U.S. patent application number 14/927763 was filed with the patent office on 2017-08-10 for triazine compounds as pi3 kinase and mtor inhibitors.
The applicant listed for this patent is WYETH LLC. Invention is credited to Semiramis AYRAL-KALOUSTIAN, Zecheng CHEN, Kevin Joseph CURRAN, Christoph Martin DEHNHARDT, Efren Guillermo DELOS SANTOS, Osvaldo DOS SANTOS, Ariamala GOPALSAMY, Joshua Aaron KAPLAN, Tarek Suhayl MANSOUR, David James RICHARD, Mengxiao SHI, Aranapakam Mudumbai VENKATESAN, Jeroen Cunera VERHEIJEN, Arie ZASK.
Application Number | 20170224696 14/927763 |
Document ID | / |
Family ID | 58638139 |
Filed Date | 2017-08-10 |
United States Patent
Application |
20170224696 |
Kind Code |
A9 |
VENKATESAN; Aranapakam Mudumbai ;
et al. |
August 10, 2017 |
TRIAZINE COMPOUNDS AS PI3 KINASE AND MTOR INHIBITORS
Abstract
Compounds of formula I ##STR00001## wherein: R.sup.1 is
##STR00002## and R.sup.2, R.sup.4, and R.sup.6-9 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.
Inventors: |
VENKATESAN; Aranapakam
Mudumbai; (Rego Park, NY) ; CHEN; Zecheng;
(New City, NY) ; DEHNHARDT; Christoph Martin; (New
York, NY) ; DOS SANTOS; Osvaldo; (Astoria, NY)
; DELOS SANTOS; Efren Guillermo; (Nanuet, NY) ;
ZASK; Arie; (New York, NY) ; VERHEIJEN; Jeroen
Cunera; (Highland Mills, NY) ; KAPLAN; Joshua
Aaron; (Nyack, NY) ; RICHARD; David James;
(Warwick, NY) ; AYRAL-KALOUSTIAN; Semiramis;
(Tarrytown, NY) ; MANSOUR; Tarek Suhayl; (New
City, NY) ; GOPALSAMY; Ariamala; (Mahwah, NJ)
; CURRAN; Kevin Joseph; (Congers, NY) ; SHI;
Mengxiao; (Eastchester, NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
WYETH LLC |
New York |
NY |
US |
|
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20170119778 A1 |
May 4, 2017 |
|
|
Family ID: |
58638139 |
Appl. No.: |
14/927763 |
Filed: |
October 30, 2015 |
Related U.S. Patent Documents
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Application
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Patent Number |
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14477650 |
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9174963 |
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14927763 |
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14259414 |
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13950584 |
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8748421 |
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14259414 |
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13718928 |
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8575159 |
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13950584 |
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13490309 |
Jun 6, 2012 |
8445486 |
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13718928 |
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13218571 |
Aug 26, 2011 |
8217036 |
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13490309 |
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12470521 |
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8039469 |
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13218571 |
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61055661 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 33/24 20130101;
A61K 33/24 20130101; A61K 31/5377 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 31/5377 20130101 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61K 33/24 20060101 A61K033/24 |
Claims
1-47. (canceled)
48. A method of treating cancer 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-dimorph-
olin-4-yl-1,3,5-triazin-2-yl)phenyl]urea or a pharmaceutically
acceptable salt thereof; and a second compound cisplatin, in an
amount effective to treat said cancer.
49. The method of claim 48, wherein said 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.
50. The method of claim 49, wherein said cancer is lung cancer.
51. The method of claim 50, wherein said cancer is non-small cell
lung cancer.
52. The method of claim 49, wherein said cancer is bladder
cancer.
53. The method of claim 49, wherein said cancer is breast
cancer.
54. The method of claim 53, wherein said breast cancer is triple
negative breast cancer.
55. The method of claim 48, wherein the first compound is a lactic
acid salt form (lactate) of
1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorph-
olin-4-yl-1,3,5-triazin-2-yl)phenyl]urea.
56. The method of claim 48, wherein the first compound is a free
base form of
1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-
-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea.
Description
FIELD OF THE INVENTION
[0001] 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
[0002] 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)].
[0003] Phosphatidylinositol-3 kinase ("PI3K") is an enzyme that
phosphorylates the 3-position of the inositol ring of
phosphatidylinositol [D. Whitman et al., Nature, 332, 664 (1988)].
Pluralities of PI3K subtypes exist. Three major subtypes of PI3Ks
have now been identified on the basis of their in vitro substrate
specificity, and these three are designated class I (a & b),
class II, and class III [B. Vanhaesebroeck, Trend in Biol. Sci.,
22, 267(1997)].
[0004] The class Ia PI3K subtype has been most extensively
investigated to date. Within the class Ia subtype there are three
isoforms (.alpha., .beta., & .delta.) that exist as hetero
dimers of a catalytic 110-kDa subunit and regulatory subunits of
50-85 kDa. The regulatory subunits contain SH2 domains that bind to
phosphorylated tyrosine residues within growth factor receptors or
adaptor molecules and thereby localize PI3K to the inner cell
membrane. At the inner cell membrane PI3K converts PIP2 to PIP3
(phosphatidylinositol-3,4,5-trisphosphate) that serves to localize
the downstream effectors PDK1 and Akt to the inner cell membrane
where Akt activation occurs. Activated Akt mediates a diverse array
of effects including inhibition of apoptosis, cell cycle
progression, response to insulin signaling, and cell proliferation.
Class Ia PI3K subtypes also contain Ras binding domains (RBD) that
allow association with activated Ras providing another mechanism
for PI3K membrane localization. Activated, oncogenic forms of
growth factor receptors, Ras, and even PI3K kinase have been shown
to aberrantly elevate signaling in the PI3K/Akt/mTOR pathway
resulting in cell transformation. As a central component of the
PI3K/Akt/mTOR signaling pathway PI3K (particularly the class Ia a
isoform) has become a major therapeutic target in cancer drug
discovery.
[0005] Substrates for class I PI3Ks are PI, PI(4)P and PI(4,5)P2,
with PI(4,5)P2 being the most favored. Class I PI3Ks are further
divided into two groups, class Ia and class Ib, because of their
activation mechanism and associated regulatory subunits. The class
Ib PI3K is p110.gamma. that is activated by interaction with G
protein-coupled receptors. Interaction between p110.gamma. and G
protein-coupled receptors is mediated by regulatory subunits of
110, 87, and 84 kDa.
[0006] 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 C2.alpha., C2.beta. and C2.gamma. isoforms,
which contain C2 domains at the C terminus, implying that their
activity is regulated by calcium ions.
[0007] The substrate for class III PI3Ks is PI only. A mechanism
for activation of the class III PI3Ks has not been clarified.
Because each subtype has its own mechanism for regulating activity,
it is likely that activation mechanism(s) depend on stimuli
specific to each respective class of P3K.
[0008] The compound PI103
(3-(4-(4-morpholinyl)pyrido[3',2':4,5]furo[3,2-d]pyrimidin-2-yl)phenol)
inhibits PI3Ka and PI3Kg as well as the mTOR enzymes with IC.sub.50
values of 2, 3, and 50-80 nM respectively. I.P. dosing in mice of
this compound in human tumor xenograft models of cancer
demonstrated activity against a number of human tumor models,
including the glioblastoma (PTEN null U87MG), prostate (PC3),
breast (MDA-MB-468 and MDA-MB-435) colon carcinoma (HCT 116); and
ovarian carcinoma (SKOV3 and IGROV-1); (Raynaud et al,
Pharmacologic Characterization of a Potent Inhibitor of Class I
Phosphatidylinositide 3-Kinases, Cancer Res. 2007 67:
5840-5850).
[0009] The compound ZSTK474
(2-(2-difluoromethylbenzoimidazol-1-yl)-4, 6-dimorpholino-1,
3,5-triazine) inhibits PI3Ka and PI3Kg but not the mTOR enzymes
with an IC.sub.50 values of 16, 4.6 and >10,000 nM respectively
(Dexin Kong and Takao Yamori, ZSTK474 is an ATP-competitive
inhibitor of class I phosphatidylinositol 3 kinase isoforms, Cancer
Science, 2007, 98:10 1638-1642). Chronic oral administration of
ZSTK474 in mouse human xenograft cancer models, completely
inhibited growth which originated from a non-small-cell lung cancer
(A549), a prostate cancer (PC-3), and a colon cancer (WiDr) at a
dose of 400 mg/kg. (Yaguchi et al, Antitumor Activity of ZSTK474, a
New Phosphatidylinositol 3-Kinase Inhibitor, J. Natl. Cancer Inst.
98: 545-556).
[0010] The compound NVP-BEZ-235
(2-methyl-2-(4-(3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4-
,5-c]quinolin-1-yl)phenyl)propanenitrile) inhibits both PI3Ka and
PI3Kg as well as the mTOR enzymes with IC.sub.50 values 4, 5, and
"nanomolar". Testing in human tumor xenograft models of cancer
demonstrated activity against human tumor models of prostrate
(PC-3) and glioblastoma (U-87) cancer. It entered clinical trials
in December of 2006 (Verheijen, J. C. and Zask, A.,
Phosphatidylinositol 3-kinase (PI3K) inhibitors as anticancer
drugs, Drugs Fut. 2007, 32(6): 537-547).
[0011] 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).
[0012] Although it seems clear that inhibition of the a isoform is
essential for the antitumor activity of PI3K inhibitors, it is not
clear whether a more selective inhibitor of a particular PI3K
isoform may lead to fewer unwanted biological effects. It has
recently been reported that non-PI3K.alpha. class I isoforms
(PI3K.beta., .delta. and .gamma.) have the ability to induce
oncogenic transformation of cells, suggesting that
nonisoform-specific inhibitors may offer enhanced therapeutic
potential over specific inhibitors.
[0013] 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., PI3K.alpha. 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.
[0014] 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.
[0015] 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.
[0016] There are three mTOR inhibitors, which have progressed into
clinical trials. These compounds are Wyeth's Torisel, also known as
42-(3-hydroxy-2-(hydroxymethyl)-rapamycin 2-methylpropanoate,
CCI-779 or Temsirolimus; Novartis' Everolimus, also known as
42-O-(2-hydroxyethyl)-rapamycin, or RAD 001; and Ariad's AP23573
also known as 42-(dimethylphopsinoyl)-rapamycin. The FDA has
approved Torisel for the treatment of advanced renal cell
carcinoma. In addition, Torisel is active in a NOS/SCID xenograft
mouse model of acute lymphoblastic leukemia [Teachey et al, Blood,
107(3), 1149-1155, 2006]. On Mar. 30, 2009, the U. S. Food and Drug
Administration (FDA) approved Everolimus (AFINITOR.TM.) 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.
[0017] 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
[0018] This invention provides compounds of formula I
##STR00003##
[0019] wherein:
[0020] R.sup.1 is
##STR00004##
[0021] and R.sup.2, R.sup.4, and R.sup.6-9 are defined below, and
pharmaceutically acceptable salts and esters thereof. These
compounds are useful as inhibitors of mTOR and PI3 kinases.
[0022] This invention further provides compositions containing one
or more of the aforementioned compounds, which compositions may
contain a pharmaceutically acceptable carrier.
[0023] 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
[0024] In one aspect, the present invention provides compounds of
formula I
##STR00005##
[0025] wherein:
[0026] R.sup.1 is
##STR00006##
[0027] wherein:
[0028] R.sup.6, R.sup.7, R.sup.8, R.sup.9 are each independently
selected from the group consisting of a hydrogen atom, and a
C.sub.1-C.sub.6alkyl optionally substituted with
C.sub.2-C.sub.6alkenyl, C.sub.4-C.sub.6alkadienyl,
C.sub.2-C.sub.6alkynyl or C.sub.4-C.sub.6alkadiynyl;
[0029] or one of R.sup.6 and R.sup.7 or R.sup.8 and R.sup.9,
together with the carbon atoms to which they are attached form an
optionally substituted 5-8 membered saturated or unsaturated ring
containing 0, 1 or 2 atoms independently selected from O, NH and
S;
[0030] the dashed line - - - - - represents an optional second
bond;
[0031] R.sup.2 is optionally substituted
C.sub.6-C.sub.14aryl-NH--COR.sup.3, optionally substituted
C.sub.1-C.sub.9heteroaryl-NH--COR.sup.3,
--CH.dbd.CH--C.sub.6-C.sub.10aryl-NH--COR.sup.3 or
--CH.dbd.CH--C.sub.1-C.sub.9heteroaryl-NH--COR.sup.3;
[0032] R.sup.3 is OR.sup.5, NR.sup.5R.sup.5 or NHR.sup.5;
[0033] R.sup.5 is independently selected from the group consisting
of C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6alkenyl,
C.sub.3-C.sub.6alkynyl, optionally substituted
C.sub.6-C.sub.10aryl, C.sub.1-C.sub.6haloalkyl, optionally
substituted C.sub.1-C.sub.9heteroaryl,
C.sub.1-C.sub.6hydroxylalkyl-, C.sub.3-C.sub.10saturated or
unsaturated mono or bicyclic C.sub.3-C.sub.10cycloalkyl optionally
substituted with OH, NR.sup.11R.sup.11 or 3-7 membered
C.sub.1-C.sub.6heterocyclyl, and 3-10 membered saturated or
unsaturated mono or bicyclic C.sub.1-C.sub.9heterocyclyl, with the
proviso that three-membered cycloalkyl and heterocyclyl rings are
saturated;
[0034] or two R.sup.5 groups taken together with the nitrogen atom
to which they are attached form a 3 to 8 membered ring system
optionally substituted with C.sub.1-C.sub.6alkyl, 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).sub.2 and NR.sup.10;
[0035] R.sup.10 is selected from the group consisting of H,
C.sub.1-C.sub.6alkyl, --SO.sub.2(C.sub.1-C.sub.6alkyl),
--COO(C.sub.1-C.sub.6alkyl), --CONH(C.sub.1-C.sub.6alkyl),
--CON(C.sub.1-C.sub.6alkyl).sub.2, --CO(C.sub.1-C.sub.6alkyl), and
--SO.sub.2NHR.sup.11;
[0036] R.sup.11 is selected from the group consisting of H,
C.sub.1-C.sub.6alkyl optionally substituted with OH,
NR.sup.11R.sup.11 or a 3-7 membered C.sub.1-C.sub.6heterocyclyl,
--CO(C.sub.1-C.sub.6alkyl), optionally substituted
C.sub.6-C.sub.10aryl, and optionally substituted
C.sub.1-C.sub.9heteroaryl;
[0037] R.sup.4 is selected from the group consisting of: a)
C.sub.1-C.sub.6alkyl optionally substituted with: i) 3-10 membered
C.sub.1-C.sub.9heterocyclyl optionally substituted with
C.sub.1-C.sub.6alkyl-, ii) H.sub.2N--, iii)
(C.sub.1-C.sub.6alkyl)NH--, iv) (C.sub.1-C.sub.6alkyl).sub.2N--, v)
NH(CH.sub.2).sub.aN(C.sub.1-C.sub.6alkyl).sub.2 wherein a is 2, 3
or 4, and vi) CHO, b) C.sub.3-C.sub.6alkenyl, c)
C.sub.3-C.sub.6alkynyl, d) --O--C.sub.1-C.sub.8alkyl optionally
substituted with --O--C.sub.1-C.sub.8alkyl, e)
--O--C.sub.3-C.sub.8alkenyl, f) --O--C.sub.3-C.sub.8alkynyl, g)
saturated or unsaturated mono or bicyclic
C.sub.3-C.sub.8cycloalkyl, and h) saturated or unsaturated mono or
bicyclic --O--C.sub.3-C.sub.12cycloalkyl, all the above optionally
substituted with OH, NR.sup.11R.sup.11 or a 3-7 membered
C.sub.1-C.sub.6heterocyclyl optionally substituted with
C.sub.1-C.sub.6alkyl-, provided that an OH or NR.sup.11R.sup.11 is
not directly bonded to a carbon atom that is double- or
triple-bonded to another carbon atom; i)
--CH.dbd.CH--C.sub.6-C.sub.10aryl; j)
--CH.dbd.CH--C.sub.1-C.sub.9heteroaryl; k) optionally substituted
C.sub.6-C.sub.10aryl; l) optionally substituted 5-10 membered
C.sub.1-C.sub.9heteroaryl attached to the triazine moiety via a
carbon atom; m) 3-10 membered saturated or unsaturated monocyclic
C.sub.1-C.sub.9heterocyclyl attached to the triazine moiety through
a carbon or nitrogen atom and optionally substituted with from 1 to
3 substituents independently selected from: OH, NR.sup.11R.sup.11,
C.sub.1-C.sub.6alkyl, (C.sub.1-C.sub.6alkyl)amido-,
(C.sub.1-C.sub.6alkyl)C(O)--, (C.sub.1-C.sub.6alkoxy)carbonyl-,
adamantyl, C.sub.1-C.sub.6hydroxylalkyl-,
(C.sub.1-C.sub.6alkyl)amido-; or a 3-7 membered
C.sub.1-C.sub.6heterocyclyl, with the proviso that 3 membered
heterocyclyl is saturated and attached to the triazine moiety
through a nitrogen atom, and 5 membered bicyclic heterocyclyl is
saturated; n) optionally substituted --O--C.sub.6-C.sub.10aryl; o)
optionally substituted --O--C.sub.1-C.sub.9heteroaryl; p) --O-(3-12
membered saturated or unsaturated mono or
bicyclic)C.sub.1-C.sub.9heterocyclyl optionally substituted with
(C.sub.1-C.sub.6alkoxy)carbonyl-, H.sub.2NS(O).sub.2--, or
C.sub.1-C.sub.6alkyl further optionally substituted with OH,
NR.sup.11R.sup.11 or a 3-7 membered C.sub.1-C.sub.6heterocyclyl,
with the proviso that three membered heterocyclyl is saturated; q)
--NHC.sub.6-C.sub.10aryl, r) --NHC.sub.1-C.sub.9heteroaryl, s)
--NHNH.sub.2, t) --NHNHC.sub.1-C.sub.6alkyl, u)
--NHN(C.sub.1-C.sub.6alkyl).sub.2, v) --NHOH, w) --COOH, x)
--COO--C.sub.1-C.sub.6alkyl, y) --CONR.sup.12R.sup.13, z)
--NR.sup.12R.sup.13,
##STR00007##
wherein Z is CH.sub.2, O, S(O).sub.n or NR.sup.10 and n is 0, 1 or
2; ee) halogen, ff) C.sub.6-C.sub.14aryl-S(O).sub.2--NH--, gg)
R.sup.11NHC(O)NH--O--, and hh) optionally substituted 5-membered
monocyclic C.sub.1-C.sub.4heteroaryl attached to the triazine
moiety via a nitrogen atom;
[0038] R.sup.12 and R.sup.13 are each independently selected from
H, optionally mono or disubstituted C.sub.1-C.sub.8alkyl,
optionally substituted C.sub.3-C.sub.8alkenyl, and optionally
substituted C.sub.3-C.sub.8alkynyl, the optional substituents being
selected from C.sub.1-C.sub.6alkoxy, OH, NR.sup.11R.sup.11, and 3-7
membered C.sub.1-C.sub.6heterocyclyl, provided that an OH or
NR.sup.11R.sup.11 is not directly bonded to a carbon atom that is
double- or triple-bonded to another carbon atom;
[0039] or R.sup.12 and R.sup.13 taken together with the nitrogen
atom to which they are attached form a 3 to 8 membered monocyclic
ring system optionally substituted with C.sub.1-C.sub.6alkyl, 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).sub.n and NR.sup.10;
##STR00008##
[0040] or R.sup.12 and R.sup.13 taken together with the nitrogen
atom to which they are attached form
[0041] wherein a and b are each independently --CH.sub.2--, O, S,
or NR.sup.10, and x is 1-3;
[0042] C.sub.1-C.sub.9heteroaryl refers to a 5-10 membered aromatic
ring system having one or more rings and 1, 2, 3 or 4 ring members
independently selected from O, NR.sup.10, and S(O).sub.n;
[0043] C.sub.1-C.sub.9heterocyclyl refers to a 3-10 membered ring
system having one or more rings and 1, 2, 3 or 4 ring members
independently selected from O, NR.sup.10, and S(O).sub.n; and
[0044] optionally substituted aryl and heteroaryl groups are
unsubstituted or are substituted with 1 or 2 moieties selected from
the group consisting of: a) C.sub.1-C.sub.6alkyl optionally
substituted with OH, NH.sub.2, NH(C.sub.1-C.sub.6alkyl),
N(C.sub.1-C.sub.6alkyl).sub.2,
--NH(CH.sub.2).sub.wN(C.sub.1-C.sub.6alkyl).sub.2 wherein w is 2, 3
or 4, or 3-10 membered C.sub.1-C.sub.9heterocyclyl optionally
substituted with from 1 to 3 independently selected
C.sub.1-C.sub.6alkyl-substituents; b) halogen; c) hydroxy; d)
NH.sub.2; e) NO.sub.2; f) SO.sub.2NH.sub.2; g) COOH; h)
COO(C.sub.1-C.sub.6alkyl); i) NHCOO(C.sub.1-C.sub.6alkyl); j)
NH(C.sub.1-C.sub.6alkyl); k) N(C.sub.1-C.sub.6alkyl).sub.2; l)
C(O)NR.sup.aR.sup.b, wherein R.sup.a is H or C.sub.1-C.sub.6alkyl,
and R.sup.b is H, C.sub.1-C.sub.6alkyl,
(C.sub.6-C.sub.14aryl)alkyl-, or (C.sub.1-C.sub.9heteroaryl)alkyl-;
m) --Y-Q, wherein Y is: i) O, ii) NH, iii) N(C.sub.1-C.sub.6alkyl),
iv) NHSO.sub.2, v) SO.sub.2NH, vi) NHCONH, vii)
NHCON(C.sub.1-C.sub.6alkyl), viii) S(O).sub.q, q is 0, 1 or 2, ix)
--C(O)NH--, x) --NHC(O)-- xi) --C(O)N(CH.sub.3)--, xii) C(O), or
xiii) absent, and Q is selected from: i) C.sub.6-C.sub.10aryl,
optionally substituted with from 1 to 3 substituents independently
selected from: A) C.sub.1-C.sub.6alkoxy- optionally substituted
with 1) H.sub.2N--, 2) (C.sub.1-C.sub.6alkyl)amino-, 3)
di(C.sub.1-C.sub.6alkyl)amino-, 4)
C.sub.1-C.sub.9heterocyclyl-optionally substituted by
C.sub.1-C.sub.6alkyl-, or 5) hydroxyl, B)
(C.sub.1-C.sub.6alkoxy)carbonyl-, C)
(C.sub.1-C.sub.6alkoxy)C(O)NH--, D) C.sub.1-C.sub.6alkyl-
optionally substituted with 1) H.sub.2N--, 2)
(C.sub.1-C.sub.6alkyl)amino-, or 3) di(C.sub.1-C.sub.6alkyl)amino-,
E) (C.sub.1-C.sub.6alkyl)amino-, F) di(C.sub.1-C.sub.6alkyl)amino-,
G) (C.sub.1-C.sub.6alkyl)amido-optionally substituted with 1)
H.sub.2N--, 2) (C.sub.1-C.sub.6alkyl)amino-, or 3)
di(C.sub.1-C.sub.6alkyl)amino-, H)
(C.sub.1-C.sub.6alkyl)carboxyamido-, I)
C.sub.1-C.sub.9heterocyclyl- optionally substituted by
C.sub.1-C.sub.6alkyl- or C.sub.1-C.sub.6hydroxylalkyl-, J)
heterocyclyl(C.sub.1-C.sub.6alkyl)- optionally substituted by
C.sub.1-C.sub.6alkyl-, K) halogen, L) hydroxyl, M)
C.sub.1-C.sub.6hydroxylalkyl-, N) perfluoro(C.sub.1-C.sub.6)alkyl-,
O) H.sub.2N--, P) O.sub.2N--, Q) H.sub.2NSO.sub.2--, R)
HO.sub.2C--, and S) NC--, ii) 5-10 membered
C.sub.1-C.sub.9heteroaryl, optionally substituted with from 1 to 3
substituents independently selected from: A) C.sub.1-C.sub.6alkoxy-
optionally substituted with 1) H.sub.2N--, 2)
(C.sub.1-C.sub.6alkyl)amino-, 3) di(C.sub.1-C.sub.6alkyl)amino-, 4)
C.sub.1-C.sub.9heterocyclyl- optionally substituted by
C.sub.1-C.sub.6alkyl-, or 5) hydroxyl, B)
(C.sub.1-C.sub.6alkoxy)carbonyl-, C)
(C.sub.1-C.sub.6alkoxy)C(O)NH--, D) C.sub.1-C.sub.6alkyl-optionally
substituted with 1) H.sub.2N--, 2) (C.sub.1-C.sub.6alkyl)amino-, or
3) di(C.sub.1-C.sub.6alkyl)amino-, E) (C.sub.1-C.sub.6alkyl)amino-,
F) di(C.sub.1-C.sub.6alkyl)amino-, G) (C.sub.1-C.sub.6alkyl)amido-
optionally substituted with 1) H.sub.2N--, 2)
(C.sub.1-C.sub.6alkyl)amino-, or 3) di(C.sub.1-C.sub.6alkyl)amino-,
H) (C.sub.1-C.sub.6alkyl)carboxyamido-, I)
C.sub.1-C.sub.9heterocyclyl- optionally substituted by
C.sub.1-C.sub.6alkyl- or C.sub.1-C.sub.6hydroxylalkyl-, J)
heterocyclyl(C.sub.1-C.sub.6alkyl)- optionally substituted by
C.sub.1-C.sub.6alkyl-, K) halogen, L) hydroxyl, M)
C.sub.1-C.sub.6hydroxylalkyl-, N) perfluoro(C.sub.1-C.sub.6)alkyl-,
O) H.sub.2N--, P) O.sub.2N--, Q) H.sub.2NSO.sub.2--, R)
HO.sub.2C--, and S) NC--, iii) 3-10 membered
C.sub.1-C.sub.9heterocyclyl, optionally substituted with from 1 to
3 substituents independently selected from: A)
C.sub.1-C.sub.6alkyl-, B) heterocyclyl(C.sub.1-C.sub.6alkyl)-, C)
(C.sub.6-C.sub.14aryl)alkyl-, D) C.sub.1-C.sub.8acyl-, E)
(C.sub.1-C.sub.6alkoxy)carbonyl-, F)
(C.sub.1-C.sub.6alkyl)carboxyl-, G) halogen, H)
C.sub.1-C.sub.6haloalkyl-, I) hydroxyl, J)
C.sub.1-C.sub.6hydroxyalkyl-, K) H.sub.2N--, L)
(C.sub.1-C.sub.6alkyl)amino-, M) di(C.sub.1-C.sub.6alkyl)amino-, N)
HO.sub.2C--, O) (C.sub.1-C.sub.6alkoxy)carbonyl-, P)
(C.sub.1-C.sub.6alkyl)carboxyl-, Q) (C.sub.1-C.sub.6alkyl)amido-,
R) H.sub.2NC(O)--, S) (C.sub.1-C.sub.6alkyl)carboxyamido-, T) 5-10
membered C.sub.1-C.sub.9heteroaryl, U) C.sub.6-C.sub.14ary, V)
C.sub.3-C.sub.8cycloalkyl W) 3-10 membered
C.sub.1-C.sub.9heterocyclyl, X) NC--; and Y) --NO.sub.2; iv)
C.sub.3-C.sub.10cycloalkyl, v) C.sub.1-C.sub.6alkyl, vi)
C.sub.2-C.sub.6alkenyl, vii) C.sub.2-C.sub.6alkynyl, viii)
C.sub.1-C.sub.6hydroxyalkyl-, ix)
(CH.sub.2).sub.vO(C.sub.1-C.sub.6alkyl), x)
(CH.sub.2).sub.vNH.sub.2, Xi)
(CH.sub.2).sub.vNH(C.sub.1-C.sub.6alkyl), xii)
(CH.sub.2).sub.vN(C.sub.1-C.sub.6alkyl).sub.2, xiii)
O(CH.sub.2).sub.vN(C.sub.1-C.sub.6alkyl).sub.2, xiv)
(CH.sub.2).sub.vC.sub.6-C.sub.10aryl, xv) --CN, xvi)
(CH.sub.2).sub.v 5-10 membered C.sub.1-C.sub.9heteroaryl, xvii)
(CH.sub.2).sub.v 3-10 membered C.sub.1-C.sub.9heterocyclyl,
optionally substituted by C.sub.1-C.sub.6alkyl-, wherein v is 1, 2,
3 or 4, and xviii) C.sub.1-C.sub.6perfluoroalkyl-; and n)
C(O)R.sup.c wherein R.sup.c is: i) H, ii) C.sub.1-C.sub.6alkyl, or
iii) C.sub.3-C.sub.6cycloalkyl,
[0045] and pharmaceutically acceptable salts and esters
thereof.
[0046] In some embodiments of the invention, R.sup.1 and/or R.sup.4
is
##STR00009##
[0047] In some embodiments, R.sup.1 and/or R.sup.4 is
##STR00010##
[0048] In some embodiments, one of R.sup.1 or R.sup.4 is
##STR00011##
[0049] and the other is
##STR00012##
[0050] In some embodiments, R.sup.2 is optionally substituted
C.sub.6-C.sub.14aryl-NH--COR.sup.3; in others R.sup.2 is optionally
substituted phenyl-NH--COR.sup.3.
[0051] In some embodiments, R.sup.3 is NHR.sup.5 or OR.sup.5. In
some embodiments, R.sup.5 is optionally substituted
C.sub.6-C.sub.10aryl, such as optionally substituted phenyl or
C.sub.1-C.sub.9heteroaryl. In some embodiments, the optionally
substituted C.sub.6-C.sub.10aryl or phenyl is substituted with
-Y-Q, C(O)NR.sup.aR.sup.b or C(O)R.
[0052] In some embodiments, R.sup.5 is phenyl substituted with
-Y-Q.
[0053] The following compounds exemplify illustrative compounds of
Formula I: [0054]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-
-4-ylurea; [0055]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-3-ylurea;
[0056]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-phenylurea-
; [0057]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-thiophen--
2-ylurea; [0058]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-methyl
phenyl)urea; [0059]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-fluorophenyl)u-
rea; [0060]
1-(2,4-dimethoxyphenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phe-
nyl]-urea; [0061]
1-(4-chlorophenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]u-
rea; [0062]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-methoxyphenyl)-
urea; [0063]
(4-chlorophenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ure-
a; [0064]
(2,4-difluorophenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2--
yl)phenyl]urea; [0065]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-ethylurea;
[0066] tert-butyl
3-{[4-(4-{[(4-fluorophenyl)carbamoyl]amino}phenyl)-6-morpholin-4-yl-1,3,5-
-triazin-2-yl]amino}azetidine-1-carboxylate; [0067] tert-butyl
3-[(4-morpholin-4-yl-6-{4-[(phenylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-
-yl)amino]azetidine-1-carboxylate; [0068] tert-butyl
3-[(4-morpholin-4-yl-6-{4-[(pyridine-3-ylcarbamoyl)amino]phenyl}-1,3,5-tr-
iazin-2-yl)amino]azetidine-1-carboxylate; [0069] tert-butyl
3-{[4-(4-{[(4-methylphenyl)carbamoyl]amino}phenyl)-6-morpholin-4-yl-1,3,5-
-triazin-2-yl]amino}azetidine-1-carboxylate; [0070]
1-{4-[4-(azetidin-3-ylamino)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}--
3-phenylurea; [0071]
1-{4-[4-(azetidin-3-ylamino)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}--
3-pyridin-3-ylurea; [0072]
1-{4-[4-(azetidin-3-ylamino)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}--
3-(4-fluorophenyl)urea; [0073]
1-{4-[4-(azetidin-3-ylamino)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}--
3-(4-methylphenyl)urea; [0074] tert-butyl
3-[(4-morpholin-4-yl-6-{4-[(pyridine-4-ylcarbamoyl)amino]phenyl}-1,3,5-tr-
iazin-2-yl)amino]azetidine-1-carboxylate; [0075]
1-{4-[4-(azetidin-3-ylamino)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}--
3-pyridin-4-ylurea [0076]
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; [0077]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(2-methyl
pyridin-4-yl)urea; [0078]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(2-hydroxyethy-
l)phenyl]urea; [0079]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxymethyl-
)phenyl]urea; [0080]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-hydroxyphenyl]-
urea; [0081]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(1-hydroxyethy-
l)phenyl]urea; [0082]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(trifluorometh-
yl)phenyl]urea; [0083]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-hydroxyphenyl)-
urea; [0084]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[5-(trifluorometh-
yl)pyridin-2-yl]urea; [0085]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[2,2,2-trifluo-
ro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}urea; [0086]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[3-(1-hydroxyethy-
l)phenyl]urea; [0087] methyl
4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)be-
nzoate; [0088]
1-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl-
]phenyl}-3-pyridin-4-ylurea; [0089]
1-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl-
]phenyl}-3-phenylurea; [0090]
1-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl-
]phenyl}-3-pyridin-3-ylurea; [0091]
1-[4-(hydroxymethyl)phenyl]-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-
-4-yloxy)-1,3,5-triazin-2-yl]phenyl}urea; [0092]
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; [0093]
1-[2-(methylamino)ethyl]-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4--
yloxy)-1,3,5-triazin-2-yl]phenyl}urea; [0094]
1-(3-acetylphenyl)-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-
-1,3,5-triazin-2-yl]phenyl}urea; [0095]
1-[4-(dimethylamino)phenyl]-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-
-4-yloxy)-1,3,5-triazin-2-yl]phenyl}urea; [0096]
4-[3-{4-(4,6-dimorpholino-1,3,5-triazin-2yl)phenyl}ureido]benzoic
acid; [0097]
N-(2-(dimethylamino)ethyl)-4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-
-2-yl)phenyl)ureido)benzamide; [0098]
N-(2-(dimethylamino)ethyl)-4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)p-
henyl)ureido)benzamide HCl salt; [0099]
1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-
e-1-carbonyl)phenyl)urea; [0100]
4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)-N-methylbenza-
mide; [0101]
N-(2-(dimethylamino)ethyl)-4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)p-
henyl)ureido)-N-methylbenzamide; [0102]
1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-morpholinopiper-
idine-1-carbonyl)phenyl)urea; [0103]
4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)-N-(quinuclidi-
n-3-yl)benzamide; [0104]
1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(pyrrolidin-1-y-
l)piperidine-1-carbonyl)phenyl)urea; [0105]
1-(4-(1,4'-bipiperidine-1'-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5--
triazin-2-yl)phenyl)urea; [0106]
1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholi-
no-1,3,5-triazin-2-yl)phenyl)urea; [0107]
1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazine-1-carb-
onyl)phenyl)urea; [0108]
1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(pyridin-2-yl)a-
cetyl)phenyl)urea; [0109]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(1-hydroxyethy-
l)phenyl]urea; [0110]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(2-methylpyridin--
4-yl)urea; [0111]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxymethyl-
)phenyl]urea; [0112]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(trifluorometh-
yl)phenyl]urea; [0113]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[2,2,2-trifluo-
ro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}urea; [0114]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[5-(trifluorometh-
yl)pyridin-2-yl]urea; [0115]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[3-(1-hydroxyethy-
l)phenyl]urea; [0116]
1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl-
}phenyl)-3-pyridin-4-ylurea; [0117]
1-[4-(2-hydroxyethyl)phenyl]-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morp-
holin-4-yl-1,3,5-triazin-2-yl}phenyl)urea; [0118]
1-[4-(2-hydroxymethyl)phenyl]-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-mor-
pholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea; [0119]
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; [0120]
1-[4-(1-hydroxyethyl)phenyl]-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morp-
holin-4-yl-1,3,5-triazin-2-yl}phenyl)urea; [0121]
1-[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin--
4-ylurea; [0122] methyl
4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl-
}-amino)benzoate; [0123]
1-[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-m-
ethylpiperazin-1-yl)carbonyl]phenyl}urea; [0124]
4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl-
}amino)-N-(1-methylpiperidin-4-yl)benzamide; [0125]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(1-methylpiperidi-
n-4-yl)urea; [0126]
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; [0127]
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; [0128]
1-{4-[4-Morpholin-4-yl-6-(tetrahydro-pyran-4-yl)-[1,3,5]triazin-2-yl]-phe-
nyl}-3-pyridin-4-yl-urea; [0129]
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;
[0130]
1-(4-{4-[(azetidin-3-ylmethyl)-amino]-6-morpholin-4-yl-[1,3,5]triazin-2-y-
l}-phenyl)-3-pyridin-4-yl-urea; [0131]
1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazi-
n-2-yl]phenyl}-3-pyridin-4-ylurea; [0132]
1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazi-
n-2-yl]phenyl}-3-pyridin-3-ylurea; [0133]
1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazi-
n-2-yl]phenyl}-3-phenylurea; [0134]
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; [0135]
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; [0136]
1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazi-
n-2-yl]phenyl}-3-(2-methylpyridin-4-yl)urea; [0137]
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; [0138]
1-[4-(4-morpholin-4-yl-6-quinolin-3-yl-1,3,5-triazin-2-yl)phenyl]-3-pyrid-
in-4-ylurea; [0139]
1-[4-(4-azetidin-1-yl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyrid-
in-4-ylurea; [0140] methyl
4-({[4-(4-azetidin-1-yl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbam-
oyl}amino)benzoate; [0141]
1-[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-m-
ethylpiperazin-1-yl)carbonyl]phenyl}urea; [0142]
4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl-
}amino)-N-(1-methylpiperidin-4-yl)benzamide; [0143]
4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-
-(2-piperidin-1-ylethyl)benzamide; [0144]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(morpholin-4-y-
lcarbonyl)phenyl]urea; [0145]
1-[4-(4-methyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-yl-
urea; [0146]
4-({[4-(4-methyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}ami-
no)benzoate; [0147]
1-{4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]p-
henyl}-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea; [0148]
4-({[4-(4-methyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}ami-
no)-N-(1-methylpiperidin-4-yl)benzamide; [0149]
N-[2-(dimethylamino)ethyl]-N-methyl-4-({[4-(4-methyl-6-morpholin-4-yl-1,3-
,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide; [0150]
1-[4-(4-methyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methy-
lpiperazin-1-yl)carbonyl]phenyl}urea; [0151]
1-(4-{[3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorp-
holin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; [0152]
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; [0153]
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; [0154]
4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amin-
o)benzoic acid;
N-[2-(dimethylamino)ethyl]-4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-tr-
iazin-2-yl)phenyl]carbamoyl}amino)-N-methylbenzamide; [0155]
1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylu-
rea; [0156]
N-[2-(dimethylamino)ethyl]-4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-tr-
iazin-2-yl)phenyl]carbamoyl}amino)benzamide; [0157]
4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amin-
o)benzoate; [0158]
4-({[4-(4-azetidin-1-yl-6-morpholin-4-yl-1,3,5-triazin-2yl)phenyl]carbamo-
yl}amino)benzoic acid; mp 204.degree. C.; [0159]
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.degree. C.;
[0160]
4-({[4-(4-azetidin-1-yl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbam-
oyl}amino)-N-[2-(dimethylamino)ethyl]-N-methylbenzamide; [0161]
4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amin-
o)-N-[2-(dimethylamino)ethyl]-N-methylbenzamide; [0162]
1-{4-[4-(1-ethoxyvinyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyr-
idin-4-ylurea; [0163]
1-{4-[4-(2-methoxyethoxy)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-p-
yridin-4-ylurea; [0164]
1-[4-(4-acetyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-yl-
urea; [0165] methyl
4-[({4-[4-(2-methoxyethoxy)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}ca-
rbamoyl)amino]benzoate; [0166]
1-{4-[4-(1-hydroxyethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-py-
ridin-4-ylurea; [0167] 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; [0168]
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; [0169]
1-(4-{4-morpholin-4-yl-6-[2-(pyridin-4-ylamino)ethyl]-1,3,5-triazin-2-yl}-
phenyl)-3-pyridin-4-ylurea; [0170]
4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amin-
o)-N-[2-(dimethylamino)ethyl]benzamide; [0171]
1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methyl-
piperazin-1-yl)carbonyl]phenyl}urea; [0172]
1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methyl-
piperazin-1-yl)carbonyl]phenyl}urea; [0173]
N-[2-(dimethylamino)ethyl]-4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-
-2-yl)phenyl]carbamoyl}amino)benzamide; [0174]
1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4-ethyl-6-m-
orpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; [0175]
1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxyme-
thyl)phenyl]urea; [0176]
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;
[0177]
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; [0178]
N-[2-(dimethylamino)ethyl]-4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-
-2-yl)phenyl]carbamoyl}amino)-N-methyl benzamide; [0179] N-[2-(di
methylamino)ethyl]-4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)-
phenyl]carbamoyl}amino)-N-methyl benzamide; [0180] N-[2-(di
methylamino)ethyl]-4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)-
phenyl]carbamoyl}amino)benzamide; [0181]
4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}am-
ino)-N-methyl-N-[2-(methylamino)ethyl]benzamide; [0182]
1-[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-meth-
ylpiperazin-1-yl)carbonyl]phenyl}urea; [0183] 1-{4-[(3,3-dimethyl
piperazin-1-yl)carbonyl]phenyl}-3-[4-(4-methoxy-6-morpholin-4-yl-1,3,5-tr-
iazin-2-yl)phenyl]urea; [0184]
4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}am-
ino)-N-(2-piperidin-1-ylethyl)benzamide; [0185]
4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amin-
o)-N-[4-(4-methylpiperazin-1-yl)phenyl]benzamide; [0186]
1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-({[2-(dime-
thylamino)ethyl]amino}methyl)phenyl]urea; [0187]
4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amin-
o)-N-[4-(4-methylpiperazin-1-yl)phenyl]benzamide; [0188]
1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methyl-
piperazin-1-yl)methyl]phenyl}urea;
[0189]
1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-for-
mylphenyl)urea; [0190]
4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-
-(pyridin-2-ylmethyl)benzamide; [0191]
1-(4-{4-[2-(1,3-dioxan-2-yl)ethyl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}ph-
enyl)-3-pyridin-4-ylurea; [0192]
1-(4-{4-[2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-morpholin-4-yl-1,3,5-tr-
iazin-2-yl}phenyl)-3-pyridin-4-ylurea; [0193]
4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amin-
o)-N-{4-[2-(dimethylamino)ethoxy]phenyl}benzamide; [0194]
1-{4-[(4-benzylpiperidin-1-yl)carbonyl]phenyl}-3-[4-(4-butyl-6-morpholin--
4-yl-1,3,5-triazin-2-yl)phenyl]urea; [0195]
4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amin-
o)-N-(1-methylpiperidin-4-yl)benzamide; [0196]
4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amin-
o)-N-(1-methylpiperidin-4-yl)benzamide; [0197]
1-(4-{4-[3-(dimethylamino)propyl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phe-
nyl)-3-pyridin-4-ylurea; [0198]
1-[4-(4-{3-[(1-methylethyl)amino]propyl}-6-morpholin-4-yl-1,3,5-triazin-2-
-yl)phenyl]-3-pyridin-4-ylurea; [0199]
1-{4-[4-morpholin-4-yl-6-(3-pyrrolidin-1-ylpropyl)-1,3,5-triazin-2-yl]phe-
nyl}-3-pyridin-4-ylurea; [0200]
1-(4-{4-[3-(4-methylpiperazin-1-yl)propyl]-6-morpholin-4-yl-1,3,5-triazin-
-2-yl}phenyl)-3-pyridin-4-ylurea; [0201]
1-{4-[4-(3-{[2-(dimethylamino)ethyl]amino}propyl)-6-morpholin-4-yl-1,3,5--
triazin-2-yl]phenyl}-3-pyridin-4-ylurea; [0202]
1-{4-[4-(3-hydroxypropyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-p-
yridin-4-ylurea; [0203]
1-{4-[4-morpholin-4-yl-6-(3-oxopropyl)-1,3,5-triazin-2-yl]phenyl}-3-pyrid-
in-4-ylurea; [0204]
1-{4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]p-
henyl}-3-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)urea;
[0205]
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;
[0206]
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-[4-(4-morpholin-4-yl-6-propyl-1,3,-
5-triazin-2-yl)phenyl]urea; [0207]
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-[4-(4-ethyl-6-morpholin-4-yl-1,3,-
5-triazin-2-yl)phenyl]urea; [0208]
1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(4-methyl
piperazin-1-yl)phenyl]urea; [0209]
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(2-methylpropyl)-6-morpholin-
-4-yl-1,3,5-triazin-2-yl]phenyl}urea; [0210]
1-{4-[(3,3-dimethylpiperazin-1-yl)carbonyl]phenyl}-3-[4-(4-ethyl-6-morpho-
lin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; [0211]
4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amin-
o)-N-(1-methylazetidin-3-yl)benzamide; [0212] methyl
4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carb-
amoyl)amino]benzoate [0213]
N-[2-(dimethylamino)ethyl]-4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3-
,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; [0214]
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; [0215]
N-(1-methylazetidin-3-yl)-4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,-
5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; [0216]
1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-(1-methyl-
ethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea; [0217]
4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carb-
amoyl)amino]-N-pyridin-4-ylbenzamide; [0218]
4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carb-
amoyl)amino]-N-pyridin-3-ylbenzamide; [0219]
N-cyclobutyl-4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-y-
l]phenyl}carbamoyl)amino]benzamide; [0220]
1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-phenyl-
piperidin-1-yl)carbonyl]phenyl}urea; [0221]
4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amin-
o)-N-(pyridin-4-ylmethyl)benzamide; [0222]
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; [0223]
1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-(2-methyl
propyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea; [0224]
N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-(2-methylpropyl)-6-morpholi-
n-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; [0225]
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; [0226]
N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-(4-methylphenyl)-6-morpholi-
n-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; [0227]
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; [0228]
1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-py-
ridin-4-ylurea; [0229]
1-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-3-[4-(4-ethyl-6-morpholin-4-
-yl-1,3,5-triazin-2-yl)phenyl]urea; [0230]
4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}car-
bamoyl)amino]benzoic acid; [0231]
1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-[4-
-(4-methylpiperazin-1-yl)phenyl]urea; [0232] methyl
4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}car-
bamoyl)amino]benzoate; [0233]
1-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-3-[4-(4-morpholin-4-yl-6-ph-
enyl-1,3,5-triazin-2-yl)phenyl]urea; [0234]
1-[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-yl-
urea; [0235]
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;
[0236]
1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyrid-
in-4-yl)urea; [0237]
1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyrid-
in-3-yl)urea; [0238]
1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4--
methylpiperazin-1-yl)phenyl)urea; [0239]
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; [0240]
1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((d-
imethylamino)methyl)phenyl)urea; [0241]
1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2--
(dimethylamino)ethoxy)phenyl)urea; [0242]
1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2--
(pyrrolidin-1-yl)ethoxy)phenyl)urea; [0243]
(R)-1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triaz-
in-2-yl)phenyl)-3-(pyridin-3-yl)urea; [0244]
(R)-1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triaz-
in-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea; [0245]
(R)-1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triaz-
in-2-yl)phenyl)-3-(4-(piperazin-1-yl)phenyl)urea; [0246]
1-(4-(4-((R)-3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triaz-
in-2-yl)phenyl)-3-(4-((S)-3-methylpiperazin-1-yl)phenyl)urea;
[0247]
1-(4-(4-((R)-3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triaz-
in-2-yl)phenyl)-3-(4-((R)-3-methylpiperazin-1-yl)phenyl)urea;
[0248]
1-(4-((3R,5S)-3,5-dimethylpiperazin-1-yl)phenyl)-3-(4-(4-((R)-3-methylmor-
pholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea;
[0249]
(R)-1-(4-(2-(dimethylamino)ethoxy)phenyl)-3-(4-(4-(3-methylmorphol-
ino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea;
[0250]
(R)-1-(4-(4-ethylpiperazin-1-yl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(t-
etrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; [0251]
(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; [0252]
(R)-1-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)-3-(4-(4-(3-methylmorpho-
lino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea;
[0253]
(R)-1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triaz-
in-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;
[0254]
(R)-1-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(3-methylmorph-
olino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea;
[0255]
(R)-1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triaz-
in-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea;
[0256]
1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4--
ethylpiperazin-1-yl)phenyl)urea; [0257]
1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4--
isopropylpiperazin-1-yl)phenyl)urea; [0258]
1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4--
(dimethylamino)piperidin-1-yl)phenyl)urea; [0259]
1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4--
methylpiperazine-1-carbonyl)phenyl)urea; [0260]
1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4--
isopropylpiperazine-1-carbonyl)phenyl)urea; [0261]
4-(3-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido-
)-N,N-dimethylbenzamide; [0262]
1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(py-
rrolidin-1-ylmethyl)phenyl)urea; [0263]
4-({[4-(4-{4-[(methylcarbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triaz-
in-2-yl)phenyl]carbamoyl}amino)benzamide; [0264]
1-{4-[4-(3,5-dimethylmorpholin-4-yl)-6-{4-[(methylcarbamoyl)amino]phenyl}-
-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea; [0265]
3-({[4-(4-{4-[(methylcarbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triaz-
in-2-yl)phenyl]carbamoyl}amino)benzamide; [0266]
1-methyl-3-[4-(4-morpholin-4-yl-6-{4-[(pyridin-3-ylcarbamoyl)amino]phenyl-
}-1,3,5-triazin-2-yl)phenyl]urea; [0267]
1-methyl-3-[4-(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl-
}-1,3,5-triazin-2-yl)phenyl]urea; [0268]
3-[({4-[4-(3,5-dimethylmorpholin-4-yl)-6-{4-[(methylcarbamoyl)amino]pheny-
l}-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; [0269]
4-[({4-[4-(3,5-dimethylmorpholin-4-yl)-6-{4-[(methylcarbamoyl)amino]pheny-
l}-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; [0270]
1-{4-[4-(3,5-dimethylmorpholin-4-yl)-6-{4-[(methylcarbamoyl)amino]phenyl}-
-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea; [0271]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-methylurea;
[0272]
1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-mo-
rpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl]phenyl}urea;
[0273]
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;
[0274]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridazin--
4-ylurea; [0275]
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; [0276]
1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-d-
imorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; [0277]
1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-d-
imorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; [0278]
1-[4-(4-isopropyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-me-
thylpiperazin-1-yl)carbonyl]phenyl}urea; [0279]
1-{4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-(4--
pyrimidin-5-ylphenyl)urea; [0280]
1-(4-{4-[(2,2-dimethoxyethyl)amino]-6-morpholin-4-yl-1,3,5-triazin-2-yl}p-
henyl)-3-pyridin-3-ylurea; [0281]
1-{4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-(4--
pyridin-4-ylphenyl)urea; [0282]
1-(4-iodophenyl)-3-{4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-
-yl]phenyl}urea; [0283]
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; [0284]
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; [0285]
1-{4-[2-(dimethylamino)pyrimidin-5-yl]phenyl}-3-{4-[4-(1-methylethyl)-6-m-
orpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea; [0286] tert-butyl
3-[(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-tri-
azin-2-yl)oxy]azetidine-1-carboxylate; [0287]
1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorph-
olin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; [0288]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-nitrophenyl)ur-
ea; [0289]
1-(4-aminophenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl-
)phenyl]urea; [0290]
N-[4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino-
)phenyl]-4-methylpiperazine-1-carboxamide; [0291]
4-(dimethylamino)-N-[4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phen-
yl]carbamoyl}amino)phenyl]piperidine-1-carboxamide; [0292]
1-[2-(dimethylamino)ethyl]-3-[4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin--
2-yl)phenyl]carbamoyl}amino)phenyl]-1-methylurea; [0293]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-{[(2-piperidin-
-1-ylethyl)carbamoyl]amino}phenyl)urea; [0294]
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; [0295]
N-[4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino-
)phenyl]-4-ethylpiperazine-1-carboxamide; [0296]
1-{4-[(dimethylcarbamoyl)amino]phenyl}-3-[4-(4,6-dimorpholin-4-yl-1,3,5-t-
riazin-2-yl)phenyl]urea; [0297]
1-{4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]p-
henyl}-3-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)urea;
[0298]
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;
[0299]
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;
[0300]
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;
[0301]
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;
[0302]
N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyra-
n-4-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; [0303]
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; [0304]
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; [0305]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-{[4-(1-methyle-
thyl)piperazin-1-yl]carbonyl}phenyl)urea; [0306] N-[2-(di
methylamino)ethyl]-N-methyl-4-{[(4-{4-morpholin-4-yl-6-[(3S)-tetrahydrofu-
ran-3-yloxy]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide;
[0307]
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;
[0308]
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;
[0309]
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;
[0310]
1-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)-3-{4-[4-mo-
rpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl]phenyl}urea;
[0311]
N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-morpholin-4-yl-6-(te-
trahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamid-
e; [0312]
4-[({4-[4-(2-methylpropyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]p-
henyl}carbamoyl)amino]benzoic acid; [0313]
1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-[4-
-(4-methylpiperazin-1-yl)phenyl]urea; [0314]
4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}car-
bamoyl)amino]benzoic acid; [0315] methyl
4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}car-
bamoyl)amino]benzoate; [0316]
1-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-3-[4-(4-ethyl-6-morpholin-4-
-yl-1,3,5-triazin-2-yl)phenyl]urea; [0317]
1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-py-
ridin-4-ylurea; [0318]
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; [0319]
N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-(4-methylphenyl)-6-morpholi-
n-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; [0320]
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; [0321]
1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-pyridi-
n-2-ylpiperazin-1-yl)carbonyl]phenyl}urea; [0322]
1-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-3-[4-(4-morpholin-4-yl-6-ph-
enyl-1,3,5-triazin-2-yl)phenyl]urea; [0323]
1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methyl-
piperazin-1-yl)carbonyl]phenyl}urea; [0324]
1-[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-yl-
urea; methyl
4-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2-yl)phenyl]carbamoyl}ami-
no)benzoate; [0325]
N-[2-(dimethylamino)ethyl]-N-methyl-4-({[4-(4-morpholin-4-yl-6-phenyl-1,3-
,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide; [0326] methyl
4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)ca-
rbamoyl]amino}benzoate; [0327]
4-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2-yl)phenyl]carbamoyl}ami-
no)benzoic acid; [0328]
N-[2-(dimethylamino)ethyl]-4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,-
3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; [0329]
1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-[4-(4-morpholin-4-yl-6-p-
henyl-1,3,5-triazin-2-yl)phenyl]urea; [0330]
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; [0331]
N-[2-(dimethylamino)ethyl]-4-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazi-
n-2-yl)phenyl]carbamoyl}amino)benzamide; [0332]
4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)ca-
rbamoyl]amino}-N-[2-(dimethylamino)ethyl]benzamide; [0333]
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; [0334]
4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}car-
bamoyl)amino]-N-(2-pyrrolidin-1-ylethyl)benzamide; [0335]
4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)ca-
rbamoyl]amino}benzoic acid; [0336]
N-(2-methoxyethyl)-4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-tria-
zin-2-yl]phenyl}carbamoyl)amino]benzamide; [0337]
N-(2-methoxyethyl)-4-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2-yl)p-
henyl]carbamoyl}amino)benzamide; [0338]
4-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2-yl)phenyl]carbamoyl}ami-
no)-N-(2-pyrrolidin-1-ylethyl)benzamide; [0339]
1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-[4-
-(pyrrolidin-1-ylcarbonyl)phenyl]urea; [0340]
N-[3-(dimethylamino)propyl]-4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1-
,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; [0341]
1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-[4-
-(piperidin-1-ylcarbonyl)phenyl]urea; [0342]
N-[3-(dimethylamino)propyl]-4-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triaz-
in-2-yl)phenyl]carbamoyl}amino)benzamide; [0343]
1-{4-[4-morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-
-4-ylurea; [0344]
4-[({4-[4-morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2-yl]phenyl}carbamoy-
l)amino]benzoic acid; [0345]
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; [0346] methyl
4-[({4-[4-morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2-yl]phenyl}carbamoy-
l)amino]benzoate; [0347]
N-(2-methoxyethyl)-4-[({4-[4-morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2-
-yl]phenyl}carbamoyl)amino]benzamide; [0348]
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; [0349]
N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6-(2-thienyl)-1,3,5-t-
riazin-2-yl]phenyl}carbamoyl)amino]benzamide; [0350]
4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)ca-
rbamoyl]amino}-N-[2-(dimethylamino)ethyl]-N-methylbenzamide; [0351]
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; [0352]
1-{4-[4-morpholin-4-yl-6-(1,4-oxazepan-4-yl)-1,3,5-triazin-2-yl]phenyl}-3-
-pyridin-4-ylurea; [0353] methyl
4-[({4-[4-morpholin-4-yl-6-(1,4-oxazepan-4-yl)-1,3,5-triazin-2-yl]phenyl}-
carbamoyl)amino]benzoate; [0354]
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; [0355]
4-[({4-[4-morpholin-4-yl-6-(1,4-oxazepan-4-yl)-1,3,5-triazin-2-yl]phenyl}-
carbamoyl)amino]benzoic acid; [0356]
N-[3-(dimethylamino)propyl]-4-[({4-[4-morpholin-4-yl-6-(2-thienyl)-1,3,5--
triazin-2-yl]phenyl}carbamoyl)amino]benzamide; [0357]
1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)-3-[-
4-(pyrrolidin-1-ylcarbonyl)phenyl]urea; [0358]
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; [0359]
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; [0360]
N-(2-methoxyethyl)-4-[({4-[4-morpholin-4-yl-6-(1,4-oxazepan-4-yl)-1,3,5-t-
riazin-2-yl]phenyl}carbamoyl)amino]benzamide; [0361]
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; [0362]
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; [0363]
3-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}car-
bamoyl)amino]benzoic acid; [0364] methyl
3-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}car-
bamoyl)amino]benzoate; [0365]
1-(3-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-(4-methyl
phenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea; [0366]
N-[2-(dimethylamino)ethyl]-N-methyl-3-[({4-[4-(4-methylphenyl)-6-morpholi-
n-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; [0367]
methyl
3-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amin-
o)benzoate; [0368] methyl
3-({[4-(4-morpholin-4-yl-6-thiophen-2-yl-1,3,5-triazin-2-yl)phenyl]carbam-
oyl}amino)benzoate; [0369]
N-[2-(dimethylamino)ethyl]-3-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,-
3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; [0370]
N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-morpholin-4-yl-6-(1,4-oxaze-
pan-4-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
[0371]
3-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amin-
o)benzoic acid; [0372] methyl
3-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2-yl)phenyl]carbamoyl}ami-
no)benzoate; [0373]
1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{3-[(4-pyridi-
n-2-ylpiperazin-1-yl)carbonyl]phenyl}urea; [0374]
N-[2-(dimethylamino)ethyl]-3-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-
-2-yl)phenyl]carbamoyl}amino)-N-methylbenzamide; [0375]
1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{3-[(4-methyl-
piperazin-1-yl)carbonyl]phenyl}urea; [0376]
3-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2-yl)phenyl]carbamoyl}ami-
no)benzoic acid; [0377] methyl
4-({[4-(4-morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin-2-yl)phenyl]carba-
moyl}amino)benzoate; [0378]
1-[4-(4-morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin-2-yl)phenyl]-3-pyri-
din-4-ylurea; [0379]
4-({[4-(4-morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin-2-yl)phenyl]carba-
moyl}amino)benzoic acid; [0380] methyl
4-({[4-(4-morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin-2-yl)phenyl]carb-
amoyl}amino)benzoate; [0381]
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; [0382]
1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-[4-(4-morpholin-4-yl-6-pi-
peridin-1-yl-1,3,5-triazin-2-yl)phenyl]urea; [0383]
1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-[4-(4-morpholin-4-yl-6-p-
iperidin-1-yl-1,3,5-triazin-2-yl)phenyl]urea; [0384]
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; [0385]
4-({[4-(4-morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin-2-yl)phenyl]carb-
amoyl}amino)benzoic acid; [0386]
1-[4-(4-morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin-2-yl)phenyl]-3-pyr-
idin-4-ylurea; [0387]
N-[2-(dimethylamino)ethyl]-4-({[4-(4-morpholin-4-yl-6-piperidin-1-yl-1,3,-
5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide; [0388]
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; [0389]
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; [0390]
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; [0391]
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; [0392]
1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-[4-(4-morpholin-4-yl-6-py-
rrolidin-1-yl-1,3,5-triazin-2-yl)phenyl]urea; [0393]
1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-[4-(4-morpholin-4-yl-6-p-
yrrolidin-1-yl-1,3,5-triazin-2-yl)phenyl]urea; [0394]
N-[2-(dimethylamino)ethyl]-4-({[4-(4-morpholin-4-yl-6-pyrrolidin-1-yl-1,3-
,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide; [0395]
1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)-3-p-
yridin-4-ylurea; [0396]
N-[3-(dimethylamino)propyl]-4-({[4-(4-morpholin-4-yl-6-piperidin-1-yl-1,3-
,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide; [0397]
N-(2-methoxyethyl)-4-({[4-(4-morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazi-
n-2-yl)phenyl]carbamoyl}amino)benzamide; [0398]
1-[4-(4-morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin-2-yl)phenyl]-3-[4--
(pyrrolidin-1-ylcarbonyl)phenyl]urea; [0399]
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; [0400]
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; [0401]
methyl
4-{[(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2--
yl}phenyl)carbamoyl]amino}benzoate; [0402]
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; [0403]
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; [0404]
1-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)-3-(4-{4-[(3S)-3-m-
ethylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea;
[0405]
4-{[(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-tri-
azin-2-yl}phenyl)carbamoyl]amino}benzoic acid; [0406]
1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4-[(3S)-3-methylmorph-
olin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea; [0407]
N-[3-(dimethylamino)propyl]-4-{[(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-mor-
pholin-4-yl-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide;
[0408]
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;
[0409]
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-
; [0410]
1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phe-
nyl)-3-(4-{[4-(dipropylamino)piperidin-1-yl]carbonyl}phenyl)urea;
[0411]
1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4-[(3R)-3-methyl
morpholin-4-yl]-6-[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl-
)urea; [0412] 4-{[(4-{4-[(3R)-3-methyl
morpholin-4-yl]-6-[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl-
)carbamoyl]amino}benzoic acid; [0413]
1-{4-[(4-butylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4-[(3R)-3-methylmorph-
olin-4-yl]-6-[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)urea;
[0414] 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; [0415]
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; [0416]
1-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)-3-(4-{4-[(3R)-3-m-
ethylmorpholin-4-yl]-6-[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}ph-
enyl)urea; [0417]
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; [0418]
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; [0419]
4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)ca-
rbamoyl]amino}-N-[2-(4-methylpiperazin-1-yl)ethyl]benzamide; [0420]
N-[2-(di
methylamino)ethyl]-4-{[(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[(3-
S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benza-
mide; [0421]
4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)ca-
rbamoyl]amino}-N-(2-pyrrolidin-1-ylethyl)benzamide; [0422]
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; [0423]
1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)-3-[-
4-(piperidin-1-ylcarbonyl)phenyl]urea; [0424]
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; [0425]
4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)ca-
rbamoyl]amino}-N-(2-methoxyethyl)benzamide; [0426]
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; [0427] methyl
4-{[(4-{4-[4-(dimethylcarbamoyl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5-tr-
iazin-2-yl}phenyl)carbamoyl]amino}benzoate; [0428]
N,N-dimethyl-4-(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]pheny-
l}-1,3,5-triazin-2-yl)piperazine-1-carboxamide; [0429]
N,N-dimethyl-4-(4-{4-[({4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}carbam-
oyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)piperazine-1-carboxa-
mide; [0430]
N,N-dimethyl-4-{4-morpholin-4-yl-6-[4-({[4-(pyridazin-4-ylcarbamoyl)pheny-
l]carbamoyl}amino)phenyl]-1,3,5-triazin-2-yl}piperazine-1-carboxamide;
[0431]
N,N-dimethyl-4-(4-morpholin-4-yl-6-{4-[({4-[(4-propylpiperidin-1-y-
l)carbonyl]phenyl}carbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)piperazine-1--
carboxamide; [0432]
4-{[(4-{4-[4-(dimethylcarbamoyl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5-tr-
iazin-2-yl}phenyl)carbamoyl]amino}benzoic acid; [0433]
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;
[0434]
4-[4-(4-{[(4-{[2-(dimethylamino)ethyl](methyl)carbamoyl}phenyl)car-
bamoyl]amino}phenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]-N,
N-dimethylpiperazine-1-carboxamide; [0435]
4-(4-{4-[({4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}carbamoyl)amino]phen-
yl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)-N,N-dimethylpiperazine-1-carboxam-
ide; [0436]
1-(4-{4-[4-(ethylsulfonyl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5-triazin--
2-yl}phenyl)-3-pyridin-4-ylurea; [0437] methyl
4-{[(4-{4-[4-(ethylsulfonyl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5-triazi-
n-2-yl}phenyl)carbamoyl]amino}benzoate; [0438]
4-{[(4-{4-[4-(ethylsulfonyl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5-triazi-
n-2-yl}phenyl)carbamoyl]amino}benzoic acid; [0439]
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;
[0440]
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;
[0441]
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; [0442]
methyl
4-{[(4-{4-[4-(acetylamino)piperidin-1-yl]-6-morpholin-4-yl-1,3,5-triazin--
2-yl}phenyl)carbamoyl]amino}benzoate; [0443]
1-(4-{4-[4-(1-methylethyl)-1,4-diazepan-1-yl]-6-morpholin-4-yl-1,3,5-tria-
zin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea;
[0444]
N-[1-(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}--
1,3,5-triazin-2-yl)piperidin-4-yl]acetamide; [0445]
4-{[(4-{4-[4-(acetylamino)piperidin-1-yl]-6-morpholin-4-yl-1,3,5-triazin--
2-yl}phenyl)carbamoyl]amino}benzoic acid; [0446]
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;
[0447]
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; [0448]
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;
[0449]
1-(4-{4-[4-(1-methylethyl)-1,4-diazepan-1-yl]-6-morpholin-4-yl-1,3,5-tria-
zin-2-yl}phenyl)-3-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)ur-
ea; [0450]
1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}p-
henyl)-3-(4-{[(3S)-3-methylmorpholin-4-yl]carbonyl}phenyl)urea;
[0451]
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;
[0452]
1-(4-{4-[(4-methylpiperazin-1-yl)amino]-6-morpholin-4-yl-1,3,5-triazin-2--
yl}phenyl)-3-phenylurea; [0453]
1-(4-{4-[(1-methylpiperidin-4-yl)oxy]-6-morpholin-4-yl-1,3,5-triazin-2-yl-
}phenyl)-3-pyridin-4-ylurea; [0454]
1-{4-[4-morpholin-4-yl-6-(piperidin-4-yloxy)-1,3,5-triazin-2-yl]phenyl}-3-
-pyridin-4-ylurea; [0455] ethyl
4-[(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-tri-
azin-2-yl)oxy]piperidine-1-carboxylate; [0456]
N-ethyl-4-[(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1-
,3,5-triazin-2-yl)oxy]piperidine-1-carboxamide; [0457] tert-butyl
4-[(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-tri-
azin-2-yl)oxy]piperidine-1-carboxylate; [0458]
4-[(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-tri-
azin-2-yl)oxy]piperidine-1-sulfonamide; [0459]
1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazi-
n-2-yl]phenyl}-3-pyridin-4-ylurea; [0460]
1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazi-
n-2-yl]phenyl}-3-pyridin-3-ylurea; [0461]
1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazi-
n-2-yl]phenyl}-3-phenylurea; [0462]
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; [0463]
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; [0464]
1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazi-
n-2-yl]phenyl}-3-(2-methylpyridin-4-yl)urea; [0465]
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; [0466]
1-[4-(4-morpholin-4-yl-6-quinolin-3-yl-1,3,5-triazin-2-yl)phenyl]-3-pyrid-
in-4-ylurea; [0467]
1-{4-[4-(2-methoxyethoxy)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-p-
yridin-4-ylurea; [0468] methyl
4-[({4-[4-(2-methoxyethoxy)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}ca-
rbamoyl)amino]benzoate; [0469]
1-(4-{4-morpholin-4-yl-6-[2-(pyridin-4-ylamino)ethyl]-1,3,5-triazin-2-yl}-
phenyl)-3-pyridin-4-ylurea; [0470]
N-[2-(dimethylamino)ethyl]-4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triaz-
in-2-yl)phenyl]carbamoyl}amino)-N-methylbenzamide; [0471]
N-[2-(dimethylamino)ethyl]-4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triaz-
in-2-yl)phenyl]carbamoyl}amino)benzamide; [0472]
4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}am-
ino)-N-methyl-N-[2-(methylamino)ethyl]benzamide; [0473]
1-[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-meth-
ylpiperazin-1-yl)carbonyl]phenyl}urea; [0474]
1-{4-[(3,3-dimethylpiperazin-1-yl)carbonyl]phenyl}-3-[4-(4-methoxy-6-morp-
holin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; [0475]
4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}am-
ino)-N-(2-piperidin-1-ylethyl)benzamide; [0476]
1-(4-{4-[2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-morpholin-4-yl-1,3,5-tr-
iazin-2-yl}phenyl)-3-pyridin-4-ylurea; [0477]
1-(4-{4-[2-(1,3-dioxan-2-yl)ethyl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}ph-
enyl)-3-pyridin-4-ylurea; [0478]
1-(4-{4-[3-(dimethylamino)propyl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phe-
nyl)-3-pyridin-4-ylurea; [0479]
1-[4-(4-{3-[(1-methylethyl)amino]propyl}-6-morpholin-4-yl-1,3,5-triazin-2-
-yl)phenyl]-3-pyridin-4-ylurea; [0480]
1-{4-[4-morpholin-4-yl-6-(3-pyrrolidin-1-ylpropyl)-1,3,5-triazin-2-yl]phe-
nyl}-3-pyridin-4-ylurea; [0481]
1-(4-{4-[3-(4-methylpiperazin-1-yl)propyl]-6-morpholin-4-yl-1,3,5-triazin-
-2-yl}phenyl)-3-pyridin-4-ylurea; [0482]
1-{4-[4-(3-{[2-(dimethylamino)ethyl]amino}propyl)-6-morpholin-4-yl-1,3,5--
triazin-2-yl]phenyl}-3-pyridin-4-ylurea; [0483]
1-{4-[4-(3-hydroxypropyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-p-
yridin-4-ylurea; [0484]
1-{4-[4-morpholin-4-yl-6-(3-oxopropyl)-1,3,5-triazin-2-yl]phenyl}-3-pyrid-
in-4-ylurea; [0485]
N-(4-morpholin-4-yl-6-{4-[(pyridin-4-ylcarbamoyl)amino]phenyl}-1,3,5-tria-
zin-2-yl)benzenesulfonamide; [0486]
N-{4-[4-({[4-(4-methylpiperazin-1-yl)phenyl]carbamoyl}amino)phenyl]-6-mor-
pholin-4-yl-1,3,5-triazin-2-yl}benzenesulfonamide; [0487]
N-(4-{4-[({4-[2-(dimethylamino)ethoxy]phenyl}carbamoyl)amino]phenyl}-6-mo-
rpholin-4-yl-1,3,5-triazin-2-yl)benzenesulfonamide; [0488]
N-(4-{4-[({4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}carbamoyl)amino]phe-
nyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)benzenesulfonamide; [0489]
N-{4-morpholin-4-yl-6-[4-({[4-(piperazin-1-ylcarbonyl)phenyl]carbamoyl}am-
ino)phenyl]-1,3,5-triazin-2-yl}benzenesulfonamide; [0490]
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;
[0491]
N-[2-(dimethylamino)ethyl]-N-methyl-4-{[(4-{4-morpholin-4-yl-6-[(p-
henylsulfonyl)amino]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide;
[0492]
N-[2-(dimethylamino)ethyl]-4-{[(4-{4-morpholin-4-yl-6-[(phenylsulf-
onyl)amino]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide;
[0493] methyl
4-{[(4-{4-morpholin-4-yl-6-[(phenylsulfonyl)amino]-1,3,5-triazin-2-
-yl}phenyl)carbamoyl]amino}benzoate; [0494]
4-{[(4-{4-morpholin-4-yl-6-[(phenylsulfonyl)amino]-1,3,5-triazin-2-yl}phe-
nyl)carbamoyl]amino}benzoic acid; [0495]
1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-[4-(6-morpholin-4-yl-4-o-
xo-4,5-dihydro-1,3,5-triazin-2-yl)phenyl]urea; [0496]
1-(4-(2,4-dimethylpiperazine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,-
3,5-triazin-2-yl)phenyl)urea; [0497]
1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropyl-2-met-
hylpiperazine-1-carbonyl)phenyl)urea; [0498]
1-(4-(4-cyclobutyl-2-methylpiperazine-1-carbonyl)phenyl)-3-(4-(4,6-dimorp-
holino-1,3,5-triazin-2-yl)phenyl)urea; [0499]
1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropyl-3-met-
hylpiperazine-1-carbonyl)phenyl)urea; [0500]
1-(4-(3,4-dimethylpiperazine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,-
3,5-triazin-2-yl)phenyl)urea; [0501]
1-(4-(4-cyclobutyl-3-methylpiperazine-1-carbonyl)phenyl)-3-(4-(4,6-dimorp-
holino-1,3,5-triazin-2-yl)phenyl)urea; [0502]
1-(4-(4-cyclobutylpiperazine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,-
3,5-triazin-2-yl)phenyl)urea; [0503]
1-(4-(2,4-dimethylpiperazine-1-carbonyl)phenyl)-3-(4-(4-morpholino-6-(tet-
rahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; [0504]
1-(4-(4-isopropyl-2-methylpiperazine-1-carbonyl)phenyl)-3-(4-(4-morpholin-
o-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea;
[0505]
1-(4-(4-cyclobutyl-2-methylpiperazine-1-carbonyl)phenyl)-3-(4-(4-morpholi-
no-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea;
[0506]
1-(4-(4-isopropyl-3-methylpiperazine-1-carbonyl)phenyl)-3-(4-(4-morpholin-
o-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea;
[0507]
1-(4-(3,4-dimethylpiperazine-1-carbonyl)phenyl)-3-(4-(4-morpholino-6-(tet-
rahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; [0508]
1-(4-(4-cyclobutyl-3-methylpiperazine-1-carbonyl)phenyl)-3-(4-(4-morpholi-
no-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea;
[0509]
1-(4-(4-cyclobutylpiperazine-1-carbonyl)phenyl)-3-(4-(4-morpholino-6-(tet-
rahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; [0510]
1-(4-(2-methylpiperazine-1-carbonyl)phenyl)-3-(4-(4-morpholino-6-(tetrahy-
dro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; [0511]
1-(4-(3-methylpiperazine-1-carbonyl)phenyl)-3-(4-(4-morpholino-6-(tetrahy-
dro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; [0512]
1-(4-(4,6-di
morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(3-methylpiperazine-1-carbonyl-
)phenyl)urea; [0513] 1-(4-(4,6-di
morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-methylpiperazine-1-carbonyl-
)phenyl)urea; [0514]
1-(4-(3,3-dimethylpiperazine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,-
3,5-triazin-2-yl)phenyl)urea; [0515] 1-(4-(3,3-di
methylpiperazine-1-carbonyl)phenyl)-3-(4-(4-morpholino-6-(tetrahydro-2H-p-
yran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; [0516]
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; [0517]
1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(3,3,4-trimethylpi-
perazine-1-carbonyl)phenyl)urea; [0518]
1-(4-(2,4-dimethylpiperazine-1-carbonyl)phenyl)-3-(4-(4-morpholino-6-(tet-
rahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; [0519]
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; [0520]
1-(4-(4-isopropyl-2-methylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(3-methyl-
morpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea;
[0521]
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; [0522]
1-(4-(4-isopropyl-3-methylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(3-methyl-
morpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea;
[0523]
1-(4-(3,4-dimethylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(3-methylm-
orpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea;
[0524]
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; [0525]
1-(4-(4-cyclobutylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(3-methylmorpholi-
no)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea;
[0526]
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;
[0527]
1-(4-(3,3-dimethylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(3-methylmorpholi-
no)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea;
[0528]
N-(2-(dimethylamino)ethyl)-N-methyl-4-(3-(4-(4-(3-methylmorpholino)-6-(te-
trahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide;
[0529]
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; [0530]
1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4-(3-methylmor-
pholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea;
[0531]
1-(4-(2,4-dimethylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(2-methylm-
orpholino)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; [0532]
1-(4-(2,4-dimethylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(2-methylmorpholi-
no)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; [0533]
1-(4-(4-isopropyl-2-methylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(2-methyl-
morpholino)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; [0534]
1-(4-(4-cyclobutyl-2-methylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(2-methy-
lmorpholino)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; [0535]
N-(2-(dimethylamino)ethyl)-N-methyl-4-(3-(4-(4-(2-methylmorpholino)-6-mor-
pholino-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; [0536]
1-(4-(4-isopropyl-3-methylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(2-methyl-
morpholino)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; [0537]
1-(4-(4-(2-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-
-(3-methylpiperazine-1-carbonyl)phenyl)urea; [0538]
1-(4-(3,4-dimethylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(2-methylmorpholi-
no)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; [0539]
1-(4-(4-cyclobutyl-3-methylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(2-methy-
lmorpholino)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; [0540]
1-(4-(3,3-dimethylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(2-methylmorpholi-
no)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; [0541]
1-(4-(4-(2-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-
-(3,3,4-trimethylpiperazine-1-carbonyl)phenyl)urea; [0542]
1-(4-(4-cyclobutylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(2-methylmorpholi-
no)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; [0543]
N-(2-(dimethylamino)ethyl)-4-(3-(4-(4-(2-methylmorpholino)-6-morpholino-1-
,3,5-triazin-2-yl)phenyl)ureido)benzamide; [0544]
1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4-(2-methylmor-
pholino)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; [0545]
1-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)-3-(4-(4-(2-methylmo-
rpholino)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; [0546]
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; [0547]
1-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)-3-(4-(4-(3-methylmo-
rpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea;
[0548]
1-(4-(4-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-6-((R)-3-methylmorph-
olino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea-
; [0549]
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)p-
henyl)urea; [0550]
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;
[0551]
1-(4-(4-cyclopropylpiperazin-1-yl)phenyl)-3-(4-(4-((2R,5S)-2,5-dimethylpy-
rrolidin-1-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)urea;
[0552]
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-y-
l)phenyl)urea; [0553]
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;
[0554]
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;
[0555]
1-(4-(4-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-6-((R)-3-methylmorph-
olino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phen-
yl)urea; [0556]
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)u-
rea; [0557]
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)ph-
enyl)urea; [0558]
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;
[0559]
1-(4-(4-cyclopropylpiperazine-1-carbonyl)phenyl)-3-(4-(4-((2R,5S)--
2,5-dimethyl
pyrrolidin-1-yl)-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ure-
a; [0560]
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-tr-
iazin-2-yl)phenyl)urea; [0561]
1-(4-(4-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-6-((R)-3-methylmo-
rpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)u-
rea; [0562]
1-(4-(4-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-6-((R)-3-methylmo-
rpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl-
)phenyl)urea; [0563]
1-(4-(4-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-6-((R)-3-methylmo-
rpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(quinuclidin-4-yl)phenyl)urea;
[0564]
1-(4-(4-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-6-((R)-3-m-
ethylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazin-1-
-yl)phenyl)urea; [0565]
1-(4-(4-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-6-((R)-3-methylmo-
rpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazin--
1-yl)phenyl)urea; [0566]
1-(4-(4-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-6-((R)-3-methylmo-
rpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazin-1-yl)phenyl)ur-
ea; [0567]
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; [0568]
1-(4-(4-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-6-((R)-3-methylmo-
rpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)p-
henyl)urea; [0569]
1-(4-(4-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-6-((R)-3-methylmo-
rpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-isopropylpiperazine-1-carbony-
l)phenyl)urea; [0570]
1-(4-(4-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-6-((R)-3-methylmo-
rpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidine-1-c-
arbonyl)phenyl)urea; [0571]
1-(4-(4-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-6-((R)-3-methylmo-
rpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-ethylpiperazine-1-carbonyl)ph-
enyl)urea; [0572]
1-(4-(4-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-6-((R)-3-methylmo-
rpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-cyclopropylpiperazine-1-carbo-
nyl)phenyl)urea; [0573]
1-(4-(4-((2S,5R)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-6-((R)-3-methylmo-
rpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(cyclopropylmethyl)piperazine-
-1-carbonyl)phenyl)urea; [0574]
1-(4-(4-morpholino-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)-
-3-(pyridin-4-yl)urea; [0575]
1-(4-(4-morpholino-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)-
-3-(pyridin-3-yl)urea; [0576]
1-(4-(4-morpholino-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)-
-3-(pyridazin-4-yl)urea; [0577]
1-(4-(4-morpholino-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)-
-3-(pyrimidin-5-yl)urea; [0578]
4-(3-(4-(4-morpholino-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phen-
yl)ureido)benzamide; [0579]
N-(2-(dimethylamino)ethyl)-4-(3-(4-(4-morpholino-6-(tetrahydrofuran-3-ylo-
xy)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; [0580]
N-(2-(dimethylamino)ethyl)-N-methyl-4-(3-(4-(4-morpholino-6-(tetrahydrofu-
ran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; [0581]
N-(2-(methylamino)ethyl)-4-(3-(4-(4-morpholino-6-(tetrahydrofuran-3-yloxy-
)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; [0582]
N-methyl-N-(2-(methylamino)ethyl)-4-(3-(4-(4-morpholino-6-(tetrahydrofura-
n-3-yloxy)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; [0583]
1-(4-((R)-3-(di
methylamino)pyrrolidine-1-carbonyl)phenyl)-3-(4-(4-morpholino-6-(tetrahyd-
rofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)urea; [0584]
1-(4-(4-morpholino-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)-
-3-(4-(piperazine-1-carbonyl)phenyl)urea; [0585]
1-(4-(4-methylpiperazine-1-carbonyl)phenyl)-3-(4-(4-morpholino-6-(tetrahy-
drofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)urea; [0586]
1-(4-(4-ethylpiperazine-1-carbonyl)phenyl)-3-(4-(4-morpholino-6-(tetrahyd-
rofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)urea; [0587]
1-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)-3-(4-(4-morpholino-6-(tetr-
ahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)urea; [0588]
1-(4-(4-((S)-3-methylmorpholino)-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazi-
n-2-yl)phenyl)-3-(pyridin-4-yl)urea; [0589]
1-(4-(4-((S)-3-methylmorpholino)-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazi-
n-2-yl)phenyl)-3-(pyridin-3-yl)urea; [0590]
1-(4-(4-((S)-3-methylmorpholino)-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazi-
n-2-yl)phenyl)-3-(pyridazin-4-yl)urea; [0591]
1-(4-(4-((S)-3-methylmorpholino)-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazi-
n-2-yl)phenyl)-3-(pyrimidin-5-yl)urea; [0592]
4-(3-(4-(4-((S)-3-methylmorpholino)-6-(tetrahydrofuran-3-yloxy)-1,3,5-tri-
azin-2-yl)phenyl)ureido)benzamide; [0593]
1-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)-3-(4-(4-((S)-3-meth-
ylmorpholino)-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)urea;
[0594]
1-(4-(4-((S)-3-methylmorpholino)-6-(tetrahydrofuran-3-yloxy)-1,3,5-
-triazin-2-yl)phenyl)-3-(4-(piperazine-1-carbonyl)phenyl)urea;
[0595]
1-(4-(4-((S)-3-methylmorpholino)-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazi-
n-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;
[0596]
1-(4-(4-ethylpiperazine-1-carbonyl)phenyl)-3-(4-(4-((S)-3-methylmorpholin-
o)-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)urea;
[0597]
1-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)-3-(4-(4-((S)-3-methylmorph-
olino)-6-(tetrahydrofuran-3-yloxy)-1,3,5-triazin-2-yl)phenyl)urea;
[0598]
1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(py-
ridin-3-yl)urea; [0599]
1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(py-
ridazin-4-yl)urea; [0600]
1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(py-
rimidin-5-yl)urea; [0601]
1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(py-
ridin-4-yl)urea; [0602]
1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-phe-
nylurea; [0603]
1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4--
chlorophenyl)urea; [0604]
1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4--
fluorophenyl)urea; [0605]
methyl4-(3-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2yl)pheny-
l)ureido)benzoate; [0606]
4-(3-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)ure-
ido)benzoic acid; [0607]
4-(3-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)ure-
ido)-N-(2-(dimethylamino)ethyl)benzamide; [0608]
4-(3-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)ure-
ido)-N-(2-(dimethylamino)ethyl)-N-methylbenzamide; [0609]
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; [0610]
4-(3-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)ure-
ido)benzamide; [0611]
1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4--
(piperazine-1-carbonyl)phenyl)urea; [0612]
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; [0613]
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; [0614]
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; [0615]
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;
[0616]
1-(4-(4-(4-methyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl)-3-(4-(piperazine-1-carbonyl)phenyl)urea; [0617]
1-(4-(4-(4-methyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea; [0618]
1-(4-(4-(4-methyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea; [0619]
1-(4-(4-(4-methyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl)-3-(4-(4-n-propylpiperazine-1-carbonyl)phenyl)urea; [0620]
1-(4-(4-(4-methyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea; [0621]
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;
[0622]
N-(2-(dimethylamino)ethyl)-4-(3-(4-(4-(4-methyl-1,4-diazepan-1-yl)-6-morp-
holino-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; [0623]
N-(2-(dimethylamino)ethyl)-N-methyl-4-(3-(4-(4-(4-methyl-1,4-diazepan-1-y-
l)-6-morpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; [0624]
1-(4-(4-(4-methyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl)-3-phenylurea; [0625]
1-(4-chlorophenyl)-3-(4-(4-(4-methyl-1,4-diazepan-1-yl)-6-morpholino-1,3,-
5-triazin-2-yl)phenyl)urea; [0626]
1-(4-fluorophenyl)-3-(4-(4-(4-methyl-1,4-diazepan-1-yl)-6-morpholino-1,3,-
5-triazin-2-yl)phenyl)urea; [0627]
1-(4-(4-(4-methyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl)-3-(pyridin-3-yl)urea; [0628]
1-(4-(4-(4-methyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl)-3-(pyridin-4-yl)urea; [0629]
1-(4-(4-(4-methyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl)-3-(pyridazin-4-yl)urea; [0630]
1-(4-(4-(4-methyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl)-3-(pyrimidin-5-yl)urea; [0631]
1-(4-(4-(4-ethyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)pheny-
l)-3-(4-(piperazine-1-carbonyl)phenyl)urea; [0632]
1-(4-(4-(4-ethyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)pheny-
l)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea; [0633]
1-(4-(4-(4-ethyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)pheny-
l)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea; [0634]
1-(4-(4-(4-ethyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)pheny-
l)-3-(4-(4-n-propylpiperazine-1-carbonyl)phenyl)urea; [0635]
1-(4-(4-(4-ethyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)pheny-
l)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea; [0636]
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;
[0637]
N-(2-(dimethylamino)ethyl)-4-(3-(4-(4-(4-ethyl-1,4-diazepan-1-yl)-6-morph-
olino-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; [0638]
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; [0639]
1-(4-(4-(4-ethyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)pheny-
l)-3-phenylurea; [0640]
1-(4-chlorophenyl)-3-(4-(4-(4-ethyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-
-triazin-2-yl)phenyl)urea; [0641]
1-(4-fluorophenyl)-3-(4-(4-(4-ethyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-
-triazin-2-yl)phenyl)urea; [0642]
1-(4-(4-(4-ethyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)pheny-
l)-3-(pyridin-3-yl)urea; [0643]
1-(4-(4-(4-ethyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)pheny-
l)-3-(pyridin-4-yl)urea; [0644]
1-(4-(4-(4-ethyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)pheny-
l)-3-(pyridazin-4-yl)urea; [0645]
1-(4-(4-(4-ethyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)pheny-
l)-3-(pyrimidin-5-yl)urea; [0646]
1-(4-(4-(4-propyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl)-3-(4-(piperazine-1-carbonyl)phenyl)urea; [0647]
1-(4-(4-(4-propyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea; [0648]
1-(4-(4-(4-propyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea; [0649]
1-(4-(4-(4-propyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl)-3-(4-(4-n-propylpiperazine-1-carbonyl)phenyl)urea; [0650]
1-(4-(4-(4-propyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea; [0651]
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;
[0652]
N-(2-(dimethylamino)ethyl)-4-(3-(4-(4-(4-propyl-1,4-diazepan-1-yl)-6-morp-
holino-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; [0653]
N-(2-(dimethylamino)ethyl)-N-methyl-4-(3-(4-(4-(4-propyl-1,4-diazepan-1-y-
l)-6-morpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; [0654]
1-(4-(4-(4-propyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl)-3-phenylurea; [0655]
1-(4-chlorophenyl)-3-(4-(4-(4-propyl-1,4-diazepan-1-yl)-6-morpholino-1,3,-
5-triazin-2-yl)phenyl)urea; [0656]
1-(4-fluorophenyl)-3-(4-(4-(4-propyl-1,4-diazepan-1-yl)-6-morpholino-1,3,-
5-triazin-2-yl)phenyl)urea; [0657]
1-(4-(4-(4-propyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl)-3-(pyridin-3-yl)urea; [0658]
1-(4-(4-(4-propyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl)-3-(pyridin-4-yl)urea; [0659]
1-(4-(4-(4-propyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl)-3-(pyridazin-4-yl)urea; [0660]
1-(4-(4-(4-propyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl)-3-(pyrimidin-5-yl)urea; [0661]
1-(4-(4-(4-isopropyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)p-
henyl)-3-(pyridin-3-yl)urea; [0662]
1-(4-(4-(4-isopropyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)p-
henyl)-3-(pyridin-4-yl)urea; [0663]
1-(4-(4-(4-isopropyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)p-
henyl)-3-(pyridazin-4-yl)urea; [0664]
1-(4-(4-(4-isopropyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)p-
henyl)-3-(pyrimidin-5-yl)urea;
[0665]
1-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2--
yl)phenyl)-3-(pyridin-3-yl)urea; [0666]
1-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl)-3-(pyridin-4-yl)urea; [0667]
1-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl)-3-(pyridazin-4-yl)urea; [0668]
1-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl)-3-(pyrimidin-5-yl)urea; [0669]
1-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl)-3-phenylurea; [0670]
1-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl)-3-(4-chlorophenyl)urea; [0671]
1-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl)-3-(4-fluorophenyl)urea; [0672]
Methyl-4-(3-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-
-2-yl)phenyl)ureido)benzoate; [0673]
4-(3-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)p-
henyl)ureido)benzoic acid; [0674]
4-(3-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)p-
henyl)ureido)-N-(2-(dimethylamino)ethyl)benzamide; [0675]
4-(3-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)p-
henyl)ureido)-N-(2-(dimethylamino)ethyl)-N-methylbenzamide; [0676]
1-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl)-3-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)urea;
[0677]
4-(3-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)p-
henyl)ureido)benzamide; [0678]
1-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea; [0679]
1-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl)-3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)urea; [0680]
1-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl)-3-(4-(4-n-propylpiperazine-1-carbonyl)phenyl)urea; [0681]
1-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl)-3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)urea; [0682]
1-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl)-3-(4-(piperazine-1-carbonyl)phenyl)urea; [0683]
1-(4-(4-(4-acetyl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl)-3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)urea;
[0684] 1-(4-(4-(di
methylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4-(4-isobutyryl-1,4-diaze-
pan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; [0685]
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; [0686]
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; [0687]
1-(4-(4-ethyl
piperazine-1-carbonyl)phenyl)-3-(4-(4-(4-isobutyryl-1,4-diazepan-1-yl)-6--
morpholino-1,3,5-triazin-2-yl)phenyl)urea; [0688]
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; [0689]
1-(4-(3-(di
methylamino)pyrrolidine-1-carbonyl)phenyl)-3-(4-(4-(4-isobutyryl-1,4-diaz-
epan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; [0690]
1-(4-(4-(4-isobutyryl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-
phenyl)-3-phenylurea; [0691]
1-(4-chlorophenyl)-3-(4-(4-(4-isobutyryl-1,4-diazepan-1-yl)-6-morpholino--
1,3,5-triazin-2-yl)phenyl)urea; [0692]
1-(4-fluorophenyl)-3-(4-(4-(4-isobutyryl-1,4-diazepan-1-yl)-6-morpholino--
1,3,5-triazin-2-yl)phenyl)urea; [0693]
1-(4-(4-(4-isobutyryl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-
phenyl)-3-(pyridin-4-yl)urea; [0694]
1-(4-(4-(4-isobutyryl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-
phenyl)-3-(pyridazin-4-yl)urea; [0695]
1-(4-(4-(4-isobutyryl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-
phenyl)-3-(pyridin-3-yl)urea; [0696]
1-(4-(4-(4-isobutyryl-1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-
phenyl)-3-(pyrimidin-5-yl)urea; [0697] tert-butyl
4-(4-(4-(3-(4-(methoxycarbonyl)phenyl)ureido)phenyl)-6-morpholino-1,3,5-t-
riazin-2-yl)-1,4-diazepane-1-carboxylate; [0698]
methyl4-(3-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phen-
yl) ureido)benzoate; [0699]
1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-phe-
nylurea; [0700]
1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4--
chlorophenyl)urea; [0701]
1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(4--
fluorophenyl)urea; [0702]
1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(py-
ridin-3-yl)urea; [0703]
1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(py-
ridin-4-yl)urea; [0704]
1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(py-
ridazin-4-yl)urea; [0705]
1-(4-(4-(1,4-diazepan-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(py-
rimidin-5-yl)urea; [0706]
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; [0707]
4-(4-(4-(3-(4-chlorophenyl)ureido)phenyl)-6-morpholino-1,3,5-triazin-2-yl-
)-N-methyl-1,4-diazepane-1-carboxamide; [0708]
4-(4-(4-(3-(4-fluorophenyl)ureido)phenyl)-6-morpholino-1,3,5-triazin-2-yl-
)-N-methyl-1,4-diazepane-1-carboxamide; [0709]
4-(4-(4-(3-(4-(2-(dimethylamino)ethylcarbamoyl)phenyl)ureido)phenyl)-6-mo-
rpholino-1,3,5-triazin-2-yl)-N-methyl-1,4-diazepane-1-carboxamide;
[0710]
4-(4-(4-(3-(4-((2-(dimethylamino)ethyl)(methyl)carbamoyl)phenyl)ureido)ph-
enyl)-6-morpholino-1,3,5-triazin-2-yl)-N-methyl-1,4-diazepane-1-carboxamid-
e; [0711]
4-(4-(4-(3-(4-carbamoylphenyl)ureido)phenyl)-6-morpholino-1,3,5--
triazin-2-yl)-N-methyl-1,4-diazepane-1-carboxamide; [0712]
4-(4-(4-(3-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)ureido)phen-
yl)-6-morpholino-1,3,5-triazin-2-yl)-N-methyl-1,4-diazepane-1-carboxamide;
[0713]
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;
[0714]
N-methyl-4-(4-(4-(3-(4-(4-methylpiperazine-1-carbonyl)phenyl)ureido)pheny-
l)-6-morpholino-1,3,5-triazin-2-yl)-1,4-diazepane-1-carboxamide;
[0715]
4-(4-(4-(3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)ureido)phenyl)-6-morph-
olino-1,3,5-triazin-2-yl)-N-methyl-1,4-diazepane-1-carboxamide;
[0716]
4-(4-(4-(3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)ureido)phenyl)-6-m-
orpholino-1,3,5-triazin-2-yl)-N-methyl-1,4-diazepane-1-carboxamide;
[0717]
4-(4-(4-(3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)ureido)pheny-
l)-6-morpholino-1,3,5-triazin-2-yl)-N-methyl-1,4-diazepane-1-carboxamide;
[0718]
4-(4-(4-(3-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)ureid-
o)phenyl)-6-morpholino-1,3,5-triazin-2-yl)-N-isopropyl-1,4-diazepane-1-car-
boxamide; [0719]
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;
[0720]
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;
[0721]
N-isopropyl-4-(4-(4-(3-(4-(4-methylpiperazine-1-carbonyl)phenyl)ur-
eido)phenyl)-6-morpholino-1,3,5-triazin-2-yl)-1,4-diazepane-1-carboxamide;
[0722]
N-isopropyl-4-(4-morpholino-6-(4-(3-(4-(piperazine-1-carbonyl)phen-
yl)ureido)phenyl)-1,3,5-triazin-2-yl)-1,4-diazepane-1-carboxamide;
[0723]
N-isopropyl-4-(4-morpholino-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-tria-
zin-2-yl)-1,4-diazepane-1-carboxamide; [0724]
N-isopropyl-4-(4-morpholino-6-(4-(3-pyridazin-4-ylureido)phenyl)-1,3,5-tr-
iazin-2-yl)-1,4-diazepane-1-carboxamide; [0725]
N-isopropyl-4-(4-morpholino-6-(4-(3-pyrimidin-5-ylureido)phenyl)-1,3,5-tr-
iazin-2-yl)-1,4-diazepane-1-carboxamide; [0726]
N-isopropyl-4-(4-morpholino-6-(4-(3-pyridin-3-ylureido)phenyl)-1,3,5-tria-
zin-2-yl)-1,4-diazepane-1-carboxamide; [0727]
1-(4-(4-morpholino-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyri-
din-3-yl)urea; [0728]
1-(4-(4-morpholino-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyri-
din-4-yl)urea; [0729]
1-(4-(4-morpholino-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyri-
dazin-4-yl)urea; [0730]
1-(4-(4-morpholino-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyri-
midin-5-yl)urea; [0731]
1-(4-(4-morpholino-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-pheny-
lurea; [0732]
1-(4-chlorophenyl)-3-(4-(4-morpholino-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-
-yl)phenyl)urea; [0733]
1-(4-fluorophenyl)-3-(4-(4-morpholino-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-
-yl)phenyl)urea; [0734]
1-(4-(4-(2-methyl-1H-imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)pheny-
l)-3-phenylurea; [0735]
1-(4-chlorophenyl)-3-(4-(4-(2-methyl-1H-imidazol-1-yl)-6-morpholino-1,3,5-
-triazin-2-yl)phenyl)urea; [0736]
1-(4-fluorophenyl)-3-(4-(4-(2-methyl-1H-imidazol-1-yl)-6-morpholino-1,3,5-
-triazin-2-yl)phenyl)urea; [0737]
1-(4-(4-(2-methyl-1H-imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)pheny-
l)-3-(pyridin-4-yl)urea; [0738]
1-(4-(4-(2-methyl-1H-imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)pheny-
l)-3-(pyridazin-4-yl)urea; [0739]
1-(4-(4-(2-methyl-1H-imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)pheny-
l)-3-(pyrimidin-5-yl)urea; [0740]
1-(4-acetylphenyl)-3-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2--
yl)phenyl)urea; [0741]
1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pi-
perazin-1-yl)phenyl)urea; [0742]
1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2--
(dimethylamino)acetyl)phenyl)urea; [0743]
1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2--
morpholinoacetyl)phenyl)urea; [0744]
1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2--
hydroxyacetyl)phenyl)urea; [0745]
1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(me-
thoxymethyl)phenyl)urea; [0746]
1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2--
methoxyethyl)phenyl)urea; [0747]
1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(1--
hydroxyethyl)phenyl)urea; [0748]
1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2--
hydroxypropan-2-yl)phenyl)urea; [0749]
1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2--
hydroxypropyl)phenyl)urea; [0750]
1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2--
hydroxy-2-methylpropyl)phenyl)urea; [0751]
1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4--
(dimethylamino)piperidine-1-carbonyl)phenyl)urea; [0752]
1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-cya-
nophenyl)urea; [0753]
4-(3-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido-
)-N-methylbenzamide; [0754]
4-(3-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido-
)-N,N-dimethylbenzamide; [0755]
4-(3-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido-
)benzamide; [0756]
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; [0757] (R)-1-(4-((di
methylamino)methyl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H--
pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; [0758]
(R)-1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triaz-
in-2-yl)phenyl)-3-(pyridin-4-yl)urea; [0759]
(R)-1-(4-acetylphenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyra-
n-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; [0760]
(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; [0761]
(R)-1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triaz-
in-2-yl)phenyl)-3-(4-(2-morpholinoacetyl)phenyl)urea; [0762]
(R)-1-(4-(2-hydroxyacetyl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahy-
dro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; [0763]
(R)-1-(4-(methoxymethyl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydr-
o-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; [0764]
(R)-1-(4-(2-methoxyethyl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahyd-
ro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; [0765]
1-(4-(1-hydroxyethyl)phenyl)-3-(4-(4-((R)-3-methylmorpholino)-6-(tetrahyd-
ro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; [0766]
(R)-1-(4-(2-hydroxypropan-2-yl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(te-
trahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; [0767]
1-(4-(2-hydroxypropyl)phenyl)-3-(4-(4-((R)-3-methylmorpholino)-6-(tetrahy-
dro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; [0768]
(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; [0769]
(R)-1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4-(3-methy-
lmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea;
[0770]
(R)-1-(4-cyanophenyl)-3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2-
H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea; [0771]
(R)--N-methyl-4-(3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl-
)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide; [0772] (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; [0773]
(R)-4-(3-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-tr-
iazin-2-yl)phenyl)ureido)benzamide; [0774]
(R)-1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triaz-
in-2-yl)phenyl)-3-(6-(4-methylpiperazine-1-carbonyl)pyridin-3-yl)urea;
[0775]
1-(4-(4-(3-methyl-1H-pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl-
)phenyl)-3-(pyrimidin-5-yl)urea; [0776]
1-(4-(4-(3-methyl-1H-pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl-
)-3-(pyridin-3-yl)urea; [0777]
1-(4-(4-(3-methyl-1H-pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl-
)-3-(pyridin-4-yl)urea; [0778]
1-(4-(4-(3-methyl-1H-pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl-
)-3-(pyridazin-4-yl)urea; [0779]
1-(4-(4-(3-methyl-1H-pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl-
)-3-phenylurea; [0780]
1-(4-chlorophenyl)-3-(4-(4-(3-methyl-1H-pyrazol-1-yl)-6-morpholino-1,3,5--
triazin-2-yl)phenyl)urea; [0781]
1-(4-fluorophenyl)-3-(4-(4-(3-methyl-1H-pyrazol-1-yl)-6-morpholino-1,3,5--
triazin-2-yl)phenyl)urea; [0782] methyl
4-(3-(4-(4-(3-methyl-1H-pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phe-
nyl)ureido)benzoate; [0783]
4-(3-(4-(4-(3-methyl-1H-pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phe-
nyl)ureido)benzoic acid; [0784]
4-(3-(4-(4-(3-methyl-1H-pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phe-
nyl)ureido)benzamide; [0785]
1-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)-3-(4-(4-(3-methyl-1-
H-pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; [0786]
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; [0787]
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; [0788]
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; [0789]
1-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(3-methyl-1H-pyraz-
ol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)urea; [0790]
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;
[0791]
1-{4-[(4-butylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4-[4-(1-methyl-
ethyl)-1,4-diazepan-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea;
[0792]
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}ph-
enyl)urea; [0793]
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;
[0794]
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; [0795]
1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-d-
imorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; [0796]
1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-d-
imorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; [0797]
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;
[0798]
N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-morpholin-4-yl-6-(tetrahydr-
o-2H-pyran-4-yl)-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide;
[0799]
1-{4-[4-(azetidin-3-yloxy)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phe-
nyl}-3-pyridin-4-ylurea; [0800]
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; [0801]
N-{1-[(4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}ph-
enyl)carbamoyl]amino}phenyl)carbonyl]piperidin-4-yl}acetamide;
[0802]
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;
[0803]
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; [0804]
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; [0805]
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;
[0806]
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;
[0807]
1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-(4-{4-(mo-
rpholin-4-yl)-6-[4-(propan-2-yl)-1,4-diazepan-1-yl]-1,3,5-triazin-2-yl}phe-
nyl)urea; [0808]
1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-(4-{4-(mo-
rpholin-4-yl)-6-[4-(propan-2-yl)-1,4-diazepan-1-yl]-1,3,5-triazin-2-yl}phe-
nyl)urea; [0809]
1-{4-[4,6-di(morpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}-3-{4-[(2-methylpi-
perazin-1-yl)carbonyl]phenyl}urea; [0810]
1-(4-{4-(morpholin-4-yl)-6-[4-(propan-2-yl)-1,4-diazepan-1-yl]-1,3,5-tria-
zin-2-yl}phenyl)-3-[4-(piperazin-1-ylcarbonyl)phenyl]urea; [0811]
1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-(4-{4-(mo-
rpholin-4-yl)-6-[4-(propan-2-yl)-1,4-diazepan-1-yl]-1,3,5-triazin-2-yl}phe-
nyl)urea; [0812]
1-{4-[4,6-di(morpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}-3-{4-[(3,3,4-trim-
ethylpiperazin-1-yl)carbonyl]phenyl}urea; [0813]
1-{4-[4,6-di(morpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}-3-(4-{[(3R)-3-met-
hylpiperazin-1-yl]carbonyl}phenyl)urea; [0814]
1-(4-{[(3R)-3,4-dimethylpiperazin-1-yl]carbonyl}phenyl)-3-{4-[4,6-di(morp-
holin-4-yl)-1,3,5-triazin-2-yl]phenyl}urea; [0815]
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; [0816]
1-{4-[4,6-di(morpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}-3-(4-{[(3R)-3-met-
hyl-4-(propan-2-yl)piperazin-1-yl]carbonyl}phenyl)urea; [0817]
1-{4-[4,6-di(morpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}-3-(4-{[(3S)-3-met-
hylpiperazin-1-yl]carbonyl}phenyl)urea; [0818]
N-[2-(dimethylamino)ethyl]-N-methyl-4-{[(4-{4-[(3S)-3-methyl
morpholin-4-yl]-6-[4-(propan-2-yl)-1,4-diazepan-1-yl]-1,3,5-triazin-2-yl}-
phenyl)carbamoyl]amino}benzamide; [0819]
1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-[4-(propan-2-yl)-1,4-diazepan-1-y-
l]-1,3,5-triazin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-1-yl)carbonyl]pheny-
l}urea; [0820]
1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-(4-{4-[(3-
S)-3-methylmorpholin-4-yl]-6-[4-(propan-2-yl)-1,4-diazepan-1-yl]-1,3,5-tri-
azin-2-yl}phenyl)urea; [0821]
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;
[0822]
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]ami-
no}benzamide; [0823]
1-[4-(morpholin-4-ylcarbonyl)phenyl]-3-(4-{4-(morpholin-4-yl)-6-[4-(propa-
n-2-yl)-1,4-diazepan-1-yl]-1,3,5-triazin-2-yl}phenyl)urea; [0824]
N-(2-methoxyethyl)-4-{[(4-{4-(morpholin-4-yl)-6-[4-(propan-2-yl)-1,4-diaz-
epan-1-yl]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzamide;
[0825]
1-[4-(1,4-diazepan-1-ylcarbonyl)phenyl]-3-(4-{4-(morpholin-4-yl)-6-[4-(pr-
opan-2-yl)-1,4-diazepan-1-yl]-1,3,5-triazin-2-yl}phenyl)urea;
[0826]
1-(4-{4-(morpholin-4-yl)-6-[4-(propan-2-yl)-1,4-diazepan-1-yl]-1,3,5-tria-
zin-2-yl}phenyl)-3-(4-{[4-(propan-2-yl)-1,4-diazepan-1-yl]carbonyl}phenyl)-
urea; [0827]
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; [0828]
1-(4-{[(3S)-3,4-dimethylpiperazin-1-yl]carbonyl}phenyl)-3-{4-[4,6-di(morp-
holin-4-yl)-1,3,5-triazin-2-yl]phenyl}urea; [0829]
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;
[0830]
1-(4-{[(3S)-3,4-dimethylpiperazin-1-yl]carbonyl}phenyl)-3-{4-[4-(morpholi-
n-4-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl]phenyl}urea;
[0831]
1-(4-{[(3S)-3-methylpiperazin-1-yl]carbonyl}phenyl)-3-{4-[4-(morph-
olin-4-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl]phenyl}urea;
[0832]
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 [0833]
1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-{4-[4-mor-
pholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl]phenyl}urea.
[0834] 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.
[0835] In other aspects, the invention provides that the
pharmaceutically acceptable carrier suitable for oral
administration and the composition comprises an oral dosage
form.
[0836] 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.
[0837] In other aspects, the second compound is Avastin.
[0838] In other aspects, the invention provides a method of
treating a PI3K-related disorder, comprising administering to a
mammal in need thereof a compound of Formula I in an amount
effective to treat a PI3K-related disorder.
[0839] 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.
[0840] In other aspects, the PI3K-related disorder is cancer.
[0841] 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.
[0842] 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.
[0843] 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.
[0844] In other aspects, the mTOR-related disorder is cancer.
[0845] 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.
[0846] 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.
[0847] 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.
[0848] In other aspects, the hSMG-1-related disorder is cancer.
[0849] 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.
[0850] 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.
[0851] 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.
[0852] 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.
[0853] 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.
##STR00013##
[0854] 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.
[0855] 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.
[0856] 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.
[0857] 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.
[0858] 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.
[0859] In another aspect, the invention provides a method of
synthesizing compounds of the Formula I, which are:
##STR00014##
said method comprising reacting 2,4,6-trichloro[1,3,5]triazine with
to form the intermediate dichlorotriazine compound.
[0860] The method of synthesizing compounds of the Formula I
further comprising reacting the intermediate dichlorotriazine
compound with
##STR00015##
to form the intermediate compound
##STR00016##
[0861] The method of synthesizing compounds of the Formula I
further comprising reacting the intermediate dichlorotriazine
compound with
##STR00017##
to form the intermediate compound
##STR00018##
wherein each R.sup.6, R.sup.7, R.sup.8 and R.sup.9 is independently
selected and defined according to formula I.
##STR00019##
The method of synthesizing compounds of the Formula I wherein the
reacting moiety
##STR00020##
[0862] 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:
##STR00021##
[0863] 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.degree. C.
to give the mono morpholine derivative 2. This pivotal intermediate
2 can be reacted with different nucleophiles. In this present
invention, intermediates 2 were reacted with different amines and
alcohols to give 3 and 5 respectively. The third chlorine atom in
intermediates 3 and 5 was replaced with 4-aminoaryl and
aminoheteroaryl boronic acid in the presence of
(Ph.sub.3).sub.4P(Pd)/Na.sub.2CO.sub.3/DME/Reflux or microwave
condition to yield 4 and 8 respectively. The amino group was
converted to the urea derivatives by different two procedures
depending upon the availability of the starting material. Some of
the examples reported here were transformed into the urea
derivative by reacting 4 or 8 with an appropriately substituted
isocyanate derivative. Many of the urea derivatives reported here
were prepared by reacting intermediates 4 or 8 with
triphosgene/Et.sub.3N 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.
##STR00022##
[0864] Certain compounds of the invention were prepared by the
methods outlined in Scheme 2.
##STR00023##
[0865] Compounds of the invention were also prepared according to
the method illustrated in Scheme 3.
##STR00024##
[0866] The benzene-1,4-diamine intermediates were prepared from
4-fluoronitrobenzene and
the appropriate amine as shown in Scheme 4.
##STR00025##
[0867] The 4-(alkoxy)aniline intermediates were prepared from
4-fluoronitrobenzene and the appropriate alcohol as shown in Scheme
5.
##STR00026## ##STR00027##
[0868] 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.
##STR00028## ##STR00029##
[0869] 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.
##STR00030##
[0870] The (4-aminophenyl)(piperazin-1-yl)methanone intermediates
were prepared from 4-nitrobenzoyl chloride and the appropriate
amine as shown in Scheme 8.
##STR00031##
[0871] The
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((R)-3-methylmo-
rpholino)-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.
##STR00032##
[0872] 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.
##STR00033##
[0873] 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.
##STR00034##
[0874] Compounds of formula I can be prepared from cyanuric
chloride as shown in Scheme 12.
DEFINITIONS
[0875] The following definitions are used in connection with the
compounds of the present invention unless the context indicates
otherwise. In general, the number of carbon atoms present in a
given group is designated "C.sub.x-C.sub.y", where x and y are the
lower and upper limits, respectively. For example, a group
designated as "C.sub.1-C.sub.6" contains from 1 to 6 carbon atoms.
The carbon number as used in the definitions herein refers to
carbon backbone and carbon branching, but does not include carbon
atoms of the substituents, such as alkoxy substitutions and the
like. Unless indicated otherwise, the nomenclature of substituents
that are not explicitly defined herein are arrived at by naming
from left to right the terminal portion of the functionality
followed by the adjacent functionality toward the point of
attachment. For example, the substituent "arylalkyloxycabonyl"
refers to the group
(C.sub.6-C.sub.14aryl)-(C.sub.1-C.sub.6alkyl)-O--C(O)--. Terms not
defined herein have the meaning commonly attributed to them by
those skilled in the art.
[0876] "Acyl-" refers to a group having a straight, branched, or
cyclic configuration or a combination thereof, attached to the
parent structure through a carbonyl functionality. Such groups may
be saturated or unsaturated, aliphatic or aromatic, and carbocyclic
or heterocyclic. Examples of a C.sub.1-C.sub.8acyl-group include
acetyl-, benzoyl-, nicotinoyl-, propionyl-, isobutyryl-, oxalyl-,
and the like. Lower-acyl refers to acyl groups containing one to
four carbons. An acyl group can be unsubstituted or substituted
with one or more of the following groups: halogen, H.sub.2N--,
(C.sub.1-C.sub.6alkyl)amino-, di(C.sub.1-C.sub.6alkyl)amino-,
(C.sub.1-C.sub.6alkyl)C(O)N(C.sub.1-C.sub.3alkyl)-,
(C.sub.1-C.sub.6alkyl)carboxyamido-, HC(O)NH--, H.sub.2NC(O)--,
(C.sub.1-C.sub.6alkyl)NHC(O)--, di(C.sub.1-C.sub.6alkyl)NC(O)--,
--CN, hydroxyl, C.sub.1-C.sub.6alkoxy-, C.sub.1-C.sub.6alkyl-,
HO.sub.2C--, (C.sub.1-C.sub.6alkoxy)carbonyl-,
(C.sub.1-C.sub.6alkyl)C(O)--, C.sub.6-C.sub.14aryl-,
C.sub.1-C.sub.9heteroaryl-, or C.sub.3-C.sub.8cycloalkyl-.
[0877] "Alkyl" refers to a hydrocarbon chain that may be a straight
chain or branched chain, containing the indicated number of carbon
atoms, for example, a C.sub.1-C.sub.12alkyl group may have from 1
to 12 (inclusive) carbon atoms in it. Examples of
C.sub.1-C.sub.6alkyl groups include, but are not limited to,
methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl,
sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl. Examples
of C.sub.1-C.sub.8alkyl groups include, but are not limited to,
methyl, propyl, pentyl, hexyl, heptyl, 3-methylhex-1-yl,
2,3-dimethylpent-2-yl, 3-ethylpent-1-yl, octyl, 2-methylhept-2-yl,
2,3-dimethylhex-1-yl, and 2,3,3-trimethylpent-1-yl. An alkyl group
can be unsubstituted or substituted with one or more groups,
including: halogen, --NH.sub.2, (C.sub.1-C.sub.6alkyl)N--,
(C.sub.1-C.sub.6alkyl)(C.sub.1-C.sub.6alkyl)N--,
--N(C.sub.1-C.sub.3alkyl)C(O)(C.sub.1-C.sub.6alkyl),
--NHC(O)(C.sub.1-C.sub.6alkyl), --NHC(O)H, --C(O)NH.sub.2,
--C(O)NH(C.sub.1-C.sub.6alkyl),
--C(O)N(C.sub.1-C.sub.6alkyl)(C.sub.1-C.sub.6alkyl), --CN,
hydroxyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6alkyl, --C(O)OH,
--C(O)O(C.sub.1-C.sub.6alkyl), --C(O)(C.sub.1-C.sub.6alkyl),
C.sub.6-C.sub.14aryl, C.sub.1-C.sub.9heteroaryl,
C.sub.3-C.sub.8cycloalkyl, C.sub.1-C.sub.6haloalkyl-,
C.sub.1-C.sub.6aminoalkyl-, --OC(O)(C.sub.1-C.sub.6alkyl),
C.sub.1-C.sub.6carboxyamidoalkyl-, and --NO.sub.2.
[0878] "Alkadienyl" refer to a straight or branched chain
unsaturated hydrocarbon containing at least two double bonds, and
either may exist in the E or Z conformation. Examples of a
C.sub.4-C.sub.6alkadienyl 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.
[0879] "Alkadiynyl" refer to a straight or branched chain
unsaturated hydrocarbon containing at least two triple bonds.
Examples of a C.sub.4-C.sub.6alkadiynyl group include, but are not
limited to, buta-1,3-diynyl, buta-2,3-diynyl, penta-1,3-diynyl, and
penta-2,4-diynyl.
[0880] "Alkenyl" refer to a straight or branched chain unsaturated
hydrocarbon containing at least one double bond, and may exist in
the E or Z conformation. Examples of a C.sub.2-C.sub.58alkenyl
group include, but are not limited to, ethylene, propylene,
1-butylene, 2-butylene, isobutylene, sec-butylene, 1-pentene,
2-pentene, isopentene, 1-hexene, 2-hexene, 3-hexene, isohexene,
1-heptene, 2-heptene, 3-heptene, 1-octene, 2-octene, 3-octene, and
4-octene. Examples of a C.sub.2-C.sub.6alkenyl group include, but
are not limited to, ethylene, propylene, 1-butylene, 2-butylene,
isobutylene, sec-butylene, 1-pentene, 2-pentene, isopentene,
1-hexene, 2-hexene, 3-hexene, and isohexene. Examples of a
C.sub.3-C.sub.8alkenyl group include, but are not limited to,
propylene, 1-butylene, 2-butylene, isobutylene, sec-butylene,
1-pentene, 2-pentene, isopentene, 1-hexene, 2-hexene, 3-hexene,
isohexene, 1-heptene, 2-heptene, 3-heptene, 1-octene, 2-octene,
3-octene, and 4-octene. Examples of a C.sub.3-C.sub.6alkenyl group
include, but are not limited to, prop-2-enyl, but-3-enyl,
but-2-enyl, 2-methyallyl, pent-4-enyl, and hex-5-enyl. An alkenyl
group can be unsubstituted or substituted with one or more groups,
including: halogen, --NH.sub.2, (C.sub.1-C.sub.6alkyl)N--,
(C.sub.1-C.sub.6alkyl)(C.sub.1-C.sub.6alkyl)N--,
--N(C.sub.1-C.sub.3alkyl)C(O)(C.sub.1-C.sub.6alkyl),
--NHC(O)(C.sub.1-C.sub.6alkyl), --NHC(O)H, --C(O)NH2,
--C(O)NH(C.sub.1-C.sub.6alkyl),
--C(O)N(C.sub.1-C.sub.6alkyl)(C.sub.1-C.sub.6alkyl), --CN,
hydroxyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6alkyl, --C(O)OH,
--C(O)O(C.sub.1-C.sub.6alkyl), --C(O)(C.sub.1-C.sub.6alkyl),
C.sub.6-C.sub.14aryl, C.sub.1-C.sub.9heteroaryl, and
C.sub.3-C.sub.8cycloalkyl.
[0881] "Alkynyl" refers to a straight or branched chain unsaturated
hydrocarbon containing at least one triple bond. Examples of a
C.sub.2-C.sub.6alkynyl group include, but are not limited to,
acetylene, propyne, 1-butyne, 2-butyne, isobutyne, sec-butyne,
1-pentyne, 2-pentyne, isopentyne, 1-hexyne, 2-hexyne, 3-hexyne, and
isohexyne. Examples of a C.sub.3-C.sub.6alkynyl group include, but
are not limited to, prop-2-ynyl, but-3-ynyl, but-2-ynyl,
pent-4-ynyl, and hex-5-ynyl. Examples of a C.sub.3-C.sub.8alkynyl
group include, but are not limited to, prop-2-ynyl, but-3-ynyl,
but-2-ynyl, pent-4-ynyl, hex-5-ynyl, hept-3-ynyl,
2-methylhex-3-ynyl, oct-4-ynyl, and 2-methylhept-3-ynyl. An alkynyl
group can be unsubstituted or substituted with one or more groups,
including: halogen, --NH.sub.2, (C.sub.1-C.sub.6alkyl)N--,
(C.sub.1-C.sub.6alkyl)(C.sub.1-C.sub.6alkyl)N--,
--N(C.sub.1-C.sub.3alkyl)C(O)(C.sub.1-C.sub.6alkyl),
--NHC(O)(C.sub.1-C.sub.6alkyl), --NHC(O)H, --C(O)NH2,
--C(O)NH(C.sub.1-C.sub.6alkyl),
--C(O)N(C.sub.1-C.sub.6alkyl)(C.sub.1-C.sub.6alkyl), --CN,
hydroxyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6alkyl, --C(O)OH,
--C(O)O(C.sub.1-C.sub.6alkyl), --C(O)(C.sub.1-C.sub.6alkyl),
C.sub.6-C.sub.14aryl, C.sub.1-C.sub.9heteroaryl, and
C.sub.3-C.sub.8cycloalkyl.
[0882] "Alkoxy-" refers to the group R--O-- where R is an alkyl
group, as defined above. Exemplary C.sub.1-C.sub.6alkoxy- groups
include but are not limited to methoxy, ethoxy, n-propoxy,
1-propoxy, n-butoxy and t-butoxy. An alkoxy group can be
unsubstituted or substituted with one or more of the following
groups: halogen, hydroxyl, C.sub.1-C.sub.6alkoxy-, H.sub.2N--,
(C.sub.1-C.sub.6alkyl)amino-, di(C.sub.1-C.sub.6alkyl)amino-,
(C.sub.1-C.sub.6alkyl)C(O)N(C.sub.1-C.sub.3alkyl)-,
(C.sub.1-C.sub.6alkyl)carboxyamido-, HC(O)NH--, H.sub.2NC(O)--,
(C.sub.1-C.sub.6alkyl)NHC(O)--, di(C.sub.1-C.sub.6alkyl)NC(O)--,
NC--, C.sub.1-C.sub.6alkoxy-, HO.sub.2C--,
(C.sub.1-C.sub.6alkoxy)carbonyl-, (C.sub.1-C.sub.6alkyl)C(O)--,
C.sub.6-C.sub.14aryl-, C.sub.1-C.sub.9heteroaryl-,
C.sub.3-C.sub.8cycloalkyl-, C.sub.1-C.sub.6haloalkyl-,
amino(C.sub.1-C.sub.6alkyl)-, (C.sub.1-C.sub.6alkyl)carboxyl-,
C.sub.1-C.sub.6carboxyamidoalkyl-, or O.sub.2N--.
[0883] "(Alkoxy)carbonyl-" refers to the group alkyl-O--C(O)--.
Exemplary (C.sub.1-C.sub.6alkoxy)carbonyl-groups include but are
not limited to methoxy, ethoxy, n-propoxy, 1-propoxy, n-butoxy and
t-butoxy. An (alkoxy)carbonyl group can be unsubstituted or
substituted with one or more of the following groups: halogen,
hydroxyl, H.sub.2N--, (C.sub.1-C.sub.6alkyl)amino-,
di(C.sub.1-C.sub.6alkyl)amino-,
(C.sub.1-C.sub.6alkyl)C(O)N(C.sub.1-C.sub.3alkyl)-,
(C.sub.1-C.sub.6alkyl)carboxyamido-, HC(O)NH--, H.sub.2NC(O)--,
(C.sub.1-C.sub.6alkyl)NHC(O)--, di(C.sub.1-C.sub.6alkyl)NC(O)--,
NC--, C.sub.1-C.sub.6alkoxy-, HO.sub.2C--,
(C.sub.1-C.sub.6alkoxy)carbonyl-, (C.sub.1-C.sub.6alkyl)C(O)--,
C.sub.6-C.sub.14aryl-, C.sub.1-C.sub.9heteroaryl-,
C.sub.3-C.sub.8cycloalkyl-, C.sub.1-C.sub.6haloalkyl-,
amino(C.sub.1-C.sub.6alkyl)-(C.sub.1-C.sub.6alkyl)carboxyl-,
C.sub.1-C.sub.6carboxyamidoalkyl-, or O.sub.2N--.
[0884] "(Alkyl)amido-" refers to a --C(O)NH-- group in which the
nitrogen atom of said group is attached to a C.sub.1-C.sub.6alkyl
group, as defined above. Representative examples of a
(C.sub.1-C.sub.6alkyl)amido- group include, but are not limited to,
--C(O)NHCH.sub.3, --C(O)NHCH.sub.2CH.sub.3,
--C(O)NHCH.sub.2CH.sub.2CH.sub.3,
--C(O)NHCH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--C(O)NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
C(O)NHCH(CH.sub.3).sub.2, --C(O)NHCH.sub.2CH(CH.sub.3).sub.2,
--C(O)NHCH(CH.sub.3)CH.sub.2CH.sub.3, --C(O)NH--C(CH.sub.3).sub.3
and --C(O)NHCH.sub.2C(CH.sub.3).sub.3.
[0885] "(Alkyl)amino-" refers to an --NH group, the nitrogen atom
of said group being attached to a alkyl group, as defined above.
Representative examples of an (C.sub.1-C.sub.6alkyl)amino- group
include, but are not limited to CH.sub.3NH--, CH.sub.3CH.sub.2NH--,
CH.sub.3CH.sub.2CH.sub.2NH--, CH.sub.3CH.sub.2CH.sub.2CH.sub.2NH--,
(CH.sub.3).sub.2CHNH--, (CH.sub.3).sub.2CHCH.sub.2NH--,
CH.sub.3CH.sub.2CH(CH.sub.3)NH-- and (CH.sub.3).sub.3CNH--. An
(alkyl)amino group can be unsubstituted or substituted with one or
more of the following groups: halogen, H.sub.2N--,
(C.sub.1-C.sub.6alkyl)amino-, di(C.sub.1-C.sub.6alkyl)amino-,
(C.sub.1-C.sub.6alkyl)C(O)N(C.sub.1-C.sub.3alkyl)-,
(C.sub.1-C.sub.6alkyl)carboxyamido-, HC(O)NH--, H.sub.2NC(O)--,
(C.sub.1-C.sub.6alkyl)NHC(O)--, di(C.sub.1-C.sub.6alkyl)NC(O)--,
NC--, hydroxyl, C.sub.1-C.sub.6alkoxy-, C.sub.1-C.sub.6alkyl-,
HO.sub.2C--, (C.sub.1-C.sub.6alkoxy)carbonyl-,
(C.sub.1-C.sub.6alkyl)C(O)--, C.sub.6-C.sub.14aryl-,
C.sub.1-C.sub.9heteroaryl-, C.sub.3-C.sub.8cycloalkyl-,
C.sub.1-C.sub.6haloalkyl-, amino(C.sub.1-C.sub.6alkyl)-,
(C.sub.1-C.sub.6alkyl)carboxyl-, C.sub.1-C.sub.6carboxyamidoalkyl-,
or O.sub.2N--.
[0886] "Aminoalkyl-" refers to an alkyl group, as defined above,
wherein one or more of the alkyl group's hydrogen atoms has been
replaced with --NH.sub.2; one or both H of the NH.sub.2 may be
replaced by a substituent.
[0887] "Alkylcarboxyl-" refers to an alkyl group, defined above
that is attached to the parent structure through the oxygen atom of
a carboxyl (C(O)--O--) functionality. Examples of
(C.sub.1-C.sub.6alkyl)carboxyl-include acetoxy, propionoxy,
propylcarboxyl, and isopentylcarboxyl.
[0888] "(Alkyl)carboxyamido-" refers to a --NHC(O)-- group in which
the carbonyl carbon atom of said group is attached to a
C.sub.1-C.sub.6alkyl group, as defined above. Representative
examples of a (C.sub.1-C.sub.6alkyl)carboxyamido- group include,
but are not limited to, --NHC(O)CH.sub.3, --NHC(O)CH.sub.2CH.sub.3,
--NHC(O)CH.sub.2CH.sub.2CH.sub.3,
--NHC(O)CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--NHC(O)CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
NHC(O)CH(CH.sub.3).sub.2, --NHC(O)CH.sub.2CH(CH.sub.3).sub.2,
--NHC(O)CH(CH.sub.3)CH.sub.2CH.sub.3, --NHC(O)--C(CH.sub.3).sub.3
and --NHC(O)CH.sub.2C(CH.sub.3).sub.3.
[0889] "Alkylene", "alkenylene", and "alkynylene" refers to alkyl,
alkenyl and alkynyl groups, as defined above, having two points of
attachment within a chemical structure. Examples of
C.sub.1-C.sub.6alkylene include ethylene, propylene, and
dimethylpropylene. Likewise, examples of C.sub.2-C.sub.6alkenylene
include ethenylene and propenylene. Examples of
C.sub.2-C.sub.6alkynylene include ethynylene and propynylene.
[0890] Aryl refers to an aromatic hydrocarbon group. Examples of a
C.sub.6-C.sub.14aryl group include, but are not limited to, phenyl,
.alpha.-naphthyl, .beta.-naphthyl, biphenyl, anthryl,
tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, and
acenanaphthyl. Examples of a C.sub.6-C.sub.10aryl group include,
but are not limited to, phenyl, .alpha.-naphthyl, .beta.-naphthyl,
biphenyl, and tetrahydronaphthyl. An aryl group can be
unsubstituted or substituted with one or more groups, including:
C.sub.1-C.sub.6alkyl, halo, haloalkyl-, hydroxyl,
hydroxyl(C.sub.1-C.sub.6alkyl)-, --NH.sub.2, aminoalkyl-,
dialkylamino-, --COOH, --C(O)O--(C.sub.1-C.sub.6alkyl),
--OC(O)(C.sub.1-C.sub.6alkyl), N-alkylamido-, --C(O)NH.sub.2,
(C.sub.1-C.sub.6alkyl)amido-, or --NO.sub.2.
[0891] "(Aryl)alkyl" refers to an alkyl group, as defined above,
wherein one or more of the alkyl group's hydrogen atoms has been
replaced with an aryl group as defined above.
(C.sub.6-C.sub.14Aryl)alkyl-moieties include benzyl, benzhydryl,
1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl,
1-naphthylmethyl, 2-naphthylmethyl and the like. An (aryl)alkyl
group can be unsubstituted or substituted with one or more of the
following groups: halogen, H.sub.2N--, hydroxyl,
(C.sub.1-C.sub.6alkyl)amino-, di(C.sub.1-C.sub.6alkyl)amino-,
(C.sub.1-C.sub.6alkyl)C(O)N(C.sub.1-C.sub.3alkyl)-,
(C.sub.1-C.sub.6alkyl)carboxyamido-, HC(O)NH--, H.sub.2NC(O)--,
(C.sub.1-C.sub.6alkyl)NHC(O)--, di(C.sub.1-C.sub.6alkyl)NC(O)--,
NC--, hydroxyl, C.sub.1-C.sub.6alkoxy-, C.sub.1-C.sub.6alkyl-,
HO.sub.2C--, (C.sub.1-C.sub.6alkoxy)carbonyl-,
(C.sub.1-C.sub.6alkyl)C(O)--, C.sub.6-C.sub.14aryl-,
C.sub.1-C.sub.9heteroaryl-, C.sub.3-C.sub.8cycloalkyl-,
C.sub.1-C.sub.6haloalkyl-, amino(C.sub.1-C.sub.6alkyl)-,
(C.sub.1-C.sub.6alkyl)carboxyl-, C.sub.1-C.sub.6carboxyamidoalkyl-,
or O.sub.2N--.
[0892] "(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.
[0893] "Cycloalkyl" refers to a non-aromatic, saturated,
monocyclic, bicyclic or polycyclic hydrocarbon ring system.
Representative examples of a C.sub.3-C.sub.12cycloalkyl include,
but are not limited to, cyclopropyl, cyclopentyl, cycloheptyl,
cyclooctyl, decahydronaphthalen-1-yl, octahydro-1H-inden-2-yl,
decahydro-1H-benzo[7]annulen-2-yl, and dodecahydros-indacen-4-yl.
Representative examples of a C.sub.3-C.sub.10cycloalkyl include,
but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, cyclooctyl, decahydronaphthalen-1-yl, and
octahydro-1H-inden-2-yl. Representative examples of a
C.sub.3-C.sub.8cycloalkyl include, but are not limited to,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, and octahydropentalen-2-yl. A cycloalkyl can be
unsubstituted or substituted with one or more groups, including:
halogen, --NH.sub.2, (C.sub.1-C.sub.6alkyl)N--,
(C.sub.1-C.sub.6alkyl)(C.sub.1-C.sub.6alkyl)N--,
--N(C.sub.1-C.sub.3alkyl)C(O)(C.sub.1-C.sub.6alkyl),
--NHC(O)(C.sub.1-C.sub.6alkyl), --NHC(O)H, --C(O)NH.sub.2,
--C(O)NH(C.sub.1-C.sub.6alkyl),
--C(O)N(C.sub.1-C.sub.6alkyl)(C.sub.1-C.sub.6alkyl), --CN,
hydroxyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6alkyl, --C(O)OH,
--C(O)O(C.sub.1-C.sub.6alkyl), --C(O)(C.sub.1-C.sub.6alkyl),
C.sub.6-C.sub.14aryl, C.sub.1-C.sub.9heteroaryl,
C.sub.3-C.sub.8cycloalkyl, C.sub.1-C.sub.6haloalkyl-,
C.sub.1-C.sub.6aminoalkyl-, --OC(O)(C.sub.1-C.sub.6alkyl),
C.sub.1-C.sub.6carboxyamidoalkyl-, and --NO.sub.2. Additionally,
each of any two hydrogen atoms on the same carbon atom of the
carbocyclic ring can be replaced by an oxygen atom to form an oxo
(.dbd.O) substituent.
[0894] "Cycloalkenyl" refers to a non-aromatic, unsaturated,
monocyclic, bicyclic or polycyclic hydrocarbon ring system
containing at least one double bond connecting two ring carbon
atoms. Representative examples of a C.sub.5-C.sub.8cycloalkenyl
include, but are not limited to, cyclopentenyl, cyclohexenyl,
4,4a-octalin-3-yl, and cyclooctenyl. A cycloalkenyl can be
unsubstituted or substituted with one or more groups, including:
halogen, --NH.sub.2, (C.sub.1-C.sub.6alkyl)N--,
(C.sub.1-C.sub.6alkyl)(C.sub.1-C.sub.6alkyl)N--,
--N(C.sub.1-C.sub.3alkyl)C(O)(C.sub.1-C.sub.6alkyl),
--NHC(O)(C.sub.1-C.sub.6alkyl), --NHC(O)H, --C(O)NH.sub.2,
--C(O)NH(C.sub.1-C.sub.6alkyl),
--C(O)N(C.sub.1-C.sub.6alkyl)(C.sub.1-C.sub.6alkyl), --CN,
hydroxyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6alkyl, --C(O)OH,
--C(O)O(C.sub.1-C.sub.6alkyl), --C(O)(C.sub.1-C.sub.6alkyl),
C.sub.6-C.sub.14aryl, C.sub.1-C.sub.9heteroaryl, and
C.sub.3-C.sub.6cycloalkyl. 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 (.dbd.O) substituent.
[0895] "Di(alkyl)amino-" refers to a nitrogen atom attached to two
alkyl groups, as defined above. Each alkyl group can be
independently selected. Representative examples of an
di(C.sub.1-C.sub.6alkyl)amino- group include, but are not limited
to, --N(CH.sub.3).sub.2, --N(CH.sub.2CH.sub.3)(CH.sub.3),
--N(CH.sub.2CH.sub.3).sub.2, --N(CH.sub.2CH.sub.2CH.sub.3).sub.2,
--N(CH.sub.2CH.sub.2CH.sub.2CH.sub.3).sub.2,
--N(CH(CH.sub.3).sub.2).sub.2, --N(CH(CH.sub.3).sub.2)(CH.sub.3),
--N(CH.sub.2CH(CH.sub.3).sub.2).sub.2,
--NH(CH(CH.sub.3)CH.sub.2CH.sub.3).sub.2,
--N(C(CH.sub.3).sub.3).sub.2, --N(C(CH.sub.3).sub.3)(CH.sub.3), and
--N(CH.sub.3)(CH.sub.2CH.sub.3). The two alkyl groups on the
nitrogen atom, when taken together with the nitrogen to which they
are attached, can form a 3- to 7-membered nitrogen containing
heterocycle wherein up to two of the carbon atoms of the
heterocycle can be replaced with --N(H)--,
--N(C.sub.1-C.sub.6alkyl)-, --N(C.sub.3-C.sub.8cycloalkyl)-,
--N(C.sub.6-C.sub.14aryl)-, --N(C.sub.1-C.sub.9heteroaryl)-,
--N(amino(C.sub.1-C.sub.6alkyl))-, --N(C.sub.6-C.sub.14arylamino)-,
--O--, --S--, --S(O)--, or --S(O).sub.2--.
[0896] "Halo" or "halogen" refers to --F, --Cl, --Br and --I.
[0897] "C.sub.1-C.sub.6Haloalkyl-" refers to a C.sub.1-C.sub.6alkyl
group, as defined above, wherein one or more of the
C.sub.1-C.sub.6alkyl group's hydrogen atoms has been replaced with
--F, --Cl, --Br, or --I. Each substitution can be independently
selected from --F, --Cl, --Br, or --I. Representative examples of
an C.sub.1-C.sub.6haloalkyl-group include, but are not limited to,
--CH.sub.2F, --CCl.sub.3, --CF.sub.3, CH.sub.2CF.sub.3,
--CH.sub.2Cl, --CH.sub.2CH.sub.2Br, --CH.sub.2CH.sub.2I,
--CH.sub.2CH.sub.2CH.sub.2F, --CH.sub.2CH.sub.2CH.sub.2Cl,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2Br,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2I,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2Br,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2I,
--CH.sub.2CH(Br)CH.sub.3, --CH.sub.2CH(Cl)CH.sub.2CH.sub.3,
--CH(F)CH.sub.2CH.sub.3 and --C(CH.sub.3).sub.2(CH.sub.2Cl).
[0898] "Heteroaryl" refers to a monocyclic, bicyclic, or polycyclic
aromatic ring system containing at least one ring atom selected
from the heteroatoms oxygen, sulfur and nitrogen. Examples of
C.sub.1-C.sub.9heteroaryl groups include furan, thiophene, indole,
azaindole, oxazole, thiazole, isoxazole, isothiazole, imidazole,
N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole,
N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole,
1,2,4-triazole, 1-methyl-1,2,4-triazole, 1H-tetrazole,
1-methyltetrazole, benzoxazole, benzothiazole, benzofuran,
benzisoxazole, benzimidazole, N-methylbenzimidazole,
azabenzimidazole, indazole, quinazoline, quinoline, and
isoquinoline. Bicyclic C.sub.1-C.sub.9heteroaryl groups include
those where a phenyl, pyridine, pyrimidine or pyridazine ring is
fused to a 5 or 6-membered monocyclic heteroaryl ring having one or
two nitrogen atoms in the ring, one nitrogen atom together with
either one oxygen or one sulfur atom in the ring, or one O or S
ring atom. Examples of monocyclic C.sub.1-C.sub.4heteroaryl groups
include 2H-tetrazole, 3H-1,2,4-triazole, furan, thiophene, oxazole,
thiazole, isoxazole, isothiazole, imidazole, and pyrrole. A
heteroaryl group can be unsubstituted or substituted with one or
more groups, including: C.sub.1-C.sub.6alkyl, halo, haloalkyl-,
hydroxyl, hydroxyl(C.sub.1-C.sub.6alkyl)-, --NH.sub.2, aminoalkyl-,
dialkylamino-, --COOH, --C(O)O--(C.sub.1-C.sub.6alkyl),
--OC(O)(C.sub.1-C.sub.6alkyl), N-alkylamido-, --C(O)NH.sub.2,
(C.sub.1-C.sub.6alkyl)amido-, or --NO.sub.2.
[0899] "(Heteroaryl)alkyl-" refers to an alkyl group, as defined
above, wherein one or more of the alkyl group's hydrogen atoms has
been replaced with a heteroaryl-group as defined above. Examples of
(C.sub.1-C.sub.9heteroaryl)alkyl-moieties include 2-pyridylmethyl,
2-thiophenylethyl, 3-pyridylpropyl, 2-quinolinylmethyl,
2-indolylmethyl, and the like. A (heteroaryl)alkyl group can be
unsubstituted or substituted with one or more of the following
groups: halogen, H.sub.2N--, hydroxyl,
(C.sub.1-C.sub.6alkyl)amino-, di(C.sub.1-C.sub.6alkyl)amino-,
(C.sub.1-C.sub.6alkyl)C(O)N(C.sub.1-C.sub.3alkyl)-,
(C.sub.1-C.sub.6alkyl)carboxyamido-, HC(O)NH--, H.sub.2NC(O)--,
(C.sub.1-C.sub.6alkyl)NHC(O)--, di(C.sub.1-C.sub.6alkyl)NC(O)--,
NC--, hydroxyl, C.sub.1-C.sub.6alkoxy-, C.sub.1-C.sub.6alkyl-,
HO.sub.2C--, (C.sub.1-C.sub.6alkoxy)carbonyl-,
(C.sub.1-C.sub.6alkyl)C(O)--, C.sub.6-C.sub.14aryl-,
C.sub.1-C.sub.9heteroaryl-, C.sub.3-C.sub.8cycloalkyl-,
C.sub.1-C.sub.6haloalkyl-, amino(C.sub.1-C.sub.6alkyl)-,
(C.sub.1-C.sub.6alkyl)carboxyl-, C.sub.1-C.sub.6carboxyamidoalkyl-,
or O.sub.2N--.
[0900] The term "heteroatom" refers to a sulfur, nitrogen, or
oxygen atom.
[0901] "Heterocycle" or "heterocyclyl" refers to monocyclic,
bicyclic and polycyclic groups in which at least one ring atom is a
heteroatom. A heterocycle may be saturated or partially saturated.
Exemplary C.sub.1-C.sub.9heterocyclyl-groups include but are not
limited to aziridine, oxirane, oxirene, thiirane, pyrroline,
pyrrolidine, dihydrofuran, tetrahydrofuran, dihydrothiophene,
tetrahydrothiophene, dithiolane, piperidine,
1,2,3,6-tetrahydropyridine-1-yl, tetrahydropyran, pyran, thiane,
thiine, piperazine, oxazine, 5,6-dihydro-4H-1,3-oxazin-2-yl,
2,5-diazabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.2]octane,
3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane,
6-oxa-3,8-diazabicyclo[3.2.1]octane,
7-oxa-2,5-diazabicyclo[2.2.2]octane,
2,7-dioxa-5-azabicyclo[2.2.2]octane,
2-oxa-5-azabicyclo[2.2.1]heptane-5-yl,
2-oxa-5-azabicyclo[2.2.2]octane,
3,6-dioxa-8-azabicyclo[3.2.1]octane,
3-oxa-6-azabicyclo[3.1.1]heptane,
3-oxa-8-azabicyclo[3.2.1]octan-8-yl,
5,7-dioxa-2-azabicyclo[2.2.2]octane,
6,8-dioxa-3-azabicyclo[3.2.1]octane,
6-oxa-3-azabicyclo[3.1.1]heptane,
8-oxa-3-azabicyclo[3.2.1]octan-3-yl,
2-methyl-2,5-diazabicyclo[2.2.1]heptane-5-yl,
1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl,
3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl-,
7-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl,
9-oxa-3-azabicyclo[3.3.1]nonan-3-yl,
3-oxa-9-azabicyclo[3.3.1]nonan-9-yl,
3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl,
4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl, thiazine, dithiane,
and dioxane. The contemplated heterocycle rings or ring systems
have a minimum of 3 members. Therefore, for example,
C.sub.1heterocyclyl-radicals would include but are not limited to
oxaziranyl, diaziridinyl, and diazirinyl,
C.sub.2heterocyclyl-radicals include but are not limited to
aziridinyl, oxiranyl, and diazetidinyl,
C.sub.9heterocyclyl-radicals include but are not limited to
azecanyl, tetrahydroquinolinyl, and perhydroisoquinolinyl. A
heterocyclyl group can be unsubstituted or substituted with one or
more groups, including: C.sub.1-C.sub.6alkyl, halo, haloalkyl-,
hydroxyl, hydroxyl(C.sub.1-C.sub.6alkyl)-, --NH.sub.2, aminoalkyl-,
dialkylamino-, --COOH, --C(O)O--(C.sub.1-C.sub.6alkyl),
--OC(O)(C.sub.1-C.sub.6alkyl), N-alkylamido-, --C(O)NH.sub.2,
(C.sub.1-C.sub.6alkyl)amido-, or --NO.sub.2.
[0902] "Heterocyclyl(alkyl)-" refers to an alkyl group, as defined
above, wherein one or more of the alkyl group's hydrogen atoms has
been replaced with a heterocycle group as defined above.
Heterocyclyl(C.sub.1-C.sub.6alkyl)-moieties include
2-pyridylmethyl, 1-piperazinylethyl, 4-morpholinylpropyl,
6-piperazinylhexyl, and the like. A heterocyclyl(alkyl) group can
be unsubstituted or substituted with one or more of the following
groups: halogen, H.sub.2N--, (C.sub.1-C.sub.6alkyl)amino-,
di(C.sub.1-C.sub.6alkyl)amino-,
(C.sub.1-C.sub.6alkyl)C(O)N(C.sub.1-C.sub.3alkyl)-,
(C.sub.1-C.sub.6alkyl)carboxyamido-, HC(O)NH--, H.sub.2NC(O)--,
(C.sub.1-C.sub.6alkyl)NHC(O)--, di(C.sub.1-C.sub.6alkyl)NC(O)--,
NC--, hydroxyl, C.sub.1-C.sub.6alkoxy-, C.sub.1-C.sub.6alkyl-,
HO.sub.2C--, (C.sub.1-C.sub.6alkoxy)carbonyl-,
(C.sub.1-C.sub.6alkyl)C(O)--, 4- to 7-membered monocyclic
heterocycle, C.sub.6-C.sub.14aryl-, C.sub.1-C.sub.9heteroaryl-, or
C.sub.3-C.sub.8cycloalkyl-.
[0903] "Hydroxylalkyl-" refers to a alkyl group, as defined above,
wherein one or more of the alkyl group's hydrogen atoms has been
replaced with hydroxyl groups. Examples of
C.sub.1-C.sub.6hydroxylalkyl-moieties include, for example,
--CH.sub.2OH, --CH.sub.2CH.sub.2OH, --CH.sub.2CH.sub.2CH.sub.2OH,
--CH.sub.2CH(OH)CH.sub.2OH, --CH.sub.2CH(OH)CH.sub.3,
--CH(CH.sub.3)CH.sub.2OH and higher homologs.
[0904] "Monocyclic heterocyclyl" refers to monocyclic groups in
which at least one ring atom is a heteroatom. A heterocycle may be
saturated or partially saturated. Exemplary monocyclic
C.sub.1-C.sub.9heterocyclyl-groups include but are not limited to
aziridine, oxirane, oxirene, thiirane, pyrroline, pyrrolidine,
dihydrofuran, tetrahydrofuran, dihydrothiophene,
tetrahydrothiophene, dithiolane, piperidine,
1,2,3,6-tetrahydropyridine-1-yl, tetrahydropyran, pyran, thiane,
thiine, piperazine, oxazine, 5,6-dihydro-4H-1,3-oxazin-2-yl,
4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl, thiazine, dithiane,
and dioxane. The contemplated heterocycle ring systems have a
minimum of 3 members. Therefore, for example,
C.sub.1heterocyclyl-radicals would include but are not limited to
oxaziranyl, diaziridinyl, and diazirinyl,
C.sub.2heterocyclyl-radicals include but are not limited to
aziridinyl, oxiranyl, and diazetidinyl,
C.sub.9heterocyclyl-radicals include but are not limited to
azecanyl. A heterocyclyl group can be unsubstituted or substituted
with one or more groups, including: C.sub.1-C.sub.6alkyl, halo,
haloalkyl-, hydroxyl, hydroxyl(C.sub.1-C.sub.6alkyl)-, --NH.sub.2,
aminoalkyl-, dialkylamino-, --COOH,
--C(O)O--(C.sub.1-C.sub.6alkyl), --OC(O)(C.sub.1-C.sub.6alkyl),
N-alkylamido-, --C(O)NH.sub.2, (C.sub.1-C.sub.6alkyl)amido-, or
--NO.sub.2.
[0905] "Perfluoroalkyl-" refers to alkyl group, defined above,
having two or more fluorine atoms. Examples of a
C.sub.1-C.sub.6perfluoroalkyl-group include CF.sub.3,
CH.sub.2CF.sub.3, CF.sub.2CF.sub.3 and CH(CF.sub.3).sub.2.
[0906] 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.
[0907] The term "optionally substituted" as used herein means that
at least one hydrogen atom of the optionally substituted group has
been substituted with halogen, --NH.sub.2,
--NH(C.sub.1-C.sub.6alkyl),
--N(C.sub.1-C.sub.6alkyl)(C.sub.1-C.sub.6alkyl),
--N(C.sub.1-C.sub.3alkyl)C(O)(C.sub.1-C.sub.6alkyl),
--NHC(O)(C.sub.1-C.sub.6alkyl), --NHC(O)H, --C(O)NH.sub.2,
--C(O)NH(C.sub.1-C.sub.6alkyl),
--C(O)N(C.sub.1-C.sub.6alkyl)(C.sub.1-C.sub.6alkyl), --CN,
hydroxyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6alkyl, --C(O)OH,
--C(O)O(C.sub.1-C.sub.6alkyl), --C(O)(C.sub.1-C.sub.6alkyl),
C.sub.6-C.sub.14aryl C.sub.1-C.sub.9heteroaryl, or
C.sub.3-C.sub.8cycloalkyl.
[0908] 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.
[0909] 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.
[0910] 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.
[0911] 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.
[0912] 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.
[0913] 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.
[0914] 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.
[0915] 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.
[0916] 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.
[0917] 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.
[0918] 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.
[0919] In one embodiment, the compound of the present invention or
a pharmaceutically acceptable salt thereof is administered
concurrently with another therapeutic agent.
[0920] 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.
[0921] 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.
[0922] Methods useful for making the compounds of Formula I are set
forth in the Examples below and generalized in Schemes 1-3:
[0923] Scheme 1:
[0924] 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.
[0925] The following abbreviations are used herein and have the
indicated definitions: ACN is acetonitrile, AcOH is acetic acid,
ATP is adenosine triphosphate, CHAPS is
3[(3-cholamidopropyl)dimethylammonio]-propanesulfonic acid, DEAD is
diethyl azodicarboxylate, DIAD is diisopropyl azodicarboxylate,
DMAP is dimethyl aminopyridine, DMF is N,N-dimethylformamide,
DMF-DMA is dimethylformamide dimethyl acetal, DMSO is
dimethylsulfoxide. Dowtherm.TM. is a eutectic mixture of biphenyl
(C.sub.12H.sub.10) and diphenyl oxide (C.sub.12H.sub.10O).
Dowtherm.TM. is a registered trademark of Dow Corning Corporation.
DPBS is Dulbecco's Phosphate Buffered Saline Formulation, EDTA is
ethylenediaminetetraacetic acid, ESI stands for Electrospray
Ionization, EtOAc is ethyl acetate, EtOH is ethanol, HEPES is
4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, GMF is Glass,
Hunig's Base is diisopropylethylamine, HPLC is high pressure liquid
chromatography, LPS is lipopolysaccharide, MeCN is acetonitrile,
MeOH is methanol, MS is mass spectrometry, NEt.sub.3 is
triethylamine, NMR is nuclear magnetic resonance, PBS is
phosphate-buffered saline (pH 7.4), RPMI 1640 is a buffer
(Sigma-Aldrich Corp., St. Louis, Mo., USA), SDS is dodecyl sulfate
(sodium salt), SRB is Sulforhodamine B, TBSCl is
tert-butyldimethylsilyl chloride, TCA is tricholoroacetic acid, TFA
is trifluoroacetic acid, THF is tetrahydrofuran, TLC is thin-layer
chromatography, and TRIS is tris(hydroxymethyl)aminomethane.
Methods
[0926] 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
[0927] 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
[0928] 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.degree. 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
[0929] A mixture of 2-chloro-4,6-di-morpholin-4-yl-[1,3,5]triazine
(1.4 g, 4.9 mmoles), a catalytic amount of
tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.061 mmoles),
sodium carbonate solution 2 M (3 mL), 4-aminophenylboronic acid
pinacol ester (1.6 g, 7.3 mmoles) and DME (100 mL) was refluxed for
24 hours. The solvent was evaporated, and the residue was dissolved
in methylene chloride and filtered through Celite.TM.. 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
[0930] 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.degree. C. was added
triphosgene (0.25 mg, 0.84 mmoles) and triethylamine (3 mL). The
mixture was stirred for 20 minutes at 0.degree. 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:
[0931] 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.
[0932] The following compounds were prepared according to Procedure
A:
Example 2
[0933] Preparation of
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-3-ylurea
[0934] 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
[0935] Preparation of
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-phenylurea
[0936] 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
[0937] Preparation of
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-thiophen-2-ylurea
[0938] 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
[0939] Preparation of
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-methylphenyl)u-
rea
[0940] 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
[0941] Preparation of
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-fluorophenyl)u-
rea
[0942] 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
[0943] Preparation of
1-(2,4-dimethoxyphenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phe-
nyl]-urea
[0944] 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
[0945] Preparation of
1-(4-chlorophenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]--
urea
[0946] 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
[0947] Preparation
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-methoxyphenyl)-
urea
[0948] 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
[0949] Preparation of
(4-chlorophenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ure-
a
[0950] 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
[0951] Preparation of
(2,4-difluorophenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl-
]urea
[0952] 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
[0953] Preparation of
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-ethylurea
[0954] 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
[0955] 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
[0956] 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.degree. 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-carboxylat-
e
[0957] 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)az-
etidine-1-carboxylate
[0958] A mixture of tert-butyl
3-(4-chloro-6-morpholine-1,3,5-triazin-2-2-ylamino)azetidine-1-carboxylat-
e (1.1 g, 3.0 mmoles), tetrakis(triphenylphosphine)palladium (0) in
catalytic amount (70 mg, 0061 mmoles), sodium carbonate solution 2
M (3 mL), 4-aminophenylboronic acid pinacol ester (0.97 g, 4.5
mmoles), DME (100 mL) was refluxed for 24 hours. The solvent was
evaporated and the residue was dissolved in methylene chloride and
filtered though Celite.TM.. 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)az-
etidine-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
[0959] 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
[0960] Preparation of tert-butyl
3-[(4-morpholin-4-yl-6-{4-[(phenylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-
-yl)amino]azetidine-1-carboxylate
[0961] 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 HPLC, using ACN/water and TFA. White solid;
Yield 40 mg (31%); (M+H) 547.6
Example 15
[0962] Preparation of tert-butyl
3-[(4-morpholin-4-yl-6-{4-[(pyridine-3-ylcarbamoyl)amino]phenyl}-1,3,5-tr-
iazin-2-yl)amino]azetidine-1-carboxylate
[0963] 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 HPLC, using ACN/water and TFA. White solid;
Yield 40 mg (23%); (M+H) 548.7.
Example 16
[0964] 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
[0965] 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 HPLC, using ACN/water and TFA. White solid;
Yield 85 mg (47%); (M+H) 561.6.
Example 17
[0966] Preparation of
1-{4-[4-(azetidin-3-ylamino)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}--
3-phenylurea
[0967] 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
[0968] 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
[0969] Preparation of
1-{4-[4-(azetidin-3-ylamino)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}--
3-pyridin-3-ylurea
[0970] To a stirred solution of tert-butyl
3-[(4-morpholin-4-yl-6-{4-[(pyridin-3-ylcarbamoyl)amino]phenyl}-1,3,5-tri-
azin-2-yl)amino]azetidine-1-carboxylate
[0971] 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
[0972] Preparation of
1-{4-[4-(azetidin-3-ylamino)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}--
3-(4-fluorophenyl)urea
[0973] 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
[0974] 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
[0975] Preparation of
1-{4-[4-(azetidin-3-ylamino)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}--
3-(4-methylphenyl)urea
[0976] 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
[0977] 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
[0978] Preparation of tert-butyl
3-[(4-morpholin-4-yl-6-{4-[(pyridine-4-ylcarbamoyl)amino]phenyl}-1,3,5-tr-
iazin-2-yl)amino]azetidine-1-carboxylate
[0979] 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.degree. 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
[0980] Preparation of
1-{4-[4-(azetidin-3-ylamino)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}--
3-pyridin-4-ylurea
[0981] To a stirred solution of tert-butyl
3-[(4-morpholin-4-yl-6-{4-[(pyridine-4-ylcarbamoyl)amino]phenyl}-1,3,5-tr-
iazin-2-yl)amino]azetidine-1-carboxylate
[0982] 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
[0983] Preparation of
1-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazi-
n-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
[0984] 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
[0985] 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 Celite.TM.. 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-triazi-
n-2-yl]phenyl}-3-phenylurea
[0986] 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 HPLC, using ACN/water and TFA. White solid; mp: 242;
Yield 35 mg (28%); (M+H) 488.56
Example 24
[0987] 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
[0988] 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
[0989] 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
[0990] 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
[0991] Following the procedure as outlined in example 25, compounds
described in examples 26 to 32 were prepared.
Example 26
[0992]
1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)p-
henyl]-3-methylurea (M+H) 452.53
Example 27
[0993] 2-hydroxyethyl
[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)phenyl]ca-
rbamate (M+H) 483.54
Example 28
[0994]
1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)p-
henyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea (M+H) 612.8
Example 29
[0995]
1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)p-
henyl]-3-ethylurea (M+H) 466.56
Example 30
[0996]
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
[0997]
1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)p-
henyl]-3-pyridin-4-ylurea (M+H) 515
Example 32
[0998]
1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)p-
henyl]-3-[4-(hydroxymethyl)phenyl]urea (M+H) 544.6
Example 33
[0999] 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
[1000] To a solution of cyanuric chloride (2.5 g, 13.5 mmol) in
CH.sub.2Cl.sub.2 (150 mL) was added dropwise morpholine (1.14 g,
13.5 mmol) at -78.degree. C., followed by addition of Et3N (3.0 mL,
21.5 mmol). The resulting reaction mixture was stirred at
-78.degree. C. for 20 min, and then diluted with CH.sub.2Cl.sub.2.
The organic phase was washed with water and brine, and dried over
MgSO.sub.4. The solvent was removed in vacuum to give the title
compound as white crystalline solid (3.027 g, 95% yield). MS(ESI)
m/z 235.1.
Step 2: Synthesis of
8-(4-chloro-6-morpholino-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3,2,1]oct-
ane
[1001] To a solution of
4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine (2.34 g, 10 mmol) in
CH.sub.2Cl.sub.2 (100 mL) were added
3-oxa-8-azabicyclo[3,2,1]octane hydrochloride (1.645 g, 11 mmol)
and Et3N (4.2 mL, 30 mmol). The mixture was stirred at room
temperature over night. The reaction mixture was washed with water
and brine, and dried over MgSO.sub.4. The solvent was removed in
vacuum to give the title compound as white solid (3.0 g, 96%
yield). MS(ESI) m/z 312.1.
Step 3: Synthesis of
4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
-yl]aniline
[1002] 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]oct-
ane (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.degree. C. for 30 min in
microwave oven. The reaction mixture was cooled to room
temperature. The aqueous phase was extracted with EtOAc, and the
combined organic phases were dried over (MgSO.sub.4). The solvent
was removed under reduced pressure and the residue was subjected to
HPLC separation to give the title compound as off-white solid (280
mg, 76% yield). MS(ESI) m/z 369.2.
Example 34
[1003] Preparation of
1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazi-
n-2-yl]phenyl}-3-pyridin-4-ylurea
[1004] 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
[1005] Preparation of
4-[({4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-tria-
zin-2-yl]phenyl}carbamoyl)amino]benzamide
[1006] 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
[1007] Preparation of
1-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazi-
n-2-yl]phenyl}-3-pyridin-3-ylurea
[1008] 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
[1009] 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
[1010] 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
[1011] 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
[1012] 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
[1013] 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
[1014] 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
[1015] 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-tria-
zin-2-yl]phenyl}carbamoyl)amino]benzoate
[1016] 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
[1017] 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
[1018] 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
[1019] 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
[1020] 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-aminobenzonitrile (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
[1021] Preparation of
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-az-
abicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea
[1022] 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
[1023] 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
[1024] 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
[1025] 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
[1026] 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
[1027] 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
[1028] Preparation of
1-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazi-
n-2-yl]phenyl}-3-pyridin-3-ylurea, MS (ESI) m/z 489.3.
Example 48
[1029] Preparation of
1-{4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazi-
n-2-yl]phenyl}-3-pyridin-4-ylurea, mp 258.degree. C.; MS (ESI) m/z
489.3.
[1030] Following the procedure as outlined in example 1, step 3 the
following compounds were prepared.
Example 49
[1031]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(2-methylpy-
ridin-4-yl)urea MS (ESI) m/z 477.3.
Example 50
[1032]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(2-hydro-
xyethyl)phenyl]urea MS (ESI) m/z 506.4.
Example 51
[1033]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxy-
methyl)phenyl]urea.
Example 52
[1034]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(1-hydro-
xyethyl)phenyl]urea MS (ESI) m/z 506.4.
Example 53
[1035]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(trifluo-
romethyl)phenyl]urea MS (ESI) m/z 530.2.
Example 54
[1036]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-hydroxyp-
henyl)urea MS (ESI) m/z 478.2.
Example 55
[1037]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[5-(trifluo-
romethyl)pyridin-2-yl]urea MS (ESI) m/z 530.5.
Example 56
[1038]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[2,2,2-t-
rifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}urea MS (ESI)
m/z 621.54.
Example 57
[1039]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[3-(1-hydro-
xyethyl)phenyl]urea MS (ESI) m/z 506.3.
Example 58
[1040] methyl
4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)be-
nzoate MS (ESI) m/z 520.3.
Example 59
[1041] 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:
[1042] 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 CHCl.sub.3; washed well
with water and dried over anhydrous MgSO.sub.4. 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.degree. C.; MS (ESI) m/z 301.52
Step 2:
[1043]
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.degree. C.; MS (ESI) m/z
358.2.
Step 3:
[1044]
1-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazi-
n-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]an-
iline (212 mg. 0.59 mmol) 190 mg (Yield, 67%) of the final product
was isolated as a white solid. mp 238.degree. C.; MS (ESI) m/z
478.3.
Example 60
[1045] Preparation of
1-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl-
]phenyl}-3-phenylurea
[1046]
1-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazi-
n-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]an-
iline and the corresponding phenylisocyanate. Product was purified
by Gilson, HPLC. MS (ESI) m/z 476.5.
Example 61
[1047] 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
[1048]
1-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazi-
n-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]an-
iline and the corresponding 3-pyridylisocyanate. Product was
purified by Gilson, HPLC. MS (ESI) m/z 477.53.
Example 62
[1049] 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
[1050]
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
[1051] 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
[1052]
1-(2-methylpyridin-4-yl)-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-py-
ran-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
[1053] 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
[1054]
1-[2-(methylamino)ethyl]-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-py-
ran-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
[1055] 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
[1056]
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]an-
iline and the corresponding 3-acetylisocyanate. Product was
purified by Gilson, HPLC. MS (ESI) m/z 518.58.
Example 66
[1057] 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
[1058]
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-y-
l]aniline and the corresponding 4-(N,N-dimethyl
amino)phenylisocyanate. Product was purified by Gilson, HPLC. MS
(ESI) m/z 519.61.
Example 67
[1059] Preparation of
4-[3-{4-(4,6-dimorpholino-1,3,5-triazin-2yl)phenyl}ureido]benzoic
acid
[1060] 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
[1061] Preparation of
N-(2-(dimethylamino)ethyl)-4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)p-
henyl)ureido)benzamide
[1062] To a stirred solution of
4-[3-{4-(4,6-dimorpholino-1,3,5-triazin-2yl)phenyl}ureido]benzoic
acid (150 mg; 0.297 mmol), Hunig's base (303 .mu.L, 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
.mu.L, 1.188 mmol) then stirred overnight. Added CH.sub.2Cl.sub.2
(40 mL) and washed with sat. NaHCO3 and H2O. Concentrated and
purified by silica gel chromatography CH.sub.2Cl.sub.2: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
[1063] Preparation
N-(2-(dimethylamino)ethyl)-4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)p-
henyl)ureido)benzamide as an HCl salt
[1064] To the
N-(2-(dimethylamino)ethyl)-4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)p-
henyl)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
[1065] Preparation of
1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-
e-1-carbonyl)phenyl)urea hydrochloride
[1066] To a stirred solution of
4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2yl)phenyl)ureido)benzoic
acid (150 mg; 0.297 mmol), Hunig's base (303 .mu.L, 1.782 mmol),
HBTU (563 mg, 1.485 mmol) in 2 mL of NMP was reacted according to
example 68 with 1-methylpiperazine (132 .mu.L, 1.188 mmol) to give
1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-
e-1-carbonyl)phenyl)urea as a white solid (95 mg, 54% yield); MS
(ESI) m/z=588.4.
[1067] To a
1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-
e-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
[1068] Preparation of
4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)-N-methylbenza-
mide
[1069] To the stirred solution of
4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2yl)phenyl)ureido)benzoic
acid (150 mg; 0.297 mmol), Hunig's base (303 .mu.L, 1.782 mmol),
HBTU (563 mg, 1.485 mmol) in 2 mL of NMP was reacted according to
example 68 with methylamine (594 .mu.L, 2M solution. in THF) to
give the product as a white solid (118 mg, 77% yield); MS (ESI)
m/z=519.3.
Example 71
[1070] Preparation of
N-(2-(dimethylamino)ethyl)-4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)p-
henyl)ureido)-N-methylbenzamide hydrochloride
[1071] To the stirred solution of
4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2yl)phenyl)ureido)benzoic
acid (150 mg; 0.297 mmol), Hunig's base (303 .mu.L, 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 .mu.L,
1.188 mmol) to give
N-(2-(dimethylamino)ethyl)-4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)p-
henyl)ureido)-N-methylbenzamide as a white solid (88 mg, 50%
yield); MS (ESI) m/z=590.2.
[1072] To the
N-(2-(dimethylamino)ethyl)-4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)p-
henyl)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
[1073] Preparation of
1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-morpholinopiper-
idine-1-carbonyl)phenyl)urea
[1074] To the stirred solution of
4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2yl)phenyl)ureido)benzoic
acid (50 mg; 0.099 mmol), Hunig's base (103 .mu.L, 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
[1075] Preparation of
4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)-N-(quinuclidi-
n-3-yl)benzamide
[1076] To the solution of
4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2yl)phenyl)ureido)benzoic
acid (50 mg; 0.099 mmol), Hunig's base (103 .mu.L, 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
[1077] Preparation of
1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-(pyrrolidin-1-y-
l)piperidine-1-carbonyl)phenyl)urea
[1078] To the solution of
4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2yl)phenyl)ureido)benzoic
acid (50 mg; 0.099 mmol), Hunig's base (103 .mu.L, 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
[1079] Preparation of
1-(4-(1,4'-bipiperidine-1'-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5--
triazin-2-yl)phenyl)urea
[1080] To the solution of
4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2yl)phenyl)ureido)benzoic
acid (50 mg; 0.099 mmol), Hunig's base (103 .mu.L, 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
[1081] Preparation of
1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholi-
no-1,3,5-triazin-2-yl)phenyl)urea
[1082] To the solution of
4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2yl)phenyl)ureido)benzoic
acid (50 mg; 0.099 mmol), Hunig's base (103 .mu.L, 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
[1083] Preparation of
1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(piperazine-1-carb-
onyl)phenyl)urea
[1084] To the solution of
4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2yl)phenyl)ureido)benzoic
acid (50 mg; 0.099 mmol), Hunig's base (103 .mu.L, 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
[1085] Preparation of
1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(2-(pyridin-2-yl)a-
cetyl)phenyl)urea
[1086] To the solution of
4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2yl)phenyl)ureido)benzoic
acid (50 mg; 0.099 mmol), Hunig's base (103 .mu.L, 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
[1087] To a solution of cyanuric chloride (2.00 g, 10.85 mmoles) in
acetone (20 mL) and water (10 mL) at 0.degree. 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.degree. 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
[1088] 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.degree. 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. [1089]
3-(4-chloro-6-(piperidin-1-yl)-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2-
.1]octane: [1090] (310.3, M+H) [1091]
3-(4-chloro-6-(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.-
2.1]octane [1092] (296.3, M+H) [1093] t-butyl
2-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-ylami-
no)ethylcarbamate [1094] (385.3, M+H) [1095]
2-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-ylami-
no)ethanol [1096] (286.3, M+H) [1097]
4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-N-phenyl-1,3,5-triazin-2-
-amine [1098] (318.3, M+H) [1099]
4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-N-cyclohexyl-1,3,5-triaz-
in-2-amine [1100] (324.3, M+H) [1101] t-butyl
3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-ylami-
no)azetidine-1-carboxylate [1102] (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
[1103] 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.degree. C. for 1 hour. The mixture was cooled and
filtered through Celite.TM.. 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. [1104]
4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperidin-1-yl)-1,3,5-triaz-
in-2-yl)aniline [1105] (367.4, M+H) [1106]
4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(pyrrolidin-1-yl)-1,3,5-tria-
zin-2-yl)aniline [1107] (353.3, M+H) [1108]
2-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazi-
n-2-ylamino)ethanol; [1109] (343.3, M+H) [1110]
4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-phenyl-1,3,5--
triazin-2-amine; [1111] (375.3, M+H) [1112]
4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-cyclohexyl-1,-
3,5-triazin-2-amine; [1113] (381.4, M+H) [1114] t-butyl
3-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazi-
n-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
[1115] A solution of triphosgene (0.034 mgs, 0.114 mmoles) in
CH.sub.2Cl.sub.2 (1 mL) was prepared. A solution of the desired
triazine aniline derivative (0.23 mmoles) in CH.sub.2Cl.sub.2 (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
[1116] Preparation of
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperidin-1-yl)-1,3,5-tr-
iazin-2-yl)phenyl)-3-(pyridin-4-yl)urea; 487.2, M+H.
Example 80
[1117] Preparation of
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(pyrrolidin-1-yl)-1,3,5-t-
riazin-2-yl)phenyl)-3-(pyridin-4-yl)urea; 474.2, M+H.
Example 81
[1118] Preparation of
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(1-hydroxyethy-
l)phenyl]urea
[1119] 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.degree. C. was added triphosgene
(0.25, 0.84 mmoles) and Et3N (3 mL). The reaction mixture was
stirred for 20 minutes at 0.degree. 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-hydr-
oxyethyl)phenyl]urea. M+H 506.4.
Example 82
[1120] Preparation of
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(2-methylpyridin--
4-yl)urea
[1121] 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
[1122]
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(2-methylpy-
ridin-4-yl)urea was isolated by HPLC purification. Yield: 60 mg,
27%; MS (ESI) m/z=477.3.
Example 83
[1123] Preparation of
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxymethyl-
)phenyl]urea
[1124] 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
[1125] Preparation of
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-hydroxyphenyl]-
urea
[1126] 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
[1127] Preparation of
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(trifluorometh-
yl)phenyl]urea
[1128] 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-(trifluorometh-
yl)phenyl]urea was isolated by HPLC purification. Yield: 25 mg,
13%; MS (ESI) m/z=430.2.
Example 86
[1129] Preparation of
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[2,2,2-trifluo-
ro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}urea
[1130] 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-trifluo-
ro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}urea was isolated by
HPLC purification. Yield: 40 mg, 16%; MS (ESI) m/z=628.3.
Example 87
[1131] Preparation of
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[5-(trifluorometh-
yl)pyridin-2-yl]urea
[1132] 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-(trifluorometh-
yl)pyridin-2-yl]urea was isolated by HPLC purification. Yield: 10
mg, 4.1%; MS (ESI) m/z=531.3.
Example 88
[1133] Preparation of
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[3-(1-hydroxyethy-
l)phenyl]urea
[1134] 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-hydroxyethy-
l)phenyl]urea was isolated by HPLC purification. Yield: 10 mg,
4.1%; MS (ESI) m/z=531.3.
Example 89
[1135] 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-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazine
[1136] To a stirred solution of dichoromonomorpholino derivative of
1,3,5-triazine (2.0 g, 8.5 mmoles) in methylene chloride 200 mL,
was added 3S-3-methylmorpholine (0.85 g, 8.5 mmoles) combined with
two equivalents of triethylamine 1.7 mL dropwise manner. After the
addition reaction mixture was stirred at room temperature for 3
hours and quenched with water. The aqueous layer was washed well
with water; dried over anhydrous MgSO.sub.4 and filtered. The
solvent was evaporated and the residue obtained was triturated with
diethyl ether/hexane (1:1) and filtered. The solid was used without
further purification. (1.0 g, 40% yield). M+H 357.3.
Step 2: Preparation of
4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}an-
iline
[1137] A mixture of
2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazine
(1.26, 4.2 mmol), sodium carbonate solution (2M, 2 mL), tetrakis
palladium triphenylphosphine 70 mg (catalytic amount) and
4-aminophenyl boronic pinacol ester (1.37 g, 6.3 mmoles) in DME
(100 mL) was heated to reflux for 24 hours. The solvent was
evaporated, the residue was re-dissolved in methylene chloride and
filtered through Celite.TM.. The solvent was evaporated and the
residue was chromatographed on silica gel eluting with first 26/4
hexanes/ethyl acetate then increased to 1/1 hexanes ethyl acetate
to give 1.0 of
4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}an-
iline (71% yield); M+H 357.2.
Step 3: Preparation of
1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl-
}phenyl)-3-pyridin-4-ylurea
[1138] Starting from
4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}an-
iline (0.160, 0.44 mmoles) and 4-aminopyridine (100 mg, 1.06
mmoles) and following the procedure as outlined in example 81,
1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl-
}phenyl)-3-pyridin-4-ylurea was isolated by HPLC purification.
Yield: 125 mg, 60%; MS (ESI) m/z 477.3.
Example 90
[1139] Preparation of
1-[4-(2-hydroxyethyl)phenyl]-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morp-
holin-4-yl-1,3,5-triazin-2-yl}phenyl)urea
[1140] Starting from
4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}an-
iline (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-[(3S)-3-methylmorpholin-4-yl]-6-morp-
holin-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
[1141] Preparation of
1-[4-(2-hydroxymethyl)phenyl]-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-mor-
pholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea
[1142] Starting from
4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}an-
iline (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-hydroxymethyl)phenyl]-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-mor-
pholin-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
[1143] Preparation of
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
[1144] Starting from
4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}an-
iline (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-[(3S)-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
[1145] Preparation of
1-[4-(1-hydroxyethyl)phenyl]-3-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morp-
holin-4-yl-1,3,5-triazin-2-yl}phenyl)urea
[1146] Starting from
4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}an-
iline (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-[(3S)-3-methylmorpholin-4-yl]-6-morp-
holin-4-yl-1,3,5-triazin-2-yl}phenyl)urea was isolated by HPLC
purification. MS (ESI) m/z 519.6.
Example 94
[1147] Preparation of
1-[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin--
4-ylurea
Step 1:
[1148] To a stirred solution of isopropanol (250 mg, 4.1 mmol) in
dry THF (50 ml) at -78.degree. 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:
[1149] A mixture of (crude)
4-(chloro-6-isopropoxyl-1,2,3-triazin-2yl)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
Celite.TM.. 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:
[1150] 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
[1151] Preparation of methyl
4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl-
}amino)benzoate
[1152] 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
[1153] Preparation of
1-[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-m-
ethylpiperazin-1-yl)carbonyl]phenyl}urea
[1154] 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
[1155] 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
[1156] 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
[1157] Preparation of
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(1-methylpiperidi-
n-4-yl)urea
[1158] 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
[1159] Preparation of
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
[1160] Starting from
4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}an-
iline (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
[1161] 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
[1162] In a three necked flask under nitrogen equipped was
dissolved 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (610 mg,
2.6 mmol), tributyldihydropyranylstanane (1.45 g, 3.89 mmol, 1.5
eq), and (Ph.sub.3P).sub.2PdCl.sub.2 (150 mg, 0.21 mmol, 0.1 eq) in
anhydrous dioxan (5 ml). The reaction mixture was heated under
stirring to 90.degree. 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]-ph-
enylamine
[1163] To a microwave processing tube was added dimethoxyethane (4
mL), aqueous Na.sub.2CO.sub.3 (2 molar)(1 mL, 2 mmol, 2 eq),
(Ph.sub.3P).sub.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.degree. C. for 60 minutes. The solvents were
distilled and the crude compound was purified by silica gel
chromatography using CH.sub.2Cl.sub.2/ethyl acetate (10:1) and
later CH.sub.2Cl.sub.2/MeOH/NH3 (20:1:0.1) to give the product as a
off-white solid (520 mg, 87% yield); MS (ESI) m/z 340.2
Step 3: Preparation of
1-{4-[4-(3,6-Dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-
-phenyl}-3-pyridin-4-yl-urea
[1164] To a stirred solution of triphosgene (140 mg, 0.47 mmol) in
CH.sub.2Cl.sub.2 (6 mL) was added
4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-ph-
enylamine (200 mg, 0.59 mmol) at 25.degree. C. The reaction mixture
was stirred for 15 min and 4-aminopyridine (166 mg, 1.77 mmol) and
NEt.sub.3 (814 .mu.L, 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
[1165] Preparation of
1-{4-[4-Morpholin-4-yl-6-(tetrahydro-pyran-4-yl)-[1,3,5]triazin-2-yl]-phe-
nyl}-3-pyridin-4-yl-urea
[1166]
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/CH.sub.2Cl.sub.2 (4:1:1) (30 mL) and hydrogenated (at
1 atm pressure) for 3 h. After completion, the catalyst was removed
by filtration over Celite.TM. 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]-phe-
nyl}-3-pyridin-4-yl-urea; MS (ESI) m/z 462.
Example 102
[1167] 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-bicyc-
lo[3.2.1]octane
[1168] In a three neck flask equipped with stirring bar under
N.sub.2 atmosphere tropine (1 g, 4.24 mmol) was suspended in
(anhydrous) THF (15 mL). The mixture was cooled to -78.degree. C.
and BuLi (2M in THF) (5.53 ml, 1.2 eq) was added dropwise and the
mixture was allowed to warm to 25.degree. 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 MgSO.sub.4.
filtered and the solvents were removed to obtain a colorless oil.
Further purification by flash-chromatography using
CH.sub.2Cl.sub.2/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]t-
riazin-2-yl]-phenylamine
[1169] 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-bicyc-
lo[3.2.1]octane (500 mg, 1.47 mmol) and the vessel was sealed. The
mixture was heated to 140.degree. C. for 60 minutes. The solvents
were distilled and the crude compound was purified by silica gel
chromatography using CH.sub.2Cl.sub.2/ethyl acetate (10:1) and
later with CH.sub.2Cl.sub.2/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
[1170] To a stirred solution of triphosgene (60 mg, 0.20 mmol) in
CH.sub.2Cl.sub.2 (3 mL) was added
4-[4-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]t-
riazin-2-yl]-phenylamine (100 mg, 0.25 mmol) at 25.degree. C. The
reaction mixture was stirred for 15 min and 4-aminopyridine (70 mg,
0.75 mmol) and NEt.sub.3 (346 .mu.L, 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
[1171] 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
[1172] To a stirred solution of triphosgene (120 mg, 0.40 mmol) in
CH.sub.2Cl.sub.2 (3 mL) was added
4-[4-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]t-
riazin-2-yl]-phenylamine (200 mg, 0.5 mmol) at 25.degree. C. The
reaction mixture was stirred for 15 min and 4-aminobenzamide (204
mg, 1.5 mmol) and NEt.sub.3 (692 .mu.L, 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
[1173] 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
[1174] To a solution of the 3-aminomethyl-azetidine-1-carboxylic
acid tert-butyl ester HCl salt (945 mg, 4.24 mmol) and NEt.sub.3
(856 mg, 8.48 mmol) in THF (10 mL) at 0.degree. C. was added a
suspension of 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (996
mg, 4.24 mmol) at 0.degree. C. The reaction mixture was stirred for
another 1 hr at 0.degree. C. and allowed to warm to 20.degree. 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 CH.sub.2Cl.sub.2/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
[1175] 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.degree. C. for 60
minutes. The solvents were removed and the crude compound was
purified by silica gel chromatography using CH.sub.2Cl.sub.2/Ethyl
acetate (10:1) and later CH.sub.2Cl.sub.2/MeOH/NH3 (15:1:0.1) to
give the product as a off-white solid (1.3 g, 53% yield).
[1176] 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
[1177] To a stirred solution of triphosgene (269 mg, 0.90 mmol) in
CH.sub.2Cl.sub.2 (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.degree. C. The reaction mixture was stirred for 15 min and
4-aminopyridine (319 mg, 3.39 mmol) and NEt.sub.3 (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
[1178] Preparation of
1-(4-{4-[(azetidin-3-ylmethyl)-amino]-6-morpholin-4-yl-[1,3,5]triazin-2-y-
l}-phenyl)-3-pyridin-4-yl-urea
[1179]
3-({4-Morpholin-4-yl-6-[4-(3-pyridin-4-yl-ureido)-phenyl]-[1,3,5]tr-
iazin-2-ylamino}-methyl)-azetidine-1-carboxylic acid tert-butyl
ester (100 mg, 0.18 mmol) was dissolved CH.sub.2Cl.sub.2 (1 mL) and
TFA (1 mL) was added. It was stirred for 16 hrs at 25.degree. 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
[1180] Preparation of Tert-butyl
4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phe-
nyl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate
[1181] Tert-butyl
4-(4,6-dichloro-1,3,5-triazin-2-yl)piperazine-1-carboxylate was
prepared according to Lowik, 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)pi-
perazine-1-carboxylate
[1182] 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 OC 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.
[1183] 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-triazi-
n-2-yl)piperazine-1-carboxylate
[1184] 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)pi-
perazine-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.degree. 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.
[1185] 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)phe-
nyl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate
[1186] Crude tert-butyl
4-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazi-
n-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)phe-
nyl)-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.
[1187] MS (ES+) 588.2 (M+H)+
Example 107
[1188] Preparation of
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-tr-
iazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
[1189] Crude tert-butyl
4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phe-
nyl)-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
[1190] 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
[1191]
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.degree. 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
[1192] 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
[1193]
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
[1194] Preparation of
1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[4-(pyridin-3-ylmethyl)pipe-
razin-1-yl]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
[1195]
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
[1196] 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
[1197]
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
[1198] 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
[1199]
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
[1200] 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
[1201]
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
[1202] Preparation of Methyl
4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-{4-[(pyridin-4-ylcarbamoyl)ami-
no]phenyl}-1,3,5-triazin-2-yl]piperazine-1-carboxylate
[1203]
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
[1204] 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
[1205] 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.degree. C.
for two hours. The title compound was collected by filtration,
washed with water, and dried under vacuum.
[1206] 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)pi-
peridin-4-one
[1207] 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.degree. 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-triazi-
n-2-yl)piperidin-4-one
[1208] A suspension of
1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-yl)pi-
peridin-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.degree. 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.
[1209] 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
[1210] A mixture of crude
1-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazi-
n-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
[1211] 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
[1212]
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-y-
l)-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.degree. 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
[1213] 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
[1214]
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-y-
l)-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.
[1215] MS (ES+) 592.3 (M+H)+
Example 118
[1216] 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
[1217]
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-y-
l)-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
[1218] 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
[1219]
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-y-
l)-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
[1220] Preparation of
1-{4-[4-(4-{[2-(dimethylamino)ethyl]amino}piperidin-1-yl)-6-(8-oxa-3-azab-
icyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea
[1221] 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
[1222] 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
[1223] 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
[1224] Preparation of
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(4-methylpiperazin-1-y-
l)piperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
[1225] 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
[1226] Preparation of
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(2-hydroxyethylamino)p-
iperidin-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
[1227] Preparation of
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(2-morpholinoethylamin-
o)piperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
[1228] 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
[1229] 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
[1230] 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
[1231] 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
[1232] 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
[1233] 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
[1234] 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
[1235] 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.
[1236] MS (ES+) 560.2 (M+H)+.
Example 129
[1237] 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
[1238] Preparation of
1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazi-
n-2-yl]phenyl}-3-pyridin-4-ylurea; MS (ES+) 519.58 (M+H)+.
Example 131
[1239] Preparation of
1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazi-
n-2-yl]phenyl}-3-pyridin-3-ylurea; MS (ES+) 519.58 (M+H)+.
Example 132
[1240] Preparation of
1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazi-
n-2-yl]phenyl}-3-phenylurea; MS (ES+) 518.59 (M+H)+.
Example 133
[1241] 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
[1242] 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
[1243] Preparation of
1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazi-
n-2-yl]phenyl}-3-(2-methylpyridin-4-yl)urea; MS (ES+) 533.61
(M+H)+
Example 136
[1244] 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
[1245] Preparation of
1-[4-(4-morpholin-4-yl-6-quinolin-3-yl-1,3,5-triazin-2-yl)phenyl]-3-pyrid-
in-4-ylurea
[1246] HRMS: calcd for C28H24N8O2+H+, 505.20950; found (ESI, [M+H]+
Obs'd), 505.2098.
[1247] HRMS: calcd for C28H24N8O2+H+, 505.20950; found (ESI, [M+H]+
Calc'd), 505.2095.
Example 138
[1248] Preparation of
2-(difluoromethyl)-1-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-tria-
zin-2-yl)-1H-benzimidazole
[1249] 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]o-
ctane). 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
[1250] 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
[1251] 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
[1252] Preparation of
1-[4-(4-azetidin-1-yl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyrid-
in-4-ylurea; mp 212.degree. C.; MS (ESI) m/z 433.3.
Example 141
[1253] Preparation of methyl
4-({[4-(4-azetidin-1-yl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbam-
oyl}amino)benzoate; mp 212.degree. C.; MS (ESI) m/z 490.2.
Example 142
[1254] Preparation of
1-[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-m-
ethylpiperazin-1-yl)carbonyl]phenyl}urea; MS (ESI) m/z 561.6.
Example 143
[1255] 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
[1256] MS (ESI) m/z 575.6
Example 144
[1257] 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
[1258] 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)carbamat-
e; MS (ESI) m/z 650.7
Example 146
[1259] Preparation of
1-cyclopropyl-3-(4-{4-[4-({[4-(4-methylpiperazin-1-yl)phenyl]carbamoyl}am-
ino)phenyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}pheny-
l)urea; MS (ESI) m/z 675.8
Example 147
[1260] Preparation of
N',N'''-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazine-2,4-diyl]d-
i-4,1-phenylene}bis{1-[4-(4-methylpiperazin-1-yl)phenyl]urea}; MS
(ESI) m/z 809.9
Example 148
[1261] Preparation of
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oc-
t-3-yl)-6-{4-[(pyridin-4ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]pheny-
l}urea; MS (ESI) m/z 712.8
Example 149
[1262] 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
[1263] HRMS: calcd for C23H27N9O2+H+, 462.23605; found (ESI, [M+H]+
Obs'd), 462.2358.
Example 150
[1264] 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
[1265] HRMS: calcd for C27H26N8O2+H+, 495.22515; found (ESI, [M+H]+
Obs'd), 495.2249.
Example 151
[1266] Preparation of
4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-
-(2-piperidin-1-ylethyl)benzamide
[1267] 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
[1268] Preparation of
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(morpholin-4-y-
lcarbonyl)phenyl]urea
[1269] 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
[1270] 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
[1271] 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
[1272] 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
[1273] 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
[1274] 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
[1275]
1-{4-[4-isopropoxy-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-tria-
zin-2-yl]phenyl}-3-pyridin-4-ylurea; MS (ESI) m/z 462.53
Example 159
[1276] 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
[1277] Preparation of
1-{4-[4-chloro-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]p-
henyl}-3-pyridin-4-ylurea; MS (ESI) m/z 438.8
Example 161
[1278] Preparation of
1-[4-(4-methyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-yl-
urea; MS (ESI) m/z 391.5
Example 162
[1279] Preparation of methyl
4-({[4-(4-methyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}ami-
no)benzoate; MS (ESI) m/z 449.2.
Example 163
[1280] Preparation of
1-{4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]p-
henyl}-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea; MS (ESI)
m/z 584.7
Example 164
[1281] Preparation of
4-({[4-(4-methyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}ami-
no)-N-(1-methylpiperidin-4-yl)benzamide; MS (ESI) m/z 530.63.
Example 165
[1282] 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
[1283] Preparation of
1-[4-(4-methyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methy-
lpiperazin-1-yl)carbonyl]phenyl}urea; MS (ESI) m/z 516.6.
Example 167
[1284] Preparation of
1-(4-{[3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorp-
holin-4-yl-1,3,5-triazin-2-yl)phenyl]urea
[1285] HRMS: calcd for C31H39N9O4+H+, 602.31978; found (ESI, [M+H]+
Obs'd), 602.3192.
Example 168
[1286] 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
[1287] Preparation of
1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(piperidin-4-ylmethyl)amin-
o]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea; MS (ESI) m/z
515.6
Example 170
[1288] Preparation of
1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(2-piperidin-4-ylethyl)ami-
no]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea; MS (ESI) m/z
529.65.
Example 171
[1289] 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
[1290] 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
[1291] 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
[1292] Preparation of
1-(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]o-
ct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea; MS (ESI)
m/z 521.58
Example 175
[1293] Preparation of
1-(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]o-
ct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]ur-
ea; MS (ESI) m/z 618.7.
Example 176
[1294] 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
[1295] Preparation of
1-(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azabicyclo[3.2.1]o-
ct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-methylurea; MS (ESI) m/z
458.52.
Example 178
[1296] Preparation of
1-cyclopropyl-3-(4-{4-[2-methoxy-1-(methoxymethyl)ethoxy]-6-(8-oxa-3-azab-
icyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea; MS (ESI) m/z
484.56.
Example 179
[1297] 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
[1298] MS (ESI) m/z 642.4; HRMS: calcd for C34H43N9O4+H+,
642.35108; found (ESI-FTMS, [M+H]1+), 642.3491.
Example 180
[1299] 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
[1300] Preparation of
1-{4-[4-(4-aminobutoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triaz-
in-2-yl]phenyl}-3-pyridin-3-ylurea; MS (ESI) m/z 490.57
Example 182
[1301] 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
[1302] 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
[1303] Preparation
4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amin-
o)benzoic acid; MS (ESI) m/z 476.53
Example 185
[1304] Preparation of
N-[2-(dimethylamino)ethyl]-4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-tr-
iazin-2-yl)phenyl]carbamoyl}amino)-N-methylbenzamide; MS (ESI) m/z
562.6
Example 186
[1305] Preparation of
1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylu-
rea; MS (ESI) m/z 433.5
Example 187
[1306] Preparation of
N-[2-(dimethylamino)ethyl]-4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-tr-
iazin-2-yl)phenyl]carbamoyl}amino)benzamide; MS (ESI) m/z
548.67
Example 188
[1307] Preparation of methyl
4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amin-
o)benzoate; MS (ESI) m/z 490.56.
Example 189
[1308] Preparation of 1-(4-{4-morpholin-4-yl-6-[(1
S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-1,3,5-triazin-2-yl}phenyl)-3-py-
ridin-4-ylurea
[1309] HRMS: calcd for C24H26N8O3+H+, 475.22006; found (ESI, [M+H]+
Obs'd), 475.2201.
Example 190
[1310] 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
[1311] 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
[1312] Preparation of
1-{4-[4-(dimethylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triaz-
in-2-yl]phenyl}-3-pyridin-3-ylurea; MS (ESI) m/z 446.52.
Example 193
[1313] Preparation of
1-{4-[4-(isopropylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-tria-
zin-2-yl]phenyl}-3-pyridin-3-ylurea; MS (ESI) m/z 460.54
Example 194
[1314] Preparation of
1-{4-[4-(diethylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazi-
n-2-yl]phenyl}-3-pyridin-3-ylurea; MS (ESI) m/z 474.57.
Example 195
[1315] Preparation of
4-({[4-(4-azetidin-1-yl-6-morpholin-4-yl-1,3,5-triazin-2yl)phenyl]carbamo-
yl}amino)benzoic acid; mp 204.degree. C.; MS (ESI) m/z 476.2;
Example 196
[1316] 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.degree. C.; MS
(ESI) m/z 558.2.
Example 197
[1317] Preparation of
4-({[4-(4-azetidin-1-yl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbam-
oyl}amino)-N-[2-(dimethylamino)ethyl]-N-methylbenzamide
[1318] MS (ESI) m/z 280.7;
Example 198
[1319] Preparation of
4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amin-
o)-N-[2-(dimethylamino)ethyl]-N-methylbenzamide
Example 199
[1320] Preparation of
1-{4-[4-(1-ethoxyvinyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyr-
idin-4-ylurea; MS (ESI) m/z 447.499.
Example 200
[1321] Preparation of
1-{4-[4-(2-methoxyethoxy)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-p-
yridin-4-ylurea
[1322] HRMS: calcd for C22H25N7O4+H+, 452.20408; found (ESI, [M+H]+
Obs'd), 452.2047.
Example 201
[1323] 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
[1324] HRMS: calcd for C30H38N9O4+H+, 589.31195; found (ESI,
[M+H]+), 589.3035.
Example 202
[1325] 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
[1326] Preparation of
1-{4-[4-(sec-butylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-tria-
zin-2-yl]phenyl}-3-pyridin-3-ylurea; MS (ESI) m/z 474.57.
Example 204
[1327] 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
[1328] 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
[1329] 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
[1330] 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
[1331] Preparation of
1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)am-
ino]-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea; MS (ESI) m/z
578.68.
Example 209
[1332] Preparation of
1-[4-(4-acetyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-yl-
urea; MS (ESI) m/z 419.406
Example 210
[1333] 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]ph-
enyl}urea; MS (ESI) m/z 654.3; HRMS: calcd for C35H43N9O4+H+,
654.35108; found (ESI-FTMS, [M+H]1+), 654.35129.
Example 211
[1334] Preparation of methyl
4-[({4-[4-(2-methoxyethoxy)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}ca-
rbamoyl)amino]benzoate
[1335] HRMS: calcd for C25H28N6O6+H+, 509.21431; found (ESI, [M+H]+
Obs'd), 509.214.
Example 212
[1336] 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
[1337] 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
[1338] 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
[1339] 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
[1340] 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
[1341] 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
[1342] Preparation of
1-{4-[(2,2-dimethylhydrazino)carbonyl]phenyl}-3-(4-{4-[(1-methylethyl)ami-
no]-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
[1343] 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
[1344] 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
[1345] Preparation of
1-[4-(hydroxymethyl)phenyl]-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-aza-
bicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea; MS (ESI)
m/z 489.58
Example 222
[1346] Preparation of
1-[4-(2-hydroxyethyl)phenyl]-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-az-
abicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)urea; MS (ESI)
m/z 503.61.
Example 223
[1347] Preparation of
1-{4-[4-(1-hydroxyethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-py-
ridin-4-ylurea; MS (ESI) m/z 421.46.
Example 224
[1348] 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
[1349] Preparation of methyl
4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amin-
o)benzoate; MS (ESI) m/z 462.51
Example 226
[1350] 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
[1351] 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
[1352] 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
[1353] HRMS: calcd for C26H27N9O2+H+, 498.23605; found (ESI, [M+H]+
Obs'd), 498.2383.
Example 229
[1354] Preparation of
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-az-
abicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea
[1355] HRMS: calcd for C31H39N9O3+H+, 586.32486; found (ESI, [M+H]+
Obs'd), 586.3245.
Example 230
[1356] 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
[1357] HRMS: calcd for C28H31N7O4+H+, 530.25103; found (ESI, [M+H]+
Obs'd), 530.2508.
Example 231
[1358] Preparation of
4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amin-
o)-N-[2-(dimethylamino)ethyl]benzamide; MS (ESI) m/z 546.676.
Example 232
[1359] Preparation of
1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methyl-
piperazin-1-yl)carbonyl]phenyl}urea
[1360] MS (ESI) m/z 559.4.
Example 233
[1361] Preparation of
4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amin-
o)benzoic acid; MS (ESI) m/z 448.483
Example 234
[1362] Preparation of
1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(9-oxa-3,7-diazabi-
cyclo[3.3.1]non-3-yl)-1,3,5-triazin-2-yl]phenyl}urea
[1363] HRMS: calcd for C23H30N8O3+H+, 467.25136; found (ESI, [M+H]+
Obs'd), 467.2525.
Example 235
[1364] 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
[1365] HRMS: calcd for C27H31N9O3+H+, 530.26226; found (ESI, [M+H]+
Obs'd), 530.2638.
Example 236
[1366] Preparation of
1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methyl-
piperazin-1-yl)carbonyl]phenyl}urea; MS (ESI) m/z 531.1.
Example 237
[1367] 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
[1368] Preparation of
1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4-ethyl-6-m-
orpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; MS (ESI) m/z
558.711
Example 239
[1369] Preparation of
1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(hydroxyme-
thyl)phenyl]urea; MS (ESI) m/z 462.554.
Example 240
[1370] 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
[1371] Preparation of
1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-{[4-(dimet-
hylamino)piperidin-1-yl]carbonyl}phenyl)urea; MS (ESI) m/z
586.741.
Example 242
[1372] 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
[1373] Preparation of
N-[2-(dimethylamino)ethyl]-4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triaz-
in-2-yl)phenyl]carbamoyl}amino)-N-methylbenzamide; MS (ESI) m/z
534.62.
Example 244
[1374] Preparation of
N-[2-(dimethylamino)ethyl]-4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triaz-
in-2-yl)phenyl]carbamoyl}amino)benzamide; MS (ESI) m/z 520.60.
Example 245
[1375] Preparation of
4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}am-
ino)-N-methyl-N-[2-(methylamino)ethyl]benzamide; MS (ESI) m/z
520.60.
Example 246
[1376] Preparation of
1-[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-meth-
ylpiperazin-1-yl)carbonyl]phenyl}urea; MS (ESI) m/z 532.61.
Example 247
[1377] Preparation of
1-{4-[(3,3-dimethylpiperazin-1-yl)carbonyl]phenyl}-3-[4-(4-methoxy-6-morp-
holin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; MS (ESI) m/z 546.63.
Example 248
[1378] Preparation of
4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}am-
ino)-N-(2-piperidin-1-ylethyl)benzamide; MS (ESI) m/z 560.66.
Example 249
[1379] Preparation of
1-(4-ethenylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oc-
t-8-yl)-1,3,5-triazin-2-yl]phenyl}urea; MS (ESI) m/z 514.3;
[1380] HRMS: calcd for C28H31N7O3+H+, 514.25611; found (ESI, [M+H]+
Obs'd), 514.2561.
Example 250
[1381] 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;
[1382] HRMS: calcd for C32H41N9O3+H+, 600.34051; found (ESI, [M+H]+
Obs'd), 600.3405.
Example 251
[1383] Preparation of
4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amin-
o)-N-[4-(4-methylpiperazin-1-yl)phenyl]benzamide; MS (ESI) m/z
621.77.
Example 252
[1384] Preparation of
1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-({[2-(dime-
thylamino)ethyl]amino}methyl)phenyl]urea; MS (ESI) m/z 532.71.
Example 253
[1385] Preparation of
4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amin-
o)-N-[4-(4-methylpiperazin-1-yl)phenyl]benzamide; MS (ESI) m/z
649.82.
Example 254
[1386] Preparation of
1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-methyl-
piperazin-1-yl)methyl]phenyl}urea; MS (ESI) m/z 544.728.
Example 255
[1387] Preparation of
1-[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-(4-formylphen-
yl)urea; MS (ESI) m/z 461.2.
Example 256
[1388] 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.degree. C.; MS (ESI) m/z 574.3.
Example 257
[1389] Preparation of tert-butyl
(1R,4R)-5-[4-(4-{[(4-acetylphenyl)carbamoyl]amino}phenyl)-6-morpholin-4-y-
l-1,3,5-triazin-2-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate;
mp 202.degree. C.; MS (ESI) m/z 615.3;
Example 258
[1390] 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
[1391] 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
[1392] 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
[1393] 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
[1394] Preparation of
1-{4-[4-(tert-butylamino)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-tri-
azin-2-yl]phenyl}-3-pyridin-3-ylurea; MS (ESI) m/z 474.57.
Example 263
[1395] Preparation of
4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)-N-
-(pyridin-2-ylmethyl)benzamide;
[1396] mp 296-298.degree. C.; MS (ESI) m/z 298.6;
[1397] HRMS: calcd for C31H33N9O4+H+, 596.27283; found (ESI, [M+H]+
Obs'd), 596.2724.
[1398] HRMS: calcd for C31H33N9O4+H+, 596.27283; found (ESI, [M+H]+
Calc'd), 596.2728.
Example 264
[1399] 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;
[1400] HRMS: calcd for C32H39N9O3+H+, 598.32486; found (ESI, [M+H]+
Obs'd), 598.3247.
[1401] HRMS: calcd for C32H39N9O3+H+, 598.32486; found (ESI, [M+H]+
Calc'd), 598.3249.
Example 265
[1402] 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;
[1403] HRMS: calcd for C33H41N9O3+H+, 612.34051; found (ESI, [M+H]+
Obs'd), 612.3402.
Example 266
[1404] Preparation of
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-8-a-
zabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}urea
[1405] HRMS: calcd for C30H38N8O4+H+, 575.30888; found (ESI, [M+H]+
Obs'd), 575.3088.
[1406] HRMS: calcd for C30H38N8O4+H+, 575.30888; found (ESI, [M+H]+
Calc'd), 575.3089.
Example 267
[1407] Preparation of
1-(4-{4-[2-(1,3-dioxan-2-yl)ethyl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}ph-
enyl)-3-pyridin-4-ylurea
[1408] HRMS: calcd for C25H29N7O4+H+, 492.23538; found (ESI, [M+H]+
Obs'd), 492.2364.
Example 268
[1409] Preparation of
1-(4-{4-[2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-morpholin-4-yl-1,3,5-tr-
iazin-2-yl}phenyl)-3-pyridin-4-ylurea
[1410] HRMS: calcd for C25H30N8O4+H+, 507.24628; found (ESI, [M+H]+
Obs'd), 507.2471.
Example 269
[1411] Preparation of
4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amin-
o)-N-{4-[2-(dimethylamino)ethoxy]phenyl}benzamide; MS (ESI) m/z
638.773.
Example 270
[1412] 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
[1413] Preparation of
4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amin-
o)-N-(1-methylpiperidin-4-yl)benzamide; MS (ESI) m/z 545.3.
Example 272
[1414] Preparation of
4-({[4-(4-butyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amin-
o)-N-(1-methylpiperidin-4-yl)benzamide; MS (ESI) m/z 573.4.
Example 273
[1415] 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
[1416] Preparation of
1-(4-{4-[3-(dimethylamino)propyl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phe-
nyl)-3-pyridin-4-ylurea; MS (ESI) m/z 462.56.
Example 275
[1417] 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
[1418] Preparation of
1-{4-[4-morpholin-4-yl-6-(3-pyrrolidin-1-ylpropyl)-1,3,5-triazin-2-yl]phe-
nyl}-3-pyridin-4-ylurea; MS (ESI) m/z 488.60.
Example 277
[1419] 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
[1420] 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
[1421] Preparation of
1-{4-[4-(3-hydroxypropyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-p-
yridin-4-ylurea; MS (ESI) m/z 435.49.
Example 280
[1422] Preparation of
1-{4-[4-morpholin-4-yl-6-(3-oxopropyl)-1,3,5-triazin-2-yl]phenyl}-3-pyrid-
in-4-ylurea; MS (ESI) m/z 433.47.
Example 281
[1423] 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
[1424] HRMS: calcd for C30H37N9O5+H+, 604.29904; found (ESI, [M+H]+
Obs'd), 604.2993.
Example 282
[1425] Preparation of
1-{4-[4-(6,8-dioxa-3-azabicyclo[3.2.1]oct-3-yl)-6-morpholin-4-yl-1,3,5-tr-
iazin-2-yl]phenyl}-3-pyridin-4-ylurea
[1426] HRMS: calcd for C24H26N8O4+H+, 491.21498; found (ESI, [M+H]+
Obs'd), 491.2155.
Example 283
[1427] Preparation of
1-{4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]p-
henyl}-3-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)urea;
MS (ESI) m/z 612.759.
Example 284
[1428] 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
[1429] 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
[1430] 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
[1431] 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
[1432] 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
[1433] 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
[1434] Preparation of
1-{4-[4-morpholin-4-yl-6-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-1,3,5-tr-
iazin-2-yl]phenyl}-3-pyridin-4-ylurea; MS (ESI) m/z 503.57.
Example 291
[1435] 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
[1436] 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
[1437] Preparation of
1-(4-{4-[7-(methylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-6-morp-
holin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea; MS (ESI)
m/z 581.66.
Example 294
[1438] 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
[1439] 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
[1440] Preparation of
1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-[4-(4-methylp-
iperazin-1-yl)phenyl]urea; MS (ESI) m/z 503.
Example 297
[1441] 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
[1442] Preparation of
1-{4-[(3,3-dimethylpiperazin-1-yl)carbonyl]phenyl}-3-[4-(4-ethyl-6-morpho-
lin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; MS (ESI) m/z 544.684.
Example 299
[1443] Preparation of
4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amin-
o)-N-(1-methylazetidin-3-yl)benzamide
[1444] MS (ESI) m/z 517.3;
[1445] MS (ESI) m/z 259.2;
Example 300
[1446] Preparation of methyl
4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carb-
amoyl)amino]benzoate
[1447] mp 218.degree. C.;
[1448] MS (ESI) m/z 477.3.
Example 301
[1449] Preparation of
4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carb-
amoyl)amino]benzoic acid
[1450] MS (ESI) m/z 463.3.
Example 302
[1451] Preparation of
tert-butyl-(1R,4R)-5-{4-[4-({[4-(1-hydroxyethyl)phenyl]carbamoyl}amino)ph-
enyl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}-2,5-diazabicyclo[2.2.1]heptane--
2-carboxylate
[1452] MS (ESI) m/z 617.4.
Example 303
[1453] Preparation of
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oc-
t-8-yl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}ur-
ea
[1454] HRMS: calcd for C33H41N9O3+H+, 612.34051; found (ESI, [M+H]+
Obs'd), 612.3402.
[1455] HRMS: calcd for C33H41N9O3+H+, 612.34051; found (ESI, [M+H]+
Calc'd), 612.3405.
Example 304
[1456] 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
[1457] 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
[1458] 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
[1459] 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
[1460] Preparation of
1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-(1-methyl-
ethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea; MS (ESI)
m/z 572.72.
Example 309
[1461] Preparation of
4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carb-
amoyl)amino]-N-pyridin-4-ylbenzamide; MS (ESI) m/z 538.61.
Example 310
[1462] Preparation of
4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}carb-
amoyl)amino]-N-pyridin-3-ylbenzamide; MS (ESI) m/z 538.61.
Example 311
[1463] Preparation of
N-cyclobutyl-4-[({4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2-y-
l]phenyl}carbamoyl)amino]benzamide; MS (ESI) m/z 515.62.
Example 312
[1464] Preparation of
1-{4-[4,6-di-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1,3,5-triazin-2-y-
l]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea; MS (ESI) m/z
583.70.
Example 313
[1465] Preparation of
1-{4-[4,6-di-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1,3,5-triazin-2-y-
l]phenyl}-3-(4-piperazin-1-ylphenyl)urea; MS (ESI) m/z 569.67.
Example 314
[1466] Preparation of
1-{4-[4,6-di-(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1,3,5-triazin-2-y-
l]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea; MS (ESI) m/z
583.70.
Example 315
[1467] 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
[1468] 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
[1469] Preparation of
1-methyl-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-aza-
bicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea; MS (ESI)
m/z 529.67.
Example 318
[1470] 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
[1471]
1-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-azabic-
yclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}-3-phenylurea; MS
(ESI) m/z 591.72.
Example 320
[1472] Preparation of
1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-{4-[(4-phenyl-
piperidin-1-yl)carbonyl]phenyl}urea
[1473] MS m/z 08-301429LMS.
Example 321
[1474] Preparation of
4-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amin-
o)-N-(pyridin-4-ylmethyl)benzamide
[1475] MS (ESI) m/z 539.4;
[1476] MS (ESI) m/z 270.2.
Example 322
[1477] Preparation of 1-{4-[(4-methyl
piperazin-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
[1478] Preparation of
1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-{4-[4-(2-methyl-
propyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea; MS (ESI)
m/z 586.765.
Example 324
[1479] Preparation of
N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-(2-methylpropyl)-6-morpholi-
n-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; MS
(ESI) m/z 560.727.
Example 325
[1480] Preparation of
1-methyl-3-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-yl-
phenyl)amino]-1,3,5-triazin-2-yl}phenyl)urea; MS (ESI) m/z
515.62.
Example 326
[1481] 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
[1482] Preparation of
1-(2-fluoroethyl)-3-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piper-
azin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)urea; MS (ESI) m/z
547.64.
Example 328
[1483] Preparation of
1-(2-hydroxyethyl)-3-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-pipe-
razin-1-ylphenyl)amino]-1,3,5-triazin-2-yl}phenyl)urea; MS (ESI)
m/z 545.65.
Example 329
[1484] 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
[1485] Preparation of
1-(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-[(4-piperazin-1-ylphenyl)am-
ino]-1,3,5-triazin-2-yl}phenyl)-3-phenylurea; MS (ESI) m/z
577.69.
Example 331
[1486] Preparation of
1-methyl-3-{4-[4-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(8-oxa-3-aza-
bicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]phenyl}urea; MS (ESI)
m/z 529.67.
Example 332
[1487] 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
[1488] 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
[1489] 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
[1490] 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
[1491] 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
[1492] MS (ESI) m/z 566.4; HRMS: calcd for C30H31N9O3+H+,
566.26226; found (ESI, [M+H]+ Calc'd), 566.2623.
Example 337
[1493] 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
[1494] MS (ESI) m/z 593.5.
Example 338
[1495] Preparation of
N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-(4-methylphenyl)-6-morpholi-
n-4-yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide; MS
(ESI) m/z 595.5.
Example 339
[1496] 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
[1497] MS (ESI) m/z 593.4.
Example 340
[1498] Preparation of
1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-py-
ridin-4-ylurea. MS (ESI) m/z 468.3.
Example 341
[1499] 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
[1500] Preparation of
4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}car-
bamoyl)amino]benzoic acid, MS (ESI) m/z 511.4.
Example 343
[1501] 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
[1502] Preparation of methyl
4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}car-
bamoyl)amino]benzoate; MS (ESI) m/z 525.4.
Example 345
[1503] Preparation of
1-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-3-[4-(4-morpholin-4-yl-6-ph-
enyl-1,3,5-triazin-2-yl)phenyl]urea; MS (ESI) m/z 578.745
Example 346
[1504] Preparation of
1-[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-yl-
urea; MS (ESI) m/z 454.1.
Preparation of (2S,5R)-pyrrolidine-2,5-diyldimethanol
hydrochloride
[1505] ((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 Celite.TM. 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.sup.+)=132.2 (M+H).sup.+
Preparation of
((2S,5R)-1-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-
-diyl)dimethanol
[1506] 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.degree. 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 Buchner 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.sup.+)=417.2 (M+morpholine-Cl).sup.+
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
[1507] 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.degree. 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.sup.+)=443.2 (M+H).sup.+
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
[1508] 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.sup.+)=671.4
(M+H).sup.+
Preparation of
4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis((tert-butyl-
dimethylsilyloxy)methyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)aniline
[1509] A suspension of palladium on charcoal (10%, 50 mg) and
8-(4-((2S,5R)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidin-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 Celite.TM. diatomaceous earth and concentrated under reduced
pressure to provide the title compound as a tan foam (0.42 g, 80%).
MS (ES.sup.+)=642.4 (M+H).sup.+
Example 347
[1510] Preparation of
1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-(3-oxa-8-azabic-
yclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
[1511] A solution of
4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis((tert-butyl-
dimethylsilyloxy)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 .mu.L) and a triphosgene (24 mg, 0.08
mmol) solution in dichloromethane (500 .mu.L). 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.sup.+)=533.3
(M+H).sup.+
Example 348
[1512] Preparation of
1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-(3-oxa-8-azabic-
yclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1--
yl)phenyl]urea
[1513] A solution of
4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((2S,5R)-2,5-bis((tert-butyl-
dimethylsilyloxy)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 .mu.L) and a triphosgene (24 mg, 0.08
mmol) solution in dichloromethane (500 .mu.L). 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.sup.+)=630.4 (M+H).sup.+
Example 349
[1514] 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
[1515] 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
[1516] Preparation of
1-(4-aminophenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ur-
ea; MS (ESI) m/z 477.1.
Example 352
[1517] Preparation of
N-[4-({[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)ph-
enyl]carbamoyl}amino)phenyl]-N2,N2-dimethylglycinamide
[1518] 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
[1519] Preparation of
N-[4-({[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-1,3,5-triazin-2-yl)ph-
enyl]carbamoyl}amino)phenyl]-2-pyrrolidin-1-ylacetamide
[1520] 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
[1521] Preparation of
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenyl-
amino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea
[1522] 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
[1523] Preparation of
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenyl-
amino)-1,3,5-triazin-2-yl)phenyl)-3-cyclopropylurea
[1524] 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
[1525] Preparation of
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenyl-
amino)-1,3,5-triazin-2-yl)phenyl)-3-(2-fluoroethyl)urea
[1526] 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
[1527] Preparation of
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenyl-
amino)-1,3,5-triazin-2-yl)phenyl)-3-(2-hydroxyethyl)urea
[1528] 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
[1529] Preparation of
4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phe-
nylamino)-1,3,5-triazin-2-yl)phenyl)ureido)benzamide
[1530] 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
[1531] Preparation of
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(piperazin-1-yl)phenyl-
amino)-1,3,5-triazin-2-yl)phenyl)-3-phenylurea
[1532] 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
[1533] 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
[1534] 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
[1535] 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
[1536] Prepared as shown in Scheme 1, using
N1-(2-(dimethylamino)ethyl)-N1-methylbenzene-1,4-diamine in the
urea formation step. (M+H) 614.3.
[1537] The required benzene-1,4-diamine intermediates for the
following compounds were prepared as outlined in Scheme 4.
Example 362
[1538] 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
[1539] 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
[1540] Prepared from 4-fluoronitrobenzene and the appropriate amine
as shown in Scheme 4.
Example 363
[1541] 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
[1542] 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
[1543] Prepared from 4-fluoronitrobenzene and the appropriate amine
as shown in Scheme 4.
Example 364
[1544] 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
[1545] 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
[1546] Prepared from 4-fluoronitrobenzene and the appropriate amine
as shown in Scheme 4.
Example 365
[1547] 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
[1548] 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
[1549] Prepared from 4-fluoronitrobenzene and the appropriate amine
as shown in Scheme 4.
Example 366
[1550] Preparation of
1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phen-
yl)-3-(4-(piperazin-1-ylmethyl)phenyl)urea
[1551] 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
[1552] Preparation of
1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phen-
yl)-3-(4-((dimethylamino)methyl)phenyl)urea
[1553] Prepared as shown in Scheme 1, using commercially available
4-((dimethylamino)methyl)aniline in the urea formation step. (M+H)
571.3.
Example 368
[1554] Preparation of
1-(4-(aminomethyl)phenyl)-3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-y-
l)-1,3,5-triazin-2-yl)phenyl)urea
[1555] 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
[1556] Preparation of
1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phen-
yl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)urea
[1557] 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
[1558] Preparation of
1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phen-
yl)-3-(4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)urea
[1559] Prepared as shown in Scheme 1, using
4-(2-(4-methylpiperazin-1-yl)ethoxy)aniline in the urea formation
step. (M+H) 656.4.
[1560] The required 4-(alkoxy)aniline intermediates for the
following compounds were prepared as outlined in Scheme 5.
Example 371
[1561] Preparation of
1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phen-
yl)-3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)urea
[1562] 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
[1563] Prepared from 4-fluoronitrobenzene and the appropriate
alcohol as shown in Scheme 5.
Example 372
[1564] Preparation of
1-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)phen-
yl)-3-(4-(2-hydroxyethoxy)phenyl)urea
[1565] 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
[1566] Prepared from 4-fluoronitrobenzene and the appropriate
alcohol as shown in Scheme 5.
Example 373
[1567] Preparation of
N-(4-(3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-y-
l)phenyl)ureido)phenyl)-2-(dimethylamino)acetamide
[1568] 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
[1569] Preparation of
N-(4-(3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-y-
l)phenyl)ureido)phenyl)-2-(4-methylpiperazin-1-yl)acetamide
[1570] 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
[1571] Preparation of
N-(4-(3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-y-
l)phenyl)ureido)phenyl)-2-(pyrrolidin-1-yl)acetamide
[1572] 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
[1573] Preparation of
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-tr-
iazin-2-yl)phenyl)-3-(pyridin-3-yl)urea
[1574] Prepared as shown in Scheme 1, using commercially available
pyridin-3-amine in the urea formation step. (M+H) 461.2.
Example 377
[1575] Preparation of
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-tr-
iazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
[1576] Prepared as shown in Scheme 1, using commercially available
pyridin-4-amine in the urea formation step. (M+H) 461.2.
Example 378
[1577] Preparation of
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-tr-
iazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea
[1578] 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
[1579] Preparation of
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-tr-
iazin-2-yl)phenyl)-3-(4-((4-methyl
piperazin-1-yl)methyl)phenyl)urea
[1580] 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
[1581] Preparation of
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-tr-
iazin-2-yl)phenyl)-3-(4-(piperazin-1-ylmethyl)phenyl)urea
[1582] 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
[1583] Preparation of
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-tr-
iazin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea
[1584] Prepared as shown in Scheme 1, using commercially available
4-((dimethylamino)methyl)aniline in the urea formation step. (M+H)
517.3.
Example 382
[1585] Preparation of
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-tr-
iazin-2-yl)phenyl)-3-(4-(aminomethyl)phenyl)urea
[1586] 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
[1587] Preparation of
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-tr-
iazin-2-yl)phenyl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)urea
[1588] 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
[1589] Preparation of
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-tr-
iazin-2-yl)phenyl)-3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)urea
[1590] 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
[1591] Preparation of
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-tr-
iazin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea
[1592] 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
[1593] Prepared from 4-fluoronitrobenzene and the appropriate
alcohol as shown in Scheme 5.
Example 386
[1594] Preparation of
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-tr-
iazin-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea
[1595] 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
[1596] Preparation of
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-tr-
iazin-2-yl)phenyl)-3-(4-(piperazin-1-yl)phenyl)urea
[1597] 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
[1598] Preparation of
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(isopropylamino)-1,3,5-tr-
iazin-2-yl)phenyl)-3-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)urea
[1599] 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
[1600] 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
[1601] 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
[1602] 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
[1603] Prepared as shown in Scheme 1, using commercially available
4-((dimethylamino)methyl)aniline in the urea formation step. (M+H)
531.3.
Example 391
[1604] 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
[1605] Prepared as shown in Scheme 1, using
4-(2-(dimethylamino)ethoxy)aniline in the urea formation step.
(M+H) 561.3.
Example 392
[1606] Preparation of
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-tria-
zin-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
[1607] 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.degree. 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-azabicy-
clo[3.2.1]octane
[1608] 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).
[1609] The resulting light tan suspension was allowed to stir at
60.degree. 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-azabicy-
clo[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
[1610] A suspension of
8-(4-(4-nitrophenyl)-6-thiomorpholino-1,3,5-triazin-2-yl)-3-oxa-8-azabicy-
clo[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-tria-
zin-2-yl)phenyl)-3-(pyridin-3-yl)urea
[1611] 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-tria-
zin-2-yl)phenyl)-3-(pyridin-3-yl)urea (0.032 g, 63%) as an
off-white solid. (M+H) 505.2.
Example 393
[1612] Preparation of
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-tria-
zin-2-yl)phenyl)-3-(pyridin-4-yl)urea
[1613] 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
[1614] Preparation of
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-tria-
zin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea
[1615] 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
[1616] Preparation of
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-tria-
zin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea
[1617] 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
[1618] Preparation of
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-tria-
zin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea
[1619] 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
[1620] Preparation of
1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyrid-
in-4-yl)urea
[1621] 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
[1622] Preparation of
1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyrid-
in-3-yl)urea
[1623] 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
[1624] 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
[1625] 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
[1626] 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
[1627] 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
[1628] Preparation of
1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((d-
imethylamino)methyl)phenyl)urea
[1629] 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
[1630] Preparation of
1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(2--
(dimethylamino)ethoxy)phenyl)urea
[1631] 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
[1632] 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
[1633] 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
[1634] Preparation of
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3,6-dihydro-2H-pyran-4-y-
l)-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
[1635] 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
[1636] 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.degree. 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.degree. C. by
microwave for additional 90 minutes. The suspension was then cooled
to room temperature and filtered through Celite.TM.. 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
[1637] A mixture of iron powder (0.071 g, 1.27 mmoles) in acetic
acid (2 ml) was heated to 55.degree. 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.times.)
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-pyra-
n-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-y-
l)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
[1638] 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-y-
l)-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
[1639] Preparation of
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3,6-dihydro-2H-pyran-4-y-
l)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methyl
piperazin-1-yl)phenyl)urea:
[1640] 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
[1641] 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:
[1642] 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
[1643] 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 Celite.TM., 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
[1644] 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
[1645] 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:
[1646] 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
[1647] 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:
[1648] 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
[1649] 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:
[1650] 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
[1651] Preparation of
1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmor-
pholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea:
[1652] 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
[1653] Preparation of
1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmor-
pholino)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-3-yl)urea
[1654] 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
[1655] Preparation of
1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmor-
pholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)ur-
ea:
[1656] 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
[1657] Preparation of
1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmor-
pholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)p-
henyl)urea:
[1658] 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
[1659] Preparation of
1-(4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-((R)-3-methylmor-
pholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(pyrrolidin-1-ylmethyl)phenyl)ure-
a:
[1660] 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
[1661] 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:
[1662] 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
[1663] 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:
[1664] 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
[1665] 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:
[1666] 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
[1667] 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:
[1668] 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
[1669] 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:
[1670] 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
[1671] Preparation of
(R)-1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triaz-
in-2-yl)phenyl)-3-(pyridin-3-yl)urea:
[1672] 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
[1673] Preparation of
(R)-1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triaz-
in-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea:
[1674] 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
[1675] Preparation of
(R)-1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triaz-
in-2-yl)phenyl)-3-(4-(piperazin-1-yl)phenyl)urea:
[1676] 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
[1677] Preparation of
1-(4-(4-((R)-3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triaz-
in-2-yl)phenyl)-3-(4-((S)-3-methylpiperazin-1-yl)phenyl)urea:
[1678] 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
[1679] Prepared from 4-fluoronitrobenzene and the appropriate amine
as shown in Scheme 4.
Example 424
[1680] Preparation of
1-(4-(4-((R)-3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triaz-
in-2-yl)phenyl)-3-(4-((R)-3-methylpiperazin-1-yl)phenyl)urea:
[1681] 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
[1682] Prepared from 4-fluoronitrobenzene and the appropriate amine
as shown in Scheme 4.
Example 425
[1683] Preparation of
1-(4-((3R,5S)-3,5-dimethylpiperazin-1-yl)phenyl)-3-(4-(4-((R)-3-methylmor-
pholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea:
[1684] 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
[1685] Prepared from 4-fluoronitrobenzene and the appropriate amine
as shown in Scheme 4.
Example 426
[1686] Preparation of
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-sulfoxymorpholino-1,3,5-t-
riazin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea:
[1687] 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-tria-
zin-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-t-
riazin-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
[1688] 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:
[1689] 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
[1690] Preparation of
(R)-1-(4-(4-ethylpiperazin-1-yl)phenyl)-3-(4-(4-(3-methylmorpholino)-6-(t-
etrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea:
[1691] 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
[1692] 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:
[1693] 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
[1694] Prepared from 4-fluoronitrobenzene and the appropriate amine
as shown in Scheme 4.
Example 430
[1695] Preparation of
(R)-1-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)-3-(4-(4-(3-methylmorpho-
lino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea:
[1696] 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
[1697] Preparation of
(R)-1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triaz-
in-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea:
[1698] 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.
[1699] The (4-aminophenyl)(piperazin-1-yl)methanone intermediates
prepared as shown in Scheme 8 were used to make the following
compounds.
Example 432
[1700] Preparation of
(R)-1-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)-3-(4-(4-(3-methylmorph-
olino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)phenyl)urea:
[1701] 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
[1702] Prepared from 4-nitrobenzoyl chloride and the appropriate
amine as shown in Scheme 8.
Example 433
[1703] Preparation of
(R)-1-(4-(4-(3-methylmorpholino)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triaz-
in-2-yl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)urea:
[1704] 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
[1705] 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:
[1706] 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
[1707] 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:
[1708] 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
[1709] 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-
:
[1710] 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.
[1711] Preparation of 4-(4-cyclopropylpiperazin-1-yl)aniline:
[1712] Prepared from 4-fluoronitrobenzene and the appropriate amine
as shown in Scheme 4.
Example 437
[1713] 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:
[1714] 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
[1715] 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)ur-
ea:
[1716] 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
[1717] 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:
[1718] 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.
[1719] 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
[1720] 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
[1721] 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.degree.
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
[1722] 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.degree. 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
[1723] A solution of
8-(4-((R)-3-methylmorpholino)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-
-8-azabicyclo[3.2.1]octane (0.915 g, 2.22 mmol) in ethyl acetate
(10 ml), methanol (10 ml), and methylene chloride (5 ml--added due
to poor solubility of SM in EA/methanol) was prepared and 10%
palladium on carbon (0.270 g, 30% by weight) was added. The flask
was purged with hydrogen gas (balloon) and allowed to stir under
positive pressure of hydrogen for 16 hours. The suspension was
filtered through Celite.TM., 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-methylmorphol-
ino)-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
[1724] 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
[1725] 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:
[1726] 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
[1727] 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:
[1728] 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
[1729] 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)ur-
ea:
[1730] 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
[1731] 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-
:
[1732] 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
[1733] 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)u-
rea:
[1734] 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
[1735] 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-methyl
piperazin-1-yl)pyridin-3-yl)urea:
[1736] 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
[1737] 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:
[1738] 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
[1739] 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:
[1740] 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
[1741] 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:
[1742] 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
[1743] 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:
[1744] 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
[1745] 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:
[1746] 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
[1747] Preparation of
4-(3-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)ureido-
)-N,N-dimethylbenzamide:
[1748] 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
[1749] Preparation of
1-(4-(4,6-bis((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-(4-(py-
rrolidin-1-ylmethyl)phenyl)urea:
[1750] 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
[1751] 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:
[1752] 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
[1753] 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:
[1754] 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
[1755] 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:
[1756] 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
[1757] Prepared from 4-nitrobenzoyl chloride and the appropriate
amine as shown in Scheme 8.
Example 457
[1758] 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-
:
[1759] 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
[1760] Prepared from 4-nitrobenzoyl chloride and the appropriate
amine as shown in Scheme 8.
Example 458
[1761] 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:
[1762] 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
[1763] Prepared from 4-nitrobenzoyl chloride and the appropriate
amine as shown in Scheme 8.
Example 459
[1764] 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-methyl-
benzamide:
[1765] 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
[1766] Prepared from 4-nitrobenzoyl chloride and the appropriate
amine as shown in Scheme 8.
Example 460
[1767] 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:
[1768] 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
[1769] Prepared from 4-nitrobenzoyl chloride and the appropriate
amine as shown in Scheme 8.
Example 461
[1770] Preparation of
1-(4-(2-aminoethylamino)phenyl)-3-(4-(4,6-di(3-oxa-8-azabicyclo[3.2.1]oct-
an-8-yl)-1,3,5-triazin-2-yl)phenyl)urea:
[1771] 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
[1772] Prepared from 4-fluoronitrobenzene and the appropriate amine
as shown in Scheme 4.
Example 462
[1773] Preparation of
4-({[4-(4-{4-[(methylcarbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triaz-
in-2-yl)phenyl]carbamoyl}amino)benzamide
Step 1: Preparation of phenyl 4-(4, 4, 5, 5-tetramethyl-1, 3,
2-dioxaborolan-2-yl)phenylcarbamate
[1774] 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.degree. C. The reaction mixture was stirred at -10.degree. 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.times.70 mL). The organic layer was dried over
anhydrous Na.sub.2SO.sub.4 and concentrated to get the crude
product. Then the crude product was dissolved in diethyl ether (15
mL) and sonicated for 10 min and then pentane (30 mL) was added.
the resulting solid was filtered and washed with pentane to give
phenyl 4-(4, 4, 5, 5-tetramethyl-1, 3,
2-dioxaborolan-2-yl)phenylcarbamate (26 g, 88% yield).
[1775] .sup.1HNMR (300 MHz, CDCl.sub.3): .delta. 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
[1776] A mixture of phenyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (26
g, 76.6 mmol)), 2.0M Methylamine/THF (265 mL, 530 mmol) in 150 mL
of THF was stirred at room temperature for 6 hours, then excess
solvent was distilled off from the reaction mixture; residue was
dissolved into water, extracted with ethyl acetate. The organic
layer was dried over anhydrous Na.sub.2SO.sub.4, concentrated under
reduced pressure. The crude product was purified by silica gel
column chromatography by using 5-60% ethyl acetate in pet-ether as
an eluent. to give
1-methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea-
. (20 g, 88% yield) as white solid.
[1777] .sup.1HNMR (300 MHz, CDCl.sub.3): .delta. 7.7 (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
[1778] 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.degree. C. for 1 hour. Reaction mixture was diluted
with water, extracted with dichloromethane. The organic layer was
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure. Crude product was purified by silica gel
(100-200 mesh) column chromatography using 5% ethyl acetate in
pet-ether as an eluent to give
4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine (10 g, 39%
yield).
Step 4: Preparation of
1-(4-(4-chloro-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea
[1779] A mixture of compound
4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine (10 g, 42.7 mmol), Pd
(PPh.sub.3).sub.4 (2.46 g, 2.1 mmol),
1-methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea-
. (11.7 g, 42.4 mmol) and 1N Na.sub.2CO.sub.3 (168 mL, 168 mmol) in
degassed 1,2-dimethoxyethane (400 mL) was heated to 65.degree. C.
for 8 hours under N.sub.2 atmosphere. The reaction mixture
filtered, diluted with water, extracted with ethyl acetate and
washed with water, brine, dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure. Crude product was
purified by silica gel (100-200 mesh) column chromatography using
20-60% ethyl acetate in pet-ether as an eluent. To give
1-(4-(4-chloro-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea
(5.0 g, 34% yield).
[1780] .sup.1HNMR (300 MHz, DMSO-d6): .delta. 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-methylu-
rea
[1781] 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
[1782] To a solution of 4-aminobenzamide (5.0 g, 36.7 mmol) and
pyridine (2.9 g, 36.7 mmol)) in dry CH.sub.2Cl.sub.2 (100 mL) at
-10.degree. C., phenyl chloroformate (6.9 g, 44.1 mmol) was added
dropwise, stirred at -10.degree. C. for 30 min and then at room
temperature for 30 minutes The reaction mixture was diluted with
CH.sub.2Cl.sub.2 (100 mL) and washed with water (2.times.70 mL).
The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and
concentrated to get the crude product. The crude product was
dissolved in diethyl ether (15 mL) and sonicated for 10 minutes and
then pentane (30 mL) was added, the resulting solid was filtered
and washed with pentane to give phenyl 4-carbamoylphenylcarbamate
(7.2 g, 77% yield).
Step 7: Preparation of
4-({[4-(4-{4-[(methylcarbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triaz-
in-2-yl)phenyl]carbamoyl}amino)benzamide
[1783] To a solution of
1-(4-(4-(4-aminophenyl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylu-
rea (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.degree. 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-triaz-
in-2-yl)phenyl]carbamoyl}amino)benzamide (45 mg, 5.3% yield).
Example 463
[1784] 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
[1785] 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.
[1786] .sup.1HNMR (300 MHz, CDCl.sub.3): .delta. 4.6 (m, 2H), 3.6
(m, 2H), 2.8 (m, 2H), 1.2 (d, 6H).
Step 2: Preparation of
1-(4-(4-chloro-6-(3,5-dimethylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-me-
thylurea
[1787] The title compound was prepared by following the procedure
of example 462 step 4 using
4-(4,6-dichloro-1,3,5-triazin-2-yl)-3,5-dimethylmorpholine and
1-methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea-
. Yield 1.15 g, 16% yield.
Step 3: Preparation of
1-(4-(4-(4-aminophenyl)-6-(3,5-dimethylmorpholino)-1,3,5-triazin-2-yl)phe-
nyl)-3-methylurea
[1788] 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-me-
thylurea 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
[1789] 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
[1790] 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)phe-
nyl)-3-methylurea and phenyl pyridin-3-ylcarbamate. Yield 77 mg, 6%
yield.
Example 464
[1791] 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
[1792] 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
[1793] 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-tri-
azin-2-yl)phenyl)-3-methylurea
[1794] 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
[1795] 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-tri-
azin-2-yl)phenyl)-3-methylurea and phenyl
4-carbamoylphenylcarbamate. Yield 90 mg, 13% yield.
Example 465
[1796] 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
[1797] 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
[1798] 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-tri-
azin-2-yl)phenyl)-3-methylurea and phenyl
3-carbamoylphenylcarbamate. Yield 90 mg, 13% yield.
Example: 466
[1799] Preparation of
3-({[4-(4-{4-[(methylcarbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triaz-
in-2-yl)phenyl]carbamoyl}amino)benzamide
[1800] 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-methylu-
rea and phenyl 3-carbamoylphenylcarbamate. Yield 51 mg, 4%
yield.
Example 467
[1801] 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
[1802] 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-methylu-
rea and phenyl pyridin-3-ylcarbamate. Yield 77 mg, 6% yield.
Example 468
[1803] 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
[1804] 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
[1805] 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-methylu-
rea and phenyl pyridin-4-ylcarbamate. Yield 75 mg, 3.9% yield.
Example 469
[1806] Preparation of
3-[({4-[4-(3,5-dimethylmorpholin-4-yl)-6-{4-[(methylcarbamoyl)amino]pheny-
l}-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide
[1807] 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)phe-
nyl)-3-methylurea and phenyl 3-carbamoylphenylcarbamate. Yield 56
mg, 4.1% yield.
Example 470
[1808] Preparation of
4-[({4-[4-(3,5-dimethylmorpholin-4-yl)-6-{4-[(methylcarbamoyl)amino]pheny-
l}-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzamide
[1809] 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)phe-
nyl)-3-methylurea and phenyl 4-carbamoylphenylcarbamate. Yield 70
mg, 12.8% yield.
Example 471
[1810] Preparation of
1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-{4-[(pyridin-4-ylc-
arbamoyl)amino]phenyl}-1,3,5-triazin-2-yl]phenyl}urea
[1811] 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-tri-
azin-2-yl)phenyl)-3-methylurea and phenyl pyridin-4-ylcarbamate.
Yield 51 mg, 4% yield.
Example 472
[1812] 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
[1813] 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)phe-
nyl)-3-methylurea and phenyl pyridin-4-ylcarbamate. Yield 15 mg,
0.8% yield.
Example 473
[1814] 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
[1815] 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.degree. C. Then the reaction mixture was
stirred at 0.degree. 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
[1816] 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.degree. 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-difluoroacetami-
de
[1817] 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.degree. 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
[1818] Preparation of
N-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-4,
5-dihydro-1H-imidazol-2-amine
[1819] A mixture of 4-(4,6-dimorpholino-1,3,5-triazin-2-yl)aniline
(40 mg, 0.12 mmol), imidazolidine-2-thione (15 mg, 0.15 mmol0 and
mercury(II) chloride (40 mg, 0.15 mmol) in 2 mL of DMF was stirred
at 140.degree. C. 16 hr. Then the reaction mixture was cooled to
room temperature and filtered through Celite.TM.. 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
[1820] 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
[1821] 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
[1822] 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.degree. 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
[1823] 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
[1824] 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
[1825] 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
[1826] Preparation of
2-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-N-pyridin-3-ylaceta-
mide
Step 1: Preparation of
2-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)acetic acid
[1827] 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.degree.
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-ylaceta-
mide
[1828] 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
[1829] 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.sup.+)=443.2
(M+H).sup.+
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
[1830] 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.sup.+)=671.4 (M+H).sup.+
Preparation of
4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis((tert-butyl-
dimethylsilyloxy)methyl)pyrrolidin-1-yl)-1,3,5-triazin-2-yl)aniline
[1831] A suspension of palladium on charcoal (10%, 100 mg) and
crude
3-(4-((2S,5R)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidin-yl)-6-
-(4-nitrophenyl)-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane
(3.4 mmol maximum) in tetrahydrofuran (30 mL) was shaken for 8
hours under 50 psi of hydrogen. The mixture was filtered through a
pad of Celite.TM. diatomaceous earth and concentrated under reduced
pressure to provide the title compound as an orange foam. MS
(ES.sup.+)=642.4 (M+H).sup.+
Example 667
[1832] Preparation of
1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-(8-oxa-3-azabic-
yclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea
[1833] A solution of
4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis((tert-butyl-
dimethylsilyloxy)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 .mu.L) 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.sup.+)=533.3
(M+H).sup.+
Example 668
[1834] Preparation of
1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6-(8-oxa-3-azabic-
yclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1--
yl)phenyl]urea
[1835] A solution of
4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-((2S,5R)-2,5-bis((tert-butyl-
dimethylsilyloxy)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 .mu.L) 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.sup.+)=630.4 (M+H).sup.+
Example 823
[1836] Preparation of
1-[4-(4,6-di-3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl-1,3,5-triazin-2-yl)phe-
nyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea
[1837] To a solution of cyanuric chloride (0.368 g, 2 mmol) in
CH.sub.2Cl.sub.2 (20 mL) was added
3,7-dioxa-9-azabicyclo[3.3.1]nonane. HCO.sub.2H (0.718 g, 4.1
mmol), followed by addition of Et.sub.3N (0.98 mL, 7 mmol). The
resulting reaction mixture was stirred for 24 h, and then diluted
with CH.sub.2Cl.sub.2. The organic phase was washed with aqueous 1N
HCl (3.times.) and dried over MgSO.sub.4. 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]n-
onane) as white solid (0.15 g, 95% yield).
[1838] 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]n-
onane) (150 mg, 0.406 mmol), 4-aminophenylboronic acid pinacol
ester (133 mg, 0.61 mmol), Pd(PPh.sub.3).sub.4 (10 mg), toluene (1
mL), EtOH (1 mL) and 2M Na.sub.2CO.sub.3 aqueous solution (0.305
mL). The resulting mixture was heated at 120.degree. 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 (MgSO.sub.4). 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)ani-
line as a white solid (120 mg).
[1839] 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)ani-
line (120 mg, 0.281 mmol) in CH.sub.2Cl.sub.2 was added Et.sub.3N
(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
[1840] (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)
[1841] 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 LiBH.sub.4 solution (2M in THF, 34.7
mL, 69.4 mmol) at 0.degree. C. The resulting mixture was stirred at
room temperature for 3 hours, then cooled to 0.degree. 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
(MgSO.sub.4). The organic solvent was removed in vacuo to give the
crude product, which was purified by flash chromatography in silica
gel with EtOAc:Hex:MeOH(50:50:10) 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-1
H-pyrrole-1-carboxylate
[1842] 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.degree. 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 (MgSO.sub.4). The organic solvent was removed in
vacuo to give the crude product, which was purified by flash
chromatography in silica gel with EtOAc:Hex (10:90) to give 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-carbox-
ylate (trans-alcohol)
[1843] To a solution of (2R',5S')-tert-butyl
2,5-bis((tert-butyldimethylsilyloxy)methyl)-2,5-dihydro-1H-pyrrole-1-carb-
oxylate (4.8 g, 10.5 mmol) in THF (50 mL) was added slowly of
BH.sub.3 DMS solution (2M in THF, 6.97 mL, 13.9 mmol) at 0.degree.
C. The resulting mixture was stirred at room temperature for 3
hours, then cooled to 0.degree. C. again. NaOH solution (5M, 12.6
mL, 63.2 mmol) was added to the reaction mixture, followed by
addition of H.sub.2O.sub.2 (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 (MgSO.sub.4). The organic solvent was removed in
vacuo to give the crude product, which was purified by flash
chromatography in silica gel with EtOAc:Hex (30:70) to give the
title compound (3.8 g, 77%).
Step 5: Benzyl Protection of the Trans Alcohol
[1844] To a solution of (2R',3S',5R')-tert-butyl
2,5-bis((tert-butyldimethylsilyloxy)methyl)-3-hydroxypyrrolidine-1-carbox-
ylate (2.515 g, 5.3 mmol) in THF (50 mL) were added NaH (60%, 0.423
g, 10.6 mmol). The mixture was stirred at room temperature for 30
minutes, and benzyl bromide (1.085 g, 6.3 mmol) and TBAl (0.195 g,
0.5 mmol) were added. The mixture was stirred at room temperature
for 12 hours, and quenched by addition of sat.NH.sub.4CL solution
(20 mL). Concentrated in vacuo, and the residue was taken up in
water and EtOAc. The organic layer was separated, and the aqueous
phase was extracted with EtOAc. Combined organic phases were washed
with water and brine, and dried (MgSO.sub.4). The organic solvent
was removed in vacuo to give the crude product, which was purified
by flash chromatography in silica gel with EtOAc:Hex (10:90) to
give (2R',3S',5R')-tert-butyl
3-(benzyloxy)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidine-1-ca-
rboxylate (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)
[1845] To a solution of (2R',3S',5R')-tert-butyl
3-(benzyloxy)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidine-1-ca-
rboxylate (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.degree. C. The
resulting mixture was stirred at room temperature for 6, and
quenched by addition of sat.NH.sub.4Cl solution (10 mL).
Concentrated in vacuo, and the residue was treated with water and
EtOAc. The organic layer was separated, and the aqueous phase was
extracted with EtOAc. Combined organic phases were washed with
water and brine, and dried (MgSO.sub.4). The organic solvent was
removed in vacuo to give the crude product, which was purified by
flash chromatography in silica gel with EtOAc:Hex:MeOH (50:50:5) to
give the title compound (1.15 g, 62.5%).
Step 7: Synthesis of (6S')-tert-butyl
6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate by
cyclization
[1846] 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.degree. C. A solution of p-TsCl (0.65 g, 3.4
mmol) in THF (5 mL) was slowly added to the mixture. The reaction
mixture was then stirred at room temperature for 12 hours, and
quenched by addition of sat.NH.sub.4Cl solution (20 mL).
Concentrated in vacuo, and the residue was taken up in water and
EtOAc. The organic layer was separated, and the aqueous phase was
extracted with EtOAc. Combined organic phases were washed with
water and brine, and dried (MgSO.sub.4). The organic solvent was
removed in vacuo to give the crude product, which was purified by
flash chromatography in silica gel with EtOAc:Hex (20:80) to give
the title compound (716 mg, 66%) as off-white solid.
[1847] The compounds in Table I were made by the proceeding
methods.
TABLE-US-00001 TABLE ! MS (ESI) Example Name m/z 478
1-(4-{[4-(dimethylamino)piperidin-1- 615.5
yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-
(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2- yl]phenyl}urea 479
1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-(4- 589.6
{4-morpholin-4-yl-6-[(3S)-tetrahydrofuran-3-yloxy]-
1,3,5-triazin-2-yl}phenyl)urea 480
1-{4-[4-(5-hydroxy-3-oxa-7-azabicyclo[4.1.1]oct-7-yl)- 505.3 253.2
6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin- 273.8
4-ylurea 481
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3- 464.2
253.1 pyridazin-4-ylurea 482
1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4- 575.5
[4-morpholin-4-yl-6-(oxetan-3-yloxy)-1,3,5-triazin-2-
yl]phenyl}urea 483 1-{4-[4-morpholin-4-yl-6-(3-oxa-8- 490.6
azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-
pyridazin-4-ylurea 484 1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-
602.5 yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-
triazin-2-yl)phenyl]urea 485
1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1- 602.6
yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-
triazin-2-yl)phenyl]urea 486
1-[4-(4-isopropyl-6-morpholin-4-yl-1,3,5-triazin-2- 545.1 293.5
yl)phenyl]-3-{4-[(4-methylpiperazin-1- 273 yl)carbonyl]phenyl}urea
487 1-{4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin- 497.3
2-yl]phenyl}-3-(4-pyrimidin-5-ylphenyl)urea 488
1-(4-{4-[(2,2-dimethoxyethyl)amino]-6-morpholin-4- 481.2 241.1
yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-3-ylurea 261.6 489
1-{4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin- 496.3 248.6
2-yl]phenyl}-3-(4-pyridin-4-ylphenyl)urea 269.1 490
1-(4-iodophenyl)-3-{4-[4-(1-methylethyl)-6-morpholin- 545.1
4-yl-1,3,5-triazin-2-yl]phenyl}urea 491
1-{4-[4-(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin- 573.4 287.2
2-yl]phenyl}-3-(4-{[4-(1-methylethyl)piperazin-1-
yl]carbonyl}phenyl)urea 492
1-[4-(4-azetidin-1-yl-6-morpholin-4-yl-1,3,5-triazin-2- 586.6
yl)phenyl]-3-(4-{[4-(1-methylethyl)piperazin-1-
yl]carbonyl}phenyl)urea 493
1-{4-[2-(dimethylamino)pyrimidin-5-yl]phenyl}-3-{4-[4- 540.5
(1-methylethyl)-6-morpholin-4-yl-1,3,5-triazin-2- yl]phenyl}urea
494 tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(pyridin-4- 549.6
ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-
yl)oxy]azetidine-1-carboxylate 495
1-(4-{[4-(dimethylamino)piperidin-1- 616.4 308.7
yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-
triazin-2-yl)phenyl]urea 496
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3- 507.1
(4-nitrophenyl)urea 497
1-(4-aminophenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5- 477.1 259.6
triazin-2-yl)phenyl]urea 498
N-[4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2- 603.2 302.1
yl)phenyl]carbamoyl}amino)phenyl]-4- 322.6
methylpiperazine-1-carboxamide 499
4-(dimethylamino)-N-[4-({[4-(4,6-dimorpholin-4-yl- 631.3
1,3,5-triazin-2- yl)phenyl]carbamoyl}amino)phenyl]piperidine-1-
carboxamide 500
1-[2-(dimethylamino)ethyl]-3-[4-({[4-(4,6-dimorpholin- 605.3
4-yl-1,3,5-triazin-2-
yl)phenyl]carbamoyl}amino)phenyl]-1-methylurea 501
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3- 631.3
(4-{[(2-piperidin-1- ylethyl)carbamoyl]amino}phenyl)urea 502
N-[4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2- 617.3
yl)phenyl]carbamoyl}amino)phenyl]-4-methyl-1,4-
diazepane-1-carboxamide 503
N-[4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2- 617.3
yl)phenyl]carbamoyl}amino)phenyl]-4- ethylpiperazine-1-carboxamide
504 1-{4-[(dimethylcarbamoyl)amino]phenyl}-3-[4-(4,6- 548.3
dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea 505
1-{4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl- 613.4
1,3,5-triazin-2-yl]phenyl}-3-(4-{[4-
(dimethylamino)piperidin-1-yl]carbonyl}phenyl)urea 506
4-[({4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4- 587.4
yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-[2-
(dimethylamino)ethyl]-N-methylbenzamide 507
1-{4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl- 585.3
1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1-
yl)carbonyl]phenyl}urea 508
4-[({4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4- 573.3
yl-1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-[2-
(dimethylamino)ethyl]benzamide 509
N-[4-({[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl- 668.4
1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]-2-
(4-methylpiperazin-1-yl)acetamide 510
1-(4-{[4-(dimethylamino)piperidin-1- 615.5
yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-
(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2- yl]phenyl}urea 511
1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4- 587.3
[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-
triazin-2-yl]phenyl}urea 512
N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6- 575.3
(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-
yl]phenyl}carbamoyl)amino]benzamide 513
4-[({4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)- 601.3
1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-
pyrrolidin-1-ylethyl)benzamide 514
4-[({4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)- 615.3
1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-
piperidin-1-ylethyl)benzamide 515
1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3- 616.3
308.6 (4-{[4-(1-methylethyl)piperazin-1- 329.2
yl]carbonyl}phenyl)urea 516
1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1- 627.7
yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-
8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 517
1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1- 449.4
yl]carbonyl}phenyl)-3-{4-[4-morpholin- 518
4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5- 616.4
triazin-2-yl]phenyl}urea 519
N-[2-(dimethylamino)ethyl]-N-methyl-4-{[(4-{4- 616.4
morpholin-4-yl-6-[(3S)-tetrahydrofuran-3-yloxy]-1,3,5-
triazin-2-yl}phenyl)carbamoyl]amino}benzamide 520
4-{[(4-{4-morpholin-4-yl-6-[(3S)-tetrahydrofuran-3- 616.4
yloxy]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}-N-
(2-piperidin-1-ylethyl)benzamide 521
4-{[(4-{4-morpholin-4-yl-6-[(3S)-tetrahydrofuran-3- 616.4
yloxy]-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}-N-
(2-pyrrolidin-1-ylethyl)benzamide 522
1-(4-{[4-(1-methylethyl)piperazin-1- 616.4
yl]carbonyl}phenyl)-3-(4-{4-morpholin-4-yl-6-[(3S)-
tetrahydrofuran-3-yloxy]-1,3,5-triazin-2- yl}phenyl)urea 523
1-(4-{[4-(1-methylethyl)piperazin-1- 616.4
yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-
(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2- yl]phenyl}urea 524
N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4- 616.4
morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-
triazin-2-yl]phenyl}carbamoyl)amino]benzamide 525
4-[({4-[4-(2-methylpropyl)-6-morpholin-4-yl-1,3,5- 477.3
triazin-2-yl]phenyl}carbamoyl)amino]benzoic acid 526
1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 565.4
triazin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1- yl)phenyl]urea 527
4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 511.4
triazin-2-yl]phenyl}carbamoyl)amino]benzoic acid 528 methyl
4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl- 525.4
1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate 529
1-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-3-[4-(4- 531.4
ethyl-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea 530
1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 468.3
triazin-2-yl]phenyl}-3-pyridin-4-ylurea 531
1-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-3-{4-[4- 593.4
(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2- yl]phenyl}urea
532 N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4-(4- 595.5
methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-
yl]phenyl}carbamoyl)amino]benzamide 533
1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 593.5
triazin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1-
yl)carbonyl]phenyl}urea 534
1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2- 594.5
yl)phenyl]-3-{4-[(4-pyridin-2-ylpiperazin-1-
yl)carbonyl]phenyl}urea 535
1-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-3-[4-(4- 579.5
morpholin-4-yl-6-phenyl-1,3,5-triazin-2- yl)phenyl]urea 536
1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2- 531.1
yl)phenyl]-3-{4-[(4-methylpiperazin-1- yl)carbonyl]phenyl}urea 537
1-[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2- 454.1
yl)phenyl]-3-pyridin-4-ylurea 538 methyl
4-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5- 511
triazin-2-yl)phenyl]carbamoyl}amino)benzoate 539
N-[2-(dimethylamino)ethyl]-N-methyl-4-({[4-(4- 581.2
morpholin-4-yl-6-phenyl-1,3,5-triazin-2-
yl)phenyl]carbamoyl}amino)benzamide 540 methyl
4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]- 548
1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzoate 541
4-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2- 497
yl)phenyl]carbamoyl}amino)benzoic acid 542
N-[2-(dimethylamino)ethyl]-4-[({4-[4-(4- 581.3
methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-
yl]phenyl}carbamoyl)amino]benzamide 543
1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-[4- 579.2
(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2- yl)phenyl]urea 544
1-(4-{[4-(dimethylamino)piperidin-1- 661.5
yl]carbonyl}phenyl)-3-[4-(4-morpholin-4-yl-6-phenyl-
1,3,5-triazin-2-yl)phenyl]urea 545
N-[2-(dimethylamino)ethyl]-4-({[4-(4-morpholin-4-yl- 567.2
6-phenyl-1,3,5-triazin-2- yl)phenyl]carbamoyl}amino)benzamide 546
4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 604.4
triazin-2-yl}phenyl)carbamoyl]amino}-N-[2-
(dimethylamino)ethyl]benzamide 547
1-{4-[(4-isopropylpiperazin-1-yl)carbonyl]phenyl}-3- 621.5
{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-
2-yl]phenyl}urea 548
4-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 607.5
triazin-2-yl]phenyl}carbamoyl)amino]-N-(2-pyrrolidin-
1-ylethyl)benzamide 549
4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 534.5
triazin-2-yl}phenyl)carbamoyl]amino}benzoic acid 550
N-(2-methoxyethyl)-4-[({4-[4-(4-methylphenyl)-6- 568.2
morpholin-4-yl-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide
551 N-(2-methoxyethyl)-4-({[4-(4-morpholin-4-yl-6- 554.2
phenyl-1,3,5-triazin-2- yl)phenyl]carbamoyl}amino)benzamide 552
4-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2- 593.5
yl)phenyl]carbamoyl}amino)-N-(2-pyrrolidin-1- ylethyl)benzamide 553
1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 567.6
triazin-2-yl]phenyl}-3-[4-(pyrrolidin-1- ylcarbonyl)phenyl]urea 554
N-[3-(dimethylamino)propyl]-4-[({4-[4-(4- 595.4
methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-
yl]phenyl}carbamoyl)amino]benzamide 555
1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 578.1
triazin-2-yl]phenyl}-3-[4-(piperidin-1- ylcarbonyl)phenyl]urea 556
N-[3-(dimethylamino)propyl]-4-({[4-(4-morpholin-4-yl- 581.4 291.2
6-phenyl-1,3,5-triazin-2- yl)phenyl]carbamoyl}amino)benzamide 557
1-{4-[4-morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2- 460.2 230.6
yl]phenyl}-3-pyridin-4-ylurea 558
4-[({4-[4-morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2- 503.4
yl]phenyl}carbamoyl)amino]benzoic acid 559
1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4- 585.5
[4-morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2- yl]phenyl}urea 560
methyl 4-[({4-[4-morpholin-4-yl-6-(2-thienyl)-1,3,5- 517.2
triazin-2-yl]phenyl}carbamoyl)amino]benzoate 561
N-(2-methoxyethyl)-4-[({4-[4-morpholin-4-yl-6-(2- 560.3
thienyl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 562
N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4- 587.3 294.1
morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2-
yl]phenyl}carbamoyl)amino]benzamide 563
N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6- 573.1
(2-thienyl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide
564 4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 618.4 309.7
triazin-2-yl}phenyl)carbamoyl]amino}-N-[2-
(dimethylamino)ethyl]-N-methylbenzamide
565 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 616.4 329.2
triazin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-1- 308.7
yl)carbonyl]phenyl}urea 566
1-{4-[4-morpholin-4-yl-6-(1,4-oxazepan-4-yl)-1,3,5- 477.2
triazin-2-yl]phenyl}-3-pyridin-4-ylurea 567 methyl
4-[({4-[4-morpholin-4-yl-6-(1,4-oxazepan-4- 534.4
yl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzoate 568
1-(4-{[4-(dimethylamino)piperidin-1- 613.4 307.2
yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(2-
thienyl)-1,3,5-triazin-2-yl]phenyl}urea 569
4-[({4-[4-morpholin-4-yl-6-(1,4-oxazepan-4-yl)-1,3,5- 520.3
triazin-2-yl]phenyl}carbamoyl)amino]benzoic acid 570
N-[3-(dimethylamino)propyl]-4-[({4-[4-morpholin-4-yl- 587.3 294.2
6-(2-thienyl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide
571 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 587.5
triazin-2-yl}phenyl)-3-[4-(pyrrolidin-1- ylcarbonyl)phenyl]urea 572
N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6- 590.3 295.6
(1,4-oxazepan-4-yl)-1,3,5-triazin-2-
yl]phenyl}carbamoyl)amino]benzamide 573
1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4- 602.3 322.2
[4-morpholin-4-yl-6-(1,4-oxazepan-4-yl)-1,3,5-triazin- 301.7
2-yl]phenyl}urea 574
N-(2-methoxyethyl)-4-[({4-[4-morpholin-4-yl-6-(1,4- 577.2
oxazepan-4-yl)-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide
575 1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4- 599.3
300.2 morpholin-4-yl-6-(2-thienyl)-1,3,5-triazin-2- 320.7
yl]phenyl}urea 576 1-{4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5-
593.3 317.7 triazin-2-yl]phenyl}-3-{3-[(4-methylpiperazin-1- 521.3
yl)carbonyl]phenyl}urea 577
3-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl-1,3,5- 511.2
triazin-2-yl]phenyl}carbamoyl)amino]benzoic acid 578 methyl
3-[({4-[4-(4-methylphenyl)-6-morpholin-4-yl- 525.2
1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate 579
1-(3-{[4-(dimethylamino)piperidin-1- 521.3
yl]carbonyl}phenyl)-3-{4-[4-(4-methylphenyl)-6-
morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}urea 580
N-[2-(dimethylamino)ethyl]-N-methyl-3-[({4-[4-(4- 595.3 298.2
methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-
yl]phenyl}carbamoyl)amino]benzamide 581 methyl
3-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin- 463.5
2-yl)phenyl]carbamoyl}amino)benzoate 582 methyl
3-({[4-(4-morpholin-4-yl-6-thiophen-2-yl-1,3,5- 517.2
triazin-2-yl)phenyl]carbamoyl}amino)benzoate 583
N-[2-(dimethylamino)ethyl]-3-[({4-[4-(4- 581.3 291.1
methylphenyl)-6-morpholin-4-yl-1,3,5-triazin-2-
yl]phenyl}carbamoyl)amino]benzamide 584
N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4- 604.4 302.7
morpholin-4-yl-6-(1,4-oxazepan-4-yl)-1,3,5-triazin-2-
yl]phenyl}carbamoyl)amino]benzamide 585
3-({[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2- 449.4
yl)phenyl]carbamoyl}amino)benzoic acid 586 methyl
3-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5- 511.4
triazin-2-yl)phenyl]carbamoyl}amino)benzoate 587
1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2- 594.6
yl)phenyl]-3-{3-[(4-pyridin-2-ylpiperazin-1-
yl)carbonyl]phenyl}urea 588
N-[2-(dimethylamino)ethyl]-3-({[4-(4-ethyl-6- 533.3 267.1
morpholin-4-yl-1,3,5-triazin-2-
yl)phenyl]carbamoyl}amino)-N-methylbenzamide 589
1-[4-(4-ethyl-6-morpholin-4-yl-1,3,5-triazin-2- 531.3 266.1
yl)phenyl]-3-{3-[(4-methylpiperazin-1- 286.7
yl)carbonyl]phenyl}urea 590
3-({[4-(4-morpholin-4-yl-6-phenyl-1,3,5-triazin-2- 497.3
yl)phenyl]carbamoyl}amino)benzoic acid 591 methyl
4-({[4-(4-morpholin-4-yl-6-piperidin-1-yl-1,3,5- 518.3
triazin-2-yl)phenyl]carbamoyl}amino)benzoate 592
1-[4-(4-morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin-2- 461.3
yl)phenyl]-3-pyridin-4-ylurea 593
4-({[4-(4-morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin- 504..3
2-yl)phenyl]carbamoyl}amino)benzoic acid 594 methyl
4-({[4-(4-morpholin-4-yl-6-pyrrolidin-1-yl- 504.5
1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoate 595
1-(4-{[4-(1-methylethyl)piperazin-1- 604.5
yl]carbonyl}phenyl)-3-[4-(4-morpholin-4-yl-6-
piperidin-1-yl-1,3,5-triazin-2-yl)phenyl]urea 596
1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-[4-(4- 600.5
morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin-2- yl)phenyl]urea 597
1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-[4- 586.5
(4-morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin-2- yl)phenyl]urea
598 1-(4-{[4-(dimethylamino)piperidin-1- 614.5
yl]carbonyl}phenyl)-3-[4-(4-morpholin-4-yl-6-
piperidin-1-yl-1,3,5-triazin-2-yl)phenyl]urea 599
4-({[4-(4-morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin- 490.5
2-yl)phenyl]carbamoyl}amino)benzoic acid 600
1-[4-(4-morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin- 447.5
2-yl)phenyl]-3-pyridin-4-ylurea 601
N-[2-(dimethylamino)ethyl]-4-({[4-(4-morpholin-4-yl- 474.6
6-piperidin-1-yl-1,3,5-triazin-2-
yl)phenyl]carbamoyl}amino)benzamide 602
1-(4-{[4-(dimethylamino)piperidin-1- 600.4 300.7
yl]carbonyl}phenyl)-3-[4-(4-morpholin-4-yl-6-
pyrrolidin-1-yl-1,3,5-triazin-2-yl)phenyl]urea 603
1-(4-{[4-(1-methylethyl)piperazin-1- 600.4 300.7
yl]carbonyl}phenyl)-3-[4-(4-morpholin-4-yl-6-
pyrrolidin-1-yl-1,3,5-triazin-2-yl)phenyl]urea 604
N-[2-(dimethylamino)ethyl]-N-methyl-4-({[4-(4- 574.6
morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin-2-
yl)phenyl]carbamoyl}amino)benzamide 605
N-[2-(dimethylamino)ethyl]-N-methyl-4-({[4-(4- 588.3 294.6
morpholin-4-yl-6-piperidin-1-yl-1,3,5-triazin-2-
yl)phenyl]carbamoyl}amino)benzamide 606
1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-[4-(4- 586.3 293.7
morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin-2- 286.7
yl)phenyl]urea 607
1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-[4- 572.3
(4-morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin-2- yl)phenyl]urea
608 N-[2-(dimethylamino)ethyl]-4-({[4-(4-morpholin-4-yl- 560.1
280.6 6-pyrrolidin-1-yl-1,3,5-triazin-2-
yl)phenyl]carbamoyl}amino)benzamide 609
1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 491.2 266.6
triazin-2-yl}phenyl)-3-pyridin-4-ylurea 246.1 610
N-[3-(dimethylamino)propyl]-4-({[4-(4-morpholin-4-yl- 588.3 294.6
6-piperidin-1-yl-1,3,5-triazin-2-
yl)phenyl]carbamoyl}amino)benzamide 611
N-(2-methoxyethyl)-4-({[4-(4-morpholin-4-yl-6- 561.4 281.2
piperidin-1-yl-1,3,5-triazin-2- yl)phenyl]carbamoyl}amino)benzamide
612 1-[4-(4-morpholin-4-yl-6-pyrrolidin-1-yl-1,3,5-triazin- 543.3
2-yl)phenyl]-3-[4-(pyrrolidin-1-ylcarbonyl)phenyl]urea 613
1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 630.6
triazin-2-yl}phenyl)-3-{4-[(4-ethylpiperazin-1-
yl)carbonyl]phenyl}urea 614
1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 644.7
triazin-2-yl}phenyl)-3-(4-{[4-(1-methylethyl)piperazin-
1-yl]carbonyl}phenyl)urea 615 methyl
4-{[(4-{4-[(3S)-3-methylmorpholin-4-yl]-6- 534.3
morpholin-4-yl-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzoate
616 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 644.6
triazin-2-yl}phenyl)-3-(4-{[4-(dimethylamino)piperidin-
1-yl]carbonyl}phenyl)urea 617
1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4- 602.3 322.2
yl-1,3,5-triazin-2-yl}phenyl)-3-{4-[(4-methylpiperazin- 301.7
1-yl)carbonyl]phenyl}urea 618 1-(4-{[4-(1-methylethyl)piperazin-1-
630.4315.7 yl]carbonyl}phenyl)-3-(4-{4-[(3S)-3-methylmorpholin-
4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)urea 619
4-{[(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin- 520.2
4-yl-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzoic acid 620
1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4- 616.4 308.7
[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5- 329.2
triazin-2-yl}phenyl)urea 621
N-[3-(dimethylamino)propyl]-4-{[(4-{4-[(3S)-3- 604.6
methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-
2-yl}phenyl)carbamoyl]amino}benzamide 622
4-{[(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin- 616.5
4-yl-1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}-N-(2-
pyrrolidin-1-ylethyl)benzamide 623
1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[(3S)-3- 616.4 308.7
methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)-3-{4- 329.2
[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea 624
1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 700.6 350.8
triazin-2-yl}phenyl)-3-(4-{[4-(dipropylamino)piperidin-
1-yl]carbonyl}phenyl)urea 625
1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4- 630.5 315.7
[(3R)-3-methylmorpholin-4-yl]-6-[(3S)-3-
methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)urea 626
4-{[(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[(3S)-3- 534.3
methylmorpholin-4-yl]-1,3,5-triazin-2-
yl}phenyl)carbamoyl]amino}benzoic acid 627
1-{4-[(4-butylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4- 658.6
[(3R)-3-methylmorpholin-4-yl]-6-[(3S)-3-
methylmorpholin-4-yl]-1,3,5-triazin-2-yl}phenyl)urea 628 methyl
4-{[(4-{4-[(3R)-3-methylmorpholin-4-yl]-6- 548.2
[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-
yl}phenyl)carbamoyl]amino}benzoate 629
1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 658.5 329.7
triazin-2-yl}phenyl)-3-{4-[(4-butylpiperazin-1-
yl)carbonyl]phenyl}urea 630 1-(4-{[4-(1-methylethyl)piperazin-1-
644.5 yl]carbonyl}phenyl)-3-(4-{4-[(3R)-3-methylmorpholin-
4-yl]-6-[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-
yl}phenyl)urea 631
1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 658.5
triazin-2-yl}phenyl)-3-(4-{[4-(2-
methylpropyl)piperazin-1-yl]carbonyl}phenyl)urea 632
1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 658.6
triazin-2-yl}phenyl)-3-(4-{[4-(1-
methylpropyl)piperazin-1-yl]carbonyl}phenyl)urea 633
4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 659.6
triazin-2-yl}phenyl)carbamoyl]amino}-N-[2-(4-
methylpiperazin-1-yl)ethyl]benzamide 634
N-[2-(dimethylamino)ethyl]-4-{[(4-{4-[(3R)-3- 604.5
methylmorpholin-4-yl]-6-[(3S)-3-methylmorpholin-4-
yl]-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzamide 635
4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 626.5
triazin-2-yl}phenyl)carbamoyl]amino}-N-(2-pyrrolidin-
1-ylethyl)benzamide 636
1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 643.4 322.2
triazin-2-yl}phenyl)-3-{4-[(4-propylpiperidin-1-
yl)carbonyl]phenyl}urea 637
1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 601.5
triazin-2-yl}phenyl)-3-[4-(piperidin-1- ylcarbonyl)phenyl]urea 638
1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 643.5
triazin-2-yl}phenyl)-3-{4-[(4-propylpiperazin-1-
yl)carbonyl]phenyl}urea 639
4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 591.6
triazin-2-yl}phenyl)carbamoyl]amino}-N-(2- methoxyethyl)benzamide
640 1-{4-[4-morpholin-4-yl-6-(4-tricyclo[3.3.1.13,7]dec-1- 596.7
ylpiperazin-1-yl)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4- ylurea
641 methyl 4-{[(4-{4-[4-(dimethylcarbamoyl)piperazin-1- 590.5
yl]-6-morpholin-4-yl-1,3,5-triazin-2-
yl}phenyl)carbamoyl]amino}benzoate 642
N,N-dimethyl-4-(4-morpholin-4-yl-6-{4-[(pyridin-4- 533.6
ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-
yl)piperazine-1-carboxamide 643
N,N-dimethyl-4-(4-{4-[({4-[(4-methylpiperazin-1- 658.3 329.7
yl)carbonyl]phenyl}carbamoyl)amino]phenyl}-6-
morpholin-4-yl-1,3,5-triazin-2-yl)piperazine-1- carboxamide 644
N,N-dimethyl-4-{4-morpholin-4-yl-6-[4-({[4-(pyridazin- 653.3
4-ylcarbamoyl)phenyl]carbamoyl}amino)phenyl]-
1,3,5-triazin-2-yl}piperazine-1-carboxamide 645
N,N-dimethyl-4-(4-morpholin-4-yl-6-{4-[({4-[(4- 685.6
propylpiperidin-1-
yl)carbonyl]phenyl}carbamoyl)amino]phenyl}-1,3,5-
triazin-2-yl)piperazine-1-carboxamide 646
4-{[(4-{4-[4-(dimethylcarbamoyl)piperazin-1-yl]-6- 576.2
morpholin-4-yl-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzoic
acid 647 4-(4-{4-[({4-[(2- 633.3 317.1
methoxyethyl)carbamoyl]phenyl}carbamoyl)amino]phenyl}-
6-morpholin-4-yl-1,3,5-triazin-2-yl)-N,N-
dimethylpiperazine-1-carboxamide 648 4-[4-(4-{[(4-{[2- 660.3 330.7
(dimethylamino)ethyl](methyl)carbamoyl}phenyl)carbamoyl]amino}phenyl)-
6-morpholin-4-yl-1,3,5-triazin-
2-yl]-N,N-dimethylpiperazine-1-carboxamide 649
4-(4-{4-[({4-[(4-ethylpiperazin-1- 672.6
yl)carbonyl]phenyl}carbamoyl)amino]phenyl}-6-
morpholin-4-yl-1,3,5-triazin-2-yl)-N,N-
dimethylpiperazine-1-carboxamide 650
1-(4-{4-[4-(ethylsulfonyl)piperazin-1-yl]-6-morpholin- 554.2
4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea 651 methyl
4-{[(4-{4-[4-(ethylsulfonyl)piperazin-1-yl]-6- 611.2
morpholin-4-yl-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzoate
652 4-{[(4-{4-[4-(ethylsulfonyl)piperazin-1-yl]-6-morpholin-
597.7
4-yl-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzoic acid 653
N-[3-(dimethylamino)propyl]-4-{[(4-{4-[4- 681.2 341.1
(ethylsulfonyl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5-
triazin-2-yl}phenyl)carbamoyl]amino}benzamide 654
N-[2-(dimethylamino)ethyl]-4-{[(4-{4-[4- 667.3 334.2
(ethylsulfonyl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5-
triazin-2-yl}phenyl)carbamoyl]amino}benzamide 655
4-{[(4-{4-[4-(1-methylethyl)-1,4-diazepan-1-yl]-6- 561.5
morpholin-4-yl-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzoic
acid 656 methyl 4-{[(4-{4-[4-(acetylamino)piperidin-1-yl]-6- 575.4
morpholin-4-yl-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzoate
657 1-(4-{4-[4-(1-methylethyl)-1,4-diazepan-1-yl]-6- 643.6
morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-{4-[(4-
methylpiperazin-1-yl)carbonyl]phenyl}urea 658
N-[1-(4-morpholin-4-yl-6-{4-[(pyridin-4- 518.5
ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-
yl)piperidin-4-yl]acetamide 659
4-{[(4-{4-[4-(acetylamino)piperidin-1-yl]-6-morpholin- 561.5
4-yl-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzoic acid 660
N-[2-(dimethylamino)ethyl]-4-{[(4-{4-[4-(1- 631.5
methylethyl)-1,4-diazepan-1-yl]-6-morpholin-4-yl- 1,3,5-triazin-2-
yl}phenyl)carbamoyl]amino}benzamide 661
N-{1-[(4-{[(4-{4-[4-(1-methylethyl)-1,4-diazepan-1-yl]- 685.6
6-morpholin-4-yl-1,3,5-triazin-2-
yl}phenyl)carbamoyl]amino}phenyl)carbonyl]piperidin- 4-yl}acetamide
662 1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4- 657.4
329.2 [4-(1-methylethyl)-1,4-diazepan-1-yl]-6-morpholin-4- 219.8
yl-1,3,5-triazin-2-yl}phenyl)urea 663
1-(4-{4-[4-(1-methylethyl)-1,4-diazepan-1-yl]-6- 671.4 336.2
morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-(4-{[4-(1- 224.5
methylethyl)piperazin-1-yl]carbonyl}phenyl)urea 664
1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 617.5
triazin-2-yl}phenyl)-3-(4-{[(3S)-3-methylmorpholin-4-
yl]carbonyl}phenyl)urea 665
1-{4-[(4-butylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4- 685.6
[4-(1-methylethyl)-1,4-diazepan-1-yl]-6-morpholin-4-
yl-1,3,5-triazin-2-yl}phenyl)urea 666
N-[4-({[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-yl-
1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)phenyl]-2-
(4-methylpiperazin-1-yl)acetamide 667
1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1- 533.3
yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-
2-yl}phenyl)-3-pyridin-4-ylurea 668
1-(4-{4-[(2R,5S)-2,5-bis(hydroxymethyl)pyrrolidin-1- 630.4
yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-
2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea 669
1-{4-[4-morpholin-4-yl-6-(3-oxa-8- 489.3
azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-
pyridin-4-ylurea 670 4-[({4-[4-morpholin-4-yl-6-(3-oxa-8- 531.2
azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
yl]phenyl}carbamoyl)amino]benzamide 671
1-{4-[4-morpholin-4-yl-6-(3-oxa-8- 489.5
azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-
pyridin-3-ylurea 672
1-(4-fluorophenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8- 506.5
azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 673
1-[4-(hydroxymethyl)phenyl]-3-{4-[4-morpholin-4-yl- 518.5
6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
yl]phenyl}urea 674
1-[4-(2-hydroxyethyl)phenyl]-3-{4-[4-morpholin-4-yl- 532.5
6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
yl]phenyl}urea 675 2-(diethylamino)ethyl
4-[({4-[4-morpholin-4-yl-6-(3- 631.6
oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
yl]phenyl}carbamoyl)amino]benzoate 676
1-(4-methylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa- 502.5
8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 677
1-(4-cyanophenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8- 513.5
azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 678
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4- 586.6
morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-
1,3,5-triazin-2-yl]phenyl}urea 679
1-isopropyl-3-{4-[4-morpholin-4-yl-6-(3-oxa-8- 454.5
azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 680
1-(2-hydroxyethyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8- 456.5
azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 681
4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct- 369.2
8-yl)-1,3,5-triazin-2-yl]aniline 682
{3-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct- 384.4
8-yl)-1,3,5-triazin-2-yl]phenyl}methanol 683
3-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct- 370.4
8-yl)-1,3,5-triazin-2-yl]phenol 684
5-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct- 409.4
8-yl)-1,3,5-triazin-2-yl]-1H-benzimidazol-2-amine 685
1-{4-[4-(3-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-6- 502.5
morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3- phenylurea 686
1-(4-{4-[(4-methylpiperazin-1-yl)amino]-6-morpholin- 490.5
4-yl-1,3,5-triazin-2-yl}phenyl)-3-phenylurea 687
1-(4-{4-[(1-methylpiperidin-4-yl)oxy]-6-morpholin-4- 491.5
yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea 688
1-{4-[4-morpholin-4-yl-6-(piperidin-4-yloxy)-1,3,5- 477.5
triazin-2-yl]phenyl}-3-pyridin-4-ylurea 689 ethyl
4-[(4-morpholin-4-yl-6-{4-[(pyridin-4- 549.5
ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-
yl)oxy]piperidine-1-carboxylate 690
N-ethyl-4-[(4-morpholin-4-yl-6-{4-[(pyridin-4- 548.5
ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-
yl)oxy]piperidine-1-carboxamide 691 tert-butyl
4-[(4-morpholin-4-yl-6-{4-[(pyridin-4- 577.3
ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-
yl)oxy]piperidine-1-carboxylate 692
4-[(4-morpholin-4-yl-6-{4-[(pyridin-4- 556.5
ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-
yl)oxy]piperidine-1-sulfonamide 693 methyl
4-[({4-[4-morpholin-4-yl-6-(3-oxa-8- 546.3
azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
yl]phenyl}carbamoyl)amino]benzoate 694
N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6- 602.4
(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
yl]phenyl}carbamoyl)amino]benzamide 695
N,N-dimethyl-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8- 559.2
azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
yl]phenyl}carbamoyl)amino]benzamide 696
N-methyl-4-[({4-[4-morpholin-4-yl-6-(3-oxa-8- 545.2
azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
yl]phenyl}carbamoyl)amino]benzamide 697
1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4- 614.3
[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-
yl)-1,3,5-triazin-2-yl]phenyl}urea 698
N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4- 616.4
morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-
1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 699
N-(2-hydroxyethyl)-4-[({4-[4-morpholin-4-yl-6-(3-oxa- 575.4
8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
yl]phenyl}carbamoyl)amino]benzamide 700
N-[3-(dimethylamino)propyl]-4-[({4-[4-morpholin-4-yl- 616.4
6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
yl]phenyl}carbamoyl)amino]benzamide 701
N-methyl-N-[2-(methylamino)ethyl]-4-[({4-[4- 602.4
morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-
1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 702
N-(2-morpholin-4-ylethyl)-4-[({4-[4-morpholin-4-yl-6- 644.4
(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
yl]phenyl}carbamoyl)amino]benzamide 703
1-{4-[(3,5-dimethylpiperazin-1-yl)carbonyl]phenyl}-3- 628.4
{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-
8-yl)-1,3,5-triazin-2-yl]phenyl}urea 704
4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-morpholin- 399.3
4-yl-1,3,5-triazin-2-yl]aniline 705
1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6- 519.7
morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4- ylurea 706
1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6- 519.2
morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3- ylurea 707
1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6- 518.2
morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3- phenylurea 708
1-[4-(dimethylamino)phenyl]-3-{4-[4-(1,4-dioxa-8- 561.3
azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-
2-yl]phenyl}urea 709 1-(4-cyanophenyl)-3-{4-[4-(1,4-dioxa-8- 543.2
azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-
2-yl]phenyl}urea 710 1-{4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-
533.7 morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-(2-
methylpyridin-4-yl)urea 711
1-[2-(dimethylamino)ethyl]-3-{4-[4-(1,4-dioxa-8- 513.7
azaspiro[4.5]dec-8-yl)-6-morpholin-4-yl-1,3,5-triazin-
2-yl]phenyl}urea 712
1-[4-(4-morpholin-4-yl-6-quinolin-3-yl-1,3,5-triazin-2- 505.7
yl)phenyl]-3-pyridin-4-ylurea 713
1-(diethylcarbamoyl)-4-[({4-[4-morpholin-4-yl-6-(3- 588.3
oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
yl]phenyl}carbamoyl)amino]pyridinium 714
1-{4-[4-(2-methoxyethoxy)-6-morpholin-4-yl-1,3,5- 452.6
triazin-2-yl]phenyl}-3-pyridin-4-ylurea 715 methyl
4-[({4-[4-(2-methoxyethoxy)-6-morpholin-4-yl- 509.4
1,3,5-triazin-2-yl]phenyl}carbamoyl)amino]benzoate 716
4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5- 395.3
triazin-2-yl)aniline 717
1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-yl-1,3,5- 515.8
triazin-2-yl)phenyl]-3-pyridin-4-ylurea 718
1-(4-{4-morpholin-4-yl-6-[2-(pyridin-4-ylamino)ethyl]- 498.6
1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea 719
1-(4-acetylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-8- 530.4
azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 720
N-[2-(dimethylamino)ethyl]-4-({[4-(4-methoxy-6- 535.5
morpholin-4-yl-1,3,5-triazin-2-
yl)phenyl]carbamoyl}amino)-N-methylbenzamide 721
N-[2-(dimethylamino)ethyl]-4-({[4-(4-methoxy-6- 521.5
morpholin-4-yl-1,3,5-triazin-2- yl)phenyl]carbamoyl}amino)benzamide
722 4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2- 521.5
yl)phenyl]carbamoyl}amino)-N-methyl-N-[2-
(methylamino)ethyl]benzamide 723
1-[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2- 533.5
yl)phenyl]-3-{4-[(4-methylpiperazin-1- yl)carbonyl]phenyl}urea 724
1-{4-[(3,3-dimethylpiperazin-1-yl)carbonyl]phenyl}-3- 547.5
[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2- yl)phenyl]urea 725
4-({[4-(4-methoxy-6-morpholin-4-yl-1,3,5-triazin-2- 561.5
yl)phenyl]carbamoyl}amino)-N-(2-piperidin-1- ylethyl)benzamide 726
1-(4-ethenylphenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa- 514.3
8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 727
1-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-{4-[4- 601.1
morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-
1,3,5-triazin-2-yl]phenyl}urea 728
1-(4-{4-[2,5-bis(hydroxymethyl)pyrrolidin-1-yl]-6- 508
morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4- ylurea 729
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4- 575.5
morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-
1,3,5-triazin-2-yl]phenyl}urea 730
1-(4-{4-[2-(1,3-dioxan-2-yl)ethyl]-6-morpholin-4-yl- 492.9
1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea 731
1-(4-{4-[3-(dimethylamino)propyl]-6-morpholin-4-yl- 463.4
1,3,5-triazin-2-yl}phenyl)-3-pyridin-4-ylurea 732
1-[4-(4-{3-[(1-methylethyl)amino]propyl}-6-morpholin- 477.4
4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea 733
1-{4-[4-morpholin-4-yl-6-(3-pyrrolidin-1-ylpropyl)- 489.4
1,3,5-triazin-2-yl]phenyl}-3-pyridin-4-ylurea 734
1-(4-{4-[3-(4-methylpiperazin-1-yl)propyl]-6- 518.4
morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-pyridin-4- ylurea 735
1-{4-[4-(3-{[2-(dimethylamino)ethyl]amino}propyl)-6- 506.5
morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4- ylurea 736
1-{4-[4-(3-hydroxypropyl)-6-morpholin-4-yl-1,3,5- 436.3
triazin-2-yl]phenyl}-3-pyridin-4-ylurea 737
1-{4-[4-morpholin-4-yl-6-(3-oxopropyl)-1,3,5-triazin-2- 434.3
yl]phenyl}-3-pyridin-4-ylurea 738
4-[4-(6,8-dioxa-3-azabicyclo[3.2.1]oct-3-yl)-6- 371.3
morpholin-4-yl-1,3,5-triazin-2-yl]aniline 739 tert-butyl
7-[4-(4-aminophenyl)-6-morpholin-4-yl- 484.4
1,3,5-triazin-2-yl]-9-oxa-3,7-
diazabicyclo[3.3.1]nonane-3-carboxylate 740
1-{4-[4-(6,8-dioxa-3-azabicyclo[3.2.1]oct-3-yl)-6- 491.3
morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4- ylurea 741
tert-butyl 7-(4-morpholin-4-yl-6-{4-[(pyridin-4- 604.4
ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)-9-oxa-
3,7-diazabicyclo[3.3.1]nonane-3-carboxylate 742
1-{4-[4-morpholin-4-yl-6-(9-oxa-3,7- 504.4
diazabicyclo[3.3.1]non-3-yl)-1,3,5-triazin-2-
yl]phenyl}-3-pyridin-4-ylurea 743
1-{4-[4-(7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3- 518.4
yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3- pyridin-4-ylurea
744 1-{4-[4-(7-acetyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3- 546.4
yl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3- pyridin-4-ylurea
745 1-(4-{4-[7-(methylsulfonyl)-9-oxa-3,7- 582.5
diazabicyclo[3.3.1]non-3-yl]-6-morpholin-4-yl-1,3,5-
triazin-2-yl}phenyl)-3-pyridin-4-ylurea 746
1-(2-chloropyridin-4-yl)-3-{4-[4-morpholin-4-yl-6-(3- 523.3
oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea
747 1-(2,3'-bipyridin-4-yl)-3-{4-[4-morpholin-4-yl-6-(3-oxa- 566.4
8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 748
tert-butyl N-[4-morpholin-4-yl-6-(4-nitrophenyl)-1,3,5- 417.2
triazin-2-yl]glycinate 749
1-(6-chloropyridin-3-yl)-3-{4-[4-morpholin-4-yl-6-(3- 523.3
oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea
750 N-[4-morpholin-4-yl-6-(4-nitrophenyl)-1,3,5-triazin-2- 361.3
yl]glycine 751 1,3-bis{4-[4-morpholin-4-yl-6-(3-oxa-8- 763.5
azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 752
1-(4-{[4-(dimethylamino)piperidin-1- 642.4
yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-
8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 753
N-[2-(4-methylpiperazin-1-yl)ethyl]-4-[({4-[4- 657.4
morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-
1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 754
1-{4-[(4-isopropylpiperazin-1-yl)carbonyl]phenyl}-3- 642.4
{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-
8-yl)-1,3,5-triazin-2-yl]phenyl}urea 755
1-{4-[(4-cyclopentylpiperazin-1-yl)carbonyl]phenyl}-3- 668.4
{4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-
8-yl)-1,3,5-triazin-2-yl]phenyl}urea 756
1-{4-[4-morpholin-4-yl-6-(3-oxa-8- 600.4
azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-
[4-(piperazin-1-ylcarbonyl)phenyl]urea 757
1-{4-[4-morpholin-4-yl-6-(3-oxa-8- 684.4
azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-
{4-[(4-morpholin-4-ylpiperidin-1- yl)carbonyl]phenyl}urea 758
4-[({4-[4-morpholin-4-yl-6-(3-oxa-8- 628.4
azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
yl]phenyl}carbamoyl)amino]-N-(2-pyrrolidin-1- ylethyl)benzamide 759
4-[({4-[4-morpholin-4-yl-6-(3-oxa-8- 642.4
azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
yl]phenyl}carbamoyl)amino]-N-(2-piperidin-1- ylethyl)benzamide 760
1-[4-(1,4'-bipiperidin-1'-ylcarbonyl)phenyl]-3-{4-[4- 682.5
morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-
1,3,5-triazin-2-yl]phenyl}urea 761
1-{4-[4-morpholin-4-yl-6-(3-oxa-8- 668.5
azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-
{4-[(4-pyrrolidin-1-ylpiperidin-1- yl)carbonyl]phenyl}urea 762
1-{4-[4-morpholin-4-yl-6-(3-oxa-8- 617.3
azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl}-3-
[4-(thiomorpholin-4-ylcarbonyl)phenyl]urea 763
1-[4-(morpholin-4-ylcarbonyl)phenyl]-3-{4-[4- 601.4
morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-
1,3,5-triazin-2-yl]phenyl}urea 764
4-[({4-[4-morpholin-4-yl-6-(3-oxa-8- 532.3
azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-
yl]phenyl}carbamoyl)amino]benzoic acid 765
1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 505.3
morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-pyridin-4- ylurea 766
1-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-3-{4-[4- 587.4
morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-
1,3,5-triazin-2-yl]phenyl}urea 767
1-(4-{[4-(dimethylamino)piperidin-1- 658.4
yl]carbonyl}phenyl)-3-{4-[4-(3,7-dioxa-9-
azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-
triazin-2-yl]phenyl}urea 768
N-[2-(dimethylamino)ethyl]-4-[({4-[4-(3,7-dioxa-9- 632.4
azabicyclo[3.3.1]non-9-yl)-6-morpholin-4-yl-1,3,5-
triazin-2-yl]phenyl}carbamoyl)amino]-N- methylbenzamide 769
1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 630.4
morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-
methylpiperazin-1-yl)carbonyl]phenyl}urea 770 methyl
4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9- 562.3
yl)-6-morpholin-4-yl-1,3,5-triazin-2-
yl]phenyl}carbamoyl)amino]benzoate 771
4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 548.3
morpholin-4-yl-1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzoic
acid 772 1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 616.3
morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-[4-
(piperazin-1-ylcarbonyl)phenyl]urea 773
1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 658.3
morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-
isopropylpiperazin-1-yl)carbonyl]phenyl}urea 774
4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 644.3
morpholin-4-yl-1,3,5-triazin-2-
yl]phenyl}carbamoyl)amino]-N-(2-pyrrolidin-1- ylethyl)benzamide 775
4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 658.4
morpholin-4-yl-1,3,5-triazin-2-
yl]phenyl}carbamoyl)amino]-N-(2-piperidin-1- ylethyl)benzamide 776
1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 684.4
morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-
pyrrolidin-1-ylpiperidin-1-yl)carbonyl]phenyl}urea 777
1-[4-(1,4'-bipiperidin-1'-ylcarbonyl)phenyl]-3-{4-[4- 698.4
(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-morpholin-
4-yl-1,3,5-triazin-2-yl]phenyl}urea 778
4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 652.4
morpholin-4-yl-1,3,5-triazin-2-
yl]phenyl}carbamoyl)amino]-N-(2-pyridin-2- ylethyl)benzamide 779
4-[({4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 652.4
morpholin-4-yl-1,3,5-triazin-2-
yl]phenyl}carbamoyl)amino]-N-(2-pyridin-4- ylethyl)benzamide 780
N-[4-(4-aminophenyl)-6-morpholin-4-yl-1,3,5-triazin- 413.2
2-yl]benzenesulfonamide 781 N-(4-morpholin-4-yl-6-{4-[(pyridin-4-
533.4 ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-
yl)benzenesulfonamide 782 N-{4-[4-({[4-(4-methylpiperazin-1- 630.3
yl)phenyl]carbamoyl}amino)phenyl]-6-morpholin-4-yl-
1,3,5-triazin-2-yl}benzenesulfonamide 783 N-(4-{4-[({4-[2- 619.3
(dimethylamino)ethoxy]phenyl}carbamoyl)amino]phenyl}-
6-morpholin-4-yl-1,3,5-triazin-2- yl)benzenesulfonamide 784
N-(4-{4-[({4-[(4-methylpiperazin-1- 658.3
yl)carbonyl]phenyl}carbamoyl)amino]phenyl}-6-
morpholin-4-yl-1,3,5-triazin-2-yl)benzenesulfonamide 785
N-{4-morpholin-4-yl-6-[4-({[4-(piperazin-1- 644.4
ylcarbonyl)phenyl]carbamoyl}amino)phenyl]-1,3,5-
triazin-2-yl}benzenesulfonamide 786
N-[4-(4-{[(4-{[4-(dimethylamino)piperidin-1- 686.4
yl]carbonyl}phenyl)carbamoyl]amino}phenyl)-6-
morpholin-4-yl-1,3,5-triazin-2-yl]benzenesulfonamide 787
N-[2-(dimethylamino)ethyl]-N-methyl-4-{[(4-{4- 660.4
morpholin-4-yl-6-[(phenylsulfonyl)amino]-1,3,5-
triazin-2-yl}phenyl)carbamoyl]amino}benzamide 788
N-[2-(dimethylamino)ethyl]-4-{[(4-{4-morpholin-4-yl- 646.4
6-[(phenylsulfonyl)amino]-1,3,5-triazin-2-
yl}phenyl)carbamoyl]amino}benzamide 789 methyl
4-{[(4-{4-morpholin-4-yl-6- 590.3
[(phenylsulfonyl)amino]-1,3,5-triazin-2-
yl}phenyl)carbamoyl]amino}benzoate 790
4-{[(4-{4-morpholin-4-yl-6-[(phenylsulfonyl)amino]- 576.2
1,3,5-triazin-2-yl}phenyl)carbamoyl]amino}benzoic acid 791
1-{4-[4-morpholin-4-yl-6-(3-oxa-9- 503.2
azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}-
3-pyridin-4-ylurea 792
1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4- 628.5
[4-morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-
yl)-1,3,5-triazin-2-yl]phenyl}urea 793
1-{4-[4-morpholin-4-yl-6-(3-oxa-9- 614.5
azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}-
3-[4-(piperazin-1-ylcarbonyl)phenyl]urea 794
1-(4-{[4-(dimethylamino)piperidin-1- 656.5
yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-
9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2- yl]phenyl}urea 795
N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4- 630.4
morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-
1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 796
N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6- 616.4
(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-
yl]phenyl}carbamoyl)amino]benzamide 797
N-(2-methoxyethyl)-4-[({4-[4-morpholin-4-yl-6-(3-oxa- 603.4
9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-
yl]phenyl}carbamoyl)amino]benzamide 798
4-[({4-[4-morpholin-4-yl-6-(3-oxa-9- 642.4
azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-
yl]phenyl}carbamoyl)amino]-N-(2-pyrrolidin-1- ylethyl)benzamide 799
4-[({4-[4-morpholin-4-yl-6-(3-oxa-9- 656.4
azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-
yl]phenyl}carbamoyl)amino]-N-(2-piperidin-1- ylethyl)benzamide 800
1-{4-[4-morpholin-4-yl-6-(3-oxa-9- 682.5
azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2-yl]phenyl}-
3-{4-[(4-pyrrolidin-1-ylpiperidin-1- yl)carbonyl]phenyl}urea 801
N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-[({4-[4- 656.6
morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-
1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 802
N-methyl-N-[2-(methylamino)ethyl]-4-[({4-[4- 616.5
morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-
1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 803
1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4- 628.3
morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-
1,3,5-triazin-2-yl]phenyl}urea 804
1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4- 642.5
morpholin-4-yl-6-(3-oxa-9-azabicyclo[3.3.1]non-9-yl)-
1,3,5-triazin-2-yl]phenyl}urea 805
1-(4-{[4-(1-methylethyl)piperazin-1- 656.3
yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa-
9-azabicyclo[3.3.1]non-9-yl)-1,3,5-triazin-2- yl]phenyl}urea 806
1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6- 644.5
morpholin-4-yl-1,3,5-triazin-2-yl]phenyl}-3-{4-[(4-
ethylpiperazin-1-yl)carbonyl]phenyl}urea 807
1-{4-[4-morpholin-4-yl-6-(2-oxa-5- 489.2
azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}-3-
pyridin-4-ylurea 808
1-(1,3-dimethyl-1H-pyrazol-5-yl)-3-{4-[4-morpholin-4- 506.2
yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-
2-yl]phenyl}urea 809 1-{4-[4-morpholin-4-yl-6-(2-oxa-5- 478.2
azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}-3-
(1H-pyrazol-3-yl)urea 810 1-(4-{[4-(dimethylamino)piperidin-1-
642.2 yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(2-oxa-
5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2- yl]phenyl}urea 811
1-(4-{[4-(1-methylethyl)piperazin-1- 642.5
yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(2-oxa-
5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2- yl]phenyl}urea 812
1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4- 628.2
morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-
1,3,5-triazin-2-yl]phenyl}urea 813
1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4- 614.2
[4-morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-
yl)-1,3,5-triazin-2-yl]phenyl}urea 814
1-{4-[4-morpholin-4-yl-6-(2-oxa-5- 600.3
azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-yl]phenyl}-3-
[4-(piperazin-1-ylcarbonyl)phenyl]urea 815
N-[2-(dimethylamino)ethyl]-4-[({4-[4-morpholin-4-yl-6- 602.5
(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-1,3,5-triazin-2-
yl]phenyl}carbamoyl)amino]benzamide 816
N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4- 616.3
morpholin-4-yl-6-(2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-
1,3,5-triazin-2- yl]phenyl}carbamoyl)amino]benzamide 817
2-tert-butoxy-4-morpholin-4-yl-6-(4-nitrophenyl)- 360.1
1,3,5-triazine 818
1-(4-{4-[(6S)-6-hydroxy-3-oxa-8-azabicyclo[3.2.1]oct- 505.2
8-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-
pyridin-4-ylurea 819
1-(4-{4-[6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]oct- 595.2
8-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-
pyridin-4-ylurea 820
1-(4-{4-[(6R)-6-hydroxy-3-oxa-8-azabicyclo[3.2.1]oct- 505.2
8-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-
pyridin-4-ylurea 821 1-(4-{4-[(6R)-6-(benzyloxy)-3-oxa-8- 595.2
azabicyclo[3.2.1]oct-8-yl]-6-morpholin-4-yl-1,3,5-
triazin-2-yl}phenyl)-3-pyridin-4-ylurea 822
1-{4-[(1,1-dioxidothiomorpholin-4- 649.1
yl)carbonyl]phenyl}-3-{4-[4-morpholin-4-yl-6-(3-oxa-
8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 823
1-[4-(4,6-di-3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl- 644.3306
1,3,5-triazin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-
yl)phenyl]urea 824 1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-
628.5, yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa- 314.8,
356.8 8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea
825 1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1- 628.5,
yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-(3-oxa- 314.8, 356.8
8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2- yl]phenyl}urea 826
1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-[4- 519.1,
(6-morpholin-4-yl-4-oxo-4,5-dihydro-1,3,5-triazin-2- 280.5, 260
yl)phenyl]urea 827
1-{4-[(4-butylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4-
[4-(1-methylethyl)-1,4-diazepan-1-yl]-6-morpholin-4-
yl-1,3,5-triazin-2-yl}phenyl)urea 828
1-(4-{4-[4-(1-methylethyl)-1,4-diazepan-1-yl]-6- 671.4; 336.2;
morpholin-4-yl-1,3,5-triazin-2-yl}phenyl)-3-(4-{[4-(1- 224.5;
methylethyl)piperazin-1-yl]carbonyl}phenyl)urea 829
1-{4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}-3-(4-{4- 657.4;
329.2; [4-(1-methylethyl)-1,4-diazepan-1-yl]-6-morpholin-4- 219.8;
yl-1,3,5-triazin-2-yl}phenyl)urea 830
1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4- 587.6; 314.8;
[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5- 294.3;
triazin-2-yl]phenyl}urea 831
1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-
yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-
triazin-2-yl)phenyl]urea 832
1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-
yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-
triazin-2-yl)phenyl]urea 833 1-(4-{[4-(1-methylethyl)piperazin-1-
615.5; 308.3; yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6- 328.8;
(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2- yl]phenyl}urea 834
N-[2-(dimethylamino)ethyl]-N-methyl-4-[({4-[4- 589.5; 295.3;
morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-
triazin-2-yl]phenyl}carbamoyl)amino]benzamide 835
1-{4-[4-(azetidin-3-yloxy)-6-morpholin-4-yl-1,3,5- 449.1; 225.1;
triazin-2-yl]phenyl}-3-pyridin-4-ylurea 836
N-(1-methylethyl)-3-[(4-morpholin-4-yl-6-{4-[(pyridin- 534.4;
267.7; 4-ylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-
yl)oxy]azetidine-1-carboxamide 837
N-{1-[(4-{[(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]- 658.5; 329.8;
1,3,5-triazin-2-
yl}phenyl)carbamoyl]amino}phenyl)carbonyl]piperidin- 4-yl}acetamide
838 1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 658.8; 329.8;
triazin-2-yl}phenyl)-3-(4-{[4-(1-methylethyl)-1,4-
diazepan-1-yl]carbonyl}phenyl)urea 839
1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5- 629.7; 315.3;
triazin-2-yl}phenyl)-3-[4-(3-oxa-8-
azabicyclo[3.2.1]oct-8-ylcarbonyl)phenyl]urea 840
1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-
triazin-2-yl}phenyl)-3-{4-[(4-cyanopiperidin-1-
yl)carbonyl]phenyl}urea 841
1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-
triazin-2-yl}phenyl)-3-(4-{[(3S)-3-
(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)urea 842
1-(4-{4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-
triazin-2-yl}phenyl)-3-(4-{[(3R)-3-
(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)urea 843
1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1- 657.6; 329.3;
yl]carbonyl}phenyl)-3-(4-{4-(morpholin-4-yl)-6-[4- 233.6;
(propan-2-yl)-1,4-diazepan-1-yl]-1,3,5-triazin-2- yl}phenyl)urea
844 1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1- 657.5; 329.3;
yl]carbonyl}phenyl)-3-(4-{4-(morpholin-4-yl)-6-[4-
(propan-2-yl)-1,4-diazepan-1-yl]-1,3,5-triazin-2- yl}phenyl)urea
845 1-{4-[4,6-di(morpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}-
3-{4-[(2-methylpiperazin-1-yl)carbonyl]phenyl}urea 846
1-(4-{4-(morpholin-4-yl)-6-[4-(propan-2-yl)-1,4-
diazepan-1-yl]-1,3,5-triazin-2-yl}phenyl)-3-[4-
(piperazin-1-ylcarbonyl)phenyl]urea 847
1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-
yl]carbonyl}phenyl)-3-(4-{4-(morpholin-4-yl)-6-[4-
(propan-2-yl)-1,4-diazepan-1-yl]-1,3,5-triazin-2- yl}phenyl)urea
848 1-{4-[4,6-di(morpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}- 616.3;
638.3; 3-{4-[(3,3,4-trimethylpiperazin-1- 654.3;
yl)carbonyl]phenyl}urea 849
1-{4-[4,6-di(morpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}-
3-(4-{[(3R)-3-methylpiperazin-1- yl]carbonyl}phenyl)urea 850
1-(4-{[(3R)-3,4-dimethylpiperazin-1-
yl]carbonyl}phenyl)-3-{4-[4,6-di(morpholin-4-yl)-1,3,5-
triazin-2-yl]phenyl}urea 851
1-(4-{[(3R)-4-cyclobutyl-3-methylpiperazin-1-
yl]carbonyl}phenyl)-3-{4-[4,6-di(morpholin-4-yl)-1,3,5-
triazin-2-yl]phenyl}urea 852
1-{4-[4,6-di(morpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}-
3-(4-{[(3R)-3-methyl-4-(propan-2-yl)piperazin-1-
yl]carbonyl}phenyl)urea 853
1-{4-[4,6-di(morpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}-
3-(4-{[(3S)-3-methylpiperazin-1- yl]carbonyl}phenyl)urea 854
N-[2-(dimethylamino)ethyl]-N-methyl-4-{[(4-{4-[(3S)-
3-methylmorpholin-4-yl]-6-[4-(propan-2-yl)-1,4-
diazepan-1-yl]-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzamide
855 1-(4-{4-[(3S)-3-methylmorpholin-4-yl]-6-[4-(propan-2-
yl)-1,4-diazepan-1-yl]-1,3,5-triazin-2-yl}phenyl)-3-{4-
[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea 856
1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-
yl]carbonyl}phenyl)-3-(4-{4-[(3S)-3-methylmorpholin-
4-yl]-6-[4-(propan-2-yl)-1,4-diazepan-1-yl]-1,3,5-
triazin-2-yl}phenyl)urea 857
N-[3-(dimethylamino)propyl]-4-{[(4-{4-(morpholin-4-
yl)-6-[4-(propan-2-yl)-1,4-diazepan-1-yl]-1,3,5-triazin-
2-yl}phenyl)carbamoyl]amino}benzamide 858
N-[2-(dimethylamino)ethyl]-N-methyl-4-{[(4-{4-
(morpholin-4-yl)-6-[4-(propan-2-yl)-1,4-diazepan-1-
yl]-1,3,5-triazin-2- yl}phenyl)carbamoyl]amino}benzamide 859
1-[4-(morpholin-4-ylcarbonyl)phenyl]-3-(4-{4-
(morpholin-4-yl)-6-[4-(propan-2-yl)-1,4-diazepan-1-
yl]-1,3,5-triazin-2-yl}phenyl)urea 860
N-(2-methoxyethyl)-4-{[(4-{4-(morpholin-4-yl)-6-[4-
(propan-2-yl)-1,4-diazepan-1-yl]-1,3,5-triazin-2-
yl}phenyl)carbamoyl]amino}benzamide 861
1-[4-(1,4-diazepan-1-ylcarbonyl)phenyl]-3-(4-{4- 643.4;
(morpholin-4-yl)-6-[4-(propan-2-yl)-1,4-diazepan-1-
yl]-1,3,5-triazin-2-yl}phenyl)urea 862
1-(4-{4-(morpholin-4-yl)-6-[4-(propan-2-yl)-1,4-
diazepan-1-yl]-1,3,5-triazin-2-yl}phenyl)-3-(4-{[4-
(propan-2-yl)-1,4-diazepan-1-yl]carbonyl}phenyl)urea 863
1-(4-{[(3S)-4-cyclobutyl-3-methylpiperazin-1-
yl]carbonyl}phenyl)-3-{4-[4,6-di(morpholin-4-yl)-1,3,5-
triazin-2-yl]phenyl}urea 864 1-(4-{[(3S)-3,4-dimethylpiperazin-1-
yl]carbonyl}phenyl)-3-{4-[4,6-di(morpholin-4-yl)-1,3,5-
triazin-2-yl]phenyl}urea 865
1-{4-[4-(morpholin-4-yl)-6-(tetrahydro-2H-pyran-4-yl)-
1,3,5-triazin-2-yl]phenyl}-3-{4-[(3,3,4-
trimethylpiperazin-1-yl)carbonyl]phenyl}urea 866
1-(4-{[(3S)-3,4-dimethylpiperazin-1-
yl]carbonyl}phenyl)-3-{4-[4-(morpholin-4-yl)-6-
(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2- yl]phenyl}urea 867
1-(4-{[(3S)-3-methylpiperazin-1-yl]carbonyl}phenyl)-
3-{4-[4-(morpholin-4-yl)-6-(tetrahydro-2H-pyran-4-yl)-
1,3,5-triazin-2-yl]phenyl}urea 868
1-(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-
yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-
(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2- yl]phenyl}urea 869
1-(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-
yl]carbonyl}phenyl)-3-{4-[4-morpholin-4-yl-6-
(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2- yl]phenyl}urea
Biological Evaluation
mTOR Kinase Assay Methods
[1848] 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 .beta.-glycerophosphate, 10 mM MnCl.sub.2, 0.5 mM
DTT, 0.25 mM microcystin LR, and 100 mg/mL BSA). To each well, 12
.mu.L of the diluted enzyme is mixed briefly with 0.5 .mu.L test
inhibitor or control vehicle dimethylsulfoxide (DMSO). The kinase
reaction is initiated by adding 12.5 .mu.L kinase assay buffer
containing ATP and His6-S6K to give a final reaction volume of 25
.mu.L 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 .mu.L Stop buffer (20 mM HEPES (pH 7.4), 20
mM EDTA, 20 mM EGTA). The DELFIA detection of the phosphorylated
(Thr-389) His6-S6K is performed at room temperature using a
monoclonal anti-P(T389)-p70S6K antibody (1A5, Cell Signaling)
labeled with Europium-N1-ITC (Eu) (10.4 Eu per antibody,
PerkinElmer). The DELFIA Assay buffer and Enhancement solution can
be purchased from PerkinElmer. 45 .mu.L of the terminated kinase
reaction mixture is transferred to a MaxiSorp plate (Nunc)
containing 55 .mu.L PBS. The His6-S6K is allowed to attach for 2
hours after which the wells are aspirated and washed once with PBS.
100 .mu.L 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 .mu.L 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
[1849] The reaction buffer was 20 mM HEPES, pH 7.5, 2 mM
MgCl.sub.2, 0.05% CHAPS; and 0.01% .beta.ME (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
.mu.M. Nunc 384-well black polypropylene fluorescent plates were
used for PI3K assays.
[1850] The assay is run by placing 5 .mu.L of diluted enzyme per
well, then 5 .mu.L of diluted compound (or 9.5 .mu.L enzyme then
0.5 .mu.L compound in DMSO) is added and mixed. Then, 10 .mu.L
substrate is added to start the reaction. The samples are incubated
30-60 minutes, then the reaction is stopped by adding 20 .mu.L
stop/detector mix. PI3K is diluted with reaction buffer (e.g., 5
.mu.L or 7.5 .mu.L PI3K into 620 .mu.L reaction buffer), and 5
.mu.L of diluted enzyme is used per well. A 5 .mu.L portion of
reaction buffer or of drug diluted in buffer (e.g., 4 .mu.L/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 .mu.L. In this case 9.8 .mu.L is added per well and 0.2 .mu.L
compound is added in DMSO.
[1851] To prepare 1 mL of substrate solution, 955 .mu.L reaction
buffer, 40 .mu.L PIP2, and 2.5 .mu.L ATP are mixed. 10 .mu.L of
substrate is added to each well to start the reaction. This results
in 20 .mu.M PIP2, and 25 .mu.M ATP per reaction. The stop/detector
mix is prepared by mixing 4 .mu.L Red detector and 1.6 .mu.L or 2.0
.mu.L GST-GRP with 1 mL stop buffer, which results in 10 nM probe
and 70 nM GST-GRP. 20 .mu.L 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 .mu.L per 20 .mu.L (0.015
.mu.g/20 .mu.L) or 0.01125 .mu.g/15 .mu.L or 0.75 .mu.g/mL.
[1852] 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
[1853] Cell Lines used are human breast MDA-MB-361, human prostate
PC3-mm2, and human prostate LNCap tumor cell lines. Cells are
plated in 96-well culture plates at approximately 3000 cells per
well. One day following plating, various concentrations of PI3K
inhibitors in DMSO are added to cells (final DMSO concentration in
cell assays is 0.25%). Three days after drug treatment, viable cell
densities are determined by cell mediated metabolic conversion of
the dye MTS, a well-established indicator of cell proliferation in
vitro. Cell growth assays are performed using kits purchased from
Promega Corporation (Madison, Wis.), following the protocol
provided by the vendor. Measuring absorbance at 490 nm generates
MTS assay results. Compound effect on cell proliferation is
assessed relative to untreated control cell growth. The drug
concentration that conferred 50% inhibition of growth is determined
as IC.sub.50 (.mu.M).
hSMG-1 Kinase Assay
[1854] 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 .beta.-glycerophosphate, 0.5 .mu.M
microcystin LR, 10 mM MnCl.sub.2). To each well, 12 .mu.L of the
diluted enzyme were mixed briefly with 0.5 .mu.L test inhibitor or
control vehicle dimethylsulfoxide (DMSO). The kinase reaction was
initiated by adding 12.5 .mu.L kinase assay buffer containing ATP
and GST-p53 to give a final reaction volume of 25 .mu.L containing
400-800 ng/mL FLAG-hSMG-1, 0.5 .mu.g GST-p53, 10 .mu.M ATP. The
reaction was carried out at room temperature for 1.0 hour before
terminated by addition of 25 .mu.l 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.degree. 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 .mu.L DELFIA assay
buffer (PerkinElmer #1244-111). Plates were then washed and
incubated for 0.5 hour with 100 .mu.l 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.
[1855] Table 2 shows the results of the described PI3K-.alpha.,
PI3K-.gamma., and mTOR kinase assays.
TABLE-US-00002 TABLE 2 Example IC.sub.50 PI3K.alpha. nM IC.sub.50
PI3K.gamma. nM IC.sub.50 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
[1856] Table 3 shows the results of the described hSMG-1 kinase
assay.
TABLE-US-00003 TABLE 3 hSMG-1 IC.sub.50 Example (.mu.M) 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
[1857] Table 4 shows the results of the described MDA-MB-361,
PC3-mm2, and LNCap assays.
TABLE-US-00004 TABLE 4 IC.sub.50 IC.sub.50 IC.sub.50 MDA-MB-361
PC3-mm2 LNCap Example (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
[1858] 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.
[1859] 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.
* * * * *