-{4-[4-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-ureido)-benzamide (42 mg, 15% yield) MS (ESI) m/z 559.
Example 104
Preparation of 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
Step 1: Preparation of 3-[(4-Chloro-6-morpholin-4-yl-[1,3,5]triazin-2-ylamino)-methyl]-azetidine-1-carboxylic acid tert-butyl ester
To a solution of the 3-aminomethyl-azetidine-1-carboxylic acid tert-butyl ester HCl salt (945 mg, 4.24 mmol) and NEt3 (856 mg, 8.48 mmol) in THF (10 mL) at 0° C. was added a suspension of 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (996 mg, 4.24 mmol) at 0° C. The reaction mixture was stirred for another 1 hr at 0° C. and allowed to warm to 20° C. and stirred for 1-4 hrs to drive the reaction to completion. Silica gel (20 g) was added to the reaction mixture and the solvent was removed so that product was adsorbed on the silica gel. The silica gel plug was placed on top of a column to purify by flash chromatography using CH2Cl2/MeOH/NH3 (20:1:01) eluent. After unifying the product fraction, and evaporation of solvent, (750 mg, 46% yield) product was obtained as yellow solid; MS (ESI) m/z 385
Step 2: Preparation of 3-{[4-(4-Amino-phenyl)-6-morpholin-4-yl-[1,3,5]triazin-2-ylamino]-methyl}-azetidine-1-carboxylic acid tert-butyl ester
To a microwave processing tube was added dimethoxyethane (15 mL), aqueous Na2CO3 (2 molar)(4 mL, 8 mmol, 2 eq), (Ph3P)4Pd (317 mg, 0.55 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (1.81 g, 8.30 mmol, 1.5 eq) and 3-[(4-Chloro-6-morpholin-4-yl-[1,3,5]triazin-2-ylamino)-methyl]-azetidine-1-carboxylic acid tert-butyl ester (1.3 g, 5.53 mmol) and the vessel was sealed. The mixture was heated to 140° C. for 60 minutes. The solvents were removed and the crude compound was purified by silica gel chromatography using CH2Cl2/Ethyl acetate (10:1) and later CH2Cl2/MeOH/NH3 (15:1:0.1) to give the product as a off-white solid (1.3 g, 53% yield).
MS (ESI) m/z=442
Step 3: Preparation of 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
To a stirred solution of triphosgene (269 mg, 0.90 mmol) in CH2Cl2 (5 mL) was added 3-{[4-(4-Amino-phenyl)-6-morpholin-4-yl-[1,3,5]triazin-2-ylamino]-methyl}-azetidine-1-carboxylic acid tert-butyl ester (500 mg, 1.13 mmol) at 25° C. The reaction mixture was stirred for 15 min and 4-aminopyridine (319 mg, 3.39 mmol) and NEt3 (1.56 mL, 11.3 mmol) were added and the reaction mixture was stirred for additional 1 hr. The solvents were removed on a rotary evaporator and the crude mixture was purified by semi-prep-HPLC (TFA-method) to give 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 (150 mg, 16% yield); MS (ESI) m/z 562.
Example 105
Preparation of 1-(4-{4-[(azetidin-3-ylmethyl)-amino]-6-morpholin-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 (100 mg, 0.18 mmol) was dissolved CH2Cl2 (1 mL) and TFA (1 mL) was added. It was stirred for 16 hrs at 25° C. and then the solvents were removed under reduced pressure and the residue was treated with acetonitrile/MeOH (1:1) (2 mL) to obtain a white solid, which was collected by filtration to obtain the product as bis-TFA salt (59 mg, 46% yield). MS (ESI) m/z 462.
Example 106
Preparation of Tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate
Tert-butyl 4-(4,6-dichloro-1,3,5-triazin-2-yl)piperazine-1-carboxylate was prepared according to Löwik, D. W. P. M. and Lowe, C. R. Eur. J. Org. Chem. 2001, 2825-2839.
Step 1: Preparation of tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-yl)piperazine-1-carboxylate
To a solution of 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (0.49 g, 3.3 mmol) in water (18 mL) was added a suspension of tert-butyl 4-(4,6-dichloro-1,3,5-triazin-2-yl)piperazine-1-carboxylate (1.0 g, 3.0 mmol) in acetone (about 10 mL). The suspension was stirred magnetically while solid sodium carbonate (0.70 g, 6.6 mmol) was added in a single portion. The mixture was stirred for two hours while heating in a 70-75° C. in an oil bath. After allowing the mixture to cool to room temperature, the title compound was removed by filtration, washed with water, and dried under vacuum.
MS (ES+) 411.0, 412.3 (M+H)+
Step 2: Preparation of tert-butyl 4-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate
A suspension of tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-yl)piperazine-1-carboxylate (1.0 g, 2.4 mmol), 4-aminophenylboronic acid, pinacol ester (0.69 g, 3.2 mmol), and tetrakis(triphenylphosphine) palladium (0.28 g, 0.24 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.
MS (ES+) 468.1 (M+H)+
Step 3: Preparation of tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate
Crude tert-butyl 4-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate (approx. 1.4 mmol) was dissolved in tetrahydrofuran (20 mL) and then treated sequentially with triphosgene (0.30 g, 1.0 mmol) and triethylamine (2 mL). After 5 minutes, the mixture was treated with a solution of 4-aminopyridine (0.53 g, 5.6 mmol) in tetrahydrofuran. The mixture was concentrated under reduced pressure to give crude tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate, a sample of which was purified by reversed phase HPLC to give a pure title compound.
MS (ES+) 588.2 (M+H)+
Example 107
Preparation of 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
Crude tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate (approx 1.4 mmol) was taken up in dichloromethane (20 mL) and treated with trifluoroacetic acid (5 mL). The mixture was concentrated under reduced the pressure. To the residue was added diethyl ether to give the title compound as a solid di-TFA salt, which was collected by filtration and dried under house vacuum; MS (ES+) 488.1 (M+H)+
Example 108
Preparation of 1-{4-[4-(4-methylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea.2TFA (115 mg) in 1:1 98% formic acid and 37% formalin (4 mL) was heated at 75° C. for 90 minutes, then concentrated to dryness and purified on HPLC to give the title compound as its di-TFA salt; MS (ES+) 502.3 (M+H)+
Example 109
Preparation of 1-{4-[4-(4-benzylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea.2TFA (130 mg) in dichloromethane (4 mL) and triethylamine (0.10 mL) was treated with benzaldehyde (0.10 mL), followed by sodium triacetoxyborohydride (80 mg). The mixture was concentrated to dryness and purified on HPLC to give the title compound as its di-TFA salt; MS (ES+) 578.3 (M+H)+.
Example 110
Preparation of 1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[4-(pyridin-3-ylmethyl)piperazin-1-yl]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea.2TFA (150 mg) in dichloromethane (4 mL) and triethylamine (0.12 mL) was treated with 3-pyridinecarboxaldehyde (0.1 mL), followed by sodium triacetoxyborohydride (80 mg). The mixture was concentrated to dryness and purified on HPLC to give the title compound as its tri-TFA salt; MS (ES+) 579.3 (M+H)+
Example 111
Preparation of 1-{4-[4-(4-acetylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea.2TFA (230 mg) in dichloromethane (4 mL) and triethylamine (1 mL) was treated with acetyl chloride. The mixture was concentrated to dryness and purified on HPLC to give the title compound as its TFA salt; MS (ES+) 530.3 (M+H)+.
Example 112
Preparation of 1-(4-{4-[4-(N,N-dimethylglycyl)piperazin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea.2TFA (64 mg) in dichloromethane (4 mL) and triethylamine (1 mL) was treated with dimethylaminoacetyl chloride hydrochloride (100 mg). The mixture was heated with a heat gun, then concentrated to dryness and purified on HPLC to give the title compound as its di-TFA salt; MS (ES+) 573.3 (M+H)+.
Example 113
Preparation of 1-{4-[4-(4-isonicotinoylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea.2TFA (100 mg) in dichloromethane (4 mL) and triethylamine (1 mL) was treated with isonicotinoyl chloride (100 mg). The mixture was concentrated to dryness and purified on HPLC to give the title compound as its di-TFA salt; MS (ES+) 593.1 (M+H)+
Example 114
Preparation of Methyl 4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]piperazine-1-carboxylate
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea.2TFA (75 mg) in dichloromethane (2 mL), tetrahydrofuran (2 mL), and triethylamine (1 mL) was treated with methyl chloroformate (0.10 mL). The mixture was concentrated to dryness and purified on RP-HPLC to give the title compound as its TFA salt. MS (ES+) 546.3 (M+H)+
Example 115
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
Step 1: Preparation of 1-(4,6-dichloro-1,3,5-triazin-2-yl)piperidin-4-one
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)+
Example 116
Preparation of 1-{4-[4-(4-hydroxypiperidin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
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.TFA (56 mg) was taken up in methanol/tetrahydrofuran (1:1, 6 mL), and the mixture at 0° C. was treated with sodium borohydride (10 mg). After warming to room temperature, the mixture was concentrated to a residue which then was purified by HPLC to give the title compound as its TFA salt; MS (ES+) 503.0 (M+H)+
Example 117
Preparation of 1-(4-{4-[4-(benzylamino)piperidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
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.TFA (85 mg) in dichloromethane (3 mL) and tetrahydrofuran (3 mL) was treated with benzylamine (0.030 mL), followed by glacial acetic acid (0.016 mL) and sodium triacetoxyborohydride (89 mg). After completion of the reaction, methanol was added and mixture was concentrated to dryness. The residue was purified by HPLC to give the title compound as its di-TFA salt.
MS (ES+) 592.3 (M+H)+
Example 118
Preparation of 1-(4-{4-[4-(methylamino)piperidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
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.TFA (50 mg) in tetrahydrofuran (5 mL) was treated with methylamine (2.0 M solution in tetrahydrofuran, 0.16 mL), followed by glacial acetic acid (0.009 mL) and sodium triacetoxyborohydride (51 mg). After completion of the reaction, methanol was added and mixture was concentrated to dryness. The residue was purified by HPLC to give the title compound as its di-TFA salt; MS (ES+) 516.3 (M+H)+
Example 119
Preparation of 1-(4-{4-[4-(ethylamino)piperidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
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.TFA (50 mg) in tetrahydrofuran (5 mL) was treated with ethylamine (2.0 M solution in tetrahydrofuran, 0.16 mL), followed by glacial acetic acid (0.009 mL) and sodium triacetoxyborohydride (51 mg). After completion of the reaction, methanol was added and mixture was concentrated to dryness. The residue was purified by HPLC to give the title compound as its di-TFA salt; MS (ES+) 530.3 (M+H)+
Example 120
Preparation of 1-{4-[4-(4-{[2-(dimethylamino)ethyl]amino}piperidin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
The titled compound was prepared by the procedure as outlined in example 118, by reacting 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.TFA (50 mg) with N,N-dimethylethylenediamine (0.026 mL) and purified by HPLC and isolated as its tri-TFA salt; MS (ES+) 573.7 (M+H)+.
Example 121
Preparation of 1-{4-[4-(4-morpholin-4-ylpiperidin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
By reacting 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.TFA (50 mg) with 1-(2-aminoethyl)pyrrolidine (0.030 mL) and following the procedure as mentioned in Experimental 118, the title product was isolated as its tri-TFA salt; MS (ES+) 599.8 (M+H)+.
Example 122
Preparation of 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
By reacting 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.TFA (40 mg) and 1-methylpiperazine (0.050 mL) and following the procedure as outlined in example 118, the titled compound was isolated after HPLC purification as its tri-TFA salt; MS (ES+) 585.9 (M+H)+
Example 123
Preparation of 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(2-hydroxyethylamino)piperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
Starting from 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.TFA (50 mg) and ethanolamine (0.020 mL) and following the procedure as outlined in example 118, the title compound was isolated as its di-TFA salt after HPLC purification. MS (ES+) 546.7 (M+H)+
Example 124
Preparation of 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(2-morpholinoethylamino)piperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
Starting from 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.TFA (50 mg) and 1-(2-aminoethyl)morpholine (0.031 mL) and following the procedure as outlined in example 118, the titled compound was isolated as its tri-TFA salt after HPLC purification; MS (ES+) 615.9 (M+H)+
Example 125
Preparation of Methyl 2-(1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperidin-4-ylamino)acetate
Starting from 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.TFA (50 mg) and glycine methyl ester hydrochloride (20 mg) and triethylamine (10 drops) and following the procedure as outlined in example 118 the title compound was isolated as its di-TFA salt after HPLC purification; MS (ES+) 574.8 (M+H)+.
Example 126
Preparation of 2-(1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperidin-4-ylamino)acetamide
Starting from 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.TFA (50 mg) and glycinamide hydrochloride (18 mg) and triethylamine (10 drops) and following the procedure as outlined in example 118 the title compound was isolated as its di-TFA salt after HPLC purification; MS (ES+) 559.8 (M+H)+
Example 127
Preparation of Tert-butyl 2-(1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperidin-4-ylamino)acetate
Starting from 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.TFA (60 mg) and glycine tert-butyl ester hydrochloride (33 mg) and triethylamine (10 drops) and following the procedure as outlined in example 118, the title compound was isolated as its di-TFA salt after HPLC purification; MS (ES+) 616.9 (M+H)+.
Example 128
Preparation of 2-(1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperidin-4-ylamino)acetic acid
Tert-butyl 2-(1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperidin-4-ylamino)acetate (28 mg) in dichloromethane (3 mL) was treated with trifluoroacetic acid (1 mL) and then concentrated to dryness to give the title compound as its TFA salt.
MS (ES+) 560.2 (M+H)+.
Example 129
Preparation of 4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]aniline; MS (ES+) 399.47 (M+H)+
Example 130
Preparation of 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; MS (ES+) 519.58 (M+H)+
Example 131
Preparation of 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; MS (ES+) 519.58 (M+H)+
Example 132
Preparation of 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; MS (ES+) 518.59 (M+H)+
Example 133
Preparation of 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; MS (ES+) 561.66 (M+H)+
Example 134
Preparation of 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; MS (ES+) 543.60 (M+H)+
Example 135
Preparation of 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; MS (ES+) 533.61 (M+H)+
Example 136
Preparation of 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; MS (ES+) 513.62 (M+H)+
Example 137
Preparation of 1-[4-(4-morpholin-4-yl-6-quinolin-3-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea
HRMS: calcd for C28H24N8O2+H+, 505.20950. found (ESI, [M+H]+ Obs'd), 505.2098;
HRMS: calcd for C28H24N8O2+H+, 505.20950. found (ESI, [M+H]+ Calc'd), 505.2095;
Example 138
Preparation of 2-(difluoromethyl)-1-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)-1H-benzimidazole
A solution of cyanuric chloride (922 mg, 5 mmol) in acetone (5 mL) was added to ice. A solution of 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (750 mg, 5 mmol) and triethylamine (2.1 mL, 15 mmol) in aqueous acetone was then added. After 20 min the precipitate was collected to give 1.0 g of a white powder which was a 7:3 mixture of 3-(4,6-dichloro-1,3,5-triazine-2,4-diyl)-8-oxa-3-azabicyclo[3.2.1]octane and 3,3′-(6-chloro-1,3,5-triazine-2,4-diyl)bis(8-oxa-3-azabicyclo[3.2.1]octane). Treatment of the mixture (400 mg) with 2-(difluoromethyl)-1H-benzo[d]imidazole (146 mg, 0.87 mmol) and K2CO3 (967 mg, 7 mmol) in DMF (2.5 mL) for 18 hours, followed by addition of 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (150 mg) gave, after 1 h, 3,3′-(6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)bis(8-oxa-3-azabicyclo[3.2.1]octane) after purification by HPLC. (M+H) 475.
Example 139
Preparation of 2-(difluoromethyl)-1-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]-1H-benzimidazole
To a stirred solution of 3-(4,6-dichloro-1,3,5-triazine-2,4-diyl)(8-oxa-3-azabicyclo[3.2.1]octane) (2.61 g, 10 mmol) in acetone/ice, morpholine (900 mg, 12 mmol) and triethylamine (5 ml) was added. The reaction mixture was stirred at room temperature for 3 hours. Separated white solid was filtered and washed with water. The crude product obtained was pure enough and taken to next step without purification. Treatment of the mixture (270 mg. 0.87 mmol) with 2-(difluoromethyl)-1H-benzo[d]imidazole (146 mg, 0.87 mmol) and K2CO3 (967 mg, 7 mmol) in DMF (2.5 mL) for 18 hours gave 2-(difluoromethyl)-1-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]-1H-benzimidazole after purification by HPLC. (M+H) 445.
Example 140
Preparation of 1-[4-(4-azetidin-1-yl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea; mp 212° C.; MS (ESI) m/z 433.3
Example 141
Preparation of methyl 4-({[4-(4-azetidin-1-yl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoate; mp 212° C.; MS (ESI) m/z 490.2
Example 142
Preparation of 1-[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea; MS (ESI) m/z 561.6
Example 143
Preparation of 4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(1-methylpiperidin-4-yl)benzamide
MS (ESI) m/z 575.6
Example 144
Preparation of 1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(2-piperidin-1-ylethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; MS (ESI) m/z 531.5
Example 145
Preparation of methyl(4-{4-[4-({[4-(4-methylpiperazin-1-yl)phenyl]carbamoyl}amino)phenyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)carbamate; MS (ESI) m/z 650.7
Example 146
Preparation of 1-cyclopropyl-3-(4-{4-[4-({[4-(4-methylpiperazin-1-yl)phenyl]carbamoyl}amino)phenyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea; MS (ESI) m/z 675.8
Example 147
Preparation of N′,N′′′-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazine-2,4-diyl]di-4,1-phenylene}bis{1-[4-(4-methylpiperazin-1-yl)phenyl]urea}; MS (ESI) m/z 809.9
Example 148
Preparation of 1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]phenyl}urea; MS (ESI) m/z 712.8
Example 149
Preparation of 1-(4-{4-[(2-aminoethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea
HRMS: calcd for C23H27N9O2+H+, 462.23605. found (ESI, [M+H]+ Obs'd), 462.2358.
Example 150
Preparation of 1-{4-[4-anilino-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea
HRMS: calcd for C27H26N8O2+H+, 495.22515. found (ESI, [M+H]+ Obs'd), 495.2249.
Example 151
Preparation of 4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(2-piperidin-1-ylethyl)benzamide
MS (ESI) m/2 308.6; HRMS: calcd for C32H41N9O4+H+, 616.33543. found (ESI, [M+H]+ Obs'd), 616.3347; HRMS: calcd for C32H41N9O4+H+, 616.33543. found (ESI, [M+H]+ Calc'd), 616.3354;
Example 152
Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(morpholin-4-ylcarbonyl)phenyl]urea
MS (ESI) m/z 575.3; HRMS: calcd for C29H34N8O5+H+, 575.27249. found (ESI, [M+H]+Obs'd), 575.2722; HRMS: calcd for C29H34N8O5+H+, 575.27249. found (ESI, [M+H]+ Calc'd), 575.2725.
Example 153
Preparation of 1-(4-{4-[(2-hydroxyethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea; MS (ESI) m/z 463.5
Example 154
Preparation of 1-{4-[4-(azetidin-3-ylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea; MS (ESI) m/z 474.5
Example 155
Preparation of 1-(4-{4-[(2-morpholin-4-ylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea; MS (ESI) m/z 532.6
Example 156
Preparation of 1-(4-{4-[(3-aminopropyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea; MS (ESI) m/z 476.5
Example 157
Preparation of 1-(4-{4-[(4-cyclopentylpiperazin-1-yl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea; MS (ESI) m/z 571.7
Example 158
1-{4-[4-isopropoxy-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; MS (ESI) m/z 462.53
Example 159
Preparation of 1-{4-[4-isopropoxy-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
Example 160
Preparation of 1-{4-[4-chloro-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; MS (ESI) m/z 438.8
Example 161
Preparation of 1-[4-(4-methyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea; MS (ESI) m/z 391.5
Example 162
Preparation of methyl 4-({[4-(4-methyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoate; MS (ESI) m/z 449.2
Example 163
Preparation of 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; MS (ESI) m/z 584.7
Example 164
Preparation of 4-({[4-(4-methyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(1-methylpiperidin-4-yl)benzamide; MS (ESI) m/z 530.63
Example 165
Preparation of N-[2-(dimethylamino)ethyl]-N-methyl-4-({[4-(4-methyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide; MS (ESI) m/z 518.6
Example 166
Preparation of 1-[4-(4-methyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea; MS (ESI) m/z 516.6
Example 167
Preparation of 1-(4-{[3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea
HRMS: calcd for C31H39N9O4+H+, 602.31978. found (ESI, [M+H]+Obs'd), 602.3192;
Example 168
Preparation of 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; HRMS: calcd for C33H44N10O4+H+, 645.36198. found (ESI, [M+H]+Obs'd), 645.3615
Example 169
Preparation of 1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(piperidin-4-ylmethyl)amino]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea; MS (ESI) m/z 515.6
Example 170
Preparation of 1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(2-piperidin-4-ylethyl)amino]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea; MS (ESI) m/z 529.65
Example 171
Preparation of 1-{4-[4-(3-methylimidazolidin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea; MS (ESI) m/z 487.5
Example 172
Preparation of 1-{4-[4-(3-methyltetrahydropyrimidin-1(2H)-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea; MS (ESI) m/z 501.6
Example 173
Preparation of 1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(2-piperidin-1-ylethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea; MS (ESI) m/z 530.6
Example 174
Preparation of 1-(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea; MS (ESI) m/z 521.58
Example 175
Preparation of 1-(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-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; MS (ESI) m/z 618.7
Example 176
Preparation of 2-hydroxyethyl (4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)carbamate; MS (ESI) m/z 489.53
Example 177
Preparation of 1-(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-methylurea; MS (ESI) m/z 458.52
Example 178
Preparation of 1-cyclopropyl-3-(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea; MS (ESI) m/z 484.56
Example 179
Preparation of 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
MS (ESI) m/z 642.4; HRMS: calcd for C34H43N9O4+H+, 642.35108. found (ESI-FTMS, [M+H]1+), 642.3491;
Example 180
Preparation of 1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(piperidin-3-ylmethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea; MS (ESI) m/z 516.61
Example 181
Preparation of 1-{4-[4-(4-aminobutoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea; MS (ESI) m/z 490.57
Example 182
Preparation of 1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(2-piperidin-4-ylethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea; MS (ESI) m/z 530.63
Example 183
Preparation of 1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(piperidin-4-ylmethoxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea; MS (ESI) m/z 516.61
Example 184
Preparation 4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoic acid; MS (ESI) m/z 476.53
Example 185
Preparation of N-[2-(dimethylamino)ethyl]-4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-methylbenzamide; MS (ESI) m/z 562.6
Example 186
Preparation of 1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea; MS (ESI) m/z 433.5
Example 187
Preparation of N-[2-(dimethylamino)ethyl]-4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide; MS (ESI) m/z 548.67
Example 188
Preparation of methyl 4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoate; MS (ESI) m/z 490.56
Example 189
Preparation of 1-(4-{4-morpholin-4-yl-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
HRMS: calcd for C24H26N8O3+H+, 475.22006. found (ESI, [M+H]+Obs'd), 475.2201.
Example 190
Preparation of 1-{4-[4-(methylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea; MS (ESI) m/z 432.49
Example 191
Preparation of 1-{4-[4-(ethylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea; MS (ESI) m/z 446.52
Example 192
Preparation of 1-{4-[4-(dimethylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea; MS (ESI) m/z 446.52
Example 193
Preparation of 1-{4-[4-(isopropylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea; MS (ESI) m/z 460.54
Example 194
Preparation of 1-{4-[4-(diethylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea; MS (ESI) m/z 474.57
Example 195
Preparation of 4-({[4-(4-azetidin-1-yl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoic acid; mp 204° C.; MS (ESI) m/z 476.2
Example 196
Preparation of 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.; MS (ESI) m/z 558.2
Example 197
Preparation of 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
MS (ESI) m/z 280.7;
Example 198
Preparation of 4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-[2-(dimethylamino)ethyl]-N-methylbenzamide
Example 199
Preparation of 1-{4-[4-(1-ethoxyvinyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; MS (ESI) m/z 447.499
Example 200
Preparation of 1-{4-[4-(2-methoxyethoxy)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
HRMS: calcd for C22H25N7O4+H+, 452.20408. found (ESI, [M+H]+Obs'd), 452.2047;
Example 201
Preparation of 1-(diethylcarbamoyl)-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]pyridinium
HRMS: calcd for C30H38N9O4+H+, 589.31195. found (ESI, [M+H]+), 589.3035;
Example 202
Preparation of 1-(4-{4-[ethyl(methyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea; MS (ESI) m/z 460.54
Example 203
Preparation of 1-{4-[4-(sec-butylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea; MS (ESI) m/z 474.57
Example 204
Preparation of 1-{4-[4-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea; MS (ESI) m/z 492.54
Example 205
Preparation of 1-(4-{4-[bis(2-hydroxyethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea; MS (ESI) m/z 506.57
Example 206
Preparation of 1-(4-{4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea; MS (ESI) m/z 499.58
Example 207
Preparation of 1-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea; MS (ESI) m/z 592.71
Example 208
Preparation of 1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea; MS (ESI) m/z 578.68
Example 209
Preparation of 1-[4-(4-acetyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea; MS (ESI) m/z 419.406
Example 210
Preparation of 1-(4-{4-morpholin-4-yl-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-1,3,5-triazin-2-yl}phenyl)-3-{4-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]phenyl}urea; MS (ESI) m/z 654.3; HRMS: calcd for C35H43N9O4+H+, 654.35108. found (ESI-FTMS, [M+H]1+), 654.35129
Example 211
Preparation of methyl 4-[({4-[4-(2-methoxyethoxy)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate
HRMS: calcd for C25H28N6O6+H+, 509.21431. found (ESI, [M+H]+Obs'd), 509.214.
Example 212
Preparation of 1-methyl-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea; MS (ESI) m/z 397.48
Example 213
Preparation of 1-cyclopropyl-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea; MS (ESI) m/z 423.52
Example 214
Preparation of 1-(2-hydroxyethyl)-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea; MS (ESI) m/z 427.51
Example 215
Preparation of 1-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea; MS (ESI) m/z 460.54
Example 216
Preparation of 1-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]urea; MS (ESI) m/z 460.54
Example 217
Preparation of 1-(4-{4-[(1-methylethyl)amino]-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; MS (ESI) m/z 557.70
Example 218
Preparation of 1-{4-[(2,2-dimethylhydrazino)carbonyl]phenyl}-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea; MS (ESI) m/z 545.65
Example 219
Preparation of 4-{[(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}-N-pyrrolidin-1-ylbenzamide; MS (ESI) m/z 571.69
Example 220
Preparation of 1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea; MS (ESI) m/z 546.68
Example 221
Preparation of 1-[4-(hydroxymethyl)phenyl]-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea; MS (ESI) m/z 489.58
Example 222
Preparation of 1-[4-(2-hydroxyethyl)phenyl]-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea; MS (ESI) m/z 503.61
Example 223
Preparation of 1-{4-[4-(1-hydroxyethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; MS (ESI) m/z 421.46
Example 224
Preparation of 1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea; MS (ESI) m/z 514.59
Example 225
Preparation of methyl 4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoate; MS (ESI) m/z 462.51
Example 226
Preparation of 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; MS (ESI) m/z 516.55
Example 227
Preparation of 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; MS (ESI) m/z 502.53
Example 228
Preparation of 1-(4-{4-morpholin-4-yl-6-[2-(pyridin-4-ylamino)ethyl]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
HRMS: calcd for C26H27N9O2+H+, 498.23605. found (ESI, [M+H]+Obs'd), 498.2383;
Example 229
Preparation of 1-[4-(4-methylpiperazin-1-yl)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
HRMS: calcd for C31H39N9O3+H+, 586.32486. found (ESI, [M+H]+Obs'd), 586.3245;
Example 230
Preparation of 1-(4-acetylphenyl)-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
HRMS: calcd for C28H31N7O4+H+, 530.25103. found (ESI, [M+H]+Obs'd), 530.2508;
Example 231
Preparation of 4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-[2-(dimethylamino)ethyl]benzamide; MS (ESI) m/z 546.676
Example 232
Preparation of 1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea
MS (ESI) m/z 559.4.
Example 233
Preparation of 4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoic acid; MS (ESI) m/z 448.483
Example 234
Preparation of 1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-1,3,5-triazin-2-yl]phenyl}urea
HRMS: calcd for C23H30N8O3+H+, 467.25136. found (ESI, [M+H]+Obs'd), 467.2525.
Example 235
Preparation of 1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea
HRMS: calcd for C27H31N9O3+H+, 530.26226. found (ESI, [M+H]+Obs'd), 530.2638;
Example 236
Preparation of 1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea; MS (ESI) m/z 531.1
Example 237
Preparation of N-[2-(dimethylamino)ethyl]-4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide
Example 238
Preparation of 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; MS (ESI) m/z 558.711
Example 239
Preparation of 1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxymethyl)phenyl]urea; MS (ESI) m/z 462.554
Example 240
Preparation of 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; MS (ESI) m/z 586.721
Example 241
Preparation of 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; MS (ESI) m/z 586.741
Example 242
Preparation of N-[2-(dimethylamino)ethyl]-4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-methylbenzamide; MS (ESI) m/z 532.649
Example 243
Preparation of N-[2-(dimethylamino)ethyl]-4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-methylbenzamide; MS (ESI) m/z 534.62
Example 244
Preparation of N-[2-(dimethylamino)ethyl]-4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide; MS (ESI) m/z 520.60
Example 245
Preparation of 4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-methyl-N-[2-(methylamino)ethyl]benzamide; MS (ESI) m/z 520.60
Example 246
Preparation of 1-[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea; MS (ESI) m/z 532.61
Example 247
Preparation of 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; MS (ESI) m/z 546.63
Example 248
Preparation of 4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(2-piperidin-1-ylethyl)benzamide; MS (ESI) m/z 560.66
Example 249
Preparation of 1-(4-ethenylphenyl)-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; MS (ESI) m/z 514.3
HRMS: calcd for C28H31N7O3+H+, 514.25611. found (ESI, [M+H]+Obs'd), 514.2561.
Example 250
Preparation of 1-{4-[(4-methylpiperazin-1-yl)methyl]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
HRMS: calcd for C32H41N9O3+H+, 600.34051. found (ESI, [M+H]+Obs'd), 600.3405.
Example 251
Preparation of 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; MS (ESI) m/z 621.77
Example 252
Preparation of 1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]urea; MS (ESI) m/z 532.71
Example 253
Preparation of 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; MS (ESI) m/z 649.82
Example 254
Preparation of 1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea; MS (ESI) m/z 544.728
Example 255
Preparation of 1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-formylphenyl)urea; MS (ESI) m/z 461.2
Example 256
Preparation of tert-butyl(1R,4R)-5-(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate; mp 192° C.; MS (ESI) m/z 574.3
Example 257
Preparation of tert-butyl (1R,4R)-5-[4-(4-{[(4-acetylphenyl)carbamoyl]amino}phenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate; mp 202° C.; MS (ESI) m/z 615.3
Example 258
Preparation of 1-(4-{4-[(2-methoxyethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea; MS (ESI) m/z 476.54
Example 259
Preparation of 1-{4-[4-{[(1S)-2-hydroxy-1-methylethyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea; MS (ESI) m/z 476.54
Example 260
Preparation of 1-{4-[4-{[(1R)-2-hydroxy-1-methylethyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea; MS (ESI) m/z 476.54
Example 261
Preparation of 1-(4-{4-[(2-hydroxy-1,1-dimethylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea; MS (ESI) m/z 490.57
Example 262
Preparation of 1-{4-[4-(tert-butylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea; MS (ESI) m/z 474.57
Example 263
Preparation of 4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(pyridin-2-ylmethyl)benzamide
mp 296-298° C.; MS (ESI) m/z 298.6;
HRMS: calcd for C31H33N9O4+H+, 596.27283. found (ESI, [M+H]+Obs'd), 596.2724;
HRMS: calcd for C31H33N9O4+H+, 596.27283. found (ESI, [M+H]+ Calc'd), 596.2728.
Example 264
Preparation of 1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-piperazin-1-ylphenyl)urea
HRMS: calcd for C32H39N9O3+H+, 598.32486. found (ESI, [M+H]+Obs'd), 598.3247;
HRMS: calcd for C32H39N9O3+H+, 598.32486. found (ESI, [M+H]+ Calc'd), 598.3249;
Example 265
Preparation of 1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea
HRMS: calcd for C33H41N9O3+H+, 612.34051. found (ESI, [M+H]+Obs'd), 612.3402;
Example 266
Preparation of 1-{4-[2-(dimethylamino)ethoxy]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
HRMS: calcd for C30H38N8O4+H+, 575.30888. found (ESI, [M+H]+Obs'd), 575.3088;
HRMS: calcd for C30H38N8O4+H+, 575.30888. found (ESI, [M+H]+ Calc'd), 575.3089.
Example 267
Preparation of 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
HRMS: calcd for C25H29N7O4+H+, 492.23538. found (ESI, [M+H]+Obs'd), 492.2364.
Example 268
Preparation of 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
HRMS: calcd for C25H30N8O4+H+, 507.24628. found (ESI, [M+H]+Obs'd), 507.2471.
Example 269
Preparation of 4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-{4-[2-(dimethylamino)ethoxy]phenyl}benzamide; MS (ESI) m/z 638.773
Example 270
Preparation of 1-{4-[(4-benzylpiperidin-1-yl)carbonyl]phenyl}-3-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; MS (ESI) m/z 633.821
Example 271
Preparation of 4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(1-methylpiperidin-4-yl)benzamide; MS (ESI) m/z 545.3
Example 272
Preparation of 4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(1-methylpiperidin-4-yl)benzamide; MS (ESI) m/z 573.4
Example 273
Preparation of 1-{4-[4-(6-hydroxy-3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; MS (ESI) m/z 504.551
Example 274
Preparation of 1-(4-{4-[3-(dimethylamino)propyl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea; MS (ESI) m/z 462.56
Example 275
Preparation of 1-[4-(4-{3-[(1-methylethyl)amino]propyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea; MS (ESI) m/z 476.59
Example 276
Preparation of 1-{4-[4-morpholin-4-yl-6-(3-pyrrolidin-1-ylpropyl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; MS (ESI) m/z 488.60
Example 277
Preparation of 1-(4-{4-[3-(4-methylpiperazin-1-yl)propyl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea; MS (ESI) m/z 517.64
Example 278
Preparation of 1-{4-[4-(3-{[2-(dimethylamino)ethyl]amino}propyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; MS (ESI) m/z 505.63
Example 279
Preparation of 1-{4-[4-(3-hydroxypropyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; MS (ESI) m/z 435.49
Example 280
Preparation of 1-{4-[4-morpholin-4-yl-6-(3-oxopropyl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; MS (ESI) m/z 433.47
Example 281
Preparation of tert-butyl-7-(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate
HRMS: calcd for C30H37N9O5+H+, 604.29904. found (ESI, [M+H]+Obs'd), 604.2993.
Example 282
Preparation of 1-{4-[4-(6,8-dioxa-3-azabicyclo[3.2.1]oct-3-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
HRMS: calcd for C24H26N8O4+H+, 491.21498. found (ESI, [M+H]+Obs'd), 491.2155.
Example 283
Preparation of 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; MS (ESI) m/z 612.759
Example 284
Preparation of 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; MS (ESI) m/z 572.694
Example 285
Preparation of 1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea; MS (ESI) m/z 625.78
Example 286
Preparation of N-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]piperazine-1-carboxamide; MS (ESI) m/z 506.61
Example 287
Preparation of 1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxymethyl)phenyl]urea; MS (ESI) m/z 543.63
Example 288
Preparation of 1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(methylamino)methyl]phenyl}urea; MS (ESI) m/z 556.67
Example 289
Preparation of 1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5-triazin-2-yl)phenyl]urea; MS (ESI) m/z 600.73
Example 290
Preparation of 1-{4-[4-morpholin-4-yl-6-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; MS (ESI) m/z 503.57
Example 291
Preparation of 1-{4-[4-(7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; MS (ESI) m/z 517.60
Example 292
Preparation of 1-{4-[4-(7-acetyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; MS (ESI) m/z 545.61
Example 293
Preparation of 1-(4-{4-[7-(methylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl)-3-pyridin-4-ylurea; MS (ESI) m/z 581.66
Example 294
Preparation of 1-[4-(4-methylpiperazin-1-yl)phenyl]-3-[4-(4-morpholin-4-yl-6-propyl-1,3,5-triazin-2-yl)phenyl]urea; MS (ESI) m/z 517.4
Example 295
Preparation of 1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; MS (ESI) m/z 492.2
Example 296
Preparation of 1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea; MS (ESI) m/z 503
Example 297
Preparation of 1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(2-methylpropyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea; MS (ESI) m/z 530.701
Example 298
Preparation of 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; MS (ESI) m/z 544.684
Example 299
Preparation of 4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(1-methylazetidin-3-yl)benzamide
MS (ESI) m/z 517.3;
MS (ESI) m/z 259.2;
Example 300
Preparation of methyl 4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate
mp 218° C.;
MS (ESI) m/z 477.3.
Example 301
Preparation of 4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoic acid
MS (ESI) m/z 463.3.
Example 302
Preparation of tert-butyl-(1R,4R)-5-{4-[4-({[4-(1-hydroxyethyl)phenyl]carbamoyl}amino)phenyl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate
MS (ESI) m/z 617.4.
Example 303
Preparation of 1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea
HRMS: calcd for C33H41N9O3+H+, 612.34051. found (ESI, [M+H]+Obs'd), 612.3402;
HRMS: calcd for C33H41N9O3+H+, 612.34051. found (ESI, [M+H]+ Calc'd), 612.3405.
Example 304
Preparation of 1-{4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea; MS (ESI) m/z 544.66
Example 305
Preparation of N-[2-(dimethylamino)ethyl]-4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; MS (ESI) m/z 532.65
Example 306
Preparation of 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; MS (ESI) m/z 546.68
Example 307
Preparation of N-(1-methylazetidin-3-yl)-4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; MS (ESI) m/z 530.63
Example 308
Preparation of 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; MS (ESI) m/z 572.72
Example 309
Preparation of 4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-pyridin-4-ylbenzamide; MS (ESI) m/z 538.61
Example 310
Preparation of 4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-pyridin-3-ylbenzamide; MS (ESI) m/z 538.61
Example 311
Preparation of N-cyclobutyl-4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; MS (ESI) m/z 515.62
Example 312
Preparation of 1-{4-[4,6-di-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1,3,5-triazin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea; MS (ESI) m/z 583.70
Example 313
Preparation of 1-{4-[4,6-di-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1,3,5-triazin-2-yl]phenyl}-3-(4-piperazin-1-ylphenyl)urea; MS (ESI) m/z 569.67
Example 314
Preparation of 1-{4-[4,6-di-(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1,3,5-triazin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea; MS (ESI) m/z 583.70
Example 315
Preparation of 1-(2-fluoroethyl)-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea; MS (ESI) m/z 561.6
Example 316
Preparation of 1-cyclopropyl-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea; MS (ESI) m/z 555.71
Example 317
Preparation of 1-methyl-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea; MS (ESI) m/z 529.67
Example 318
Preparation of 4-[({4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; MS (ESI) m/z 634.745
Example 319
1-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-phenylurea; MS (ESI) m/z 591.72
Example 320
Preparation of 1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-phenylpiperidin-1-yl)carbonyl]phenyl}urea
MS m/z 08-301429LMS.
Example 321
Preparation of 4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-(pyridin-4-ylmethyl)benzamide
MS (ESI) m/z 539.4;
MS (ESI) m/z 270.2.
Example 322
Preparation of 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; MS (ESI) m/z 558.711
Example 323
Preparation of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-(2-methylpropyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea; MS (ESI) m/z 586.765
Example 324
Preparation of 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; MS (ESI) m/z 560.727
Example 325
Preparation of 1-methyl-3-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)urea; MS (ESI) m/z 515.62
Example 326
Preparation of 1-cyclopropyl-3-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)urea; MS (ESI) m/z 541.66
Example 327
Preparation of 1-(2-fluoroethyl)-3-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)urea; MS (ESI) m/z 547.64
Example 328
Preparation of 1-(2-hydroxyethyl)-3-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)urea; MS (ESI) m/z 545.65
Example 329
Preparation of 4-{[(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide; MS (ESI) m/z 620.72
Example 330
Preparation of 1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)-3-phenylurea; MS (ESI) m/z 577.69
Example 331
Preparation of 1-methyl-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea; MS (ESI) m/z 529.67
Example 332
Preparation of 1-cyclopropyl-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea; MS (ESI) m/z 555.71
Example 333
Preparation of 1-(2-fluoroethyl)-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea; MS (ESI) m/z 561.69
Example 334
Preparation of 4-[({4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-yl]phenyl}carbamoyl)amino]benzamide; MS (ESI) m/z 634.745
Example 335
Preparation of 1-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-phenylurea; MS (ESI) m/z 591.72
Example 336
Preparation of 1-(2,3′-bipyridin-4-yl)-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
MS (ESI) m/z 566.4; HRMS: calcd for C30H31N9O3+H+, 566.26226. found (ESI, [M+H]+ Calc'd), 566.2623.
Example 337
Preparation of 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
MS (ESI) m/z 593.5.
Example 338
Preparation of 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; MS (ESI) m/z 595.5
Example 339
Preparation of 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
MS (ESI) m/z 593.4.
Example 340
Preparation of 1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea. MS (ESI) m/z 468.3
Example 341
Preparation of 1-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-3-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; MS (ESI) m/z 531.4
Example 342
Preparation of 4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoic acid, MS (ESI) m/z 511.4
Example 343
Preparation of 1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea; MS (ESI) m/z 565.4
Example 344
Preparation of methyl 4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate; MS (ESI) m/z 525.4
Example 345
Preparation of 1-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-3-[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2-yl)phenyl]urea; MS (ESI) m/z 578.745
Example 346
Preparation of 1-[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea; MS (ESI) m/z 454.1
Preparation of (2S,5R)-pyrrolidine-2,5-diyldimethanol hydrochloride
((2S,5R)-1-benzylpyrrolidine-2,5-diyl)dimethanol (2.2 g, 10 mmol) was dissolved in ethanol/tetrahydrofuran (200 mL, 1:1), and the mixture was treated with 10% palladium on carbon (250 mg). The suspension was shaken under 50 psi of hydrogen until the consumption of hydrogen had ceased. The mixture was filtered through a pad of CeliteTM diatomaceous earth, eluting with ethanol. The filtrate was concentrated to dryness to provide the title compound as a golden oil that solidified upon prolonged storage. MS (ES+)=132.2 (M+H)+
Preparation of ((2S,5R)-1-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-diyl)dimethanol
A suspension of 2,4-dichloro-6-(4-nitrophenyl)-1,3,5-triazine (2.2 g, 8.0 mmol) in acetone (40 mL) was added to magnetically stirred ice water (60 mL). The mixture was treated with a solution of (2S,5R)-pyrrolidine-2,5-diyldimethanol hydrochloride (1.0 g, 6.0 mmol) in acetone/water (20 mL, 3:1), followed by a suspension of sodium hydrogen carbonate (1.0 g, 12 mmol) in water (12 mL). After 30 minutes of stirring at 0° C., the mixture was treated with an additional quantity of (2S,5R)-pyrrolidine-2,5-diyldimethanol hydrochloride (0.26 g, 1.6 mmol) in water (3 mL), followed by sodium hydrogen carbonate (0.35 g) in water (5 mL). The suspension was allowed to stir overnight while regaining room temperature. The title compound was isolated by Büchner filtration, washed with water, and dried under house vacuum. Compound identification by mass spectrometry was achieved via the analysis of the product reaction product of ((2S,5R)-1-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-diyl)dimethanol with excess morpholine in ethanol. MS (ES+)=417.2 (M+morpholine —Cl)+
Preparation of ((2S,5R)-1-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-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 (0.91 g, 2.5 mmol), 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (0.37 g, 2.5 mmol) in ethanol (13 mL) was treated with triethylamine (1 mL) and heated in a microwave reactor for 20 minutes at 130° C. 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 8-(4-((2S,5R)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidin-1-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane
A solution of ((2S,5R)-1-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-diyl)dimethanol (approximately 2.7 mmol) in dichloromethane (15 mL) was treated successively with tert-butyl dimethyl chlorosilane (1.0 g, 6.8 mmol) and imidazole (0.55 g, 8.1 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 was purified by automated flash chromatography (hexanes/ethyl acetate) to provide the title material. MS (ES+)=671.4 (M+H)+
Preparation of 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-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%, 50 mg) and 8-(4-((2S,5R)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidin-1-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.55 g, 1.2 mmol) in tetrahydrofuran (20 mL) was stirred under a balloon of hydrogen overnight. The mixture was filtered through a pad of CeliteTM diatomaceous earth and concentrated under reduced pressure to provide the title compound as a tan foam (0.42 g, 80%). MS (ES+)=642.4 (M+H)+
Example 347
Preparation of 1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
A solution of 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)aniline (0.16 mmol) in dichloromethane (4 mL) was treated successively with triethylamine (1.6 mmol, 210 μL) and a triphosgene (24 mg, 0.08 mmol) solution in dichloromethane (500 μL). After 5 minutes, the mixture was treated with a solution of 4-aminopyridine (45 mg, 0.48 mmol) in warm tetrahydrofuran. After 1 hour, the reaction mixture was quenched with methanol and concentrated to dryness. The crude residue was treated with a saturated solution of hydrogen chloride in methanol. Upon complete desilylation, the mixture was concentrated to dryness and the residue purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy column running a gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 50% acetonitrile over 25 minutes. After concentration, the title compound was obtained as it trifluoroacetic acid salt (132 mg). MS (ES+)=533.3 (M+H)+
Example 348
Preparation of 1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea
A solution of 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)aniline (0.16 mmol) in dichloromethane (4 mL) was treated successively with triethylamine (1.6 mmol, 210 μL) and a triphosgene (24 mg, 0.08 mmol) solution in dichloromethane (500 μL). After 5 minutes, the mixture was treated with 4-(4-methylpiperazin-1-yl)aniline (61 mg, 0.32 mmol). After 1 hour, the reaction mixture was quenched with methanol and concentrated to dryness. The crude residue was treated with a saturated solution of hydrogen chloride in methanol. Upon complete desilylation, the mixture was concentrated to dryness and the residue purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy column running a gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 50% acetonitrile over 25 minutes. After concentration, the title compound was obtained as it trifluoroacetic acid salt (100 mg). MS (ES+)=630.4 (M+H)+
Example 349
Preparation of 1-(6-chloropyridin-3-yl)-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. HRMS: calcd for C25H27ClN8O3+H+, 523.19674. found (ESI, [M+H]+Obs'd), 523.1975
Example 350
Preparation of 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; MS (ESI) m/z 614.8
Example 351
Preparation of 1-(4-aminophenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; MS (ESI) m/z 477.1
Example 352
Preparation of 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]-N2,N2-dimethylglycinamide
The 4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)aniline (50 mg, 0.127 mmol) was dissolved in dichloromethane (1.5 mL) and triethylamine (0.120 mL) and added to a solution of triphosgene (17 mg) in dichloromethane (0.5 mL). Stir for 5 minutes then added N-(4-aminophenyl)-N2,N2-dimethylglycinamide (27 mg, 0.14 mmol). Purified by Gilson HPLC to provide the title compound as the TFA salt: 31.8 mg (35%) (M+H) m/z 614.3.
Example 353
Preparation of 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-pyrrolidin-1-ylacetamide
The 4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)aniline (50 mg, 0.127 mmol) was dissolved in dichloromethane (1.5 mL) and triethylamine (0.120 mL) and added to a solution of triphosgene (17 mg) in dichloromethane (0.5 mL). Stir for 5 minutes then added N-(4-aminophenyl)-2-pyrrolidin-1-ylacetamide (30 mg, 0.14 mmol) Purified by Gilson HPLC to provide the title compound as the TFA salt: 63.1 mg (66%) (M+H) m/z 640.3.
Example 354
Preparation of 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea
Prepared as shown in Scheme 1, using commercially available tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate in the second nucleophilic aromatic substitution step. Following urea formation using methylamine, the Boc-piperazine intermediate was treated with TFA to provide the title compound. (M+H) 516.3.
Example 355
Preparation of 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-cyclopropylurea
Prepared as shown in Scheme 1, using commercially available tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate in the second nucleophilic aromatic substitution step. Following urea formation using cyclopropylamine, the Boc-piperazine intermediate was treated with TFA to provide the title compound. (M+H) 542.3.
Example 356
Preparation of 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-(2-fluoroethyl)urea
Prepared as shown in Scheme 1, using commercially available tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate in the second nucleophilic aromatic substitution step. Following urea formation using 2-fluoroethylamine, the Boc-piperazine intermediate was treated with TFA to provide the title compound. (M+H) 548.3.
Example 357
Preparation of 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-(2-hydroxyethyl)urea
Prepared as shown in Scheme 1, using commercially available tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate in the second nucleophilic aromatic substitution step. Following urea formation using 2-aminoethanol, the Boc-piperazine intermediate was treated with TFA to provide the title compound. (M+H) 546.3.
Example 358
Preparation of 4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide
Prepared as shown in Scheme 1, using commercially available tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate in the second nucleophilic aromatic substitution step.
Following urea formation using 4-aminobenzamide, the Boc-piperazine intermediate was treated with TFA to provide the title compound. (M+H) 621.3.
Example 359
Preparation of 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenylamino)-1,3,5-triazin-2-yl)phenyl)-3-phenylurea
Prepared as shown in Scheme 1, using commercially available tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate in the second nucleophilic aromatic substitution step. Following urea formation using aniline, the Boc-piperazine intermediate was treated with TFA to provide the title compound. (M+H) 578.3.
Example 360
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea
Prepared as shown in Scheme 1, using commercially available tert-butyl 4-aminopiperidine-1-carboxylate in the second nucleophilic aromatic substitution step. Following urea formation using ethylamine, the Boc-piperidine intermediate was treated with TFA to provide the title compound.
(M+H) 453.6.
Example 361
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea
Prepared as shown in Scheme 1, using N1-(2-(dimethylamino)ethyl)-N-1-methylbenzene-1,4-diamine in the urea formation step. (M+H) 614.3.
The required benzene-1,4-diamine intermediates for the following compounds were prepared as outlined in Scheme 4.
Example 362
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea
Prepared as shown in Scheme 1, using 1-(4-aminophenyl)-N,N-dimethylpiperidin-4-amine in the urea formation step. (M+H) 640.4.
Preparation of 1-(4-aminophenyl)-N,N-dimethylpiperidin-4-amine
Prepared from 4-fluoronitrobenzene and the appropriate amine as shown in Scheme 4.
Example 363
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea
Prepared as shown in Scheme 1, using N1-(2-methoxyethyl)benzene-1,4-diamine in the urea formation step. (M+H) 587.3.
Preparation of N1-(2-methoxyethyl)benzene-1,4-diamine
Prepared from 4-fluoronitrobenzene and the appropriate amine as shown in Scheme 4.
Example 364
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea
Prepared as shown in Scheme 1, using 2-(4-aminophenylamino)ethanol in the urea formation step.
(M+H) 573.3.
Preparation of 2-(4-aminophenylamino)ethanol
Prepared from 4-fluoronitrobenzene and the appropriate amine as shown in Scheme 4.
Example 365
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(piperidin-4-ylamino)-1,3,5-triazin-2-yl)phenyl)-3-ethylurea
Prepared as shown in Scheme 1, using N1-(1-methylpiperidin-4-yl)benzene-1,4-diamine in the urea formation step. (M+H) 626.3.
Preparation of N1-(1-methylpiperidin-4-yl)benzene-1,4-diamine
Prepared from 4-fluoronitrobenzene and the appropriate amine as shown in Scheme 4.
Example 366
Preparation of 1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazin-1-ylmethyl)phenyl)urea
Prepared as shown in Scheme 1, using commercially available tert-butyl 4-(4-aminobenzyl)piperazine-1-carboxylate in the urea formation step. Following urea formation, the Boc-piperidine intermediate was treated with TFA to provide the title compound. (M+H) 612.3.
Example 367
Preparation of 1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea
Prepared as shown in Scheme 1, using commercially available 4-((dimethylamino)methyl)aniline in the urea formation step. (M+H) 571.3.
Example 368
Preparation of 1-(4-(aminomethyl)phenyl)-3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)urea
Prepared as shown in Scheme 1, using commercially available tert-butyl 4-aminobenzylcarbamate in the urea formation step. Following urea formation, the Boc-amine intermediate was treated with TFA to provide the title compound. (M+H) 543.3.
Example 369
Preparation of 1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)urea
Prepared as shown in Scheme 1, using commercially available 4-(pyrrolidin-1-ylmethyl)aniline in the urea formation step. (M+H) 597.3.
Example 370
Preparation of 1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)urea
Prepared as shown in Scheme 1, using 4-(2-(4-methylpiperazin-1-yl)ethoxy)aniline in the urea formation step. (M+H) 656.4.
The required 4-(alkoxy)aniline intermediates for the following compounds were prepared as outlined in Scheme 5.
Example 371
Preparation of 1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)urea
Prepared as shown in Scheme 1, using 4-(2-(pyrrolidin-1-yl)ethoxy)aniline in the urea formation step. (M+H) 627.3.
Preparation of 4-(2-(pyrrolidin-1-yl)ethoxy)aniline
Prepared from 4-fluoronitrobenzene and the appropriate alcohol as shown in Scheme 5.
Example 372
Preparation of 1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-hydroxyethoxy)phenyl)urea
Prepared as shown in Scheme 1, using 2-(4-aminophenoxy)ethanol in the urea formation step.
(M+H) 574.3.
Preparation of 2-(4-aminophenoxy)ethanol
Prepared from 4-fluoronitrobenzene and the appropriate alcohol as shown in Scheme 5.
Example 373
Preparation of N-(4-(3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)ureido)phenyl)-2-(dimethylamino)acetamide
Prepared as shown in Scheme 1, using commercially available N-(4-aminophenyl)-2-(dimethylamino)acetamide in the urea formation step. (M+H) 614.3.
Example 374
Preparation of N-(4-(3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)ureido)phenyl)-2-(4-methylpiperazin-1-Aacetamide
Prepared as shown in Scheme 1, using commercially available N-(4-aminophenyl)-2-(4-methylpiperazin-1-yl)acetamide in the urea formation step. (M+H) 669.4.
Example 375
Preparation of N-(4-(3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)ureido)phenyl)-2-(pyrrolidin-1-yl)acetamide
Prepared as shown in Scheme 1, using commercially available N-(4-aminophenyl)-2-(pyrrolidin-1-yl)acetamide in the urea formation step. (M+H) 640.3.
Example 376
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea
Prepared as shown in Scheme 1, using commercially available pyridin-3-amine in the urea formation step. (M+H) 461.2.
Example 377
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
Prepared as shown in Scheme 1, using commercially available pyridin-4-amine in the urea formation step. (M+H) 461.2.
Example 378
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea
Prepared as shown in Scheme 1, using commercially available 4-(4-methylpiperazin-1-yl)aniline in the urea formation step. (M+H) 558.3.
Example 379
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)urea
Prepared as shown in Scheme 1, using commercially available 4-((4-methylpiperazin-1-yl)methyl)aniline in the urea formation step. (M+H) 572.3.
Example 380
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazin-1-ylmethyl)phenyl)urea
Prepared as shown in Scheme 1, using commercially available tert-butyl 4-(4-aminobenzyl)piperazine-1-carboxylate in the urea formation step. Following urea formation, the Boc-piperazine intermediate was treated with TFA to provide the title compound. (M+H) 558.3.
Example 381
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea
Prepared as shown in Scheme 1, using commercially available 4-((dimethylamino)methyl)aniline in the urea formation step. (M+H) 517.3.
Example 382
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(aminomethyl)phenyl)urea
Prepared as shown in Scheme 1, using commercially available tert-butyl 4-aminobenzylcarbamate in the urea formation step. Following urea formation, the Boc-amine intermediate was treated with TFA to provide the title compound. (M+H) 489.3.
Example 383
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)urea
Prepared as shown in Scheme 1, using commercially available 4-(pyrrolidin-1-ylmethyl)aniline in the urea formation step. (M+H) 543.3.
Example 384
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)urea
Prepared as shown in Scheme 1, using 4-(2-(pyrrolidin-1-yl)ethoxy)aniline in the urea formation step. (M+H) 573.3.
Example 385
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea
Prepared as shown in Scheme 1, using 4-(2-(dimethylamino)ethoxy)aniline in the urea formation step. (M+H) 547.3.
Preparation of 4-(2-(dimethylamino)ethoxy)aniline
Prepared from 4-fluoronitrobenzene and the appropriate alcohol as shown in Scheme 5.
Example 386
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-111)pyridin-3-yl)urea
Prepared as shown in Scheme 1, using commercially available 5-(4-methylpiperazin-1-yl)pyridin-2-amine in the urea formation step. (M+H) 559.3.
Example 387
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazin-1-yl)phenyl)urea
Prepared as shown in Scheme 1, using commercially available tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate in the urea formation step. Following urea formation, the Boc-amine intermediate was treated with TFA to provide the title compound. (M+H) 544.3.
Example 388
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea
Prepared as shown in Scheme 1, using 1-(4-aminophenyl)-N,N-dimethylpiperidin-4-amine in the urea formation step. (M+H) 586.4.
Example 389
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropyl(methyl)amino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea
Prepared as shown in Scheme 1, using commercially available 4-(4-methylpiperazin-1-yl)aniline in the urea formation step. (M+H) 572.3.
Example 390
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropyl(methyl)amino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea
Prepared as shown in Scheme 1, using commercially available 4-((dimethylamino)methyl)aniline in the urea formation step. (M+H) 531.3.
Example 391
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropyl(methyl)amino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea
Prepared as shown in Scheme 1, using 4-(2-(dimethylamino)ethoxy)aniline in the urea formation step. (M+H) 561.3.
Example 392
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea (Scheme 6)
Step 1: Preparation of 8-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane
A solution of 2,4-dichloro-6-(4-nitrophenyl)-1,3,5-triazine (1.25 g, 4.61 mmol) in acetone (20 mL) and ice water (20 mL) was prepared. To this was added dropwise over 10 minutes a suspension of 3-oxa-8-azabicyclo[3.2.1]octane-hydrochloride (0.655 g, 4.38 mmol) and sodium bicarbonate (0.775 g, 9.22 mmol) in acetone (15 mL) and water (15 mL). 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. The crude product was purified by silica gel column chromatography, eluting with 0-1.5% methanol in methylene chloride to provide 8-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.89 g, 56%) as an off-white solid. (M+H) 348.1.
Step 2: Preparation of 8-(4-(4-nitrophenyl)-6-thiomorpholino-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane
A solution of 8-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.450 g, 1.29 mmol) in acetone (5 mL) and water (10 mL) was prepared. To this was added sodium carbonate (0.274 g, 2.59 mmoles), followed by thiomorpholine (0.134 ml, 1.42 mmol). The resulting light tan suspension was allowed to stir at 60° C. for 2.5 hours. The suspension was filtered and the solid was washed with water and dried in vacuo to provide 8-(4-(4-nitrophenyl)-6-thiomorpholino-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.455 g, 85%) as a white solid. HRMS 415.1546 (M+H, calc.), 415.1526 (M+H, obs.).
Step 3: Preparation of 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)aniline
A suspension of 8-(4-(4-nitrophenyl)-6-thiomorpholino-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.418 g, 1.01 mmol) in pyridine (3 ml) and DMF (6 ml) was prepared. Tin(II) chloride dihydrate (0.569 g, 2.52 mmol) was then added and the off-white suspension was allowed to stir at room temperature for 16 hours, at which time the suspension was light yellow. The suspension was filtered, washing with methanol, and concentrated. LCMS indicated reaction had not gone to completion. The crude product was dissolved in DMF (6 ml) and pyridine (3 ml) and additional tin(II) chloride dihydrate (0.569 g, 2.52 mmol) was added. The solution was allowed to stir at room temperature for 18 hours, then filtered. The precipitate was washed with methanol and the filtrate was concentrated to provide 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)aniline (0.195 g, 50%) as a yellow solid. (M+H) 385.1.
Step 4: Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea
The method of urea formation using triphosgene and triethylamine in methylene chloride, described in Scheme 1, was utilized using commercially available pyridin-3-amine 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-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea (0.032 g, 63%) as an off-white solid. (M+H) 505.2.
Example 393
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
Prepared as shown in Scheme 6, using commercially available pyridin-4-amine in the urea formation step. Yield; 28 mg (54%); (M+H) 505.2.
Example 394
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea
Prepared as shown in Scheme 6, using commercially available 4-(4-methylpiperazin-1-yl)aniline in the urea formation step. Yield; 44 mg (73%); (M+H) 602.3.
Example 395
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea
Prepared as shown in Scheme 6, using commercially available 4-((dimethylamino)methyl)aniline in the urea formation step. Yield; 19 mg (34%); (M+H) 561.3.
Example 365
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea
Prepared as shown in Scheme 6, using 4-(2-(dimethylamino)ethoxy)aniline in the urea formation step. Yield; 35 mg (59%); (M+H) 591.3.
Example 397
Preparation of 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
Prepared as shown in Scheme 1, using commercially available pyridin-4-amine in the urea formation step. Yield; 44 mg (75%); (M+H) 491.2.
Example 398
Preparation of 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea
Prepared as shown in Scheme 1, using commercially available pyridin-3-amine in the urea formation step. Yield; 46 mg (79%); (M+H) 491.2.
Example 399
Preparation of 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea
Prepared as shown in Scheme 1, using commercially available 4-((dimethylamino)methyl)aniline in the urea formation step. Yield; 57 mg (81%); (M+H) 588.3.
Example 400
Preparation of 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
Prepared as shown in Scheme 1, using commercially available 5-(4-methylpiperazin-1-yl)pyridin-2-amine in the urea formation step. Yield; 56 mg (79%); (M+H) 589.3.
Example 401
Preparation of 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea
Prepared as shown in Scheme 1, using commercially available 4-((dimethylamino)methyl)aniline in the urea formation step. Yield; 28 mg (43%); (M+H) 547.3.
Example 402
Preparation of 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea
Prepared as shown in Scheme 1, using 4-(2-(dimethylamino)ethoxy)aniline in the urea formation step. Yield; 50 mg (72%); (M+H) 577.3.
Example 403
Preparation of 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)urea
Prepared as shown in Scheme 1, using 4-(2-(pyrrolidin-1-yl)ethoxy)aniline in the urea formation step. Yield; 41 mg (57%); (M+H) 603.3.
Example 404
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3,6-dihydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea (Scheme 7)
Step 1: Preparation of 8-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane
Prepared as shown in Scheme 6, described in Example 392, Step 1.
Step 2: Preparation of 8-(4-(3,6-dihydro-2H-pyran-4-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane
A microwave vial was charged with 8-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.440 g, 1.27 mmoles). Toluene (6 mL) was then added and the solution was sparged with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.088 g, 0.076 mmol) and tributyl(3,6-dihydro-2H-pyran-4-yl)stannane (0.567 g, 1.52 mmol) were added. The vial was sealed and heated to 100° C. for 40 minutes via microwave. Additional tributyl(3,6-dihydro-2H-pyran-4-yl)stannane (0.283 g, 0.76 mmoles) and tetrakis(triphenylphosphine)palladium(0) (0.022 g, 0.019 mmol) were added and the suspension was heated to 110° C. by microwave for additional 90 minutes. The suspension was then cooled to room temperature and filtered through CeliteTM. The filter cake was washed with ethyl acetate and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with 0-2% methanol in methylene chloride, to provide 8-(4-(3,6-dihydro-2H-pyran-4-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.430 g, 86%) as a light yellow solid. HRMS 396.1666 (M+H, calc.), 396.1668 (M+H, obs.).
Step 3: Preparation of 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3,6-dihydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)aniline
A mixture of iron powder (0.071 g, 1.27 mmoles) in acetic acid (2 ml) was heated to 55° C. for 15 minutes. Water (2 ml) was then added and oil bath was turned off. A solution of 8-(4-(3,6-dihydro-2H-pyran-4-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.100 g, 0.253 mmol) in ethyl acetate (2 ml) was then added to this warm solution over 5 minutes. The mixture was cooled to RT and allowed to stir for 16 hours. The mixture was extracted with ethyl acetate by decantation (4×) into a sep. funnel containing saturated aqueous sodium carbonate. The combined organic extracts were washed with water, brine, dried, and concentrated to provide 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3,6-dihydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)aniline (0.068 g, 74%), which was used in the next step without purification. (M+H) 366.4.
Step 4: Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3,6-dihydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
The method of urea formation using triphosgene and triethylamine in methylene chloride, described in Scheme 1, was utilized using commercially available pyridin-4-amine 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-(3,6-dihydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea (0.034 g, 75%) as a light yellow solid. (M+H) 486.2.
Example 405
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3,6-dihydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea
Prepared as shown in Scheme 7, using commercially available 4-(4-methylpiperazin-1-yl)aniline in the urea formation step. Yield; 44 mg (82%); (M+H) 583.3.
Example 406
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
Prepared as shown in Scheme 7; representative synthesis described below.
Preparation of 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)aniline
A solution of 8-(4-(3,6-dihydro-2H-pyran-4-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (prepared as described in Example DJR-51, Step 2) (0.260 g, 0.658 mmol) in ethyl acetate (5 ml), methanol (5 ml), and methylene chloride (2 ml—added due to poor solubility of SM in EA/methanol) was prepared and 10% palladium on carbon (0.078 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. Additional palladium on carbon (0.039 g) was added and the suspension was purged with hydrogen gas (balloon) and stirred for an additional 3 hours. The flask was purged with hydrogen gas and stirred for an additional 1 hour. The suspension was filtered through CeliteTM, 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-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)aniline (0.220 g, 91%) as an off-white solid. HRMS 368.2080 (M+H, calc.), 368.2085 (M+H, obs.).
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
The method of urea formation using triphosgene and triethylamine in methylene chloride, described in Scheme 1, was utilized using commercially available pyridin-4-amine 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-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea (0.0461 g, 82%) as an off-white solid. (M+H) 488.2.
Example 407
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea
Prepared as shown in Scheme 7, using commercially available 4-(4-methylpiperazin-1-yl)aniline in the urea formation step. Yield; 54 mg (79%); (M+H) 585.3.
Example 408
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea
Prepared as shown in Scheme 7, using 4-(2-(dimethylamino)ethoxy)aniline in the urea formation step. Yield; 49 mg (73%); (M+H) 572.3.
Example 409
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea
Prepared as shown in Scheme 7, using commercially available 4-((dimethylamino)methyl)aniline in the urea formation step. Yield; 21 mg (33%); (M+H) 544.3.
Example 410
Preparation of 1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
Prepared as shown in Scheme 1, using commercially available pyridin-4-amine in the urea formation step. Yield; 45 mg (70%); (M+H) 489.2.
Example 411
Preparation of 1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea
Prepared as shown in Scheme 1, using commercially available pyridin-3-amine in the urea formation step. Yield; 60 mg (95%); (M+H) 489.2.
Example 412
Preparation of 1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea
Prepared as shown in Scheme 1, using commercially available 4-(4-methylpiperazin-1-yl)aniline in the urea formation step. Yield; 69 mg (90%); (M+H) 586.3.
Example 413
Preparation of 1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)urea
Prepared as shown in Scheme 1, using commercially available 4-((4-methylpiperazin-1-yl)methyl)aniline in the urea formation step. Yield; 73 mg (94%); (M+H) 600.3.
Example 414
Preparation of 1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)urea
Prepared as shown in Scheme 1, using commercially available 4-(pyrrolidin-1-ylmethyl)aniline in the urea formation step. Yield; 56 mg (75%); (M+H) 571.3.
Example 415
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-(pyridin-3-yl)urea
Prepared as shown in Scheme 1, using commercially available pyridin-3-amine in the urea formation step. Yield; 44 mg (66%); (M+H) 503.2.
Example 416
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-(pyridin-4-yl)urea
Prepared as shown in Scheme 1, using commercially available pyridin-4-amine in the urea formation step. Yield; 35 mg (53%); (M+H) 503.2.
Example 417
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-methylpiperazin-1-yl)phenyl)urea
Prepared as shown in Scheme 1, using commercially available 4-(4-methylpiperazin-1-yl)aniline in the urea formation step. Yield; 58 mg (62%); (M+H) 600.3.
Example 418
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-(pyrrolidin-1-ylmethyl)phenyl)urea
Prepared as shown in Scheme 1, using commercially available 4-(pyrrolidin-1-ylmethyl)aniline in the urea formation step. Yield; 41 mg (45%); (M+H) 585.5.
Example 419
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-(2-(dimethylamino)ethoxy)phenyl)urea
Prepared as shown in Scheme 1, using 4-(2-(dimethylamino)ethoxy)aniline in the urea formation step. Yield; 43 mg (47%); (M+H) 589.3.
Example 420
Preparation of (R)-1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea
Prepared as shown in Scheme 7, using commercially available pyridin-3-amine in the urea formation step. Yield; 45 mg (77%); (M+H) 476.2.
Example 421
Preparation of (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
Prepared as shown in Scheme 7, using commercially available 4-(4-methylpiperazin-1-yl)aniline in the urea formation step. Yield; 53 mg (75%); (M+H) 573.3.
Example 422
Preparation of (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
Prepared as shown in Scheme 7, using commercially available tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate in the urea formation step. Following urea formation, the Boc-piperazine intermediate was treated with TFA to provide the title compound. Yield; 63 mg (90%); (M+H) 559.3.
Example 423
Preparation of 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
Prepared as shown in Scheme 7, using (S)-tert-butyl 4-(4-aminophenyl)-3-methylpiperazine-1-carboxylate in the urea formation step. Following urea formation, the Boc-piperazine intermediate was treated with TFA to provide the title compound. Yield; 60 mg (71%); (M+H) 573.3.
Preparation of (S)-tert-butyl 4-(4-aminophenyl)-3-methylpiperazine-1-carboxylate
Prepared from 4-fluoronitrobenzene and the appropriate amine as shown in Scheme 4.
Example 424
Preparation of 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
Prepared as shown in Scheme 7, using (R)-tert-butyl 4-(4-aminophenyl)-3-methylpiperazine-1-carboxylate in the urea formation step. Following urea formation, the Boc-piperazine intermediate was treated with TFA to provide the title compound. Yield; 68 mg (90%); (M+H) 573.3.
Preparation of (R)-tert-butyl 4-(4-aminophenyl)-3-methylpiperazine-1-carboxylate
Prepared from 4-fluoronitrobenzene and the appropriate amine as shown in Scheme 4.
Example 425
Preparation of 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
Prepared as shown in Scheme 7, using (3,5-cis)-tert-butyl 4-(4-aminophenyl)-3,5-dimethylpiperazine-1-carboxylate in the urea formation step. Following urea formation, the Boc-piperazine intermediate was treated with TFA to provide the title compound. Yield; 67 mg (77%); (M+H) 587.3.
Preparation of (3,5-cis)-tert-butyl 4-(4-aminophenyl)-3,5-dimethylpiperazine-1-carboxylate
Prepared from 4-fluoronitrobenzene and the appropriate amine as shown in Scheme 4.
Example 426
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-sulfoxymorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea
Prepared as shown in Scheme 6. A solution of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea (0.020 g, 0.033 mmol) in acetonitrile (1.5 ml) and water (0.5 ml) was prepared and oxone (0.020 g, 0.033 mmol) was added. The solution was stirred at room temperature for 16 hours. The suspension was diluted with ethyl acetate and washed with saturated sodium bicarbonate. The organic phase was washed with brine, dried, and concentrated, then purified by HPLC (5-95% acetonitrile in water over 20 minutes, 0.05% TFA buffer, Waters Atlantis column) to provide the TFA salt of the sulfoxide of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-sulfoxymorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea (0.0029 g, 14%) as a white solid. (M+H) 618.4.
Example 427
Preparation of (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
Prepared as shown in Scheme 7, using 4-(2-(dimethylamino)ethoxy)aniline in the urea formation step. Yield; 34 mg (51%); (M+H) 562.3.
Example 428
Preparation of (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
Prepared as shown in Scheme 7, using commercially available 4-(4-ethylpiperazin-1-yl)aniline in the urea formation step. Yield; 66 mg (93%); (M+H) 587.3.
Example 429
Preparation of (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
Prepared as shown in Scheme 7, using 4-(4-isopropylpiperazin-1-yl)aniline in the urea formation step. Yield; 66 mg (91%); (M+H) 601.4.
Preparation of 4-(4-isopropylpiperazin-1-yl)aniline
Prepared from 4-fluoronitrobenzene and the appropriate amine as shown in Scheme 4.
Example 430
Preparation of (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
Prepared as shown in Scheme 7, using 1-(4-aminophenyl)-N,N-dimethylpiperidin-4-amine in the urea formation step. Yield; 69 mg (95%); (M+H) 601.4.
Example 431
Preparation of (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
Prepared as shown in Scheme 7, using (4-aminophenyl)(4-methylpiperazin-1-yl)methanone in the urea formation step. Yield; 38 mg (52%); (M+H) 601.3.
The (4-aminophenyl)(piperazin-1-yl)methanone intermediates prepared as shown in Scheme 8 were used to make the following compounds.
Example 432
Preparation of (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
Prepared as shown in Scheme 7, using (4-aminophenyl)(4-isopropylpiperazin-1-yl)methanone in the urea formation step. Yield; 68 mg (89%); (M+H) 629.3.
Preparation of (4-aminophenyl)(4-isopropylpiperazin-1-yl)methanone
Prepared from 4-nitrobenzoyl chloride and the appropriate amine as shown in Scheme 8.
Example 433
Preparation of (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
Prepared as shown in Scheme 7, using commercially available 6-(4-methylpiperazin-1-yl)pyridin-3-amine in the urea formation step. Yield; 69 mg (99%); (M+H) 574.3.
Example 434
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea
Prepared as shown in Scheme 7, using commercially available 4-(4-ethylpiperazin-1-yl)aniline in the urea formation step. Yield; 32 mg (43%); (M+H) 599.3.
Example 435
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea
Prepared as shown in Scheme 7, using 4-(4-isopropylpiperazin-1-yl)aniline in the urea formation step. Yield; 51 mg (66%); (M+H) 613.4.
Example 436
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-yl)phenyl)urea
Prepared as shown in Scheme 7, using 4-(4-cyclopropylpiperazin-1-yl)aniline in the urea formation step. Yield; 11 mg (14%); (M+H) 611.3.
Preparation of 4-(4-cyclopropylpiperazin-1-yl)aniline
Prepared from 4-fluoronitrobenzene and the appropriate amine as shown in Scheme 4.
Example 437
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea
Prepared as shown in Scheme 7, using 1-(4-aminophenyl)-N,N-dimethylpiperidin-4-amine in the urea formation step. Yield; 28 mg (36%); (M+H) 613.4.
Example 438
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea
Prepared as shown in Scheme 7, using (4-aminophenyl)(4-methylpiperazin-1-yl)methanone in the urea formation step. Yield; 36 mg (46%); (M+H) 613.3.
Example 439
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea
Prepared as shown in Scheme 7, using (4-aminophenyl)(4-isopropylpiperazin-1-yl)methanone in the urea formation step. Yield; 41 mg (50%); (M+H) 641.3.
The following 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 as shown in Scheme 9.
Example 440
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
Step 1: Preparation of (R)-4-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-methylmorpholine
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 CeliteTM, 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.
Example 441
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-isopropylpiperazin-1-yl)phenyl)urea
Prepared as shown in Scheme 9, using 4-(4-isopropylpiperazin-1-yl)aniline in the urea formation step. Yield; 82 mg (100%); (M+H) 628.4.
Example 442
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-cyclopropylpiperazin-1-yl)phenyl)urea
Prepared as shown in Scheme 9, using 4-(4-cyclopropylpiperazin-1-yl)aniline in the urea formation step. Yield; 32 mg (39%); (M+H) 626.3.
Example 443
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-(dimethylamino)piperidin-1-yl)phenyl)urea
Prepared as shown in Scheme 9, using 1-(4-aminophenyl)-N,N-dimethylpiperidin-4-amine in the urea formation step. Yield; 77 mg (93%); (M+H) 628.4.
Example 444
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-methylpiperazine-1-carbonyl)phenyl)urea
Prepared as shown in Scheme 9, using (4-aminophenyl)(4-methylpiperazin-1-yl)methanone in the urea formation step. Yield; 43 mg (52%); (M+H) 628.3.
Example 445
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-isopropylpiperazine-1-carbonyl)phenyl)urea
Prepared as shown in Scheme 9, using (4-aminophenyl)(4-isopropylpiperazin-1-yl)methanone in the urea formation step. Yield; 72 mg (84%); (M+H) 656.4.
Example 446
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-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea
Prepared as shown in Scheme 9, using commercially available 6-(4-methylpiperazin-1-yl)pyridin-3-amine in the urea formation step. Yield; 74 mg (94%); (M+H) 601.3.
Example 447
Preparation of 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)urea
Prepared as shown in Scheme 1, using commercially available 4-(4-ethylpiperazin-1-yl)aniline in the urea formation step. Yield; 80 mg (99%); (M+H) 602.3.
Example 448
Preparation of 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazin-1-yl)phenyl)urea
Prepared as shown in Scheme 1, using 4-(4-isopropylpiperazin-1-yl)aniline in the urea formation step. Yield; 74 mg (88%); (M+H) 616.4.
Example 449
Preparation of 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea
Prepared as shown in Scheme 1, using 1-(4-aminophenyl)-N,N-dimethylpiperidin-4-amine in the urea formation step. Yield; 80 mg (96%); (M+H) 616.4.
Example 450
Preparation of 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea
Prepared as shown in Scheme 1, using (4-aminophenyl)(4-methylpiperazin-1-yl)methanone in the urea formation step. Yield; 79 mg (95%); (M+H) 616.3.
Example 451
Preparation of 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea
Prepared as shown in Scheme 1, using (4-aminophenyl)(4-isopropylpiperazin-1-yl)methanone in the urea formation step. Yield; 18 mg (20%); (M+H) 644.4.
Example 452
Preparation of 4-(3-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido)-N,N-dimethylbenzamide
Prepared as shown in Scheme 1, using commercially available 4-amino-N,N-dimethylbenzamide in the urea formation step. Yield; 43 mg (57%); (M+H) 561.3.
Example 453
Preparation of 1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)urea
Prepared as shown in Scheme 1, using commercially available 4-(pyrrolidin-1-ylmethyl)aniline in the urea formation step. Yield; 61 mg (79%); (M+H) 573.3.
Example 454
Preparation of 4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide
Prepared as shown in Scheme 7, using commercially available 4-aminobenzamide in the urea formation step. Yield; 22 mg (21%); (M+H) 530.2.
Example 455
Preparation of 4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)-N,N-dimethylbenzamide
Prepared as shown in Scheme 7, using commercially available 4-amino-N,N-dimethylbenzamide in the urea formation step. Yield; 22 mg (21%); (M+H) 558.3.
Example 456
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidine-1-carbonyl)phenyl)urea
Prepared as shown in Scheme 7, using (4-aminophenyl)(pyrrolidin-1-yl)methanone in the urea formation step. Yield; 41 mg (36%); (M+H) 584.3.
Preparation of (4-aminophenyl)(pyrrolidin-1-yl)methanone
Prepared from 4-nitrobenzoyl chloride and the appropriate amine as shown in Scheme 8.
Example 457
Preparation of 4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(dimethylamino)ethyl)benzamide
Prepared as shown in Scheme 7, using 4-amino-N-(2-(dimethylamino)ethyl)benzamide in the urea formation step. Yield; 36 mg (32%); (M+H) 601.3.
Preparation of 4-amino-N-(2-(dimethylamino)ethyl)benzamide
Prepared from 4-nitrobenzoyl chloride and the appropriate amine as shown in Scheme 8.
Example 458
Preparation of 4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(methylamino)ethyl)benzamide
Prepared as shown in Scheme 7, using tert-butyl 2-(4-aminobenzamido)ethyl(methyl)carbamate in the urea formation step. Following urea formation, the Boc-amine intermediate was treated with TFA to provide the title compound. Yield; 25 mg (22%); (M+H) 587.3.
Preparation of tert-butyl 2-(4-aminobenzamido)ethyl(methyl)carbamate
Prepared from 4-nitrobenzoyl chloride and the appropriate amine as shown in Scheme 8.
Example 459
Preparation of 4-(3-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)-N-(2-(dimethylamino)ethyl)-N-methylbenzamide
Prepared as shown in Scheme 7, using 4-amino-N-(2-(dimethylamino)ethyl)-N-methylbenzamide in the urea formation step. Yield; 10 mg (9%); (M+H) 615.3.
Preparation of 4-amino-N-(2-(dimethylamino)ethyl)-N-methylbenzamide
Prepared from 4-nitrobenzoyl chloride and the appropriate amine as shown in Scheme 8.
Example 460
Preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)-3-(4-(morpholine-4-carbonyl)phenyl)urea
Prepared as shown in Scheme 7, using (4-aminophenyl)(morpholino)methanone in the urea formation step. Yield; 25 mg (21%); (M+H) 600.3.
Preparation of (4-aminophenyl)(morpholino)methanone
Prepared from 4-nitrobenzoyl chloride and the appropriate amine as shown in Scheme 8.
Example 461
Preparation of 1-(4-(2-aminoethylamino)phenyl)-3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phenyl)urea
Prepared as shown in Scheme 1, using di-Boc protected N1-(2-aminoethyl)benzene-1,4-diamine in the urea formation step. Following urea formation, the di-Boc-amine intermediate was treated with TFA to provide the title compound. Yield; x mg (x %); HRMS 572.3092 (M+H, calc.), 572.3098 (M+H, obs.).
Preparation of di-Boc protected N1-(2-aminoethyl)benzene-1,4-diamine
Prepared from 4-fluoronitrobenzene and the appropriate amine as shown in Scheme 4.
Example 462
Preparation of 4-({[4-(4-{4-[(methylcarbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide
Step 1: Preparation of phenyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate
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 Na2SO4 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).
1HNMR (300 MHz, CDCl3): 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).
Step 2: Preparation of 1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea
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 Na2SO4, 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.
1HNMR (300 MHz, CDCl3): δ7.7 (d, 2H), 7.2 (d, 2H), 6.7 (s, 1H), 5.0 (s, 1H), 2.8 (s, 3H), 1.2 (s, 12H).
Step 3: Preparation of 4-(4,6-dichloro-1,3,5-triazin-2-yl) morpholine
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 Na2SO4, 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).
Step 4: Preparation of 1-(4-(4-chloro-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea
A mixture of compound 4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine (10 g, 42.7 mmol), Pd (PPh3)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 Na2CO3 (168 mL, 168 mmol) in degassed 1,2-dimethoxyethane (400 mL) was heated to 65° C. for 8 hours under N2 atmosphere. The reaction mixture filtered, diluted with water, extracted with ethyl acetate and washed with water, brine, dried over anhydrous Na2SO4, 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).
1HNMR (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).
Step 5: Preparation of 1-(4-(4-(4-aminophenyl)-6-morpholino-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-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.
Step 6: Preparation of phenyl 4-carbamoylphenylcarbamate
To a solution of 4-aminobenzamide (5.0 g, 36.7 mmol) and pyridine (2.9 g, 36.7 mmol)) in dry CH2Cl2 (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 CH2Cl2 (100 mL) and washed with water (2×70 mL). The organic layer was dried over anhydrous Na2SO4 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).
Example 463
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
Step 1: Preparation of 4-(4,6-dichloro-1,3,5-triazin-2-yl)-3,5-dimethylmorpholine
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.
1HNMR (300 MHz, CDCl3): δ4.6 (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-dimethyl morpholino)-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.
Step 4: Preparation of phenyl pyridin-3-ylcarbamate
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.
Example 464
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
Step 1: Preparation of 3-(4,6-dichloro-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane
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.
Example 465
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
Step 1: Preparation of phenyl 3-carbacarbamoylphenylcarbamate
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.
Example 467
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.
Example 468
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
Step 1: Preparation of phenyl pyridin-4-ylcarbamate
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.
Example 469
Preparation of 3-[({4-[4-(3,5-dimethylmorpholin-4-yl)-6-{4-[(methylcarbamoyl)amino]phenyl}-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-(3,5-dimethylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl 3-carbamoylphenylcarbamate. Yield 56 mg, 4.1% yield.
Example 470
Preparation of 4-[({4-[4-(3,5-dimethylmorpholin-4-yl)-6-{4-[(methylcarbamoyl)amino]phenyl}-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-(3,5-dimethylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl 4-carbamoylphenylcarbamate. Yield 70 mg, 12.8% yield.
Example 471
Preparation of 1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-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-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl pyridin-4-ylcarbamate. Yield 51 mg, 4% yield.
Example 472
Preparation of 1-{4-[4-(3,5-dimethylmorpholin-4-yl)-6-{4-[(methylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-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-4-ylcarbamate. Yield 15 mg, 0.8% yield.
Example 473
Preparation of N-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-2,2-difluoroacetamide
Step 1: Preparation of 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine
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].
Step 2: Preparation of 4-(4,6-dimorpholino-1,3,5-triazin-2-yl)aniline
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].
Step 3: Preparation of N-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-2,2-difluoroacetamide
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].
Example 474
Preparation of N-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-4,5-dihydro-1 H-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 mmol 0 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 CeliteTM. 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].
Example 475
Preparation of 2,4-dimorpholin-4-yl-6-[4-(2H-tetrazol-5-yl)phenyl]-1,3,5-triazine
Step 1: Preparation of 4-(4,6-dimorpholino-1,3,5-triazin-2-yl)benzonitrile
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].
Step 2: Preparation of 2,4-dimorpholin-4-yl-6-[4-(2H-tetrazol-5-yl)phenyl]-1,3,5-triazine
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].
Example 476
Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-methylurea
Step 1: Preparation of 1-Methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea
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].
Step 2: Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-methylurea
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].
Example 477
Preparation of 2-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-N-pyridin-3-ylacetamide
Step 1: Preparation of 2-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)acetic acid
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].
Step 2: Preparation of 2-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-N-pyridin-3-ylacetamide
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-1-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 CeliteTM diatomaceous earth and concentrated under reduced pressure to provide the title compound as an orange foam. MS (ES+)=642.4 (M+H)+
Example 667
Preparation of 1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
A solution 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 (0.24 g, 0.37 mmol) in dichloromethane (5 mL) was treated successively with triethylamine (500 μL) and a triphosgene (56 mg) solution in dichloromethane (1 mL). After 5 minutes, the mixture was treated with a solution of 4-aminopyridine (70 mg) in warm tetrahydrofuran. After 1 hour, the reaction mixture was quenched with methanol and concentrated to dryness. Half of the crude residue was treated with a saturated solution of hydrogen chloride in methanol. Upon complete desilylation, the mixture was concentrated to dryness and the residue purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy column running a gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 50% acetonitrile over 25 minutes. After concentration, the title compound was obtained as it trifluoroacetic acid salt (75 mg). MS (ES+)=533.3 (M+H)+
Example 668
Preparation of 1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1-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
A solution 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 (0.25 g, 0.39 mmol) in dichloromethane (5 mL) was treated successively with triethylamine (500 μL) and a triphosgene (59 mg, 0.08 mmol) solution in dichloromethane (1 mL). After 5 minutes, the mixture was treated with 4-(4-methylpiperazin-1-yl)aniline (150 mg). After 1 hour, the reaction mixture was quenched with methanol and concentrated to dryness. The crude residue was treated with a saturated solution of hydrogen chloride in methanol. Upon complete desilylation, the mixture was concentrated to dryness and the residue purified by reverse-phase high performance liquid chromatography using a Phenomenex Gemini column running a gradient elution of 5% acetonitrile/55% of 0.1% aqueous trifluoroacetic acid to 50% acetonitrile over 15 minutes. After concentration, the title compound was obtained as it trifluoroacetic acid salt (130 mg). MS (ES+)=630.4 (M+H)+
Example 823
Preparation of 1-[4-(4,6-di-3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea
To a solution of cyanuric chloride (0.368 g, 2 mmol) in CH2Cl2 (20 mL) was added 3,7-dioxa-9-azabicyclo[3.3.1]nonane. HCO2H (0.718 g, 4.1 mmol), followed by addition of Et3N (0.98 mL, 7 mmol). The resulting reaction mixture was stirred for 24 h, and then diluted with CH2Cl2. The organic phase was washed with aqueous 1N HCl (3×) and dried over MgSO4. The solvent was removed in vacuum to give 9,9′-(6-chloro-1,3,5-triazine-2,4-diyl)bis(3,7-dioxa-9-azabicyclo[3.3.1]nonane) as white solid (0.15 g, 95% yield).
To a 10 mL vial were added 9,9′-(6-chloro-1,3,5-triazine-2,4-diyl)bis(3,7-dioxa-9-azabicyclo[3.3.1]nonane) (150 mg, 0.406 mmol), 4-aminophenylboronic acid pinacol ester (133 mg, 0.61 mmol), Pd(PPh3)4 (10 mg), toluene (1 mL), EtOH (1 mL) and 2M Na2CO3 aqueous solution (0.305 mL). The resulting mixture was heated at 120° C. for 20 minutes 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 (MgSO4). The solvent was removed under reduced pressure and the residue was subjected to HPLC separation to give 4-(4,6-di(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl)aniline as a white solid (120 mg).
To a solution of 4-(4,6-di(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl)aniline (120 mg, 0.281 mmol) in CH2Cl2 was added Et3N (0.237 mL, 1.69 mmol) and triphosgene (42 mg, 0.14 mmol). The mixture was stirred at room temperature for 15 minutes and 4-(4-methylpiperazin-1-yl)aniline (107 mg, 0.56 mmol) was added. The mixture was stirred at room temperature overnight. The solvent was removed, and the residue was subjected to HPLC separation to give the title compound (1TFA salt) MS (ESI) m/z 644.3306.
Preparation of (6S)-tert-butyl 6-hydroxy-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate (Scheme 10)
Step 1: (2R′,5S′)-1-tert-butyl 2,5-dimethyl 1H-pyrrole-1,2,5(2H,5H)-tricarboxylate (cis-diester) was synthesized by following the procedure described in literature: Organic Letters 2004, 6(18), 3055-8
Step 2: Reduction of cis-diester to (2R′,5S′)-tert-butyl 2,5-bis(hydroxymethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (cis-diol
To a solution of (2R′,5S′)-1-tert-butyl 2,5-dimethyl 1H-pyrrole-1,2,5(2H,5H)-tricarboxylate (6.6 g, 23.1 mmol) in THF (100 mL) was added slowly of LiBH4 solution (2M in THF, 34.7 mL, 69.4 mmol) at 0° C. The resulting mixture was stirred at room temperature for 3 hours, then cooled to 0° C. again. HCl solution (1M, 30 mL) was added to the reaction mixture, and stirred for 10 minutes before diluted with EtOAc. The organic layer was separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with water and brine, and dried (MgSO4). 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 (50:50:10) to give the cis-diol (3.8 g, 72%).
Step 3: Preparation of (2R′,5S′)-tert-butyl 2,5-bis((tert-butyldimethylsilyloxy)methyl)-2,5-dihydro-1H-pyrrole-1-carboxylate
To a solution of the cis-diol (3.57 g, 15.6 mmol) in DMF (15 mL) were added TBSCl (5.16 g, 34.3 mmol) and imidazole (3.18 g, 46.7 mmol). The mixture was heated at 80° C. for 30 minutes in microwave oven (150 watt). Cooled to room temperature, the mixture was taken up in water (50 mL) and EtOAc (50 mL). The organic layer was separated, and the aqueous phase was extracted with EtOAc. Combined organic phases were washed with water and brine, and dried (MgSO4). 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 the title compound (7.12 g, 98%).
Step 4: Synthesis of (2R′,3S′,5R′)-tert-butyl 2,5-bis((tert-butyldimethylsilyloxy)methyl)-3-hydroxypyrrolidine-1-carboxylate (trans-alcohol
To a solution of (2R′,5S′)-tert-butyl 2,5-bis((tert-butyldimethylsilyloxy)methyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (4.8 g, 10.5 mmol) in THF (50 mL) was added slowly of BH3 DMS solution (2M in THF, 6.97 mL, 13.9 mmol) at 0° C. The resulting mixture was stirred at room temperature for 3 hours, then cooled to 0° C. again. NaOH solution (5M, 12.6 mL, 63.2 mmol) was added to the reaction mixture, followed by addition of H2O2 (30%, 6.33 mL, 62.0 mmol). The resulting mixture was stirred for 5 hours before diluted with 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 (MgSO4). The organic solvent was removed in vacuo to give the crude product, which was purified by flash chromatography in silica gel with EtOAc:Hex (30:70) to give the title compound (3.8 g, 77%).
Step 5: Benzyl protection of the trans alcohol
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 TBAI (0.195 g, 0.5 mmol) were added. The mixture was stirred at room temperature for 12 hours, and quenched by addition of sat.NH4Cl 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 (MgSO4). 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.NH4Cl 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 (MgSO4). 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.NH4Cl 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 (MgSO4). 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 I









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 




6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-

253.3




4-ylurea

273.8


481

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

464.2




pyridazin-4-ylurea

253.1


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




yl)phenyl]-3-{4-[(4-methylpiperazin-1-

293.5




yl)carbonyl]phenyl}urea

273


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 




2-yl]phenyl}-3-(4-[4-(1-methylethyl)piperazin-1-

287.2




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 




yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5- 

308.7




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 




triazin-2-yl)phenyl]urea

259.6


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-yl]carbonyl}phenyl)urea

329.2


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 




6-phenyl-1,3,5-triazin-2-

291.2




yl)phenyl]carbamoyl}amino)benzamide




557

1-{4-[4-morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2-

460.2 




yl]phenyl}-3-pyridin-4-ylurea

230.6


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 




morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2-

294.1




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 




triazin-2-yl}phenyl)carbamoyl]amino}-N-[2-

309.7




(dimethylamino)ethyl]-N-methylbenzamide




565

1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-

616.4 




triazin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-1-

329.2




yl)carbonyl]phenyl}urea

308.7


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 




yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(2-

307.2




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 




(1,4-oxazepan-4-yl)-1,3,5-triazin-2-

295.6




yl]phenyl}carbamoyl)amino]benzamide




573

1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4-

602.3 




[4-morpholin-4-yl-6-(1,4-oxazepan-4-yl)-1,3,5-triazin-

322.2




2-yl]phenyl}urea

301.7


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-yl]phenyl}urea

320.7


576

1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-

593.3 




triazin-2-yl]phenyl}-3-{3-[(4-methylpiperazin-1-

317.7




yl)carbonyl]phenyl}urea

521.3


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 




methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-

298.2




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 




methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-

291.1




yl]phenyl}carbamoyl)amino]benzamide




584

N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-

604.4 




morpholin-4-yl-6-(1,4-oxazepan-4-yl)-1,3,5-triazin-2- 

302.7




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 




morpholin-4-yl-1,3,5-triazin-2-

267.1




yl)phenyl]carbamoyl}amino)-N-methylbenzamide




589

1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-

531.3 




yl)phenyl]-3-{3-[(4-methylpiperazin-1-

266.1




yl)carbonyl]phenyl}urea

286.7


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 




yl]carbonyl}phenyl)-3-[4-(4-morpholin-4-yl-6-

300.7




pyrrolidin-1-yl-1,3,5-triazin-2-yl)phenyl]urea




603

1-(4-{[4-(1-methylethyl)piperazin-1-

600.4 




yl]carbonyl}phenyl)-3-[4-(4-morpholin-4-yl-6-

300.7




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 




morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin-2-

294.6




yl)phenyl]carbamoyl}amino)benzamide




606

1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-[4-(4-

586.3 




morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin-2-

293.7




yl)phenyl]urea

286.7


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 




6-pyrrolidin-1-yl-1,3,5-triazin-2-

280.6




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 




6-piperidin-1-yl-1,3,5-triazin-2-

294.6




yl)phenyl]carbamoyl}amino)benzamide




611

N-(2-methoxyethyl)-4-({[4-(4-morpholin-4-yl-6-

561.4 




piperidin-1-yl-1,3,5-triazin-2-

281.2




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 




yl-1,3,5-triazin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-

322.2




1-yl)carbonyl]phenyl}urea

301.7


618

1-(4-{[4-(1-methylethyl)piperazin-1-

630.4




yl]carbonyl}phenyl)-3-(4-{4-[(3S)-3-methylmorpholin-

315.7




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 




[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-

308.7




triazin-2-yl}phenyl)urea

329.2


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 




triazin-2-yl}phenyl)-3-(4-{[4-(dipropylamino)piperidin-

350.8




1-yl]carbonyl}phenyl)urea




625

1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4-

630.5 




[(3R)-3-methylmorpholin-4-yl]-6-[(3S)-3-

315.7




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 




triazin-2-yl}phenyl)-3-{4-[(4-butylpiperazin-1-

329.7




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 




triazin-2-yl}phenyl)-3-{4-[(4-propylpiperidin-1-

322.2




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 




yl)carbonyl]phenyl}carbamoyl)amino]phenyl}-6-

329.7




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-methoxyethyl)carbamoyl]phenyl}

633.3 




carbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-

317.1




triazin-2-yl)-N,N-dimethylpiperazine-1-carboxamide




648

4-[4-(4-{[(4-{[2-

660.3




(dimethylamino)ethyl](methyl)carbamoyl}phenyl)carb

330.7




amoyl]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 




(ethylsulfonyl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5- 

341.1




triazin-2-yl}phenyl)carbamoyl]amino}benzamide




654

N-[2-(dimethylamino)ethyl]-4-{[(4-{4-[4-

667.3 




(ethylsulfonyl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5-

334.2




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 




[4-(1-methylethyl)-1,4-diazepan-1-yl]-6-morpholin-4-

329.2




yl-1,3,5-triazin-2-yl}phenyl)urea

219.8


663

1-(4-{4-[4-(1-methylethyl)-1,4-diazepan-1-yl]-6-

671.4 




morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-(4-{[4-(1-

336.2




methylethyl)piperazin-1-yl]carbonyl}phenyl)urea

224.5


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-azabicyclo[3.2.1]oct-

489.5




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-(dimethylamino)ethoxy]phenyl}carbamoyl)

619.3




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, 




8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-

356.8




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, 




8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-

356.8




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, 




yl)phenyl]urea

260


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;




morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-(4-{[4-(1-

336.2;




methylethyl)piperazin-1-yl]carbonyl}phenyl)urea

224.5; 


829

1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4-

657.4;




[4-(1-methylethyl)-1,4-diazepan-1-yl]-6-morpholin-4-

329.2;




yl-1,3,5-triazin-2-yl}phenyl)urea

219.8;


830

1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4-

587.6;




[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-

314.8;




triazin-2-yl]phenyl}urea

294.3;


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;




yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-

308.3;




(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl]phenyl}urea

328.8;


834

N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-

589.5;




morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-

295.3;




triazin-2-yl]phenyl}carbamoyl)amino]benzamide




835

1-{4-[4-(azetidin-3-yloxy)-6-morpholin-4-yl-1,3,5-

449.1;




triazin-2-yl]phenyl}-3-pyridin-4-ylurea

225.1;


836

N-(1-methylethyl)-3-[(4-morpholin-4-yl-6-{4-[(pyridin-

534.4;




4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-

267.7;




yl)oxy]azetidine-1-carboxamide




837

N-{1-[(4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-

658.5;




1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}phenyl)

329.8;




carbonyl]piperidin-4-yl}acetamide




838

1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-

658.8;




triazin-2-yl}phenyl)-3-(4-{[4-(1-methylethyl)-1,4- 

329.8;




diazepan-1-yl]carbonyl}phenyl)urea




839

1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-

629.7;




triazin-2-yl}phenyl)-3-[4-(3-oxa-8-

315.3;




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;




yl]carbonyl}phenyl)-3-(4-{4-(morpholin-4-yl)-6-

329.3;




(propan-2-yl)-1,4-diazepan-1-yl]-1,3,5-triazin-2-

233.6;




yl}phenyl)urea




844

1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-

657.5;




yl]carbonyl}phenyl)-3-(4-{4-(morpholin-4-yl)-6-[4-

329.3;




(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;




3-{4-[(3,3,4-trimethylpiperazin-1-yl)carbonyl]phenyl}

638.3;




urea

654.3;


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 MnCl2, 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-N-1-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 MgCl2, 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 IC50 (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 MnCl2). 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 2





Example
IC50 PI3Kα nM
IC50 PI3Kγ nM
IC50 mTOR M


















1
3
29
0.0013


2
2
35
0.001


3
3
27
0.00385


4
2
23
0.0017


5
17
438
0.0063


6
6
53
0.006


7
>10000
>100000
>4,0000


8
20
220
0.008


9
10
65
0.004


10
75
289
0.068


11
61
528
0.00925


12
248
815
0.011


13
51
879
0.0115


14
25
154
0.00845


15
23
177
0.0025


16
>10,000
>100000
0.01205


17
8
90
0.01395


18
9
71
0.036


19
23
206
0.039


20
41
258
0.0305


21
22
92
0.00175


22
12
142
0.00475


23
18
51
0.00205


24
22
99
0.0027


25
58
105
0.00405


26
680
10,000
0.0025


27
1230
>10,000
0.00415


28
54
5550
0.00095


29
2690
>10,000
0.0028


30
2120
>10,000
0.00265


31
142
3520
0.00049


32
45
2540
0.00029


33
NA
NA
0.091


34
9
95
0.00049


35
6
54
0.00021


36
17
150
0.00051


37
39
155
0.00195


38
7
91
0.00028


39
14
75
0.00032


40
21
136
0.00066


41
69
122
0.0013


42
86
290
0.00335


43
28
35
0.00165


44
NA
NA
0.0135


45
NA
NA
0.0036


46
208
4920
0.024


47
13
52
0.0016


48
6
40
0.0018


49
3
21
0.01


50
1
21
0.002


51
1
15
0.0019


52
2
38
0.001


53
45
403
0.024


54
10
88
0.00475


55
205
1580
0.05


56
122
444
0.015


57
8
74
0.0165


58
13
85
0.0025


59
3
30
0.00105


60
5
36
0.0018


61
9
32
0.00076


62
2
24
0.00068


63
5
36
0.00195


64
1457
1190
1.5


65
15
83
0.00505


66
7
30
0.00165


67
6
48
0.00145


68
0.3
7
0.00057


69
0.4
8
0.00085


70
2
20
0.0007


71
0.4
8
0.00067


72
2
19
0.00085


73
0.3
7
0.00077


74
0.4
8
0.00063


75
0.6
10
0.00075


76
0.4
8
0.00067


77
0.3
4
0.00068


78
3
23
0.00085


79
773
193
0.0051


80
851
2120
0.00715


81
2
38
0.001


82
3
21
0.0089


83
1
15
0.0019


84
10
88
0.00475


85
45
403
0.018


86
122
444
0.01


87
205
1580
0.05


88
8
74
0.0165


89
10
31
0.0016


90
8
42
0.00083


91
6
73
0.00071


92
11
92
0.00235


93
12
133
0.00855


94
5
56
0.001


95
48
101
0.00275


96
NA
NA
0.0012


97
NA
NA
0.0011


98
1350
9000
2.1


99
1520
7500
0.46


100
5
38
0.0035


101
6
33
0.00044


102
6
84
0.0061


103
3
73
0.0053


104
19
234
0.015


105
14
112
0.0305


106
393
1840
0.00755


107
115
1490
0.019


108
586
4150
0.019


109
1460
2960
0.0735


110
884
3510
0.029


111
116
1830
0.0023


112
488
777
0.012


113
NA
NA
0.0037


114
106
1180
0.00315


115
109
2000
0.0032


116
1740
2310
0.0027


117
177
3000
0.083


118
379
297
0.195


119
1240
7530
0.14


120
262
1550
0.079


121
1850
4000
0.0435


122
1160
9500
0.0745


123
760
6350
0.115


124
1650
9650
0.155


125
840
8750
0.016


126
510
5510
0.0195


127
1390
4730
0.0515


128
1330
10,000
0.031


129
7217
10,000
2.35


130
14
132
0.008


131
25
336
0.0145


132
14
234
0.026


133
39
8890
0.043


134
20
183
0.0245


135
15
143
0.034


136
208
4920
0.024


137
9
117
0.00855


138
123.5
459
0.0435


139
24
43
0.074


140
27
100
0.027


141
241
3380
0.026


142
3
50
0.0011


143
2
22
0.0012


144
NA
NA
NA


145
574
1000
0.009


146
>10000
>100000
0.003


147
1930
6830
0.006


148
300
620
0.008


149
889
1400
0.08


150
832
>10,000
0.005


151
0.6
8117
0.007


152
2
5
0.002


153
868
10,000
0.015


154
275
3820
0.064


155
2300
4940
0.016


156
746
10,000
0.053


157
1451
7090
0.17


158
300
1290
0.007


159
133
3920
0.002


160
358
9070
0.007


161
39
155
0.03


162
10
495
0.023


163
2
9
0.0039


164
378
1380
4


165
9
101
0.028


166
4
33
0.06


167
0.8
7
0.00068


168
1
3
0.0036


169
408
7960
0.0083


170
384
9500
0.004


171
300
9500
0.0012


172
435
10,000
0.008


173
1210
10,000
0.084


174
861
727
0.0021


175
549
453
0.0048


176
1120
3730
0.022


177
5840
4120
0.0016


178
>10,000
>10,000
0.014


179
1
13
0.001


180
531
8000
0.0016


181
426
6730
0.011


182
308
5000
0.003


183
526
11000
0.014


184
30
143
0.004


185
1
18
0.0029


186
28
221
0.006


187
3
24
0.0035


188
7540
2380
0.011


189
19
203
0.028


190
780
1320
0.0063


191
435
4630
0.016


192
1120
453
0.043


193
401
3133
0.0008


194
NA
NA
0.027


195
115
498
0.021


196
6
55
0.013


197
2
36
0.024


198
2
33
0.002


199
44
144
0.001


200
14
128
0.0065


201
28
606
0.0009


202
NA
NA
0.0055


203
NA
NA
0.001


204
NA
NA
0.0035


205
NA
NA
0.002


206
NA
NA
0.056


207
NA
NA
0.00084


208
Na
NA
0.0005


209
24
99
0.009


210
6
31
NA


211
80
108
0.006


212
902
8770
0.0064


213
5280
10,000
0.0095


214
2670
10,000
0.0029


215
187
3160
0.0012


216
521
7030
0.003


217
253
3230
0.0032


218
279
2780
0.0026


219
561
8280
0.0059


220
275
2830
0.0035


221
214
4280
0.0027


222
152
572
0.0005


223
2
200
NA


224
444
5870
0.0004


225
109
388
0.047


226
75
294
0.062


227
23
81
0.0073


228
46
280
0.051


229
19
70
0.00077


230
22
119
0.0012


231
4
63
0.0025


232
6
37
0.083


233
55
121
0.0079


234
4534
9534
NA


235
3206
4110
NA


236
3
15
0.011


237
2
23
0.003


238
1
10
0.0036


239
11
38
0.0032


240
1
6
0.0016


241
6
23
0.009


242
2
24
0.007


243
1
9
0.0077


244
1
9
0.0051


245
1
13
0.01


246
1
12
0.015


247
2
5
0.019


248
2
18
0.0064


249
25
216
0.002


250
21
190
0.0009


251
2
21
0.006


252
22
184
0.018


253
8
267
0.009


254
63
253
0.017


255
48
85
0.016


256
68
182
0.032


257
90
323
0.085


258
403
6170
0.0023


259
408
5410
0.0024


260
417
4730
0.0009


261
158
2530
0.00031


262
105
954
0.00029


263
3
20
0.001


264
947
5440
NA


265
1079
10,000
0.0015


266
16
93
0.0017


267
17
58
0.0035


268
12
41
0.00039


269
6
140
0.08


270
68
318
0.16


271
2
23
0.013


272
5
54
0.03


273
4
33
0.0008


274
34
616
0.059


275
46
711
0.07


276
34
597
0.06


277
30
276
0.06


278
26
344
0.25


279
10
70
0.035


280
5
29
0.004


281
2188
4981
2.8


282
10
32
0.0047


283
1
11
0.0031


284
0.7
12
0.0009


285
1127
3433
0.001


286
4195
10,000
120


287
253
3304
0.00016


288
226
2784
0.00097


289
955
3880
0.0015


290
97
166
0.15


291
368
711
0.19


292
1501
3693
0.07


293
764
533
0.5


294
9
26
0.018


295
19
81
0.029


296
13
35
0.021


297
38
70
0.01


298
2
24
0.021


299
3
34
0.08


300
39
106
0.0053


301
21
58
0.0008


302
35
263
0.036


303
NA
NA
0.017


304
2
18
0.0025


305
1
18
0.0006


306
1
19
0.0021


307
3
30
0.0028


308
3
14
0.0029


309
12
95
0.0035


310
14
82
0.0059


311
40
125
0.012


312
3440
10,000
0.037


313
1730
7490
0.037


314
1820
10,000
0.08


315
1100
7900
0.005


316
1410
2690
0.071


317
216
6830
0.084


318
15.5
679
0.855


319
80
1446
0.0044


320
3.3
25
0.0129


321
25
116
0.0165


322
2.4
30
0.006


323
2.9
32
0.007


324
1
22
0.0052


325
74
6244
0.0046


326
830
6189
0.0122


327
394
5899
0.0063


328
261
14,000
0.0046


329
9.5
385
0.00068


330
42
827
0.0033


331
NA
NA
0.0035


332
NA
NA
0.011


333
NA
NA
0.0058


334
16
680
0.0009


335
81
144
0.004


336
40
44
0.0036


337
7
98
0.07


338
3
77
0.022


339
71
485
0.09


340
92
706
0.046


341
10
48
0.012


342
20
127
0.0066


343
97
6700
0.04


344
1610
4140
1.5


345
43
112
0.08


346
43
89
0.023


347
796
8440
NA


348
1030
10,000
NA


349
59
163
NA


350
1
7
NA


351
3
16
0.0042


352
13.5
732
0.00024


353
8.5
501
0.00022


354
69
6224
0.0046


355
830
6189
0.012


356
394
5899
0.0063


357
261
14000
0.0046


358
9
363
0.00068


359
42
827
0.0034


360
6672
>10000
0.082


361
6028
>10000
0.0013


362
3090
>10000
0.00074


363
1097
7142
0.00077


364
1465
8038
0.0035


365
6340
>10000
0.0012


366
585
2996
0.0011


367
499
4076
0.001


368
109
1936
0.00068


369
362
2560
0.0013


370
483
3502
0.00085


371
389
2256
0.00084


372
961
7245
0.00025


373
70
2962
0.00016


374
64
3915
0.00014


375
44
2589
0.00015


376
2602
>10000
0.0023


377
2614
4718
0.0039


378
2506
5375
0.0054


379
4749
5255
0.0073


380
3344
3559
0.0051


381
2955
5395
0.0059


382
522
4306
0.0045


383
2978
3609
0.0061


384
4220
5381
0.0064


385
3397
4692
0.0057


386
5122
4476
0.0042


387
3416
2858
0.0032


388
3450
4285
0.0048


389
4766
5663
0.0065


390
2467
2354
0.012


391
2398
4000
0.0096


392
1178
2781
0.0055


393
444
1539
0.0036


394
592
3226
0.0088


395
584
2221
0.014


396
586
2432
0.01


397
173
2073
0.00016


398
644
3909
0.00021


399
330
1691
0.0011


400
846
4099
0.0017


401
413
3247
0.002


402
543
3643
0.0018


403
314
2383
0.00075


404
63
433
0.00069


405
50
193
0.00064


406
478
1881
0.00038


407
766
2255
0.00052


408
876
3342
0.00072


409
856
4487
0.0015


410
826
5684
0.0023


411
1896
>10000
0.0036


412
1230
7483
0.0073


413
1518
>10000
0.0092


414
969
5453
0.0069


415
787
3263
0.00038


416
446
2505
0.00055


417
656
4299
0.0011


418
520
3476
0.0015


419
610
4272
0.0017


420
593
4363
0.00063


421
414
1571
0.00072


422
269
1221
0.00079


423
610
1854
0.0011


424
576
1871
0.0014


425
309
2383
0.0012


426
1224
8477
0.053


427
580
1419
0.0013


428
450
840
0.0014


429
483
1005
0.0019


430
402
484
0.0017


431
43
340
0.001


432
90
480
0.00069


433
220
1510
0.0023


434
571
4740
0.00056


435
643
4603
0.00075


436
749
3119
0.00062


437
381
1612
0.00056


438
77
663
0.00081


439
182
1283
0.00042


440
1006
>10000
0.0012


441
970
>10000
0.0012


442
1756
>10000
0.0015


443
427
1883
0.00089


444
60
1099
0.00057


445
100
1002
0.00041


446
835
4013
0.00082


447
390
2802
0.0019


448
519
>10000
0.0023


449
287
1640
0.0019


450
76
888
0.0017


451
85
702
0.0014


452
41
502
0.00055


453
659
4273
0.0033


454
278
1490
0.0002


455
113
1390
0.0003


456
150
1547
0.0007


457
63
839
0.0002


458
33
512
0.0002


459
26
483
0.0003


460
143
1083
0.0004


461
482
4415
0.0011


462


<0.001


463


0.017


464


0.001


465


0.001


466


0.001


467


<0.001


468


<0.001


469


0.023


470


0.007


471


0.000


472


0.035


473


0.035


474


0.048


475


18.500


476


0.005


477


14.000


478
1.1
6.0
0.00089


479
<2.1
14.0
0.0017


480
13.0
53.0
0.0029


481
11.0
65.0
0.0023


482
0.6
10.0
0.00305


483
28.5
150.0
0.00155


484
1.0
8.0
0.00063


485
1.4
10.0
0.00125


486
1.1
7.0
0.0045


487
32.3
27.0
0.0018


488
42.0
180.0
0.0034


489
3671.7
9045.0
0.0022


490
586.0
1077.0
0.0116


491
3.5
17.0
0.0011


492
6.5
35.0
0.018


493
2924.0
1078.0
0.0325


494
16.5
104.0
0.0042


495
<1.00
6.0
0.00195


496
NA
NA
NA


497
3.0
19.0
0.0046


498
<1.70
2.5
0.00235


499
<1.90
4.5
0.0022


500
0.4
10.0
0.00109


501
<1.75
6.5
0.00069


502
0.5
6.0
0.001


503
0.5
1.8



504
1.8
10.0
0.00135


505
0.6
5.0
NA


506
0.3
7.0
NA


507
1.6
8.7
0.0032


508
<1.9
12.5
0.00097


509
11.5
662.5
0.00045


510
1.1
6.3
0.00089


511
2.3
10.3
0.00052


512
<1.9
10.0
0.00012


513
<2.4
12.0
0.00012


514
1.6
15.0
0.00017


515
0.4
7.6
0.00155


516
2.1
17.0
NA


517
3.4
18.5
0.00106


518
0.9
6.5
0.0011


519
<1.1
4.8
0.00071


520
1.4
8.0
0.00038


521
1.4
6.0
0.0003


522
1.4
7.5
0.00106


523
3.2
9.5
0.00043


524
0.8
10.0
0.00026


525
NA
NA
NA


526
96.5
6701.5
0.0475


527
20.5
127.0
0.0093


528
1612.0
4140.0
1.6


529
10.5
48.5
0.0155


530
92.0
705.5
0.0495


531
71.5
484.5
0.08


532
3.0
76.5
0.019


533
7.0
98.5
0.0705


534
2.1
11.1
0.0534


535
43.5
112.0
0.0815


536
1.5
13.0
0.0094


537
43.5
89.0
0.000022


538
333.0
197.0
0.000125


539
1.1
16.0
0.0000085


540
54.0
121.0
0.0000034


541
28.000
57.000
0.017


542
8.000
67.000
0.0215


543
3.500
15.500
0.042


544
3.500
20.500
0.017


545
4.000
17.000
0.0109


546
3.500
73.500
0.000225


547
11.000
70.000
0.00775


548
40.000
387.000
0.00975


549
724.000
4541
0.0265


550
47.000
374.000
0.0124


551
24.000
117.500
0.01


552
11.500
127.000
0.00355


553
12.500
72.000
0.0195


554
15.000
156.500
0.0119


555
87.500
378.500
0.405


556
8.500
54.000
0.0044


557
18.000
64.000
0.00855


558
17.000
41.000
0.0061


559
2.000
13.500
0.01005


560
269.000
504.500
0.1


561
11.5
59.0
0.006


562
1.0
10.5
0.004


563
2.5
33.5
0.003


564
0.6
16.5
0.001


565
4.1
38.0
0.001


566
2.6
18.0
0.002


567
14.5
90.0
0.002


568
3.5
18.0
0.010


569
74.5
375.0
0.008


570
5.5
48.0
0.013


571
21.0
108.0
0.000


572
0.9
15.0
0.000


573
6.5
64.0
0.004


574
1.0
12.5
0.006


575
3.0
19.0
0.015


576
761.0
2081.0
0.140


577
63.0
104.0
0.030


578
2406.0
2511.0
2.100


579
462.0
658.0
0.120


580
465.0
1315.0
0.100


581
113.5
461.0
0.037


582
513.0
1094.0
0.230


583
123.0
718.0
0.048


584





585
65.0
131.0
0.012


586
947.0
1246.0
0.365


587
350.0
675.0
0.100


588
524.5
2249.0
0.054


589
718.0
1615.0
0.057


590
343.0
403.5
0.049


591
250.0
726.0
0.033


592
25.5
122.0
0.009


593
40.0
143.0
0.012


594
349.5
744.0
0.022


595
6.5
58.5
0.010


596
5.0
40.5
0.013


597
5.0
58.0
0.011


598
5.5
40.0
0.010


599
64.5
190.0
0.013


600
45.5
161.5
0.008


601
3.5
57.5
0.003


602
7.0
46.5
0.011


603
8.5
50.5
0.017


604
3.5
55.5
0.010


605
2.2
46.0
0.003


606
12.0
87.0
0.026


607
12.0
94.0
0.019


608
9.0
107.0
0.005


609
11.5
93.5
0.003


610
3.5
50.5
0.005


611
18.5
151.5
0.013


612
5.5
67.0
0.061


613
3.8
53.5
0.001


614
2.7
32.5
0.001


615
26.5
115.5
0.001


616
4.0
58.5
0.001


617
2.5
27.0
0.001


618
2.0
18.5
0.001


619
33.0
137.0
0.001


620
4.0
32.5
0.003


621
3.5
43.5
0.001


622
3.0
50.5
0.000


623
12.5
104.0
0.001


624
17.5
58.5
0.001


625
16.5
102.5
0.003


626
59.0
207.5
0.001


627
18.5
101.5
0.002


628





629
26.0
95.0
0.004


630
13.5
84.5
0.001


631
28.0
133.0
0.004


632
15.0
74.5
0.001


633
11.5
175.0
0.001


634
6.0
121.5
0.000


635
22.0
377.5
0.000


636
231.0
468.5
0.027


637
21.5
190.5
0.004


638
16.0
113.5
0.002


639
14.5
123.0
0.001


640
345.0
795.0
2.800


641
88.5
275.5
0.007


642
69.0
254.5
0.001


643
6.2
42.5
0.007


644
7.8
59.5
0.001


645
105.0
230.5
0.120


646
23.0
85.5
0.006


647
24.3
107.0
0.003


648
2.0
27.0
0.003


649
6.4
38.0
0.006


650
23.5
103.5
0.022


651
71.0
247.5
0.014


652
36.0
84.5
0.004


653
4.1
34.0
0.007


654
6.0
70.0
0.008


655
91.5
745.5
0.625


656
73.0
651.0
0.019


657
11.5
127.5
0.385


658
41.5
265.0
0.020


659
3621.0
10000.0
0.720


660
7.5
168.5
0.305


661
56.5
461.5
0.580


662
34.3
197.0
0.770


663
47.3
296.0
0.590


664
NA
NA
NA


665
71.0
283.5
0.445


666
11.5
662.5
0.000


667
102
1081
0.000405


668
122
625.000
0.00056


669
8.0
89.0
0.00048


670
5.0
53.0
0.000212


671
17.5
150.5
0.000505


672
39.5
154.5
0.00195


673
7.0
98.7
0.00043


674
14.0
74.5
0.000325


675
21.0
135.5
0.00066


676
69.5
122.0
0.0013


677
86.5
290.0
0.00335


678
21.3
45.3
0.001168


679
1575.0
9500.0
0.0135


680
504.0
2083.0
0.0036


681
2547
>10,000
0.091


682
84.3
1282.5
0.0885


683
121.3
1329.0
0.025


684
154.3
2345.0
0.0235


685
7.0
26.5
0.000825


686
77.0
540.0
0.026


687
4.0
39.5
0.00485


688
3.0
35.5
0.008


689
217.4
2482
0.03902


690
5.0
83.5
0.000525


691
6.0
199.0
0.00135


692
3.2
29.0
0.00375


693
69.0
289.0
0.00135


694
2.0
40.0
0.000245


695
4.0
70.5
0.00028


696
4.5
73.5
0.000275


697
2.7
42.7
0.000459


698
2.7
44.7
0.000302


699
5.0
62.5
0.0003


700
2.5
41.5
0.00053


701
2.0
25.0
0.00036


702
6.5
125.5
0.000555


703
1.5
23.5
0.00051


704
7217
>10,000
2.35


705
13.5
132.0
0.0124


706
25.5
336.0
0.0145


707
14.0
234.5
0.034


708
39.5
8890.5
0.043


709
20.0
182.5
0.0245


710
15.5
143.5
0.034


711
207.5
4919.5
0.02


712
9.5
117.0
0.00855


713
36.0
444.0
0.0009


714
15.5
69.0
0.00645


715
59.5
146.5
0.006


716
NA
NA
NA


717
444.0
5874.0
0.000395


718
40.5
210.5
0.055


719
17.5
96.0
0.00015


720
0.4
7.0
0.0077


721
0.6
10.5
0.00565


722
0.8
9.5
0.0145


723
1.3
13.5
0.0225


724
1.5
4.0
0.0185


725
2.0
20.5
0.0082


726
25.0
216.5
0.0025


727
21.0
189.5
0.000805


728
10.5
47.0
0.00038


729
14.5
100.0
0.00185


730
15.5
64.5
0.0043


731
33.0
413.0
0.059


732
44.0
478.0
0.069


733
31.5
412.0
0.0755


734
25.5
210.0
0.0595


735
26.5
289.5
0.1225


736
9.5
53.5
0.0036


737
7.0
30.0
0.00445


738
NA
NA
NA


739
NA
NA
NA


740
11.5
34.5
0.00405


741
2188
4981
2.80


742
97.0
166.0
0.145


743
368.0
711.0
0.19


744
1501.0
3693.0
0.068


745
764.0
533.0
0.47


746
23.5
99.0
0.001265


747
40.0
44.0
0.00345


748
NA
NA
NA


749
59.0
163.5
0.002


750
NA
NA
NA


751
143.0
403.5
0.003


752
1.2
18.5
0.00029


753
2.0
31.0
0.000315


754
3.0
28.0
0.000327


755
2.0
26.5
0.00057


756
0.5
7.0
0.0002


757
5.5
37.5
0.00028


758
2.0
16.0
0.00017


759
2.0
38.0
0.00016


760
4.3
28.3
0.00021


761
2.0
19.0
0.00012


762
2.7
19.7
0.000428


763
3.0
24.0
0.000445


764
8.5
67.5
0.00021


765
8.5
78.5
0.000195


766
24.0
85.5
0.001315


767
2.1
17.0
0.0002


768
1.2
18.5
0.000115


769
2.1
17.5
0.00023


770
30.5
99.0
0.00027


771
19.5
66.0
0.000215


772
0.8
9.5
0.00029


773
3.0
36.5
0.000305


774
2.0
41.5
0.00023


775
2.5
46.5
0.00023


776
3.0
29.5
0.000345


777
4.0
39.0
0.000265


778
11.5
126.0
0.00028


779
4.2
49.7
0.00023


780
NA
NA
NA


781
136.0
374.5
0.0305


782
124.5
251.5
0.11


783
346.0
736.0
0.295


784
40.5
174.0
0.088


785
6.0
45.5
0.0555


786
30.5
129.0
0.089


787
10.5
145.5
0.0585


788
13.0
160.0
0.026


789
870.0
1163.0
0.059


790
244.0
593.0
0.065


791
12.5
64.5
0.00068


792
3.3
35.5
0.00081


793
1.0
15.0
0.00042


794
4.1
26.0
0.00063


795
2.7
26.5
0.000425


796
2.6
31.5
0.00039


797
11.5
76.0
0.0013


798
4.1
43.5
0.000445


799
5.0
71.5
0.0005


800
5.5
35.5
0.00072


801
5.0
38.0
0.000455


802
3.5
23.0
0.000675


803
3.0
29.0
0.00019


804
6.0
59.5
0.000425


805
6.5
64.0
0.000415


806
4.5
47.0
0.00024


807
Na
NA
NA


808
381.0
1261.0
0.26


809
395.0
2189.0
0.067


810
2.8
30.5
0.00205


811
3.2
33.5
0.0015


812
2.8
30.5
0.002


813
3.1
30.0
0.0019


814
0.8
10.0
0.00105


815
1.9
24.0
0.000765


816
2.4
26.0
0.001065


817
NA
NA
NA


818
37.7
185.0
0.002


819
44.0
357.5
0.017


820
6.1
67.0
0.000515


821
9.3
58.3
0.0034


822
3.0
31.5
0.000335


823
661.0
2788.0
0.0000015


824
2
17
NA


825
2
13
NA


826
15
96
1.200


827
71.000
283.500
445.000


828
47.333
296.000
590.000


829
34.333
197.000
770.000


830
2.125
10.800
0.393


831
0.950
7.500
0.635


832
1.350
10.500
1.250


833
2.575
8.250
0.430


834
0.750
10.000
0.255


835
4.150
18.500
8.550


836
5.000
17.500
4.050


837
11.900
75.000
1.450


838
4.950
24.500
0.965


839
6.650
29.000
2.500


840
5.150
15.000
1.700


841
6.500
107.500
0.990


842
3.550
54.500
0.325


843
28.500
291.000
1500.000


844
21.000
237.500
345.000


845
0.250
2.750
1.300


846
3.500
22.500
485.000


847
10.500
87.500
165.000


848
1.050
6.000
2.200


849
0.300
3.167
0.865


850
0.650
6.100
1.200


851
0.850
5.600
1.010


852
0.400
5.550
1.250


853
0.300
5.050
1.400


854
8.840
164.000
260.000


855
54.000
864.000
305.000


856
28.500
532.000
11.000


857
10.000
145.500
660.000


858
5.000
134.500
290.000


859
17.850
239.500
830.000


860
57.000
434.500
150.000


861
4.000
56.000
425.000


862
23.500
154.000
835.000


863
2.100
8.000
3.600


864
1.000
7.500
5.250


865
2.450
12.000
1.350


866
1.600
16.500
0.980


867
0.400
7.000
0.610


868
0.650
4.500



869
0.600
6.500









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









TABLE 3









hSMG-1 IC50










Example
μM)













462
0.001



463
0.510



464
0.003



465
0.005



466
0.000



467
0.000



468
<0.000



469
0.130



470
0.195



471
0.005



472
0.200



473
3.650



474
5.650



475
>20



476
0.019



477
9.250









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











TABLE 4







IC50 MDA-MB-
IC50 PC3-mm2 
IC50 LNCap



Example
361 (nM)
(nM)
(nM)




















1
45.0
43.0




2
45.0
43.0




3
45.0
43.0




4
45.0
43.0




5
45.0
43.0




6
45.0
43.0




7
ND
ND




8
407.0
293.0




9
102.0
161.0




10
2709.0
1782.0




11
794.0
5630.5




12
ND
ND




13
603.0
845.0




14
376.0
590.0




15
255.0
328.0




16
ND
ND




17
501.0
994.0




18
2656.0
7102.0




19
1031.0
1596.0




20
>10000
>10000




21
129.0
246.0




22
1424.0
2445.0




23
104.0
147.0




24
122.0
142.0




25
264.0
258.0




26
ND
ND
190.0



27
ND
ND
350.0



28
ND
ND
2.4



29
ND
ND
180.0



30
ND
ND
90.0



31
ND
ND
45.0



32
ND
ND
0.7



33
ND
ND




34
28.0
41.0




35
22.5
27.5




36
73.0
98.0




37
98.0
176.0




38
15.0
28.0




39
22.0
30.0




40
<30
62.0




41
167.0
301.0




42
345.0
3600.0




43
35.8
40.0




44
ND
ND




45
ND
ND




46
ND
ND




47
116.0
95.0




48
38.0
48.0




49
84.0
79.0




50
36.0
39.0




51
<30
<30




52
<30
49.0




53
662.0
987.0




54
133.0
214.0




55
ND
ND




56
ND
ND




57
119.0
187.0




58
115.0
45.0




59
14.0
16.0




60
83.0
92.0




61
48.0
23.0




62
27.0
34.0




63
69.0
62.0




64
ND
ND




65
151.0
267.0




66
59.0
66.0




67
816.0
28.0




68
<3
11.0




69
10.0
13.0




70
19.0
24.0




71
<9.8
18.3




72
1.0
13.0




73
30.0
107.0




74
<3
8.3




75
<3
7.0




76
4.0
13.1




77
<30
<30




78
68.0
31.0




79
ND
320.0




80
ND
320.0




81
ND
ND




82
ND
ND




83
ND
ND




84
ND
ND




85
ND
ND




86
ND
ND




87
ND
ND




88
ND
ND




89
30.0
47.0




90
19.0
19.0




91
25.0
1567.0




92
140.0
87.0




93
42.0
60.0




94
54.0
82.0




95
333.0
364.0




96
5.0
33.0




97
<30
52.0




98
ND
ND




99
ND
ND




100
56.0
56.0




101
32.7
37.3
3.0



102
592.0
854.0




103
2917.0
4453.0




104
412.0
684.0




105
3710.0
>10000




106
ND
ND
370.0



107
ND
ND
1000.0



108
ND
ND
320.0



109
ND
ND
1900.0



110
ND
ND
220.0



111
ND
ND
58.0



112
ND
ND
300.0



113
ND
ND
120.0



114
ND
ND
38.0



115
ND
ND
200.0



116
ND
ND
70.0



117
ND
ND
700.0



118
ND
ND
3000.0



119
ND
ND
2800.0



120
ND
ND
1200.0



121
ND
ND
1000.0



122
ND
ND
900.0



123
ND
ND
4100.0



124
ND
ND
1950.0



125
ND
ND
1000.0



126
ND
ND
1300.0



127
ND
ND
1350.0



128
ND
ND
30000.0



129
ND
ND




130
191.0
416.0




131
696.0
839.0




132
586.0
1012.0




133
795.0
1950.0




134
805.0
857.0




135
533.0
509.0




136
ND
ND




137
582.0
551.0




138
ND
ND
680.0



139
ND
ND
180.0



140
225
279




141
ND
ND




142
5
33




143
ND
52




144
ND
ND
1500



145
ND
ND
120



146
ND
ND
5



147
ND
ND
1000



148
ND
ND
680



149
ND
ND
32000



150
ND
ND
290



151
ND
14




152
9
14




153
ND
ND
4200



154
ND
ND
22000



155
ND
ND
400



156
ND
ND
22000



157
ND
ND
2700



158
ND
ND
49



159
ND
ND
1.2



160
ND
ND
220



161
328
675




162
ND
ND




163
10.7
28.3




164
ND
ND




165
210
333




166
134
249




167
ND
10




168
ND
ND




169
ND
ND
5000



170
ND
ND
4500



171
ND
ND
5200



172
ND
ND
9500



173
ND
ND
2500



174
ND
ND
4.25



175
ND
ND
9.5



176
ND
ND
1000



177
ND
ND
600



178
ND
ND
850



179
ND
8.333




180
ND
ND
5800



181
ND
ND
3400



182
ND
ND
3500



183
ND
ND
8500



184
1246
2094




185
5
13




186
473
703




187
11
41




188
ND
ND




189
84
99




190
ND
ND
950



191
ND
ND
220



192
ND
ND
620



193
ND
ND
105



194
ND
ND
600



195
ND
ND




196
50
82




197
17
49




198
ND
43




199
96
93




200
162
248




201
29
44




202
ND
ND
700



203
ND
ND
78



204
ND
ND
6000



205
ND
ND
400



206
ND
ND
5100



207
ND
ND
33.333



208
ND
ND
50



209
174
278




210
ND
ND




211
254
389




212
ND
ND
420



213
ND
ND
420



214
ND
ND
700



215
ND
ND
30



216
0
ND
50



217
ND
ND
13



218
ND
ND
12



219
ND
ND
40



220
ND
ND
40



221
ND
ND
120



222
ND
ND
10



223
187
229




224
ND
ND




225
ND
ND




226
ND
ND




227
1495
4026




228
3924
7174




229
35.75
40




230
ND
ND




231
20
121




232
38
177




233
1214
3337




234
ND
ND
10000



235
ND
ND
7900



236
22.333
67




237
28
69




238
23
61




239
184
317




240
ND
12




241
24
135




242
11
49




243
15
34




244
ND
71




245
110
374




246
35
91




247
30
111




248
ND
69




249
92
142




250
14
31




251
ND
65




252
219
747




253
12
574




254
ND
ND




255
174
328




256
ND
ND




257
ND
ND




258
ND
ND
60



259
ND
ND
580



260
ND
ND
380



261
ND
ND
30



262
ND
ND
22



263
68
31




264
ND
ND




265
ND
ND
1.7



266
ND
ND




267
94
200




268
59
107
38



269
ND
144




270
397
953




271
68
129




272
70
340




273
32
80




274
1000
1491




275
3100
4309




276
1347
1654




277
530
572




278
2297
3701




279
176
247




280
176
404




281
ND
ND




282
83
84




283
12.333
33.333




284
12
36.333




285
ND
ND
4



286
ND
ND
32000



287
ND
ND




288
ND
ND
3



289
ND
ND
3



290
ND
ND




291
ND
ND




292
ND
ND




293
ND
ND




294
69
154




295
133
189




296
83
133




297
115
290




298
38
165




299
73
219




300
297
340




301
430
759




302
299
539




303
ND
ND
0.8



304
7
39.333




305
4
46




306
7
30




307
ND
362




308
4
53




309
64
109




310
44
117




311
126
366




312
ND
ND
80



313
ND
ND
100



314
ND
ND
550



315
ND
ND
300



316
ND
ND
320



317
ND
ND
120



318
ND
ND
1000



319
ND
ND
220



320
32.333
73.667




321
106
325




322
13
86




323
ND
77




324
4
35




325
ND
ND
310



326
ND
ND
580



327
ND
ND
400



328
ND
ND
1500



329
ND
ND
5900



330
ND
ND
260



331
0
0
0



332
0
0
0



333
0
0
0



334
0
0
0



335
0
0
0



336
56
45
0



337
142
373




338
122
266




339
ND
ND




340
ND
ND




341
150
237




342
1256
2429




343
ND
ND




344
ND
ND




345
554
395




346
ND
ND




347
ND
ND
9



348
ND
ND




349
87
81




350
ND
8.5




351
50
66




352
ND
ND
< 0.8



353
ND
ND
< 0.8



354
ND
ND
310



355
ND
ND
580



356
ND
ND
400



357
ND
ND
1500



358
ND
ND
5900



359
ND
ND
260



360
ND
ND
10000



361
ND
ND
2.2



362
ND
ND
1



363
ND
ND
1.2



364
ND
ND
70



365
ND
ND
3



366
ND
ND
2.8



367
ND
ND
5



368
ND
ND
0.7



369
ND
ND
3



370
ND
ND
0.8



371
ND
ND
0.8



372
ND
ND
0.8



373
ND
ND
1



374
ND
ND
<0.8



375
ND
ND
<0.8



376
ND
ND
50



377
ND
ND
90



378
ND
ND
50



379
ND
ND
140



380
ND
ND
300



381
ND
ND
140



382
ND
ND
48



383
ND
ND
150



384
ND
ND
50



385
ND
ND
70



386
ND
ND
140



387
ND
ND
70



388
ND
ND
110



389
ND
ND
240



390
ND
ND
650



391
ND
ND
300



392
ND
ND
480



393
ND
ND
580



394
ND
ND
800



395
ND
ND
590



396
ND
ND
280



397
ND
ND
7



398
ND
ND
12



399
ND
ND
3



400
ND
ND
12



401
ND
ND
21



402
ND
ND
7



403
ND
ND
8



404
ND
ND
60



405
ND
ND
25



406
ND
ND
2.4



407
ND
ND
0.8



408
ND
ND
9



409
ND
ND
50



410
ND
ND
110



411
ND
ND
250



412
ND
ND
25



413
ND
ND
150



414
ND
ND
120



415
ND
ND
29



416
ND
ND
12



417
ND
ND
6



418
ND
ND
40



419
ND
ND
12



420
ND
ND
2



421
ND
ND
1



422
ND
ND
2



423
ND
ND
2.8



424
ND
ND
1



425
ND
ND
2.8



426
ND
ND
700



427
ND
ND
7



428
ND
ND
1



429
ND
ND
9



430
ND
ND
16



431
ND
ND
<0.8



432
ND
ND
<0.8



433
ND
ND
40



434
ND
ND
<0.8



435
ND
ND
4



436
ND
ND
10



437
ND
ND
1



438
ND
ND
<0.8



439
ND
ND
1



440
ND
ND
1



441
ND
ND
6



442
ND
ND
13



443
ND
ND
8



444
ND
ND
< 0.8



445
ND
ND
< 0.8



446
ND
ND
15



447
ND
ND
8



448
ND
ND
18



449
ND
ND
40



450
ND
ND
<0.8



451
ND
ND
<0.8



452
ND
ND
<0.8



453
ND
ND
30



454
ND
ND
<0.8



455
ND
ND
<0.8



456
ND
ND
<0.8



457
ND
ND
<0.8



458
ND
ND
8



459
ND
ND
<0.8



460
ND
ND
<0.8



461
ND
ND
68



462
ND
ND
ND



463
ND
ND
ND



464
ND
ND
ND



465
ND
ND
ND



466
ND
ND
420



467
ND
ND
170



468
ND
ND
50



469
ND
ND
2800



470
ND
ND
1000



471
ND
ND
130



472
ND
ND
3800



473
ND
ND
ND



474
ND
ND
ND



475
ND
ND
ND



476
ND
ND
ND



477
ND
ND
ND



478
<3.080
8.5




479
6
21




480
ND
ND




481
ND
ND




482
ND
ND




483
ND
ND




484
ND
ND




485
ND
ND




486
7.0
39.3




487
175.0
339.0




488
ND
ND




489
ND
ND
4300



490
ND
ND




491
8.0
35.0




492
26.0
57.0




493
ND
ND




494
115.0
276.0




495
4.0
13.1




496
ND
ND




497
50.0
66.0




498
4.0
16.5




499
21.0
31.0




500
1.0
6.5




501
<31
41




502
4.0
11.0




503
7.5
12.5




504
22.5
25.5




505
12.3
33.3




506
<21.7
12




507
10.7
28.3




508
12.0
36.3




509
ND
ND
<0.8



510
ND
ND




511
2.0
10.0




512
1.0
8.0




513
2.0
13.0




514
<3.2
12




515
3
12




516
ND
ND




517
18.0
7.0




518
4.0
24.0




519
3.0
9.0




520
5.0
18.0




521
8.0
27.0




522
3.0
11.0




523
ND
ND




524
ND
ND




525
ND
ND




526
ND
ND




527
1256.0
2429.0




528
ND
ND




529
150.0
237.0




530
ND
ND




531
ND
ND




532
122.0
266.0




533
142.0
373.0




534
32.3
73.7




535
554.0
395.0




536
22.3
67.0




537
<31
<31




538
ND
ND




539
9.0
161.0




540
165.0
309.0




541
964.0
1764.0




542
281.0
569.0




543
<31
262.0




544
58.0
253.0




545
30.0
219.0




546
7.0
25.0




547
68.0
197.0




548
524.0
869.0




549
ND
ND




550
315.0
711.0




551
106.0
270.0




552
105.0
243.0




553
113.0
522.0




554
521.0
>1000




555
ND
ND




556
128.0
379.0




557
34.0
31.0




558
751.0
939.0




559
8.0
149.0




560
ND
ND




561
66.0
218.0




562
3.0
93.0




563
10.0
171.0




564
1.0
7.0




565
9.0
27.0




566
28.0
55.0




567
106.0
130.0




568
18.0
107.0




569
ND
ND




570
28.0
344.0




571
90.0
168.0




572
13.0
56.0




573
99.0
206.0




574
6.0
25.0




575
15.0
242.0




576
ND
ND




577
ND
ND




578
ND
ND




579
ND
ND




580
ND
ND




581
ND
ND




582
ND
ND




583
ND
ND




584
ND
ND




585
ND
ND




586
ND
ND




587
ND
ND




588
ND
ND




589
ND
ND




590
ND
ND




591
ND
ND




592
239.0
718.0




593
>1000
>1000




594
ND
ND




595
43.0
193.0




596
26.0
155.0




597
45.0
229.0




598
22.0
214.0




599
ND
ND




600
ND
ND




601
22.0
155.0




602
17.0
122.0




603
17.0
137.0




604
4.0
73.0




605
7.0
92.0




606
28.0
173.0




607
24.0
213.0




608
52.0
298.0




609
24.0
26.0




610
28.0
297.0




611
194.0
581.0




612
38.0
227.0




613
6.0
21.0




614
4.0
15.0




615
88.0
123.0




616
4.0
21.0




617
4.0
17.0




618
2.0
13.0




619
ND
ND




620
4.0
16.0




621
8.0
35.0




622
5.0
25.0




623
6.0
32.0




624
4.0
19.0




625
12.0
43.0




626
ND
ND




627
16.0
55.0




628
ND
ND




629
28.0
133.0




630
5.0
23.0




631
28.0
120.0




632
9.0
38.0




633
15.0
64.0




634
5.0
16.0




635
26.0
106.0




636
ND
ND




637
26.0
62.0




638
9.0
44.0




639
16.0
27.0




640
ND
ND




641
ND
ND




642
ND
ND




643
19.0
59.0




644
51.0
185.0




645
ND
ND




646
32.0
223.0




647
46.0
136.0




648
12.0
34.0




649
9.0
37.0




650
ND
ND




651
ND
ND




652
ND
ND




653
ND
ND




654
ND
ND




655
ND
ND




656
ND
ND




657
ND
ND




658
ND
ND




659
ND
ND




660
ND
ND




661
ND
ND




662
ND
ND




663
ND
ND




664
ND
ND




665
ND
ND




666
ND
ND




667
ND
ND
60.0



668
ND
ND
0.8



669
28.0
41.0




670
22.5
27.5




671
73.0
98.0




672
98.0
176.0




673
15.0
28.0




674
22.0
30.0




675
<30
62.0




676
167.0
301.0




677
345.0
3600.0




678
35.8
40.0




679
ND
ND




680
ND
ND




681
ND
ND




682
1044.0
766.0




683
673.0
584.0




684
806.0
1015.0




685
>10000
>10000




686
569.0
1105.0




687
355.0
389.0




688
1412.0
1950.0




689
53.0
85.0




690
112.0
405.0




691
52.0
131.0




692
97.0
326.0




693
ND
ND




694
<3
11.0




695
6.0
7.0




696
13.0
13.0




697
<30
<30




698
<3
6.0




699
36.0
40.0




700
5.0
20.0




701
<30
<30




702
4.0
14.0




703
<3
13.0




704
ND
ND




705
191.0
416.0




706
696.0
839.0




707
586.0
1012.0




708
795.0
1950.0




709
805.0
857.0




710
533.0
509.0




711
ND
ND




712
582.0
551.0




713
29.0
44.0




714
162.0
248.0




715
254.0
389.0




716
ND
ND




717
ND
ND
< 0.8



718
3924.0
7174.0




719
<31
<31




720
15.0
34.0




721
<31
71.0




722
110.0
374.0




723
35.0
91.0




724
30.0
111.0




725
<31
69.0




726
92.0
142.0




727
14.0
31.0




728
59.0
107.0
38.000



729
<31
<31




730
94.0
200.0




731
1000.0
1491.0




732
3100.0
4309.0




733
1347.0
1654.0




734
530.0
572.0




735
2297.0
3701.0




736
176.0
247.0




737
176.0
404.0




738
ND
ND




739
ND
ND




740
83.0
84.0




741
ND
ND




742
ND
ND




743
ND
ND




744
ND
ND




745
ND
ND




746
93.0
118.0




747
56.0
45.0




748
ND
ND




749
87.0
81.0




750
ND
ND




751
144.0
238.0




752
<3
6.0




753
4.0
14.0




754
31.3
70.8




755
3.0
13.0




756
<3
12.000




757
<3
6.000




758
3.0
14.0




759
1.0
10.0




760
0.0
4.0




761
< 3
4.0




762
8.0
7.0




763
4.0
7.0




764
628.0
678.0




765
21.0
27.0




766
26.0
50.0




767
5.0
13.0




768
7.0
8.0




769
6.0
14.0




770
40.0
25.0




771
>1000
>1000




772
5.0
15.0




773
4.0
6.0




774
14.0
19.0




775
5.0
7.0




776
<3.2
6.0




777
2.0
4.0




778
17.0
29.0




779
13.0
23.0




780
ND
ND




781
ND
ND




782
ND
ND




783
ND
ND




784
>1000
>1000




785
>1000
>1000




786
>1000
>1000




787
>1000
>1000




788
>1000
>1000




789
ND
ND




790
ND
ND




791
11.0
42.0




792
2.0
16.0




793
2.0
26.0




794
2.0
20.0




795
<3.2
10.0




796
2.0
18.0




797
11.0
29.0




798
3.0
24.0




799
<3.2
24.0




800
1.0
11.0




801
3.0
32.0




802
3.0
50.0




803
1.0
6.0




804
3.0
11.0




805
3.0
13.0




806
<3.2
9.0




807
35.000
37.000




808
ND
ND




809
ND
ND




810
2.0
26.0




811
2.0
19.0




812
3.0
23.0




813
<3.2
24.0




814
4.0
37.0




815
3.0
24.0




816
2.0
11.0




817
ND
ND




818
129.0
237.0




819
442.0
768.0




820
ND
ND




821
ND
ND




822
ND
ND




823
ND
ND
55.0



823
ND
ND




825
ND
ND




826
>1000
>1000










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.

## Claims

1. 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, brain cancer, soft-tissue sarcoma, and bone sarcoma, comprising concurrently administering to a mammal in need thereof a first compound of Formula I:



wherein:
R1 is





or



wherein:
R6, R7, R8, R9 are each independently selected from the group consisting of a hydrogen atom, and a C1-C6alkyl optionally substituted with C2-C6alkenyl, C4-C6alkadienyl, C2-C6alkynyl or C4-C6alkadiynyl;
or one of R6 and R7 or R8 and R9, 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;
R2 is optionally substituted C6-C14aryl-NH—COR3, optionally substituted C1-C9heteroaryl-NH-COR3, —CH═CH—C6-C10aryl-NH—COR3 or —CH═CH—C1-C9heteroaryl-NH—COR3;
R3 is OR5, NR5R5 or NHR5;
R5 is independently selected from the group consisting of C1-C6alkyl, C3-C6alkenyl, C3-C6alkynyl, optionally substituted C6-C10aryl, C1-C6haloalkyl, optionally substituted C1-C9heteroaryl, C1-C6hydroxylalkyl-, C3-C10saturated or unsaturated mono or bicyclic C3-C10cycloalkyl optionally substituted with OH, NR11R11 or 3-7 membered C1-C6heterocyclyl, and 3-10 membered saturated or unsaturated mono or bicyclic C1-C9heterocyclyl, with the proviso that three-membered cycloalkyl and heterocyclyl rings are saturated;
or two R5 groups taken together with the nitrogen atom to which they are attached form a 3 to 8 membered ring system optionally substituted with C1-C6alkyl, 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 NR10;
R10 is selected from the group consisting of H, C1-C6alkyl, —SO2(C1-C6alkyl), —COO(C1-C6alkyl), —CONH(C1-C6alkyl), —CON(C1-C6alkyl)2, —CO(C1-C6alkyl), and —SO2NHR11;
R11 is selected from the group consisting of H, C1-C6alkyl optionally substituted with OH, NR11R11 or a 3-7 membered C1-C6heterocyclyl, —CO(C1-C6alkyl), optionally substituted C6-C10aryl, and optionally substituted C1-C9heteroaryl;
R4 is selected from the group consisting of: a) C1-C6alkyl optionally substituted with: i) 3-10 membered C1-C9heterocyclyl optionally substituted with C1-C6alkyl-, ii) H2N—, iii) (C1-C6alkyl)NH—, iv) (C1-C6alkyl)2N—, v) NH(CH2)aN(C1-C6alkyl)2 wherein a is 2, 3 or 4, and vi) CHO, b) C3-C6alkenyl, c) C3-C6alkynyl, d) —O—C1-C8alkyl optionally substituted with —O—C1-C8alkyl, e) —O—C3-C8alkenyl, f) —O—C3-C8alkynyl, g) saturated or unsaturated mono or bicyclic C3-C8cycloalkyl, and h) saturated or unsaturated mono or bicyclic —O—C3-C12cycloalkyl, all the above optionally substituted with OH, NR11R11 or a 3-7 membered C1-C6heterocyclyl optionally substituted with C1-C6alkyl-, provided that an OH or NR11R11 is not directly bonded to a carbon atom that is double- or triple-bonded to another carbon atom; i) —CH═CH—C6-C10aryl; j) —CH═CH—C1-C9heteroaryl; k) optionally substituted C6-C10aryl; l) optionally substituted 5-10 membered C1-C9heteroaryl attached to the triazine moiety via a carbon atom; m) 3-10 membered saturated or unsaturated monocyclic C1-C9heterocyclyl attached to the triazine moiety through a carbon or nitrogen atom and optionally substituted with from 1 to 3 substituents independently selected from: OH, NR11R11, C1-C6alkyl, (C1-C6alkyl)amido-, (C1-C6alkyl)C(O)—, (C1-C6alkoxy)carbonyl-, adamantyl, C1-C6hydroxylalkyl-, (C1-C6alkyl)amido-; or a 3-7 membered C1-C6heterocyclyl, 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—C6-C10aryl; o) optionally substituted —O—C1-C9heteroaryl; p) —O-(3-12 membered saturated or unsaturated mono or bicyclic)C1-C9heterocyclyl optionally substituted with (C1-C6alkoxy)carbonyl-, H2NS(O)2—, or C1-C6alkyl further optionally substituted with OH, NR11R11 or a 3-7 membered C1-C6heterocyclyl, with the proviso that three membered heterocyclyl is saturated; q) —NHC6-C10aryl, r) —NHC1-C9heteroaryl, s) —NHNH2, t) —NHNHC1-C6alkyl, u) —NHN(C1-C6alkyl)2, v) —NHOH, w) —COOH, x) —COO—C1-C6alkyl, y) —CONR12R13, z) —NR12R13,

















wherein Z is CH2, O, S(O)n or NR10 and n is 0, 1 or 2;
ee) halogen, ff) C6-C14aryl-S(O)2—NH—, gg) R11NHC(O)NH—O—, and hh) optionally substituted 5-membered monocyclic C1-C4heteroaryl attached to the triazine moiety via a nitrogen atom;
R12 and R13 are each independently selected from H, optionally mono or disubstituted C1-C8alkyl, optionally substituted C3-C8alkenyl, and optionally substituted C3-C8alkynyl, the optional substituents being selected from C1-C6alkoxy, OH, NR11R11, and 3-7 membered C1-C6heterocyclyl, provided that an OH or NR11R11 is not directly bonded to a carbon atom that is double- or triple-bonded to another carbon atom;
or R12 and R13 taken together with the nitrogen atom to which they are attached form a 3 to 8 membered monocyclic ring system optionally substituted with C1-C6alkyl, 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 NR10;

















or



or R12 and R13 taken together with the nitrogen atom to which they are attached form
wherein a and b are each independently —CH2—, O, S, or NR10, and x is 1-3;
C1-C9heteroaryl 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, NR10, and S(O)n;
C1-C9heterocyclyl 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, NR10, 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) C1-C6alkyl optionally substituted with OH, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, —NH(CH2)wN(C1-C6alkyl)2 wherein w is 2, 3 or 4, or 3-10 membered C1-C9heterocyclyl optionally substituted with from 1 to 3 independently selected C1-C6alkyl- substituents; b) halogen; c) hydroxy; d) NH2; e) NO2; SO2NH2; g) COOH; h) COO(C1-C6alkyl); i) NHCOO(C1-C6alkyl); j) NH(C1-C6alkyl); k) N(C1-C6alkyl)2; l) C(O)NRaRb, wherein Ra is H or C1-C6alkyl, and Rb is H, C1-C6alkyl, (C6-C14aryl)alkyl-, or (C1-C9heteroaryl)alkyl-; m) —Y-Q, wherein Y is: i) O, ii) NH, iii) N(C1-C6alkyl), iv) NHSO2, v) SO2NH, vi) NHCONH, vii) NHCON(C1-C6alkyl), viii) S(O)q, q is 0, 1 or 2, ix) —C(O)NH—, x) —NHC(O)— xi) —C(O)N(CH3)—, xii) C(O), or xiii) absent, and Q is selected from: i) C6-C10aryl, optionally substituted with from 1 to 3 substituents independently selected from: A) C1-C6alkoxy- optionally substituted with 1) H2N—, 2) (C1-C6alkyl)amino-, 3) di(C1-C6alkyl)amino-, 4) C1-C9heterocyclyl- optionally substituted by C1-C6alkyl-, or 5) hydroxyl, B) (C1-C6alkoxy)carbonyl-, C) (C1-C6alkoxy)C(O)NH—, D) C1-C6alkyl- optionally substituted with 1) H2N—, 2) (C1-C6alkyl)amino-, or 3) di(C1-C6alkyl)amino-, E) (C1-C6alkyl)amino-, F) di(C1-C6alkyl)amino-, G) (C1-C6alkyl)amido- optionally substituted with 1) H2N—, 2) (C1-C6alkyl)amino-, or 3) di(C1-C6alkyl)amino-, H) (C1-C6alkyl)carboxyamido-, I) C1-C9heterocyclyl- optionally substituted by C1-C6alkyl- or C1-C6hydroxylalkyl-, J) heterocyclyl(C1-C6alkyl)- optionally substituted by C1-C6alkyl-, K) halogen, L) hydroxyl, M) C1-C6hydroxylalkyl-, N) perfluoro(C1-C6)alkyl-, O) H2N—, P) O2N—, Q) H2NSO2—, R) HO2C—, and S) NC—, ii) 5-10 membered C1-C9heteroaryl, optionally substituted with from 1 to 3 substituents independently selected from: A) C1-C6alkoxy- optionally substituted with 1) H2N—, 2) (C1-C6alkyl)amino-, 3) di(C1-C6alkyl)amino-, 4) C1-C9heterocyclyl- optionally substituted by C1-C6alkyl-, or 5) hydroxyl, B) (C1-C6alkoxy)carbonyl-, C) (C1-C6alkoxy)C(O)NH—, D) C1-C6alkyl- optionally substituted with 1) H2N—, 2) (C1-C6alkyl)amino-, or 3) di(C1-C6alkyl)amino-, E) (C1-C6alkyl)amino-, F) di(C1-C6alkyl)amino-, G) (C1-C6alkyl)amido-optionally substituted with 1) H2N—, 2) (C1-C6alkyl)amino-, or 3) di(C1-C6alkyl)amino-, H) (C1-C6alkyl)carboxyamido-, I) C1-C9heterocyclyl- optionally substituted by C1-C6alkyl- or C1-C6hydroxylalkyl-, J) heterocyclyl(C1-C6alkyl)- optionally substituted by C1-C6alkyl-, K) halogen, L) hydroxyl, M) C1-C6hydroxylalkyl-, N) perfluoro(C1-C6)alkyl-, O) H2N—, P) O2N—, Q) H2NSO2—, R) HO2C—, and S) NC—, iii) 3-10 membered C1-C9heterocyclyl, optionally substituted with from 1 to 3 substituents independently selected from: A) C1-C6alkyl-, B) heterocyclyl(C1-C6alkyl)-, C) (C6-C14aryl)alkyl-, D) C1-C8acyl-, E) (C1-C6alkoxy)carbonyl-, F) (C1-C6alkyl)carboxyl-, G) halogen, H) C1-C6haloalkyl-, I) hydroxyl, J) C1-C6hydroxyalkyl-, K) H2N—, L) (C1-C6alkyl)amino-, M) di(C1-C6alkyl)amino-, N) HO2C—, O) (C1-C6alkoxy)carbonyl-, P) (C1-C6alkyl)carboxyl-, Q) (C1-C6alkyl)amido-, R) H2NC(O)—, S) (C1-C6alkyl)carboxyamido-, T) 5-10 membered C1-C9heteroaryl, U) C6-C14ary, V) C3-C8cycloalkyl W) 3-10 membered C1-C9heterocyclyl, X) NC—; and Y) —NO2; iv) C3-C10cycloalkyl, v) C1-C6alkyl, vi) C2-C6alkenyl, vii) C2-C6alkynyl, viii) C1-C6hydroxyalkyl-, ix) (CH2)vO(C1-C6alkyl), x) (CH2)vNH2, xi) (CH2)vNH(C1-C6alkyl), xii) (CH2)vN(C1-C6alkyl)2, xiii) O(CH2)vN(C1-C6alkyl)2, xiv) (CH2)vC6-C10aryl, xv) —CN, xvi) (CH2), 5-10 membered C1-C9heteroaryl, xvii) (CH2), 3-10 membered C1-C9heterocyclyl, optionally substituted by C1-C6alkyl-, wherein v is 1, 2, 3 or 4, and xviii) C1-C6 perfluoroalkyl-; and n) C(O)Rc wherein Rc is: i) H, ii) C1-C6alkyl, or iii) C3-C6cycloalkyl, or optionally a pharmaceutically acceptable salt thereof:
and 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, oxaliplatin, imatinib mesylate, bevacizumab, hexamethylmelamine, topotecan, tyrosine kinase inhibitors, tyrphostins, herbimycin A, genistein, erbstatin, hydroxyzine, glatiramer acetate, interferon beta-1a, interferon beta-1b, natalizumab and lavendustin A, or optionally a pharmaceutically acceptable salt thereof;
in amounts effective to treat said cancer.

2. The method of claim 1 wherein R1 is

3. The method of claim 1 wherein R2 is optionally substituted C6-C14aryl-NH—COR3.

4. The method of claim 1 wherein R2 is optionally substituted phenyl-NH—COR3.

5. The method of claim 1 wherein R3 is NHR5.

6. The method of claim 1, wherein said cancer is renal cell carcinoma.

7. The method of claim 1, wherein said cancer is acute lymphoblastic leukemia.

8. The method of claim 1, wherein said cancer is acute malignant melanoma.

9. A method of claim 1 wherein said cancer is soft-tissue or bone sarcoma.

10. A method of treating 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, brain cancer, soft-tissue sarcoma, and bone sarcoma, said method comprising concurrently administering to a mammal in need thereof a first compound: 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea, or optionally a pharmaceutically acceptable salt thereof; and 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, oxaliplatin, imatinib mesylate, bevacizumab, hexamethylmelamine, topotecan, tyrosine kinase inhibitors, tyrphostins, herbimycin A, genistein, erbstatin, hydroxyzine, glatiramer acetate, interferon beta-1a, interferon beta-1b, natalizumab and lavendustin A, or optionally a pharmaceutically acceptable salt thereof in an amount effective to treat the cancer.

11. The method of claim 1, wherein said second compound is a MEK 1/2 inhibitor.

12. The method of claim 10, wherein said compound is a MEK 1/2 inhibitor.