Note: Descriptions are shown in the official language in which they were submitted.
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SUBSTITUTED NITROGEN-CONTAINING SIX-MEMBERED AMINO-
HETEROCYCLES AS VANILLOID-1 RECEPTOR ANTAGONISTS FOR
TREATING PAIN
The present invention is concerned with substituted nitrogen-containing
six-membered amino-heterocycles and analogues and derivatives thereof as well
as pharmaceutically acceptable salts thereof, which are useful as therapeutic
compounds, particularly in the treatment of pain and other conditions
ameliorated by the modulation of the function of the vanilloid-1 receptor
(VR.1).
The pharmacologically active ingredient of chilli peppers has been
recognised for some time to be the phenolic amide capsaicin. The application
of
capsaicin to mucous membranes or when injected intradermally, causes intense
burning-like pain in humans. The beneficial effects of topical administration
of
capsaicin as an analgesic is also well established. However, understanding of
the
underlying molecular pharmacology mediating these responses to capsaicin has
been a more recent development.
The receptor for capsaicin, termed the vanilloid VR,1 receptor, was cloned
by Caterina and colleagues at UCSF in 1997 (Nature, 398:816, 1997). VR,l
receptors are cation channels that are found on sensory nerves that innervate
the
skin, viscera, peripheral tissues and spinal cord. Activation of VR1 elicits
action
potentials in sensory fibres that ultimately generate the sensation of pain.
Importantly the VR,1 receptor is activated not only by capsaicin but alabby
acidic
pH and by noxious heat stimuli. It is also sensitized by a number of .
inflammatory mediators and thus appears to be a polymodal in~egr-ator of
painful
stimuli. -
The prototypical VR,1 antagonist is capsazepine (Walpole~ e~ a1;
J. Med. Chem., 37:1942, 1994) - VR,1 ICso of 420nM. A novel series of sub-
micromolar antagonists has also been reported recently (Lee~et=aT,~~
Bioorg. Med. Chem., 9:1713, 2001), but these reports provide no evidence for
in
vivo efficacy. A much higher affinity antagonist has been derived from the
'ultra-
potent' agonist resiniferatoxin. Iodo-resiniferatoxin (Wahl et al.,
Mol. Pharmacol., 69:9, 2001) is a nanomolar antagonist of VR,l but does not
possess properties suitable for an oral pharmaceutical. This last is also true
of
the micromolar peptoid antagonists described by Garcia-Martinez (Proc. Natl.
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2
Acad. Sci., USA, 99:2374, 2002). WO-A-0208221 has described a novel series of
VR,1 antagonists, which are stated to show efficacy in a number of animal
models.
We herein describe another novel series of VR,l modulators. These comprise
predominantly VR,1 antagonists but encompass VR,1 partial antagonists and VR,1
partial agonists. Such compounds have been shown to be efficacious in animal
models of pain.
Related compounds are disclosed in WO-A-03099284 (Amgen Inc.). There
is no disclosure of compounds in which Y is quinoline or isoquinoline.
Preferred
compounds of the present invention have improved pharmacokinetics with lower
clearance and thus improved half-life.
The present invention provides compounds of formula I:
Y-J-L-Z
(I)
wherein:
L is NRl, O, S or CH2
J is a six-membered heterocycle containing one, two or three nitrogen
atoms which is unsubstituted or substituted with up to three substituents,
depending on the number of nitrogen atoms present, chosen independently from:
halogen hydroxyl nitro~ cyano~ isonitrile~ Ca-~cycloalkyh Ci-salkyh Ca-
salkenyh
Cz-salkynyh Ci-salkoxy~ Cs-~cycloalkoxy~ hydroxyCi-salkyh aminoCi-salkyh
Ci-salkoxycarbonyh haloCi-salkyh haloCi-salkoxy~ -NR2R3a -CONR2R3; ;
-S(O)nCi-salkyh -S(O)nNR~R3~ -NHCORI~ -NHS(O)nCi-salkyh -COH, carboxyl
-(CH2)pNR~R3i -O(CH~)qNR2R3~ -(CH2)py -O(CHz)PQ~ and phenyl, a five-membered
heterocyclic ring containing one, two, three or four heteroatoms. chosen .from
O, ~ N
and S, at most one heteroatom being O or S, or a six-membered-_heterocyclic
ring
containing one, two or three nitrogen atoms, wherein this substituent, is ' ;
. . .
unsubstituted or substituted by one, two or three groups chosen from halogen;
hydroxy, nitro, cyano, isonitrile, Ci-salkyl, Ci-salkoxy, haloCi-salkyl, ' - ,
.
. haloCi-2alkoxy, -NR~R3, -CONR2R3, -S(O)nNR2R3, -NHCORI, NHS(O)nRl, -COH,
COzH and -S(O)nCi-salkyh
when J is substituted by hydroxy, tautomerism may occur, in which case
any nitrogen atom ortho or para to the resulting carbonyl group may be
substituted as defined above
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3
Q is phenyl, a five-membered heterocyclic ring containing one, two, three
or four heteroatoms chosen from O, N and S, at most one heteroatom being O or
S, or a six-membered heterocyclic ring containing one, two or three nitrogen
atoms, optionally substituted by halogen, Ci-4alkyl or haloCi-aalkyh
wherein J is substituted at positions meta to each other by L and Y
Y is naphthalene or a fused 9- or 10-membered heteroaromatic system
containing a six-membered heterocyclic ring, as defined above, or a phenyl
ring,
or a six-membered nitrogen-containing partially saturated ring, fused either
to a
six-membered heterocyclic ring as defined above or to a five-membered
heterocyclic ring as defined above, Y being unsubstituted or substituted with
one,
two or three groups independently chosen from halogen, hydroxy, cyano, nitro,
isonitrile, Ci-salkyl, C~-salkenyl, Ca-salkynyl, haloCi-salkyl, hydroxyCi-
salkyl,
aminoCi-salkyl, Ci-salkoxy, Ci-salkylthio, haloCi-salkoxy,
-NR2R3, -CONR2R3, -S(O)nNR2R3, -(CHz)pNR~R3, -NHCORl, NHS(O)nRl, -COH,
-COSH and Ci-salkoxycarbonyh
Z is phenyl, naphthyl, a six-membered heterocyclic ring containing one,
two, or three nitrogen atoms or a five-membered heterocyclic ring containing
one,
two, three or four heteroatoms chosen from O, N and S, at most one heteroatom
being O or S, Z being unsubstituted or substituted with one, two or three
substituents independently chosen from halogen, hydroxy, cyano, nitro,
isonitrile,
Ci-salkyl, Ca-salkenyl, C2-salkynyl, haloCi-salkyl, hydroxyCi-salkyl,
aminoCi=salkyl;
Ci-salkoxy, Ci-salkylthio, haloCi-salkoxy, -NR2R3, -CONR~R3, -S(O)"NR,2R3; .~
'..
-NHCORI, -NHS(O)"Rl, -COH, -C02H and Ci-salkoxycarbonyl; ,
each Rl is H or Ci-salkyh ' : '
each R2 and R3 is chosen from H and Ci-salkyl, or R2 and' R3~ together with
the nitrogen atom to which they are attached, may form a 4-6 membered ring'
optionally containing an oxygen atom or a further nitrogen ato~i,, which ring
is.. ' , .. -
optionally substituted by Ci-salkyl or Q
each'n is 0, 1 or 2~
each p is 1, 2, 3 or 4~
q is 2, 3 or 4~
or a pharmaceutically acceptable salt thereof.
L is preferably NRI, particularly NH.
L may be CHz or NRI.
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4
J is preferably unsubstituted or substituted by one or two substituents.
Most preferably J is unsubstituted or monosubstituted. J may be disubstituted.
J is thus preferably an unsubstituted or substituted pyrimidine, pyrazine,
pyridazine or triazine. Pyrimidine is particularly favoured. J may be
pyridine,
which is unsubstituted or substituted, such as unsubstituted pyridine.
Substituents on J are preferably chosen independently from halogen,
hydroxy, vitro, cyano, Ci-4alkyl, Cz-4alkenyl, Ca-4alkynyl, Ci-4alkoxy,
Ci-4cycloalkoxy, hydroxyCi-4alkyl, aminoCi-aalkyl, haloCi-4alkyl, haloCi-
4alkoxy,
Ci-4alkoxycarbonyl, -NR2R3, Ci-aalkylthio, Q, CH2Q, OCH2Q, -(CHz)pNR2R3,
-CONR~R3 and -C02H. Substituents on J may be chosen independently from
halogen, hydroxy, vitro, cyano, Ci-aalkyl, Ca-4alkenyl, C~-4alkynyl, Ci-
4alkoxy,
hydroxyCi-4alkyl, aminoCi-4alkyl, haloCi-4alkyl, haloCi-4alkoxy,
Ci-aalkoxycarbonyl, -NR2R3, -(CH2)PNR2R3, -CONR~R3 and -C02H. In particular
substituents are independently chosen from halogen, hydroxy, vitro, amino,
Ci-4alkyl, haloCi-aalkyl, Ca-scycloalkyl and Ci-aalkoxy. Thus substituents can
be
chosen from chloro, fluoro, methyl, ethyl, isopropyl, cyclopropyl,
trifluoromethyl,
methoxy, vitro, amino, tertiarybutyl, hydroxymethyl, 2,6-dimethylmorpholino,
bromo, methylthio, cyano, 2-methylpyrrolidino, morpholino, trifluoromethoxy,
hydroxy, N-phenylpiperazinyl, 2,2,2-trifluoroethyl, morpholinomethyl,
imidazomethyl, cyclopropylmethoxy, pyridomethoxy, morpholinoethoxy and
tetrazolyl. Most preferably any substituents are chosen from chloro, fluoro,
methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, vitro and
amino.
More preferably any substituents are independently chosen from halogen,
hydroxy,-vitro, amino, Ci-4alkyl and Ci-aalkoxy. Most preferably the
substituent
is fluoro, methyl, methoxy, vitro or amino. . , . _ .
Particular embodiments of J are pyrimidin-2-yl, pyrazin-2-yl, pyridazin-.3-.
y1, pyrimidin-4-yl, pyridazin-4-yl, 1,3,5-triazin-2-yl, 5-methoxypyrimidin-.4-
yl,~ 5-
methylpyrimidin-4-yl, 5-fluoropyrimidin-4-yl, 2-methoXypyrimidin-4-yl, 2-
methylpyrimidin-4-yl, 5-nitropyrimidin-4-yl and 5-aminopyrimidin-4-yl..
Further
particular embodiments of J are 5-tertiarybutylpyrimidin-4-yl, 2'
trifluoromethylpyrimidin-4-yl, 2-hydroxymethylpyrimidin-4-yl, (cis-2,6-
dimethylmorpholin-4-yl)methylpyrimidin-4-yl, 5-bromopyrimidin-4-yl, 2-
methylthio-5-methylpyrimidin-4-yl, 2-cyano-5-methylpyrimidin-4-yl, 2-(2-
methylpyrrolidin-1-yl)-5-methylpyrimidin-4-yl, 2-(morpholin-4-yl)-5-
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methylpyrimidin-4-yl, 2-(2,2,2-trifluoroethoxy)-5-methylpyrimidin-4-yl, 2-
methyl-
5-aminopyrimidin-4-yl, 2-hydroxypyrimidin-4-yl, 2-cyanopyrimidin-4-yl, 2-
(morpholin-4-yl)pyrimidin-4-yl,
2-(1-phenylpiperazin-4-yl)pyrimidin-4-yl, 2-(2,2,2-trifluoroethyl)pyrimidin-4-
yl, 2-
5 methyltriazin-4-yl, 2-tertiarybutyl-5-methylpyrimidin-4-yl, 2-(morpholin-4-
ylmethyl)pyrimidin-4-yl, 2-(imidazol-1-ylmethyl)pyrimidin-4-yl, 2-isopropyl-5-
methylpyrimidin-4-yl, 2-methylthiopyrimidin-4-yl, 2-
cyclopropylmethoxypyrimidin-4-yl, 2-(pyridine-3-ylmethoxyl)pyrimidin-4-yl, 2-
trifluoromethyl-5-methylpyrimidin-4-yl, 2-(morpholin-4-ylethoxy)pyrimidin-4-yl
and 2-(tetrazol-1-yl)pyrimidin-4-yl. For the avoidance of doubt the preceding
lists
indicate the position of attachment to L.
J may also be 2-chloropyrimidin-4-yl, 5-trifluoromethylpyridin-4-yl, 5-
ethylpyrimidin-4-yl, 2-cyclopropyl-5-methylpyrimidin-4-yl, 5-
isopropylpyrimidin-
4-yl or pyridin-4-yl.
p can be one or two.
Q can be pyridyl or phenyl. Q can be unsubstituted.
Y is thus preferably an unsubstituted or substituted quinoline,
quinazoline, quinoxaline, phthalazine, isoquinoline, cinnoline, naphthyridine,
indole, indazole, benzimidazole, benzothiazole, benzoxazole, imidazopyridine,
imidazopyridazine, imidazopyrimidine, pyrazolopyridine, pyrazolopyridazine,
pyrazolopyrimidine or triazolopyridine. Y may be substituted benzimidazole
attached to J via the benzene portion. Y may be quinoxaline attached to L via
the
benzene portion. Y may be naphthyridine such as 1,8-naphthyridine,,or 1,5- .
naphthyridine. Y is most preferably an unsubstituted or substituted quinoline,
or:
isoquinoline, particularly a quinoline. ,_ , _ . : y _
Substituents on Y are preferably independently chosen from ~ha~logen,
hydroxy, cyano, vitro, amino, Ci-4alkyl, C2-4alkenyl, Cz-aalkynyl, haloCi-
4alkyl,'
hydroxyCi-aalkyl, aminoCl-aalkyl, Ci-aalkoxy and haloCi-4alkoxy. Particular
substituents are hydroxy, halogen, Ci-aalkyl and haloCi-aalkyl such as
hydroxy,
fluorine, methyl, ethyl and trifluoromethyl. The substituents can be halogen,
Ci-aalkyl and haloCi-4alkyl such as fluorine, methyl and trifluoromethyl.
Y is preferably unsubstituted or substituted with one or two substituents.
More preferably Y is unsubstituted or monosubstituted. Y may be naphthalene
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6
or a fused 10-membered heteroaromatic ring. Y is generally a fused 10-
membered heteroaromatic system.
Particular values of Y include quinolin-8-yl, quinoline-7-yl, 3-
methylquinolin-7-yl, quinolin-5-yl, quinolin-6-yl, 6-fluoroquinolin-7-yl, 8-
fluoroquinolin-7-yl, 6-trifluoromethylquinolin-7-yl, 8-fluoroquinolin-7-yl and
isoquinolin-7-yl. Further particular values of Y include 8-ethylquinolin-'7-
yl, 1,8-
naphthyridin-7-yl, 4-trifluoromethylquinolin-7-yl, 5-fluoroquinolin-7-yl, 1,5-
naphthyridin-7-yl, 1-methyl-1H-benzimidazol-5-yl, 1H-benzimidazol-6-yl, 3-
fluoroquinolin-7-yl, 4-hydroxyquinolin-7-yl and quinoxalin-6-yl.
Z is preferably a six-membered ring such as pyridazinyl, phenyl or pyridyl,
preferably phenyl or pyridyl. Z is preferably monosubstituted, particular para
to
the attachment to L. Particular embodiments of Z include 4-
trifluoromethylphenyl, 3-trifluoromethylpyrid-6-yl and 2-trifluoromethylpyrid-
5-
yl. Further embodiments include 4-trifluoromethoxyphenyl and 2-fluoro-4-
trifluoromethylphenyl. Yet further embodiments include 3-
trifluoromethylpyridazin-6-yl and 3-fluoro-5-trifluoromethylpyridin-2-yl.
Substituents on Z are preferably independently chosen from halogen,
amino, Ci-4alkyl, haloCi-aalkyl, hydroxyCi-aalkyl, aminoCi-4alkyl, Ci-aalkoxy
and
haloCi-4alkoxy. Particular substituents are haloCi-4alkyl such as
trifluoromethyl.
Z may be substituted by halogen, haloCi-4alkyl or haloCi=4alkoxy. Thus Z
may be substituted by trifluoromethyl, trifluoromethoxy or fluorine.
Each Rl is preferably hydrogen or Ci-4alkyl such as methyl. R1 is
particularly hydrogen. , .., ,;. ".. ,
Each R2 and R3 is preferably independently hydrogen or Ci-4alkyl such as
methyl. R2 and R3 are preferably hydrogen. R2 and R3 may form=a piperidine,
.,.. ;
piperazine or morpholine ring, R2 and R3 may then be substituted by Ci-4alkyl,
-. ~. . .
r
phenyl or pyridyl, particularly when they form a piperazine ring. , ' .. - '.
. . - -
A particularly preferred subclass of corizpounds is of formula Ia:
Y-J-NH-Z
(Ia)
wherein:
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Y is a quinoline or isoquinoline optionally substituted with one or two
substituents independently chosen from hydroxy, halogen, haloCi-aalkyl,
Ci-aalkyl, Ci-aalkoxy, haloCi-4alkoxy, vitro and amino
J is pyridine, pyridazine, pyrazine, pyrimidine or triazine optionally
substituted with one or two substituents independently chosen from hydroxy,
halogen, haloCi-4alkyl, Ci-aalkyl, Cs-scycloalkyl, Ci-4alkoxy, hydroxyCi-
aalkyl,
cyano, hydroxy, Ci-acycloalkoxy, Ci-aalkylthio, haloCi-4alkoxy, vitro, Q,
(CHz)pQ,
-NR2R3, -(CH2)PNR~R3 and -O(CH~)pNR2R3~
wherein J is substituted at positions meta to each other by NH and Y~ and
Z is phenyl or pyridyl optionally substituted with one or two substituents
independently selected from halogen, haloCi-øalkyl, Ci-aalkyl, Ci-4alkoxy,
haloCi-4alkoxy, vitro and amino
Q is phenyl, a five-membered heterocyclic ring containing one, two, three
or four heteroatoms chosen from O, N and S, at most one heteroatom being O or
S, or a six-membered heterocyclic ring containing one, two or three nitrogen
atoms, optionally substituted by Ci-4alkyl~
each R2 and R3 is chosen from H and Ci-4alkyl, or R2 and R3, together with
the nitrogen atom to which they are attached, may form a six-membered ring
optionally containing an oxygen atom or a further nitrogen atom, which ring is
optionally substituted by Ci-4alkyl or (a~
pisl,2or3~
or a pharmaceutically acceptable salt thereof.
In one embodiment:
Y is a quinoline or isoquinoline optionally substituted with one ox~two - '- .
substituents independently chosen from halogen, haloCi-4alkyl, Ci-4alkyl, ~ .
.
Ci-4alkoxy, haloCi-4alkoxy, vitro and amino
J is pyridine, pyridazine, pyrazine, pyrimidine or triazine optionally
substituted with one or two substituents independently chosen from ha~ogeri,
haloCi-4alkyl, Ci-4alkyl, Cs-scycloalkyl, Ci-aalkoxy, haloCi-4alkoxy,
nitrosand
amino
wherein J is substituted at positions meta to each other by NH and Y~ and
Z is phenyl or pyridyl optionally substituted with one or two substituents
independently selected from halogen, haloCi-aalkyl, Ci-aalkyl, Ci-4alkoxy,
haloCi-4alkoxy, vitro and amino
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or a pharmaceutically acceptable salt thereof.
In another embodiment Y is a quinoline or isoquinoline optionally
substituted with one or two substituents independently chosen from halogen,
haloCi-alkyl, Ci-aalkyl, Ci-4alkoxy, haloCi-~alkoxy, nitro and amino
J is pyridazine, pyrazine, pyrimidine or triazine optionally substituted
with one or two substituents independently chosen from halogen, haloCi-4alkyl,
Ci-aalkyl, Ci-aalkoxy, haloCi-~alkoxy, nitro and amino
wherein J is substituted at positions meta to each other by NH and Y
Z is phenyl or pyridyl optionally substituted with one or two substituents
independently selected from halogen, haloCi-aalkyl, Ci-4alkyl, Ci-4alkoxy,
haloCi-~alkoxy, nitro and amino
or a pharmaceutically acceptable salt thereof.
Y is particularly quinoline or isoquinoline and is unsubstituted or
monosubstituted. Preferred substituents include hydroxy, trifluoromethyl,
fluorine, methyl and ethyl such as fluoro and methyl. Y may be quinoline.
J can be unsubstituted, monosubstituted or disubstituted with
substituents preferably chosen from chloro, fluoro, methyl, ethyl, isopropyl,
cyclopropyl, trifluoromethyl, methoxy, nitro, amino, tertiarybutyl,
hydroxymethyl, 2,6-dimethylmorpholino, bromo, methylthio, cyano, 2-
methylpyrrolidino, morpholino, trifluoromethoxy, hydroxy, N-phenylpiperazinyl,
2,2,2-trifluoroethyl, morpholinomethyl, imidazomethyl, cyclopropylmethoxy,
pyridomethoxy, morpholinoethoxy and tetrazolyl. The substituents are
preferably chloro, fluoro, methyl, ethyl, isopropyl, cyclopropyI,
trifluoromethyl,
methoxy, nitro and amino. . ,
J is preferably unsubstituted or monosubstituted with fluorine, methoXy,,
methyl, amino or nitro. J is preferably pyrimidine. J may be pyridine: ~J may
be
triazine. : _ : . .... . _ -
Z is preferably monosubstituted at a position para to the point of . .
attachment to NH. Z may be.substituted by F, CFa or OCFs. The substituent is
preferably CFs. ~ . - . .
Particularly preferred are compounds of formula Ia in which:
Y is a quinoline or isoquinoline optionally substituted with one or two
substituents independently chosen from halogen, haloCi-aalkyl, Ci-aalkyl,
Ci-4alkoxy, haloCi-aalkoxy, nitro and amino
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J is pyrimidine optionally substituted with one or two substituents
independently chosen from halogen, haloCi-aalkyl, Ci-aalkyl, Cs-scycloalkyl,
Ci-aalkoxy, haloCi-4alkoxy, nitro and amino
wherein J is substituted at positions mete to each other by NH and Y~ and
Z is pyridyl substituted at at least the position pare to the point of
attachment to NH by CFs or OCFs and which is optionally further substituted by
halogen
or a pharmaceutically acceptable salt thereof.
Particular embodiments of Y, J and Z are described above.
Particular embodiments of the invention include:
4-quinolin-8-yl-N-[4-trifluoromethylphenyl]pyrimidin-2-amine~
6-quinolin-8-yl-N-[4-trifluoromethylphenyl]pyrazin-2-amine~
5-quinolin-8-yl-N-[4-trifluoromethylphenyl]pyridazin-3-amine~
6-quinolin-8-yl-N-[4-trifluoromethylphenyl]pyrimidin-4-amine~
6-quinolin-7-yl-N-[4-trifluoromethylphenyl]pyrazin-2-amine~
4-quinolin-7-yl-N-[4-trifluoromethylphenyl]pyrimidin-2-amine~
6-quinolin-7-yl-N-[4-trifluoromethylphenyl]pyrimidin-4-amine~
5-quinolin-7-yl-N-[4-trifluoromethylphenyl]pyridazin-3-amine~
6-quinolin-7-yl-N-[5-trifluoromethylpyridin-2-yl]pyrimidin-4-amine~
6-quinolin-7-yl-N-[6-trifluoromethylpyridin-3-yl]pyrimidin-4-amine .
5-methoxy-6-quinolin-7-yl-N- [4-trifluoromethylphenyl] pyrimidin-4-amine
5-methyl-6-quinolin-7-yl-N-[4-trifluoromethylphenyl]pyrimidin-4-amines
5-fluoro-6-quinolin-7-yl-N-[4-trifluoromethylphenyl]pyrimidin-4-amines.-... :
,- _ ..
2-methoxy-6-quinolin-7-yl-N-[4-trifluoromethylphenyl]pyrimidin=4-amines
~2-methyl-6-quinolin-7-yl-N-[4-trifluoromethylphenyl]pyrimidin-4-amine-' ~-
... ~ _ -
6-(3-methylquinolin-7-yl)-N-[4-trifluoromethylphenyl]pyrimidin-4-amine~ ~ _ ---
- - w--
6-quinolin-5-yl-N-[4-trifluoromethylphenyl]pyrimidin-4-amine~
6-quinolin-6-yl-N-[4-trifluoromethylphenyl]pyrimidin-4-amine~ - - - ~ - -
6-(2-methylquinolin-7-yl)-N-[4-trifluoromethylphenyl]pyrimidin-4-amines
6-(6-fluoroquinolin-7-yl)-N [4-trifluoromethylphenyl]pyrimidin-4-amine
6-(8-fluoroquinolin-7-yl)-N-[4-trifluoromethylphenyl]pyrimidin-4-amines
N-[4-(trifluoromethyl)phenyl]-6-[6-trifluoromethylquinolin-7-yl]pyrimidin-4-
amine
6-(8-methylquinolin-7-yl)-N-[4-trifluoromethylphenyl]pyrimidin-4-amines
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5-fluoro-6-(8-methylquinolin-7-yl)-N-[4-trifluoromethylphenyl]pyrimidin-4-
amine~
6-isoquinolin-7-yl-N-[4-trifluoromethylphenyl]pyrimidin-4-amine
6-quinolin-8-yl-N-[4-trifluoromethylphenyl]pyridazin-4-amine~
4-quinolin-8-yl-N-[4-trifluoromethylphenyl]-1,3,5-triazin-2-amine
5-nitro-6-quinolin-7-yl-N-[4-trifluoromethylphenyl]pyrimidin-4-amined
6-quinolin-7-yl-N4-[4-trifluoromethylphenyl] pyrimidine-4, 5-diamine~
and the pharmaceutically acceptable salts thereof.
Further particular embodiments include=
6-(8-fluoroquinolin-7-yl)-5-methyl-N [5-trifluoromethylpyridin-2- yl]pyrimidin-
4-
10 amine
6-(8-ffuoroquinolin-7-yl)-5-methyl-N [4-trifluoromethylphenyl]pyrimidin-4-
amine~
5-methoxy-2-methyl-6-quinolin-7-yl-N [4-trifluoromethylphenyl]pyrimidin-4-
amine
2-methyl-6-(8-methylquinolin-7-yl)-N [4-trifluoromethylphenyl] pyrimidin-4-
amine
N [2-fluoro-4-trifluoromethylphenyl]-5-methoxy-6-quinolin-7-ylpyrimidin-4-
amine
5-methoxy-6-quinolin-7-yl-N [4-trifluoromethoxyphenyl]pyrimidin-4-amine~
5-methyl-6-(8-methylquinolin-7-yl)-N [4-trifluoromethylphenyl]pyrimidin-4-
amine
5-methyl-6-(8-methylquinolin-7-yl)-N- [5-trifluoromethylpyridin-2-yl]
pyrimidin-4-
amine ' _
6- .quinolin-7-yl-5-trifluoromethyl-N[4-trifluoxoniethylphenyl]pyrimidin-4-
,am~nes
5-ethyl-6-quinolin-7-yl-N [4-trifluoromethylphenyl]pyriin.idin-4-amine, ._
5- ._ .ethyl-6-quinolin-7-yl-N[5-tritluoromethylpyridin-2-yl]pyrimic~in-4-
~;mine~e-~;-.,.~,;;»;
5-methyl-6-quinolin-7-yl-N[5-trifluoromethylpyridin-2-yl]pyrimidin-4-amine~~-
._..
2-cyclopropyl-5-methyl-6-quinolin-7-yl-l~ [5-trifluoromethylpyridin- 2- . , .
.
yl]pyrimidin-4-amine - _ '~. - . '
2-cyclopropyl-5-methyl-6-quinolin-7-yl-N [4-trifluoroznethylphenyl]pyrimidin-4-
.
amine - ~ ~ ~ ' . .
5-isopropyl-6-quinolin-7-yl-N [5-trifluoromethylpyridin-2-yl]pyrimidin-~1-
amine~
6-(6-fluoroquinolin-7-yl)-5-methyl-N [5-trifluoromethylpyridin-2-yl]pyrimidin-
4-
amines
6-(6-fluoroquinolin-7-yl)-5-methyl-N [4-trifluoromethylphenyl]pyrimidin-4-
amine~
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11
5-fluoro-6-(8-methylquinolin-7-yl)-N [5-trifluoromethylpyridin-2-yl]pyrimidin-
4-
amine~
N (2-quinolin-7-ylpyridin-4-yl)-5-trifluoromethylpyridin-2-amine~
2-quinolin-7-yl-N-[4-trifluoromethylphenyl]pyridin-4-amine~
5-chloro-6-quinolin-7-yl-N [4-trifluoromethylphenyl]pyrimidin-4-amine~
5-chloro-6-quinolin-7-yl-N [5-trifluoromethylpyridin-2-yl) pyrimidin-4-amine~
and the pharmaceutically acceptable salts thereof.
Further preferred embodiments include:
5-tert-butyl-6-quinolin-7-yl-N [4-trifluoromethylpheny~]pyrimidin-4-amine~
5-tertbutyl-6-quinolin-7-yl-N [5-trifluoromethylpyridin-2-yl]pyrimidin-4-
amine~
6-(8-ethylquinolin-7-yl)-N [4-trifluoromethylphenyl]pyrimidin-4-amine~
6-(8-ethylquinolin-7-yl)-N [5-trifluoromethylpyridin-2-yl]pyrimidin-4-amine
6-(8-ethylquinolin-7-yl)-5-methyl-N [4-trifluoromethylphenyl~pyrimidin-4-
amine~
6-(8-ethylquinolin-7-yl)-5-methyl-N [5-trifluoromethylpyridin-2-yl]pyrimidin-4-
amine
N [2-fluoro-4-trifluoromethylphenyl]-5-methyl-6-quinolin-7-ylpyrimidin-4-
amine~
6-(8-methylquinolin-7-yl)-2-trifluoromethyl-N [4-trifluoromethylphenyl]
pyrimidin-4-amine~
6-(8-methylquinolin-7-yl)-2-trifluoromethyl-N [5-trifluoromethylpyridin-2-
y~]pyrimidin-4-amine~
2-methoxymethyl-5-methyl-6-quinolin-.7-yl-N [5-trifluoromethylpyridin-2-
yl]pyrimidin-4-amine~ _ ~ .
5-fluoro-6-(8-fluoroquinolin-7-yl)-N [4-trifluoromethylphenyl]pyrimidin-4-
amine -
5-fluoro-6-(8-fluoroquinolin-7-yl)-N [5-trifluoromethylpyridin-2-yl].pyrimidin-
4-
amine . ': : ... , ,
N(5-methyl-6-quinolin-7-ylpyrimidin-4-yl)-6-trifluoromethylpyridazin-3-amine~;
6-(1,8-naphthyridin-2-yl)-N [4-trifluoromethylphenyl]pyrimidin-4-amine~
5-methyl-6-quinolin-8-yl-N [4-trifluoromethylphenyl]pyrimidin-4-amine~
5-methyl-6-quinolin-8-yl-N [5-trifluoromethylpyridin-2-yl]pyrimidin-4-amine~
N [4-tritluoromethylphenyl]-6-[4-trifluoromethylquinolin-7-yl]pyrimidin-4-
amine~
5-methyl-N [4-trifluoromethylpheny)J-6-[4-trifluoromethylquinolin-7-'
y1] pyrimidin-4-amine
5-methyl-N [5-trifluoromethylpyridin-2-yl]-6-[4-trifluoromethylquinolin-7-
yl]pyrimidin-4-amine~
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12
6-quinolin-7-yl-N~-[5-tr ifluoromethylpyridin-2-yl] pyr imidine-4, 5-diamine~
N [3-fluoro-5-trifluoromethylpyridin-2-yl]-5-methyl-6-quinolin-7-ylpyrimidin-4-
amine~
(5-methyl-4-quinolin-7-yl-6-{5-trifluoromethylpyridin-2-ylamino}pyrimidin-2-
yl)methanoh
2-[(cis2,6-dimethylmorpholin-4-yl)methyl]-5-methyl-6-quinolin-7-yl-N [5-
trifluoromethylpyridin-2-yl] pyrimidin-4-amine
5-methyl-6-(1,8-naphthyridin-2-yl)-N [4-trifluoromethylphenyl]pyrimidin-4-
amine~
5-methyl-6-(1,8-naphthyridin-2-yl)-N[5-trifluoromethylpyridin-2-yl]pyrimidin-4-
amine~
5-isopropyl-6-(1,8-naphthyridin-2-yl)-N [4-trifluoromethylphenyl]pyrimidin-4-
amine~
5-tert-butyl-6-(1,8-naphthyridin-2-yl)-N [4-trifluoromethylphenyl]pyrimidin-4-
amine
6-(5-fluoroquinolin-7-yl)-5-methyl-N [5-trifluoromethylpyridin-2-yl]pyrimidin-
4-
amine~
5-methyl-6-(1,5-naphthyridin-3-yl)-N [4-trifluoromethylphenyl]pyrimidin-4-
amine~
5-methyl-6-(1,5-naphthyridin-3-yl)-N [5-trifluoromethylpyridin-2-yl]pyrimidin-
4-
amine '
5-methyl-6-(1-methyl-1H benzimidazol-5-yl)-N [4-trifluoromethyl '
phenyl)pyrimidin-4-amine~ - , . . _,.
6-(lHbenzimidazol-6-yl)-N [4-trifluoromethylphenyl]pyrimidin-4-amine~
5-bromo-6-quinolin-7-yl-N [4-trifluoromethylphenyl]pyrimidin-~=amirie~ ;
5-methyl-2-methylthio-6-quinolin-7-yl-N [4-trifluoromethylphenyl]pyri~nidin-4-
-
amine
5-methyl-4-quinolin-7-yl-6-{4-trifluoromethylphenylamino}pyrimidine-; 2- ' . :
. -
carbonitrile~ - ..
6-(3-fluoroquinolin-7-yl)-5-methyl-N[5-trifluoromethylpyridin-2-yl]pyrimidin-4-
amine~
5-methyl-2-(2-methylpyrrolidin-1-yl)-6-quinolin-7-yl-N [5-
trifluoromethylpyridin-
2-yl]pyrimidin-4-amine~ .
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13
5-methyl-2-morpholin-4-yl-6-quinolin-7-yl-N [5-trifluoromethylpyridin-2-
yl]pyrimidin-4-amine~
5-methyl-6-quinolin-7-yl-2-(2,2,2-trifluoroethoxy)-N [5-trifluoromethylpyridin-
2-
yl]pyrimidin-4-amine~ .
7-(5-methyl-6-{5-trifluoromethylpyridin-2-ylamino}pyrimidin-4-yl)quinolin-4-oh
5-5-methyl-6-{5-trifluoromethylpyridin-2-ylamino~pyrimidin-4-ylquinolin-4-oh
2-methyl-6-quinolin-7-yl-N~-[4-trifluoromethylphenyl]pyrimidine-4,5-diamine~
4-quinolin-7-yl-6-{4-trifluoromethylphenylamino~pyrimidin-2-oh
2-chloro-6-quinolin-7-yl-N [4-trifluoromethylphenyl]pyrimidin-4-amine
2-morpholin-4-yl-6-quinolin-7-yl-N [4-trifluoromethylphenyl]pyrimidin-4-amine~
2-(4-phenylpiperazin-1-yl)-6-quinolin-7-yl-N [4-
trifluoromethylphenyl]pyrimidin-
4-amine~
6-quinolin-7-yl-l~-(2,2,2-trifluoroethyl)-1V~-[4-
trifluoromethylphenyl]pyrimidine-
2,4-diamine~
4-methyl-6-quinolin-7-yl-N [4-trifluoromethylphenyl]-1,3,5-triazin-2-amine~
2-(l,1-dimethylethyl)-5-methyl-6-quinolin-7-yl-N [4-trifluoromethylphenyl]
pyrimidin-4-amine~
5-methyl-6-quinolin-5-yl-N [5-trifluoromethylpyridin-2-yl]pyrimidin-4-amine~
2-(morpholin-4-ylmethyl)-6-quinolin-7-yl-N [4-trifluoromethylphenyl]pyrimidin-
4-
amine
(4-quinolin-7-yl-6-{4-trifluoromethylphenylamino}pyrimidin-2-yl)methanoh
2-(1H imidazol-1-ylmethyl)-6-quinolin-7-yl-N 4-
trifluoromethylphenyl]pyrimidin=
4-amine
2-isopropyl-5-methyl-6-quinolin-7-yl-N [4-trifluoromethyl phenyl].pyrimidin-4-
amine '. ,
2-methylthio-6-quinolin-7-yl-N [4-trifluoromethylphenyl]pyrimidin-4-aW ine~
4-quinolin-7-yl-6-{4-trifluoromethylphenylamino}pyrimidine-2-carboriitrile~
2-cyclopropylmethoxy-6-quinolin-7-yl-N [4-trifluoromethylphenyl]-pyrimidin-4-
amine
2-(pyridin-3-ylmethoxy)-6-quinolin-7-yl-N [4-trifluoromethylphenyl]-pyrimidin-
4-
amine
2-(2-morpholin-4-ylethoxy)-6-quinolin-7-yl-N [4-trifluoromethylphenyl]-
pyrimidin-4-aminea
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14
6-quinolin-7-yl-2-(lHtetrazol-5-yl)-N [4-trifluoromethylphenyl]-pyrimidin-4-
amine trifluoroacetic acid salt
6-quinolin-7-yl-2-trifluoromethyl-N [4-trifluoromethylphenyl]-pyrimidin-4-
amine~
6-quinoxalin-6-yl-N [4-trifluoromethylphenyl]pyrimidin-4-amine
5-methyl-6-quinoxalin-6-yl-N [4-trifluoromethylphenyl]pyrimidin-4-amine~
5-methyl-6-quinolin-7-yl-2-trifluoromethyl-N-[4-
trifluoromethylphenyl]pyrimidin-
4-amine
5-methyl-2-methylthio-6-quinolin-7-yl-N [5-trifluoromethylpyridin-2-
yl]pyrimidin-4-amine~
5-methyl-2-methylsulfonyl-6-quinolin-7-yl-N [4-trifluoromethylphenyl]pyrimidin-
4-amine~
5-methyl-2-methylsulfonyl-6-quinolin-7-yl-N [5-trifluoromethylpyridin-2-
y1] pyrimidin-4-amine
2-methylsulfonyl-6-quinolin-7-yl-N [4-trifluoromethylphenyl]pyrimidin-4-amine~
and the pharmaceutically acceptable salts thereof.
Preferred pharmaceutically acceptable salts are the besylate salts.
Further particular embodiments include=
7-(5-methyl-6-{5-trifluoromethylpyridin-2-ylamino}pyrimidin-4-yl)quinolinium
benzenesulfonate~
7-(2-cyclopropyl-5-methyl-6-~5-trifluoromethylpyridin-2-ylamino}pyrimidin-4-
yl)quinolinium benzenesulfonate~ . _. .- .
7-(2-cyclopropyl-5-methyl-6-f4-trifluoromethylphenylamino}pyrimidin-4-
yl)quinolinium benzenesulfonate~ ~ ,. ~ - :. .
7-(5-isopropyl-6-~5-trifluoromethylpyridin-2-yla~iino}pyrimidin-4-y1)
quin~linium
benzenesulfonate~ ._ _. ~ ',. ~ . _, , .
6-fluoro-7-(5-methyl-6-{5-trifluoromethylpyridin-2-ylamino}pyrimidin=4= . ... -
yl)quinolinium benzenesulfonate~ , : , . :.. .
6-fluoro-7-(5-methyl-6-{4-trifluoromethylphenylamino}pyrimidin-
4=yl);qui~nolinium
benzenesulfonate.
As used herein, the term "alkyl" or "alkoxy" as a group or part of a group
means that the group is straight or branched. Examples of suitable alkyl
groups
include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl.
Examples
of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy,
n-butoxy, s-butoxy and t-butoxy. "Alkylthio" shall be construed in an
analogous
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manner. Examples of "Ca-~cycloalkyl" groups are cyclohexyl, cyclopentyl,
cyclobutyl, cyclopropyl and methylcyclopropyl groups.
As used herein, the term "hydroxyCi-salkyl" means a Ci-salkyl group in
which one or more (in particular 1 to 3, and especially 1) hydrogen atoms have
5 been replaced by hydroxy groups. Particularly preferred are hydroxyCi-salkyl
groups, for example, CHaOH, CHzCH20H, CH(CHa)OH or C(CHa)~OH, and most
especially CHzOH. "AminoCi-salkyl" shall be construed in an analogous manner.
As used herein, the terms "haloCi-salkyl" and "haloCi-salkoxy" means a
Ci-salkyl or Ci-salkoxy group in which one or more (in particular, 1 to 3)
hydrogen
10 atoms have been replaced by halogen atoms, especially fluorine or chlorine
atoms.
Preferred are fluoroCi-salkyl and fluoroCi-salkoxy groups, in particular,
fluoroCi-salkyl and fluoroCi-aalkoxy groups, for example, CFa, CH2CH2F,
CH2CHF2, CHaCFs, OCFs, OCH2CH2F, OCHaCHFz or OCHzCFs, and most
especially CFa and OCFa.
15 As used herein, the terms "alkenyl" and "alkynyl" as a group or part of a
group means that the group is straight or branched. Examples of suitable
alkenyl groups include vinyl and allyl. A suitable alkynyl group is acetylene
or
propargyl.
When used herein, the term "halogen" means fluorine, chlorine, bromine
and iodine. The most preferred halogens are fluorine-and chlorine, especially
fluorine.
When used herein, the term "Ci-salkoxycarbonyl" denotes a Ci-salkoxy
radical attached via the oxygen atom thereof to a carbonyl (C=O) radical thus
forming a Ci-salkoxycarbonyl or haloCnsalkoxycarbonyl radical. Suitable
examples of such esterified carboxy groups include, for example, .
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl and
tert-butoxycarbonyl. . . ..
Examples of 6-membered heterocycles are pyridine, pyrimidine;' pyrazine,
pyridazine and triazine.
Examples of 5-membered heterocycles are thiophene, furan, pyrrole,
imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-
triazole, 1,2,4-
triazole, oxadiazole, thiadiazole and tetrazole.
"Heterocyclic" in the above is interchangeable with "heteroaromatic".
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In a further aspect of the present invention, the compounds of for mula I
may be prepared in the form of a pharmaceutically acceptable salt, especially
an
acid addition salt.
For use in medicine, the salts of the compounds of formula I will be
non-toxic pharmaceutically acceptable salts. Other salts may, however, be
useful
in the preparation of the compounds according to the invention or of their
non-toxic pharmaceutically acceptable salts. Suitable pharmaceutically
acceptable salts of the compounds of this invention include acid addition
salts
which may, for example, be formed by mixing a solution of the compound
according to the invention with a solution of a pharmaceutically acceptable
acid
such as hydrochloric acid, fumaric acid, p-toluenesulphonic acid, malefic
acid,
succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid,
phosphoric acid
or sulphuric acid. A further salt is the acid addition salt with
benzenesulfonic
acid. Preferred pharmaceutically acceptable salts of the compounds of the
present invention are the besylate salts. The hydrochloride salt can also be
used.
Salts of amine groups may also comprise quaternary ammonium salts in which
the amino nitrogen atom carries a suitable organic group such as an alkyl,
alkenyl, alkynyl or aralkyl moiety. Furthermore, where the compounds of the
invention carry an acidic moiety, suitable pharmaceutically acceptable salts
thereof may include metal salts such as alkali metal salts, e.g. sodium or
potassium salts and alkaline earth metal salts, e.g. calcium or magnesium
salts. -
The salts may be formed by conventional means, such as by reacting the .
free base form of the compound of formula I with one or more equivalents of
the..
appropriate acid in a solvent or medium in which the salt is insoluble; or
in_a ::-. = , .
solvent such as water which is removed in vacuo or by freeze dry.~ng o~. by '
.
exchanging the anions of an existing salt for another anion- on a suitable ion
exchange resin. ~ . ....' .. _ ,
v The present invention also includes within its scope N-oxides of the y;',
..._ . .
compounds of formula I above. In general, such N-oxides may be~ formed on any
available nitrogen atom. The N-oxides may be formed by conventional means,
such as reacting the compound of formula I with oxone in the presence of wet
alumina.
The present invention includes within its scope prodrugs of the compounds
of formula I above. In general, such prodrugs will be functional derivatives
of the
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17
compounds of formula I which are readily convertible in vivo into the required
compound of formula I. Conventional procedures for the selection and
preparation of suitable prodrug derivatives are described, for example, in
"Design
of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
A prodrug may be a pharmacologically inactive derivative of a biologically
active substance (the "parent drug" or "parent molecule") that requires
transformation within the body in order to release the active drug, and that
has
improved delivery properties over the parent drug molecule. The transformation
in vivo may be, for example, as the result of some metabolic process, such as
chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate
ester, or
reduction or oxidation of a susceptible functionality.
The present invention includes within its scope solvates of the compounds
of formula I and salts thereof, for example, hydrates.
The compounds according to the invention may have one or more
asymmetric centres, and may accordingly exist both as enantiomers and as
diastereoisomers. It is to be understood that all such isomers and mixtures
thereof are encompassed within the scope of the present invention.
Furthermore,
the compounds of formula I may also exist in tautomeric forms and the
invention
includes within its scope both mixtures and separate individual tautomers.
. The present invention further provides pharmaceutical compositions
comprising one or more compounds of formula I in association with a
pharmaceutically acceptable carrier or excipient.
Preferably the compositions according to the invention are in unit dosage
forms such as tablets, pills, capsules, powders; granules, sterile parenteral
solutions or suspensions, metered aerosol or liquid sprays~drops, ampoules,
auto-
injector devices, suppositories, creams or gels for oral, parenteral,
intrathecal, '
intranasal, sublingual, rectal or topical administration, or for
administration by
inhalation or insufflation. Oral compositions such as tablets, pills, capsules
or
wafers are particularly preferred. For preparing solid compositions such as
tablets, the principal active ingredient is mixed with a pharmaceutical
carrier,
e.g. conventional tabletting ingredients such as corn starch, lactose,
sucrose;
sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums,
and other pharmaceutical diluents, e.g. water, to form a solid pre-formulation
composition containing a homogeneous mixture of a compound of the present
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18
invention, or a pharmaceutically acceptable salt thereof. When referring to
these
pre-formulation compositions as homogeneous, it is meant that the active
ingredient is dispersed evenly throughout the composition so that the
composition may be readily subdivided into equally effective unit dosage forms
such as tablets, pills and capsules. This solid pre-formulation composition is
then
subdivided into unit dosage forms of the type described above containing from
0.1
to about 500 mg of the active ingredient of the present invention. Favoured
unit
dosage forms contain from 1 to 500 mg, for example 1, 5, 10, 25, 50, 100, 300
or
500 mg, of the active ingredient. The tablets or pills of the novel
composition can
be coated or otherwise compounded to provide a dosage form affording the
advantage of prolonged action. For example, the tablet or pill can comprise an
inner dosage and an outer dosage component, the latter being in the form of an
envelope over the former. The two components can be separated by an enteric
layer that serves to resist disintegration in the stomach and permits the
inner
component to pass intact into the duodenum or to be delayed in release. A
variety of materials can be used for such enteric layers or coatings, such
materials including a number of polymeric acids and mixtures of polymeric
acids
with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention
may be incorporated for administration orally or by injection include aqueous
solutions, suitably flavoured syrups, aqueous or oil suspensions, and
flavoured
emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil
or~peanut
oil, as well as elixirs and similar pharmaceutical vehicles. Suitable
dispersing ox . ,
suspending agents for aqueous suspensions include synthetic and natural.guins,
: '
such as tragacanth, acacia, alginate, dextran, sodium
carboxyniethylcelli~lose:, . .~ .
methylcellulose, polyvinyl-pyrrolidone or gelatin. . ... ..; . . . .
In the treatment of painful conditions such as those listed below, a :' . '
suitable dosage level is about 1.0 mg to 15 g per day, preferably about 5'.0
mg to
1 g per day, more preferably about 5 mg to 500 mg per day, especially 10_mg
to, ,
100 mg per day. The compounds may be administered on a regimen of 1~ to 4
times per day. ' '
It will be appreciated that the amount of a compound of formula I required
for use in any treatment will vary not only with the particular compounds or
composition selected but also with the route of administration, the nature of
the
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19
condition being treated, and the age and condition of the patient, and will
ultimately be at the discretion of the attendant physician.
The invention further provides a compound of formula I as defined above,
or a pharmaceutically acceptable salt thereof, for use in treatment of the
human
or animal body. Preferably, said treatment is for a condition which is
susceptible
to treatment by modulation (preferably antagonism) of VR.1 receptors.
The compounds of the present invention will be of use in the prevention or
treatment of diseases and conditions in which pain and/or inflammation
predominates, including chronic and acute pain conditions. Such conditions
include rheumatoid arthritis osteoarthritis~ post-surgical pain musculo-
skeletal
pain, particularly after trauma spinal pain myofascial pain syndromes
headache, including migraine, acute or chronic tension headache, cluster
headache, temporomandibular pain, and maxillary sinus pain ear pain
episiotomy pain burns, and especially primary hyperalgesia associated
therewith deep and visceral pain, such as heart pain, muscle pain, eye pain,
orofacial pain, for example, odontalgia, abdominal pain, gynaecological pain,
for
example, dysmenorrhoea, pain associated with cystitis and labour pain, chronic
pelvic pain, chronic prostatitis and endometriosis~ pain associated with nerve
and
root damage, such as pain associated with peripheral nerve disorders, for
example, nerve entrapment and brachial plexus avulsions, amputation,
peripheral neuropathies, tic douloureux, atypical facial pain, nerve root
damage,
and arachnoiditis~ itching conditions including pruritis, itch due to
hemodialysis,
and contact dermatitis pain (as well as broncho-constriction and inflammation)
due to exposure (e.g. via ingestion, inhalation, or eye contact) of~mucous
membranes to capsaicin and related irritants such as tear~gas; hot peppers.or
pepper spray neuropathic pain conditions such as diabetic neuropathy, -
chemotherapy-induced neuropathy and post-herpetic neuralgia "non-.painful"
neuropathies~ complex regional pain syndromesa pain associated with carcinoma,
often referred to as cancer pain central nervous system pain, such as pain due
to
spinal cord or brain stem damage, low back pain, sciatica and ankylosing
spondylitis~ gout scar pain irritable bowel syndrome inflammatory bowel
diseases urinary incontinence including bladder detrusor hyper-reflexia and
bladder hypersensitivity respiratory diseases including chronic obstructive
pulmonary disease (COPD), chronic bronchitis, cystic fibrosis, asthma and
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rhinitis, including allergic rhinitis such as seasonal and perennial rhinitis,
and
non-allergic rhinitis~ autoimmune diseases and immunodeficiency disorders. In
particular conditions that can be treated or prevented by the compounds of the
present invention include respiratory diseases such as chronic obstructive
5 pulmonary disease (COPD); chronic bronchitis; cystic fibrosis; asthma; and
rhinitis, including allergic rhinitis such as seasonal and perennial rhinitis,
non-
allergic rhinitis and cough. The compounds of the present invention may also
be
useful in the treatment of depression. They may also be used to treat gastro-
oesophageal reflux disease (GERD), particularly the pain associated with GERD.
10 Thus, according to a further aspect, the present invention provides a
compound of formula I for use in the manufacture of a medicament for the
treatment or prevention of physiological disorders that may be ameliorated by
modulating VR,l activity.
The present invention also provides a method for the treatment or
15 prevention of physiological disorders that may be ameliorated by modulating
VR,l
activity, which method comprises administration to a patient in need thereof
of
an effective amount of a compound of formula I or a composition comprising a
compound of formula I.
According to a further or alternative aspect, the present invention
20 provides a compound of formula I for use in the manufacture of a medicament
for
the treatment or prevention of a disease or condition in which pain and/or
inflammation predominates.
According to a further alternative aspect, the present invention provides a ,~
. , compound of formula I for use in the manufacture of a medicament for the
...
treatment or prevention of respiratory diseases such as cough. y _ ~ . ,
The present invention also provides a method for the treatment or .
prevention of a disease or condition in which pain and/or inflammation, _ _: _
. _ _ .
predominates, which method comprises administration to a patient in need ' : ,
thereof of an effective amount of a compound of formula I or a composition
comprising a compound of formula I.
The present invention also provides a method for the treatment or w
prevention of respiratory diseases, such as cough, which method comprises
administration to a patient in need thereof of an effective amount of a
compound
of formula I or a composition comprising a compound of formula I.
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21
According to a further aspect of the present invention, it may be desirable
to treat any of the aforementioned conditions with a combination of a compound
according to the present invention and one or more other pharmacologically
active agents suitable for the treatment of the specific condition. The
compound
of formula I and the other pharmacologically active agents) may be
administered
to a patient simultaneously, sequentially or in combination.
Thus, for example, for the treatment or prevention of pain and/or
inflammation, a
compound of the present invention may be used in conjunction with other
analgesics, such as acetaminophen (paracetamol), aspirin and other NSAIDs,
including selective cyclooxygenase-2 (COX-2) inhibitors, as well as opioid
analgesics, especially morphine, NR2B antagonists, bradykinin antagonists,
anti-migraine agents, anticonvulsants such as oxcarbazepine and carbamazepine,
antidepressants (such as TCAs, SSRIs, SNRIs, substance P antagonists, etc.),
spinal blocks, gabapentin, pregabalin and asthma treatments (such as
9~z-adrenergic receptor agonists or leukotriene D~antagonists (e.g.
montelukast).
Specific anti-inflammatory agents include diclofenac, ibuprofen,
indomethacin, nabumetone, ketoprofen, naproxen, piroxicam and sulindac,
etodolac, meloxicam, rofecoxib, celecoxib, etoricoxib, parecoxib, valdecoxib
and
tilicoxib. Suitable opioid analgesics of use in conjunction with a compound of
the
present invention include morphine, codeine, dihydrocodeine, diacetylmorphine,
hydrocodone, hydromorphone, levorphanol, oxymorphone, alfentanil,
buprenorphine, butorphanol, fentanyl, sufentanyl, meperidine, methadone,
nalbuphine, propoxyphene and pentazocine~ or a pharmaceutically acceptable
salt
thereof. Suitable anti-migraine agents of use in conjunction with a coxnpound
of
the present invention include CGRP-antagon'ists, ergotamines or 5-HTi
agonists, :-'.
especially sumatriptan, naratriptan, zolmatriptan or rizatriptan.
Therefore, in a further aspect of the present invention, there is provided a
pharmaceutical composition comprising a compound of the present invention and
an analgesic, together with at least one pharmaceutically acceptable carrier
or
"excipient.
In a further or alternative aspect of the present invention; there is
provided a product comprising a compound of the present invention and an
analgesic as a combined preparation for simultaneous, separate or sequential
use
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22
in the treatment or prevention of a disease or condition in which pain and/or
inflammation predominates.
The compounds of formula I can be made by reacting a compound of
formula II with a compound of formula III
Y-J-Ll HL-Z
(II) (III)
wherein J, L, Y and Z are as defined above and Ll is a leaving group such as
chlorine. The reaction can be carried out in the presence of a base such as
sodium tertiarybutoxide or sodium hydrogencarbonate and a coupling agent such
as 2'-(dimethylamino)-2-biphenylyl palladium (II) chloride
dinorbornylphosphine
complex generally in a solvent such as toluene or tetrahydrofuran with heating
to
reflux for several hours to several days. Alternatively the reaction can be
carried
out in the presence of cesium carbonate, a coupling agent such as 4,5-
bis(diphenylphosphino)-9,9-dimethylxanthene and a catalyst such as Pds(dba)s,
generally in a solvent such as anhydrous dioxane at reflux for several hours.
The
reaction can also be carried out in the presence of a base such as
diisopropylethylamine in a solvent such as an anhydrous dimethylformamide
between 0°C and room temperature for about 2 hours.
In an alternative process a compound of formula I can be made by reacting
a compound of formula IV with a compound of formula V: . . _ .. . .
Y-B(OH)~ Ll-J-L-Z
(rv> (v)
wherein J, L, Ll, Y and Z are as defined above. The reaction can be carried o
_u_t
under conditions suitable for a Suzuki Coupling Reaction (for review, see for
. . .
25~ instance A. Suzuki, Pure Appl. Chem., 1991, 63, 419-422), for example, in
the
presence of a palladium catalyst such as
tetrakis(triphenylphosphine)palladium(0), ~ '
tris(dibenzylideneacetone)dipalladium(0),
(1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium or dichloro-(1,4-
bis(diphenylphosphino)butane)palladium, in a suitable solvent such as an
ether,
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23
for example, dimethoxyethane or dioxane or an aromatic hydrocarbon, for
example toluene, at an elevated temperature and in the presence of a base such
as sodium carbonate or potassium phosphate.
The B(OHz) moiety can be replaced by, for example, a 4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl moiety. This group can be introduced by converting a
methoxy group to a hydroxy group by refluxing with an acid catalyst such as
aqueous hydrogen bromide for about five days, or boron tribromide in a solvent
such as dichloromethane rising from 0°C to reflux and reacting for
several hours.
The hydroxy substituent is then reacted successively with
trifluoromethanesulfonic acid anhydride in the presence of a base such as
pyridine and a solvent such as dichloromethane at about room temperature for
several hours and then with bis(pinacolato)diboron and a base such as
potassium
acetate in a solvent such as 1,4-dioxane and a coupling agent such as
Pd(dppf)Cl2
at about 80°C for several hours.
The B(OH)a moiety can also be replaced by, for example, tributyltin.
When Ll is iodine a Stille coupling can then take place in the presence of
lithium
chloride, copper(I)iodide and a palladium catalyst. The stannane group can be
introduced either by adding a di(trialkyltin) compound to the reaction mixture
or
prereacting it with a compound of formula YCl in the presence of lithium
chloride, copper(I)iodide and a palladium catalyst and a solvent such as 1,4-
dioxane at about 100°C for several hours.
When moiety Y is quinoline it can be made by reacting an aniline ,
derivative with 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) in a
solvent .
such as acetonitrile, followed by trimethyl orthoformate generally at reflux
for .
about three hours or with an appropriate malonate ester under- similar ~- -. .
. - - .: ' .
conditions. The product is heated in a high boiling solvent, such as Dowtherm
Afl for about one hour to obtain a quinolin-4(1H)-one. If a mixture of
isomers.is~
obtained these can be separated either before or after aromatising the
quinoline ~.
which can be done by reacting with phosphorous oxychloride at about
80°C for
about 1 hour. Quinolin-2(IH)-ones can be obtained by reacting with an
appropriate acetoacetate derivative generally in a solvent such as toluene at
about reflux for about 1 day, followed by addition of an acid such as toluene
sulphonic acid and further heating at about reflux for about 1 day.
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Compounds of formula II can be made by reacting a compound of
formula IV with a compound of formula VI~
L~_ J_L~
(VI)
wherein J and Ll are as defined above. The reaction is again a Suzuki Coupling
Reaction. If necessary the compound of formula VI can be protected. For
example when J is a pyridazine the starting chloropyridazinone can be
protected
with a tetrahydropyran group by heating with 3,4-dihydro-2H-pyran and an acid
catalyst such as p-toluenesulfonic acid monohydrate at reflux for about 60
hours.
After the Suzuki coupling the protecting group can be removed and the product
chlorinated to produce the resulting compound of formula II using phosphorous
oxychloride with heating to about ~5°C.
Compounds of formula V can be made by reacting a compound of formula
III with a compound of formula VI under conditions as described for the
reaction
between compounds of formulae II and III above. The compound of formula VI
may be protected as described above.
A further process for making compounds of formula I involves reacting a
compound of formula VII with a compound of formula VIII:
Y-J-LH L~-Z
(VII) (VIII)
wherein J, L, Y and Z are as defined above and L2 is a leaving group such .as
bromine. The reaction conditions are as described above for the reaction
between
compounds of formulae II and III. . . _ . ' _ . ..
The compound of formula VII can be made by reacting a compound of ""
formula IV with a compound of formula IX: ~ '
Ll-J-LH
(IX)
wherein L, L1 and J are as defined above for a Suzuki or Stille Coupling
Reaction.
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The LH moiety in the compound of for mula IX can be made by reacting a
chlorine moiety with aqueous ammonia in a solvent such as butanol generally
under pressure at about 90°C for about 21/2 hours.
These compounds can be made by reacting compounds bearing two
5 hydroxy moieties with phosphorous oxychloride generally in a solvent such as
anhydrous toluene at about reflux in the presence of a base such as
triethylamine
for about one hour.
This compound when J is pyrimidine can be made by reacting a compound
of formula X with a compound of formula XI:
NH O
Rzo/\NH Rai Iris
_O
O ~0
Ris
~X) ~XI)
wherein R2o and R21 are optional substituents on J as defined above, and R19
are
generally Ci-salkyl groups. The reaction is carried out in a solvent such as
ethanol generally for several hours in the presence of a strong base, such as
sodium ethoxide. The amidine is usually introduced as the hydrochloride or
acetate salt.
Compounds of formula VI where Ll is chlorine can be made in a variation
of this process: when R2o is SH a 6-hydroxy-4-oxo-1,4-dihydropyrimidin-2-
thiolate
results. The desired thioether can be made by reacting with the appropriate
alkyliodide in a solvent such as DMF at about room temperature for several
hours. This compound can be converted to a compound of formula VI in which' Ll
is chlorine by reacting with POCla in an aprotic solvent such as . , .
diethylisopropylamide at about 100°C for several hours.
Compounds of formula X can be made by bubbling ammonia gas through a
solution containing a compound of formula XIII:
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26
NH2+Cl -
Rzo/\O/R
(XIII)
where R is an alkyl group and R~° is as defined above, and the solvent
is ROH at
about -15°C.
The compound of formula XIII can be made by reacting a compound of
formula XIV:
Ra°-CN
(XIV)
wherein R2° is as defined above with an alcohol of formula ROH where R
is as
defined above in an aprotic solvent such as diethyl ether or the ether ROR and
hydrogen chloride gas at about -15°C for about one hour
A yet further process for making compounds of formula I in which Y is
quinoline involves cyclizing a compound of formula XII: °
0
0 Ris
Iris
O
J-L-Z
(XII)
wherein J, L, Z and Rls are as defined above by heating to reflux in a heat
transfer fluid such as Dowtherm A~ for about one hour.
Compounds of formula I can be converted to other compounds of formula I
by standard methods. For example, vitro groups can be converted to amino
groups using a reducing agent such as 10% palladium on carbon under a
hydrogen atmosphere generally in the presence of solvents such as methanol and
dichloromethane for about two hours. Indeed such reactions can be carried out
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27
on any of the starting materials to introduce desired substituents. For
example a
methoxy group can be introduced on moiety J by displacing a chlorine using
sodium methoxide and methanol at reflux for about two hours. A chlorine moiety
can be removed by a reducing agent such as 10% palladium on carbon under a
hydrogen atmosphere in the presence of a base such as triethylamine and a
solvent such as methanol for several hours.
A carboxy group can be converted to an amino group by reacting with
diphenylphosphoryl azide in the presence of a base such as triethylamine in a
solvent such as toluene. A Curtius rearrangement of the resulting azide, by
heating in a solvent such as toluene at reflux for about one hour, following
by
reacting with 2-methyl-2-propanol for about five hours in a solvent such as
toluene and then deprotecting with an acid such as trifluoroacetic acid in a
solvent such as dichloromethane yields the desired amine.
A hydroxymethyl group can be converted to a morpholine derivative by
reacting with an equivalent of methylsulfoxychloride in the presence of a base
such as pyridine in a solvent such as dichloromethane for several hours at
about
room temperature, and then repeating the process at reflux. The resulting
methylsulfoxy compound can then be reacted with the appropriate morpholine in
a solvent such as DMF at about 90°C for several hours to yield the
desired
morpholine derivative. An analogous procedure can be used to introduce 5- or 6-
membered heterocyclic groups, generally using a solvent such as ethanol at a
temperature of about 80°C for about 18 hours. ..
Bromine groups can be introduced by reacting with a brom~inating agent
such as N-bromosuccinimide in an aprotic solvent such as tetrachloromethane at
reflux for about 90 minutes. -
A thioether can be converted to the sulfonyl analogue by reacting with
Oxone~ in a solvent such as methanol at about room temperature for several
hours and then at reflux for about two hours. This compound can be converted
to
the cyanide analogue by reacting with a compound such as sodium cyanide in a
solvent such as DMSO for about three days at about room temperature. The
sulfonyl compound can be converted to the morpholine or pyrrolidine analogue
by
reacting with the appropriate morpholine or pyrrolidine in a solvent such as
1,4-
dioxane at about 180°C for about 20 minutes in a microwave reactor. The
sulfonyl compound can be converted to a haloalkoxy, alkoxy, cycloalkoxy or
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28
heterocyclylalkoxy analogue by reacting with the appropriate haloalcohol
generally in a solvent such as tetrahydrofuran in the presence of a strong
base
such as sodium hydroxide at about 120°C for about six hours.
Ethers can be converted to alcohols by reacting with hydrochloric acid in a
erotic solvent such as water for about 2 days at about reflux.
A chlorine atom can be replaced by a haloalkyl group by reacting with the
appropriate haloalkylamine in a solvent such as 1,4-dixane at about
160°C for
about 20 minutes in a microwave oven.
A cyano group can be derivatised to a tetrazolyl group by reacting with an
azide such as sodium azide generally in the presence of ammonium chloride in a
solvent such as DMF at about 120°C for about two hours.
Where the synthesis of intermediates and starting materials is not
described these compounds are commercially available or can be made from
commercially available compounds by standard methods. Examples of
appropriate methods can be found in the Descriptions.
During any of the above synthetic sequences it may be necessary and/or
desirable to protect sensitive or reactive groups on any of the molecules
concerned. This may be achieved by means of conventional protecting groups,
such as those described in Protective Groups in Organic Chemistry, ed. J.F.W.
McOmie, Plenum Press, 1973 and T.W. Greene and P.G.M. Wuts, Protective
Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups
may be removed at a convenient subsequent stage using methods known from the
art.
The following Examples serve to illustrate the preparation of compounds
of the present invention. _~ - - .
Description 1 2-Chloro-4-(auinolin-8-~pyrimidine
Pd(PPhs)4 (334 mg, 0.29 mmol) was added to a mixture of 2,4-dichloropyrimidine
(861 mg, 5.78 mmol), quinoline-8-boronic acid (1.0 g, 5.78 mmol), and.2M
aqueous
sodium carbonate (2.89 ml, 5.78 mmol) in a mixture of toluene (50 ml) and
ethanol (10 ml). The mixture was degassed three times and heated at reflux
overnight. The reaction mixture was cooled and diluted with EtOAc (50 ml),
washed with water (2 x 100 ml), sat NaCl (100 ml), dried over NazSOa, filtered
and evaporated. The residue was purified by column chromatography on silica:
(eluent 2% MeOH in DCM + 0.5% NH40H) to give the title compound as a white
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29
solid (650 mg, 46%). 1H NMR (500 MHz, CDCIs) 7.49 (1 H, dd, J8.3 and 4.2),
7.69
(1 H, t, J7.9 and 7.6), 7.98 (1 H, d, J8.1), 8.25 (1 H, dd, J8.3 and 1.5),
8.43 (1 H,
d, J7.1), 8.46 (1 H, d, J5.2), 8.69 (1 H, d, J5.2), 8.97 (1 H, dd, J3.9 and
1.5).
Description 2 2-Chloro-6-(auinolin-8-yl)pvrazine
Prepared from 2,6-dichloropyrazine according to the procedure of Description 1
to
give a white solid (1.2 g, 86%). 1H NMR (500 MHz, CDCIs) 7.48 (1 H, dd, J8.3
and 4.2), 7.69 (1 H, t, J8.1 and 7.4), 7.95 (1 H, dd, J8.1 and 1.2), 8.24 (1
H, dd, J
8.3 and 1.7), 8.27 (1 H, dd, J7.1 and 1.5), 8.57 (1 H, s), 8.97 (1 H, dd, J4.2
and
2.0), 9.52 (1 H, s).
Description 3 5-Chloro-2-(tetrahydropyran-2-yl)pyridazin-3(2.F1)-one
To a mixture of 5-chloropyridazin-3(2l~one (ES-A-454136) (85 g, 651 mmol), p-
toluenesulfonic acid monohydrate (6.91 g, 32 mmol), and 3,4-dihydro-2Hpyran
(109 g, 1.302 mol) in tetrahydrofuran (800 ml) was heated at reflux for 60
hours.
The cooled mixture was evaporated and the residue dissolved in ethyl acetate
(800 ml). The ethyl acetate solution was washed with sat NazCOs, sat. NaCl,
dried over MgS04 , filtered and evaporated to half volume. To this mixture was
added triethylamine (100 ml) and silica gel (200 g) and the mixture evaporated
to
dryness. The residue was loaded onto a silica gel column which had been pre-
treated with EtOAc/iso-hexane/triethylamine (80:20:10) and the column eluted
with a gradient rising from 5% EtOAc in iso-hexanes to 20% EtOAc in iso-
hexanes. The product obtained was triturated with iso-hexanes filtered and
dried
to give the title compound as an orange solid (88 g, 63%). 1H NMR (500 MHz,
CDCla) 1.53-1.62 (1 H, m), 1.66-1.76 (3 H, in), 1.98-2.27 (2. H, m), 3.7.1-
3.76 (1 H,
m), 4.11-4.15 (1 H, m), 6.00 (1 H, dd, J10.7 and 2.2), 6.96 (1 H, d, J2.4),
7.79 (1
H, d, J2.4).
Description 4 5-(Quinolin-8-yl)-2-(tetrahydropyran-2-yl)pvridazin-3(2.F~-one
Prepared from 5-chloro-2-(tetrahydropyran-2-yl)pyridaziri-3(2I~-one according
to
the procedure of Description 1 to give a white solid (1.4 g, 79%). 1H NMR
(500 Hz, CDCls) 1.55-1.62 (1 H, m), 1.70-1.86 (3 H, m), 2.05-2.10 (1 H, m),
2.23-
2.32 (1 H, m), 3.77-3.84 (1 H, m), 4.19 (1 H, m), 6.18 (1 H, dd, J10.6 and
2.0), 7.18
(1 H, d, J2.2), 7.49 (1 H, dd, J8.3 and 4.2), 7.64 (1 H, dd, J8.1 and 7.2),
7.75 (1
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H, dd, J7.1 and 1.4), 7.95 (1 H, dd, J8.2 and 1.3), 8.23 (1 H, dd, J8.3 and
1.7),
8.35 (l H, d,J2.2),8.94(lH,s).
Description 5 3-Chloro-5-(auinolin-8-vl)pyridazine
5 A mixture of Description 4 (1.40 g, 4.56 mmol) and phosphorous oxychloride
(21.25 ml, 228 mmol) was warmed to 85°C then allowed to cool to room
temperature. The excess phosphorous oxychloride was removed by evaporation
and the residue partitioned between dichloromethane and sat NaHCOa. The
organic layer was washed with sat NaCl, dried over NazS04 , filtered and
10 evaporated. The residue was purified by column chromatography on silica:
(eluent 2% MeOH in DCM + 0.5% NH40H) to give the title compound as a white
solid (800 mg, 72%). 1H NMR (360 MHz, CDCla) 7.53 (1 H, dd, J8.3 and 4.1),
7.69
(1 H, t, J7.8 and 7.5), 7.83 (1 H, dd, J7.2 and 1.1), 7.97-8.01 (2 H, m), 8.27
(1 H,
dd, J8.3 and 1.5), 8.97 (1 H, d, J 1.7), 9.52 (1 H, d, J 1.7).
Description 6 4-Chloro-6-(guinolin-8-vl)pyrimidine
To a mixture of 4,6-dichloropyrimidine (1.72 g, 11.6 mmol), quinoline-8-
boronic
acid (1.0 g, 5.78 mmol) and tripotassium phosphate (2.46 g, 11.6 mmol) in 1,4-
dioxane (50 ml) was added Pd(PPha)4 (334 mg, 0.29 mmol). The mixture was
degassed three times and heated at reflux overnight. The reaction mixture was
cooled and diluted with EtOAc (50 ml), washed with water (2 x 100 ml), sat.
NaCl
(100 ml), dried over NazS04 , filtered and evaporated. The residue was
purified by
column chromatography on silica: (eluent 2% MeOH in DCM + 0.5% NHaOH) to
give the title compound as a white solid (200 mg, 14%). 1H NMR (500 MHz,
CDCla) 7.50 (1 H, dd, J8.1 and 4.2), 7.71 (1 H, t, J7.8 and 7.6),.7.98 (1 H,
dd; J w
8.1 and 1.3), 8.26 (1 H, dd, J8.4 and 1.8), 8.41 (1 H, dd, J7.3 and 1.5), 8.56
(1-H,
d, J 1.0), 9.01 (1 H, dd, J4.2 and 2.0), 9.12 (1 H, d, J 1.0).
Description 7 2-(Tetrahydro-2Hpyran-2-vl)-5-~[4-trifluorometh~phenyl~amino~
pyridazin-3(2I~-one
To a mixture of Description 3 (1.0 g, 4.66 mmol), and (4-
trifluoromethyl)aniline
(0.59 ml, 4.66 mmol) in anhydrous 1,4-dioxane (50 ml) was added cesium
carbonate (2.13 g, 6.52 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
(161 mg, 0.28 mmol), and Pdz(dba)s (90 mg, 0.09 mmol). The mixture was
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31
degassed three times and heated at reflux overnight. The mixture was cooled
and
diluted with EtOAc (50 ml), washed with water (2 x 100 ml), sat. NaCl, (100
ml),
dried over Na2S04, filtered and evaporated. The residue was purified by column
chromatography on silica: (eluent 2% MeOH in DCM + 0.5% NH40H) to give the
title compound as a white solid (1.1 g, 69%). 1H NMR (500 MHz, CDCls) 1.50-
1.60
(1 H, m), 1.60-1.78 (3 H, m), 1.95-2.08 (1 H, m), 2.08-2.22 (1 H, m), 3.69 (1
H, t, J
11.5 and 9.8), 4.08 (1 H, d, J11.0), 6.01 (1 H, d, J10.7), 6.30 (1 H, d,
J2.6), 7.24 (2
H, d, J8.4), 7.36 (1 H, s), 7.58 (2 H, d, J8.4), 7.67 (1 H, d, J2.6).
Description 8 6-Chloro-N[4-trifluoromethylphenyl]pyridazin-4-amine
Prepared from Description 7 according to the procedure of Description 5 to
give
the title compound as a pale brown solid (250 mg, 28%). 1H NMR (400 MHz,
CDCla) 7.10 (1 H, s), 7.37 (2 H, d, J8.2), 7.68 (2 H, d, J8.2), 8.92 (1 H, s).
Description 9 4-Chloro-N[4-trifluoromethylphenyl]-1,3,5-triazin-2-amine
To a solution of 2,4-dichlorotriazine [WO-A-0125220] (3.0 g, 20 mmol) in
anhydrous N,N-dimethylformamide (20 ml) cooled in an ice-bath was added
diisopropylethylamine (3.46 ml, 20 mmol) followed by 4-
(trifluoromethyl)aniline
(2.27 ml, 18.2 mmol) and the resulting mixture stirred at 0°C for 15
mins, then
allowed to warm to room temperature where it was stirred for 2 hours. The
mixture was diluted with ethyl acetate (150 ml) and washed with water (3 x 200
ml), sat. NaCl (100 ml), dried over Na2SOa, filtered and evaporated to give
the
title compound as a white solid (4.7g, 86 %). 1H NMR (500 MHz, DMSO-ds) 7.74
(2 H, d, J8.6), 7.91 (2 H, d, J8.6), 8.74 (1 H, s), 11.09 (1 H, s). : .
25, ._..
Description 10 ~uinolin-7-yl trifluoromethanesulfonate
To an ice-bath cooled suspension of 7-hydroxyquinoline (6.23 g, 42.9 mmol),
and
pyridine (4.51 ml, 55.77 mmol) in anhydrous dichloromethane (100 ml) was added
dropwise trifluoromethanesulfonic anhydride (7.94 ml, 47.19 minol) and the
resulting mixture stirred at room temperature overnight. The mixture-was
washed with water (250 ml), sat. NaCl (150 ml), dried over NaaS04, filtered
amd
evaporated to give the title compound as a beige solid (11.3 g, 95%). 1H NMR
(400 Hz, CDCIa) 7.47-7.51 (2 H, m), 7.93 (1 H, d, J9.0), 8.04 (1 H, d, J2.4),
8.22 (1
H, dd, J8.2 and 0.7), 9.00 (1 H, dd, J4.3 and 1.9).
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32
Description 11 7-(4 4 5 5-Tetramethyl-1 3.2-dioxaborolan-2-vl)auinoline
To a mixture of Description 10 (8.7 g, 31.4 mmol), bis(pinacolato)diboron (8.8
g,
34.5 mmol), and potassium acetate (9.25 g, 94.2 mmol) in anhydrous 1,4-dioxane
(150 ml) was added Pd(dppf)Cla (860 mg, 0.94 mmol). The mixture de-gassed
three times and heated at 80°C overnight. The mixture was cooled and
diluted
with ethyl acetate (200 ml), washed with water (required a filtration through
celite), sat. NaCl, dried over Na~S04, filtered and evaporated to give the
title
compound as a brown oil which solidified on standing. 1H NMR (400 MHz, CDCla)
1.39 (12 H, s), 7.42 (1 H, dd, J8.2 and 3.9), 7.79 (1 H, d, J7.8), 7.90 (1 H,
d, J9.0),
8.15 (1 H, dd, J8.6 and 1.2), 8.61 (1 H, s), 8.90 (1 H, dd, J4.3 and 2.0).
Description 12 2-Chloro-6-(auinolin-7-yl)pyrazine
Prepared from 2,6-dichloropyrazine and Description 11 according to the
procedure of Description 1 to give a white solid (825 mg, 59%). 1H NMR (500
MHz, CDCla) 7.47 (1 H, dd, J8.3 and 4.2), 7.97 (1 H, d, J8.6), 8.21 (1 H, d,
J7.8),
8.29 (1 H, dd, J8.6 and 1.7), 8.58 (1 H, s), 8.74 (1 H, s), 8.99 (1 H, dd,
J4.2 and
1.7), 9.13 (1 H, s).
Description 13 2-Chloro-4-(quinolin-7-vl)pyrimidine
Prepared from Description 11 according to the procedure of Description 1 to
give
a pale brown solid (822 mg, 59%). 1H NMR (500 MHz, CDCla) 7.50 (1 H, dd, J8.3
and 4.2), 7.85 (1 H, d, J5.2), 7.97 (1 H, d, J8.6), 8.22 (1 H, d, J7.9), 8.37
(1 H, dd,
J8.6 and 2.0), 8.57 (1 H, d, J5.2), 8.77 (1 H, s), 9.00 (1 H, dd, J4.2 and
1.5).
Description 14 6-(~uinolin-7-vl)pvrimidin-4-amine
Prepared from 4-amino-6-chloropyrimidine (WO-A-0245652) and Description 11,
according to the procedure of Description 1 to give a pale brown solid (600
mg,
38%). 1H NMR (400 MHz, DMSO-ds) '1.01 (2 H, br s), 7.12 (1 H, d, J1.0),.7.59
(1
H, dd, J8.2 and 4.2), 8.10 (1 H, d, J8.6), 8.21 (1 H, dd, J8.6 and 1.6), 8.42
(1 H,
dd, J8.2 and 0.5), 8.53 (1 H, d, J0.7), 8.62 (1 H, s), 8.98 (1 H, d, J1.6).
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Description 15 3-Chloro-5-(quinolin-7-yl~pyridazine
Prepared from Description 3 and Description 11 according to the procedures of
Descriptions 1 and 5 respectively. 1H NMR (500 MHz, CDCls) 7.53 (1 H, dd, J8.3
and 4.2), 7.82 (1 H, dd, J8.6 and 1.7), 7.85 (1 H, d, J2.0), 8.03 (1 H, d,
J8.4), 8.25
(lH,d,J8.1),8.46(lH,d,Jl.S),9.03(lH,dd,J4.2and1.5),9.54(lH,d,J2.0).
Description 16 4-Amino-6-chloro-5-methoxypyrimidine
A mixture of 4,6-dichloro-5-methoxypyrimidine (5.0 g, 27.9 mmol), 33% aqueous
ammonia (30 ml) and 1-butanol (15 ml) was heated at 90°C in a sealed
tube for
2.5 hours. The mixture was allowed to cool and the precipitate removed by
filtration, and dried to give the title compound as a white solid (1.8 g,
40%). 1H
NMR (400 MHz, DMSO-ds) 3.71 (3 H, s), 7.30 (2 H, br s), 7.96 (1 H, s).
Description 17 5-Methox -~quinolin-7-yl)-pyrimidin-4-amine
Prepared from Description 16 and Description 11 according to the procedure of
Description 1 to give an orange solid (690 mg, 47%). 1H NMR (400 MHz, CDCla)
3.57 (3 H, s), 5.49 (2 H, br s), 7.46 (1 H, dd, J8.2 and 4.2), 7.93 (1 H, d,
J8.5), 8.21
(1 H, dd, J8.5 and 1.5), 8.83 (1 H, s), 8.99 (1 H, d, J1.6).
Description 18 4-Amino-6-chloro-5-methvhyrimidine
Prepared from 4,6-dichloro-5-methylpyrimidine according to the procedure of
Description 16 to give a white solid (3.1 g, 70%). 1H NMR (400 MHz; DMSO-ds)
2.08 (3 H, s), 7.11 (2 H, br s), 8.06 (1 H, s).
Description 19 5-Meth~quinolin-7-yl)pyrimidin-4-amine
Prepared from Description 18 and Description 11 according to the procedure of
Description 1 to give a beige solid (410 mg, 29%). 1H NMR (400 MHz, CDCla)
2.22 (3 H, s), 5.09 (2 H, br s), 7.46 (1 H, dd, J8.2 and 4.2), 7.79 (1 H, dd,
J8.4 and
1.5), 7.94 (1 H, d, J8.4), 8.20-8.24 (2 H, m), 8.59 (1 H, s), 8.98 (1 H, d,
J1.5).
Description 20 4-Amino-6-chloro-5-fluoropyrimidine
Prepared from 4,6-dichloro-5-fluoropyrimidine (DE-A-10014607) according to the
procedure of Description 16 to give a white solid (5.8 g, 94%). 1H NMR (400
MHz,
DMSO-ds) 7.69 (2 H, br s), 8.07 (1 H, s).
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Description 21 5-Fluoro-6-(guinolin-7-yl)pyrimidin-4-amine
Prepared from Description 20 and Description 11 according t°o the
procedure of
Description 1 to give a beige solid (900 mg, 64%). 1H NMR (400 MHz, DMSO-ds)
7.47 (2 H, br s), 7.63 (1 H, dd, J8.2 and 4.2), 8.13 (1 H, d, J8.6), 8.19 (1
H, d, J
8.6),8.34(lH,d,J2.3),8.45(lH,d,J8.1),8.59(l H,s),9.00(lH,d,Jl.4).
Description 22 4-Amino-6-chloro-2-methoxywrimidine
Sodium methoxide (12 ml of a 25% wt solution in methanol) was added to
methanol (300 ml) and to this mixture added 4-amino-2,6-dichloropyrimidine
(5.00 g, 30.5 mmol). The resultant solution was heated at reflux for 2 hours
and
then evaporated to dryness. The residue was treated with water (250 ml) and
the
precipitate which formed filtered and dried in vacuo to give the title product
as a
white solid (3 g, 61%).1H NMR (400 MHz, CDCls) 3.92 (3 H, s), 5.21 (2 H, br
s),
6.14 (l H, s).
Description 23 2-Methoxv-6-(quinolin-7-vl)pyrimidin-4-amine
Prepared from Description 22 and Description 11 according to the procedure of
Description 1 to give an orange solid (1.15 mg, 65%). 1H NMR (400 MHz, DMSO
ds) 3.93 (3 H, s), 6.83 (1 H, s), 7.05 (2 H, br s), 7.59 (1 H, dd, J8.3 and
4.2), 8.09 (1
H, d, J8.6), 8.20 (1 H, dd, J8.6 and 1.7), 8.42 (1 H, d, J8.3), 8.63 (1 H, s),
8.98 (1
H, d, J 1.6).
Description 24 4-Amino-6-chloro-2-methvlpyrimidine
Prepared from 4,6-dichloro-2-methylpyrimidine according to the procedure of
Description 16 to give a pale yellow solid (3.5 g, 46%).1H NMR (400,MHz, DMSO--
ds) 2.29 (3 H, s), 7.16 (2 H, br s), 7.38 (1 H, s).
Description 25 2-Methvl-6-(auinolin-7-~pvrimidin-4-amine
Prepared from Description 24 and Description 11 according to the procedure of
Description 1 to give an orange solid (980 mg, 59%). 1H NMR (400 MHz, CDCIs)
2.63 (3 H, s), 5.07 (2 H, br s), 6.82 (1 H, s), 7.43 (1 H, dd, J8.3 and 4.2),
7.90 (1 H,
d, J8.6), 8.18 (1 H, d, J7.7), 8.25 (1 H, dd, J8.6 and 1.7), 8.63 (1 H, s),
8.96 (1 H,
d, J 1.7).
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Description 26 7-Methoxv-3-methylquinoline
To a nitrogen flushed suspension of 2-chloro-7-methoxy-3-methylquinoline
[Organic Preparations and Procedures International (1990), 22(5), 579-88]
(7.20
5 g, 34.7 mmol) and triethylamine (5.32 ml, 38.17 mmol) in methanol was added
a
spatula end of 10% Palladium on carbon and the resulting mixture stirred under
a balloon of hydrogen overnight. The catalyst was removed by filtration and
the
filtrate evaporated. The residue was dissolved in dichloromethane (100 ml) and
washed with water (150 ml), dried over NazS04, filtered and evaporated to give
10 the title compound as a pale brown oil (6 g, 99%). 1H NMR (400 MHz, CDCla)
2.47
(3 H, s), 3.94 (3 H, s), 7.16 (1 H, dd, J8.9 and 2.5), 7.39 (1 H, d, J2.5),
7.61 (1 H,
d, J8.9), 7.82 (1 H, t, J0.9), 8.68 (1 H, d, J2.2).
Description 27 3-Methylquinolin-7-ol
15 A mixture of Description 26 (6.0 g, 34.6 mmol) and 48% aqueous HBr (150 ml)
was heated at reflux for 5 days. The mixture was cooled and basified by the
careful addition of 33% aqueous ammonia. The resulting precipitate was removed
by filtration, washed with water, and dried in-vacuo to give the title
compound as
a pink solid (4.6 g, 84%). 1H NMR (400 MHz, DMSO-ds) 2.41 (3 H, s), 7.13 (1 H,
20 dd, J8.8 and 2.4), 7.22 (1 H, d, J2.4), 7.71 (1 H, d, J8.8), 7.96 (1 H, t,
J0.7), 8.61
(l H, d,J2.2),10.01(lH,s).
Description 28 6-(3-Methylquinolin-7-yl~pyrimidin-4-amine
Prepared from Description 27 according to the procedures of Descriptions 10,
11
25 and 14 respectively to give a light brown solid (950 mg, 57%). 1H.NMR'(400'-
MHz,
DMSO-ds) 2.51 (3 H, s), 6.99 (2 H, br s), 7.10 (1 H, s), 7.99 (1 H, d; J8 ;6),
8.16 (2
H, m), 8.52 (1 H, s), 8.57 (1 H, s), 8.62 (1 H, s), 8.82 (1 H, s). ~ ._
Description 29 6-Chloro-5-nitro-N [4-(trifluoromethyl)phenvllpyrimidin-4-amine
30 To a suspension of 4,6-dichloro-5-nitropyrimidine (5.00 g, 25.8 mmol) in
anhydrous tetrahydrofuran (100 ml) was added sodium hydrogen carbonate (2.38
g, 28.38 mmol) and 4-(trifluoromethyl)aniline (3.24 ml, 25.8 mmol), and the
resulting mixture stirred at room temperature for 3 days. The mixture was
filtered and the filtrate evaporated. The residue triturated with diethyl
ether and .
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36
filtrate from trituration evaporated to give the title compound as a yellow
solid
(3.2 g, 38%). 1H NMR (400 MHz, CDCls) '7.70 (4 H, q, J9.0), 8.55 (1 H, s),
8.92 (1
H, s), 9.25 (1 H, br s).
Description 30 4-Chloro-6-(auinolin-5y1)pyrimidine
Prepared from 4,6-dichloropyrimidine and quinoline-5-boronic acid according to
the procedure of Description 1 to give a white solid. 1H NMR (400 MHz, CDCla)
7.49 (1 H, dd, J8.6 and 4.2), 7.69 (1 H, d, J1.1), 7.76 (1 H, dd, J7.2 and
1.3), 7.83
(1 H, dd , J8.3 and 7.2), 8.28 (1 H, dd, J7.4 and 1.0), 8.65 (1 H, dd, J7.2
and 0.8),
8.65 (1 H, dd, J4.2 and 1.9), 9.17 (1 H, d, J1.0).
Description 31 6-((~uinolin-6-yl)pyrimidin-4-amine
Prepared from 4-amino-6-chloropyrimidine (WO-A-0245652) and quinoline-6-
boronic acid according to the procedure of Description 1 to give a pale brown
solid. 1H NMR (400 MHz, DMSO-ds) 7.00 (2 H, br s), 7.06 (1 H, d, J1.2), 7.59
(1
H, dd, J8.6 and 4.3), 8.11 (1 H, d, J9.0), 8.32 (1 H, d , J9.0 and 2.0), 8.50-
8.53 (2
H, m), 8.66 (1 H, d, J2.0), 8.95 (1 H, dd, J4.3 and 1.6).
Description 32 3-Methvlauinolin-7-ol
To a solution of 7-methoxy-2-methylquinoline (J. Med. Chem (1998), 41(21),
4062-
4079) (5 g, 29 mmol) in anhydrous dichloromethane (20 ml) was added boron
tribromide (58 ml of a 1M solution in CH2Cl2, 58 mmol) at 3°C. After
stirring for
wins the reaction mixture was allowed to warm to room temperature and
stirred for a further 2 hours. The reaction mixture was then refluxed for 16
25 hours. The cooled reaction mixture was adjusted to pH 7 with sad. sodium
hydrogen carbonate solution, extracted with dichloromethane (2 x 50~n1), dried
over MgS04, filtered and evaporated. The residue was purified by column
chromatography on silica: (eluent 2% MeOH in DCM) to give the title compound
(1.5 g, 32%). 1H NMR (400 MHz, CDCls) 2.65 (3 H, s), 6.84 (1 H, dd, J2.5,
8.8),
30 7.06(lH,d,J8.2),7.22(lH,d,J2.3),7.40(l H, d,J9.0),7.87(lH,d,J8.6).
Description 33 6-(2-Methylauinolin-7-yl)pyrimidin-4-amine
Prepared from Description 32 according to the procedures of Descriptions 10,
11,
and 14 respectively. 1H NMR (400 MHz, DMSO-ds) 2.68 (3 H, s), 6.97 (2 H, br
s),
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7.07(lH,d,Jl.2),7.46(lH,d,J8.2),8.02(l H, d,J8.6),8.11(lH,dd,J8.2and
1.6),8.28(lH,d,J8.6),8.49(lH,d,J2.0),8.51(lH,d,Jl.2).
Description 34 5-~[(4-Fluoro-3-methoxyphenyl)aminolmethylene}-2 2-dimeth~l-
1,3-dioxane-4,6-dione
To a stirred solution of 4-fluoro-3-methoxyaniline (20 g, 142 mmol) in
acetonitrile
(200 ml) was added 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) (22.5
g,
156 mmol) followed by trimethyl orthoformate (18.6 ml, 170 mmol). The mixture
was heated to reflux for 3 hours. The cooled mixture was filtered to give the
title
compound (30.9 g, 74%).1H NMR (400 MHz, CDCla) 1.76 (6 H, s), 3.94 (3 H, s),
6.76-6.83 (2 H, m), 7.14 (1 H, dd, J 10.5 and 8.4), 8.56 (1 H, d, J 14.4),
11.23 (1 H,
d, J14.4).
Description 35 6-Fluoro-7-methoxyquinolin-4(l F~-one
To a boiling solution of Dowtherm A~ (80 ml) was added in portions Description
34 (30.9 g, 105 mmol). Heating was continued for 1 hour after the addition was
complete and then the mixture cooled to room temperature. The mixture was
poured into hexane (200 ml) and filtered. The filtrate was washed with more
hexane to give a mixture of the title compound and 6-fluoro-5-methoxyquinolin-
4(1F~-one in a 2:1 ratio (22.6 g , 100%).
Description 36 4-Chloro-6-fluoro-7-methoxvguinoline
A suspension of the crude product of Description 35 (22.6 g, 117mmo1) in
phosphorous oxychloride (110 ml, 1.18 mol) was heated at 80°C for 1
hour. The
reaction mixture was allowed to cool and evaporated. The residue was
neutralised with saturated sodium bicarbonate solution, extracted with DCM (3
x
200 ml) and evaporated. The residue was purified by column chromatography on
silica: (eluent 2% MeOH in DCM) to give the title compound (11 g, 44%). 1H NMR
(400 MHz, CDCla) 4.05 (3 H, s), 7.40 (1 H, dd, J4.7 and 0.8), 7.53 (1 H, d,
J8.2),
7.85 (1 H, d, J11.7), 8.68 (1 H, dd, J4.7 and 0.8).
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Description 37 6-Fluoro-7-methoxyauinoline
Prepared from Description 36 according to the procedure of Description 26. 1H
NMR (400 MHz, CDCIs) 4.04 (3 H, s), 7.29-7.33 (1 H, m), 7.43 (1 H, d, J11.3),
7.52 (1 H, d, J8.2), 8.05 (1 H, dd, J8.2 and 1.6), 8.82 (1 H, dd, J4.3 and
1.2).
Description 38 6-Fluoroauinolin-7-of
Prepared from Description 37 according to the procedure of Description 2'7 to
give an off white solid (5.1 g , 60%).1H NMR (400 MHz, DMSO-ds) 7.37-7.41 (1
H,
m), 7.44 (1 H, d, J8.4), 7.78 (1 H, d, J11.9), 8.29 (1 H, dd, J8.2 and 1.4),
8.78 (1
H, dd, J4.4 and 1.4), 10.80-11.04 (1 H, br s).
Description 39 6-(6-Fluoroquinolin-7-vl)pyrimidin-4-amine
Prepared from Description 38 according to the procedures of Descriptions 10,
11
and 14 respectively. 1H NMR (400 MHz, DMSO-ds) 7.01 (1 H, s), 7.10 (2 H, s),
7.63(lH,m),7.94(lH,d,J12.1),8.40(lH,d,J8.2),8.53(lH,d,Jl.2),8.63(1
H, d,J7.4),8.96(lH,dd,J4.1and1.8).
Description 40 2-Fluoro-3-methoxyaniline
To a solution of 2-fluoro-3-methoxy benzoic acid [Synlett (1991), (10), 731-2]
(15.0
g, 88 mmol) and triethylamine (13.49 ml, 96.8 mmol) in toluene (300 ml) was
added diphenylphosphoryl azide (20.9 ml, 96.8 mmol) and the resulting mixture
heated at reflux for 1 hour. After this time 2-methyl-2-propanol (12.5 ml, 132
mmol) was added and heating continued for 5 hours. The mixture was cooled and
evaporated, and the residue partitioned between water and dichloromethane. The
dichloromethane layer was dried over NazSOa, f'~ltered through a 1 inch plug
of
silica and evaporated. The residue was dissolved in dichloromethane (200 ml)
and
trifluoroacetic acid (25 ml) added, and the resulting mixture stirred at room
temperature overnight. The mixture was evaporated and the residue partitioned
between dichloromethane and sat. KzCOa, the dichloromethane layer was dried
over Na~S04, filtered and evaporated. The residue was purified by column
chromatography on silica: (eluent with 15% EtOAc in isohexanes) to give the
title
compound as a pale yellow oil (10.8 g, 87%). 1H NMR (400 MHz, CDCls) 3.72 (2
H,
br s), 3.85 (3 H, s), 6.34-6.41 (2 H, m), 6.81-6.86 (1 H, m).
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Description 41 6-(8-Fluoroauinolin-7-yl)pyrimidin-4-amine
Prepared from Description 40 according to the procedures of Descriptions 34,
35,
36, 2G, 27, 10, 11 and 14 respectively. 1H NMR (400 MHz, MeOD) 7.14 (1 H, t, J
1.6), 7.49 (1 H, dd, J6.7 and 3.2), 7.58 (1 H, d, J7.6), 7.69 (1 H, dd, J8.2
and 4.3),
7.87 (1 H, dd, J8.7 and 0.9), 8.07 (1 H, dd, J8.5 and 6.7), 8.48 (1 H, dd,
J8.5 and
1.8), 8.51 (1 H, d , J1.2), 8.96 (1 H, dd, J4.3 and 1.5).
Description 42 6-(6-Trifluoromethylauinolin-7-yl)pyrimidin-4-amine
Prepared from 4-trifluoromethyl-3-methoxyaniline according to the procedures
of
Descriptions 34, 35, 36, 26, 27, 10, 11 and 14 respectively to give a brown
solid.
1H NMR (400 MHz, CDCla) 5.21 (2 H, br s), 6.63 (1 H, s), 7.55 (1 H, dd, J8.3
and
4.2), 8.19 (1 H, s), 8.29 (2 H, m), 8.68 (1 H, s), 9.08 (1 H, dd, J4.2 and
1.5).
Description 43 8-Methvl-7-(4,4.5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)quinoline
Prepared from 3-methoxy-2-methylaniline according to the procedures of
Descriptions 34, 35, 36, 26, 27, 10, and 11 respectively to give an orange
oil. 1H
NMR (400 MHz, CDCls) 1.40 (12 H, s), 3.08 (3 H, s), 7.40 (1 H, dd, J8.2 and
3.9),
7.62 (1 H, d, J8.2), 7.85 (1 H, d, J8.2), 8.10 (1 H, dd, J8.2 and 2.0), 8.96
(1 H, dd,
J4.3 and 2.0).
Description 44 6-(8-Methylquinolin-7-~pyrimidin-4-amine
Prepared from Description 43 according to the procedure of Description 14 to
give a pale brown solid. 1H NMR (400 MHz, CDCla) 2.85 (3 H, s),_5.12.(2 H, br
s),
6.59(lH,d,Jl.2),7.44(lH,dd,J8.3and4.2),7.58(lH,d,J8:5),7.73(lH,d,J
8.5), 8.16 (1 H, dd, J8.2 and 1.8), 8.73 (1 H, d, J1.0), 9.00 (1 H, dd~ J3.9
and 1.6).
Description 45 5-Fluoro-6-(8-meth~quinolin-7-yl)pyrimidin-4-amine '
Prepared from Description 20 and Description 43 according to the procedure~of
Description 1 to give a white solid (300 mg, 26%). 1H NMR (400 MHz, CDCla)
2.77 (3 H, d, J2.2), 5.26 (2 H, br s), 7.47 (1 H, dd, J8.2 and 4.3), 7.56 (1
H, d, J
8.6), 7.77 (1 H, d, J8.6), 8.18 (1 H, dd, J8.2 and 2.0), 8.50 (1 H, d, J2.4),
9.01 (1
H, dd, J4.3 and 2.0).
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Description 46 6-(Isoauinolin-7-yl)twrimidin-4-amine
Prepared from 7-methoxyisoquinoline according to the procedures of
Descriptions 27, 10, 11, and 14 respectively to give a white solid. 1H NMR
(500
MHz, DMSO-ds) 7.04 (2 H, br s), 7.08 (1 H, d, J1.1), 7.88 (1 H, d, J5.7), 8.08
(1 H,
5 d,J8.7),8.35(lH,dd,J8.7and1.7),8.52(lH,d,J0.9),8.56(lH,d,J5.7),8.80
(1 H, s), 9.47 (1 H, s).
Description 47 6-(8-Fluoroauinolin-7-yl)-5-methylpyrimidin-4-amine
Prepared from Description 40 according to the procedures of Descriptions 34,
35,
10 36, 26, 27, 10, 11 and 19 respectively. 1H NMR (400 MHz, CDCla) 2.10 (3 H,
d, J
3.3), 5.02 (2 H, s), 7.56-7.52 (1 H, m) 8.26-8.24 (1 H, m), 8.60 (1 H, s) ,
9.03 (1 H,
dd, J4.2 and 1.6).
Description 48 5-Methox,~2-methvlpvrimidine-4,6-diol
15 Sodium (7.00 g, 305.25 mmol), cut into small chunks, was added portionwise
to
anhydrous ethanol (300 ml). Once all the sodium had dissolved the mixture was
cooled in an ice-bath and acetamidine hydrochloride (9.57 g, 101.75 mmol) was
added and the mixture stirred for 20 mins. To this mixture was added dropwise
a
solution of methoxy dimethylmalonate (15.0 g, 92.5 mmol) in ethanol (50 ml),
and
20 once addition was complete the mixture was stirred at room temperature
overnight. The ethanol was removed by evaporation and the residue dissolved in
water. The mixture was acidified by addition of conc. HCl and the resulting
precipitate were removed by filtration and dried in vacuo to give the title
compound (8 g, 55%) as a white solid. 1H NMR (400 MHz, DMSO-ds) 2.19 (3 H,
s),.
25 3.59 (3 H, s), 11.70 (2 H, brs).
Description 49 4 6-Dichloro-5-methoxy-2-methylpvrimidine
To a suspension of Description 48 (7.99 g, 51.2 mmol) and triethylamine (7.14
ml,
51.2 mmol) in anhydrous toluene (100 ml) heated at 100°C was added
dropwise a
30 solution of phosphorous oxychloride (10.5 ml, 112.6 mmol) in toluene (50
ml).
After complete addition the mixture was heated at reflux for 1 hour. The
mixture
was cooled in an ice bath and quenched by the careful addition of cold water
(100
ml). The organic layer was washed with sat. NaHCOs, sat. NaCI, and evaporated
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41
to dryness to give the title compound (9.5 g, 96%).1H NMR (400 MHz, CDCla)
2.65
(3 H, s), 3.95 (3 H, s).
Description 50 6-Chloro-5-methoxy-2-meth~pyrimidin-4-amine
Prepared from Description 49 according to the procedure of Description 16 to
give
a white solid (6.7 g, 78%). 1H NMR (400 MHz, DMSO-ds) 2.26 (3 H, s), 3.67 (3 H
,
s), 7.15 (2 H, br s).
Descriptions 51-53 were prepared from the indicated Description compounds
following the procedure of Description 1.
Description 51 5-Methoxy-2-methyl-6-auinolin-7-ylpyrimidin-4-amine
Description 50 and Description 11 gave a beige solid (775 mg, 50%). 1H NMR
(400 MHz, CDCla) 2.57 (3 H, s), 3.54 (3 H, s), 5.17 (2 H, s), 7.45 (1 H, dd,
J8.3 and
4.1), 7.91 (1 H, d, J8.6), 8.20 (2 H, dd, J8.4 and 1.6), 8.80 (1 H, s), 8.97
(1 H, dd, J
4.2 and 1.8).
Description 52 2-Methyl-6-(8-methylquinolin-7-yl)pyrimidin-4-amine
Description 24 and Description 43 gave a beige solid (420 mg, 45%). 1H NMR
(500 MHz, CDCla) 2.62 (3 H, s), 2.82 (3 H, s), 5.04 (2 H, br s), 7.42 (1 H,
dd, J8.2
and 4.2), 7.56 (1 H, d, J8.4), 7.72 (1 H, d, J8.4), 8.14 (1 H, dd, J8.3 and
1.8), 8.99
(1 H, dd, J4.2 and 1.8).
Description 53 5-Methyl-6-(8-methylquinolin-7-yl)pyrimidin-4-amine
Description 18 and Description 43 gave a beige solid (530 mg, 57%). 1H NMR
(400 MHz, CDCIa) 1.92 (3 H, s), 2.63 (3 H, s), 4.98.(2 H, br s), 7.39(1 H, ~d,
J8~:4), v
7.45 (1 H, dd, J8.3 and 4.2), 7.75 (1 H, d, J8.4), 8.17 (1 H, dd, J8.2 and
1.8), 8.58
(1 H, s), 9.00 (1 H, dd, J4.2 and 1.8). . _ ' - _
Description 54 4-Fluoro-6-methoxy-5-trifluoromethylpyrimidine
To a rapidly stirred mixture of 1-methoxy(perfluoro-2-methylprop-1-ene) (25:0
g,
118 mmol), and formamidine acetate (18.4 g, 177 mmol) in a mixture of water
(120 ml) and dichloromethane (120 ml) cooled in an ice bath was added dropwise
a solution of sodium hydroxide (18.88 g, 472 mmol) in water (100 ml). After
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complete addition the mixture was stirred for 30 rains. Then the
dichloromethane
layer was separated, washed with 1N HCl (150 ml), water (150 ml), dried over
Na2SOa, filtered and evaporated to give the title compound (8 g, 34%) as a
Blear
oil. 1H NMR (500 MHz, CDCla) 4.15 (3 H, s), 8.60 (1 H, s).
Description 55 6-Methoxy-5-trifluoromethvlp~rimidin-4-amine
A mixture of Description 54 (8 g, 40.8 mmol) in butan-1-of and ammonium
hydroxide (50 ml) was heated in a large (200 ml capacity) sealed tube at
90°C for
1 hour. The mixture was cooled and the resulting precipitate removed by
filtration, and dried to give the title compound (3.3 g, 42%) as a white
crystalline
solid. 1H NMR (500 MHz, DMSO-ds) 3.91 (3 H, s), '7.20 (2 H, br s), 8.23 (1 H,
s).
Description 56 6-Chloro-5-trifluoromethvlpyrimidin-4-amine
A mixture of Description 55 (800 mg, 4.14 mmol) and phosphorous oxychloride
(7.7 ml, 82.8 mmol) were heated at 100°C for 4 days. Excess phosphorous
oxychloride was removed by rotary evaporation and the residue was taken up
into dichloromethane and carefully basified by the addition of sat. NaHCOa.
The
organic layer was separated and dried over NasSOø, filtered and evaporated to
give the title compound as a 4:1 mix of product and starting material (450 mg,
55%). 1H NMR (500 MHz, CDCla) 5.77 (2 H, br s), 8.39 (1 H, s).
Description 57 6-Quinolin-7-vl-5-trifluoromethvlpyrimidin-4-amine
Prepared from Description 56 and Description 11 according to the procedure of
Description 1 to give a beige solid (100 mg, 15%). 1H NMR (400 MHz, DMSO-ds)
7.61 (1 H, dd, J8.2 and 4.3), 7.64 (1 H, d, J8.3), 8.00 (1 H, s), 8.06 (1 H,
d, J8.3),
8.44 (1 H, d, J8.1), 8.58 (1 H , s), 8.98 (1 H, dd, J4.3 and 2.0), 10.13 (1. H
, br s)'.
Description 58 6-Chloro-5-ethvlp~imidin-4-amine
Prepared from ethyl diethylmalonate and formamidine acetate according to the
procedures of Descriptions 48, 49, and 16 respectively. 1H NMR (400 MHz,
DMSO-ds) 1.05 (3 H, t, J7.4), 2.57 (2 H, q, J7.4), 7.12 (2 H, br s), 8.06 (1
H, s).
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Description 59 5-Ethyl-6-quinolin-7-ylpyrimidin-4-amine
Prepared from Description 58 and Description 11 according to the procedure of
Description 1 to give a white solid (1.05 g, 84%). 1H NMR (400 MHz, CDCls)
1.06
(3 H, t, J7.3), 2.51 (2 H, q, J7.3), 6.88 (2 H, br d), 7.60 (1 H, dd, J8.3 and
4.2),
7.6 7 (1 H, dd, J8.4 and 1.2), 8.04 (1 H, s), 8.07 (1 H, d, J8.4), 8.34 (1 H,
s), 8.43 (1
H, d, J8.2), 8.96 (1 H, dd, J4.2 and 1.2).
Description 60 6-Chloro-2-cvclopropyl-5-methylpyrimidin-4-amine
Prepared from methyl diethylmalonate and cyclopropylcarbamidine
hycliochloride according to the procedures of Descriptions 48, 49, and 16
respectively. 1H NMR (500 MHz, DMSO-ds) 0.87 (4 H, m), 1.84 (1 H, quintet, J
6.1), 2.03 (3 H, s), 6.89 (2 H, br s).
Description 61 2-C~clopropyl-5-methyl-6-quinolin-7-ylpyrimidin-4-amine
Prepared from Description 60 and Description 11 according to the procedure of
Description 1 to give a brown solid (1.1 g, 79%). 1H NMR (500 MHz, CDCls) 0.94
(2 H, m), 1.09 (2 H, m), 2.08 (1 H, m), 2.13 (3 H, s), 4.90 (2 H, br s), 7.44
(1 H, dd,
J8.3 and 4.2), 7.76 (1 H, d, J8.4), 7.89 (1 H, d, J8.4), 8.19 (2 H, br s),
8.95 (1 H,
s).
Description 62 6-Chloro-5-isopropylpyrimidin-4-amine
Prepared from diethylisopropylmalonate and formamidine acetate according to
the procedures of Descriptions 48, 49, and 16 respectively. 1H NMR (360 MHz;
DMSO-ds) 1.28 (6 H, d, J7.4), 3.35 (1 H, quintet, J7.4),_7.01 (2 H, br s),
8.04 (1 H,
s).
Description 63 5-Isopropyl-6-quinolin-7-~pyrimidin-4-amine
Prepared from Description 62 and Description 11 according to the procedure. of
Description 1 to give an off white solid (900 mg, 68%). 1H NMR (400 MHz,
CDCls) 1.30 (6 H, d, J7.4), 3.33 (1 H, quintet, J7.4), 5.21 (2 H, br s), 7.45
(1 H,
dd, J8.2 and 4.3), 7.62 (1 H, dd, J8.4 and 1.7), 7.91 (1 H, d, J8.4), 8.10 (1
H,'d, J
0.6), 8.21 (1 H, dd, J8.3 and 0.9), 8.52 (1 H, s), 8.98 (1 H, dd, J4.3 and
2.0).
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Description 64 6-(6-Fluoroguinolin-7-yl)-5-methylpyrimidin-4-amine
Prepared from Description 38 and Description 18 according to the procedures of
Descriptions 10, 11 and 14 respectively. 1H NMR (400 MHz, DMSO-ds) 1.90 (3 H,
d, J1.5), 5.75 (2 H, s), 7.62 (1 H, dd, J8.4 and 4.0), 7.92 (1 H, d, J10.4),
8.03 (1 H,
d, J7.0), 8.34 (1H, s) 8.43 (1 H, d, J = 8.4 Hz), 8.94 (1 H, dd, J4.1 and
1.6).
Description 65 2-~uinolin-7-vlpyridin-4-amine
Prepared from 2-chloropyridin-4-amine and Description 11 according to the
procedure of Description 1 to give a solid (1.2 g, 67%). 1H NMR (400 MHz,
DMSO-ds) 6.20 (2 H, br s), 6.57 (1 H, d, J5.1), 7.28 (1 H, s), 7.54 (1 H, dd,
J7.9
and3.9),8.05(lH,d,J8.5),8.21(lH,d,J5.4),8.26(l H, d,J8.5),8.39(lH,d,J
8.3), 8.55 (1 H, s), 8.96 (1 H, m).
Description 66 5 6-Dichloropvrimidin-4-amine
Prepared from diethyl chloromalonate and formamidine acetate according to the
procedures of Descriptions 48, 49, and 16 respectively. 1H NMR (400 MHz,
DMSO-ds) 7.46 (1 H, br s), 7.91 (1 H, br s), 8.17 (1 H, s).
Description 67 5-Chloro-6-auinolin-7-ylpvrimidin-4-amine
Prepared from Description 66 and Description 11 according to the procedure of
Description 1 to give an off-white solid (1.1 g, 61%). 1H NMR (500 MHz, DMSO-
ds) 7.49 (2 H, br s), 7.62 (1 H, s), 7.90 (1 H, d, J7.4), 8.10 (1 H, d, J7.6),
8.35 (1 H,
s), 8.45 (3 H, m), 8.98(1 H, s).
Description 68 5-ter~Butyl-6-chloropvrimidin-4-amine ~ -
Prepared from diethyl tern-butylmalonate and formamidine acetate according to
the procedure of Descriptions 48, 49, and 16 respectively. 1H NMR (500 MHz,
DMSO-ds) 1.49 (9 H, s), 6.85 (2 H, br s), 7.94 (1 H, s). -
Description 69 5-tert-Butyl-6-auinolin-7-vlpyrimidin-4-amine
Prepared from Description 68 and Description 11 according to the procedure of
Description 1 to give an off white solid (980 mg, 70%). 1H NMR (500 MHz,
CDCls)
1.25 (9 H, s), 5.60 (2 H, br s), 7.41 (1 H, dd, J8.3 and 4.2), 7.59 (1 H, dd,
J8.3 and
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1.6), 7.86 (1 H, d, J8.3), 7.97 (1 H, s), 8.18 (1 H, d, J8.0), 8.39 (1 H , s),
8.98 (1 H,
dd, J4.2 and 1.7).
Description 70 6-(8-Ethvlquinolin-7-vhyrimidin-4-amine
5 Prepared from 2-ethyl-3-methoxyaniline Journal of Organic Chemistry (1988),
53(12), 2844-7], according to the procedures of Descriptions 34, 35, 36, 26,
27, 10,
11, and 14 respectively to give an off white solid.
Description 71 6-(8-Eth~quinolin-7-yl)-5-methylpyrimidin-4-amine
10 Prepared from 2-ethyl-3-methoxyaniline (Journal of Organic Chemistry
(1988),
53(12), 2844-7], according to the procedures of Descriptions 34, 35, 36, 26,
27, 10,
11, and 19 respectively to give an off white solid. 1H NMR (500 MHz, DMSO-ds)
1.06 (3 H, t, J7.5), 1.77 (3 H, s), 2.88 and 3.20 (2 H, m), 5.75 (2 H, br s),
7.32 (1 H,
d,J8.3),7.57(lH,dd,J8.2and4.3),7.87(lH,d,J8.4),8.33(lH,s),8.39(1H,
15 dd, J8.3 and 1.5), 8.98 (1 H, d, J1.6).
Description 72 Sodium 6-h~droxy-5-methyl-4-oxo-1,4-dihydropyrimidine-2-
thiolate
A mixture of diethyl methylmalonate (50 g, 287 mmol) and thiourea (21.85 g,
287
20 mmol) in ethanol (100 ml) was stirred at room temperature for 20 min. To
this
mixture was added a solution of sodium (6.6 g, 287 mmol) which had been
dissolved in ethanol (100 ml) and the resulting mixture heated at reflux for 4
hours (a thick white precipitate soon formed). The mixture was cooled to room
temperature and filtered, the solid was washed with ethanol, and dried to give
25 the title compound (51 g, 98%) 1H NMR (500 MHz, Dz0) 1..73 (3 H, s), 4.78
(2 H,
br s).
Description 73 6-H~y-5-methyl-2-methylthiopyrimidin-4(lf~-one
To a solution of Description 72 (51.0 g, 286 mmol) in anhydrous DMF (450 ml) '
-
30 was added iodomethane (23.22 ml, 373 mmol) and the mixture stirred at room
temperature overnight. The resulting white suspension was poured into water
(1 1) and the solid filtered, azeotroped with toluene (3 x) and dried to give
the title
compound (36 g, 72%). 1H NMR (500 MHz, DMSO-ds) 1.72 (3 H, s), 2.47 (3 H, s),
11.60 (2 H, br s).
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Description 74 4 6-Dichloro-5-methyl-2-methvlthiopyrimidine
To a mixture of Description 73 (36 g, 209 mmol) and phosphorous oxychloride
(390 ml, 4.18 mol) was added N,N-diethylisopropylamine (40.34 ml, 230 mmol)
and the resulting mixture heated at 100°C overnight. The excess
phosphorous
oxychloride was removed by evaporation, and the residue dissolved in DCM (300
ml), and poured onto ice/water (500 ml). The mixture was stirred for 30 min,
the
organic layer was separated, and the aqueous phase extracted with a further
portion of DCM (300 ml). The combined DCM layers were washed with water
(500 ml), dried over Na~SOa, filtered and evaporated to give the title
compound as
a brown solid (40 g, 91%). 1H NMR (500 MHz, CDCla) 2.38 (3 H, s), 2.54 (3 H,
s).
Description 75 6-Chloro-5-methyl-2-methylthiopyrimidin-4-amine
Prepared from Description 74 according to the procedure of Description 16 to
give
a white solid (6.17 g, 68%). 1H NMR (400 MHz, DMSO-ds) 2.03 (3 H, s), 2.40 (3
H,
s), 7.13 (2 H, br s).
Description 76 6-Chloro-2-trifluoromethylpvrimidin-4-amine
Prepared from 4,6-dichloro-2-trifluoromethylpyrimidine [US-A-4963678]
according to the procedure of Description 16 to give a yellow solid (5 g,
61%). 1H
NMR (400 MHz, DMSO-ds) 6.66 (1 H, s), 7.82 (1 H, br s), 7.97 (1 H, br s).
Description 77 6-(8-Methylauinolin-7-yl)-2-trifluorometh~pyrimidin-4-amine
Prepared from Description 43 and Description 76 according to the procedure of
Description 1 to give a white solid (210 mg, 27%). 1H NMR (400 MHz DMSO-ds)
2.78 (3 H, s), 6.80 (1 H, s), 7.60-7.64 (2 H, m)7.67 (2 H, br s), 7.93 (1 H,
d, J8.4),
8.41 (l H, d,J8.4),9.02(lH,d,Jl.9). , . ~....
Description 78 Ethvl 2-methoxvethanimidoate hydrochloride
Hydrogen chloride gas was bubbled through ~a solution.of methoxyacetonitrile
(50
g, 703 mmol) in a mixture of ethanol (41 ml) and diethyl ether (250 m_1) at -
15°C
until the mixture was saturated. The mixture was stirred for 1 hour at -
15°C then
the solid which had formed was removed by filtration, washed with ether, and
dried under a stream of nitrogen to give the title compound as a white solid
(90 g,
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47
83%). 1H NMR (400 MHz, DMSO-ds) 1.35 (3 H, t, J7.0), 3.38 (3 H, s), 4.42 (2 H,
s), 4.56 (2 H, q, J7.0), 11.70 (2 H, br s).
Description 79 2-Methoxyethanimidamide hydrochloride
Ethanol (500 ml) was cooled to -15°C and anhydrous ammonia gas
passed
through until the mixture was saturated. Description 78 (90 g, 585 mmol) was
added and the mixture stirred at room temperature overnight. The mixture was
retooled to -15°C and a small amount of solid removed by filtration.
The filtrate
was evaporated to dryness and the residue crystallised on standing to give the
title compound (70 g, 96%). 1H NMR (360 MHz, DMSO-ds) 3.35 (3 H, s), 4.24 (2
H,
s), 8.85 (4 H, br s).
Description 80 6-Chloro-2-methox~yl-5-methylpyrimidin-4-amine
Prepared from Description 79 and methyl diethylmalonate according to the
procedures of Descriptions 48, 49 and 16 respectively to give a white solid.
1H
NMR (400 MHz, DMSO-ds) 2.06 (3 H, s), 3.30 (3 H, s), 4.22 (2 H, s), 7.10 (2 H,
br
s).
Description 81 2-Methoxymethvl-5-methyl-6-quinolin-7-~pyrimidin-4-amine
Prepared from Description 11 and Description 80 according to the procedure of
Description 1 to give a dark solid (4.5 g, 75%). 1H NMR (500 MHz, CDCIa) 2.17
(3
H, s), 3.53 (3 H, s), 4.56 (2 H, s), 5.37 (2 H, br s), 7.44 (1 H, dd, J8.4 and
4.2), 7.75
(1 H, dd, J8.4 and 1.6), 7.91 (1 H, d, J8.4), 8.20 (2 H, m), 8.97 (1 H, d,
J1~.7). - --
Description 82 5-Fluoro-6-(8-fluoroquinolin-7-yl)pyrimidin-4-amine
Prepared from Description 40 according. to the procedures of Descriptions 34,
35,
36, 26, 27, 10, 11 respectively, then the resulting compound treated with
Description 20 according to the procedure of Description 1. 1H NMR (400-MHz;
DMSO-ds) 7.60 (2 H, br s), 7.74-7.81 (2 H, m), 7.98 (1 H, d, J8.2), 8.37 (1 H,
s),
8.55 (1 H, d, J7.8), 9.06 (1 H, s).
Descri-ption 83 4-Isopropyl-2-trifluoromethyl-1,3-oxazol-5(2.F.~-one
Trifluoroacetic anhydride (120 ml, 854 mmol) was cooled in an ice bath, and DL-
Valine (50.0 g, 427 mmol) was added portionwise. After complete addition the
mixture was heated at 80°C for 30 min, then at 130°C for 30 min.
The
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48
temperature was kept at 130°C, and excess trifluoroacetic anhydride and
trifluoroacetic acid were distilled off. The residue was partitioned between
diethyl
ether and water, the ether layer washed with sat. NaHCOa, dried over NasSOa ,
filtered and evaporated. The residue was distilled under vacuum to give the
title
compound (b.p. 56-58°C @ 11 mmHg ) as a clear oil (54 g, 65%). 1H NMR
(500
MHz, CDCls) 1.18 (6 H, m), 2.91 (1 H, m), 5.93 (1 H, m).
Description 84 ter~Butyl 3-[4-isopropyl-5-oxo-2-trifluoromethyl-2 5-dihydro-1
3-
oxazol-2-Yl]propanoate
To Description 83 (54.4 g, 279 mmol) dissolved in anhy drous dichloromethane
(150 ml) and cooled in an ice bath, was added tent-butt' 1 acrylate (49.0 ml,
334.8
mmol) followed by triethylamine (48.6 ml, 348.75 mmol), and the resulting
mixture stirred at room temperature overnight. The mixture was washed with
10% citric acid solution (500 ml), sat. NaHCOa, sat. NaCl, dried over Na2S04 ,
filtered and evaporated to give the title compound as a pale yellow oil (90 g,
100%). 1H NMR (400 MHz, CDCla) 1.32 (6 H, t, J6.9), 1.44 (9 H, s), 2.09 (2 H,
t, J
7.8), 2.53 (2 H, m), 3.05 (1 H, septet, J6.9).
Description 85 6-Trifluoromethyl-4,5-dihydropyridazin-3(2I-~-one
A mixture of Description 84 (90.2 g, 279 mmol) and hydrazine hydrochloride
(95.6
g, 1.4 mol) in glacial acetic acid (500 ml) was heated at reflux for 2 hours.
The
cooled reaction mixture was evaporated, and the residue basified by the
careful-
addition of saturated aqueous K2COs. Water (500 ml) was added, and the mixture
extracted with dichloromethane (x 3). The combined dichloromethane layers were
dried over Na~S04 , filtered and evaporated to give the title compound as an
oil -
which crystallised on standing (50 g, quant). 1H NMR (400 MHz,v CDCls)
2.62,(2°
H, m), 2.78 (2 H, m), 9.57 (1 H, br s). ,.
Description 86 6-Trifluoromethylpyridazin-3(2H)-one
To a solution of Description 85 (46.34 g, 279 mmol) in glacial acetic acid
(300 ml)
warmed at 100°C, was added dropwise a solution of bromine (14.29 ml,
279
mmol). After complete addition the heating was continued for 4 hours. The
acetic
acid was removed by evaporation and the residue partitioned between
dichloromethane and water. The organic layer was washed with sat. NaHCOa,
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49
sat. NaCl, dried over Na2SOa, filtered and evaporated. The dark residue was
triturated with diethyl ether, and the solid filtered, and dried to give the
title
compound as a white solid (5 g, 11%). 1H NMR (400 MHz, CDCls) 7.14 (1 H, d, J
9.6), 7.53 (1 H, d, J9.6), 12.65 (1 H, br s).
Description 87 3-Chloro-6-trifluoromethylpyridazine
A mixture of Description 86 (2.00 g, 12.2 mmol) and phosphorous oxychloride
(11.4 ml, 122 mmol) was heated at 90°C for 6 hours. The excess
phosphorous
oxychloride was removed by evaporation, and the residue then dissolved in
dichloromethane (100 ml) and ice (100 g) added. The mixture was stirred for 30
min, then carefully basified by the addition of saturated aqueous K~COs,
filtered
and evaporated to give the title compound as a pale brown solid (2 g, 89%). 1H
NMR (400 MHz, CDCla) 7.79 (1 H, d, J9.0), 7.86 (1 H, d, J9.0).
Description 88 6-Chloro-5-methvl-N-[5-trifluoromethvlpvridin-2-yl]pyrimidin-4-
amore
Prepared from Description 18 and 2-chloro-5-trifluoromethylpyridine according
to
the procedure of Description 7 to give an off white solid (4 g, 66%). 1H NMR
(400
MHz, CDCla) 2.40 (3 H, s), 7.61 (1 H, br s), 7.94 (1 H, dd, J8.8 and 2.2),
8.52 (1 H,
s), 8.54 (1 H, s), 8.65 (1 H, d, J8.8).
Description 89 5-Bromo-4-chloro-7-fluoroauinoline and 7-bromo-4-chloro-5- -:
fluoroquinoline
Prepared from 3-bromo-5-fluoroaniline [WO-A-9215565] according to the ~
procedures of Descriptions 34, 35, and 36 respectively to give a mixture of
the .-
title compounds as an off white solid. -- ' - --
Description 90 7-Bromo-5-fluoroauinoline
A mixture of Description 89 (8 g, 30.7 mmol) and hydrazine hydrate (7.46 ml,
153.5 mmol) in ethanol (100 ml) was heated at reflux for 4 hours. The cooled
mixture was filtered and the filtrate evaporated. The residue was suspended in
chloroform (100 ml) and manganese dioxide (10.9 g, 153.5 mmol) added in a
portionwise manner. After complete addition the mixture was heated at reflux
for
4 hours. The mixture was cooled and filtered through Hyflo supercelTM, the
filter
cake was washed with methanol, and the combined filtrates evaporated. The
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mixture was purified and the isomers separated by column chromatography on
silica (eluent: 2% MeOH in DCM), and further purified by mass directed HPLC to
give the title compound as a light brown solid (200 mg, 3%). 1H NMR (500 MHz,
CDCIs) 7.37 (1 H, dd, J9.1 and 1.5), 7.47 (1 H, dd, J8.3 and 4.2), 8.11 (1 H,
s),
5 8.38 (1 H, d, J8.3), 8.95 (1 H, dd, J4.2 and 1.5).
Description 91 5-Methvl-2-methylthio-6-guinolin-7-ylpyrimidin-4-amine
Prepared from Description 11 and Description 75 according to the procedure of
Description 1 to give an off white solid (2.5 g, 56%). 1H NMR (400 MHz, CDCla)
10 2.15 (3 H, s), 2.54 (3 H, s), 5.06 (2 H, br s), 7.44 (1 H, dd, J8.2 and
4.2), 7.79 (1 H,
dd, J8.4 and 1.5), 7.90 (1 H, d, J8.4), 8.20 (1 H, d, J8.0), 8.23 (1 H, s),
8.97 (1 H,
dd, J4.2 and 1.5).
Description 92 2-Chloro-1,8-naphthyridine
15 Phosphorous oxychloride (86 ml, 924 mmol) was added to 1,8-naphthyridin-2-
one
[Journal of Organic Chemistry 1990, 55(15), 4744-50] (9.00 g, 61.6 mmol), and
the resulting mixture heated to 100~C for 1 hour. The mixture was cooled and
the
excess phosphorous oxychloride was removed by evaporation. The residue was
taken up in dichloromethane (100 ml) and carefully basified by the addition of
20 sat. NaHCOa. The organic layer was separated and dried over NazS04,
filtered,
and evaporated to give the title compound as a white solid (7 g, .70%). 1H NMR
(400 MHz, CDCls) 7.50 (1 H, d, J8.4), 7.52 (1~H, dd, J8.1 and 4.3), 8.16 (1 H,
d, J
8.4), 8.22 (1 H, dd, J8.1 and 2.0), 9.12 (1 H, dd, J4.3 and 2.0).
25 Description 93 6-Iodo~yrimidin-4-amine =;; ,
A mixture of 4-amino-6-chloropyrimidine [WO-A-0245652] (1.00,g; 7.72 mmol),
sodium iodide (5.79 g, 38.6 mmol) and 40% HI (20 ml) were heated at
70°C for 30
min, then allowed to cool to room temperature. The precipitate was removed byy
.
filtration, and partitioned between dichloromethane and sat. NaHCOs. The
30 organic layer was separated, and dried over NazSOø, filtered, and
evaporated to
give the title compound (1.2 g, 70%). 1H NMR (400 MHz, DMSO-ds) 6.89 (1 H, s),
7.04 (2 H, br s), 8.04 (1 H, s).
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Description 94 6-(1 8-Naphthyridin-2-~1)pyrimidin-4-amine
To a mixture of Description 92 (2.52 g, 15.3 mmol), hexamethylditin (5.0 g,
15.3
mmol), lithium chloride (1.95 g, 45.9 mmol), and copper (I) iodide (291 mg,
1.53
mmol) in anhydrous 1,4-dioxane (50 ml) was added Pd(PPhs)4 (884 g, 0.77 mmol).
The mixture was de-gassed three times, and heated at 100°C
overnight. The
mixture was cooled and diluted with EtOAc (120 ml) and washed with a 10%
potassium fluoride solution (200 ml). The organic layer was washed with sat.
NaCI (50 ml), dried over Na2SOa, filtered, and evaporated. The residue was
taken
up in anhydrous 1,4-dioxane (75 ml), and Description 93 (1.55 g, 7 mmol),
lithium chloride (1.78 g, 42 mmol), and copper (I) iodide (266 mg, 1.4 mmol)
added, followed by Pd(PPha)a (808 mg, 0.7 mmol). The mixture was degassed 3
times and heated at 100°C for 3 days. The mixture was poured into water
(200
ml), and extracted with EtOAc (2 x 100 ml), the combined EtOAc layers were
washed with water (150 ml), sat. NaCl (100 ml), dried over NaaS04, filtered
and
evaporated. The residue was purified by column chromatography on silica
(eluent: 2% MeOH in DCM + 0.5% NH40H) to give the title compound (100 mg,
3%). 1H NMR (360 MHz, DMSO-ds) 7.18 (2 H, br s), 7.66-7.86 (3 H, m), 8.55 (1
H,
dd, J8.1 and 1.8), 8.58 (1 H, d, J4.2), 8.64 (1 H, d, J8.4), 9.16 (1 H, dd,
J4.2 and
2.1).
Description 95 6-Chloro-5-methvl-N ~4-trifluoromethvlphenvl]pyrimidin-4-
amine
A mixture of 4,6-dichloro-5-methylpyrimidine (1.0 g, 6.15 mmol) and 4-
aminobenzotrifluoride (0.77 ml, 6.15 mmol) in ethanol (12 ml) was heated at
150°C for 15 min in a microwave reactor (Personal Chemistry - Emrys
Optimizer). The solid which had formed was removed by filtration and dried to
give the title compound (950 mg, 53%). 1H NMR (400 MHz, CDCla) 2.36 (3 H, s),
6.70 (2 H, br s), 7.61 (2 H, d, J8.6), 7.73 (2 H, d, J8.6), 8.44 (1 H, s).
Description 96 6-Chloro-5-isonropyl-N ~4-trifluorometh~phenvl]pyrimidiri-4-
amore
Prepared from Description 62 and 4-trifluoromethylbromobenzene according to
the procedure of Description 7 (640 mg, 67%). 1H NMR (400 MHz, CDCIs) 1.47 (6
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52
H, d, J7.4), 3.72 (1 H, quintet, J7.4), 6.85 (1 H, br s), 7.61 (2 H, d, J8.6),
7.71 (2
H, d, J8.6), 8.39 (1 H, s).
Description 97 5-ter~Butyl-6-ehloro-N [4-trifluoromethylphenyllpyrimidin-4-
amine
Prepared from Description 68 and 4-trifluoromethylbromobenzene according to
the procedure of Description 7 (640 mg, 67%). 1H NMR (400 MHz, CDCIa) 1.71 (9
H, s), 7.18 (1 H, br s), 7.61 (4 H, m), 8.30 (1 H, s).
Description 98 6-(1-f2-Trimethvlsilylethox~yl}-lHbenzimidazol-6-
yl)pyrimidin-4-amine and 6-(1-f2-trimethylsilylethoxymeth~l}-
1H benzimidazol-5-yl)pyrimidin-4-amine
Prepared from a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-
~2-
trimethylsilylethoxymethyl}-1-benzimidazole and 6-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-1-{2-trimethylsilylethoxymethyl}-lHbenzimidazole
[WO-A-0100213], and 4-amino-6-chloropyrimidine [WO-A-0245652] according to
the procedure of Description 1 (400 mg, 30%). 1H NMR (400 MHz, CDCIa) 0.02 (9
H, s), 0.96 (2 H, m), 3.60 (2 H, m). 5.09 (2 H, br s), 5.61 and 5.66 (2 H, s),
6.96 and
6.97(lH,s),7.67(lH,d,J8.5),7.92(lH,s),8.09 (l H,s)8.13(lH,m),8.36and
8.43 (1 H, s), 8.74 (1 H, s).
Description 99 N[4-Trifluoromethylphenyl]-6-(1-f2-trimethylsihilethoxymethyl}
-lHbenzimidazol-6-yl)pyrimidin-4-amine and
N[4-trifluoromethylphenyl]-6-(1-f2-trimethylsilylethoxymethyl}
-lHbenzimidazol-5-~)wrimidin-4-amine"
Prepared from Description 98 and 4-trifluoromethylbromobenzeiie according~tor
''
the procedure of Description 7 (210 mg, 37%). 1H NMR (500 MHz, CD~ls)'0:00 (9'
H, s), 0.96 (2 H, t, J8.2), 3.58 (2 H, t, J8.2), 5.61 (2 H, s), 7.27 (1' H,'
d, J0.9), 7:32
(1 H, s), 7.69 (5 H, m), 8.09 (1 H, s), 8.16 (1 H, dd, J8.5 and 1.5),~ 8:44
~(ll~~,ld; J"'~~
1.1), 8.91 (1 H, s).
Description 100 5-Methyl-6-quinolin-8-ylpyrimidin-4-amine
Prepared from quinoline-8-boronic acid and Description 18 according to the
procedure of Description 1 (0.98 mg, 91%). 1H NMR (500 MHz, DMSO-ds) 1.63 (3
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53
H, s), 6.66 (2 H, br s), 7.55 (1 H, dd, J8.2 and 4.3), 7.65-7.70 (2 H, m),
8.05 (1 H,
d,J7.7),8.30(lH,s),8.44(lH,d,J8.2),8.83(lH,s).
Description 101 7-Methoxv-4-trifluoromethylguinolin-2(1.F~-one
A solution of m-anisidine (22.8 ml, 203 mmol), and ethyl 2,2,2-
trifluoroacetoacetate (35.6 ml, 243.6 mmol) in toluene (500 ml) was heated at
reflux for 24 hours. Toluene sulfonic acid (3.86 g, 20.3 mmol) was added, and
heating continued for a further 24 hours. The cooled mixture was evaporated
and
the residue treated with diethyl ether and solid removed by filtration to give
the
title compound as a yellow solid (9 g, 18%). 1H NMR (400 MHz, DMSO-ds) 3.85 (3
H, s), 6.77 (1 H, s), 6.93 (2 H, m), 7.61 (1 H, dd, J9.8 and 2.1), 12.16 (1 H,
br s).
Description 102 2-Chloro-7-methoxy-4-trifluoromethvlauinoline
Prepared from Description 101 according to the procedure of Description 92
(8.63
g, 89%). 1H NMR (400 MHz, CDCls) 3.96 (3 H, s), 7.31 (1 H, dd, J9.4 and 2.7),
7.43 (1 H, d, J2.7), 7.54 (1 H , s), 7.98 (1 H, dd, J9.4 and 2.0).
Description 103 7-Methoxv-4-trifluoromethvlquinoline
Prepared from Description 102 according to the procedure of Description 26
(4.6
g, 61%). 1H NMR (400 MHz, CDCla) 3.98 (3 H, s), 7.33 (1 H, dd, J9.4 and 2.6),
7.51 (1 H, d, J2.6), 7.54 (1 H, d, J4.3), 8.03 (1 H, dd, J9.4 and 2.0), 8.95
(1 H, d, J,
4.3).
Description 104 7-~6-Chloro-5-methyl-2-meth l~pvrimidin-4-yl]duinoline
Prepared from Description 11 (3.2 g, 12 mmol) and Description 74 (5.2 g, 24
mmol) according to the procedure of Description l to give a solid (2.9g,
77°/d). 1H ~'
NMR (400 MHz, CDCla) 2.43 (3 H, s), 2.60 (3 H, s), 7.49 (1 H, dd, J8.3 and
4.2),
7.77 (1 H, dd, J8.4 and 1.7), 7.94 (1 H, d, J8.4),~8.23 (1 H, d, J~.3), 8.29
(1 H, s),
8.98-9.00 (1 H, m). -
Description 105 Ethyl 7-methoxv-4-oxo-1,4-dihydroquinoline-3-carbox 1y ate
A solution of 3-methoxyaniline (30 ml, 0.27 mol) and diethyl
ethoxymethylenemalonate (54 ml, 0.27 mol) was heated at 100°C for 3hrs.
The
cooled reaction mixture was slowly added to boiling Dowtherm~ A (300m1). The
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54
reaction mixture was stirred until gas evolution had ceased ~30 min. The
cooled
reaction mixture was poured into hexane and the solid which formed was
collected by filtration and washed with hexane to give the title compound
(28.6 g,
43%). 1H NMR (400 MHz, DMSO-ds) 1.27 (3 H, t, J7.1), 3.87 (3 H, s), 4.20 (2 H,
q,
J7.1), 7.00 (2 H, m), s.o5 (1 H, d, J9.5), 8.48 (1 H, s).
Description 106 Ethyl 4-chloro-7-methox~auinoline-3-carboxylate
A suspension of Description 105 (28.6 g, 0.12 mol) in POCIs (34 ml, 0.36 mol)
was
heated at 115°C for 45mins. The cooled reaction mixture was poured onto
ice (500
ml) and cooled in an ice bath. 33% aqueous ammonia was added until a pH of 7
was obtained (80-90 ml). The solid which formed was collected by filtration.
Ether
was added to the solid, the mixture stirred then filtered. This procedure was
repeated 4 times and the combined ether extracts were evaporated to give a
yellow solid (ll.lg, 36%). 1H NMR (400 MHz, DMSO-ds) 1.38 (3 H, t, J7.1), 3.99
(3 H, s), 4.41 (2 H, q, J7.1), 7.48 (1 H, dd, J9.3 and 2.6), 7.53 (1 H, d,
J2.5), 8.28
(l H, d,J9.2),9.10(lH,s).
Description 107 4-Chloro-7-methoxyquinoline-3-carboxylic acid
To a stirring suspension of Description 106 (11.1 g, 41 mmol) in ethanol (100
ml)
was added 2M NaOH (100m1). The reaction mixture was stirred at room
temperature for 3 days. The reaction mixture was diluted with water (100 ml),
cooled in an ice/water bath and acidified to pH 4 by addition of conc. HCl.
The
resulting solid was collected by filtration, washed with water and dried under
w
vacuum in a drying pistol at 50°C (8.8 g, 89%). 1H NMR (400 M~z, DMSO-
ds)
3.98 (3 H, s), 7.48 (1H, dd, J9.2 and 2.5), 7.52 (1 H, d-, J2:5), 8.28 (1, H,
d, J9:2), , -
9.11 (l H, s).
Description 108 and 109 ter~Butvl (4-chloro-7-methox~quinoliri-3-
yI)carbaniate_' .
(Description 108) and 4-chloro-7-methox~auinolin-3- ~ '
amine (Description 109)
To a stirred suspension of Description 107 (8.8 g, 37 mmol) in DMF (400 ml)
under Nz, was added ter~butanol (150 ml) and triethylamine (12 ml, 86 mmol),
followed by diphenylphosphorylazide (9.5 ml, 44 mmol). The mixture was heated
at 100~C for 3hours. The cooled reaction mixture was then evaporated and.the
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residue was purified by column chromatography on silica (eluant: DCM to 4%
MeOH in DCM). This gave Description 108 as a solid (2.12 g, 20%) and
Description 109 as an orange solid (4.26 g, 55%). Description 108 1H NMR (360
MHz, DMSO-ds) 1.48 (9 H, s), 3.94 (3 H, s), 7.40 (1 H, dd, J9.2 and 2.6), 7.47
(1
5 H, d, J2.4), 8.07 (1 H, d, J9.2), 8.85 (1 H, s). Description 109 1H NMR (360
MHz,
DMSO-ds) 3.86 (3 H, s), 5.76 (2 H, s), 7.25 (1 H, dd, J9.1 and 2.6), 7.30 (1
H, d, J
2.5), 7.80 (1 H, d, J9.1), 8.52 (1 H, s).
Description 110 4-Chloro-3-fluoro-7-methox~Tguinoline
10 A solution of Description 109 (4.26 g, 20 mmol) in THF (100 ml) was cooled
in an
ice/water bath and 48% fluoroboric acid (11 ml, 60 mmol) was carefully added.
The mixture was stirred for 5min, and then a solution of sodium nitrite (1.55
g,
22 mmol) in water (3 ml) was added dropwise keeping the temperature of the
reaction below 10~C. The mixture was stirred for 30 minutes in an ice/water
bath.
15 The resulting yellow solid was filtered and washed with THF. The solid was
then
heated at 170°C until gas evolution had ceased. The residue was
purified by
column chromatography on silica (eluant: 1% MeOH in DCM) to give a cream
solid (780 mg, 18%). 1H NMR (400 MHz, DMSO-ds) 3.95 (3 H, s), 7.49 (1 H, dd, J
9.0 and 2.5), 7.53 (1 H, d, J2.5), 8.09 (1 H, d, J9.3), 9.00 (1 H, d, J1.0).
Description 111 3-Fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)cruinoline
Prepared from Description 110 according to the procedures of Descriptions 26,
27,
- 10, and 11 respectively to give a solid. 1H NMR (400 MHz, DMSO-ds) 1..35 (12
H,
s), 7.85 (1 H, d, J7.8), 7.94 (1 H, s), 8.00 (1 H, d, J8.2), 8.36 (1 H,; s),
8:99 (1.H,-d,-
J2.8). .. - .~.
Description 112 6-(3-Aminophenyl)-5-methyl-N [5-trifluoromethylpyridin-2-
yl~pyrimidin-4-amine
Prepared from Description 88 and (3-aminophenyl)boronic acid according to the
procedure of Description 1 to give a light brown solid (1.58 g, 74%). 1H NMR
(400
MHz, DMSO-ds) 2.29 (3 H, s), 5.23 (2 H, s), 6.64-6.66 (2 H, m), 6.75 (1 H, t,
J1.9),
7.12 (1 H, t, J7.8), 8.14 (1 H, dd, J9.0 and 2.4), 8.32 (1 H, d, J8.9), 8.69
(2 H, s),
9.47 (1 H, s).
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Description 113 2,2-Dimethvl-5-(3-(5-methyl-6-5-trifluoromethylpyridin-2-
ylamino~pvrimidin-4-yl)phenylaminomethylene)-1.3-dioxane-
4.6-dione
Prepared from Description 112 according to the procedure of Description 34 to
give a solid (1.13 g, 100%). 1H NMR (360 MHz, DMSO-ds) 1.68 (6 H, s), 2.32 (3
H,
s),7.46(lH,d,J7.7),7.57(lH,t,J7.8),7.69(l H, d,J8.0),7.77(lH,s),8.17(1
H, dd, J9.0 and 2.5), 8.35 (1 H, d, J8.9), 8.62 (1 H, d, J14.6), 8.71 (1 H,
s), 8.75 (1
H, s), 9.61 (1 H, s), 11.36 (1 H, d, J 14.6).
Description 114 4-Chloro-6-quinolin-7-~pyrimidin-5-amine
Prepared from 4,6-dichloropyrimidin-5-amine and Description 11 according to
the
procedure of Description 1 to give a solid (1.5g, 65%). 1H NMR (360 MHz, DMSO-
ds) 5.79 (2H, s), 7.62 (1H, dd, J8.4 and 4.2), 7.92 (1H, dd, J8.6 and 1.6),
8.13 (1H,
d, J8.4), 8.39 (2H, s), 8.45 (1H, d, J8.4), 8.99 (1H, dd, J4.2 and 1.8).
Description 115 3-Chloro-5-trifluoromethylpyridine-2-carbonitrile
To 3-chloro-2-fluoro-5-trifluoromethylpyridine (10 g, 50 mmol) in DMSO (70 ml)
was added potassium cyanide (3.6 g, 55 mmol) over 20 min, ensuring the
reaction
mixture temperature stayed below 30°C. The reaction mixture was stirred
for a
further 30 minutes then poured onto ice water (150 ml). The mixture was
extracted 3 times with hexane, and the combined organic extracts were.
evaporated to give a solid (8.7 g, 84%). 1H NMR (400 MHz, CDCla) 8.15 (1 H, d,
J
1.2), 8.88 (1 H, d, J1.0). - - --
Description 116 3-Fluoro-5-trifluoronieth~yridine-2-carbonitrile . .
A suspension of cesium fluoride (9.6 g, 63 mmol) and potassium carbonate (250
mg, 1.8 mmol) in anhydrous DMSO (50 ml) under Nz was heated to 80°C and
Description 115 (8.7 g, 42 mmol) was added over 10 min. The reaction mixture
was then heated to 95°C for 20 min, cooled to 55°C and poured
into ice water. The
mixture was extracted twice with hexane and once with DCM. The combined
organic extracts were evaporated to give a solid (8 g, 100%). 1H NMR (400 MHz,
CDCls) 7.91 (1 H, d, J7.6), 8.84 (1 H, s).
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57
Description 117 3-Fluoro-5-trifluoromethvlpyridine-2-carboxamide
Description 116 (8 g, 42 mmol) was added to stirring conc. H~S04 (65m1) and
the
reaction mixture heated at 105°C for 2 hours, then cooled to room
temperature
and poured onto ice water. The solid which formed was collected by filtration
and
washed with a little water to give the title compound (5.8 g, 66%). 1H NMR
(400
MHz, DMSO-ds) 7.90 (1 H, s), 8.17 (1 H, s), 8.46 (1 H, d, J10.1), 8.88 (1 H,
s).
Description 118 3-Fluoro-5-trifluoromethylpyridin-2-amine
Bromine (630 ~.1, 1.3 mmol) was added to a solution of KOH (3.3 g, 58 mmol) in
water (30 ml) cooled at 0°C. The resulting yellow solution was stirred
for 5
minutes, then Description 117 (2 g, 9.6 mmol) was added in portions over 2
hours
and the reaction mixture stirred at room temperature for 5 days. The mixture
was then extracted 3 times with diethyl ether and the combined organic
extracts
dried over NaaSOa, filtered, and evaporated to give a solid (330 mg, 20%). 1H
NMR (400 MHz, CDCIa) 5.07 (2 H, s), 7.40 (1 H, dd, Jlo.4 and 1.6), 8.14 (1 H,
s).
Description 119 7-(6-Chloro-5-methvlpyrimidin-4-vl)auinoline
Prepared from 4,6-dichloro-5-methylpyrimidine and Description 11 according to
the procedure of Description 1 to give a solid (2.3 g, 58%). 1H NMR (400 MHz,
CDCIs) 2.53 (3 H, s), 7.50 (1 H, dd, J8.6 and 4.3), 7.79 (1 H, dd, J8.3 and
1.8),
7.98(lH,d,JS.4),8.24(lH,d,J8.4),8.2s(l H,s),8.94(lH,s),9.00(lH,dd,J
4.2 and 1.6). ,
Description 120 6-[4-Trifluoromethvlquinolin-7- T~1]p~rimidin-4-amine ~ --__ -
Prepared from Description 103 according to the procedures of Descriptions
27,.10,
and 11 respectively then reaction of the product with 6-chloropyrimidit~,4-
ami~e~,
according to the procedure of Description 1 to give a solid. 1H NMR (500
MHz,_. ~ .
CDCls) 5.03 (2 H, s), 5.65 (1H, s), 7.04 (1 H, s), 7.74 (1 H, d, J4.1), 8.25_
(1 H, d, _J
8.6),8.27(lH,s),8.39(IH,dJ8.8),9.10(lH,d,J4.2). :.' '...
..
Description 121 5-Met~l-6-[4-trifluoromethylquinolin-7-vl]pyrimidin-4-amine
Prepared from Description 103 according to the procedures of Descriptions 27,
10,
and 11 respectively then reaction of the product with 6-chloro-5-
methylpyrimidin-
4-amine according to the procedure of Description 1 to give a solid.1H NMR
(400
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58
MHz, DMSO-ds) 2.09 (3 H, s), 6.88 (2 H, s), 7.96-8.02 (2 H, m), 8.19 (1 H, dd,
J8.8
and 2.1), 8.30 (1 H, d, J 1.7), 8.36 (1 H, s), 9.19 (1 H, d, J4.3).
Description 125 4-Chloro-2-methyl-6-auinolin-7-ylpyrimidin-5-amine
Prepared from 4,6-dichloro-2-methylpyrimidin-5-amine and Description 11
according to the procedure of Description 1 to give a grey solid (64 mg, 17%).
1H
NMR (400 MHz, DMSO-ds) 2.50 (3H, s), 5.47 (2 H, s), 7.61 (1 H, dd, J8.2 and
4.1),
7.90 (1 H, dd, J8.5 and 1.8), 8.12 (1 H, d, J8.4), 8.37 (1 H, s), 8.44 (1 H,
d, J7.4),
8.98 (1 H, dd, J4.2 and 1.7).
Description 126 4-Chloro-6-methyl-N (4-trifluoromethylphenyl]-1,3,5-triazin-2-
amine
To a solution of 2,4-dichloro-6-methyltriazine (J Med Chem 805-18 (1999)] (0.3
g,
1.8 mmol) in anhydrous dioxane (4 ml) was added diisopropylethylamine (0.3 g,
2.3 mmol) followed by 4-trifluoromethylaniline (0.3 g, 1.9 mmol) and the
resulting
mixture heated at 140~C for 200 sets in a microwave apparatus. The mixture was
diluted with ethyl acetate (15 ml) and washed with 2N HCl (10 ml), sat. NaCI
(10
ml), dried over MgS04, f'~ltered and evaporated to give the title compound as
a
white solid after trituration with ether (0.25 g, 48 %). 1H NMR (360 MHz,
CDCIs)2.56 (3 H, s), 7.26 (1 H, s), 7.64 (2 H, d, J8.6), 7.75 (2 H, d, J8.6).
Description 127 4-Chloro-2-(1,1-dimeth l~yl)-5-methyl-6-quinolin-7-
ylpyrimidine
Prepared from 4,6-dichloro-2-(1,1-dimethylethyl)-5-methylpyrimidine and -
Description 11 according to the procedure of Description 1'to give a yellow
oil
(110 mg). 1H NMR (360 MHz, CDCls)1.44 (9 H, s), 2.49 (3 H, s), 7.49 (1 H, dd,
J
8.4 and 4.2), 7.83 (1 H, dd, J8.4 and 1.6), 7.95 (1 H, d, J8.4), 8.22 (1 H, d,
J8.4),
8.34 (l H,s),9.0(lH,d,Jl.6).
Description 128 4,6-Dichloro-2-iodometh~pyrimidine
A mixture of 4,6-dichloro-2-chloromethylpyrimidine [Annales Pharmaceutici
(Poznan) 12, 33-38, 1977] (3.3 g, 16.7 mmol) and sodium iodide (3.25 g, 21.7
mmol) in acetone (70 ml) was stirred at room temperature for 3 hours. The
reaction mixture was concentrated to dryness. The residue was dissolved in
ethyl
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59
acetate and the organic solution was washed with sodium thiosulfate solution
(aq), brine, dried over sodium sulfate, filtered and concentrated to give a
brown
solid (4.5 g, 93 %). 1H NMR (360 MHz, DMSO-ds) 4.53 (2 H, s), 7.93 (1 H, s).
Description 129 4-(4 6-Dichloropyrimidin-2-yl)meth lmorpholine
Description 128 (1.0 g, 3.46 mmol), morpholine (301 ~1, 3.46 mmol) and
potassium
carbonate (1.43 g, 10.4 mmol) in DMF (15 ml) were stirred at room temperature
for 18 hours. The mixture was diluted with ethyl acetate and washed with water
and brine, dried over sodium sulphate, filtered and concentrated. The residue
was purified by flash chromatography on silica gel eluting with 40:1 DCM -
MeOH to give an orange solid (318 mg, 37 %). 1H NMR (360 MHz, CDCIa) 2.63
(4H, m), 3.77 (6H, m), 7.32 (1 H, s).
Description 130 6-Chloro-2-(morpholin-4-,~lmethyl)-N-[4-
trifluorometh, l~phenyl]pvrimidin-4-amine
A mixture of Description 129 (252 mg, 1.02 mmol) and 4-trifluoromethylaniline
(128 ~l, 1.02 mmol) in ethanol (3 ml) was heated at 160°C for 90 rains
in a
microwave apparatus. The cooled mixture was diluted with ethyl acetate, washed
with sodium carbonate solution (aq), dried over sodium sulphate, filtered and
concentrated. The residue was purified by flash chromatography on silica gel
eluting with 2:1 ethyl acetate - isohexane. The product was then triturated
with a
mixture of diethyl ether and isohexane to give a pale brown solid (123 mg, 33
%).
1H NMR (500 MHz, CDCIs) _ . _.2.65 (4 H, m), 3.68 (2 H, s), 3.80 (4 H, m),
6:69.( 1 H, . ..
s),7.06(lH,brs),7.48(2H,d,J8.4),7.66(2H,d,J8.5). , ', - -.
_25 ;;~3
Description 131 ,~4,6-Dichloropvrimidin-2-yl)methvl acetate . '
A mixture of Description 128 (1.0 g, 3.46 mmol) and potassium acetate,(339
Wig, ""
3.46 mmol) in 50 % aqueous dioxane (40 ml) was stirred and heated
at~FO°C for.. .
18 hours. Further potassium acetate (339 mg, 3.46 mmol) was added arid the _ '
.
mixture was stirred and heated at 60°C for a further 18 hours. ~'he
cooled
mixture was diluted with ethyl acetate, washed with water, dried over sodium
sulphate, filtered and concentrated. The residue was purified by flash
chromatography on silica gel eluting with 10:1 isohexane - ethyl acetate to
give a
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colourless oil (600 mg, 78 %). 1H NMR (400 MHz, CDCIs) 2.22 (3 H, s), 5.24 (2
H,
s), 7.32 (1 H, s).
Descr~_ption 132 (4-Chloro-6-f4-trifluoromethvlphenylamino]pvrimidin-2-
5 yl)methanol
Prepared from Description 131 and 4-trifluoromethylaniline according to the
procedure of Description 130 to give a white solid (88 mg, 20 %). 1H NMR (360
MHz, DMSO-ds) 4.47 (2 H, d, J6.0), 5.33 (1 H, t, J6.4), 6.78 (1 H, s), 7.68 (2
H, d,
J8.6), 7.96 (2 H, d, J8.5), 10.20 (1 H, s).
Description 133 7-(6-Chloro-2-isopropyl-5-methylpyrimidin-4-yl)quinoline
Prepared from 4,6-dichloro-2-isopropyl-5-methylpyrimidine [WO-A-03087064]
and Description 11 according to the procedure of Example 109 except that the
reaction mixture was stirred and heated under reflux for 18 hours. 1H NMR (500
MHz, DMSO-ds) 1.32 (6 H, d, J6.9), 2.40 (3 H, s), 3.18-3.12 (1 H, m), 7.64 (1
H,
dd,J8.2and4.1),7.85(lH,m),8.14(lH,d,J8.4),8.27(lH,s),8.47(lH,d,J
7.8), 9.00 (1 H, dd, J4.1 and 1.6).
Description 134 7-[6-Chloro-2-methylthiopyrimidin-4-~quinoline
4,6-Dichloro-2-methylthiopyrimidine (0.99 g, 5.09 mmol), Description 11 (0.65
g,
2.54 mmol), [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) chloride (93
mg,
0.12 mmol) and 2M Na2COa(aq) (2.54 ml) were suspended in 1,4-dioxane (20 ml)
and heated to 100°C for 16 hours under nitrogen. After cooling to room
temperature the mixture was filtered through a pad of Celite~, washing the
residue ethyl acetate. The filtrate was concentrated under -reduced pressure
to
give a brown residue, which was partitioned between water and ethyl 'acetate. -
The aqueous phase was washed with ethyl acetate, the combined organic phases
were washed (brine), dried (sodium sulfate) and concentrated to give a dark-
brown oil, which was purified by flash chromatography using a Biotage-Horizon~
HPFC system (40S cartridge, gradient elution from 0-50% ethyl acetate /
isohexane) to give a pale yellow solid (0.47 g, 64%). 1H NMR (400 MHz, CDCla)
2.70 (3 H, s), 7.49 (1 H, dd, J8.3 and 4.2), 7.57 (1 H, s), 7.95 (1 H, d,
J8.6), 8.22-
8.28(2H,m),8.81(lH,s),9.00(lH,dd,J4.2and1.7).
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Description 136 6-Chloro-2-trifluoromethvl-N [4-trifluorometh~
phenyl] pyrimidin-4-amine
Prepared from 4,6-dichloro-2-trifluoromethylpyrimidine [US-A-4963678] and 4-
trifluoromethylaniline according to the procedure of Description 95 to give a
pale
yellow oil. 1H NMR (400 MHz, CDCls) 6.86 (1 H, s), 7.25 (1 H, br s), 7.55 (2
H, d, J
8.5), 7.70 (2 H, d, J8.5)~ mlz (ES+) 342 (M+H+).
Description 137 6-~uinoxalin-6-ylpyrimidin-4-amine
6-Bromoquinoxaline (210 mg, 1.44 mmol), potassium acetate (141 mg, 1.44
mmol), bis(pinacolato)diboron (383 mg, 1.51 mmol) and [l,1'-
bis(diphenylphosphino)ferrocene]palladium(II) chloride (52 mg, 0.072 mmol)
were
suspended in dioxane (10 ml) and heated to 100°C for 16 hours. 4-Amino-
6-
chloropyrimidine [WO-A-0245652] (186 mg, 1.44 mmol), [l,1'-
bis(diphenylphosphino)ferrocene]-palladium(II) chloride (52 mg, 0.072 mmol)
and
2M Na~COa(aq) (2m1) were added and the mixture was heated at 100 °C for
a
further 16 hours. The mixture was partitioned between EtOAc and water, the
aqueous phase was extracted with EtOAc, the combined organic phases were
washed (brine), dried (sodium sulfate) and concentrated under reduced
pressure.
The residue was triturated with EtOAc to give a white solid, which was used in
the next step without purification (170 mg).
Description 138 6-(6-Chloro-5-methylpvrimidin-4-~quinoxaline
Prepared from 6-bromoquinoxaline and 4,6-dichloro-5-methylpyrimidin_e " . _ ,
_"
according to the procedure of Description 137 to give an off white solid:(170
mg,
92%). 1H NMR (360 MHz, CDCla) 2.53 (3 H, s), 8.01 (1 H, d, J8~.;7), 8.27.(1,H,
da J
8.7), 8.31 (1 H, s), 8.95 (3 H, m)~ mlz (ES+) 257 (M+H+). .. , ; ; .
Description 139 5-Methyl-2-trifluorometh~pyrimidine-4,6-diol
To a suspension of sodium hydride (60% dispersion in oi.l) (52.5 g, 1311 mmol)
in
anhydrous toluene (400 ml) was added dropwise 1-butanol (118 -ml, 1311 mmol)
at such a rate so as to maintain the internal temperature at 40°C.
After complete
addition the mixture was stirred at room temperature overnight. To this
mixture
was added methyl malonamide (50 g, 430 mmol), followed by ethyl
trifluoroacetate (51.2 ml, 430 mmol), and the resulting mixture heated at
100°C
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for 3 hours, then stirred at room temperature overnight. The mixture was
extracted with water (3 x 300 ml), the combined water layers acidified to pH =
1
with conc. HCl and the resultant precipitate removed by filtration and dried
in-
vacuo to give the title compound as a white solid (35.5 g, 43%). 1H NMR (500
MHz, DMSO-ds) 1.96 (3 H, s), 12.40 (2 H, br s).
Description 140 4 6-Dichloro-5-methyl-2-trifluoromethylpyrimidine
To a mixture of Description 139 (15.00 g, 77.3 mmol) in phosphorous
oxychloride
(33.14 ml, 355.58 mmol) was added dropwise triethylamine (21.5 ml, 154.6
mmol). After complete addition the mixture was heated at 100°C for 3
hours. The
mixture was allowed to cool to room temperature and poured with stirring onto
ice/water (400 ml). The mixture was extracted with dichloromethane (3 x 100
ml),
the combined dichloromethane layers dried over Na2S04 , f"~ltered through a 2
inch plug of silica (washing with more dichloromethane) and evaporated to give
the title compound as a pale orange solid (8.5g, 48%). 1H NMR (500 MHz, CDCls)
2.58 (3 H, s).
Description 141 6-Chloro-5-methyl-2-trifluorometh,~lpyrimidin-4-amine
Prepared from Description 140 according to the procedure of Description 16 to
give a white solid (2.5 g, 32%). 1H NMR (500 MHz, DMSO-ds) 2.16 (3 H, s), 7.50
(1
H, br s), 8.00 (1 H, br s).
Description 142 5-Methyl-6-auinolin-7-yl-2-trifluorometh~pyrimictin-4-amine
Prepared from Description 141 and Description 11 according to the procedure of
Description 1 (490 mg, 68%). 1H NMR (400 MHz, DMSO-ds) 2.17 (3 H, s), 7 _62 (1
H, dd, J8.3 and 4.2), 7.77 (1 H, dd, J8.4 and 1.6), 8.11 (1 H, d, J8.4), 8.17
(1 H, d,
J0.6), 8.45 (1 H, d, J8.3), 8.99 (1 H, dd, J4.2 and 1,.2).
Example 1 4-Quinolin-8-yl-N-[4-trifluoromethylphenyllpyrimidin-2-amine
To a mixture of Description 1 (100 mg, 0.42 mmol) and 4-trifluoromethylaniline
(0.052 ml, 0.42 mmol) in anhydrous toluene (15 ml) was added sodiuvivtert-
butoxide (60 mg, 0.62 mmol) and 2'-(dimethylamino)-2-biphenylyl palladium (II)
chloride dinorbornylphosphine complex [Angew. Chem., 2002, 41, 3668 CAS
number 359803-53-5 (23 mg, 0.042 mmol), the mixture was degassed three
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times and heated at reflux overnight. The mixture was cooled and diluted with
dichloromethane (10 ml) and the resulting mixture loaded directly onto a
silica
gel chromatography column: (eluent 2% MeOH in DCM + 0.5% NH40H). The
product was further purified by mass-directed HPLC to give the title compound
as a white solid (15 mg, 10%).1H NMR (500 MHz, CDCIa) 7.37 (1 H, br s), 7.42
(1
H, dd, J8.3 and 4.2), 7.50 (1 H, d, J8.6), 7.64 (1 H, t, J7.9 and 7.6), 7.68
(1 H, d,
J4.9), 7.77 (1 H, d, J8.6), 7.90 (1 H, dd, J8.3 and 1.2), 8.18-8.21 (2 H, m),
8.51 (1
H, d, J5.2), 8.93 (1 H, dd, J3.9 and 1.7)~ mlz (ES+) 367 (M+H+).
Example 2 6-Quinolin-8-yl-N-~4-trifluorometh~phenyl~pyrazin-2-amine
To a mixture of Description 2 (200 mg, 0.83 mmol) and 4-trifluoromethylaniline
(0.104 ml, 0.83 mmol) in anhydrous 1,4-dioxane (15 ml) was added cesium
carbonate (379 mg, 1.16 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
(29 mg, 0.05 mmol), and Pd2(dba)a (15 mg, 0.017 mmol). The mixture was de-
gassed three times and heated at reflux overnight. The mixture was cooled,
diluted with dichloromethane (10 ml), filtered through hyflo and the filtrate
loaded directly onto a silica gel chromatography column: (eluent 2% MeOH in
DCM + 0.5% NH40H). The product was further purified by mass-directed HPLC
to give the title compound as a white solid (20 mg, 6.5%). 1H NMR (500 MHz,
CDCls) 6.92 (1 H, br s), 7.49 (1 H, dd, J8.3 and 4.2), 7.56 (2 H, d, J8.6),
7.68 (2 H,
d, J8.6), 7.71 (1 H, d, J7.6), 7.95 (1 H, dd, J8.3 and 1.3), 8.17 (1 H, dd,
J7.~k and
1.5), 8.25-8.27 (2 H, m), 8.95 (1 H, s), 9.00 (1 H, dd, J4.2 and 1.7)a mlz
(ES+) 367.
(M+H+). _ .
The following compounds were made by the procedure of Example 2: ~ .
Example 3 5-~uinolin-8-yl-N-C4-trifluoromethylphenyl]pyridazin-3-ainine
Prepared from Description 5 and 4-trifluoromethylaniline to give a white solid
(9
mg, 3%). 1H NMR (500 MHz, DMSO-ds) 7.57 (1 H, d, J1.7), 7.66 (1 H, dd,,J8.~3
and 4.2), 7.70 (1 H, d, J8.8), 7.79 (1 H, t, J8.1 and 7.4), 8.00 (1 H, dd,
J7:1 arid . . .
1.3), 8.05 (1 H, d, J8.3), 8.17 (1 H, d, J8.3), 8.52 (1 H, dd, J8.3 and 1.7),
9.00 (1
H, dd, J4.0 and 1.8), 9.08 (1 H, d, J1.7), 9.81 (1 H, s)~ m/z(ES+) 367 (M+H+).
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Example 4 6-~uinolin-8-yl-N-[4-trifluoromethylphenyllpyrimidin-4-amine
Prepared from Description 6 and 4-trifluoromethylaniline to give a white solid
(G
mg, 4%). 1H NMR (500 MHz, CDCIa) 7.47 (1 H, dd, J8.3 and 4.2), 7.56 (2 H, d, J
8.8), 7.62 (2 H, d, J8.8), 7.71 (1 H, t, J7.9 and 7.G), 7.78 (1 H, s), 7.82 (1
H, s),
7.94 (1 H, dd, J8.3 and 1.3), 8.26 (1 H, dd, J8.3 and 1.5), 8.32 (1 H, dd,
J7.4 and
1.3), 8.87 (1 H, s), 8.94 (1 H, dd, J4.2 and 1.7)~ mlz (ES+) 367 (M+H+).
Example 5 6-Quinolin-7-yl-N-[4-trifluoromethylphenyllpyrazin-2-amine
Prepared from Description 12 and 4-trifluoromethylaniline to give a pale
yellow
solid (70 mg, 7%). 1H NMR (500 MHz, CDCls) 6.87(1 H, br s), 7.47 (1 H, dd,
J8.3
and 4.2), 7.66 (2 H, d, JB.G), 7.77 (2 H, d, JB.G), 7.97 (1 H, d, JB.G), 8.21-
8.26 (3
H, m), 8.74 (2 H, s), 9.00 (1 H, dd, J4.2 and 1.7)~ mlz (ES+) 367 (M+H+).
Example 6 4-Q.uinolin-7-yl-N-[4-trifluoromethylphenvllpvrimidin-2-amine
Prepared from Description 13 and 4-trifluoromethylaniline to give a white
solid
(55 mg, 18%). 1H NMR (500 MHz, CDCla) 7.43 (2 H, d, J5.2), 7.46 (1 H, br s),
7.49
(1 H, dd, J8.1 and 4.2), 7.63 (2 H, d, JB.G), 7.88 (2 H, d, JB.G), 7.97 (1 H,
d, JB.G),
8.23(lH,d,J8.3),8.31(lH,dd,J8.6and1.7),8.59(lH,d,J5.4),8.78(lH,s),
9.00 (1 H, dd, J4.2 and 1.7)~ mlz (ES+) 367 (M+H+).
Example 7 6-Quinolin-7-yl-N-[4-trifluoromethylphenyllpyrimidin-4-amine
Prepared from Description 14 and 4-trifluoromethylbromobenzene to give a white
solid (180 mg, 60%). 1H NMR (500 MHz, CDCla) 7.12 (1 H, br s), 7.35 (1 H; d; J
1.2), 7.47 (1 H, dd, J8.2 and 4.3), 7.65 (4 H, q, JB.G), 7.95 (1 H., d, JB.G),
8.21 (1' ~:'_
H, dd, J8.6 and 1.2), 8.31 (1 H, dd, J8.6 and 1.G), 8.63 (1-.H, d,-J1.G), 8.91
(1 H, d,
J1.2), 8.98 (1 H, dd, J4.3 and 2.0)~ mlz(ES+) 367 (M+H+). - ' .
Example 8 5-Quinolin-7-yl-N-[4-trifluoromethylnhenyllpyridazin-3-amine v
Prepared from Description 15 and 4-trifluoromethylaniline to give a pale
yellow
solid (25 mg, 8%). 1H NMR (500 MHz, DMSO-ds) 7.60 (lFi;e d, J2.0), 7.63 (1 H,
dd,
J8.4 and 4.2), 7.70 (2 H, d, JB.G), 8.04 (3 H, m), 8.20 (1 H, d, J8.G),
8.47'(1 H, d,
J8.1), 8.49 (1 H, s), 9.01 (1 H, dd, J4.2 and 1.5), 9.35 (1 H, d, J2.0), 9.83
(1 H, s)~
mlz (ES+) 367 (M+H+).
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Example 9 6-~uinolin-7-yl-N-[5-trifluoromethylpvridin-2-yl]pyrimidin-4-amine
Prepared from Description 14 and 2-bromo-5-trifluoromethylpyridine to give a
white solid (100 mg, 60%). 1H NMR (500 MHz, CDCIs) 7.48 (1 H, dd, J8.3 and
4.2), 7.73 (1 H, d, J8.8), 7.79 (1 H, br s), 7.90 (1 H, dd, J8.7 and 2.2),
7.97 (1 H, d,
5 J8.6),8.23(lH,d,J7.7),8.31(lH,s),8.36(lH,dd,J8.5and1.7),8.67(1H,S),
8.80 (1 H, s), 9.00 (1 H, s), 9.01 (1 H, d, J 1.7)~ mlz (ES+) 368 (M+H+).
Example 10 6-~uinolin-7-vl-N-[6-trifluoromethvlpyridin-3-yl]pvrimidin-4-amine
Prepared from Description 14 and 3-bromo-6-trifluoromethylpyridine to give a
10 white solid (120 mg, 72%). 1H NMR (500 MHz, DMSO-ds) 7.57 (1 H, s), 7.62 (1
H,
dd, J8.3 and 4.2), 7.89 (1 H, d, J8.7), 8.15 (1 H, d, J8.6), 8.27 (1 H, dd,
J8.6 and
1.7), 8.45 (1 H, d, J8.1), 8.59 (1 H, dd, J8.6 and 2.2), 8.69 (1 H, s), 8.91
(1 H, s),
9.00 (2 H, s), 10.38 (1 H, br s)~ mlz (ES+) 368 (M+H+).
15 Example 11 5-Methox~quinolin-7-yl-N-[4-trifluorometh~phenyl]pyrimidin-4-
amore
Prepared from Description 17 and 4-trifluoromethylbromobenzene to give a white
solid (80 mg, 26%). 1H NMR (400 MHz, CDCls) 3.66 (3 H, s), 7.48 (1 H, dd, J8.3
and 4.2), 7.64 (1 H, d, J8.6), 7.67 (1 H, br s), 7.92 (1 H, d, J8.6), 7.96 (1
H, d, J
20 8.6)a 8.23 (1 H, dd, J8.6 and 1.6), 8.68 (1 H, s), 8.83 (1 H, s), 8.97 (1
H, d, J1.6)
mlz (ES+) 397 (M+H+). , , .. ,
Example 12 5-Methyl-6-auinolin-7-yl-N-[4-trifluoromethylphenvl]pyrimidin-4-"
amore
25 Prepared from Description 19 and 4-trifluoromethylbromobenzene to give.a
white-
solid (190 mg, 59%). 1H NMR (400 MHz, CDCls) 2.38 (3 H, s), 6.80 (1 H;
:br.s),.:7.47
(1 H, dd, J8.2 and 4.2), 7.64 (2 H, d, J8.6), 7.79-7.85 (2 H, m), 7.96 (1, H,
d, J8.4), w
8.22 (1 H, d, J1.5), 8.23 (1 H, d), 8.80 (1 H, s), 8.97 (1 H, d, J1.7)~
m/z(ES~) 381:'.., .:
(M+H+). : . ,
Example 13 5-Fluoro-6-guinolin-7-yl-N-[4-trifluoromethylphenvl]pyrimidiri-4-
amine
Prepared from Description 21 and 4-trifluoromethylbromobenzene to give a white
solid (194 mg, 61%).1H NMR (400 MHz, CDCl3) 7.27 (1 H, d, J3.1), 7.49 (1 H,
dd,
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J8.2 and 4.3), 7.66 (2 H, d, J8.6), 7.90 (2 H, d, J8.6), 7.98 (1 H, d, J8.6),
8.23 (1
H,d,J8.2),8.29(lH,d,J8.6),8.70(lH,d,Jl.6),8.83(lH,s),9.00(lH,dd,J
4.3 and 1.6)~ mlz (ES+) 385 (M+H+).
Example 14 2-Methox~quinolin-7-yl-N-[4-trifluoromethy~henyllpyrimidin-4-
amine
Prepared from Description 23 and 4-trifluoromethylbromobenzene to give an off
white solid (130 mg, 41%). 1H NMR (400 MHz, CDCls) 4.11 (3 H, s), 7.00 (1 H,
s),
7.38 (1 H, br s), 7.45 (1 H, dd, J8.2 and 4.3), 7.64 (4 H, s), 7.90 (1 H, d,
J8.6), 8.19
(lH,d,J7.4),8.27(lH,dd,J8.6and1.6),8.69(lH,s),8.96(lH,dd,J4.3and
2.0)~ mlz (ES+) 397 (M+H+).
Example 15 2-Meth~quinolin-7-yl-N-[4-trifluoromethylphenyl]pyrimidin-4-
amine
Prepared from Description 25 and 4-trifluoromethylbromobenzene to give an off
white solid (190 mg, 59%). 1H NMR (400 MHz, CDCla) 2.72 (3 H, s), 7.01 (1 H,
br
s), 7.18 (1 H, s), 7.45 (1 H, dd, J8.2 and 4.3), 7.61 (2 H, d, J8.6), 7.66 (2
H, d, J
8.6), 7.93 (1 H, d, J8.2), 8.20 (1 H, d, J8.2), 8.30 (1 H, dd, J8.6 and 2.0),
8.63 (1
H, s), 8.97 (1 H, dd, J4.3 and 2.0)~ m/z (ES+) 381 (M+H+).
Example 16 6-(3-Methylquinolin-7-yl)-N-[4-trifluoromethylphenyl]pyrimidin-4-
amine
Prepared from Description 28 and 4-trifluoromethylbromobenzene to~give a.white
solid (90 mg, 28%). 1H NMR (360 MHz, CDCls) 2.55 (3 H, s), 7.17 (1 H, br
s),_7.33'-
(1 H, s), 7.33 (1 H, s), 7.86 (1 H, d, J8.4), 7.96 (1 H, s), 8:26 (1 H, dd,
J8.4' arid
1.7), 8.59 (1 H, s), 8.82 (1 H, d, J2.1), 8.89 (1 H, s)~ mlz (ES+) 381
(1VI+H+).
Example 17 6-Quinolin-5-yl-N-[4-trifluoromethylphen~yrimidin-4-amine
Prepared from Description 30 and 4-trifluoromethylaniline to give a white
solid.
1H NMR (400 MHz DMSO-ds) 7.16 (1 H, d, J1.2), 7.59 (1 H, dd, J4.2 and 8.8),
7.72 (2 H, d, J8.8), 7.83 (1 H, dd, J 7.1 and 1.2), 7.88-7.91 (1 H, m), 8.01
(2 H; d,
J8.6), 8.17 (1 H, d, J8.3), 8.69 (1H, d, J8.6), 8.90 (1 H, d, J1.2), 8.98 (1
H, dd, J
3.9 and 1.7), 10.20 (1 H, s)~ mlz (ES+) 367 (M+H+).
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Example 18 6-~uinolin-6-yl-N- 4-trifluoromethylphenyl]pyrimidin-4-amine
Prepared from Description 31 and 4-trifluoromethylbromobenzene to give a white
solid. 1H NMR (400 MHz, DMSO-ds) 7.52 (1 H, d, J1.2), 7.63 (1 H, dd, J8.3 and
4.2), 7.72 (2 H, d, J8.6), 8.00 (2 H, d, J8.6), 8.18 (1 H, d, J8.8), 8.40 (1
H, dd, J
8.8 and 2.2), 8.57 (1 H, dd, J8.3 and 1.2), 8.75 (1 H, d, J2.0), 8.88 (1 H, d,
J1.2),
8.99 (1 H, dd, J4.2 and 1.7), 10.21 (1 H, s)~ mlz (ES+) 367 (M+H+).
Example 19 6-(2-Methylquinolin-7-yl)-N-[4-trifluoromethylphenyllpyrimidin-4-
amine
Prepared from Description 33 and 4-trifluoromethylbromobenzene to give a white
solid. 1H NMR (400 MHz, DMSO-ds) 2.70 (3 H, s), 7.49-7.52 (2 H, m), 7.72 (2 H,
d,
J8.8),8.00(2H,d,J8.6),8.08(lH,d,J8.6),8.17-8.19(lH,m),8.32 (l H,d,J
8.6), 8.58 (1 H, s), 8.88 (1 H, d, J 1.0), 10.15 (1 H, s)~ mlz (ES+) 381
(M+H+).
Example 20 6-(6-Fluoroquinolin-7-yl)-N[4-trifluoromethylphenyl]pvrimidin-4-
amine
Prepared from Description 39 and 4-trifluoromethylbromobenzene to give a white
solid (28 mg, 43%). 1H NMR (400 MHz, DMSO-ds) 7.49 (1 H, s), 7.63-7.67 (1 H,
m), 7.72 (2 H, d, J8.4), 8.01 (3 H, m), 8.44 (1 H, dd, J8.4 and 1.1), 8.75 (1
H, d, J
7.4), 8.91 (1 H, d, J1.1), 8.99 (1 H, dd, J4.2 and 1.8), 10.25 (1 H, s)~
m/z(ES+) 385
(M+H+). , ,.
Example 21 6-(8-F'luoroquinolin-7-yl)-N-[4-trifluorometh~phenyl]pyrimidiii-4-
amine
Prepared from Description 41 and 4-trifluoromethylbromobenzene to give a white
solid. 1H NMR (400 MHz DMSO-ds) 7.60 (1 H, s), 7.71-7.74 (3 H, m), 7..96 :(1H;
d;~.: :-
J8.6), 8.01 (2 H, d, J8.6), 8.28 (1 H, dd, J8.6 and 7.0), 8.52 (1 H, d, J8.6);
8:92 (1
H, d, J1.2), 9.06 (1 H, dd, J4.3 and 1.6), 10.27 (1 H, s)~ .mlz (ES+) 385
'(M+H~)'.
Example 22 N-[4-(trifluoromethyl)phenyl]-6-[6-trifluoromethylquinolin-7- -
y1] pyrimidin-4-amine
Prepared from Description 42 and 4-trifluoromethylbromobenzene to give an off
white solid (110 mg , 36%). 1H NMR (400 MHz, CDCls) 6.96 (1 H, s), 7.47 (1 H,
dd,
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J8.4 and 4.3), 7.61 (4 H, s), 7.66 (1 H, br s), 8.21 (1 H, s), 8.30-8.32 (2 H,
m), 8.87
(1 H, d, J1.0), 9.07 (1 H, dd, J4.3 and 1.7)~ mlz(ES+) 435 (M+H+).
Example 23 6-(8-Methvlctuinolin-7-yl)-N-[4-trifluoromethylphenyllpvrimidin-4-
amine
Prepared from Description 44 and 4-trifluoromethylbromobenzene to give a white
solid (190 mg , 59%). 1H NMR (400 MHz, CDCls) 2.87 (3 H, s), 6.91 (1 H, d,
J1.1),
7.26 (1 H, br s), 7.46 (1 H, dd, J8.2 and 4.3), 7.59-7.61 (5 H, m), 7.75 (1 H,
d, J
8.2), 8.17 (1 H, dd, J8.2 and 2.0), 8.91 (1 H, d, J1.1), 9.00 (1 H, dd, J4.3
and 2.0)~
mlz (ES+) 381 (M+H+).
Example 24 5-Fluoro-6-(8-methylquinolin-7-yl)-N-[4-trifluorometh~phenyll
pyrimidin-4-amine
Prepared from Description 45 and 4-trifluoromethylbromobenzene to give a white
solid (155 mg , 49%). 1H NMR (500 MHz, CDCla) 2.80 (3 H, s), 7.21 (1 H, br s),
7.49 (1 H, dd, J8.3 and 4.2), 7.58 (1 H, d, J8.5), 7.66 (2 H, d, J8.6), 7.79
(1 H, d, J
8.5), 7.90 (2 H, d, J8.6), 8.19 (1 H, dd, J8.3 and 1.7), 8.71 (1 H, d, J1.6),
9.03 (1
H, dd, J4.2 and 1.7)~ mlz (ES*) 399 (M+H+).
Example 25 6-Isoquinolin-7-yl-N-[4-trifluorometh~phenyllpyrimidin-4-amine
Prepared from Description 46 and 4-trifluoromethylbromobenzene to give a white
solid. 1H NMR (500 MHz DMSO-ds) 7.52 (1 H, s), 7.72 (2 H, d, J8.8), 7.93 (1 H,
d,
J5.6), 8.00 (2 H, d, J8.6), 8.15 (1 H, d, J8.6), 8.43 (1 H, dd, J8:7 and
1_6),.8.59_(1..
H, d, J5.6), 8.88 (2 H, d, J8.6), 9.51 (1 H, s), 10.21 (1 H, s)~ mlz (ES+) 367
(M+I3+).
_ . ' . .. . , . .
Example 26 6-fluinolin-8-yl-N-[4-trifluorometh,~lphenyllpyridazin-4=amine .
A mixture of Description 8 (100 mg, 0.38 mmol), quinoline-8-boronic
acid.(l2fi.mg,
0.73 mmol), 2M sodium carbonate (0.365 ml, 0.73 mmol), and Pd(dpp~Cl2 (l0~mg;'
0.011 mmol) was heated at 170°C for 40 rains in a Smith microwave
reactor. The
mixture was diluted with dichloromethane (20 ml) and washed with water (2 x 20
ml), sat. NaCl (15 ml), dried over NasS04 , altered and evaporated. The
residue
was purified by PREP-TLC: (eluent 10% MeOH in DCM + 0.5% NH40H), followed
by mass-directed HPLC to give the title compound as a white solid (9 ing,
6.7%).
1H NMR (500 MHz, DMSO-ds) 7.53 (2 H, d, J8.3), 7.63 (1 H, dd, J8.4 and 4.2),
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7.72(2H,d,J8.3),7.78(lH,t,J7.8and7.4),7.99(lH,d,J2.7),8.15(lH,d,J
8.3), 8.23 (1 H, dd, J7.1 and 1.2), 8.51 (1 H, dd, J8.3 and 1.7), 9.00 (1 H,
d, J2.7),
9.04 (1 H, dd, J4.2 and 1.7), 9.66 (1 H, s)~ mlz (ES+) 367 (M+H+).
Example 27 4-Quinolin-8-Yl-N-[4-trifluoromethylphenyl]-1,3,5-triazin-2-amine
To a mixture of Description 9 (790 mg, 2.89 mmol), quinoline-8-boronic acid
(500 mg, 2.89 mmol) and 2M Sodium carbonate (2.89 ml, 5.78 mmol) in a
mixture of toluene (50 ml) and ethanol (10 ml) was added Pd(PPhs)4 (171 mg,
0.14
mmol), the mixture degassed three times and heated at reflux overnight. The
reaction mixture was cooled and diluted with EtOAc (50 ml), washed with water
(2 x 100 ml), sat NaCI (100 ml), dried over Na2SOa , filtered and evaporated.
The
residue was purified by column chromatography on silica: (eluent 2% MeOH in
DCM + 0.5% NHaOH), and product further purified by mass-directed HPLC to
give the title compound as a white solid (3.4 mg, 0.32%). 1H NMR (500 MHz,
CDCla) 7.51 (1 H, dd, J8.4 and 4.2), 7.60 (2 H, d, J8.3), 7.68 (2 H, m), 7.86
(2 H,
d, J8.3), 8.01 (1 H, dd, J8.1 and 1.2), 8.17 (1 H, m), 8.26 (1 H, dd, J8.3 and
1.3),
8.99 (1 H, s), 9.02 (1 H, m)~ mlz (ES+) 368 (M+H+)
Example 28 5-Nitro-6-quinolin-7-yl-N-[4-trifluoromethylphenyl]pyrimidin-4-
amine
To a mixture of Description 29 (2.01 g, 6.3 mmol) and Description 11 (2.41 g,
9.45 mmol) in a mixture of toluene (50 ml) and ethanol (10 ml) was.added 2M.
sodium carbonate (3.15 ml, 6.3 mmol) and Pd(PPha)4 (364 mg, 0.315 mmol). The
mixture was degassed three times and heated at reflux overnight. The cooled
mixture was diluted with EtOAc (100 ml) and washed with water (2,00 ml),.
sat..
NaCl (100 ml), dried over Na~S04, filtered and evaporated. The residue was .
..-:
purified by column chromatography on silica: (eluent 1% MeOH in DCM +0:5%
NHs) then a second column (eluent 20% EtOAc in iso-hexanes). The product .
triturated with diethyl ether to give the title compound as a pale yellow
solid (100
mg, 4%). 1H NMR (500 MHz, CDCIa) 7.50 (1 H, dd, J8.3 and 4.2), 7.70 (2 H, d, J
8.1), 7.72 (1 H, dd, J8.6 and 1.7), 7.81 (2 H, d, J8.1), 7.95 (1 H, d, J8.6),
8.24 (1
H, d, J7.6), 8.36 (1 H, s), 8.87 (1 H, s), 9.00 (1 H, dd, J4.2 and 1.7)~ mlz
(ES+) 412
(M+H+).
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Example 29 6-~uinolin-7-vl-N4-(4-trifluoromethylnhenvllpyrimidine-4 5-
diamine
To a nitrogen flushed solution of Example 28 (80 mg, 0.195 mmol) in a mixture
of
methanol (5 ml) and dichloromethane (5 ml) was added 10% Palladium on carbon
5 (10 mg) and the resulting mixture stirred under a balloon of hydrogen for 2
hours. The catalyst was removed by filtration and the filtrate evaporated. The
residue was crystallised from dichloromethane/diethyl ether to give 60 mg
(Yield
80%) as an off white solid. 1H NMR (500 MHz, DMSO-ds) 5.31 (2 H, br s), 7.60
(1
H, dd, J 8.3 and 4.2), 7.69 (2 H, d, J 8.7), 7.91 ( 1 H, dd, J 8.4 and 1.6),
8.03 (2 H, d,
10 J8.7),8.11(lH,d,J8.4),8.27(lH,s),8.34(lH,s),8.43(lH,d,J7.5),8.93(1
H, s), 8.97 (1 H, dd, J4.2 and 1.7)~ mlz (ES+) 382 (M+H+).
Examples 30-51 were made from the indicated compounds according to the
procedure of Example 2.
Example 30 6-(8-Fluoroguinolin-7-yl)-5-methyl-N [5-trifluoromethylpyridin-2-
~pyrimidin-4-amine
Description 47 and 2-bromo-5-trifluoromethylpyridine gave a solid (171 mg,
72%).
1H NMR (400 MHz, DMSO-ds) 2.23 (3 H, d, J 2.2), 7.68 (1 H, dd, J8.4 and 6.5),
7.73 (1 H, dd, J8.4 and 4.2), 7.97 (1 H, d, J8.5), 8.19 (1 H, dd, J9.0 and
2.4), 8.39
(lH,d,J8.8),8.54(lH,d,JS.4),8.73(lH,s),8.81(lH,s),9.04(lH,dd,J4.2
and 1.6), 9.66 (1 H, s>; mlz (ES+) 400 (M+H+).
Example 31 6-(8-Fluoroquinolin-7-yl)-5-methyl-N (4-trifluoromethylphenyll ~ .
~ .
pyrimidin-4-amine ~o
Description 47 and 4-trifluoromethylbromobenzene gave a_white solid (22 mg;-
14%). 1H NMR (400 MHz, DMSO-ds) 2.19 (3 H, d, J2.2), 7.74-7.66 (4 H, m), 7.:96
(1 H, d, J8.5), 8.03 (2 H, d, J8.5), 8.54 (1 H, d, J8.4), 8.68 (1 H,Ts),
8.99'(1 H,-
s),9.04 (1 H, dd, J4.1 and 1.6~ mlz (ES+) 399 (M+H+).
-. . .
Example 32 'S-Methoxy-2-methyl-6-guinolin-7-yl-N [4-trifluoromethylphenyll
pyrimidin-4-amine
Description 51 and 4-trifluoromethylbromobenzene gave a white solid (78 mg,
51%). 1H NMR (400 MHz, DMSO-ds) 2.57 (3 H, s), 3.55 (3 H, s), 7.62-7.60 (1 H,
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dd, J8.3 and 4.1), 7.71 (2 H, d, J8.7), 8.24-8.12 (4 H, m), 8.45 (1 H, d,
J7.7), 8.68
(1 H, s), 8.99 (1 H, dd, J4.1 and 1.6), 9.52 (1 H, s)~ mlz (ES+) 411 (M+H+).
Example 33 2-Methyl-6-(8-methylauinolin-7-vl)-N [4-trifluorometh~ henvl]
pyrimidin-4-amine
Description 52 and 4-trifluoromethylbromobenzene gave a white solid (110 mg,
45%). 1H NMR (400 MHz, DMSO-ds) 2.60 (3 H, s), 2.80 (3 H, s), 6.88 (1 H, s),
7.59-
7.71(4H,m),7.92(lH,d,J8.4),8.01(2H,d,J8.3),8.41(lH,d,J7.9),9.01(1
H, d, J2.3), 10.02 (1 H, s)~ mlz (ES+) 395 (M+H+).
Example 34 N[2-Fluoro-4-trifluorometh~lphenvl]-5-methox~quinolin-7-yl
pyrimidin-4-amine
Description 17 and 1-bromo-2-fluoro-4-trifluoromethylbenzene gave a white
solid
(80 mg, 48%). 1H NMR (400 MHz, CDCla) 3.68 (3 H, s), 7.43 (1 H, dd, J9.5 and
1.5), 7.47-7.51 (2 H, m), 7.91 (1 H, J3.2), 7.97 (1 H, J$.6), 8.21-8.24 (2 H,
m), 8.71
(1 H, s), 8.85 (1 H, s), 8.94 (1 H, t, J8.3), 9.00 (1 H, dd, J4.2 and 1.7)~
mlz (ES+)
415 (M+H+).
Example 35 5-Methoxy-6-quinolin-7-vl-N [4-trifluoromethoxyphen T~1]pvrimidin-
4-amine
Description 17 and 1-bromo-4-trifluoromethoxybenzene gave a white solid (50
mg,
30%). 1H NMR (400 MHz, CDCla) 3.64 (3 H, s), 7.25 (2 H, d, J9.0), 7.48 (1 H~
dd, J
8.1 and 4.2), 7.79 (2 H, d, J9.0), 7.96 (1 H, d, J8.6), 8.23 (1 H, m), 8.64.
(1 H, s),.. .
8.84 (1 H, s), 9.00 (1 H, dd, J4.2 and 1.5)~ mlz (ES+) 413 (M+H+). ~ , _ ,
Example 36 5-Methyl-6-(8-methylquinolin-7-vl)-N [4-trifluoromethvlphen ~~l]
pyrimidin-4-amine
Description 53 and 4-trifluoromethylbromobenzene gave a white solid (150 mg, -
63%). 1H NMR (400 MHz, CDCla) 2.09 (3 H, s), 2.65 (3 H, s), 6.69 (1 H, br s),
7.42
(1 H, d, J8.4), 7.47 (1 H, dd, J8.2 and 4.2), 7.65 (2 H, d, J8.6), 7.78 (1 H,
d, J8.4),
7.85(2H,d,J8.6),8.19(lH,dd,J8.2and1.8),8.80(lH,s),9.01(lH,dd,J4.2
and 1.8)~ mlz (ES+) 395 (M+H+).
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Example 37 5-Methyl-6-(8-methylquinolin-7-yl)-N-[5-trifluoromethyltwridin-2-
yll ~yrimidin-4-amine
Description 53 and 2-bromo-5-trifluoromethylpyridine gave a white solid (150
mg,
63%). 1H NMR (500 MHz, CDCIa) 2.14 (3 H, s), 2.64 (3 H, s), 7.41 (1 H; d,
J8.4),
7.48 (1 H, dd, J8.3 and 4.2), 7.62 (1 H, s), 7.78 (1 .H, d, J8.3), 7.98 (1 H,
dd, J8.9
and 2.0), 8.20 (1 H, dd, J8.2 and 1.6), 8.56 (1 H, s), 8.83 (1 H, d, J8.8),
8.87 (1 H,
s), 9.02 (1 H, dd, J4.2 and 1.6)~ mlz (ES+) 396 (M+H+).
Example 38 6-~uinolin-7-yl-5-trifluoromethyl-N [4-trifluorometh~t~henyl~
pyrimidin-4-amine
Description 57 and 4-trifluoromethylbromobenzene gave a white solid (28 mg,
19%). 1H NMR (400 MHz, CDCls) 7.41 (1 H, s), 7.47 (1 H, dd, J8.1 and 4.3),
7.66
(2H,d,J8.4),7.75(lH,d,J8.4),7.92(lH,d,J8.6),8.21 (l H, d,J8.4),8.85(1
H, s), 8.98 (1 H, dd, J4.3 and 1.5)~ mlz (ES+) 435 (M+H+).
Example 39 5-Ethvl-6-auinolin-7-yl-N [4-trifluoromethylphenyllpyrimidin-4-
amine
Description 59 and 4-trifluoromethylbromobenzene gave a white solid (250 mg,
77%). 1H NMR (400 MHz, DMSO-ds) 1.09 (3 H, t, J7.4), 2.79 (2 H, q, J7.4), 7.62
(1 H, dd, J8.3 and 4.2), 7.71 (3 H, d, J8.5), 8.01 (2 H, d, J8:5), 8.09 (1 ~H,
s), 8.11
(1 H, d, J8.4), 8.46 (1 H, d, J8.3), 8.63 (1 H, s), 8.94 (1 H,_ s), ~8.9~ (1
H, dd, J4.2
and 1.7)~ mlz (ES+) 395 (M+H+). , . . , -
','. ~._. ..... ~..~ . . . _. .:
Example 40 5-Ethyl-6-auinolin-7-yl-N [5-trifluoroinetliylpyridin-2-
yllpyrimidin-
4-amine .. . - . _.= __ : _ .
Description 59 and 2-bromo-5-trifluoromethylpyridine gave a white solid (175
~mg,
55%). 1H NMR (500 MHz, CDCla) 1.34 (3 H, t, J7.6), 2.80 (2 H, d; J7.C); 7.48
~(1
H, dd, J8.3 and 4.2), 7.69-7.72 (2 H, m), 7:95-7.98 (2 H, m), 8.21'(1 H, s),
8.23 (1
H,d,J8.0),8.55(lH,s),8.81(lH,d,J8.8),-8.86(lH,s),8.99(lH;dd,J4.2ands
1.7)~ mlz (ES+) 396 (M+H+).
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Example 41 5-Methyl-6-auinolin-7-vl-N(5-trifluoromethylpyridin-2-vl]pvrimidin-
4-amine
Description 19 and 2-bromo-5-trifluoromethylpyridine gave a white solid (180
mg,
55%). 1H NMR (500 MHz, CDCla) 2.43 (3 H, s), 7.48 (1 H, dd, J8.3 and 4.2),
7.66
(1 H, s), 7.80 (1 H, dd, J8.4 and 1.5), 7.97 (2 H, d, J8.5), 8.23 (2H, m),
8.56 (1 H,
s), 8.80 (1 H, d, J8.8), 8.87 (1 H, s), 9.00 (1 H, dd, J4.2 and 1.5)~ m/z
(ES+) 382
(M+H+).
Example 42 2-C~propyl-5-methy 1-6-quinolin-7-yl-N [5-trifluoromethylpyridin-
2-vl] pvrimidin-4-amine
Description 61 and 2-bromo-5-trifluoromethylpyridine gave a white solid (120
mg,
40%). 1H NMR (500 MHz, CDCIs) 1.08 (2 H, m), 1.19 (2 H, m), 2.26 (1 H, m),
2.34
(3 H, m), 7.46 (1 H, dd, J8.2 and 4.2), 7.58 (1 H, s), 7.78 (1 H, d, J8.3),
7.93-7.97
(2 H, m), 8.21 (2 H, m), 8.54 (1 H, s), 8.71 (1 H, d, J8.8), 8.98 (1 H, d,
J2.9)~ mlz
(ES+) 422 (M+H+).
Example 43 2-Cyclopropyl-5-methvl-6-quinolin-7-yl-N (4-trifluoromethylphen
~~l]
pyrimidin-4-amine
Description 61 and 4-trifluoromethylbromobenzene gave a white solid (150 mg,
50%). 1H NMR (500 MHz, CDCls) 1.01-1.04 (2 H, m), 1.14-1.17 (2 H, m), 2.20-
2.23
(1 H, m), 2.29 (3 H, s), 6.69 (1 H, s), 7.45 (1 H, dd, J8.2 and 4.2), 7.62 (2
H, d, J
8.6), 7.78 (1 H, dd, J8.3 and 1.3), 7.83 (2 H, d, J8.6), 7.93 (1 H, d, J8.4),
8.21 (2
H, m), 8.97 (1 H, s)~ mlz (ES+) 423 (M+H+).
Example 44 5-Isopropyl-6-auinolin-7-yl-l~[5-trifluoromethylpyridin-2-~1]
pyrimidin-4-amine
Description 63 and 2-bromo-5-trifluoromethylpyridine gave a white solid
(120~mg,
40%). 1H NMR (500 MHz, DMSO-ds) 1.30 (6 H, d, J7.3), 3.36 (1 H, quintet,
J7,.3),
7.63 (1 H, dd, J8.3 and 4.2), 7.69 (1 H, dd, J8.4 and 1.4), 8.05 (1 H, s),
8.12 (1 H,
d, J8.4), 8.22 (1 H, dd, J8.8 and 1.8), 8.41 (1 H, d, J8.6), 8.47 (2 H, m),
8.72. (1 H,
s), 8.80 (1 H, s), 9.20 (1 H, dd, J4.2 and 1.0)~ mlz (ES+) 410 (M+H+).
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Example 45 6-(6-Fluoroauinolin-7-yl)-5-methyl-N [5-trifluorometh~twridin-2-
y1] pyrimidin-4-amine
Description 64 and 2-bromo-5-trifluoromethylpyridine gave a solid (5 mg, 3%).
1H
NMR (500 MHz, DMSO-ds) 2.22 (3 H, s), 7.66 (1 H, dd, J8.4 and 4.2), 7.99 (1 H,
d,Jlo.3),8.13(lH,d,J7.0),8.19(lH,d,J8.9), 8.38 (l H, d,J8.9),8.46(1H,
d,J8.2),8.73(lH,s),8.80(lH,s),8.97(l H, d,J2.8),8.97(lH,d,J2.8), 9.66
(1 H, s)~ mlz (ES+) 400 (M+H+).
Example 46 6-(6-Fluoroauinolin-7-yl)-5-methyl-N 4-trifluorometh«hhenyll
pyrimidin-4-amine
Description 64 and 4-trifluoromethylbromobenzene gave a solid (6 mg, 4%). 1H
NMR (500 MHz, DMSO-ds) 2.18 (3 H, s), 7.65 (1 H, dd, J8.2 and 4.0), 7.72 (2 H,
d,J8.6),7.98(lH,d,J10.2),8.02(2H,d,J8.4),8.12(lH, d,J7.0),8.46(lH,d,
J8.1), 8.67 (1 H, s), 8.97 (2 H, m)~ mlz (ES+) 399 (M+H+).
Example 47 5-Fluoro-6-(8-methylquinolin-7-yl)-N [5-trifluoromethylpyridin-2-
~~l] pyrimidin-4-amine
Description 45 and 2-bromo-5-trifluoromethylpyridine gave a white solid (40
mg,
41%). 1H NMR (500 MHz, CDCls) 2.80 (3 H, s), 7.26 (1 H, s), 7.49 (1 H, dd,
J8.3
and 4.2), 7.58 (1 H, J8.6), 7.80 (1 H, d, J8.6), 8.00 (1 H, J8.6), 8.07 (1 H,
s), 8.19
(1 H, J7.6), 8.59 (1 H, s), 8.78 (2 H, t, J4.5 and 3.9), 9.02 (1 H, d; J2:7)~
mlz (ES+)
400 (M+H+). ,:" . .
Example 48 N(2-Quinolin-7-ylpyridin-4-yl)-5-trifluoromethylpyridiri-2-amine
Description 65 and 2-bromo-5-trifluoromethylpyridine gave a pale~yellow solid
(250 mg, 76%). 1H NMR (400 MHz, CDCla) 6.93 (1 H, d, J8.7), 7:41-7.44 (1~H;
in),
7.55 (1 H, dd, J5.6 and 2.2), 7.74 (1 H, dd, J8:7 and 2.0 ), ,8.83 (1:H,
s~,7.90. (=1 H,
d, J8.6), 8.07 (1 H, d, J1.8), 8.19 (1 H, d, J8.2), 8.30 (1 H, dd, J8.6
and~l.6), 8.58
(3 H, m), 8.96 (1 H, d, J1.6)~ mlz(ES+) 367 (M+H+).
Exam 2-Quinolin-7-vl-N-[4-trifluoromethylphenyllpyridirl-4-arriirle
Description 65 and 4-trifluoromethylbromobenzene gave a white solid (170 mg,
52%). 1H NMR (400 MHz, DMSO-ds) 7.13 (1 H, dd, J5.5 and 1.7), 7.46 (2 H, d, J
8.4), 7.57 (1 H, dd, J8.2 and 4.2), 7.46 (2 H, d, J8.4), 7.75 (1 H, d, J1.2),
8.10 (1
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H, d, J8.6) 8.29 (1 H, dd, J8.4 and 1.0), 8.41 (1 H, d, J8.1), 8.50 (1 H, d,
J5.5),
8.61 (1 H, s), 8.97 (1 H, s), 9.41 (1 H, s)~ mlz (ES+) 366 (M+H+).
Example 50 5-Chloro-6-auinolin-7-yl-N ~4-trifluoromethylphenyl]pyrimidin-4-
5 amine
Description 67 and 4-trifluoromethylbromobenzene gave a white solid (180 mg,
57%). 1H NMR (400 MHz, DMSO-ds) 7.65 (1 H, t, J3.7), 7.74 (2 H, d, J7.9), 7.94
(lH,d,J8.2),s.01(2H,d,J7.9),8.13(lH,d,J8.2),8.41(lH,s),8.47(lH,d,J
s.o>, s.72 (1 H, s), 9.01 (1 H, s>, 9.5s (1 H, s>; mlz (ES+) 401 (M+H+).
Example 51 5-Chloro-6-quinolin-7-yl-N ~5-trif7.uorometh~l~yridin-2-yl~
pyrimidin-4-amine
Description 67 and 2-bromo-5-trifluoromethylpyridine gave a white solid (210
mg,
67%). 1H NMR (400 MHz, DMSO-ds) 7.64 (1 H, dd, J8.3 and 4.2), 7.95 (1 H, d, J
8.4), 8.15 (1 H, d, J8.5), 8.27 (1 H, d, J8.8), 8.39 (1 H, d, J8.8), s.42 (1
H, s), 8.87
(1 H, d, J8.3), 8.78 (1 H, s), 8.87 (1 H, s), 9.01(1 H, dd, J4.2 and 1.0),
9.62 (1 H,
s)~ mlz (ES+) 402 (M+H+).
Example 52 7-(5-Methyl-6-f5-trifluoromethylpyridin-2-ylamino~pvrimidin-4-
,~quinolinium benzenesulfonate
To a solution of Example 41 in DMF (40 ml) was added benzenesulfonic acid
(1.05
eq., 4.3 g, 27.2 mmol) at 40°C. Isopropyl acetate (10 ml) was added
into the
solution, which was then seeded with the product (10 mg). The solution was
aged
for 30 min, then more isopropyl acetate (70 ml) was added over 1~2 hours,
keeping the internal temperature at ca. 40°C. After addition, the batch
was
cooled to 20-25°C, aged for 2 hours, then filtered. The resulting cake
was washed -
with isopropyl acetate (10 mL), then dried to give the title compound (13.4 g,
95
%). 1H NMR (400 MHz, DMSO-d6): 8 10.07 (1H, br s), 9.26 (1H, dd, J=4.8,1.5
Hz), 8.94 (1H, d, J= 8.2 Hz), 8.90 (1H, s), 8.79 (1H, m), 8.38 (1H, d, J=8.6
Hz),
8.36 (1H, m), 8.32 (1H, d, J=8.8 Hz), 8.25 (1H, dd, J=8.9, 2.4 Hz), 8.02 (1H,
dd, J=
8.5, 1.6 Hz), 7.97 (1H, dd, J=8.4, 4.8 Hz), 7.64-7.58 (2 H, om), 7.35-7.26
(3H, om),
2.37 (3H, s)~ mlz (ES+) 382 (M+H+).
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The following compounds can be prepared according to the procedure described
in
Example 52.
Example Title
53 7-(2-Cyclopropyl-5-methyl-6-{5-trifluoromethylpyridin-2-
ylamino}pyrimidin-4-yl)quinolinium benzenesulfonate.
54 7-(2-Cyclopropyl-5-methyl-6-{4-trifluoromethylphenyl
amino~pyrimidin-4-yl)quinolinium benzenesulfonate.
55 7-(5-Isopropyl-6-{5-trifluoromethylpyridin-2-ylamino}
pyrimidin-4-yl)quinolinium benzenesulfonate.
56 6-Fluoro-7-(5-methyl-6-{5-trifluoromethylpyridin-2-
ylamino}pyrimidin-4-yl)quinolinium benzenesulfonate.
57 6-Fluoro-7-(5-methyl-6-{4-trifluoromethylphenylamino}
pyrimidin-4-yl)quinolinium benzenesulfonate.
58 7-(5-Fluoro-6-{5-trifluoromethylpyridin-2-ylamino}
pyrimidin-4-yl)-8-methylquinolinium benzenesulfonate.
Examples 59 - 79 were made from the indicated compounds according to the
procedure of Example 2. -
Example 59 5-ter~Butyl-6-guinolin-7-yl-N[4-trifluorometh~lphenyllpyrimidin- ~~
4-amine
,,. .., ~.::;-' ~~ °=
Description 69 and 4-trifluoromethylbromobenzene gave'a white solid (150 mg, -
47%). 1H NMR (500 MHz, DMSO-ds) 1.29 (9 H, s), 7.60 (1 H, dd, J8.3 and.4.2), .
7.69(3H,d,J8.7),7.80(2H,d,J8.6),7.93(lH,s);8.07(lH;d,J8.4),~8.13(1H;
s), 8.44 (1 H, d, J8.1), 8.47 (1 H, s), 8.97 (1 H, dd, J4.2 and 1.7)~ mlz
(ES~) 423 .
(M+H+). _ _ _
Example 60 5-tert-Butvl-6-quinolin-7-yl-N [5-trifluoromethylpyridiri-2-
~pyrimidin-4-amine
Description 69 and 2-bromo-5-trifluoromethylpyridine gave a white solid (190
mg,
62%). 1H NMR (500 MHz, DMSO-ds) 1.29 (9 H, s), 7.61 (1 H, dd, J8.3 and 4'.2),
7.71(lH,d,J8.3),7.96(lH,s),8.09(lH,d,J8.3),8.15(2H,m),8.45(lH,d,J
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8.1), 8.64 (1 H, s), 8.69 (1 H, s), 8.70 (1 H, s), 8.97 (1 H, d, J2.7)~ m/z
(ES+) 424
(M+H+).
Example 61 6-(8-Ethylauinolin-7=yl)-N [4-trifluoromethylphenyllpvrimidin-4-
amine
Description 70 and 4-trifluoromethylbromobenzene gave a white solid (50 mg,
42%). 1H NMR (500 MHz, DMSO-ds) 1.25 (3 H, t, J7.3), 3.32 (2 H, t, J7.3), 7.04
(1 H, s), 7.58 (1 H, d, J8.6), 7.60 (1 H, dd, J8.3 and 4.2), 7.71 (2 H, d,
J8.6), 7.93
(1 H, d, J8.5), 8.00 (2 H, d, J8.6), 8.41 (1 H, dd, J8.3 and 1.5), 8.86 (1 H,
s), 9.01
(1 H, dd, J4.2 and 1.7), 10.13 (1 H, s)~ mlz (ES+) 395 (M+H+).
Example 62 6-(8-Ethylquinolin-7-yl)-N [5-trifluoromethvlpyridin-2-yl]pyrimidin-
4-amine
Description 70 and 2-chloro-5-trifluoromethylpyridine gave a white solid (70
mg,
30%). 1H NMR (500 MHz, DMSO-ds) 1.28 (3 H, t, J7.3), 3.30 (2 H, q, J7.3), 7.59-
7.63(2H,m),7.94(lH,d,J8.5),7.98(lH,d,J8.8),8.06(lH,s),8.15(lH,dd,J
8.8 and 2.0), 8.42 (1 H, dd, J8.2 and 1.2), 8.65 (1 H, s), 8.95 (1 H, s), 9.02
(1 H,
dd, J3.9 and 1.5), 10.88 (1 H, s)~ mlz (ES+) 396 (M+H+). ..
Example 63 6-(8-Ethylquinolin-7-yl)-5-methyl-N [4-trifluoromethyl
phenyl) pyrimidin-4-amine
Description 71 and 4-trifluoromethylbromobenzene gave a white solid (60'mg,
25%). 1H .NMR (500 MHz, DMSO-ds) 1.09 (3 H, m), 2.05 (3 H, s), 2.87 and 3.25
(2 .
H,m),7.39(lH,d,J8.3),7.60(lH,dd,J8.3and4.2),7.71(2H,d,J8.7),7.91(1
H, d, J8.4), 8.04 (2 H, d, J8.7), 8.41 (1 H, dd, J8.3 and 1.6), 8:66 (1 H, s),
8.90 (1
H, s), 9.01 (1 H, dd, J4.2 and 1.6)~ mlz (ES+) 409 (M+H+). _ .
Example 64 6-(8-Ethylquinolin-7-vl)-5-methyl-N [5-trifluoromethylpvridin-2- .
y1] pyrimidin-4-amine -
Description 71 and 2-chloro-5-trifluoromethylpyridine gave a white solid (70
mg,
30%). 1H NMR (500 MHz, DMSOvds) 1.09 (3 H, t, J7.4), 2.09 (3 H, s), 2.86 and
3.25 (2 H, m), 7.39 (1 H, d, J8.3), 7.61 (1 H, dd, J8.3 and 4.2), 7.92 (1 H,
d, J8.4),
8.19 (1 H, dd, J8.9 and 2.2), 8.41-8.44 (2 H, m), 8.72 (1 H, s), 8.80 (1 H,
s), 9.01 (1
H, dd, J4.2 and 1.7), 9.50 (1 H, br s)~ mlz (ES+) 410 (M+H+).
_
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Example 65 N [2-Fluoro-4-trifluoromethvlphenyl]-5-methvl-6-quinolin-7-
ylpyrimidin-4-amine
Description 19 and 1-bromo-2-fluoro-4-trifluoromethylbenzene gave a white
solid
(45 mg, 17%). 1H NMR (500 MHz, CDCIs) 2.41 (3 H, s), 7.02 (1 H, d, J3.7), 7.43
(1
H, d, J11.2), 7.47-7.51 (2 H, m), 7.80 (1 H, dd, J8.4 and 1.3), 7.96 (1 H, d,
J8.4),
8.23 (2 H, m), 8.84 (1 H, s), 8.86 (1 H, t, J8.3), 8.99 (1 H, dd, J8.2 and
1.2)~ mlz
(ES+) 399 (M+H+).
Example 66 6-(8-Methylauinolin-7-yl)-2-trifluoromethvl-N [4-trifluorometh~
phenyl] pyrimidin-4-amine
Description 77 and 4-trifluoromethylbromobenzene gave a white solid (105 mg,
71%). 1H NMR (500 MHz, CDCla) 2.90 (3 H, s), 7.02 (1 H , s), 7.24 (1 H, s),
7.47 (1
H, dd, J8.3 and 4.2), 7.64 (2 H, d, J8.7), 7.68 (2 H, d, J8.7), 7.77 (1 H, d,
J8.5),
8.18 (1 H, dd, J8.2 and 1.6), 9.02 (1 H, d, J1.7)~ mlz(ES+) 449 (M+H+).
Example 67 6-(8-Methylauinolin-7-yl)-2-tri_fluoromethyl-N [5-trifluorometh~l
pyridin-2-yl]pyrimidin-4-amine
Description 77 and 2-bromo-5-trifluoromethylpyridine gave a white solid (90
mg,
60%). 1H NMR (500 MHz, CDCls) 2.94 (3 H, s), 7.48 (1 H, dd, J8.2 and 4.2),
7.69
(2 H, m), 7.79 (1 H, d, J8.5), 7.95 (1 H, dd, J8.6 and 1.9), 8.08 (2 H, d,
J9.6), 8.19
(1 H, dd, J8.2 and 1.3), 8.59 (1 H, s), 9.03 (1 H , d, J1.4)~ mlz (ES+) 450
(M+H+).
Example 68 2-Methoxvmethyl-5-meth~quinolin-7-yl-N [5-trifluororrieth~l
pyridin-2-yl]pyrimidin-4-amine . ; ::. ~ ;_,.;_~v. ~,..1 s-
~ Description 81 and 2-chloro-5-trifluoromethylpyridine gave a yello'vv~aolid
(3.1 g,
68%). 1H NMR (500 MHz, CDCla) 2.40 (3 H, s), 3.59 (3 H, s), 4.69 (2 H, s),
7.47 (1
H , dd, J8.3 and 4.2), 7.70 (1 H, s), 7.78 (1 H, dd, J8.4 and 1.3), '7.95 (1.
H~-d, .~Jt' r .,
8.4), 7.99 (1 H, dd, J8.8 and 1.8), 8.23 (2 H, m), 8.55 (1 H, s), 8.89 (1 H,
dd, J4:2' ~'
and 1.8), 8.99 (1 H, d, J1.4)~ mlz (ES+) 426 (M+H+). - -- .~ - ~-
Example 69 5-Fluoro-6-(8-fluoroquinolin-7-yl)-N [4-trifluoromethyl
phenyl] pyrimidin-4-amine
Description 82 and 4-trifluoromethylbromobenzene gave a white solid (210 mg,
45%). 1H NMR (500 MHz, DMSO-ds) 7.74-7.78 (3 H, m), 7.84 (1 H , dd, J8.4 and
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6.4),8.01(lH,d,J8.6),8.12(2H,d,J8.6),8.55(l H, d,J8.4),8.70(lH,d,J
1.5), 9.07 (1 H, m), 10.19 (1 H, s)~ m/z(ES+) 403 (M+H+).
Example 70 5-Fluoro-6-(8-fluoroquinolin-7-yl)-N [5-trifluorometh~pyridin-2-
y1 pyrimidin-4-amine
Description 82 and 2-chloro-5-trifluoromethylpyridine gave a yellow solid (160
mg, 34%). 1H NMR (400 MHz, CDCIa) 7.58 (1 H, dd, J8.3 and 4.2), 7.77 (1 H, d,
J
8.7), 7.84 (1 H, dd, J8.6 and 6.0), 8.01 (1 H, dd, J8.8 and 2.2), 8.12 (1 H,
s), 8.26
(1 H, d, J8.4), 8.60 (1 H, s), 8.77 (2 H, m), 9.07 (1 H, dd, J4.2 and 1.5)~
mlz (ES+)
404 (M+H*).
Example 71 N (5-Methyl-6-guinolin-7-~pyrimidin-4-yl)-6-trifluoromethyl
pyridazin-3-amine
Description 19 and Description 87 gave an off white solid (190 mg, 45%). 1H
NMR
(500 MHz, CDCla) 2.50 (3 H , s), 7.50 (1 H , dd, J8.2 and 4.2), 7.80 (1 H , dd
, J8.4
and 1.5), 7.84 (1 H, d, J9.4), 7.98 (1 H, d, J8.4), 8.26 (3 H, m), 8.87 (1 H,
s), 8.99
(1 H, dd, J4.2 and 1.5), 9.10 (1 H, d, J9.4)~ mlz (ES+) 383 (M+H+).
Example 72 6-(1,8-Naphthyridin-2-yl)-N [4-trifluoromethylphenyl~pvrimidin-4-
amine
Description 94 and 4-trifluoromethylbromobenzene gave a white solid-(80 vig,
48%). 1H NMR (500 MHz, CDCla) 7.24 (1 H, s), 7.55 (1 H, dd, J8.1 and 4.2),
7:63
(2 H, d, J8.6), 7.70 (2 H, d, J8.6), 8.22 (1 H, s), 8.27 (1 H, dd, J8.1 and
1.7), 8.38
(lH,d,J8.6),8.71(lH,d,J8.3),8.91(lH,s),9.18(lH,d,J2.2)~m/z(ES+)368
(M+H+). .
Example 73 5-Meth~l-6-quinolin-8-yl-N [4-trifluoromethylphen~pyrimidin-4-
amore
Description 100 and 4-trifluoromethylbromobenzene gave a white solid (80 mg;
48%). 1H NMR (400 MHz, DMSO-de) 1.90 (3 H, s), 7.58 (1 H, dd, J8.3 and 4.2),
7.70 (2 H, d, J8.6), 7.73-7.75 (2 H, m), 8.03 (2 H, d, J8.6), 8.11 (2 H, dd,
J6.1 and
3.5), 8.46 (1 H, dd, J8.3 and 1.6), 8.63 (1 H, s), 8.85 (1 H, s), 8.87 (1 H,
dd, J4.3
and 1.6) ~ mlz (ES''-) 381 (M+H+).
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Example 74 5-Methyl-6-cruinolin-8-yl-N [5-trifluoromethylpyridin-2-
yl~pyrimidin-4-amine
Description 100 and 2-chloro-5-trifluoromethylpyridine gave an off white solid
(180 mg, 75%). 1H NMR (400 MHz, DMSO-ds) 1.94 (3 H, s), 7.90 (1 H, dd, J8.3
5 and 4.2), 7.72-7.75 (2 H, m), 8.10-8.14 (1 H, m), 8.17 (1 H, dd, J8.9 and
2.2), 8.40
(lH,d,J8.8),8.48(lH,dd,J8.3and1.5),8.70(lH,s),8.76(lH,s),8.85(1H,
m), 9.50 (1 H, s)~ mlz (ES+) 382 (M+H+).
Example 75 N [4-Trifluoromethylphenyll-6-[4-trifluoromethylauinolin-7-
10 ~pyrimidin-4-amine
Description 120 and 4-trifluoromethylbromobenzene gave a white solid (80 mg,
48%). 1H NMR (360 MHz, DMSO-ds) 7.60 (1 H, s), 7.72 (2 H, d, J8.7), 8.01 (2 H,
d, J8.5), s.o5 (1H, d, J4.4), 8.29 (1 H, d, J9.5), 8.48 (1 H, d, J9.1), 8.86
(1 H, s),
8.92 (1 H, s), 9.23 (1 H, d, J4.1), 10.28 (1 H, s)~ mlz (ES+) 435 (M+H+).
Example 76 5-Methvl-N[4-trifluoromethyl~henyll-6-[4-trifluoromethylquinolin-
7- J~l]pyrimidin-4-amine
Description 121 and 4-trifluoromethylbromobenzene gave a white solid (80 mg,
48%). 1H NMR (500 MHz, DMSO-ds) 2.35 (3 H, s), 7.72 (2 H, d, J8.5), 8.02-8.06
(4
H,m),8.24(lH,d,J7.1),8.39(lH,s),8.68(lH,s),8.99(lH,s),9.21(lH,d,J
4.3)~ mlz (ES+) 449 (M+H+).
Example 77 5-Methyl-N [5-trifluoromethylpyridin-2-yll-6-(4-trifluoromethyl :~
auinolin-7-yl]pyrimidin-4-amine '_ ._ . . .. _..,:.. . ,. ' _
Description 121 and 2-chloro-5-trifluoromethylpyridine gave a white solid (80
mg,
48%). 1H NMR (500 MHz, DMSO-ds) 2.39 (3 H, s), 8.06 (2 H, m)8.19 (1
H,:~3.d;:aT='.=.
8.8 and 2.2), 8.25 (1 H, d, J7.1), 8.37 (1 H, d, J9.0), 8.39 (1 H~ s), 8.'7~
(1.H;-s),' - _
8.82 (1 H, s), 9.22 (1 H, d, J4.3)~ mlz (ES+) 450 (M+H+). . ~ a r ~ . .. ',...
.;
Example 78 6-Quinolin-7-yl-N~-~5-trifluoromethylpyridin-2-~lpv~imidine-4 5-
diamine
Description 114 and 5-trifluoromethylpyridin-2-amine gave a solid. 1H NMR (500
MHz, DMSO-ds) 5.52 (2 H, s), 7.60 (1 H, dd, J8.2 and 4.1), 7.92 (1 H, d,
J8.4),
8.11(lH,d,J8.4),8.15(lH,d,J8.7),8.35(2 H,s),8.44(lH,d,J7.9),8.49(1H,
d, J8.8), 8.70 (1 H, s), 8.97 (1 H, d, J2.8), 9.69 (1 H, s)~ mlz (ES+) 383
(M+H+).
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Example 79 N [3-Fluoro-5-trifluorometh~lpyridin-2-yll-5-methyl-6-auinolin-7-
~pyrimidin-4-amine
Description 119 and Description 118 gave a solid (12 mg, 4%). 1H NMR (500 MHz,
DMSO-ds) 2.35 (3 H, s), 7.63 (1 H, dd, J8.2 and 4.2), 7.85 (1 H, d, J8.4),
8.13 (1
H,d,J8.4),8.21(lH,s),8.30(lH,d,J9.2),8.47(lH, d,J8.4),8.66(2H,d,J
11.9), 8.99 (1 H, s), 9.97 (1 H, s)~ mlz (ES+) 400 (M+H+).
Example 80 (5-Methyl-4-guinolin-7-yl-6-~5-trifluoromethylpyridin-2-
ylamino~pyrimidin-2-yl)methanol
A mixture of Example 68 (0.5 g, 1.18 mmol) and 48% aqueous HBr (5 ml) was
heated at 90°C overnight. The cooled mixture was poured onto ice/water
and
carefully basified by the addition of ammonium hydroxide. The mixture was
extracted with dichloromethane (x 3) and the combined dichloromethane layers
were dried over NaaSOa, filtered and evaporated. The residue was purified by
column chromatography on silica (eluent: 4% [2M NHs in MeOH] in DCM) to give
the title compound as a yellow solid (160 mg, 32%). 1H NMR (500 MHz, DMSO-
ds) 3.31 (3 H, s), 4.58 (2 H, d, J6.1), 5.20 (1 H, t, J6.1), 7.62 (1 H, dd,
J7.9 and
3.9),7.81(lH,d,J8.3),8.13(2H,m),s.18(lH,s),8.46(lH,d,J8.1),8.56(1H,
2o d,J8.7),8.71(lH,s),8.98(lH,d,J2.4),9.57(lH,s)~m/z(ES+)412 (M+H+).
Example 81 2-[(cis2,6-Dimethylmorpholin-4-yl)methyll-5-methyl-6-quinolin-7-
yl-N [5-trifluorometh,~lpyridin-2-yl]pyrimidin-4-amine
To a suspension of Example 80 (500 mg, 1.22 mmol) in anhydrous ,
dichloromethane (15 ml) was added pyridine (0.108 ml, 1.34 m~iuol) followed by
methane sulfonyl chloride (0.094 ml, 1.22 mmol), and the resulting mixture
stirred at room temperature overnight. Further pyridine (0.108 ml, ~.3~4
minol),
and methane sulfonyl chloride (0.094 ml, 1.22 mmol) was added, ands mixture
heated at reflux overnight. DMF (10 ml) was added to the mixture followed by
cis2,6-dimethylmorpholine (0.301 ml, 2.44 mmol) and the mixture heated at 90
°C overnight. The cooled mixture was partitioned between EtOAc and
water,
extracted with EtOAc (x 3), and the combined EtOAc layers washed with water,
sat. NaCl, dried over NaaS04, filtered and evaporated. The residue was
purified
by column chromatography on silica (elutent 3% [2M NHs in MeOH] in DCM),
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and the product triturated with diethyl ether/isohexanes, filtered and dried
to
give the title compound (35 mg, 5%). 1H NMR (500 MHz, CDCls) 1.18 (6 H, d, J
6.3), 2.04 (2 H, t, J 10.8), 2.39 (3 H, s), 3.01 (2 H, d, J 10.8), 3.82 (4 H,
m), 7.47 (1
H, dd, J8.4 and 4.3), 7.69 (1 H, s), 7.76 (1 H, dd, J8.4 and 1.5), 7.95 (2 H,
d, J
8.5), 8.22 (2 H, m), 8.56 (1 H, s), 8.90 (1 H, d), 8.99 (1 H, d, J4.3 and
1.5)~ mlz
(ES+) 509 (M+H+).
Example 82 5-Methyl-6-(1,8-naphthyridin-2-yl)-N [4-trifluorometh~
phenyl~pyrimidin-4-amine
To a mixture of Description 95 (200 mg, 0.7 mmol), Description 92 (115 mg, 0.7
mmol) and Pd(PPha)4 (80 mg, 0.07 mmol) in anhydrous 1,4-dioxane (4 ml) was
added hexamethylditin (0.145 ml, 0.7 mmol). The mixture was heated at
190°C
for 15 min in a microwave reactor (Personal Chemistry - Smith synthesizer).
The
cooled reaction mixture was loaded directly onto a silica gel chromatography
column and eluted with 2% MeOH + 0.5% NH40H in DCM. The product was
further purified by mass directed HPLC to give the title compound as a white
solid (50 mg, 18%). 1H NMR (500 MHz, CDCla) 2.70 (3 H, s), 6.94 (1 H, s), 7.58
(1
H, dd, J8.1 and 4.2), 7.64 (2 H, d, J8.6), 7.84 (2 H, d, J8.6), 8.25 (1 H, d,
J8.5),
8.29(lH,dd,JB.landl.9),8.38(lH,d,J8.4),8.81(lH,s),9.20(lH,dd,J4.2
and 1.9)~ mlz (ES+) 382 (M+H+).
Examples 83 - 89 were made from the indicated compounds according to the
procedure of Example 82.
Example 83 5-Methyl-6-(1,8-nat~hthyridin-2-yl)-N [5-trifluoromethylpyrid'iri-2-
r. -
yl)pyrimidin-4-amine ~ . ~ ' ' . . w~; ° ~. .
Description 88 and Description 92 gave a white solid (50 mg, 18%~:-1H N1VIR
(500 ~-' ''
MHz, CDCls) 2.75 (3 H, s), 7.58 (1 H, dd, J8.1 and 4.2), 7.79 (1 H; s); 7.9'7
(1~ H,~': ''' ~ %~
dd, J8.9 and 1.9), 8.24 (1 H, d, J8.4), 8.29 (1 H, dd, J8.1 and 1:8), 8.39 (1
H, ~d; ~J v
8.4), 8.57 (1 H, s), 8.80 (1 H, d, J8.9), 8.89 (1 H, s), 9.21 (1'H, dd, J4.2
and 1.9)~
mlz (ES+) 383 (M+H+).
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83
Example 84 5-Isopropyl-6-(1,8-naphthyridin-2-yl)-N [4-trifluorometh~
phenyl] pyrimidin-4-amine
Description 92 and Description 96 gave a white solid (70 mg, 27%). 1H NMR (500
MHz, CDCla) 1.50 (6 H, d, J7.4), 3.86 (1 H, quintet, J7.4), 7.00 (1 H, s),
7.57 (1 H,
dd, J8.1 and 4.2), 7.64 (2 H, d, J8.5), 7.82 (2 H, d, J8.5), 8.00 (1 H, d,
J8.4), 8.28
(1 H, dd, J8.1 and 1.9), 8.37 (1 H, d, J8.4), 8.75 (1 H, s), 9.21 (1 H, dd,
J4.2 and
1.9)~ mlz (ES+) 410 (M+H+).
Example 85 5-tert-Butyl-6-(1,8-naphthyridin-2-yl)-N [4-trifluorometh~phenyl]
pyrimidin-4-amine
Description 92 and Description 97 gave a white solid (70 mg, 13%). 1H NMR (500
MHz, CDCls) 1.41 (9 H, s), 7.01 (1 H, s), 7.55 (1 H, dd, J8.1 and 4.3), 7.64
(2 H, d,
J8.5), 7.76 (2H, d, J8.5), 7.89 (1 H, d, J8.3), 8.26 (1 H, dd, J6.5 and 1.7),
8.34 (1
H, d, J8.3), 8.60 (1 H, s), 9.17 (1 H, dd, J4.3 and 1.7)~ mlz (ES+) 424
(M+H+).
Example 86 6-(5-Fluoroauinolin-7-yl)-5-methyl-~V [5-trifluoromethylpyridin-2-
y1] pyrimidin-4-amine
Description 88 and Description 90 gave a white solid (27mg, 15%). 1H NMR (400
MHz, DMSO) 2.39 (3 H, s), 7.68 (1 H, dd, J10.6 and 1.3), 7.73 (1 H, dd, J8.5
and
4.2), 8.06 (1 H, s), 8.18 (1 H, dd, J9.0 and 2.3), 8.36 (1 H, d, J8.9), 8.58
(1 H, d, J
6.8), 8.73 (1 H, s), 8.80 (1 H, s), 9.08 (1 H, dd, J4.2 and 1.6), 9.65 (1 H;
s).
Example 87 5-Methyl-6-(1,5-naphthyridin-3-yl)-N [4-trifluoromethyl:
phenyl]pyrimidin-4-amine
3-Bromo-1,5-naphthyridine [Journal of Organic Chemistry (196.8) 33(4); 1384-
.7] ' --
and Description 95 gave a white solid (130mg, 36%). 1H NMR (400 MHz~'DMSO= ,
ds) 2.38 (3 H, s), 7.72 (2 H, d, J8.7), 7.88 (1 H, dd, J8.4 and 4.1), 8.03 (2
H, d; J ~ '
8.5), 8.53 (1 H, d, J8.6), 8.62 (1 H, d, J2.0), 8.70 (1 H, s), 9.03 (1 H, s);
9.10 (1H;
dd, J4.1 and 1.6), .9.21 (1 H, d, J2.2)~ mlz (ES+) 382 (M+H+). ,v - . - . . ..
Example 88 5-Methyl-6-(1,5-naphth~ridin-3-yl)-N [5-trifluoromethylpyridiri-2-
yl]pyrimidin-4-amine
3-Bromo-1,5-naphthyridine [Journal of Organic Chemistry (1968) 33(4), 1384-7]
and Description 88 gave a white solid (4mg).1H NMR (500 MHz, DMSO-ds) 2.41
(3 H, s), 7.89 (1 H, dd, J8.4 and 4.1), 8.20 (1 H, dd, J9.0 and 2.5), 8.37 (1
H, d, J
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8.9),8.53(lH,d,J8.3),8.62(lH,d,Jl.S),8.74(l H,s),8.83(lH,s),9.11(1H,
dd, J4.1 and 1.3), 9.22 (1 H, d, J2.0), 9.70 (1 H, s). mlz (ES+) 383 (M+H+).
Example 89 5-Methyl-6-(1-methyl-lHbenzimidazol-5-~)-N[4-trifluoromethyl
phenyl] pyrimidin-4-amine
Description 95 and 5-bromo-1-methylbenzimidazole [J. Chem. Soc., Perkin Trans
2 (1978), 9, 865] gave a white solid (40 mg, 26%). 1H NMR (400 MHz, DMSO-ds)
8.85(lH,s),8.61(lH,s),8.27(lH,s),8.01(2H,d,J8.4),7.83(lH,s),7.77-
7.63 (3 H, m), 7.50 (1 H, d, J 8.4), 3.90 (3 H, s), 2.31 (3 H, s)~ mlz (ES+)
384
(M+H+).
Example 90 6-(lHBenzimidazol-6-yl)-N[4-trifluoromethylphenyllpyrimidin-4-
amine
A mixture of Description 99 (210 mg, 0.43 mmol) and tetrabutylammonium
fluoride (1.0M soln in THF: 0.86 ml, 0.86 mmol) in THF was heated at
60°C
overnight. The cooled mixture was diluted with EtOAc (50 ml), and washed with
water then brine, dried over Na2S0~, filtered, and evaporated. The residue was
purified by PREP-TLC (eluent: 7.5% MeOH in DCM +0.5% NH40H) to give the
title compound as a white solid. (110 mg, 72%). 1H NMR (400 MHz, DMSO-ds)
7.38 (1 H, d, J0.9), 7.70 (3 H, m), 7.92 (1 H, br d, J8.2), 7.99 (2 H, d,
J8.6), 8.32
(1 H, br s), 8.33 (1 H, s), 8.80 (1 H, s), 10.04 (1 H, s), 12.69 (1 H, br s)~
mlz (ES+)
356 (M+H+).
Example 91 5-Bromo-6-auinolin-7-yl-N [4-trifluoromethylphenyllpyrimidin=4-
amine ~ _
A mixture of Example 7 (370 mg, 1 mmol) and N-bromosuccinimide ~(180~mg,v 1 T
mmol) in chloroform (5 ml) was heated at reflux for 30 min. More N-
bromosuccinimide (100 mg, 0.56 mmol) was added and heating continued for 1
hour. The mixture was cooled, diluted with dichloromethane (15 ml), then
washed '5
with water, dried over Na~S04 , filtered and evaporated. A 200 mg portion was
purified by PREP-TLC (eluent: 5% MeOH in DCM + 0.5% NH40H) to give the
title compound as a white solid (120 mg, 27%). 1H NMR (400 MHz, CDCls) 7.49 (1
H, dd, J8.6 and 4.3), 7.67 (2 H, d, J8.6), 7.73 (1 H, s), 7.86 (3 H, d, J8.6),
7.96 (1
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H,d,J8.2),8.23(lH,d,J8.6),8.51(lH,s),8.76(lH,s),9.00(lH,dd,J4.3
and 1.6)~ mlz (ES+) 445/447 (M+H+).
Example 92 5-Methvl-2-methvlthio-6-quinolin-7-yl-N ~4-trifluoromethylphenyl]
5 pyrimidin-4-amine
A suspension of Description 104 (500 mg, 1.7 mmol), 4-aminobenzotrifluoride
(207 ~.1, 1.7 mmol) and ethanol (4 ml) was heated at 160°C for 80 min
in a
microwave (Personal Chemistry - Smith synthesizer). The cooled reaction
mixture was filtered, and washed with a small amount of ethanol to give a
white
10 solid (300 mg, 42%).1H NMR (500 MHz, DMSO-ds) 2.28 (3 H, s), 2.50 (3 H, s),
7.62
(1 H, dd, J8.3 and 4.1), 7.72 (2 H, d, J8.5), 7.80 (1 H, d, J8.4), 7.99 (2 H,
d, J8.4),
8.11 (1 H, d, J8.3), 8.16 (1 H, s), 8.46 (1 H, d, J8.1), 8.99 (2 H, m)~ mlz
(ES+)
427(M+H+).
15 Example 93 5-Methvl-4-auinolin-7-yl-6-~4-trifluoromethylphenylamino~
pvrimidine-2-carbonitrile
To a solution of Example 124 (100 mg, 0.22 mmol) in DMSO (2 ml) was added
sodium cyanide (13 mg, 0.27 mmol). The mixture was stirred at room
temperature for 3 days, and then partitioned between water and ethyl acetate.
20 The aqueous phase was extracted with ethyl acetate and the combined organic
extracts were washed with brine, dried over NaaS04, filtered and evaporated.
The
residue was purified by column chromatography on silica (eluant: 1:l_ ethyl ..
acetate: hexane then ethyl acetate). Further purification by mass directed
HPLC .
gave a solid (34 mg, 38%). 1H NMR (360 MHz, DMSO-ds) 2.40 (3 H, s), 7.65 (1.H,
..
25 dd, J8.3 and 4.2), 7.78-7.84 (3 H, m), 7.93 (2 H, d, J8.5), 8.15 (1.H, d;
J8.5), '8:22
(1 H, s), 8.49 (1 H, d, J8.3), 9.01 (1 H, dd, J4.2 and 1.6), 9.43 (1 H, s)~
rnlz (~~+)..
406 (M+H+). ~ . . .. -;
Example 94 6-(3-Fluoroauinolin-7-yl)-5-methyl-N (5-trifluoromethylpvridiri-2-
30 yl]pyrimidin-4-amine
To Description 111 (200 mg, 0.73 mmol) and Description 88 (106 mg, 0.37 mmol)
in 1,4-dioxane (4 ml) was added 2M Na2COs (370 ~l, 0.73 mmol) and Pd(dppf)zCh
(8 mg, 0.01 mmol). The mixture was heated at 170°C for 20 min in a
microwave
(Personal Chemistry - Smith synthesizer). The cooled reaction mixture was
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loaded directly onto a silica gel chromatography column and eluted using 2%
MeOH in DCM. The product was further purified by mass directed HPLC to give
the title compound as a white solid (6 mg, 4%). 1H NMR (400 MHz, DMSO-ds)
2.37 (3 H, s), 7.88 (1 H, d, J8.5), 8.16 (2 H, m), 8.23 (1 H, s), 8.36 (2 H,
d, J9.2),
8.72 (1 H, s), 8.80 (1 H, s), 9.03 (1 H, d, J2.7), 9.62 (1 H, s)~ mlz (ES+)
400 (M+H+).
Example 95 5-Methyl-2-(2-methylpyrrolidin-1-yl)-6-quinolin-7-yl-N 5-
trifluorometh~pyridin-2-yl]pyrimidin-4-amine
To a suspension of Example 125 (200 mg, 0.44 mmol) in 1,4-dioxane (4 ml) was
added 2-methylpyrrolidine (220 p1, 2.2 mmol). The mixture was heated at
180°C
for 20 min in a microwave (Personal Chemistry - Smith synthesizer). The cooled
reaction mixture was loaded directly onto a silica gel chromatography column
and
eluted using 1:1 ethyl acetate-hexane to give a white solid (140 mg, 70%). 1H
NMR (500 MHz, DMSO-ds) 1.25 (3 H, d, J6.3), 1.68 (1 H, bs), 1.92 (1 H, bs),
2.05
(2 H, bs), 2.20 (3 H, s), 3.51 (1 H, bs), 3.61 (1 H, bs), 4.24 (1 H, bs), 7.60
(1 H, dd, J
8.3 and 4.2), 7.77 (1 H, dd, J8.4 and 1.5), 8.08 (1 H, d, J8.4), 8.11 (1 H,
s), 8.16 (1
H, dd, J8.9 and 2.2), 8.44 (1 H, d, J7.6), 8.55 (1 H, d, J8.8), 8.67 (1 H, s),
8.96 (1
H, dd, J4.2 and 1.6), 9.10 (1 H, s)~ m/~ (ES+) 465 (M+H+).
Example 96 5-Methyl-2-morpholin-4-yl-6-auinolin-7-yl-N [5-trifluorometh"~1
pyridin-2-yl] pyrimidin-4-amine
Prepared from Example 125 and morpholine according to the procedure of
Example 95 to give a white solid (150 mg, 74%). 1H NMR (500 MHz, DMSO=ds)
2.22 (3 H, s), 3.69 (8 H, s), 7.60 (1 H, dd, J8.3 and 4.2), 7.78 (1 H, dd, 8.3
and 1.5),
8.09 (1 H, d, J8.4), 8.13 (1H, s), 8.16 (1 H, dd, J9.1 and 2:4), 8.28 (1 H, d,
J8.8),
8.44(lH,d,J8.2),8.68(lH,s),8.97(lH,dd,J4.2and1.6),9.31(lH,s)~m/z~.-
(ES+) 467 (M+H+).
Example 97 5-Methyl-6-quinolin-7-yl-2-(2,2,2-trifluoroethoxy)-N 5-
trifluoromethvlpvridin-2- T~1]pyrimidin-4-amine
To a solution of 2,2,2-trifluoroethanol (64 ~.1, 0.88 mmol) in anhydrous THF
(5m1)
was added sodium hydride (60% dispersion in mineral oil) (35 mg, 0.88 mmol).
The resulting mixture was stirred for 10 min, and then added to a solution of
Example 125 (200 mg, 0.44 mmol) in anhydrous DMF (15 ml) and this mixture
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was heated at 120°C for 6 hours. Water was added to the cooled reaction
mixture,
and this was extracted twice with ethyl acetate. The combined organic extracts
were washed with water then brine, dried over MgS04, filtered and evaporated.
The residue was purified by column chromatography on silica (eluant: 2:1 ethyl
acetate: hexane) to give a white solid (45 mg, 22%). 1H NMR (400 MHz, DMSO-
ds) 2.33 (3 H, s), 5.04 (2 H, q, J9.0), 7.63 (1 H, dd, J8.3 and 4.2), 7.84 (1
H, dd, J
8.4and1.7),8.13(lH,d,J8.4),8.23(2H,m),8.33(lH,d,J8.8),8.47(lH,d,J
7.4), 8.75 (1 H, s), 8.99 (1 H, dd, J4.2 and 1.7), 9.72 (1 H, s)~ mlz (ES+)
480
(M+H+).
Examples 98 and 99 7-(5-Methyl-6-{5-trifluoromethylpyridin-2-ylamino~
pyrimidin-4-,~quinolin-4-ol (Example 98) and 5-5-methyl-
6-f 5-trifluorometh~pyridin-2-ylamino~pyrimidin-4-
~quinolin-4-ol (Example 99)
Prepared from Description 113 according to the procedure of Deseription 35 to
give the two title compounds which were separated by preparative HPLC to give
2 white solids, Example 98 (73mg, 8%). 1H NMR (400 MHz, DMSO-ds) 2.33 (3 H,
s),6.10(lH,d,J7.4),7.50(lH,d,J8.4),7.75(l H,s),7.98(lH,d,J7.4),8.18(2
H, m), 8.35 (1 H, d, J8.8), 8.72 (1 H, s), 8.77 (1 H, s) and Example 99 (56mg,
6%).
1H NMR (400 MHz, DMSO-ds) 1.91 (3 H, s), 5.90 (1 H, dd, J7.4 and 1.l), 7.00 (1
H, dd, J7.0 and 1.2), 7.63 (1 H, dd, J8.4 and 1:$), 7.70 (1 H, dd, J8.4 and
7.1),
7.89 (1 H, dd, J7.3 and 6.0), 8.15 (1 H, dd, J9.0 and 2.5), 8.37 (1 H, d,
J9.0), 8.61
(1 H, s), 8.67 (1 H, s), 9.34 (1 H, s), 11.84 (1 H, d, J5.3).
Example 100 2-Methyl-6-quinolin-7-yl-1V~-~4-trifluorometh~phenvl~~yrimidine-
4, 5-diamine
Prepared from Description 125 and 4-aminobenzotrifluoride in 1,4-dioxane
according to the procedure of Example 92 to give a white solid (40 mg, 42%).
1H
NMR (360 MHz, DMSO-ds) 2.46 (3 H, s), 5.05 (2 H, s), 7.59 (1 H, dd, J8:3 and
4.2), 7.68 (2 H, d, J8.7), 7.90 (1 H, dd, J8.4 and 1.6), 8.05 (2 H, d, J8.6),
8.10 (1
H, d, J8.5), 8.32 (1 H, s), 8.43 (1 H, d, J8.2), 8.85 (1 H, s), 8.96 (1 H, dd,
J4.2 and
1.7)a mlz (ES+) 396 (M+H+).
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Example 101 4-~uinolin-7-yl-6-{4-trifluoromethy~henylamino~yrimidin-2-ol
A suspension of Example 14 (2.4 g, 6.1 mmol) in 2N HCl (100 ml) was heated at
reflux for 48 hours. The reaction mixture was cooled to room temperature and
neutralised with sat. NaHCOa. The solid formed was filtered and dried
overnight
in a vacuum oven to give an off white solid (1.8 g, 80%). 1H NMR (360 MHz,
DMSO-ds) 6.46 (1 H, s), 7.67 (1 H, dd, J8.3 and 4.2), 7.72 (2H, d, J8.5), 7.92
(1 H,
dd, J8.5 and 1.8), 8.08 (2 H, d, J8.0), 8.18 (1 H, d, J8.6), 8.46 (1 H, s),
8.50 (1H,
d, J7.6), 9.03 (1 H, dd, J4.2 and 1.7)~ mlz (ES+) 383 (M+H+).
Example 102 2-Chloro-6-quinolin-7-yl-N[4-trifluoromethylphenyllpyrimidin-4-
amine
Prepared from Example 101 according to the, procedure of Description 36 to
give a
light brown solid. 1H NMR (500 MHz, DMSO-ds) 7.54 (1 H, s), 7.62 (1 H, dd,
J8.2
and 4.1), 7.73 (2 H, d, J8.5), 7.90 (2 H, d, J8.3), 8.14 (1 H, d, J8.6), 8.20
(1 H, dd,
J8.5 and 1.6), 8.45 (1 H, d, J8.1), 8.64 (1 H, s), 9.00 (1 H, dd, J4.1 and
1.6)~ mlz
(ES+) 401 (M+H+).
Example 103 2-Morpholin-4-yl-6-quinolin-7-yl-N [4-trifluoromethyl
phenyl] pyrimidin-4-amine
A suspension of Example 102 (50 mg, 0.12 mmol), morpholine (55u1, 0.6mmol)
and 1,4-dioxane (2m1) were heated at 160°C for 20 mins in a microwave
(Personal
Chemistry - Smith synthesizer). The cooled reaction was loaded directly onto a
preparative TLC plate and eluted using 4% MeOH in DCM to give a white solid
(10 mg, 18%). 1H NMR (500 MHz, DMSO-ds) 3.75 (4 H, bs), 3.84 (4 H, bs), 6.86
(1
H, s), 7.59 (1 H, dd, J8.2 and 4.2), 7.69 (2 H, d, J8.6), 7.93 (2 H, d, J8.4),
8.11 (1
H, d, J8.5), 8.24 (1 H, d, J8.5), 8.43 (1 H, d, J8.0), 8.63 (1 H, s), 8.98 (1
H,,d,_.J ..
2.5), 9.89 (1 H, s)~ mlz (ES+) 452 (M+H+).
Example 104 2-(4-Phenylpiperazin-1-yl)-6-quinolin-7-yl-N [4-trifluorometh~
pheny_1]I,pyrimidin-4-amine
Prepared from Example 102 and 1-phenylpiperazine according to the procedure of
Example 103 to give a white solid.1H NMR (500 MHz, DMSO-ds) 4.03 (4 H, bs),
6.82 (1 H, t, J7.2), 6.85 (1 H, s), 7.03 (2 H, d, J8.0), 7.26 (2 H, t, J7.9),
7.60 (1 H,
dd, J8.2 and 4.2), 7.71 (2 H, d, J8.4), 7.96 (2 H, d, J8.5), 8.13 (1 H, d,
J8.4), 8.25
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(1 H, dd, J8.3 and 1.7), 8.44 (1 H, d, J7.9), 8.65 (1 H, s), 8.98 (1 H, dd,
J4.2 and
1.7), 9.88 (1 H, s)~ mlz (ES+) 527 (M+H+)
Example 105 6-quinolin-7-yl-1Vz-(2,2,2-trifluoroethyl)-1Vø-[4-trifluorometh~
phenyllpyrimidine-2.4-diamine
Prepared from Example 102 and 2,2,2-trifluoroethylamine according to the
procedure of Example 103 to give a white solid. 1H NMR (500 MHz, DMSO-ds)
6.93 (1 H, s), 7.61 (1 H, dd, J8.2 and 4.1), 7.66 (2 H, d, J8.6), 7.72 (1 H,
bs), 8.04
(2H,bs),8.13(lH,d,J8.5),8.22(lH,d,J8.2),8.44(l H, d,J7.2),8.65(lH,s),
8.99 (1 H, dd, J4.1 and 1.6), 10.00 (1 H, s)~ mlz (ES+) 464 (M+H+).
Example 106 4-Methyl-6-auinolin-7-yl-N [4-trifluoromethylphenyl]-1,3,5-
triazin-2-amine
Prepared from Description 126 and Description 11 according to the procedure of
Description 1 to give a white solid (80 mg, 18%). 1H NMR (400 MHz, CDCIs) 2.67
(3 H, s), 7.45 (1 H, br s), 7.48 (1 H, dd, J8.3 and 4.2), 7.69 (2 H, d, J8.6),
7.89-7.95
(3 H, m), 8.22 (1 H, d, J7.9), 8.60 (1 H, dd, J8.6 and 1.6), 9.03 (1 H, s),
9.26-9.27
(1 H, m)~ mlz (ES+) 382 (M+H+).
Example 107 2-(1,1-Dimethylethyl)-5-methyl-6-quinolin-7-yl-N [4-
trifluoromethylphen ~~l]pyrimidin-4-amine
Deseription 127 (0.12 g, 0.38 mmol) and 4-trifluoromethylaniline (0.12 g, 0.74
mmol) in dioxane (4 ml) was treated with 2N HCl in ether (0.5 ml) and the
resulting solution heated at 170°C for 20 mins in a microwave'
apparatus. The
precipitate was collected by filtration and the desired product isolated by
ion
exchange chromatography as a white solid (45 mg, 27%). iH NMR (360 MHz,
CDCIa) 1.46 (9 H, s), 2.37 (3 H, s), 6.73 (1 H, s), 7.47 (1 H, dd, J8.4 and
4.2), 7:64
(2 H, d, J8.6), 7.86 (1 H, dd, J8.4 and 1.6), 7.95 (2 H, d, J8.4), 7.95 (1 ~H;
d, J8.4), ,
8.23 (1 H, d, J8.4), 8.34 (1 H, s), 9.0 (1 H, d, J1.6)~ mlz(ES+) 436 (M+H+)
Example 108 5-Methyl-6-guinolin-5-yl-N [5-trifluoromethylpyridin-2-
v1] pvrimidin-4-amine
Prepared from Example 99 according to the procedures of Descriptions 36 and 26
respectively. 1H NMR (360 MHz, DMSO-ds) 2.05 (3 H, s). 7.52 (1H, dd, J4.1,
8.5)
7.61 (1H, dd, J7.1 and 1.1), 7.88 (1H, dd, J8.5 and 7.1) 7.97 (lH,.d, J8.5)
8.22-
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8.14 (2H, m), 8.43 (1H, d, J8.8), 8.73 (1H, br. s), 8.80 (1H, s), 8.96 (1H,
dd, J4.1
and 1.6), 9.59 (1H, s)~ mlz (ES+) 382 (M+H+).
Example 109 2-(Morpholin-4-ylmethyl)-6-auinolin-7-yl-N ~4-trifluoromethyl
5 phen ~~1]pyrimidin-4-amine
A mixture of Description 130 (122 mg, 0.327 mmol), Description 11 (167 mg,
0.654 mmol), Pd(dppf)C12 (12 mg, 0.016 mmol) and 2M sodium carbonate (654 ~1,
1.31 mmol) in dioxane (3 ml) was degassed and heated at 140°C for 30
mins. The
cooled mixture was diluted with ethyl acetate, washed with water and brine,
10 dried over sodium sulfate, filtered and concentrated. The residue was
purified by
flash chromatography on silica gel eluting with 5 % MeOH in 1:1 isohexane -
ethyl acetate increasing polarity to 10 % MeOH in 1:1 isohexane - ethyl
acetate.
The product was then recrystallised from toluene to give a beige coloured
solid
(40 mg, 26 %). 1H NMR (500 MHz, DMSO-ds) 2.66 (4 H, m), 3.66 (4 H, m), 3.76 (2
15 H, s), 7.41 (1 H, s), 7.61 (1 H, dd, J8.2 and 4.1), 7.71 (2 H, d, J8.6),
8.06 (2 H, d, J
8.5),8.15(lH,d,J8.6),8.26(lH,dd,J8.5and1.4),8.45(lH,d,J8.0),8.69(1
H, s), 9.00 (1 H, dd, J4.1 and 1.5), 10.15 (1 H, s)~ m/z(ES+) 466 (M+H+).
Example 110 (4-Quinolin-7-yl-6-{4-trifluoromethylphenylamino~pyrimidin-2-
20 yl)methanol
Prepared from Description.132 and Description 11 according to the procedure of
Example 109 to give a beige coloured solid. 1H NMR (500 MHz,. DMSO-ds) 4.63 (2
H, d, J6.2), 5.22 (1 H, t, J6.3), 7.42 (1 H, s), 7.62 (1 H, dd, J8.2 and 4.1),
7.70 (2
H, d, J8.6), 8.07 (2 H, d, J8.5), 8.15 (1 H, d, J8.6), 8:32 (1 H, dd, J8.5 and
1.5),
25 8.45 (1 H, d, J8.0), 8.74 (1 H, s), 9.00 (1 H, dd, J4.1 and 1.6), 10.14 (1
H, s)~ mlz
(ES+) 397 (M+H+). ~ - -
Example 111 2-(lHImidazol-1-ylmeth l~quinolin-7-yl-N4-trifluorometh~
phenyl]pyrimidin-4-amine
30 A solution of methanesulphonic anhydride (28.6 mg, 0.164~mmo1) in DCM (1
ml)
was added to an ice-cooled suspension of Example 110 (50 mg, 0.126 mmol) and
triethylamine (61 ~1, 0.442 mmol) in DCM (2 ml). The mixture was warmed to
room temperature and stirred for 18 hours. More triethylamine (61 ~1, 0.442
mmol)) and methanesulphonic anhydride (28.6 mg, 0.164 mmol) were added with
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ice-cooling, then the reaction stirred for a further 3 hours at room
temperature.
The mixture was diluted with ethyl acetate, washed with sodium hydrogen
carbonate solution (aq) and brine, dried over sodium sulphate, filtered and
concentrated to dryness to give a pale brown solid (42 mg, 70 %). 1H (360 MHz,
DMSO-ds) 3.36 (3 H, s), 5.41 (2 H, s), 7.50 (1 H, s), 7.64 (1 H, dd, J8.3 and
4.1),
7.71 (2 H, d, J8.7), 8.06 (2 H, d, J8.5), 8.17 (1 H, d, J8.6), 8.28 (1 H, d,
J8.7),
8.46 (1 H, d, J8.4), 8.72 (1 H, s), 9.01 (1 H, d, J4.2), 10.35 (1 H, s). To
this solid
(40 mg, 0.084 mmol) in ethanol (2 ml), imidazole (29 mg, 0.422 mmol) was added
and the reaction stirred and heated at 80°C for 18 hours. The cooled
mixture was
diluted with ethyl acetate and washed with sodium carbonate solution (aq). The
organic phase was dried over sodium sulphate, filtered and concentrated. The
residue was purified by flash chromatography on silica gel eluting with 20:1
DCM
- MeOH to give an off-white solid (14 mg, 37 %). 1H (360 MHz, DMSO-ds) 5.48 (2
H, s), 7.05 (1 H, s), 7.34 (1 H, s), 7.41 (1 H, s), 7.65-7.57 (3 H, m), 7.77
(2 H, d, J
8.5), '7.84 (1 H, s), 8.16 (1 H, d, J8.6), 8.24 (1 H, d, J8.6), 8.46 (1 H, d,
J8.0), 8.67
(1 H, s), 9.01 (1 H, t, J2.0), 10.23 (1 H, s)~ mlz (ESA) 447 (M+H+).
Example 112 2-Isopropyl-5-methyl-6-quinolin-7-yl-N [4-trifluorometh~
phen Tl pyrimidin-4-amine
A mixture of Description 133 (248 mg, 0.832 mmol), 4-trifluoromethylaniline
(209
~1, 1.66 mmol) and 5N HCl (5 drops) in dioxane were heated at 180°C for
30 rains
in a microwave apparatus. A precipitate was observed and the mixture was
f"~ltered. The solid was washed with ethanol and partitioned between ethyl . ~
~: ,
acetate and sodium carbonate solution (aq). The organic phase was washed with.
brine, dried over sodium sulphate, filtered and concentrated to .give a pale
beige
solid (230 mg, 65 %). 1H NMR (400 MHz, DMSO-ds) 1.30 (6 H, d, J6.9):.2.31:(3.-
H;
s), 3.07-3.01 (1 H, m), 7.61 (1 H, dd, J8.3 and 4.1), 7.70 (2 H, d, J8.7),
7.81 (1 H~, -
dd, J8.3 and 1.6), 8. 11 (3 H, d, J8.4), 8.17 (1 H, s), 8.46 (1 H, d, J7.5),
8.86 t1 H,
s), 8.98 (1 H, dd, J4.2 and 1.7)~ mlz (ES+) 423 (M+H+).
Example 113 2-Methvlthio-6-quinolin-7-yl-N [4-trifluorometh,~lphenvl~
pyrimidin-4-amine
Prepared from Description 134 according to the procedure of Example 92. 1H
NMR (400 MHz, CDCIs) 2.69 (3 H, s), 7.02 (2 H, d, J4.1), 7.47 (1 H, dd, J8.2
and
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4.1), 7.64 (4 H, q, J7.8), 7.92 (1 H, d, J8.6), 8.21 (1 H, d, J8.2), 8.29 (1
H, dd, J
8.6 and 1.8), 8.69 (1 H, s), 8.97 (1 H, dd, J4.2 and 1.7); mlz (ES+) 413
(M+H+).
Example 114 4-Quinolin-7-yl-6-~4-trifluoromethylphenylamino}pyrimidine-2-
carbonitrile
Prepared from Example 126 according to the procedure of Example 93. 1H NMR
(360 MHz, DMSO-ds) 7.65 (1 H, dd, J8.2 and 4.2), 7.71 (1 H, s), 7.80 (2 H, d,
J
8.6), 7.92 (2 H, d, J8.6), 8.18-8.26 (2 H, m), 8.48 (1 H, d, J7.4), 8.68 (1 H,
s), 9.03
(1 H, dd, J4.2 and 1.7), 10.65 (1 H, s)~ mlz (ES+) 392 (M+H+).
Example 115 2-Cvclopropylmethoxy-6-quinolin-7-yl-N [4-trifluoromethyl
phenyl]-pyrimidin-4-amine
Prepared from Example 126 and cyclopropylmethanol according to the procedure
of Example 97. 1H NMR (500 MHz, CDCls) 0.41-0.44 (2 H, m), 0.64-0.68 (2 H, m),
1.39-1.43 (1 H, m), 4.34 (2 H, d, J7.2), 7.02 (2 H, d, J3.8), 7.46 (1 H, dd,
J8.2 and
4.2), 7.62 (2 H, d, J8.6), 7.66 (2 H, d, J8.6), 7.92 (1 H, d, J8.5), 8.20 (1
H, d, J
7.9), 8.28 (1 H, dd, J8.5 and 1.7), 8.70 (1 H, s), 8.97 (1 H, dd, J4.1 and
1.6)~ mla
(ES+) 437 (M+H+).
Example 116 2-(Pyridin-3-ylmethoxy)-6-quinolin-7-yl-N [4-trifluoromethyl
phenyl] -pyrimidin-4-amine
Prepared from Example 126 and pyridin-3-ylmethanol according to the procedure
of Example 97. 1H NMR (500 MHz, DMSO-ds) 5.58 (2 H, s), 7.23 (1 H, s), 7.45 (1
H, dd, J7.8 and 4.9), 7.62 (1 H, dd, J8.2 and 4.1), 7.71 (2 H, d, J8.6)~ 7:93-
7.98 (3
H, m), 8.15 (1 H, d, J8.6), 8.25 (1 H, dd, J8.5 and 1.6), 8:45 (1 H, d, J8.3),
8.56 (1
H, dd, J4.8 and 1.6), 8.69 (1 H, s), 8.78 (1 H, d, J1.8), 9.00 (1 H, dd, J4.2
and
1.6), 10.23 (1 H, s)~ mlz (ES+) 474 (M+H+).
Example 117 2-(2-Morpholin-4-ylethoxy)-6-quinolin-7-yl-N [4-trifluoromethyl
phenyl]-pyrimidin-4-amine
Prepared from Example 126 and 2-morpholin-4-ylethanol according to the
procedure of Example 97. 1H NMR (360 MHz, CDCls) 2.63 (4 H, m), 2.90 (2 H, t,
J
5.9), 3.75 (4 H, t, J4.6), 4.66 (2 H, t, J5.9), 6.98 (1 H, s), 7.04 (1 H, s),
7.46 (1 H,
dd, J8.4 and 4.2), 7.60 (2 H, d, J8.4), 7.67 (2 H, d, J8.7), 7.92 (1 H, d,
J8.5), 8.21
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(1 H, d, J7.7), 8.27 (1 H, dd, J8.5 and 1.7), 8.70 (1 H, s), 8.98 (1 H, m)~
m/z (ES+)
496 (M+H+).
Example 118 6-~uinolin-7-yl-2-(lHtetrazol-5-yl)-N[4-trifluorometh~
phenyl] pyrimidin-4-amine trifluoroacetic acid salt
Example 114 (36 mg, 0.092 mmol), sodium azide (60 mg, 0.92 mmol) and
ammonium chloride (49 mg, 0.92 mmol) were suspended in DMF (2m1) and
heated to 120°C for 2 hours. The mixture was poured onto water (25 ml)
and
filtered, washing the residue with water. The residue was dissolved in DMSO
and
purified using mass-directed HPLC to give the title compound (5 mg, 9%). 1H
NMR (500 MHz, DMSO-ds) 7.69 (2 H, m), 7.78 (2 H, d, J8.5), 8.15 (2 H, d,
J8.5),
8.25(lH,d,J8.5),8.47(lH,d,J8.5),8.54(l H, d,J7.9),8.99(lH,s),9.07(1H,
m), 10.52 (1 H, s).
Example 119 6-Q.uinolin-7-yl-2-trif7uoromethyl-N [4-trifluoromethylphen Tl
pyrimidin-4-amine
Description 136 (0.5 g, 1.46 mmol), Description 11 (0.41 g, 1.61 mmol), [1,1'-
Bis(diphenylphosphino)ferrocene]palladium(II) chloride (53 mg, 0.073 mmol) and
2M NaaCOs(aq) (1.6 ml) were suspended in dioxane (5m1) and tb.e mixture was
heated at 160°C for 15 mins in a microwave reactor (Personal Chemistry -
Emrys
OptimizerC~). The mixture was filtered through celite, washing the residue
with
EtOAc and water. The layers were separated, and the organic phase was dried
(sodium sulfate) and concentrated to give a brown oily residue, which was
triturated with DCM followed by diethyl ether to give a white crystalline
solid .
(250 mg, 39%). 1H NMR (500 MHz, CDCIa) 7.26 (1 H, s), 7.43 ~1=~H, s),. 7.49
(1, H, . . , .
dd, J8.6 and 4.2), 7.65 (2 H, d, J8.6), 7.?2 (2 H, d, J8.6), 7.96 (1 H, ~1,
J8:6); 8.22 ~ .;_
(1 H, d, J7.8), 8.36 (1 H, dd, J8.6 and 1.7), 8.70 (1 H, s), 8.99 (1 H, dd,
J4.1 and.- w~
1.6)~ mlz (ES+) 435 (M+H+). ~ ~ _ ,
Example 120 6-~uinoxalin-6-yl-N[4-trifluoromethylphenyllpyrimidin-4-
amine
Prepared from Description 137 and 4-trifluoromethylbromobenzene according to
the procedure of Example 2 to give a white solid (40 mg, 14%). 1H NMR (400
MHz, DMSO-ds) 7.58 (1 H, d, J1.1), 7.73 (2 H, d, J8.6), 8.01 (2 H, d, J8.6),
8.28
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(lH,d,J8.8),8.52(lH,dd,J8.8and2.0),8.75(lH,d,Jl.9),8.91(lH,d,J0.9),
9.03 (1 H, d, J1.8), 9.05 (1 H, d, J1.8), 10.22 (1 H, s)~ m/z(ES+) 368 (M+H+).
Example 121 5-Methyl-6-auinoxalin-6-yl-N [4-trifluoromethylphenyll
pyrimidin-4-amine
Description 138 (100 mg, 0.39 mmol) and 4-trifluoromethylaniline (126 mg, 0.78
mmol) were dissolved in dioxane (3 ml). Hydrochloric acid (1M in diethyl
ether, 1
ml, 1 mmol) was added and the mixture was heated at 170~C for 40 mins in a
microwave reactor (Personal Chemistry - Emrys Optimizer~). The mixture was
diluted with EtOAc, and poured onto aqueous sodium bicarbonate solution. The
aqueous phase was extracted with EtOAc, the combined organic phases were
washed with brine, dried over sodium sulfate and concentrated. Purification by
flash chromatography using a Biotage-Horizon~ HPFC system (12S cartridge,
gradient elution from 20-100% ethyl acetate / isohexane) followed by mass-
directed HPLC gave a cream solid (10 mg). 1H NMR (400 MHz, DMSO-ds) 2.36 (3
H, s), 7.75 (2 H, d, J8.7), 8.02 (2 H, d, J8.6), 8.08 (1 H, dd, J8.6 and 1.9),
8.27 (1
H, d, J8.7), 8.31 (1 H, d, J1.9), 8.74 (1 H, s), 9.06 (2 H, m), 9.22 (1 H, s).
Example 122 5-Methyl-6-auinolin-7-yl-2-trifluoromethyl-N- 4-
trifluoromethylphenyllpyrimidin-4-amine
Prepared from Description 142 and 4-trifluoromethylbromobenzene according to
the procedure of Example 2 to give a white solid (150 mg, 41%). 1H NMR (500
MHz, DMSO-ds) 2.41 (3 H, s), 7.64 (1 H, dd, J8.3 and 4.2), 7.77 (2 H, d,
J8.6),
7.83 (1 H, dd, J8.4 and 1.2), 8.02 (2 H, d, J8.6), 8.15 (1 H, d, J8.5); 8.23
(1 H, s),
8.48 (1 H, d, J8.1), 9.00 (1 H, dd, J4.2 and 1.0), 9.38 (1 H, br s)~ mlz (ES+)
449
(M+H+),
Example 123 5-Methyl-2-methylthio-6-quinolin-7-yl-N 5-
trifluoromethylpvridin-2-yll pyrimidin-4-amine
Prepared from Description 91 and 2-bromo-5-trifluoromethylpyridine according
to
the procedure of Description 7 to give a brown solid (2.24g, 61%). 1H NMR (400
MHz, CDCIs) 2.37 (3 H, s), 2.63 (3 H, s), 7.45-7.53 (1 H, m), 7.62 (1 H, s),
7.80 (1
H, dd, J8.4 and 1.6), 7.94 (1H, d, J8.4), 7.99 (1H, dd, J9.0 and 2.3), 8.23 (1
H, d,
J7.2), 8.26 (1H, s), 8.55 (1 H, s), 8.73 (1 H, d, J8.8), 8.99 (1 H, dd, J1.7
and 4.2).
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Example 124 5-Methyl-2-methylsulfonyl-6-quinolin-7-yl-N 4-
trifluoromethylphen~yrimidin-4-amine
To a solution of Example 92 (230 mg, 0.54 mmol) in methanol (20 ml) was added
5 oxone~ (660 mg, 1.1 mmol). The reaction mixture was stirred at room
temperature overnight, then at reflux for 2 hours. The cooled reaction mixture
was poured onto saturated aqueous NaHCOa solution and then extracted three
times with ethyl acetate. The combined organic extracts were washed with
brine,
dried over Na2S0a, filtered, and evaporated to give a white solid (250 mg,
100%).
10 1H NMR (400 MHz, DMSO-ds) 2.43 (3 H, s), 3.35 (3 H, s), 7.65 (1 H, dd, J8.2
and
4.1),7.78(2H,d,J8.4),7.86(lH,d,J8.4),8.03(2 H, d,J8.5),8.17(lH,d,J
8.3),8.26(lH,s),8.49(lH,d,J8.2),9.01(lH,s),9.51(lH,s).
Example 125 5-Methyl-2-methylsulfon~quinolin-7-yl-N (5-
15 trifluorometh,~lpyridin-2-yl] pyrimidin-4-amine
Prepared from Description 122 according to the procedure of Description 123 to
give a yellow solid (2.26 g, 94%). 1H NMR (400 MHz, CDCla) 2.53 (3 H, s), 3.39
(3
H, s), 7.53 (1 H, dd, J8.2 and 4.2), 7.80 (1 H, dd, J8.4 and 1.7), 7.93 (1 H,
s), 7.99
(1 H, d, J4.2), 8.08 (1 H, dd, J8.8 and 2.2), 8.26 (1 H, d, J8.3), 8.29 (1 H,
s), 8.57
20 (1 H, s), 8.85 (1 H, d, J8.8), 9.02 (1 H, dd, J4.2 and 1.7).
Example 126 2-Methvlsulfonyl-6-quinolin-7-yl-N ~4-trifluorometh~
phenyl] pyrimidin-4-amine
Prepared from Example 113 according to the procedure of Description~123: 1H;
,'. , ;...
25 NMR (400 MHz, CDCls) 3.46 (3 H, m), 7.43 (1 H, s), 7.51-7.47 (1 H, m), 7.61
(2 H,
d, J8.4), 7.69 (3 H, m), 7.92 (1 H, d, J8.6), 8.24-8.20 (2 H, m), 8.68 (1
T=I,.s)s.,9.,01- y
8.97 (1 H, m)~ mlz (ES+) 445 (M+H+). m.
