Synthesis and Evaluation of Imidazo[1,2-a]pyridine Analogues of the ZSTK474 Class of Phosphatidylinositol 3-Kinase Inhibitors

Article abstract of DOI:10.1002/asia.201801762

Using a scaffold-hopping approach, imidazo[1,2-a]pyridine analogues of the ZSTK474 (benzimidazole) class of phosphatidylinositol 3-kinase (PI3K) inhibitors have been synthesized for biological evaluation. Compounds were prepared using a heteroaryl Heck reaction procedure, involving the palladium-catalysed coupling of 2-(difluoromethyl)imidazo[1,2-a]pyridines with chloro, iodo or trifluoromethanesulfonyloxy (trifloxy) substituted 1,3,5-triazines or pyrimidines, with the iodo intermediates being preferred in terms of higher yields and milder reaction conditions. The new compounds maintain the PI3K isoform selectivity of their benzimidazole analogues, but in general show less potency.

Full text of DOI:10.1002/asia.201801762

CHEMISTRY
AN ASIAN JOURNAL
www.chemasianj.org
Accepted Article
Title: Synthesis and Evaluation of Imidazo[1,2-a]pyridine Analogues of
the ZSTK474 Class of Phosphatidylinositol 3-Kinase Inhibitors
Authors: Gordon W Rewcastle, Swarna A. Gamage, Julie A. Spicer,
Kit Y. Tsang, Patrick D. O’Connor, Jack U. Flanagan, Woo-
Jeong Lee, J.M.J. Dickson, Peter R. Shepherd, and William A.
Denny
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To be cited as: Chem. Asian J. 10.1002/asia.201801762
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10.1002/asia.201801762
Chemistry - An Asian Journal
Synthesis and Evaluation of Imidazo[1,2-a]pyridine Analogues of the ZSTK474
Class of Phosphatidylinositol 3-Kinase Inhibitors
Swarna A. Gamage[a], Julie A. Spicer [a, b], Kit Y. Tsang[a], Patrick D. O’Connor[a], Jack
U. Flanagan[a, b], Woo-Jeong Lee[c], James M.J. Dickson,[b, d] Peter R. Shepherd[a, b, c]
William A. Denny[a, b], Gordon W. Rewcastle*[a, b]
,
[a] Assoc. Prof. G.W. Rewcastle, Dr S.A. Gamage, Dr J.A. Spicer, Dr K.Y. Tsang, Dr
P.D. O’Connor, Dr J.U. Flanagan, Prof. P.R Shepherd, Prof. W.A. Denny
Auckland Cancer Society Research Centre,
Faculty of Medical and Health Sciences,
The University of Auckland,
Private Bag 92019, Auckland 1142 (New Zealand)
Email: g.rewcastle@auckland.ac.nz
[b] Assoc. Prof. G.W. Rewcastle, Dr J.A. Spicer, Dr J.U. Flanagan, Dr J.M.J.
Dickson, Prof. P.R Shepherd, Prof. W.A. Denny
Maurice Wilkins Centre for Molecular Biodiscovery,
The University of Auckland,
Private Bag 92019, Auckland 1142 (New Zealand)
[c] Prof. P.R Shepherd, W-J. Lee
Department of Molecular Medicine and Pathology,
Faculty of Medical and Health Sciences,
The University of Auckland,
Private Bag 92019, Auckland 1142 (New Zealand)
[d] Dr J.M.J. Dickson,
School of Biological Sciences,
Faculty of Science,
The University of Auckland,
Private Bag 92019, Auckland 1142 (New Zealand)
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Abstract: Using a scaffold-hopping approach, imidazo[1,2-a]pyridine analogues of
the ZSTK474 (benzimidazole) class of phosphatidylinositol 3-kinase (PI3K) inhibitors
have been synthesized for biological evaluation. Compounds were prepared using a
heteroaryl Heck reaction procedure, involving the palladium-catalysed coupling of 2-
(difluoromethyl)imidazo[1,2-a]pyridines with chloro, iodo or trifluoromethanesulfonyl-
oxy (trifloxy) substituted 1,3,5-triazines or pyrimidines, with the iodo intermediates
being preferred in terms of higher yields and milder reaction conditions. The new
compounds maintain the PI3K isoform selectivity of their benzimidazole analogues,
but in general show less potency.
Introduction
Phosphatidylinositol 3-kinases (PI3Ks) comprise three separate classes (I, II and III)
of lipid kinase enzymes that play crucial roles in both cell and tissue physiology.[1]
The three class-Ia PI3Ks (PI3Kα/β/δ) link growth factor receptors to a wide range of
downstream pathways, while the single class-Ib PI3K (PI3Kγ) links to G-protein
coupled receptors (GPCRs).[2] The four enzymes have different mechanisms of
activation and display different kinetic properties, but all produce phosphatidyl-
inositol-3,4,5-trisphosphate (PIP3) from phosphatidylinositol-4,5-bisphosphate
(PIP2).[3] The amount of PIP3 produced in cells is in turn tightly controlled by
phosphatases such as PTEN, which converts PIP3 back to PIP2.[4] Defects in both
kinase and phosphatase activities are often seen with tumors, and a large
percentage of human cancers depend strongly on PI3Kα for their survival and
resistance to treatment.[5] As a result, the design and development of small molecule
inhibitors that target the p110α isoform of PI3K has been intensely investigated, and
a number of inhibitors have now entered human clinical trial.[6]
ZSTK474 (1) (Figure 1) is a pan-class I PI3K inhibitor, that has demonstrated
antitumor activity in vivo against human tumor xenografts, and has been evaluated in
phase I/II clinical trials for the treatment of solid tumors.[7] An X-ray crystal structure
obtained with the p110δ isoform of PI3K showed that ZSTK474 bound with one of
the morpholine oxygen atoms making an important H-bond to the Val828 residue,
while the benzimidazole N-3 atom formed a second H-bond to Lys779.[8] We showed
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that the addition of a methoxy group at the 4-position of the benzimidazole unit, to
give 2, improved selectivity for the p110α isoform over the other PI3K isoforms,[9]
and we further demonstrated that one of the morpholine groups could be replaced by
piperazinesulfonamide derivatives, to give compounds such as 3.[10] Unfortunately,
compounds like 3 did not possess good bioavailability, due to limited aqueous
solubility (similar to 1 itself), which led us to prepare more soluble derivatives. These
included SN32976 (4),[11] and PWT33597 (5),[12] also known as VDC-597, which
proceeded to human clinical trial.
In order to further investigate this important class of PI3K inhibitors, we have now
employed a scaffold hopping approach to prepare imidazo[1,2-a]pyridine analogues
of compounds 1-5 (Figure 1). We also synthesized imidazo[1,2-a]pyridine analogues
of piperazine-amides 6-9,[13] including the p110β selective inhibitor MIPS-9922 (8), to
determine whether PI3K isoform selectivity was conserved. Continuing this theme,
the imidazo[1,2-a]pyridine analogue of the p110δ selective inhibitor AS2541019
(10)[14] was also prepared.
Our justification for selecting imidazo[1,2-a]pyridine derivatives was not only that
their structure represented a privileged scaffold with good stability that is present in
several commercial drugs, in a variety of different therapeutic areas,[15] but also that
they are known bioisosteres of benzimidazoles, both in the PI3K field,[16] and
elsewhere. For example, we previously investigated the antibacterial activity of
imidazo[1,2-a]pyridine urea derivatives as analogues of benzimidazole urea
inhibitors of DNA Gyrase and Topoisomerase IV.[17]
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Figure 1. Structures of ZSTK474 and related phosphatidylinositol 3-kinase inhibitors
Results and Discussion
We began our work by investigating an existing literature route to morpholino-
triazinyl-imidazo[1,2-a]pyridines.[18] Reaction of moroxydine hydrochloride (11) with
the imidazo[1,2-a]pyridine ester 12 did give the desired triazine product 13 (Scheme
1), but in very low yield, and even though the subsequent steps performed much
better, this route was abandoned.
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Scheme 1. Synthesis of 16.
We next turned our attention to the use of palladium catalyzed direct arylation
(heteroaryl Heck reaction) of C-3 unsubstituted imidazo[1,2-a]pyridines with
halotriazine derivatives (Scheme 2), which is an established procedure in the PI3K
field.[15] Our initial investigations utilized the readily available 2-
(trifluoromethyl)imidazo[1,2-a]pyridine (17)[19] in reactions with the 2-chlorotriazine
18,[20] giving product 20 in moderate yield when triphenylphosphine was used as the
palladium ligand. Improved yields were obtained using di(1-adamantyl)-n-
butylphosphine (n-BuPAd2), a ligand known to be more effective for chlorinated
substrates in Heck reactions involving imidazo[1,2-a]pyridines,[21] and this phosphine
was retained for all subsequent work. The use of the 2-iodotriazine 19[22] was also
found to give superior results compared to chloride 18, in terms of higher product
yield and milder reaction conditions.
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Scheme 2. Synthesis of 20. n-BuPAd2 = di(1-adamantyl)-n-butylphosphine.
In order to prepare the direct imidazo[1,2-a]pyridine analogue of ZSTK474 (1) it was
first necessary to prepare 2-(difluoromethyl)imidazo[1,2-a]pyridine (22), which was
readily formed by treatment of the known aldehyde 21[23] with DAST (Scheme 3).
Heck reaction of 22 with chloride 18 gave the desired ZSTK474 analogue 23 in good
yield.
Scheme 3. Synthesis of 23. DAST = (diethylamino)sulfur trifluoride; n-BuPAd2 =
di(1-adamantyl)-n-butylphosphine.
For synthesis of the 4-methoxy analogue of 23, a similar approach was used
(Scheme 4), with aldehyde 25 first being prepared from 2-aminopyridine 24. Again
Heck reaction of imidazo[1,2-a]pyridine 26 with chloride 18, occurred in very good
yield to give the target compound 27.
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Scheme 4. Synthesis of 27. DAST = (diethylamino)sulfur trifluoride; n-BuPAd2 =
di(1-adamantyl)-n-butylphosphine.
For the synthesis of imidazo[1,2-a]pyridine analogues of the piperazinesulfonamides
3 and 4 (SN32976), we first prepared the iodotriazine 30 (Scheme 5). This was
readily prepared from diiodide 29, which was obtained from dichloride 28[24] by
treatment with aqueous hydriodic acid. Heck reaction of 26 with 30 gave Boc-
piperazine 31 in good yield, and after removal of the Boc protecting group,
sulfonamides 32 and 33 were readily prepared. Reaction of the vinyl sulfonamide 33
with dimethylamine then gave the desired SN32976 analogue 34.
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Scheme 5. Synthesis of 34. DIPEA = N,N-diisopropylethylamine; n-BuPAd2 = di(1-
adamantyl)-n-butylphosphine.
For the synthesis of the imidazo[1,2-a]pyridine analogue of PWT33597 (5), we
utilized the triflate intermediate 38, which was prepared by standard procedures
(Scheme 6). Heck reaction of 26 with 38 gave compound 39 in moderate yield, and
this was then successfully elaborated to target 41, by similar procedures to that used
in the synthesis of 34.
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Scheme 6. Synthesis of 41. dppf = 1,1'-bis(diphenylphosphino)ferrocene; n-BuPAd2
= di(1-adamantyl)-n-butylphosphine; DIPEA = N,N-diisopropylethylamine.
For the synthesis of imidazo[1,2-a]pyridine analogues of the PI3K isoform selective
derivatives 6-9, Heck reaction of existing intermediates 22 and 30 gave Boc-
piperazine 42, which was deprotected to give amine 43 (Scheme 7). Coupling of 43
with Boc-protected aminoacids gave amides 44 - 47, from which targets 48 - 51 were
obtained.
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Scheme 7. Synthesis of 48-51. n-BuPAd2 = di(1-adamantyl)-n-butylphosphine;
HBTU = O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate;
DIPEA = N,N-diisopropylethylamine.
Finally, synthesis of the imidazo[1,2-a]pyridine analogue of the p110δ selective
inhibitor AS2541019 (10) was achieved as shown in Scheme 8. Condensation of
tert-butyl (trans-4-hydroxycyclohexyl)carbamate with 4,6-dichloro-2-(methylthio)-
pyrimidine (52) successfully gave ether 53, but this compound failed to react cleanly
with imidazo[1,2-a]pyridine 22 under palladium catalysed conditions. Accordingly, 53
was oxidized to the analogous sulfone, and this was treated with morpholine to give
an approximately 1:1 mixture of the desired chloro derivative 54, plus sulfone 55.
Fortunately, these were readily separable by chromatography, and chloride 54 was
then converted to iodide 56, in 83% overall yield, via a 3-step procedure involving
Boc removal, iodination, and re-addition of the Boc protecting group. Heck reaction
of 56 with imidazo[1,2-a]pyridine 22 gave 57 in excellent yield, and this was then
elaborated by standard procedures to target 58.
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Scheme 8. Synthesis of 58. n-BuPAd2 = di(1-adamantyl)-n-butylphosphine; HATU =
1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide
hexafluorophosphate ; DIPEA = N,N-diisopropylethylamine.
The target compounds were tested for their biochemical inhibitory activity against the
p110α, p110β, and p110δ isoforms of PI3K using Homogeneous Time Resolved
Fluorescence (HTRF) assays, and their results are compared with those of reference
compounds 1-10 in Table 1.
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Table 1. Biological data for benzimidazole and imidazo[1,2-a]pyridine analogues
Cpd
Typea
Enzyme IC50 (nM)b
p110
9
p110
58
p110
38
1
B
I
23
2
89
750
182
750
1,500
>3,000
743
680
317
150
2
137
19
B
I
4
27
3
44
240
41
B
I
6
32
4
18
315
206
255
57
B
I
5
34
20
5
41
6
B
I
6
21
180
14
B
I
77
48
7
231
106
436
87
21
200
9
B
I
44
49
8
1186
3
234
16
B
I
50
9
310
165
732
547
340
11
228
3
B
I
221
535
734
1,386
51
10
58
110
7
B
I
16
[a] B = benzimidazole; I = imidazo[1,2-a]pyridine
[b] IC50 values are the mean of duplicate or triplicate measurements
Comparison of the benzimidazole/imidazo[1,2-a]pyridine pairs (1 and 23, 2 and 27, 3
and 32, 4 and 34, 5 and 41, 6 and 48, 7 and 49, 8 and 50, 9 and 51, 10 and 58)
shows that the benzimidazole derivatives are generally more potent (lower IC50
values), although PI3K isoform selectivity is maintained. Thus, imidazo[1,2-
a]pyridines 23, 27, 32, 34 and 41 retain the p110 selectivity of benzimidazoles 1-5,
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imidazo[1,2-a]pyridines 48 and 50 retain the p110 selectivity of benzimidazoles 6
and 8, and imidazo[1,2-a]pyridines 49, 51 and 58 retain the p110 selectivity of
benzimidazoles 7, 9 and 10.
A possible explanation for the greater potency of the benzimidazoles, compared to
the imidazo[1,2-a]pyridines, might be due to the greater basicity of the latter. For
example, the parent imidazo[1,2-a]pyridine has a pKa of 6.79,[25] whereas the pKa of
unsubstituted benzimidazole is 5.53.[26] Since the benzimidazole 3-nitrogen atom
(and presumably the imidazo[1,2-a]pyridine 1-nitrogen atom) is involved in H-
bonding to a lysine amino group in the ATP binding pocket of the PI3K (Lys802 in
p110α, Lys805 in p110β, Lys779 in p110δ and Lys833 in p110γ),[8, 9] the greater
proportion of protonation of the imidazo[1,2-a]pyridines would leave less molecules
available to form H-bonds with the lysine amino group.
Conclusions
We have developed an efficient route to imidazo[1,2-a]pyridine analogues of the
ZSTK474 class of PI3K inhibitors. Comparison of the new compounds with the
existing benzimidazole inhibitors shows that while the latter are still the most
preferred in terms of potency, the imidazo[1,2-a]pyridines retain the PI3K isoform
selectivity of their benzimidazole analogues.
Experimental Section
General information
Elemental analyses were performed by the Microchemical Laboratory, University of
Otago, Dunedin, New Zealand. Melting points were determined on an Electrothermal
IA9100 melting point apparatus and are as read. NMR spectra were obtained on a
Bruker Avance 400 spectrometer at 400 MHz for proton spectra, 376 MHz for
fluorine spectra, and 100 MHz for carbon spectra, referenced to Me4Si or solvent
resonances. Low-resolution atmospheric pressure chemical ionization (APCI) mass
spectra were measured for methanol solutions on an Agilent Technologies 6120
Quadrapole LC/MS connected to an Agilent Technologies1260 Infinity autosampler.
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High-resolution mass spectra were obtained with organic solutions on an Agilent
Technologies 6500 Series quadrupole time-of-flight (Q-TOF) LC/MS system. Thin-
layer chromatography was carried out on aluminium-backed silica gel plates (Merck
60 F254), with visualization of components by UV light (254 nm). Column
chromatography was carried out on silica gel, (Merck 230 - 400 mesh) unless
otherwise stated. Tested compounds were >95% purity, as determined by
combustion analysis, or by HPLC conducted on an Agilent 1100 system, using a
reversed-phase C8 column with diode array detection.
Materials and Methods
Reference compounds 1-10 were available from earlier work,[9-12] or were prepared
by literature procedures.[13, 14]
4,4'-(6-(2-Methylimidazo[1,2-a]pyridin-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholine
(16)
A mixture of moroxydine hydrochloride (11) (1.81 g, 8.75 mmol) and NaOMe (1.2152
g, 22.5 mmol) in MeOH (30 mL) was stirred for 35 min, and a solution of ethyl 2-
methylimidazo[1,2-a]pyridine-3-carboxylate (12)[27] (1.77 g, 8.75 mmol) in MeOH (10
mL) was added. The resulting mixture was heated at 65 °C for 48 h, and
concentrated under reduced pressure. Purification by flash column chromatography
with silica using CH2Cl2/MeOH (9:1) gave 4-(2-methylimidazo[1,2-a]pyridin-3-yl)-6-
morpholino-1,3,5-triazin-2-amine (13) (0.14 g, 9%): 1H NMR (DMSO-d6)  =10.03 (dt,
7.1, 1.1 Hz, 1H), 7.60 (dt, J = 7.8, 1.0 Hz, 1H), 7.42-7.39 (m, 1H), 7.04 (dt, J = 6.9,
1.3 Hz, 1H), 6.95 (br s, 2H), 3.76-3.75 (m, 4H), 3.68-3.66 ppm (m, 4H); MS (APCI)
m/z 312.8 (MH+).
To a solution of 13 (0.345 g, 1.11 mmol) in TFA (9 mL) at 0 °C was added NaNO2
(0.12 g, 1.74 mmol), and the mixture was stirred overnight. After dilution with water
(5 mL), the mixture was neutralized with ammonia, and extracted with CH2Cl2. After
drying and removal of the solvent, the crude product was recrystallized from CH2Cl2-
MeOH to give 4-(2-methylimidazo[1,2-a]pyridin-3-yl)-6-morpholino-1,3,5-triazin-
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2(1H)-one (14) (0.277 g, 80%) as a white powder: 1H NMR (DMSO-d6)  =9.69 (br s,
1H), 7.81 (d, J = 8.9 Hz, 1H), 7.75-7.71 (m, 1H), 7.35 (t, J = 6.8 Hz, 1H), 3.79-3.78
(m, 4H), 3.71-3.69 ppm (m, 4H); MS (APCI) m/z 313.8 (MH+).
A mixture of 14 (0.171 g, 0.55 mmol), POCl3 (0.12 mL, 1.29 mmol) and diethylaniline
(0.08 mL, 0.50 mmol) was heated to reflux for 5 h, cooled to room temperature, and
poured into ice-water. After being stirred for 30 min, the resultant mixture was diluted
with saturated aqueous Na2CO3 solution and extracted with CHCl3. The organic layer
was dried (Na2SO4) and concentrated. Purification by flash column chromatography
on silica using CH2Cl2-EtOAc (1:3) gave 4-(4-chloro-6-(2-methylimidazo[1,2-
a]pyridin-3-yl)-1,3,5-triazin-2-yl)morpholine (15) (0.122 g, 67%) as a white powder:
1H NMR (DMSO-d6) =9.69 (dt, 7.0, 1.0 Hz, 1H), 7.70 (dt, J = 7.8, 1.0 Hz, 1H), 7.55
(ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 7.22 (dt, J = 7.0, 1.3 Hz, 1H), 3.88 (d, J = 4.6 Hz, 2H),
3.80-3.70 (m, 6H), 2.77 ppm (s, 3H); elemental analysis calcd (%) for C15H15ClN6O:
C 54.5, H 4.5, N 25.4; found: C 54.7, H 4.6, N, 25.6.
To a solution of 15 in THF (2 mL) was added morpholine (0.05 mL, 0.57 mmol) and
the reaction mixture was heated at 60 °C for 2 h. After cooling and dilution with
water, the resulting solid was collected by filtration and dried, to give 16 (0.029 g,
85%) as a white powder: m.p. 250-252 °C; 1H NMR (CDCl3) =9.75 (dt, J = 7.0, 1.1
Hz, 1H), 7.60 (d, J = 8.9, 1.1 Hz, 1H), 7.28 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 6.90 (dt, J
= 6.9, 1.3 Hz, 1H), 3.89-3.85 (m, 4H), 3.80-3.77 (m, 4H), 2.87 ppm (s, 3H); 13C NMR
(CDCl3) =165.7 (C), 164.8 (C), 151.3 (C), 146.5 (C), 128.8 (CH), 126.2 (CH), 118.2
(C), 116.9 (CH), 112.7 (CH), 66.9 (CH2), 44.0 (CH2), 18.3 ppm (CH3); HRMS (APCI):
m/z calcd for C19H23N7O2+H+: 382.1986 [M+H+]; found: 382.2000.
4,4'-(6-(2-(Trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)-1,3,5-triazine-2,4-
diyl)dimorpholine (20)
Method A: A mixture of 2-(trifluoromethyl)imidazo[1,2-a]pyridine (17)[19] (82 mg,
0.044 mmol), 4,4'-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine (18)[20] (125.7 mg,
0.044 mmol), Pd(PPh3)4 (254 mg, 0.022 mmol), Pd(OAc)2 (49 mg, 0.022 mmol),
K2CO3 (122 mg, 0.088 mmol) in dioxane (5 mL) and water (1 mL) was degassed,
flushed with nitrogen, and heated under reflux overnight. After dilution with water and
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extraction with CH2Cl2, the crude product was chromatographed on silica eluting with
hexanes/EtOAc (1:1), to give 20 (100.8 mg, 52%); mp (MeOH) 271-274 oC; 1H NMR
(CDCl3) δ=9.63 (dt, J = 7.1, 1.1 Hz, 1H), 7.79 (dt, J = 9.1, 1.1 Hz, 1H), 7.41 (ddd, J =
9.0, 6.8, 1.2 Hz, 1H), 7.04 (td, J = 7.0, 1.2 Hz, 1H), 3.92-3.84 (br, 8 H), 3.79-3.76
ppm (m, 8H); 13C NMR (CDCl3) δ=164.6 (C), 163.7 (C), 145.2 (C), 138.5 (q, JCF =
38.0 Hz, C), 128.6 (CH), 127.4 (CH), 122.0 (q, JCF = 269.4 Hz, C), 121.2 (C), 118.9
(CH), 114.7 (CH), 67.0 (CH2), 43.9 ppm (CH2); 19F NMR (CDCl3) δ=-60.43 ppm (s);
HRMS (APCI): m/z calcd.for C19H20F3N7O2+H+: 436.1703 [M+H+]; found: m/z
436.1695.
Method B: A mixture of 17 (49 mg, 0.026 mmol), 4,4'-(6-iodo-1,3,5-triazine-2,4-
diyl)dimorpholine (19)[22] (94 mg, 0.025 mmol), Pd(OAc)2 (1.2 mg, 0.0053 mmol), n-
BuPAd2 (3.5 mg, 0.0098 mmol), K3PO4 (110 mg, 0.052 mmol) in dry DMF (2 mL) was
flushed with nitrogen and heated in an oil bath at 90 °C for 2 h. After dilution with
water and extraction with CH2Cl2, the crude product was chromatographed on silica,
eluting first with CH2Cl2/EtOAc (49:1), and then CH2Cl2/EtOAc (4:1), to give 20 (100
mg, 92% yield); identical to above.
4,4'-(6-(2-(Difluoromethyl)imidazo[1,2-a]pyridin-3-yl)-1,3,5-triazine-2,4-
diyl)dimorpholine (23)
A solution of imidazo[1,2-a]pyridine-2-carbaldehyde (21)[23] (2.15 g, 14.72 mmol) in
CH2Cl2 was treated with (diethylamino)sulfur trifluoride (DAST) (4 mL, excess) and
the mixture was stirred for 1h, when further DAST (3 mL) was added and stirring was
continued for a another 2 h. The reaction mixture was poured into ice water, basified
with aq NH3, extracted into CH2Cl2 (4x 30 mL) and dried (Na2SO4). Evaporation of the
solvents and chromatography of the residue on silica, eluting with CH2Cl2/hexanes
(1:1) followed by CH2Cl2/EtOAc (9:1) gave 2-(difluoromethyl)imidazo[1,2-a]pyridine
1
(22)[28] (1.0 g, 40%): H NMR (CDCl3) δ=8.13 (td, J = 6.8, 1.0 Hz, 1H), 7.79 (brs,
1H),7.61 (dd, J = 9.2, 0.6 Hz, 1H), 7.24 (ddd, J = 9.1, 6.8, 1.2 Hz, 1H), 6.88 (t, JHF
=
55.6 Hz, 1H), 6.88 ppm (dt, J = 6.8, 0.9 Hz, 1H); 13C NMR (CDCl3) δ=146.6 (C),
140.5 (t, JCF = 27.5 Hz, C), 126.4 (CH), 126.0 (CH), 118.5 (CH), 113.6 (CH), 111.9 (t,
JCF = 235.7 Hz, CH), 110.7 ppm (CH); 19F NMR (CDCl3) δ= -113.8 ppm (d, JFH
=
55.1 Hz).
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A mixture of 18 (449 mg, 1.2 mmol), 22 (220 mg, 1.3 mmol), and K2CO3 (259 mg, 2
eq) in DMA (2 mL) was degassed with N2 for 10 min, then Pd(OAc)2 (30 mg, 0.1 eq)
and n-BuPAd2 (74 mg, 0.16 mmol) was added and the mixture was heated at 120 °C
for 4 h. The reaction mixture was diluted with EtOAc, stirred and the resulting
precipitate was collected by filtration and washed with more EtOAc. The combined
filtrate was evaporated to dryness. Further material was isolated by extracting the
precipitate with CH2Cl2 (5x30 mL). The combined material was chromatographed on
silica eluting with
CH2Cl2/EtOAc (0-10%) to give 23 (353 mg, 88%): mp
1
(CH2Cl2/hexane) 272-274 °C. H NMR (CDCl3) δ 9.74 (td, J = 7.1, 1.1 Hz, 1H), 7.80
(td, J = 9.0, 1.1 Hz, 1H), 7.71 ( t, JHF = 54.5 Hz, 1H), 7.41 (ddd, J = 9.0, 6.8, 1.3 Hz,
13
1H), 7.03 (dt, J = 6.9, 1.2 Hz, 1H), 3.89-3.86 (m, 8H), 3.80-3.78 (m, 8H); C NMR
(CDCl3) δ=164.5 (C), 164.3 (C), 146.7 (C), 143.9 (t, JCF = 24.1 Hz, C), 128.9 (CH),
127.4 (CH), 120.9 (t, JCF = 6.5 Hz, C), 118.8 (CH), 114.3 (CH), 110.5 (t, JCF = 234.5
Hz, CH), 66.9 (CH2), 44.0 ppm (CH2); 19F NMR (CDCl3) δ=-116.36 ppm (d, JFH
=
54.5 Hz); elemental analysis calcd (%).for C19H21F2N7O2: C 54.7, H 5.1, N 23.5;
found: C 54.9, H 4.9, N 23.7.
4,4'-(6-(2-(difluoromethyl)-8-methoxyimidazo[1,2-a]pyridin-3-yl)-1,3,5-triazine-
2,4-diyl)dimorpholine (27)
A solution of 3-methoxypyridin-2-amine (24) (2.32 g, 18.69 mmol) in 1,2-
dimethoxyethane (DME) was treated with 1,1,3-trichloroacetone (3 mL, 22.4 mmol)
in DME (10 mL). The reaction mixture was stirred at 20 °C for 4 h and the resulting
solid was collected by filtration. The solid was suspended in ethanol (30 mL) and the
mixture was heated under reflux overnight. After cooling, the solvent was removed
under vacuum, and the residue was suspended in aq K2CO3 and heated to 90 °C for
3 h. After cooling, the mixture was extracted with CH2Cl2, and dried (Na2SO4).
Evaporation of the solvent and chromatography of the residue on silica, eluting with
CH2Cl2/EtOAc (9:1) gave 8-methoxyimidazo[1,2-a]pyridine-2-carbaldehyde (25)
(1.27 g, 30%): mp (CH2Cl2/hexane) 186-188°C, 1H NMR (CDCl3) δ 10.17 (s, 1H),
8.13 (s, 1H), 7.80 (dd, J = 6.8, 0.8 Hz, 1H), 6.82 (t, J = 8.0, 1H), 6.53 (d, J = 7.5 Hz,
1H), 4.05 (s, 3H); elemental analysis calcd (%) for C9H8N2O2: C 61.4, H 4.6, N 15.9;
found C 61.5; H 4.5, N 16.0.
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To a solution of 25 (1.16 g, 6.6 mmol) in CH2Cl2 (10 mL) was added DAST (2 ml,
excess) and the mixture was stirred at 20 °C for 2 h. More DAST (2 mL, excess) was
added and after 2 h an additional amount of DAST (2 mL) was added, and stirring
was continued for a further 2h.The reaction mixture was slowly poured into ice,
basified with aq. NH3 and the solvent evaporated to dryness. The residue was
chromatographed on silica, eluting with CH2Cl2/hexane (4:1), followed by
CH2Cl2/EtOAc (9:1) to give 2-(difluoromethyl)-8-methoxyimidazo[1,2-a]pyridine (26)
(658 mg, 50%): mp (i-Pr2O) 122-124 °C; 1H NMR (CDCl3) δ 7.78 (t, J = 1.4 Hz, 1H),
7.77 (d, J = 0.8 Hz, 1H), 6.87 (t, JHF = 55.5 Hz, 1H), 6.77 (t, J = 7.2 Hz, 1H), 6.51 (d,
J = 7.5 Hz, 1H), 4.02 (s, 3H); 13C NMR (CDCl3) δ 149.7 (C), 140.2 (C), 139.8 (C),
119.1 (CH), 113.7 (CH), 112.1 (t, JCF = 235.3 Hz, CH), 111.6 (t, JCF = 4.1 Hz, CH),
101.4 (CH), 56.1 (CH3); 19F NMR (CDCl3) δ -113.2 (d, JHF = 56.0 Hz); MS (APCI)
m/z: 199.2 (MH+); elemental analysis calcd (%) for C9H8F2N2O: C 54.5, H 4.1, N
14.1; found: C 54.7, H 3.8, N 14.2.
A mixture of compound 26 (154 mg, 0.78 mmol), compound 18 (266 mg, 0.94 mmol)
and K2CO3 (215 mg, 1.56 mmol), in DMA (1 mL) was degassed and flushed with a
balloon of nitrogen. Pd(OAc)2 (18 mg, 0.1 eq) and n-BuPAd2 (45 mg, 0.16 eq) were
then added and the mixture was degassed and flushed with nitrogen again. The
reaction mixture was heated for 2 h at 120 °C and the DMA was removed under
vacuum. The resulting residue was chromatographed on silica eluting with
CH2Cl2/EtOAc (4:1) to give 27 (386 mg, 100%): mp (CH2Cl2/MeOH) 316-320 °C; 1H
NMR (CDCl3) δ=9.33 (dd, J = 7.0, 0.8 Hz, 1H), 7.64 (t, JHF = 54.4 Hz, 1H), 6.92 (t, J
= 7.3 Hz, 1H), 6.68 (d, J = 7.2 Hz, 1H), 4.05 (s, 3H), 3.88-3.85 (m, 8H), 3.79-3.77
ppm (m, 8H); elemental analysis calcd (%) for C20H23F2N7O3: C 53.7, H 5.2, N 21.9;
found: C 53.8, H 5.1, N 22.0.
2-(Difluoromethyl)-8-methoxy-3-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-
morpholinyl)-1,3,5-triazin-2-yl]imidazo[1,2-a]pyridine (32)
To a solution of 3-methoxypyridin-2-amine (24) (0.68 g, 5.5 mmol) in DME (10 mL)
was added dropwise a solution of 1-bromo-3,3-difluoroacetone (1 g, 5.8 mmol) in
DME (1 mL), and the mixture was stirred for 4 h. The white precipitate was collected
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by filtration, washed with DME, and dissolved in EtOH (10 mL). The solution was
heated under reflux overnight and the solvent was removed. The residue was
basified with aq. Na2CO3 and extracted with CH2Cl2. After drying, the solvent was
removed to give 26 (0.826 g, 76%); identical to above.
4-(4,6-Dichloro-1,3,5-triazin-2-yl)morpholine (28)[24] (2.50 g, 10.6 mmol) was added
portion-wise to 57% aq. HI (20 mL) at 0 °C, and the resulting suspension was
allowed to warm to room temperature. After stirring overnight, the reaction mixture
was poured onto ice and carefully neutralized with saturated Na2CO3 solution. The
resulting solid was extracted into CH2Cl2 and washed with 1 M Na2SO3 and brine.
The organic layer was dried (Na2SO4), filtered, and the solvent removed under
reduced pressure to give 4-(4,6-diiodo-1,3,5-triazin-2-yl)morpholine (29) (3.41 g,
1
83%) as a crystalline white solid: mp (hexane) 191-193 °C; H NMR (CDCl3) =3.83-
3.79 (m, 4H), 3.76-3.71 ppm (m, 4H); 13C NMR (CDCl3) δ=159.9 (C), 138.0 (C),
140.6 (C), 66.6 (CH2), 44.3 ppm (CH2); MS (APCI) m/z: 418.9 (MH+); elemental
analysis calcd (%) for C7H8I2N4O: C 20.1, H 1.9, N 13.4; found: C 20.4, H 2.0, N
13.3.
To a solution of 29 (3.41 g, 8.8 mmol) and DIPEA (2.06 g, 16.0 mmol) in THF (30
mL) was added N-Boc-piperazine (2.08 g, 11.2 mmol). This mixture was stirred at
room temperature for 1 h and water was added. The resulting white solid was
collected by filtration, washed well with water and dried in a vacuum oven to give
tert-butyl 4-(4-iodo-6-morpholino-1,3,5-triazin-2-yl)piperazine-1-carboxylate (30)
1
(3.89 g, 93%) as a white solid: mp (MeOH) 210-215 °C; H NMR (CDCl3) δ=3.79-
3.67 (m, 12H), 3.47-3.42 (m, 4H), 1.48 ppm (s, 9H); 13C NMR (CDCl3) δ=162.2 (C),
154.9 (C), 140.6 (C), 80.43 (C), 66.9 (CH2), 66.7 (CH2), 44.0 (CH2), 43.7 (CH2), 43.4
(CH2), 43.2 (CH2), 28.6 ppm (CH3); MS (APCI) m/z: 477.1 (MH+); elemental analysis
calcd (%) for C16H25IN6O3: C 40.4, H 5.3, N 17.6; found: C 40.6, H 5.4, N 17.5.
A mixture of 2-(difluoromethyl)-8-methoxyimidazo[1,2-a]pyridine (26) (0.238 g, 1.2
mmol), 30 (0.476 g, 1 mmol), Pd(OAc)2 (11.2 mg, 0.005 mmol), n-BuPAd2 (36 mg,
0.01 mmol) and K3PO4 (440 mg, 2 mmol) in DMF (20 mL) was degassed, flushed
with nitrogen, and heated at 90 °C for 3 h. After cooling, dilution with water gave a
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precipitate, which was collected and washed with water. After drying the solid was
chromatographed on silica, eluting with CH2Cl2/EtOAc (4:1) to give tert-butyl 4-(4-(2-
(difluoromethyl)-8-methoxyimidazo[1,2-a]pyridin-3-yl)-6-morpholino-1,3,5-triazin-2-
yl)piperazine-1-carboxylate (31) (0.446 g, 82%): mp (MeOH) 234-236 °C; 1H NMR
(CDCl3) δ=9.32 (dd, J = 7.1, 0.7 Hz, 1H); 7.64 (t, JHF = 54.5 Hz, 1H); 6.92 (t, J = 7.4
Hz, 1H); 6.68 (t, J = 7.5 Hz, 1H); 4.05 (s, 3H); 3.89-3.82 (m, 8H), 3.81-3.76 (m, 4H),
3.56-3.50 (m, 4H), 1.50 ppm (s, 9H); MS (APCI) m/z: 547.3 (MH+).
A mixture of 31 (0.109 g, 0.2 mmol) and TFA (1 mL) in CH2Cl2 (5 mL) was stirred at
room temperature for 2 h. After cooling in ice, the mixture was basified with aq. NH3.
The CH2Cl2 solution was dried, and removed, to give 2-(difluoromethyl)-8-methoxy-3-
[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]imidazo[1,2-a]pyridine: 1H NMR
(DMSO-d6) δ 9.30 (dd, J = 7.00, 0.6 Hz, 1H), 7.72 (t, JHF = 54.3 Hz, 1H), 7.15 (t, J =
7.4 Hz, 1H); 6.99 (d, J = 7.7 Hz, 1H), 3.99 (s, 3H), 3.83-3.75 (m, 8H), 3.72-3.66 (m,
4H), 2.96-2.87 (m, 4H); MS (APCI) m/z: 447.3 (MH+).
The above crude amine (0.2 mmol) was dissolved in CH2Cl2 (25 mL) with DIPEA (65
mg, 5 mmol) and the mixture was cooled to 0 °C in an ice-bath. Methanesulfonyl
chloride (27 mg, 0.24 mmol) was added, and the mixture was stirred overnight at
room temperature. Water was added, and the organic layer was separated and
1
dried, to give 32 (0.101 g, 96%): mp (MeOH) 311-314 °C; H NMR (CDCl3) δ=9.29
(dd, J = 7.1, 0.8 Hz, 1H), 7.60 (t, JHF = 54.5, 1H), 6.93 (t, J = 7.4 Hz, 1H), 6.69 (dd, J
= 7.4, 0.4 Hz, 1H), 4.05 (s, 3H), 4.03-3.99 (m,4H ), 3.89-3.83 (m, 4H), 3.81-3.77 (m,
4H), 3.34-3.30 (m, 4H), 2.81 ppm (s, 3H); 13C NMR (CDCl3) δ=164.5 (C), 164.46 (C),
164.42 (C), 149.6 (C), 143.0 (t, JCF = 24.8 Hz, C), 141.1 (C), 121.7 (t, JCF = 5.7 Hz,
C), 121.3 (CH), 114.4 (CH), 110.5 (t, JCF = 236.4 Hz, CH), 103.5 (CH), 66.9 (CH2),
56.2 (CH3), 45.8 (CH2), 44.0 (CH2), 43.2 (CH2), 34.8 ppm (CH3); HRMS (APCI): m/z
calcd for C21H26F2N8O4+H+: 525.1865 [M+H+]; found: 525.1863.
2-((4-(4-(2-(Difluoromethyl)-8-methoxyimidazo[1,2-a]pyridin-3-yl)-6-morpholino-
1,3, 5-triazin-2-yl)piperazin-1-yl)sulfonyl)-N,N-dimethylethan-1-amine (34)
A mixture of 31 (0.191 g, 0.35 mmol) and TFA (2 mL) in CH2Cl2 (10 mL) was stirred
at room temperature for 2 h. After cooling in ice, the mixture was basified with aq.
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NH3 and extracted with CH2Cl2 to give crude 2-(difluoromethyl)-8-methoxy-3-[4-(4-
morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]imidazo[1,2-a]pyridine (identical to
above) which was combined with DIPEA (113 mg, 0.875 mmol) in CH2Cl2 (50 mL).
The solution was cooled to -15 °C in an ice-salt bath and 2-chloroethanesulfonyl
chloride (85 mg, 0.52 mmol) was added slowly over 10 min, and the mixture was
stirred at -15 °C for 1 h. After dilution with water the organic layer was separated,
dried (Na2SO4), and removed. The residue was chromatographed on silica, eluting
with CH2Cl2/EtOAc (4:1) to give 2-(difluoromethyl)-8-methoxy-3-[4-(4-morpholinyl)-6-
[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl]imidazo[1,2-a]pyridine (33) (0.124 g,
66%): 1H NMR (CDCl3) δ=9.29 (dd, J = 7.0, 0.8 Hz, 1H), 7.59 (t, JHF = 54.4 Hz, 1H),
6.93 (d, J = 7.4 Hz, 1H), 6.69 (d, J = 7.2 Hz, 1H), 6.43 (dd, J = 16.6, 9.8 Hz, 1H),
6.29 (d, J = 16.6 Hz, 1H), 6.08 (d, J = 9.8 Hz, 1H), 4.05 (s, 1H), 4.02-3.97 (m, 4H),
3.89-3.83 (m 4H), 3.81-3.76 ppm (m, 4H), 3.27-3.32 (m, 4H); MS (APCI) m/z: 536.9
(MH+).
Crude 33 was combined with 40% aq. Me2NH (10 mL) in THF (40 mL), and after 30
min the solvents were removed, and the residue was extracted with CH2Cl2. After
drying, the solvent was removed, and the residue was recrystallized from MeOH to
give 34 (118 mg, 88%): mp 258-261 °C; 1H NMR (CDCl3) δ=9.30 (dd, J = 7.1, 0.8
Hz, 1H), 7.60 (t, JHF = 54.4, 1H), 6.93 (t, J = 7.4 Hz, 1H), 6.69 (dd, J = 7.4, 0.4 Hz,
1H), 4.05 (s, 3H), 4.01-3.95 (m, 4H), 3.90-3.84 (m, 4H), 3.81-3.77 (m, 4H), 3.41-3.36
(m, 4H) (s, 3H); 3.13 (t, J = 7.3 Hz, 2H), 2.80 (d, J = 7.3 Hz, 2H), 2.28 ppm (s, 6H);
HRMS (APCI): m/z calcd for C24H33F2N9O4+H+: 582.2417 [M+H+]; found: 582.2420.
N-(4-(4-(2-(Nifluoromethyl)-8-methoxyimidazo[1,2-a]pyridin-3-yl)-6-morpholino-
1,3,5-triazin-2-yl)phenyl)-2-(dimethylamino)ethane-1-sulfonamide (41)
A mixture of 2-(benzyloxy)-4,6-dichloro-1,3,5-triazine (35)[29] (1.106 g, 4.34 mmol)
and morpholine (755 mg, 8.68 mmol) in CH2Cl2 (30 mL) was stirred at 20 °C for 2h.
The solvent was evaporated at room temperature, and the resulting residue was
stirred in water (150 mL), the precipitate was collected and chromatographed on
silica, eluting with CH2Cl2/hexane (95:5) to give 4-(4-(benzyloxy)-6-chloro-1,3,5-
triazin-2-yl)morpholine (36) (1.11g, 83%); mp (CH2Cl2/hexanes) 141-142 °C, 1H NMR
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(CDCl3) δ=7.44-7.42 (m, 2H), 7.38-7.30 (m, 3H), 5.39 (s, 2H), 3.88-3.83 (m, 4H),
3.74-3.71 ppm (m, 4H); MS (APCI) m/z: 307.0 (MH+).
A mixture of 36 (2.01g, 6.54 mmol), 4-(Boc-amino)phenylboronic acid (804 mg, 3.39
mmol) and 2M K2CO3 (2.5 mL) in dioxane was degassed and flushed with N2, then
treated with Pd(dppf)Cl2 and refluxed under N2 for 2h, evaporated to dryness and the
residue was chromatographed on silica, eluting with CH2Cl2/hexanes (1:1) and then
CH2Cl2 to give tert-butyl (4-(4-(benzyloxy)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-
carbamate (37) (718 mg, 69%): 1H NMR (CDCl3) δ=8.38 – 8.36 (m, 2H), 7.50-7.43
(m, 4H), 7.38-7.29 (m, 3H), 6.64 (br s, 1H), 5.48 (s, 2H), 4.01 and 3.88 (2 br, 4H),
3.76 (br, 4H), 1.53 ppm (s, 9H); MS (APCI) m/z: 464.0 (MH+).
A solution of 37 (2.51g, 5.42 mmol) in THF (30 mL) was hydrogenated over 10%
Pd/C for 4h, MeOH (50 mL) and CH2Cl2 (50 mL) added to dissolve the precipitated
product, and the solution filtered through a pad of celite. Removal of the solvents
gave tert-butyl (4-(4-hydroxy-6-morpholino-1,3,5-triazin-2-yl)phenyl)carbamate (1.94
g, 95%); 1H NMR (DMSO-d6) δ=11.83 (br s, 1H), 9.78 (s, 1H), 8.13 (br d, J = 8.9 Hz,
2H), 7.59 (br d, J = 8.9 Hz, 2H), 3.82 (br, 4H), 3.66-3.63 (m, 4H), 1.49 ppm (s, 9H);
MS (APCI) m/z: 374.0 (MH+).
A suspension of the above compound (780 mg, 2.1 mmol) and DIPEA (1.5 mL, 8.4
mmol) in CH2Cl2 (30 mL) was treated with triflic anhydride (0.7 mL, 4.2 mmol) and
the mixture was stirred for 2h, when more triflic anhydride (0.4 mL) and DIPEA (1
mL) were added. Stirring was continued for a further 2h before the volatiles were
removed under vacuum. The resulting residue was chromatographed on silica,
eluting with CH2Cl2/hexanes (9:1) to give 4-(4-((tert-butoxycarbonyl)amino)phenyl)-
6-morpholino-1,3,5-triazin-2-yl trifluoromethanesulfonate (38) (859 mg, 81%): mp
1
(CH2Cl2/hexane) >320 °C; H NMR (CDCl3) δ=8.34-8.30 (m, 2H), 7.47 (br d, J = 8.8
Hz, 2H), 6.69 (br s, 1H), 4.07 (br t, J = 4.9 Hz, 2H), 3.87 (br t, J = 4.7 Hz, 2H), 3.83-
3.77 (m, 4H), 1.54 ppm (s, 9H); MS (APCI) m/z: 505.9 (MH+).
A mixture of 26 (307 mg, 1.55 mmol), 38 (850 mg, 1.68 mmol), and K2CO3 (354, mg
2.56 mmol) in DMF (3 mL) in a sealed tube was degassed and flushed with N2. Then
Pd(OAc)2 (28 mg, 0.1 eq), n-BuPAd2 (73 mg, 0.16 eq) was added. The reaction
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10.1002/asia.201801762
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mixture was heated to 120 °C for 2 h. The solvents were removed under vacuum
and the resulting residue was chromatographed on silica, eluting with CH2Cl2 to give
unreacted 26 (216 mg, 70%). Further elution with CH2Cl2/EtOAc (17:3) gave tert-
butyl (4-(4-(2-(difluoromethyl)-8-methoxyimidazo[1,2-a]pyridin-3-yl)-6-morpholino-
1,3,5-triazin-2-yl)phenyl)carbamate (39) (257 mg, 30%): 1H NMR (CDCl3) δ=9.58
(dd, J = 7.0, 0.7 Hz, 1H), 8.40 (br d, J = 8.8 Hz, 2H), 7.77 (t, JHF = 54.3 Hz, 1H), 7.52
(br d, J = 8.8 Hz, 2H), 7.02-6.99 (m, 1H), 6.74 (br d, J = 7.3 Hz, 1H), 6.69 (br s, 1H),
4.07 (br, 2H), 4.07 (s, 3H), 3.94 (br, 2H), 3.86-3.84 (m, 4H), 1.55 ppm (s, 9H).
A solution of 39 (240 mg, 0.43 mmol) in CH2Cl2 (20 mL) was treated with TFA (3 mL)
and the mixture was stirred for 20 h. The solvents and excess TFA were evaporated,
and the resulting residue was stirred in aq NH3 and the precipitate collected by
filtration and washed with water to give 4-(4-(2-(difluoromethyl)-8-methoxy-
imidazo[1,2-a]pyridin-3-yl)-6-morpholino-1,3,5-triazin-2-yl)aniline (40) (179 mg, 91%);
1H NMR [DMSO-d6] δ=9.50 (dd, J = 6.9, 0.5 Hz, 1H), 8.15 (br d, J = 8.7 Hz, 2H),
7.86 (t, JHF = 54.3 Hz, 1H), 7.27-7.21 (m, 1H), 7.04 (d, J = 7.4 Hz, 1H), 6.67 (br d, J =
8.8 Hz, 2H), 5.99 (br s, 2H), 4.01 (s, 3H), 3.97 (br, 2H), 3.86 (br, 2H), 3.74 ppm (br,
4H); MS (APCI) m/z: 453.9 (MH+).
A mixture of 40 (207 mg, 0.46 mmol) and pyridine (6 mL) at 0 °C was treated with 2-
chloroethylsulfonyl chloride (0.5 mL, excess). The reaction mixture was stirred 4 h,
allowing it to warm up to 20 °C. The mixture was diluted with water, the resulting
precipitate was collected by filtration, and chromatographed on silica, eluting with
CH2Cl2/hexane (1:1) to give crude N-(4-(4-(2-(difluoromethyl)-8-methoxyimidazo[1,2-
a]pyridin-3-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)ethenesulfonamide which was
treated directly with 40% aq dimethylamine (5 mL) in THF (20 mL), and the reaction
mixture was stirred for 20 h. The volatiles were removed under vacuum and the
residue was diluted with H2O. The resulting solid was collected and purified by
column chromatography on silica, eluting with CH2Cl2/MeOH (96:4) to give 41 (183
1
mg, 68%): H NMR (DMSO-d6) δ=9.47 (d, J = 7.1 Hz, 1H), 8.39 (br d, J = 8.8 Hz,
2H), 7.85 (t, JHF = 54.2 Hz, 1H), 7.38 (br d, J = 8.8 Hz, 2H), 7.27-7.22 (m, 1H), 7.05
(d, J = 7.5 Hz, 1H), 4.01 (s, 3H), 4.01 (br, 2H), 3.87 (br 2H), 3.76 (br, 4H), 3.38-3.34
(m, 2H), 2.67-2.64 (m, 2H), 2.08 ppm (s, 6H); MS (APCI) m/z: 589.0 (MH+).
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Methanesulfonate: mp (MeOH/EtOAc) 243-246 °C; 1H NMR (DMSO-d6) δ=10.67 (s,
1H), 9.48 (br d, J = 6.6 Hz, 2H), 8.43 (br d, J = 8.8 Hz, 2H), 7.87 (t, JHF = 54.2 Hz,
1H), 7.42 (br d, J = 8.8 Hz, 2H), 7.28-7.24 (m, 1H), 7.08 (d, J = 7.6 Hz, 1H), 4.01 (s,
3H), 4.01 (br, 2H), 3.89 (br 2H), 3.76 – 3.48 (m, 6H), 2.83 (br s, 6H), 2.31ppm (s,
.
3H); elemental analysis calcd (%) for C27H34F2N8O7S2 H2O: C 46.1, H 5.1, N 15.9;
found: C 46.2, H 5.1, N 15.6.
(S)-2-Amino-1-(4-(4-(2-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)-6-
morpholino-1,3,5-triazin-2-yl)piperazin-1-yl)propan-1-one (48)
2-(Difluoromethyl)imidazo[1,2-a]pyridine (22) (200 mg, 1.19 mmol), tert-butyl 4-(4-
iodo-6-morpholino-1,3,5-triazin-2-yl)piperazine-1-carboxylate (30) (515 mg, 1.08
mmol), Pd(OAc)2 (12 mg, 0.05 mmol), n-BuPAd2 (39 mg, 0.11 mmol) and K3PO4
(548 mg, 2.38 mmol) were all weighed into a pressure tube (50 mL), dry DMF (20
mL) added, and the solution degassed and sealed under N2. This mixture was
heated with stirring at 90 oC for 2 h. Upon cooling, the reaction mixture was diluted to
100 mL with water then extracted with EtOAc (3x50 mL). The combined EtOAc
fractions were then washed with water (3x50 mL), brine (50 mL), dried (Na2SO4),
filtered, and the solvent removed under reduced pressure to give a crude solid. This
solid was purified by flash column chromatography on silica gel using a gradient of 2-
20% EtOAc in hexanes to elute tert-butyl 4-(4-(2-(difluoromethyl)imidazo[1,2-
a]pyridin-3-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazine-1-carboxylate (42) as a
cream solid (531 mg, 92%). 1H NMR (400 MHz, CDCl3) δ=9.74 (dt, J = 7.1, 1.1 Hz,
1H), 7.80 (dd, J = 9.1, 1.1 Hz, 1H), 7.70 (t, JHF = 54.6 Hz, 1H), 7.41 (ddd, J = 8.1,
6.8, 1.3 Hz, 1H), 7.04 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 3.84-3.90 (m, 8H), 3.66-3.83
(m, 4H), 3.46-3.57 (m, 4H), 1.51 ppm (s, 9H); MS (APCI) m/z: 517 (MH+).
A mixture of 42 (414 mg, 0.80 mmol) and TFA (3 mL) in CH2Cl2 (3 mL) was stirred at
room temperature for 0.5 h. All solvent was removed under reduced pressure and
the remaining oily residue was dissolved in a small amount of water, cooled
(ice/water), and basified through the dropwise addition of 2 M NaOH. The resulting
solid was collected by filtration, washed well with water and dried under vacuum to
give 4-(4-(2-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)-6-(piperazin-1-yl)-1,3,5-
triazin-2-yl)morpholine (43) as a beige solid (318 mg, 95%): 1H NMR (400 MHz,
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CDCl3) δ=9.75 (dt, J = 7.1, 1.1 Hz, 1H), 7.78 (dt, J = 9.0, 1.1 Hz, 1H), 7.73 (t, JHF
54.6 Hz, 1H), 7.40 (ddd, J = 8.1, 6.8, 1.3 Hz, 1H), 7.02 (ddd, J = 8.2, 7.0, 1.3 Hz,
1H), 3.83-4.08 (m, 8H), 3.73-3.82 (m, 4H), 2.90-2.98 ppm (m, 4H); MS (APCI) m/z:
417 (MH+),
=
N-Boc-L-Alanine (154 mg, 0.82 mmol) was dissolved in DMF (10 mL) under N2, to
which was added HBTU (310 mg, 0.82 mmol) and DIPEA (0.29 mL, 1.63 mmol).
After stirring for 10 minutes at room temperature, 43 (170 mg, 0.41 mmol) was
added and the entire mixture stirred for 2 hours. The reaction mixture was diluted
with EtOAc (80 mL), and this solution was washed with 1 M citric acid, brine,
saturated NaHCO3, brine, water, brine (all 40 mL), dried (Na2SO4), filtered, and the
solvent removed under reduced pressure. The resulting residue was purified by flash
column chromatography on silica gel, 50% EtOAc in hexanes as eluant, to give tert-
butyl (S)-(1-(4-(4-(2-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)-6-morpholino-1,3,5-
triazin-2-yl)piperazin-1-yl)-1-oxopropan-2-yl)carbamate (44) as a white foam (229
mg, 95%). 1H NMR (400 MHz, CDCl3) δ=9.72 (d, J = 7.1 Hz, 1 H), 7.81 (d, J = 9.0
Hz, 1 H), 7.68 (t, JHF = 54.7 Hz, 1 H), 7.40 (ddd, J = 8.1, 6.8, 1.2 Hz, 1 H), 7.03
(ddd, J = 8.2, 7.0, 1.2 Hz, 1 H), 5.47 (br s, 1 H), 4.65-4.72 (m, 1 H), 3.52-4.05 (m, 16
H), 1.45 (s, 9 H), 1.34 ppm (d, J = 6.9 Hz, 3 H); MS (APCI) m/z: 588 (MH+).
Trifluoroacetic acid was added to a solution of 44 (229 mg, 0.39 mmol) in CH2Cl2 (2
mL), and this mixture was stirred at room temperature under N2 for 2 hours. Removal
of all solvent under reduced pressure gave an oil that was dissolved in CH2Cl2 (50
mL) and washed with saturated NaHCO3 (50 mL), brine (50 mL), dried (Na2SO4),
filtered and the solvent removed under reduced pressure. Trituration with diethyl
ether gave the title compound 48 as a cream solid (180 mg, 95%). 1H NMR (400
MHz, CDCl3) δ=9.73 (d, J = 7.1 Hz, 1 H), 7.82 (d, J = 9.1 Hz, 1 H), 7.69 (t, JHF
=
54.6 Hz, 1 H), 7.43 (ddd, J = 8.1, 6.8, 1.2 Hz, 1 H), 7.04 (ddd, J = 8.1, 7.0, 1.2 Hz, 1
H), 3.54-3.96 (m, 17 H), 1.31 ppm (d, J = 6.8 Hz, 3 H); HRMS (APCI): m/z calcd for
C22H28F2N9O2+H+: 488.2329 [M+H+]; found 488.2334.
(R)-2-Amino-1-(4-(4-(2-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)-6-
morpholino-1,3,5-triazin-2-yl)piperazin-1-yl)propan-1-one (49)
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N-Boc-D-Alanine was reacted with 43 according to the procedure for 44. tert-Butyl
(R)-(1-(4-(4-(2-(Difluoromethyl)imidazo[1,2-a]pyridin-3-yl)-6-morpholino-1,3,5-triazin-
2-yl)piperazin-1-yl)-1-oxopropan-2-yl)carbamate (45) was isolated as a transparent
glass (80%). 1H NMR (400 MHz, CDCl3) δ=9.72 (d, J = 7.1 Hz, 1 H), 7.81 (d, J =
8.9 Hz, 1 H), 7.67 (t, JHF = 54.7 Hz, 1 H), 7.43 (ddd, J = 8.1, 6.8, 1.2 Hz, 1 H), 7.04
(ddd, J = 8.2, 7.0, 1.2 Hz, 1 H), 5.47 (br s 1 H), 4.69 (q, J = 7.2 Hz, 1 H), 3.50-4.07
(m, 16 H), 1.45 (s, 9 H), 1.34 ppm (d, J = 6.9 Hz, 3 H); MS (APCI) m/z: 587 (MH+).
Compound 45 was deprotected according to the procedure for 48. Following
trituration with diethyl ether, the title compound 49 was isolated as a cream solid
(44%). 1H NMR (400 MHz, CDCl3) δ=9.73 (d, J = 7.1 Hz, 1 H), 7.81 (d, J = 9.1 Hz,
1 H), 7.68 (t, JHF = 54.5 Hz, 1 H), 7.42 (ddd, J = 8.1, 6.8, 1.2 Hz, 1 H), 7.04 (ddd, J
= 8.1, 7.0, 1.1 Hz, 1 H), 3.53-3.97 (m, 17 H), 1.30 ppm (d, J = 6.8 Hz, 3 H); HRMS
(APCI): m/z calcd for C22H28F2N9O2+H+: 488.2329 [M+H+]; found 488.2327.
(S)-2-Amino-1-(4-(4-(2-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)-6-
morpholino-1,3,5-triazin-2-yl)piperazin-1-yl)-3-phenylpropan-1-one (50)
N-Boc-L-Phenylalanine was reacted with 43 according the procedure for 44. tert-
Butyl (S)-(1-(4-(4-(2-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)-6-morpholino-1,3,5-
triazin-2-yl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl)carbamate (46) was isolated as
a white foam (83%). 1H NMR (400 MHz, CDCl3) δ=9.68 (br s, 1 H), 7.80 (d, J = 9.1
Hz, 1 H), 7.64 (t, JHF = 54.7 Hz, 1 H), 7.42 (ddd, J = 8.0, 6.8, 1.1 Hz, 1 H), 7.17-7.34
(m, 5 H), 7.04 (ddd, J = 8.1, 7.0, 1.2 Hz, 1 H), 5.41 (br s, 1 H), 4.88 (br s, 1 H), 3.42-
4.90 (m, 14 H), 2.95-3.14 (m, 4 H), 1.44 ppm (s, 9 H); MS (APCI) m/z: 664 (MH+).
Compound 46 was deprotected according to the procedure for 48. The title
compound 50 was isolated as a cream solid (86%). 1H NMR (400 MHz, CDCl3)
δ=9.70 (d, J = 7.0 Hz, 1 H), 7.81 (d, J = 9.0 Hz, 1 H), 7.64 (t, JHF = 54.9 Hz, 1 H),
7.42 (ddd, J = 8.1, 6.8, 1.2 Hz, 1 H), 7.16-7.36 (m, 5 H), 7.04 (ddd, J = 8.1, 7.0, 1.2
Hz, 1 H), 3.67-4.04 (m, 12 H), 3.53-4.03 (m, 2 H), 3.36-3.47 (m, 1H), 3.06-3.24 (m, 2
H), 2.84-3.03 ppm (m, 2 H); HRMS (APCI): m/z calcd for C28H32F2N9O2+H+:
564.2642 [M+H+]; found 564.2641.
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(R)-4-(4-(2-(Difluoromethyl)imidazo[1,2-a]pyridin-3-yl)-6-(4-prolylpiperazin-1-yl)-
1,3,5-triazin-2-yl)morpholine (51)
N-Boc-D-Proline was reacted with 43 according to the procedure for 44. tert-Butyl
(R)-2-(4-(4-(2-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)-6-morpholino-1,3,5-triazin-
2-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (47) was isolated as a white
foam (83%). 1H NMR (400 MHz, CDCl3) δ=9.73 (d, J = 7.1 Hz, 1 H), 7.77-7.84 (m, 1
H), 7.68 (t, JHF = 54.5 Hz, 1 H), 7.37-7.46 (m, 1 H), 7.01-7.07 (m, 1 H), 3.93-4.04 (m,
2 H), 3.51-3.92 (m, 12 H), 3.30-3.50 (m, 5 H), 2.00-2.30 (m, 2 H), 1.84-1.95 (m, 2 H),
1.46 ppm (s, 9 H); MS (APCI) m/z: 614 (MH+),
Compound 47 was deprotected according to the procedure for 48. Following
trituration with diethyl ether, the title compound 51 was isolated as a white solid
(88%). 1H NMR (400 MHz, CDCl3)=δ 9.72 (d, J = 7.1 Hz, 1 H), 7.82 (d, J = 9.1 Hz,
1 H), 7.68 (t, JHF = 54.5 Hz, 1 H), 7.43 (ddd, J = 8.1, 6.8, 1.2 Hz, 1 H), 7.04 (ddd, J
= 8.1, 7.0, 1.2 Hz, 1 H), 3.52-4.04 (m, 17 H), 3.16-3.26 (m, 1 H), 2.85-2.96 (m, 1 H),
2.50-2.63 (m, 1 H), 1.77-1.96 ppm (m, 3 H); HRMS (APCI): m/z calcd for
C24H30F2N9O2+H+: 514.2485 [M+H+]; found 514.2488.
N-(trans-4-((6-(2-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)-2-morpholino-
pyrimidin-4-yl)oxy)cyclohexyl)-2-(dimethylamino)acetamide (58)
A mixture of 4,6-dichloro-2-(methylthio)pyrimidine (52) (7.804g, 0.04 mol), tert-butyl
(trans-4-hydroxycyclohexyl)carbamate (2.87 g, 13.3 mmol), 4 M NaOH (17 mL), and
THF (50 mL) was heated under reflux for 36 h, then cooled and diluted with water.
The white solid was collected and dried. Chromatography on silica, eluting with
CH2Cl2/hexanes (2:1) gave 4-chloro-2,6-bis(methylthio)pyrimidine (0.17 g): 1H NMR
(CDCl3) δ=6.85 (s, 1H), 2.56 ppm (s, 6H); MS (APCI) m/z: 207.1 (MH+).
Further elution with CH2Cl2 gave tert-butyl (trans-4-((6-chloro-2-(methylthio)pyrimidin-
4-yl)oxy)cyclohexyl)carbamate (53) (3.0 g, 60%): mp (i-Pr2O) 179-182 °C; 1H NMR
(CDCl3) δ=6.35 (s, 1H), 5.08-4.99 (m, 1H), 4.47-4.35 (m, exchangeable with D2O,
1H), 3.58-3.44 (m, 1H), 2.52 (s, 3H), 2.16-2.04 (m, 4H), 1.59-1.49 (m, 2H), 1.45 (s,
9H), 1.35-1.23 ppm (m, 2H); 13C NMR (CDCl3) δ =172.8 (C), 169.2 (C), 160.6 (C),
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155.4 (C), 103.1 (CH), 79.6 (C), 74.9 (CH), 48.8 (CH), 30.9 (CH2), 30.0 (CH2), 28.6
(CH3), 14.4 ppm (CH3); MS (APCI) m/z: 374.2 (MH+).
Acidification of the original aqueous filtrate gave 6-chloro-2-(methylthio)pyrimidin-
4(3H)-one: 1H NMR (DMSO-d6) δ=13.11 (br s, 1H), 6.29 (s, 1H), 2.49 ppm (s, 3H),
MS (APCI) m/z: 169.2 (MH+).
To a solution of 53 (3.74 g, 10 mmol) in a mixture of acetone (500 mL) and acetic
acid (50 mL) was added KMnO4 (5 g, 32 mmol) in water (100 mL), and the mixture
was stirred at room temperature overnight. The mixture was diluted with water,
extracted with CH2Cl2, and washed with aq. Na2CO3 until gas evolution ceased.
Drying (Na2SO4) and removal of solvent gave tert-butyl (trans-4-((6-chloro-2-
(methylsulfonyl)pyrimidin-4-yl)oxy)cyclohexyl)carbamate (3.99 g, 98%): 1H NMR
(CDCl3) δ=6.86 (s, 1H), 5.24-5.15 (m, 1H), 4.47-4.34 (m, 1H), 3.59-3.46 (m, 1H),
3.34 (s, 3H), 2.18-2.04 (m, 4H), 1.67-1.56 (m, 2H), 1.45 (s, 9H), 1.38-1.26 ppm (m,
2H); MS (APCI) MH+ not observed.
The above crude carbamate (3.99 g, 9.8 mmol) was dissolved in THF (100 mL) and
morpholine (1.8 g, 21 mmol) in THF (10 mL) was added. The mixture was stirred at
room temperature for 2 h, diluted with water, and extracted with CH2Cl2.
Chromatography on silica, eluting with CH2Cl2/EtOAc (95:5) gave tert-butyl (trans-4-
((6-chloro-2-morpholinopyrimidin-4-yl)oxy)cyclohexyl)carbamate (54) (2.06 g, 51%):
mp (i-Pr2O) 152-155 °C; 1H NMR (CDCl3) δ 5.97 (s, 1H), 4.89 (tt, J = 10.5, 3.8 Hz,
1H), 4.46-4.35 (m, 1H), 3.74 (m, 8H), 3.58-3.43 (m, 1H), 2.14-2.04 (m, 4H), 1.62-
1.49 (m, 2H), 1.45 (s, 9H), 1.34-1.22 (m, 2H); 13C NMR (CDCl3) δ 170.2 (C), 161.1
(C), 161.0 (C), 155.4 (C), 96.2 (CH), 79.6 (C), 74.0 (CH), 66.9 (CH2), 48.9 (CH), 44.5
(CH2), 31.0 (CH2), 30.1 (CH2), 28.6 (CH3); MS (APCI) m/z: 413.2 (MH+).
Further elution with CH2Cl2/EtOAc (95:5) gave tert-butyl (trans-4-((2-(methylsulfonyl)-
6-morpholinopyrimidin-4-yl)oxy)cyclohexyl)carbamate (55) (2.14 g, 48%): mp (i-
Pr2O) 177-179 °C; 1H NMR (CDCl3) δ=5.86 (s, 1H), 5.08-4.99 (m, 1H), 4.47-4.36 (m,
1H), 3.78-3.74 (m, 4H), 3.63-3.58 (m, 4H), 3.56-3.46 (m, 1H), 3.25 (s, 3H), 2.15-2.02
(m, 4H), 1.60-1.49 (m, 2H), 1.45 (s, 9H), 1.35-1.23 ppm (m, 2H); 13C NMR (CDCl3)
δ=170.7 (C), 164.7 (C), 164.1 (C), 155.4 (C), 87.9 (CH), 79.6 (C), 74.7 (CH), 66.5
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(CH2), 48.8 (CH), 44.8 (CH2), 38.9 (CH3), 30.9 (CH2), 30.2 (CH2), 28.6 ppm (CH3);
MS (APCI) m/z: 457.2 (MH+).
A solution of 54 (1.239 g, 3 mmol) in CH2Cl2 (10 mL) was treated with TFA (5 mL) for
2h, and the solvents were removed under vacuum. The residue was dissolved in
57% HI (20 mL) and NaI (6 g) was added. The mixture was stirred at room
temperature for 4 days, and poured onto ice. Neutralization with aq. Na2CO3, and
extraction with CH2Cl2, gave (trans-4-((6-iodo-2-morpholinopyrimidin-4-
1
yl)oxy)cyclohexan-1-amine as a white solid: H NMR (CDCl3) δ=6.42 (s, 1H), 4.87
(tt, J = 10.7, 4.2 Hz, 1H), 3.73 (s, 8H), 2.77 (tt, J = 10.6, 4.0 Hz, 1H), 2.12-2.04 (m,
2H), 1.96-1.88 (m, 2H), 1.53-1.41 (m, 4H, reduced to 2H after D2O exchange), 1.23
ppm (dq, J = 13.3, 3.4, 2H); MS (APCI) m/z: 405.1 (MH+).
The crude solid was dissolved in MeCN (200 mL), di-tert-butyldicarbonate (0.98 g,
1.5 equiv.) was added, and the mixture was stirred at room temperature overnight.
Dilution with water gave tert-butyl (trans-4-((6-iodo-2-morpholinopyrimidin-4-
yl)oxy)cyclohexyl)carbamate (56) (1.253 g, 83%): mp (i-Pr2O) 191-193 °C; 1H NMR
(CDCl3) δ=6.42 (s, 1H), 4.86 (tt, J = 10.5, 3.8 Hz, 1H), 4.49-4.32 (m, 1H), 3.73 (m,
8H), 3.56-3.41 (m, 1H), 2.12-2.03 (m, 4H), 1.61-1.47 (m, 2H), 1.44 (s, 9H), 1.33-1.21
ppm (m, 2H); 13C NMR (CDCl3) δ=168.2 (C), 160.1 (C), 155.4 (C), 128.8 (C), 107.8
(CH), 79.6 (C), 73.7 (CH), 66.9 (CH2), 48.8 (CH), 44.4 (CH2), 31.0 (CH2), 30.0 (CH2),
28.6 ppm (CH3); MS (APCI) m/z: 505.1 (MH+).
A mixture of iodide 56 (505 mg, 1 mmol), 2-(difluoromethyl)imidazo[1,2-a]pyridine
(22) (200 mg, 1.2 mmol), Pd(OAc)2 (11.2 mg, 0.05 mmol), n-BuPAd2 (36 mg, 0.1
mmol), K3PO4 (440 mg, 2.05 mmol) in dry DMF (20 mL) was degassed, flushed with
nitrogen, and heated at 90 °C for 5 h. After cooling, the mixture was diluted with
water, to give a solid, which was collected and dried. Chromatography on silica,
eluting with CH2Cl2/EtOAc (95:5) gave tert-butyl (trans-4-((6-(2-(difluoromethyl)-
imidazo[1,2-a]pyridin-3-yl)-2-morpholinopyrimidin-4-yl)oxy)cyclohexyl)carbamate (57)
(0.51 g, 94%): mp (i-Pr2O) 171-173 °C; 1H NMR (CDCl3) δ=9.03 (d, J = 7.1 Hz, 1H),
7.73 (d, J = 9.1, 1H), 7.35 (ddd, J = 9.1, 6.7, 1.2 Hz, 1H), 7.03 (t, JHF = 54.0 Hz, 1H),
6.93 (dt, J = 6.9, 1.2 Hz, 1H), 6.89 (s, 1H), 5.04-4.95 (m, 1H), 4.47-4.36 (m, 1H),
3.81 (br d, J = 1.8 Hz, 8H), 3.59-3.46 (m, 1H), 2.22-2.08 (m, 4H), 1.67-1.57 (m, 2H),
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