Title of Invention

PYRAZOLO AND IMIDAZO-PYRIMIDINE DERIVATIVES

Abstract The present invention relates to novel pyrazolo- and imidazo-pyrimidine derivatives of formula (I) wherein A, D, E, L, M, Q, R1, R2 and R3 are as defined in the description and claims and to processes for their preparation, pharmaceutical compositions containing said derivatives and their use in the prevention and treatment of diseases.
Full Text

WO 2005/040171 PCT/EP2004/010807
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Case 22228
Pyrazolo and imidazo-pyrimidine derivatives
The present invention relates to novel pyrazolo- and imidazo-pyrimidine derivatives, processes for their preparation, pharmaceutical compositions containing said derivatives and their use in the prevention and treatment of diseases.
More particularly^ the present invention relates to a compound of formula I
5
wherein
A is =C(R4)->
D is =C(R5)-,
E is =C(R6)-> 10 or one of A, D and E is =N-,
L is =N- or =C(H)-,
M is =C(R7)-, when L is =N-, or M is =N-, when L is =C(H)-, Q is CF? or CHF2,
R1 is -CN, unsubstituted pyridinyl, pyridinyl substituted by (C1-C4)-alkyl or by Q-C4
15 alkanol or is the corresponding pyridine-N-oxide,
R is hydrogens halogen, (C1-C4)-alkyl or (C3-C6)-cydoalkyl, R is hydrogen, halogen, (c1-c4)-alkyi or (C3-C6)-cydoalkyl,
R4 is hydrogen, halogen, unsubstituted (C1-C4)-allcyl or (C1-C4)-alkyl substituted by
fluorine, unsubstituted (C1-C4)-alkoxy or (C1-C4)-aIkoxy substituted by fluorine,
20 unsubstituted (C3-C6)-cycloalkyl or (C3-C6)-cycloallcyl substituted by fluorine,
R5 is hydrogen, halogen, unsubstituted (C1-C4)-alkyl or (C1-C4)-aIkyl substituted by fluorine, unsubstituted (C3-C6)-qrcloalkyl or (C3-C6)-cycloalkyl substituted by fluorine, R6 is hydrogen or halogen, and

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R is hydrogen, unsubstituted (c1-C4-alkyl or (c1-C4)-alkyl substituted by CN,
unsubstituted (C3-C6)-cycloalkyl or (C3-C6)-cycloalkyl substituted by CN, with the proviso that when A is =C(R4)-, D is =C(H) -, E is =C(H)-, L is =N-, R1 is -CN, R is hydrogen, R is hydrogen, and (a) M is =C(H)-, R is not hydrogen, chloro or 5 methoxy; or (b) M is =C(CH3)-, R4 is not hydrogen, and their pharmaceutically acceptable addition salts.
Examples for alkyl include.straight chain and branched saturated carbon chains containing from one to 4 carbon atoms, e.g. methyl, ethyl, and the isomers of propyl and butyl, eg. isopropyi and terLbutyl. Examples for substituted alkyl include CF3 and 10 CH2CN. An example for alkoxy is ethoxy, an example for substituted ethoxy is OCH2CF3. Examples for cycloalkyl include cydopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Examples for pyridinyl are pyridin-2-yl, pyridin-3-yl and pyridin-4-yl. Examples for substituted pyridinyi are metylpyridinyl, dimethylpyridinyl, hydroxymethylpyridinyl and metiiyloxypyridinyl, e.g. 2-methylpyridinyl, 2,6-dimethylpyridinyl, 2-15 hydroxymethylpyridinyl and 2-methyl-l-oxypyridinyl, e.g. 2-methylpyridin-4-yl, 2,6-dimethylpyridin-4-yl, 2-hydroxymethylpyridin-4-yl and 2-methyl-l-oxypyridin-4-yl.
Examples for halogen are chlorine and fluorine.
Unless otherwise specified, the term "alkanol" as defined therein denotes an alkyl radical having 1 to 10 carbon atoms, preferably 1 to 6 and still more preferably 1 to 4 carbon 20 atoms as defined above, which is substituted by one, "two or three, preferably one,
hydroxyl group(s),. Examples of alkanols include methanol, ethanol, n-pK>pan-2-ol, n-propan-3-ol, isopropanol, i-butanol and those specifically exemplified in the instant application among the examples.
The term "pharmaceutically acceptable addition salt" refers to any salt derived from an 25 inorganic or organic acid or base. Examples include the hydrochloride, sulfate, fumarate, mesylate, phosphate, maleate and tartrate salts. Such salts maybe prepared according to common and general methods known by the person skilled in the art.
Encompassed by formula I, are those compounds of formula wherein:
A is=C(R4)-, 30 D is =C(R5)-, E is =C(R6)-, or one of A, D and E is =N-,

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L is=N-or=C(H)-,
M is =C(R7)-, when L is =N-, or M is =N-, when L is =C(H)-, Q is CF3,
R1 is -CN, unsubstituted pyridinyl, pyridinyl substituted by (C1-C4)-aIkyl or the
5 corresponding pyridine-N-oxide,
R2 is hydrogen, halogen, (c1-C4)-alkyl or (C3-C6)-cydoaIkyl, R3 is hydrogen, halogen, (C1-C4)-alkyl or (C3-C6)-cydoaIkyl, R4 is hydrogen, halogen, unsubstituted (c1-C4)-alkyl or (c1-C4)-alkyl substituted by
fluorine, unsubstituted (C1-C4)-alkoxy or (C1-C4)-alkoxy substituted by fluorine,
10 unsubstituted (C3-C6)-cycloallcyl or (c3-c6)-cycloalkyl substituted by fluorine,
R5 is hydrogen, halogen, unsubstituted (c1-C4)-alkyl or (C1-C4)-alkyl substituted by
fluorine, unsubstituted (C3-C6)-cydoalkyl or (C3-C6)-cydoalkyl substituted by
fluorine,
R6 is hydrogen or halogen, and 15 R7 is hydrogen, unsubstituted (C1-C4)1alkyl or (C1-C4)-alkyl substituted by CN,
unsubstituted (C3-C6)-cycloallcyl or (C3-C6)-cycloalkyl substituted by CN, with the proviso that when A is =C(R4)-, D is =C(H)-, E is =C(H)-, L is =N-, R1 is -CN, R2 is hydrogen, R3 is hydrogen, and (a) M is =C(H)-, R4 is not hydrogen, chloro or methoxy; or (b) M is =C(CH3)-, R4 is not hydrogen, 20 and their pharmaceutically acceptable addition salts.
In one embodiment the present invention provides a compound of formula I wherein A is =C(R4)-, wherein R4 is hydrogen, halogen, unsubstituted (C1-c4)-alkyl or (c1-c4-alkyl substituted by fluorine, unsubstituted (c1-C4)-alkoxy or (C1-C4)-aIko:xy substituted by fluorine, unsubstituted (Cj-C^-cycloalkyl or (C3-C,s)-cydoalkyl substituted by fluorine. 25 In another embodiment the invention provides a compound of formula I wherein A is =C(R4)-, wherein R4 is hydrogen, Cl, F, CH3, CF3, OCH3, OCH2CH3 or OCH2CF3. In still another embodiment the invention provides a compound of formula I wherein A is =C(R4h wherein R4 is CF3.
In one embodiment the present invention provides a compound of formula I wherein D 30 is =C(R5)-, wherein R5 is hydrogen, halogen, unsubstituted (C1-C4)-alkyl or (c1-c4-alkyl substituted by fluorine, unsubstituted (C3-C5)-q'rcloalkyl or (C3-C6)-cycloaIkyl substituted by fluorine. In another embodiment the invention provides a compound of formula I wherein D is =C(R5)-, wherein R5 is hydrogen, Cl, F, CH3 or CF3. In still another embodiment the invention provides a compound of formula I wherein D is 35 =C(R5)-, wherein R5 is hydrogen, F or CH3.

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In one embodiment the present invention provides a compound of formula I wherein E is =C(R )-, wherein R is hydrogen or halogen. In another embodiment the invention provides a compound of formula I wherein E is =C(R6)-, wherein R6 is hydrogen.
In one embodiment the present invention provides a compound of formula I wherein L 5 is =N-. In another embodiment the invention provides a compound of formula I wherein L is =C(H)-.
In one embodiment the present invention provides a compound of formula I wherein M is =C(R )-, wherein R is hydrogen, unsubstituted (c1-C4-alkyl or (c1-C4-alkyl substituted by CN, unsubstituted (C5-C6)-cycloalkyl or (C3-C6)-cycloaHcyl substituted by 10 CN. In another embodiment the invention provides a compound of formula I wherein M is =C(R7)-, wherein R7 is hydrogen. In still another embodiment the invention provides a compound of formula I wherein M is =C(R )-, wherein R is unsubstituted (Q-Cj-alkyl or (C1-C4-alkyl substituted by CN. In still another embodiment tiie present invention
7 7
provides a compound of formula I wherein M is =C(R )-, wherein R is CH3 or CH2CN. 15 In another embodiment the present invention provides a compound of formula I wherein Mis =N-.
In one embodiment the present invention provides a compound of formula I wherein R1 is —CN. In another embodiment the invention provides a compoand of formula I wherein R1 is unsubstituted pyridinyl, pyridinyl substituted by (C1 -C4)-alkyl Or the
20 corresponding pyridine-N-oxide. In still another embodiment the invention provides a compound of formula I wherein R1 is pyridin-2-yl, pyridin-3-yl, pyridin-4-yi, methylpyridin-4-yl, dimethylpyridin-4-yl, hydroxymethylpyridin-4-"57l or methyloxypyridin-4-yl. In still another embodiment the invention provides a compound of formula I wherein R1 is pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, 236-
25 dimethylpyridin-4-yl, 2-hydrox5^methylpyridin-4-yl or 2-methyl-l-oxy-pyridin-4-yL In still another embodiment the invention provides a compound of formula I wherein R1 is pyridin-4-ylj 2-methylpyridin-4-yl or 2,6-dimethyipyridin-4-yi.
In one embodiment the present invention provides a compound of formula I wherein R2 is hydrogen.
30 In one embodiment the present invention provides a compound of formula I wherein R3 is hydrogen.
In one embodiment the present invention provides a compound of formula I wherein

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A is =C(R4)-, wherein R4 is hydrogen, halogen, unsubstituted (C1-C4-alkyl or (CrC4)~ alkyl substituted by fluorine, unsubstituted c1-c4-alkoxy or c1-c4-alkoxy substituted by fluorine, unsubstituted (C3-Ce)-cydoaIkyi or (C3-Q)-cycloaIkyl substituted by fluorine,
5 D is =C(R5)-, wherein R5 is hydrogen, halogen, unsubstituted (Q-C4)-alkyl or (Q-C4)-alkyl substituted by fluorine, unsubstituted (C3-C6)-cycloalkyI or (C3-C6)-cycloaIkyl substituted by fluorine,
E is =C(R6)-, wherein R6 is hydrogen or halogen,
L is=N-or=C(H)-,
, 10 M is =C(R7)~, wherein R7 is hydrogen, unsubstituted (C1-C4)-aIkyi or (C1-C4)-alkyl substituted by CN, unsubstituted (C3-C6)-cycloaIkyl or (C3-C6)-cycloalkyI substituted by CN, when L is =N-; or M is =N-, when L is =C(H)-,
R1 is -CN, unsubstituted pyridinyl, pyridinyl substituted by (C1-C4)-a]kyi, or the
corresponding pyridine-N-oxide, 15 R is hydrogen, halogen, (C1-C4)-allcyl or (C3-C6)-cycloalkyl,
R3 is hydrogen, halogen, (C1-C4)-alkyI or (C3-c6)-cydoalkyl,
with the proviso that when A is =C(R4)-, D is =C(H)-, E is =C(H)-, L is =N-, R1 is -CN,
R is hydrogen, R is hydrogen, and (a) M is =C(H)-, R is not hydrogen, chloro or
methox}; or (b) M is =C(CH3)-, R4 is not hydrogen.
20 In another embodiment the present invention provides a compound of formula I wherein
A is =C(R4)-, wherein R4 is hydrogen, halogen, unsubstituted (C1-C4)-aIkyl or (Q-C4)-
alkyl substituted by fluorine, unsubstituted (C1-C4)-alkoxy or (C1-C4)-aQcoxy
substituted by fluorine, unsubstituted (C3-C6)-cycloaIkyl or (C3-C6)-cydoaIkyl
25 substituted by fluorine,
D is =C(R5)-, wherein R5 is hydrogen, halogen, unsubstituted (c1-c4-alkyl or (Q-C4)-alkyl substituted by fluorine, unsubstituted (C3-C6)-qrcloaIkyl or (C3-C6)-cycIoalkyI substituted by fluorine,
E is =C(R6)-, wherein R6 is hydrogen or halogen, 30 L is =N-,
M is =C(R7)-, wherein R7 is hydrogen, unsubstituted (c1-C4-alkyl or (Ci-C4)-allcyl substituted by CN, unsubstituted (C3-C6)-cycloaIkyl or (C3-C6)-qrcloalk)d substituted by CN,
R1 is -CN, unsubstituted pyridinyl, pyridinyl substituted c1-c4-alkyl, or the
35 corresponding pyridine-N-oxide,
R is hydrogen, halogen or (c1-c4-alkyl

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R3 is hydrogen, halogen ox (C1-C4)-alkyl
with the proviso that when A is =C(R4)-, D is =C(H)-, E is =C(H)-, L is =N-, R1 is -CN, R is hydrogen, R is hydrogen, and (a) Mis =C(H)-,R is not hydrogen, chloro or methoxy; or (b) M is =C(CH3)~, R4 is not hydrogen.
5 In still another embodiment the present invention provides a compound of formula I wherein
A is =C(R4)-, wherein R4 is hydrogen, halogen, unsubstituted (C1-C4)-aIkyl or (c1-C4)-
alkyl substituted by fluorine, unsubstituted c1-c4-alkoxy or (C1-C4)-alkoxy
substituted by fluorine, unsubstituted (C3-c6)-cydoalkyl or (C3-C6)-cydoaIkyl
10 substituted by fluorine,
D is =C(R5)-, wherein R5 is hydrogen, halogen, unsubstituted c1-c4-alkyl or (Q-C4)-alkyl substituted by fluorine, unsubstituted (C3-C6)-cydoalkyl or (C3-C6)-cycloaIkyl substituted by fluorine,
E is =C(R6)-, wherein R is hydrogen or halogen, 15 L is =N-,
*7 "7
M is =C(R )-, wherein R is hydrogen, unsubstituted (C1-C4)-alkyl or c1-c4-alkyi substituted by CN, unsubstituted (C3-C6)-cydoallcyl or (C3-C6)-cycloalk}4 substituted by fluorine,
R1 is-CN, 20 R2 is hydrogen, halogen or (C1-c4)-alkyl,
R3 is hydrogen, halogen or (C1-c4)-alkyl,
with the provisothat when A is =C(R4)-, D is =C(H)-, E is =C(H)-, L is =N-, R1 is -CN,
R is hydrogen, R is hydrogen, and (a) M is =C(H)-, R is not hydrogen, chloro or
methoxy; or (b) M is =C(CH3)-, R4 is not hydrogen.
25 In still another embodiment the present invention provides a compound of formula I wherein
A is =C(R4)-, wherein R4 is hydrogen, halogen, unsubstituted c1-c4-allcyl or (Q-C4)-alkyl substituted by fluorine, unsubstituted (C1-c4)-allcoxy or (C1-C4)-allcoxy substituted by fluorine, 30 D is =C(R5)-, wherein R5 is hydrogen, halogen, unsubstituted (C1-c4)-akyl or (c1-C4)-
alkyi substituted by fluorine, E is =C(R6K wherein R6 is hydrogen or halogen, L is =N-,
M is =C(R )-, wherein R is hydrogen, unsubstituted (C1-C4)-alkyi or (C1-C4)-aIkyl
35 substituted by CN,

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R1 is -CN, and
R andR3 are hydrogen,
with the proviso that when A is =C(R4)-, D is =C(H)-, E is =C(H)-, L is =N-, R1 is -CN,
R is hydrogen, R is hydrogen, and M is =C(H)-, R is not hydrogen, chloro or naethoxy.
5 In still another embodiment the present invention provides a compound of formula I wherein
A is =C(R4)-, wherein R4 is hydrogen, halogen, unsubstituted c1-c4-alkyl or ( Q-C4)-alkyl substituted by fluorine, unsubstituted c1-c4-alkoxy or (c1-c4-alkosy substituted by fluorine, 10 D is =C(R5)-, wherein R5 is hydrogen, halogen, unsubstituted (C1-C4)-alkyl or ( Q7C4)-
alkyl substituted by fluorine, E is =C(R6)-, wherein R6 is hydrogen or halogen, L is =N-,
M is =C(R )-> wherein R is hydrogen, 15 R1 is-CN, and
R andR are hydrogen,
with the proviso that when A is =C(R4)-, D is =C(H)-, E is =C(H)-, L is =N-, R1 is -CN,
R" is hydrogen, R is hydrogen, and M is =C(H)-, R is not hydrogen, chloro or methoxy.
In still another embodiment the present invention provides a compound of formula I
20 wherein
A is =C(R )-, wherein R4 is hydrogen, halogen, unsubstituted (c1-c4-alkyi or (C1-C4)-alkyi substituted by fluorine, unsubstituted (C1-C4)-aIko:xy or (C1-C4)-alkoxy substituted by fluorine,
D is =C(R5)-, wherein R5 is hydrogen, halogen, unsubstituted (C1-C4)-all 25 alkyl substituted by fluorine,
E is =C(R6)-, wherein R6 is hydrogen,
L is =N-,
M is =C(R )-, wherein R is hydrogen,
R1 is -CN, and 30 R and R" are hydrogen,
with the proviso that when A is =C(R4)-, D is =C(H)-, E is =C(H)-, L is =N-, R1 is -CN,
R is hydrogen, R is hydrogen, and M is =C(H)-, R is not hydrogen, chloro or methoxy.
In still another embodiment the present invention provides a compound of formula I wherein

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A is =C(R4)-, wherein R4 is hydrogen, Cl, F, methyl or trifluorornethyl, or 2-
trifluoroethory?
D is =C(R5)-, wherein R5 is hydrogen, Cl, F, methyl or trifluoromethyl, £ is =C(R6)-, wherein R6 is hydrogen, 5 L is =N-,
M is =C(R )-, wherein R is hydrogen, R1 is-CN, and R and R are hydrogen,
with the proviso that when A is =C(R4)-, D is =C(H)-, E is =C(H)-, L is =N~, R1 is -CN, 10 R is hydrogen, R is hydrogen, and M is =C(H)-, R is not hydrogen, chloro or rnethoxy.
In still another embodiment the present invention provides a compound of formula I
wherein
A is =C(R4)-, wherein R4 is hydrogen, halogen, unsubstituted (c1-c4-alkyl or (Q-Q)-
allcyl substituted by fluorine, unsubstituted (c1-c4-alkoxy or (c1-c4-alkoxy
15 substituted by fluorine,
D is =C(R5)-, wherein R5 is hydrogen, halogen, unsubstituted (c1-c4-allcyl or (Q-C4)-
allcyl substituted by fluorine E is =C(R6)-, wherein R6 is hydrogen or halogen L is =N-,
"7 1
20 M is =C(R4 )-, wherein R7 is unsubstituted c1-c4-alkyl. or (c1-c4-alkyl substituted by
CN,
R1 is-CN,and R andR are hydrogen,
with the proviso that when A is =C(R4)-, D is =C(H)-, E is =C(H)-, L is =N-, R1 is -CN, 25 R2 is hydrogen, R3 is hydrogen, and M is =C(CH3)-, R4 is not hydrogen.
In stiR another embodiment the present invention provides a compound of formula I
wherein
A is =C(R4)-, wherein R4 is hydrogen, halogen, unsubstituted (c1-c4-allcyi or (C1-C4)-
alkyl substituted by fluorine, unsubstituted c1-c4)-alkoxy or (C1-C4)-alkor57'
30 substituted by fluorine ,
D is =C(R5)-, wherein R5 is hydrogen, halogen, unsubstituted (c1-c4-alkyl or (C1-C4)-
alkyl substituted by fluorine, E is =C(R6)-, wherein R6 is hydrogen or halogen, L is =N-,

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M is =C(R7)-, wherein R7 is hydrogen, unsubstituted (c1-c4)-alkyl or (c1-c4)-aIkyl
substituted by CN R1 is unsubstituted pyridinyl, pyridinyl substituted by (c1-c4-alkyl, or the
corresponding pyridine-N-oxide,
5 R is hydrogen, halogen or (c1-c4-alkyl, and
R is hydrogen, halogen or (c1-c4-alkyl.
In still another embodiment the present invention provides a compound of formula I wherein
A is =C(R4)-, wherein R4 is hydrogen, halogen, unsubstituted c1-c4-alkyl or (Q-C4)-
10 aliyl substituted by fluorine, unsubstituted (c1-c4alkoxy or c1-c4-alkoxy
substituted by fluorine, D is =C(R5)-, wherein R5 is hydrogen, halogen, unsubstituted c1-c4-alkyl or (C1-C4)-
allcyl substituted by fluorine, E is =C(R6)-, wherein R6 is hydrogen or halogen, 15 L is =N-,
M is =C(R )-, wherein R is hydrogen,
R1 is unsubstituted pyridinyl, pyridinyl substituted by (C1-c4)-alkyl, or the
corresponding pyridine-N-oxide, R" and R are hydrogen.
20 In still another embodiment the present invention provides a compound of formula I
wherein
A is =C(R4)-> wherein R4 is hydrogen, halogen, (c1-c4-alkyl substituted by fluorine, unsubstituted (c1-C4)-alkoxy,
D is =C(R5)-, wherein R5 is hydrogen, halogen, unsubstituted (c1-c4-alkyl or (C1-C4)-
25 alkyl substituted by fluorine,
E is =C(R6)-, wherein R6 is hydrogen or halogen,
L is =N-,
M is =C(R )-, wherein R is hydrogen,
R1 is unsubstituted pyridin-4-yl or pyridin-4-yl substituted by (c1-c4-alkyl, 30 R and R" are hydrogen.
In still another embodiment the present invention provides a compound of formula I wherein
A is =C(R")-> wherein R4 is (c1-c4-allcyl substituted by fluorine,
D is =C(R5)-, wherein R5 is hydrogen, halogen, unsubstituted (C1- C4)-alkyl or (C1-C4)-
35 alkyl substituted by fluorine,

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E is =C(R6)-, wherein R6 is hydrogen, L is =N-,
M is =C(R )-, wherein R is hydrogen,
R1 is unsubstituted pyridin-4-yl or pyridin-4-yl substituted by (c1-c4-alkyl, 5 R2 andR3 are hydrogen.
In another embodiment the present invention provides a compound of formula I
wherein
A is =C(R4)-, wherein R4 is hydrogen, halogen, unsubstituted (c1-c4)-alkyl or (Q -C4)-
alkyl substituted by fluorine, unsubstituted (c1-c4-alkoxy or c1-c4-alkoxy
10 substituted by fluorine,
D is =C(R5)-, wherein R5 is hydrogen, halogen, unsubstituted (c1-c4)-aIkyl or (Q-C4)-
allcyl substituted by fluorine, E is =C(R6)-, wherein R6 is hydrogen or halogen, L is =C(H)-, 15 M is =N-,
R1 is -CN, unsubstituted pyridinyl, pyridinyl substituted by (c1-c4-alkyi, or the
corresponding pyridine-N-oxide, R is hydrogen, halogen or (c1-c4-alkyl, and R is hydrogen, halogen or (c1-c4-alkyi.
20 In another embodiment the present invention provides a compound of formula I wherein
A is =C(R4)-, wherein R4 is hydrogen, halogen, unsubstituted (c1-c4-alkyl or (Q-C4)-alkyi substituted by fluorine, unsubstituted (c1-c4)-aIkoxy or (c1-c4)»a]koxy substituted by fluorine, 25 D is =C(R5)-, wherein R5 is hydrogen, halogen, unsubstituted (d-C^-alkyi or (Q-C4)-
alkyl substituted by fluorine, E is =C(R6)-, wherein R6 is hydrogen or halogen, L is =C(HK M is=N-3 30 R1 is -CN,
R is hydrogen, halogen or c1-c4-allcyl, and R is hydrogen, halogen or c1-c4-aDcyL
In another embodiment the present invention provides a compound of formula I wherein 35 A is =C(R4)-> wherein R4 is hydrogen or halogen,

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D is =C(R5)-, wherein R5 is hydrogen, E is =C(R )-, wherein R° is hydrogen or halogen, L is =C(H)-, M is=N-, 5 R1 is-CN,
R andR are hydrogen.
In one embodiment the present invention provides a compound of formula I selected from
2~phenyl-4-trifluoromethyl-imidazo [ l35-a]pyrimidine-8-carbonitrile, 10 2-(3-cUoro-pheny!)-4-trifluoro
2-(4-trifluorometiLyl-phenyl)-4-1xifluorometiyl-iinidazo[l>5-a]p
carbonitrile, 5-(4-trifluoromethyl-phenyl) -7-trifluoromethyl-pyrazolo [ 1 >5-a]pyrimidine-3-
carbonitrile, 15 5-(4-fluoro-3-1rifiuoromethyl-phenyl)-7-1rLfluoromet^yi-pyrazolo [ l,5-a]pyriinidine-3-
carbonitrile, 5-(3-cMoro-4-fluoro-phenyl)-7-trifluoromethyl-pyrazolo[l?5-a]p)oimidine-3-
carbonitrile,
5-(4-cWoro-3-meth)d-p]ienyl)-7-trifluorometiiyi-pyrazolo [ l,5-a]pyrimidine-3-
20 carbonitrile,
5-(334-dicHoro-phenyI)-7-frifluorome^ 5-(4-c3doro-3-methyl-phenyl)-7-trifluoromet^
nitrile,
5-(334-dicKioro-phenyI)-7"trifIuoromethyI-iinidazo[l?5-a]pyiim 25 5-(4-cHoro-phenyl)-3-pyridm-3-y^
5-(4-cHoro-phenyl)-3-pyridin-4-yl-7-trifluoromet]^ 5-(4-cUoro-3-metiiyl-phenyl)-3-pyridm-4-yl-7-txifiuorometiiyI-pyrazolo[l>5-
ajpyrimidine,
5-(3-cUoro-4-fluoro-phenyl)-3-pyridin-3-yl-7-1xifluoromethyl-pyrazolo[l?5-
30 ajpyrimldine,
5-(3-cUoro-4-fluoro-phenyl)-3-pyridin-4-yl-7-trifIuorometiiyl-pyrazolo[l,5-
ajp^Trimidine,
5-(3>4-dicUoro-phenyl)-3-pyridin-3-yl-7-1rifluoromethyl-pyrazolo[l^ 5- (334-dicUoro-phenyl)-3-pyridin-4-yl-7-1xifliiorome1±iyl-p)n:azolo [ l>5-a]pyrimidine3 35 5-(3-fiuoro-4-trifluoromethyl-phenyl)-^^
carbonitrile,

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5-(4-trifluorometkyl-plie^
ajpyriraidine, 5-(3-1xifiuoromet±Lyl-phe^
ajpyripm'dine,
5 5-(3-fluoro-4-trifluoromethyl^^
ajpyrimidine, 5-(4-cUoro-phenyl)-3-(2,6-dimet^
ajpyrimidine,
5-(4-cHoro-3-metliyl-phenyl)-3-^^
10 pyrazolofljS-aJpyrimidiae,
5-(3-cUoro-4-fluoro-phen7l)-3-(2>6-dimeth7l-p7ridin-4-7l)-7-1xifln^^
p)7razolo[l>5-a]pyrJTnidine? 5-(334-dicUoro-phen7l)-3-(256-dimeth7l-p7ridin^-7l)-7-1xiflu^
a]p7rimidine? 15 5-(4-trifluoromethyl-phenyl)-3-(2,6-dimethyl-py^
pyrazolo[l>5-a]pyriinidine3 5-(3-trifluoromethyi-phenyl)-3-(2,6-dimethyl-^
PTrazolo [ 1,5-ajpyrmidine,
5-(3-fluoro-4-trifluorometh7l-phen7l)-3-(2?6-dimeth7l-p7ridin-4-7l^
20 pTrazolo [ 1,5-a] pyrimidine,
5-(4-methyl-3-trifluoromeiiLyi-phenyl)-3-(2>6-diTneA
trifluoroineth7l-pyrazolo[l?5'a]p7riTTiidiTie3 5-(4-cUoro-phen7l)-3-(2-meii7l-p7ridin-4-7l)-7-txifluorometii7l-p^
ajpyrimidine, 25 5-(4-diloro-3-me1iiyl-phenyl)-3-(2-methyl^^
pyrazolo [ 1,5-a] pTrimidine, 5-(3-cKIoro-4-fluoro-phen7l)-3-(2-methyi-p7ridin-4-7l)-7-trifIuorometh
p-jTrazolo [l,5-a]p)Timidine3
5-(3>4-dicMoro-phen7l)-3-(2-meth7l-p7ridin-4-yl)-7-trifluorome1iyl-^
30 a] pyrimidine,
5-(4-iiifluorometkyl-phe^
ajpyrimidine, 5-(3-trifluoromethyl-phenyl)-3-(2-meiiiyl-p7ridin-4-7l)-7-trifluo^
a] pyrimidine,
35 5-(3-fluoro-4-trifluoromethyl-phenyl)-3-(2-metiiyl-pyridin-4-yl)-7-tri^^ pyrazolo [ 1,5-a] pyrimidine,

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2-(4-methyl-3-trifluoromet^
carbonitrile, 5 - (3-metb7l-4-trifluoroinetli7l-phenyI) - 3 -p"5nddin-4-yl-7-trifluorornethyl-pyrazolo[l?5-
ajpyrimidine, 5 5-(3-meth7l-4-trifluorome
trifluoromethyl-pyrazolo [l,5-a]pyrimidine, 5-(3-methyl-4-tiifluorom
pyrazolo[l,5-a]pyrimidine,
2-(3-metiyi-4-trifluorometh7l-phen7l)-4-trifluorometh7l-py^
0 carbonitrile,
2-(3-methyl-4-trifluorometh7l-phenyl)-4-triflnorometh7l-im
carbonitrile, 2-(4-1xifluoroethox7-3-trifluorometiyl-phen7l)-4-1iifluorome^
ajpyrimidine-8-carbonitrile, 5 2-(4-iiifluoroethox7-3-trifluoromethyi-phen7l)^trifIuor^
ajpyrimidine-8-carbonitrile, 5-(4-ethoxy-3-trifluorome^
a]pyiimidine,
5-(4-trifluorothoxy-3-trifluorometiiyl-phen7l)-3-pyridin-4-7l-7-1^
0 pyrazolo[l?5"a]pyrimid]ne>
5-(4-ethoxy-3-trifluorometii7l-phenyl)-3-(2-meti7l-p)Tddin
p}TazoIo[l?5-a]p"5aimidiiie5 5-(4-1XLfluoroethox7-3-trifluorometiL7l-phen7l)-3-(2-metiayl^
txifluorometiiyi-pyrazolo[l>5-a]pyriinidine, 5 5-(3-methyl-4-trifluorometi^
trifluorometh7l-pyra2olo[l>5-a]p)7riraidine? 5- (4-chloro-3-methyi-plieayl) -3-(2-methyi-1 -osy-pyridin-4-7l)-7-trifluoroinetiiyl-
pyrazolo [ 1,5-ajpyrimidine,
2- (4-CHoro-3-meiiyl-phen7l)-8-py^ [ 1,5-
0 a]p}Tdmidine)
2-(3-CUoxo-4-fluoro-phenyl)-8-pyridin-3-yl-4-1rifluoromethyl-ii^ ajpyrimidine,
2-(4-DicUoro-pLenyl)-8-pyridin-3-7l-4-1xifluoromeli7l-8-Pyridin-3-yl-4-txifluoromethyl-2- (4-trifLuoronietliyl-phenyl)-iinidazo [1,5-5 a]pyidinidine>
2- (3-Methyl-4-triflnoromethyl-phenyl) -8-p"5;Tidiii-3-yl-4-trifluoromethyl-iinidazo [ 1,5-ajpyrimidine,

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2-(4-CHoro-3-methyl-phenyI)-8-p^^ ajpyrimidine,
2-(3-CUoro-4-fitioro-phenyl)-8-pyridin^ ajpyrimidine,
5 2-(4-Dicbloro-phenyI)-8-pyridin-4-yM^ 8-Pyridin-4-yl-4-txifLnoromet^^ ajpyrimidine, 8-P7ridin-4-yl-4-trifluoromethyl-2-(4-trifluoromet^
ajpynrnidi-ne,
10 2-(4-Methyl-3-1xifluoromet^
aJp^Timidine,
2- (4-Ethoxy-3 -trifluoromethyl-phenyl) - 8 -pyridin-4-yl-4-1xifluoromethyl-imidazo[l?5-
ajpyriinidine,
8-Pyridin-4-yl-2- [4-(2)2>2-1xifluoro-ethox7)-3-trifluoromethyl-phenyl] -4-15 trifluoromethyl-iinidazo [l,5-a]pyrimidine,
2-(3-Methyl-4-trifluoromet^^
ajpyrimidine,
2-(4-Q3loro-phenyl)-8-(2-methyl-p7ridin-4-yl)-4-trifluorom
ajpyrimidine, 20 2-(3-CMoro-4-fluoro-phenyl)-8-(2-metiiyl-pyridin-4-yl)-4-tTifl
imidazo [ 1,5- a] pyrimidine,
2-(4-DicUoro-phenyl)-8-(2-methyl-pyridin-4-yl)-4-trifluoromeiiyl^ [1,5-
ajpyrimidine,
8-(2-Methyl-pyridin-4-yl)-4-trifIuoromethyl-2-25 ajp^rrimidine,
2-(4-Etior7-3-trifluorome1±Lyl-phenyl)-8-(2-mettyl-pyridin-4
imidazo [ 1,5- a] pyTimidine,
8-(2-Methyl-p7ridin-4-yl-2-[4-(2,2>2-trifluoro-etiioxy)-3-tr^
trifluor omethyl-imidazo [ 1 >5 -a] p'jTimidine, 30 2-(3-Methyl-4-trifluorometiiyl-phenyl)-8-(2-metiiyi-pyridin-4
imidazo [ 1,5-a] pyrimidine,
{4-[5-(4-CMoro-3-metiiyl-phenyl)-7-1rifluoromethy^
p}7ridin-2-yi}-methanol)
{4-[5-(3J4-DicMoro-phenyl)-7-trifluoromethyl-pyrazolo[lJ5-a]pyriin^ 35 2-yl}-methanoL,
5-(3-Ethoxy-4-1iifluoromethyl-phenyl)-3-p7ridin-4-yl-7-1xifluorom
ajpyrimidine,

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5-(3-Ethoxy-4-trifiuoro^
pyrazolofl^-ajp^ninridine, . *
2-(3-Ethoxy-4-triflnorometiyl-plienyl)-8-pyridin-4-yl-4-tr^ a]pyrimidine,
5 3-Pyridin-4-yl-5- [3-(2,252-trifluoro-etiiox50-4-trifluoTomethyl-plienyl] -7-1xifiuoromethyl-pyra2olo[l>5-a]p}rriiiudine,
3-(2,6-DmethyI-pyri 7-trLfinoromethyl-pyrazolo [ l,5-a]pyrimidine,
3-(2-Metii7i-pyridin-4-7i)-5-[3-(2^^-trifl ■ 10 trifluoromethyl-pyrazolofljS-alpyrimidine,
8-P}oidin-4-yl-2- [3-(2?2?2-1xifluoro-etiioxy)-4-trifluoroinetiiyl-phenyi] -4-
trifluorometiiyl-iinidazotljS-ajpyriirudine,
8-(2-Methyl-pyridin-4-)d)-2-[3-(2,2>2-1xifluoro-etioxy)-4-iJ^
trifluoromethyl-imidazo[l>5-a]pyrimidine, 15 5-(334-Bis-trifluoromethyl-phenyI)-3-pyridin-4-yl-7-1xifluorom
aJpyTimidine,
5-(334-Bis-trifluoromethyl-phenyl)-3-(2-met]iyl-p^aidm
pyrazolo[1^5-a]pyriirddine>
2-(3,4-Bis-trifluoromethyl-phenyl)-8-(2-methyl-^ 20 imidazo[l?5-a]pyrirnidine>
2-(4-Bromo-phenyl)-8-(2-methyl-pyridin-4-yi)-4-trifluorometiLyl-
a] pyrimidiiiej
5-(4-Bromo-phenyl)-3-pyridin-4-yl-7-iTifluoroinetiiyI-p}T:azoIo[l,^
5-(4-Bromo-phenyl)-3-(2-inetiiyl-pyridin-4-yl)-7-1xifluoromet^ 25 ajp^Timidine,
7-Difluoromet±iyl-3-pyridin-4-yl-5-(4-trifluoromett^^
a] pyrimidine,
7-DifluorometiLyl-3-(2-met]iyl-pyridin-4-yl)-5-(4-trifluoromethy
a]p}niraidine) and 30 7-Difluoromethyl-3-(2-methyl-^^
pyrazolo[l?5-a]pyrimidiiie. " .
In another embodiment the present invention provides a compound of formula I selected from 35 5-(4-dtforo-3-methyl-phenyl)-^
carbonitrile, 5-(4-cMoro-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyra^olo[l,5-a]pyriinidine5

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5-(4-cliLoro-3-methyl-p]i^^
a] pyrirni din e, 5-(3-cHoro-4-fluoro-phenyI)-3-pyiMin-4-y^^
a] pyrimidine> 5 5~(4-trifiuoromethyl-phenyl)-3-py^^
ajpyrimidine, 5-(3-trifluorometky!-pheny^
ajpyrimidine,
5- (3-fiuoro-4-txifluoromethyl~phenyl) - 3 -pyridin-4-yl- 7-trifluoromet±Lyi-pyrazolo [ 1 >5-
10 ajpyrixnidine,
5-(4-cHoro-3-metii7i-phenyl)-3-(2,6-dimeth}d-pyri
pyrazolo [ 1 jS-aJpyrimidiiie, 5-(3>4-dicfaloro-phenyI)-3-(2,6-dimetiiyl-pyridin
ajpyrimidlne;, 15 5-(3-fluoro-4-trifluorometiyl-phenyl)-3-(2?6-diinethyl-pyTid^-4-y^
pyrazolo [1 >5-a] pyrimidiBe, 5-(4-chloro-phenyI)-3-(2-methyl-p}rridin-4-yl)-7-trifluorometiiy^
ajpyrimidine,
5-(3>4r-dicHoro-phenyl)-3-(2-metiiyl-p3nridin-4-yl)-7-1xi£lu^
20 ajpyrimidinej
5-(4-txifluorometh)d-phenyi)-3-(2-mettyI-pyridin-4-yi)-7-trifluoro^
a] pyximidine, 5-(3-trifluoromethyl-phenyI)-3-(2-methyl-pyridin-4-yl)-7-1xiflu^^
a] pyrimidiri e, 25 5-(3-met&yM-trifluorome^
a]pyrimidine, 5-(3-metiiyi-4-1rifluorometiiyl-phenyl)-3-(2,6-dimeti^
1xifluoromet3iyl-pyrazolo[l,5-a]p}Timidine,
5-(3-inetiiyl-4-1xifluorometiyl-phenyl)-3-(2-metiLyl-py^
30 p)Tazolo [l,5-a]pyrimidine5 and
5-(4-eth.oxy-3-trifluoromethyl-phenyl)-3-pyri
ajpyrimidine.
The present invention also provides a process for the preparation of a compound of formula I comprising reacting a compound of formula II


wherein
A is =C(R4)-, wherein R4 is hydrogen, halogen, unsubstituted (c1-c4-alkyl or (C1-C4)-
alkyl substituted by fluorine, unsubstituted c1-c4-alkoxy or (Q-CJ-alkoxy
5 substituted by fluorine, unsubstituted (C3-C6)-cydoalkyl or (C3-C6)-cycloaIkyl
substituted by fluorine, D is =C(R5)-> wherein R5 is hydrogen, halogen, unsubstituted (c1-c4-alkyl or (Q-Q)-
alkyl substituted by fluorine, unsubstituted (C3-C6)-cydoalkyl or (Cs-CeVcycloalkyl
substituted by fluorine,
10 E is =C(R6)-, wherein R6 is hydrogen or halogen, or one of A, D and E is =N-,
R is hydrogen, halogen, c1-c4-alkyl or (C3-C6)-cycloalkyl, and R3 is hydrogen, halogen, (Q-GO-alkyl or (C3-Q)-cydoaIkyl3 with, a compound of formula III
15
wherein L is =N- or =C(H)-,
M is =C(R7)-, when L is =N-, or M is =N-, when L is =C(H)-,
R1 is -CN, unsubstituted pyridinyl, pyridinyl substituted by (C1-c4)-alkyl or the
20 corresponding pyridine-N-oxide, and
R is hydrogen, unsubstituted (c1-c4-allcyl or (c1-c4t)-alkyl substituted by CN, unsubstituted (C3-c6)-cycloalkyl or (C3'C6)-cycloalkyl substituted by CN.
The starting compounds of formula II and III are known or maybe prepared from corresponding known compounds.
£5 The reaction may take place in the presence of a solvent, e.g. acetic acid, under, e.g., reflux conditions. The preparation of compounds of formula I is illustrated in the following examples.

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Example SI: Preparation of l-phenyl-4,4,4-trifluoro-butane-l,3-diones (General procedure A)
To a stirred solution of ethyl trifluoroacetate (1.1 eq.) in tert-butyl-methyl-ether was added dropwise a 5.4M solution of sodium methanolate in methanol followed by a 5 solution of an acetophenone derivative (1.1 eq.) in tert-butyi-methyi-ether. The reaction mixture was stirred at room temperature for 20 h, poured into ice/water, acidified with 2N HQ and extracted with diethyl ether (two times). The combined organic layers were washed with brine (two times), dried (MgSCU) and evaporated. The product was used without further purification.





Example S2: Preparation of l-pyridin7l-4)4>4-trifluoro-butaiie-l>3-diones (General procedure A)
To a stirred solution of ethyl trifluoroacetate (1.1 eq.) in tert-butyl-rnethyl-ether was 5 added dropwise a 5.4M solution of sodium methanolate in methanol followed by a
solution of an acetylpyridine derivative (1.1 eq.) in tert-butyl-methyl-ether. The reaction mixture was stirred at room temperature for 20 h, poured into ice/water, acidified with 2N HC1 and extracted with diethyl ether (two times). The combined organic layers were washed with water (20 ml), the combined water layers neutralised with sat NaHCC>3 10 solution and evaporated to dryness. The obtained solid was stirred three times in warm dichloromethane/MeOH 9:1 and filtered. The combined organic layers were dried (MgSCU) and evaporated. The crude product can be further purified by crystallisation.

Example S3: Preparation of 3-amino-pyridinyl-pyrazoles
15 Following a procedure as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537 - 3541] the following 3-amino-pyridinyl-pyrazoles were prepared starting from the appropriate pyridine:


Example S4: Preparation of 4-(2-Methyl-pyridin-4-yI)-2H-pyrazol-3-ylainine
a) To a stirred mixture of 4'hydroxymethyi"2-methyl-pyridiiie [CAS No. 105250-16-6]
(3.37 g, 27.4 ramol), potassium cyanide (3.56 g, 54.7 mmol) and 18-crown-6 (0.72 g7 2.74
5 mmol) in acetonitrile (75 ml) was added dropwise at 15 - 20°C a solution of
tabutylphosphine (7.16 g, 30.1 mmol) in acetonitrile (25 ml). The reaction mixture was stirred at room temperature for 25 h, poured into water (100 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic layers were washed with water (3 x 100 ml), brine (100 ml) dried (MgSC>4) and evaporated. The crude product was further 10 purified by column chromatography on silica gel (ethyl acetate) to yield 4-cyanomethyi-2-methyl-pyridine (2.26 g, 62%) as a brown oil.
b) A stirred mixture of 4-cyanomethyl-2-methyl-pyridine (2.51 g, 19.0 mmol) and N>N-
oj'oethylfonnamide-diraetiLylacetal (7.63 ml, 57.0 mmol) was heated under reflux
15 conditions for 15 min, evaporated and the crude product purified by column
chromatography on silica gel (dichloromethane/methanol/NH40H 80:10:1) to give 2.08 g of a solid, which was crystallized from diethyl ether/hexane to yield 3-dimethylamino-2-(2-methyl-pyridin-4-yl)-acrylonitrile (1.94 g, 55%) as a brown solid; mp 126°C.
20 c) To stirred solution of 3-dimethylammo-2-(2-met^^ (1.8 g,
9.61 mmol) in ethanol (18 ml) was added at room temperature hydrazine monohydrate (1.03 ml, 21.1 mmol), the reaction mixture was heated under reflux conditions for loh and evaporated. Purification by column chromatography on silica gel (dichloromethane/methanol/NH40H 80:10:1) and crystallization from dlethyi ether
25 yielded 4-(2-methyl-p}nidin-4-yl)-2H-pyrazol-3-ylainine (0.6 g, 36%) as an orange solid. MS (ISP) 175.1 [(M+H)*]; mp 230°C

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Example S5: Preparation of 4-(2,6-Dimetiiyl-pyridin-4-yl)-2H-pyrazol-3-ylainixie
a) A stirred mixture of 4-cyanomethyl-2,6-dimethyl-pyridine [CAS No. 130138-46-4]
(2.20 g, 15.1 nrmol) andN,N-dimetiiy]formanude-dimethylacetal (6.04 ml, 45.2 mmol)
was heated under reflux conditions for 15 min, evaporated and the crude product
5 purified by column chiomatography on silica gel (dicHorornethane/methanol/NH4OH
80:10:1) to give 2.6 g of a solid, which was crystallized from diethyl ether/hexane to yield
3-dimethylamim-2-(2,6-di'niethy^ (2.44 g, 81%) as a brown
solid; mp 149°C.
10 b) To stirred solution of 3-dimethylammo-2-(2,6-dimethy^
(2.2 g, 10.9 mmol) in ethanol (22 ml) was added at room temperature hydrazine monohydxate (1.17 ml, 24.1 mmol), the reaction mixture was heated under reflux conditions for 23h and evaporated. Purification by column chromatography on silica gel (dichloromethane/methanol/NH40H 80:10:1) and crystallization from diethyl ether
15 yielded 4-(2,6"dimethyl-pyridin-4-yl)-2H-pyra2;ol-3-ylamine (0.8 g, 39%) as a light brown solid. MS (ISP) 189.3 [(M+H)+]; mp 222°C.
S6:2-Airuno-3-(3-pvridinyD-lH-imidazole dihydxochloride
20 a) To a stirred solution of sulphuric acid (14 ml> 95 - 97%) and HNO3 (10 ml, fum.) was added at 0°C 3-(3-pyridinyl)-lH-imidazole [CAS No. 51746-85-1, commercially available] (4.25 g, 29.3 mmol). The reaction mixture was stirred at room temperature for 45 min and at 50°C for 6h and poured into ice-water (100 ml). Solid NaHCC>3 was added to the stirred mixture until the pH reached 5-6, the precipitated product was collected by
25 filtration and washed with water and hexane to yield 2-nitro-3-(3-pyridinyl)-lH-imidazole (5.53-g, 99%) as an off-white solid; mp 261°C.
b) A stirred solution of 2-nitro-3-(3-pyridinyl)-lH-imidazole (5.14 g, 27.0 mmol) in
methanol (800 ml) was hydrogenated at room temperature on Raney Nickel (2.5 g) for
30 4h. The catalyst was removed by filtration, 3N hydrochloric acid (30 ml) was added and the solution evaporated to 50 ml. While stirring diethyl ether was added and the precipitated product was collected by filtration to yield 2-amino-3-(3-pyridinyl)-lH-imidazole dihydrochloride (5.39 g, 86%) as abrown solid. MS (ISP) 161.2 [(M+H)+]; mp 253°C.
35
S7: 2-Amino-3-(4-pvridinvlVlH-iinidazole

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a) To a stirred solution of sulphuric acid (21 ml, 95 - 97%) and HNO3 (15 ml, fum.) was added at 0DC 3-(4-pyridbyl)-lH-imidazole [CAS No. 51746-87-3] (6.36 g, 43.8 mmol). The reaction mixture was stirred at room temperature for 45 min3 at 55DC for 23h and at 5 100°C for 2h and poured into ice-water (200 ml). Sodium hydroxide solution (32%) was added to the stirred mixture until the pH reached 5-6, the precipitated product was collected by filtration and washed with water and hexane to yield 2-nitro-3-(4-pyridinyl)-lH-imidazole (7.95 g, 95%) as a light yellow solid; mp 234°C.
10 b) A stirred solution of 2-nitro-3-(4-pyridinyl)-lH-imidazole (1.19 g, 6.26 mmol) in 7N methanol/NH3 (25 ml) and methanol (25 ml) was hydrogenated at room temperature on Raney Nickel (1 g) for 4h. The catalyst was removed by filtration and the solution evaporated The crude product was purified by column chromatography on silica gel (dichloromethane/ methanol/NI^OH 40:10:1) to yield 2-amino-3-(4-pyridinyl)-lH-
15 imidazole (0.85 g, 85%) as a green solid MS (ISP) 161.2 [(M+H)*]; mp 190°C.
S8:2-Ainino-3-(r2-inethvl-4-pvridinyD-lH-iTriidazole
a) To a stirred suspension of 4-acetyl-2-methyl-pyridine [CAS No. 2732-28-7] (9.7 g,
20 71.8 mmol) in water (115 ml) was added at room temperature hydroxylairnne
hydrochloride (8.48 g, 122 mmol) and the mixture was heated to 70°C. At this temperature methanol (145 ml) was added dropwise over a period of 15 min and afterwards a solution of sodium acetate trihydrate (25.4 g, 187 mmol) in water (115 ml) was added dropwise over a period of 15 min. The reaction mixture was stirred at 80°C for
25 3.5 h, brine (150 ml) was added and the solution was extracted with ethyl acetate (2 x 250 ml). The combined organic layers were washed with brine (150 ml), dried (MgSCU) and evaporated. The crude product was purified by crystallization from ethyl acetate/hexane to give l-(2-methyl-pyridin-4-yl)-ethanone oxime (7.25 g> 67%) as an off-white solid; mp 154°C
30
b) To a stirred solution of l-(2-methyl-pyridin»4-yl)-ethanone oxime (7.14 g> 47.5
mmol) in pyridine (20 ml) was added at room temperature toluene-4-sulfonyl chloride
(9.88 g, 51.8 mmol), the reaction mixture was stirred for 3h, poured into ice-water (300
ml) and the precipitated solid collected by filtration. Hexane (100 ml) was added, the
35 mixture was stirred at room temperature for lh and the product collected by filtration to give l-(2-methyl-p")7ridin-4-yl)-(O-toluene-4-sufonyl)-ethanone oxime (11.1 g, 77%) as a white solid; mp 91°C.

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c) To a stirred suspension of l-(2-methyl-pyridin-4-yl)-(0-toluene-4-sufonyl)-ethaiione
oxime (11.0 g, 36.1 mmol) in ethanol (35 ml) was added a solution of potassium
ethanolate (5.03 g, 56.7 mmol) in ethanol (35 ml) and the reaction mixture was stirred at
5 room temperature for 17 h. The precipitated solid was collected by filtration and washed with diethyl ether (200 ml). The combined filtrates were washed with 2N HC1 (2 x 80 ml, 1 x 40 ml) and the combined water layers evaporated to give crude l-(2-methyl-pyridin-4-yl)-2-amino-ethanone dihydrochloride (8.51 g, 99%) as a light brown solid, which was used without further purification. 10
d) To a stirred solution of crude l-(2-methyl-pyridin-4-yi)-2-amino-ethanone
dihydrochloride (8.50 g, 35.8 mmol) in water (60 ml) was added at room temperature
potassium thiocyanate (16.4 g> 168 mmol) and the reaction mixture was heated under
reflux conditions for 3h and at 0°C for 2 h. The precipitated solid was collected by
15 filtration, saturated sodium bicarbonate solution (100 ml) was added and the mixture was stirred at room temperature for 2 h. The product was collected by filtration to give 4-(2-inetihyl-pyridin-4-yl)-l>3-dihydro-imidazole-2'1^one (5.44 g, 79%) as a light brown solid; MS (ISP) 192.2 [(M+H)+].
20 e) To a stirred solution of HNO3 (43.3.ml, 65%) and water (130 ml) was added at 80°C in small portions 4-(2-metiiyl-pyridin-4-yl)-13-dihydro-imidazole-2-thione (5.20 g> 27.2 romol) and the mixture was heated under reflux conditions for 2 h. The reaction mixture was cooled (ice) and solid NaHCC>3 was added to get a basic solution. Solid NaCl was added and the solution was extracted -with THF (3 x 200 ml). The combined organic
25 layers were dried (MgSOj and evaporated to give 3-(2-methyl~4-pyridinyl)-lH-imidazole (4.16 g, 96%) as a yellow solid; MS (ISP) 160.2 [(M+H)+].
f) To a stirred solution of sulphuric acid (14 ml, 95 - 97%) and HNO3 (10 irii, fum.) was
added at 0°C 3-(2-methyl-4-pyridinyl)-lH-imidazole (4.0 g, 25.1 mmol). The reaction
30 mixture was stirred at room temperature for 50 min, at 100°C for 2.5 h and at 110°C for lOh and poured into ice-water (70 ml). Solid NaHCOs was added to the stirred mixture until the pH reached 5. The solution was extracted with THF (4 x 200 ml), the combined • organic layers were dried (MgSO4) and evaporated to give 2-nitro-3-(2-methyl-4-pyridinyl)-lH-imidazole (3.4 g, 66%) as a light yellow solid; MS (ISP) 205.2 [(M+H)+j.
35
g) A stirred solution of 2-nitro-3-(2-methyl-4-pyridinyl)-lH-imidazole (3.40 g, 16.6
mmol) in 7N methanol/NH3 (70 ml) and methanol (70 ml) was hydrogenated at room

WO 2005/040171 PCT/EP2004/010807
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temperature on Raney Nickel (2.9 g) for 2h. The catalyst was removed by filtration and the solution evaporated. The crude product was purified by column chromatography on silica gel (dichloromethane/ rriethanol/NHiOH 40:10:1) to yield 2-amino-3-(2-methyl-4-pyridinyl)-lH-iinidazole (1.71 g, 59%) as a green solid. MS (ISP) 175.1 [(M+H)+]; mp 5 167°C.
Example 1: Preparation of phenyl-7-txifluoromethyl-pyrazolo [ip-ajpyrimidine-S-
carbonitriles and pyridinyl-7-txifluoroinethyi-pyra2X)lo[l?5-a]pyriinid7Be-3-carbonitriles (General Procedure B)
10 A stirred mixture of commercially available 3-amino-4-cyano-pyrazole (1 eq.) and a l-phenyl-^^-txifluoro-butane-l^-^
dione (1 eq.)? prepared according to general procedure A, in acetic acid was heated under reflux conditions for 3.5 h. The reaction mixture was evaporated and the product was isolated by column chromatography (heptane/ethyl acetate) and further purified by
15 crystallization. If the product precipitates during the reaction it can be isolated by filtration and further purified by crystallization.




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Example 1.1 5-(3-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile.
Reaction of l-(3-chloro-phenyl)-4,4,4-trifLuoro-butane-l,3-dione (251 ing, 1.0 mmol), 5 prepared from commercially available 3-chloro-acetophenone according to general procedure A, and 3-arnino-4-cyano-pyrazole (108 mg, 1.0 mrnol) according to general procedure B yielded the title compound as a yellow solid (150 mg, 46%). MS (ISP) 323.1 [(M+H)+];mp204°C.
Example 1.2
10
5-(4-MetlLyl-phenyl)-7-1xifluoromthyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile.

Reaction of l-(4-metbyl-plienyl)-4,4,4-trifluoro-butane-l?3-dione (230 mg, 1.0 mmol), prepared from commercially available 4-methyl-acetophenone according to general procedure A, and 3-amino-4-q^ano-pyrazole (108 mg, 1.0 mmol) according to general 15 procedure B yielded the title compound as a light yellow solid (151 mg, 50%). MS (ISP) 303.1 [(M+H)+];mpl21°C.
Example 1.3 5-(2-Chloro-phenyl)-7-trifluoromethyl-pyrazolo [1,5-a]pyrimidine-3-carbonitrile
20 Reaction of l-(2-chloro-phenyl)-434,4-trifluoro-butane-l>3-dione (251 mg, 1.0 mmol), prepared from commercially available 2-chloro-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg> 1.0 mmol) according to general procedure B yielded the title compound as an off-white solid (73 mg, 23%). MS (ISP) 323.1 [(M+H)+];mpl69°C.
25 Example 1.4
5-(2,4-DicUoro-phenyl)-7-trifluoromet
Reaction of l-(2>4-dichloro-phenyl)-4,4,4-trifluoro-butane-l?3-dione (285 mg, 1.0 mmol), prepared from commercially available 2,4-dichloro-acetophenone according to 30 general procedure A, and 3-anrino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a light brown solid (63 mg, 18%). MS (ISP) 357.1 [(M+H)+j; mp 180°C.
Example 1.5
35 5-(3-Methyl-phenyl)-7-trifluorothyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile.


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Reaction of l-(3-methyl-plien7l)-4>4>4-trifluoro-butane-l33-dioiie (230 ing, 1-0 mmol), prepared from cominercialLy available 3-methyl-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 ing, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (164 mg, 54%). MS (ISP) 303.2 5 [(M+H)+];mp202°C.
Example 1,6
5- (3-Trifiuoromethyl-phenyl) - 7-trifluoromethyl-pyrazolo [ 1,5-a] pyrimidine-3-carbonitrile
10 Reaction of l-(3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-l>3-dione (284 mg, 1.0 mmol), prepared from commercially available 3-txifiuoromethyl-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a white solid (151 mg, 42%). MS (ISP) 357.0 [(M+H)*]; mp 192°C.
15 Example 1.7
5-(4-Trifluorometiiyl-phenyl)-7-txifluorometiiyl-p^Tazolo[l,5-a]pyriinidine-3-carbonitrile
Reaction of l-(4-trifluoromethyl-phenyl)-434,4-trifluoro-butane-l?3-dione (284 mg, 1.0 20 mmol), prepared from commercially available 4-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as an off-white solid (137 mg, 38%). MS (ISP) 357.0 [(M+H)*]; mp 176°C.
Example 1,8
25
5-(3-HuorcHphenyl)-7-txifluoromet
Reaction of l-(3-fluoro-phenyl)-434,4-trifluoro-butane-l,3-dione (234 mg, 1.0 mmol), prepared from commercially available 3-fluoro-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general 30 procedure B yielded the title compound as a light yellow solid (141 mg, 46%). MS (ISP) 306.9 [(M+H)+]; mp 199°C.
Example 1.9 5-(4-Fluoro-phenyI)-7-trifluoromethylthyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile.
-
35 Reaction of l-(4-fluoro-phenyl)-4,4,4-trifluoro-butane-l?3-dione (234 mg, 1.0 mmol), prepared from commercially available 4-fluoro-acetophenone according to general

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procedure A, and 3-amino-4-cyano-pyrazole (108 mg> 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (118 mg> 39%). MS (ISP) 306.9 [(M+H)+];mpl98°G
Example 1.10 5
5-(2,4-Difluoro-phenyl)-7-1xiJluoro
Reaction of l-(2)4"difluoro-phenyl)-4)4>4^trifluoro-butane-l>3-dione (252 mg, 1.0 mmol)> prepared from commercially available 2,4-difluoro-acetophenone according to general procedure A, and 3-amino~4-qrano-pyrazole (108 ing, 1.0 mmol) according to 10 general procedure B yielded the title compound as a light yellow solid (72 mg, 22%). MS (ISP) 325.0 [(M+H)+]; mp 149DC.
Example 1.11 5-(2-Fluoro-phenyl)-7-trifluorometthyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile.

15 Reaction of l-(2-fluoro-phenyl)-4,4,4-trifluoro-butane-l?3-dione (234 mg? 1.0 mmol), prepared from commercially available 2-fluoro-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a light yellow solid (83 mg, 27%). MS (ISP) 307.1 [(M+H)+]; mp 165°C.
20 Example 1.12
5-(3>4-DifLuoro-phenyl)-7~trifluoromethythyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile.
l
Reaction of l-(3,4-difluoro-phenyl)-4>434-trifluoro-butane-l?3-dione (252 mg, 1.0 mmol), prepared from commercially available 3,4-difluoro-acetopbenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to 25 general procedure B yielded the title compound as a light yellow solid (137 mg> 42%).
Example 1.13
5- (4-FIuoro-3-trifluoromet±iyl-phenyl) - 7-trifl.uoromethyl-pyrazolo [ 1,5- a] pyrimidine- 3 -carbonitrile
Reaction of l-(4-fluoro-3-1xifluoromeiiiyl-phenyl)-4)4J4-trifluoro-butane-l,3-dione (302 30 mg, 1.0 mmol), prepared from commercially available 4-fluoro3-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as an off-white solid (144 mg, 38%). MS (ISP) 375.0 [(M+H)+]; mp 204°C.

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Example 1.14
5-(3-Choro-4-fluoro-phenyl)-7-trifluoromeththyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile.
yl-cafbonitrile
Reaction of l-(3-chloro-4-fluoro-phen7l)-4,4,4-trifluoro-butaiie--l?3-diorLe (269 mg> 1.0 5 mmol), prepared from commercially available 3-chloro-4-fluoro-acetophenone according to general procedure A, and 3-amino-4-qrano-pyrazole (108 ing, 1.0 mmol) according to general procedure B yielded the title compound as an off-white solid (109 mg, 32%). MS (ISP) 341.0 [(M+H)+]; mp 190°C.
Example 1.15
10 5-(4-Choro-3-metiLyl-phenyl)-7-trifluoromeththyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile.
yl carbonitrile
Reaction of l-(4-chloro-3-methyl-phenyl)-4?4J4-trifluoro-butane-l>3-dione (264 mg, 1.0 mmol), prepared from commercially available 4-chloro-3-methyl-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) 15 according to general procedure B yielded the title compound as an off-white solid (128 mg, 38%). MS (ISP) 337.1 [(M+H)+]; mp 216°C.
Example 1.16 5- (3,4-Dichlor o-phenyl) -7-trifluoromethyl-pyrazolo [ 1,5- a] pyrunidine-3-carbonitrile
Reaction of ^(S^dichloro-pheny^^A^-trifluoro-butane-l^-dione (285 mg, 1.0 20 mmol), prepared from commercially available 3,4-dichloro-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (140 ing, 39%). MS (ISP) 356.9 [(M+H)+]; mp 206°C.
Example 1.17
25 5-(3-Huoro-4-txifluoromethyl-ph^ carbonitrile
Reaction of ^(S-fluoro^-txifluoromethyl-pheny^^^^-trifluoro-butane-ljS-dione (302 mg, 1.0 mmol), prepared from commercially available 3-fluoro-4-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 30 mg, 1.0 mmol) according to general procedure B yielded the title compound as an off-white solid (139 mg, 37%). MS (ISP) 375.0 [(M+H)+]; mp 184°C.
Example 1,18 2-(3-Methyl-4-trifluorometh^
carbonitrile

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Reaction of l-(3-methyl-4-trifluthyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile.
orom
(224 mg, 0.75 mmol)> prepared from 3-methyi-4-trifluor6methyi-acetophenone (synthsesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-cyano-pjrrazole (81 mg> 0.75 mmol) according to general procedure B yielded 5 the title compound as an off-white solid (142 mg, 51%). MS (ISP) 371.1 [(M+H)+]; mp 209°C.
Example 1.19
2-(4-Trifluoroethxy-3-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrazolo[1,5-a]pyriinidine-8-carbonitrile
10 Reaction of l-(4-trifiuor-
dione (382 mg> 1.0 mmol), prepared from 4-trifluoroethosy-3-trifluorometliyl-acetophenone (synthsesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-q^ano-pyrazole (108 mg7 1.0 mmol) according to general procedure B yielded the title compound as an off-white solid (226 mg, 50%). MS (ISP)
15 453.0 [M+];mp215°C.
Example 1.20
5-Pyridin-2-yl-7-trifluorometh
Reaction of l-pyridin-2-yl-4,4,4-trifluoro-butane-l>3-dione (217 mg, 1.0 mmol), prepared from commercially available 2-acetylpyridine according to general procedure A, 20 and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a light brown solid (135 mg, 47%). MS (ISP) 289.9 [(M+H)+];mp208°C
Example 1.21 5-Pyridin-3-yl-7-trifluoroineth'yi-pyrazolo [ 1 ,5-a]pyrinidine-3-carbonitrile
25 Reaction of l-pyridin-3-yl-4,4,4-trifluoro-butane-l,3-dione (217 mg, 1.0 mmol), prepared from commercially available 3-acetylpyridine according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as an off-white solid (45 mg, 16%). MS (ISP) 290.2 [(M+H)+];mpl93°C.
30 Example 1.22
5-Pyridin-4-yl-7-tri£luoromethyl-pyrazolo [1,5- a]pyrimidineo-carb onitrile
Reaction of l-pyridin-4-yl-4,4,4-trifluoro-butane-l,3-dione (217 mg, 1.0 mmol), prepared from commercially available 4-acetylpyridine according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg; 1.0 mmol) according to general procedure B

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yielded the title compound as a light yellow solid (110 ing, 38%). MS (ISP) 289.8 [(M+H)+];mp233°Q
Example 2: Preparation of phenyl-7-trifIuoromethyl-p}T'a2olo[l,5-a]pyriinidine-3-
5 carbonitriles (General Procedure B)
A stirred mixture of commercially available 3-amino-4-cyano-5-methyl-pyrazole (1 eq.) and a l-phenyl^^^trifluoro-butane-l^-dione (1 eq,), prepared according to general procedure A, in acetic acid was heated under reflux conditions for about 3.5 h- The reaction mixture was evaporated and the product was isolated by column 10 chromatography (heptane/ethyl acetate) and farther purified by crystallisation. If the product precipitates during the reaction it can be isolated by filtration and further purified by crystallization.

Example 2.1
15 2-Me1&yl-5-(4-trifluoromethyl-ph^ carbonitrile
Reaction of l-(4-trifluoromethyl-phenyl)-4?4,4*trifluoro-butane-l?3-dione (284 mg> 1.0 mmol), prepared from commercially available 4-trifluoromethyl-acetophenone according to general procedure A, and commercially available 3-amino-4-cyano-5-20 methyl-pyrazole (122 nag, 1.0 mmol) according to general procedure B yielded the title compound as a light yellow solid (234 mg> 63%). MS (ISP) 371.1 [(M+H)*]; mp 1S4°C.

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Example 2.2
2-Methyl-5-(3-trifLnoromethyl-pHenyl^ carbonitrile
Reaction of l-(3-trifluoromethyl-phenyl)-45454-t^ (284 ing, 1.0
5 mmol), prepared from commercially available 3-trifluoromethyl-acetophenone
according to general procedure A, and commercially available 3-amino-4-cyano-5-
methyl-pyrazole (122 ing, 1.0 mmol) according to general procedure B yielded the title
■ compound as a light yellow solid (272 mg, 73%). MS (ISP) 371.1 [(M+H)+]; mp 215°C.
Exarnple 2.3
10 5- (4-CUoro-phenyl)-2-3nethyl-7-trifluoroiiiethyl-pyrazoIo [l,5-a.]pyrimidine~3-carbonitrile
Reaction of l-(4-chloro-phenyl)-4,4?4-trifluoro-butane-l,3-dione (251 mg, 1.0 mmol), prepared from commercially available 4-chloro-acetophenone according to general procedure A, and commercially available 3-amino-4-q?rano-5-metiiyl-pyrazole (122 mg, 15 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (222 mg, 66%). MS (ISP) 337.1 [(M+H)+]; mp 238°C.
Example 2.4
5-(3-CHoro-4-fluoro-phenyl)-2-methyl-7-^^ 3-carbonitrile
20 Reaction-of l-(3-chloro-4-fluoro-phenyl)-4,4,4-trifluoro-butane-l?3-dione (269 mg, 1.0 mmol), prepared from commercially available 3-chloro-4-fiuoro-acetophenone according to general procedure A, and commercially available 3-amino-4-q7ano-5-methyl-pyrazole (122 mg, 1.0 mmol) according to general procedure B yielded the title compound as alight yellow solid (243 mg, 69%). MS (ISP) 355.0 [(M+H)+3; mp 196°C.
25
Example 3: Preparation of phenyl-7-trifluoromethyl-pyrazolo [ 1,5-a] pyrimidine-3-
carbonitriles (General Procedure B)
A. stirred mixture of commercially available 3-amino-4-cyano-5-q'anomethyl-pyra2ole (1 eq.) and a l-phenyl-4,4>4-trifluoro-butane-l,3-dione (1 eq.), prepared according to 30 general procedure A, in acetic acid was heated under reflux conditions for 3.5 h. The reaction mixture was evaporated and the product was isolated by column chxomatography (heptane/ethyl acetate) and further purified by crystallization. If the product precipitates during the reaction it can be isolated by filtration and further purified by crystallization.


Example 3.1
5-(3-CMoro-4-fluoro-phenyl)-2-cyanometh^ a]pyriniidine-3-cafbonitrile
5 Reaction of l-(3-cMoro-4-fluoro-phenyi)-4,4>4-trifl.uoro-butarie-l>3-dione (269 mg, 1.0 mmol), prepared from commercially available 3-chloro-4-fluoro-acetophenone according to general procedure A, and commercially available 3-amino-4-cyanoo-cyanomethyl-pyrazole (147 mg, 1.0 mmol) according to general procedure B yielded the title compound as a light yellow solid (223 mg> 59%). MS (ISP) 380.1 [(M+H)*]; mp 10 185°C.
Example 3.2 5-(4-Cbioro-3-metii)i-phenyl)^^
a]pyrimidine-3-carbonitrile
Reaction of l"(4^cUoro-3-methyl-phen}d)-4^,4-trifluoro-b-utane-l:)3-dione (132 mg, 0.5 15 mmol), prepared from commercially available 4-chloro-3-methyl-acetophenone according to general procedure A, and commercially available 3-amrno-4-cyano-5-cyanometbyl-pyrazole (74 mg> 0.5 mmol) according to general procedure B yielded the title compound as a light yellow solid (99 mg, 53%). MS (ISP) 376.1 [(M+H)+]; mp 23S°C.
20
Example 4: Preparation of 5-phenyl-3-pyridinyl-7"faifluoroinethyl-p}7razolo [1,5-
a]pyrimidines (General Procedure B)
A stirred mixture of a 3-amino-4-pyridinyl-pyrazole (1 eq.) and a l-phenyi-4,4,4-trifluoro-butane-13-dione (1 eq.), prepared according to general procedure A> in acetic 25 acid'was heated under reflux conditions for 3.5 h. The reaction mixture was evaporated and the product was isolated by column chromatography (heptane/ethyl acetate) -and further purified by crystallization. If the product precipitates during the reaction it can be isolated by filtration and further purified by crystallization.











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Reaction of l-(4-cHoro-plienyi)-434,4-trifluoro-butane-l33-dioiie (251 xng, 1.0 mmol), prepared from commercially available 4-chloro-acetophenone according to general procedure A, and 3-aniino-4-(3-pyridinyl)-pyTazole [CAS No. 40545-68-2; prepared from 3-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett 12 (2002) 3537 -5 3541] (160 mg, 1.0 mrnol) according to general procedure B yielded the title compound as ayellowsolid (306 rng, 82%). MS (ISP) 375.3 [(M+H)*]; mp 188°C.
Example 4.2 5-(4~Chloro-phenyl)-3-pyri(H^
Reaction of l-(4-chloro-phenyl)-4?4)4-trifluorO'butane-l>3-dione (125 mg, 0.5 mmol), 10 prepared &orn commercially available 4-chloro-acetopbenone according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett 12 (2002) 3537 -. 3541] (80 mgj 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (135 mg, 72%). MS (ISP) 375.3 [(M+H)*]; mp 274°C.
15 Example 4.3
5-(4-CHoro-3-methyi-phenyl)-3-pyri Reaction of l-(4-chloro-3-methyl-ph.enyl)-4,4?4-trifluoro-butane-l>3-dione (265 mg> 1.0 mmol), prepared from commercially available 4-chloro-3-methyl-ac^tophenone 20 according to general procedure A, and 3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from S-q^anometh'jd-pyridine as described in Bioorg. Med. Chem. Lett 12 (2002) 3537 — 3541] (160 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (274 mg, 70%). MS (ISP) 375.3 [(M+H)*]; mp 193°C.
25 Example 4.4
5-(4-CUoro-3-methyI-phenyl)-3-pyridin-4-yl-7-trifluoromethyl-pyra2X)lo[l,5-a]pyrimidine
Reaction of l-(4-cMoro-3-methyl~phenyl)-4,434-tri£Luoro--butane-l>3-dione (132 mg, 0.5 mmol), prepared from commercially available 4-chloro-3-methyl-acetophenone 30 according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett 12 (2002) 3537 - 3541] (80 mg> 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (145 mg, 75%). MS (ISP) 389.2 [(M+H)+]; mp 247°C.

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Example 4.5
5- (4-Choro~3-methyl-phenyl)-3-pyridin-2-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine
Reaction of l-(4-choro-3-methyl-phenyl)-4,4,4-1xifluoro-butane-l,3-diorie (265 mg> 1.0
5 mmol), prepared from commercially available 4-cHoro-3-methyl-acetophenone
according to general procedure A, and 3-amino-4-(2-pyridinyl)-pyrazole [CAS No.
493038-87-2; prepared from 2-cyanometiiyl-pyridiQe as described in Bioorg. Med.
Chem. Lett 12 (2002) 3537 - 3541] (160 ing, L0 mmol) according to general procedure
B yielded the title compound as a yellow solid (270 mg, 69%). MS (ISP) 389.2 [(M+H)+];
10 mp 133°C
Example 4.6
5-(3-CUoro-4-fluoro-phenyI)-3-pyridin-3-yl-7-1xifluoroinetiiyI-pyrazolo [1,5-ajpyrimidine
Reaction of l-(3-chloro-4-fluoro-phenyl)-4,4)4-trifluoro-butane-l>3-dione (269 mg, 1.0 15 mmol), prepared from commercially available 3-chloro-4-fluoro-acetophenone
according to general procedure A, and 3-amino-4-(3-pyridinyl)-pyrazole [CAS No.
40545-68-2; prepared from 3-cyanomethyl-pyridine as described in Bioorg. Med. Chem.
Lett 12 (2002) 3537 - 3541] (160 mg, 1.0 mmol) according to general procedure B
yielded the title compound as a yellow solid (270 mg, 69%). MS (ISP) 393.1 [(M+H)+]; 20 mp 190°C
Example 4.7
5- (3-CUoro-4-fluoro-pIienyl)-3-pyridin-4-yl-7-trifluoromethyl-pyrazolo [1,5-a]pyrimidine
Reaction of l-(3-ciloro-4-fluoro-phenyl)-434,4-tri£uoro-butane-l,3-dione (134 mg, 0.5 25 mmol), prepared from commercially available 3-chloro-4-fluoro-acetoplienone according to general procedure A, and 3-amino-4-(4-pyridinyi)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med Chem. Lett. 12 (2002) 3537 - 3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (82 mg, 42%). MS (ISP) 393.1 [(M-hH)+]; 30 mp 265°C.
Example 4.8 5-(3-Choro-4-fluoro-phenyI)-3-pyridin-2-yl-7-trifluorometiiyl-pyrazolo[l,5-
ajpyrimidine
Reaction of l-(3-chloro-4-fluoro-plienyl)-4,4,4-trifluoro-butane-l>3-dione (269 mg, 1.0 35 mmol), prepared from commercially available 3-choro-4-fiuoro-acetophenone

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according to general procedure A, and 3-ainino-4~(2-pyridinyl)-pyrazole [CAS No. 493038-87-2; prepared from 2-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537 - 3541] (160 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (279 mg, 71%). MS (ISP) 393.1 [(M+H)+]; 5 mp 197°C.
Example 4.9 5- (3,4-Dichloro-phenyi) - 3-pyridin-3-yl- 7-trifluoromethyl-pyrazolo [1,5-a] pyrimidine
Reaction of l-(334-dicMoro-plienyl)-4)4?4-trifluoro-butane-l>3^dione (285 mg, 1.0 rnmol), prepared from commercially available 3,4-dichloro-acetophenone according to LO general procedure A, and 3-anaino-4-(3-pyridinyl)-p)7razole [CAS No. 40545-68-2; prepared from 3-cyanometbyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537 - 3541] (160 mg, 1,0 mmol) according to general procedure B yielded the title compound as a light yellow solid (274 mg, 67%). MS (ISP) 409.1 [(M+H)+]; mp 224°C.
15 Example 4.10
5-(3,4-DicHoTO~phenyl)-3-pyridm-4^
Reaction of l-(3?4-dichloro-plienyl)-4>4J4-trifluoro-butane-l>3-dione (285 mg> 1.0 mmol), prepared from commercially available 3,4-dichloro-acetophenone according to general procedure A, and 3-amino-4-(4-ppndinyl)-pyrazole [CAS No. 216661-87-9; 20 prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett 12 (2002) 3537 - 3541] (160 ing, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (94 mg, 46%). MS (ISP) 409.2 [(M+H)+]j mp 260°C.
Example 4.11 5-(3,4-DicUoro-phenyi)-3-pyridin-2-yl-7-1xif[uoromethyl-pyrazolo [1,5-ajpyrimidine
25 Reaction of l-(3J4-dichloro-phenyl)-4>4)4-trifluoro-butane-l>3-dione (285 mg, L0 mmol), prepared from commercially available 3,4-dichloro-acetophenone according to general procedure A, and 3-arrrino-4-(2-pyridinyl)-pyrazole [CAS No. 493038-87-2; prepared from 2-cyanomethyi-pyridine as described in Bioorg- Med. Chem. Lett. 12 (2002) 3537- 3541] (160 mg, 1.0 mmol) according to general procedure B yielded the
30 title compound as a yellow solid (223 mg, 55%). MS (ISP) 409.2 [(M+H)"*]; mp 188°C.
Example 4.12
5- (4-Trifluoromethyl-phenyl) - 3 -pyridin-2-yl-7-trifluoromethyl-pyrazolo [ 1,5-ajpyximidine

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Reaction of l-(4-trifluoroineth.yl-phenyl)-44)4-trifliioro-butane-l?3-dione (142 mg, 0.5 rnmol), prepared from commercially available 3,4-dichloro-acetophenone according to general procedure A, and 3-amiino~4-(2-pjTidinyl)-pyrazole [CAS No. 493038-87-2; prepared from 2-cyanometkyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 5 (2002) 3537 - 3541] (SO mg, 03 mmol) according to general procedure B yielded the title compound as a yellow solid (145 mg, 71%). MS (ISP) 409.2 [(M+H)+j; mp 202°C.
Example 4.13
5-(3-Trifluoro:methyl-phen^^ ajpyrimidine
10 Reaction of l-(3-trifluorometiiyl-phenyl)"4?4,4-trifluoro-butane-l>3-dione (142 mg, 0.5 mmol), prepared from commercially available. 3-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(3-pyridinyl)-p)a-azole [CAS No. 40545-68-2; prepared from 3-cyanomethyl«pyridine as described in Bioorg. Med. Chem. Lett 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded
15 the title compound as a yellow solid (126 mg, 62%). MS (ISP) 409.2 [(M+H)+]; mp 171°C.
Example 4,14
5- (4-Trifluoromethyl-phenyI)-3 -pyridin-3-yl-7-trifluoromethyl-p}Ta2;olo[l>5-a]pyrimidine
20 Reaction of l-(4-1^uoromethyi-phenyl)-4,4)4-trifluoro-butane-l,3-dione (142 mg, 0.5 mmol), prepared from commercially available 4-trifluoromethyl-acetophenone according to general procedure A, and 3-amiiio-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from 3-q^anomethyl-pyridine as described in Bioorg. Med. Chem. Lett 12 (2002) 3537 - 3541] (80 mg, 0.5 mmol) according to general procedure B yielded
25 the title compound as a ydkrw solid (142 mg, 70%). MS (ISP) 409.2 [(M+H)+]; mp 163°C.
Example 4> 15
5- (4-Trifluoromethyl-phenyl)- 3 -pyridin-4-yl-7-trifluor ometiyl-pyraz;olo[l,5-ajpyrimidine
30 Reaction of l-(4-1xifluorometh7l-phenyl)-4J4J4-trifluoro-b'a.tane--l>3-dione (142 mg, 0.5 mrnol), prepared from commercially available 4-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett 12 (2002) 3537 - 3541] (80 mg, 0.5 mmol) according to general procedure B
35 yielded the title compound as a yellow solid (93 ing, 46%). MS (ISP) 409.2 [(M+H)+]; mp 261°C.

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Example 4.16
5- (3-Tri£Luoromethyl-phenyl) -3-p7ridin-4-yl-7-trifluorometh7l-pyrazolo[l,5-ajpyrimidine
Reaction of l-(3-1xifluoromethyl-phenyl)-4A4-trifluoro-butane-l3-ciione (142 mg, 0.5 5 mmol), prepared from commercially available 3-trifluoromethyl-acetophenone
according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No.
216661-87-9; prepared from 4-cyanomethyi-pyridine as described in Bioorg. Med.
Chem. Lett 12 (2002) 3537 - 3541] (80 mg, 0.5 mmol) according to general procedure B
yielded the title compound as a yellow solid (95 mg, 47%). MS (ISP) 409.2 [(M+H)+]; L0 mp 241°G
Example 4.17
5- (3-Huoro-4-trifluoromethyl-ph^ [ 1,5-
a] pyrimidine
Reaction of ^(S-fluoro^-trifLuoromeliiyl-plieny^^^^-trifluoro-butane-l^-dione (151
15 ing, 0.5 mmol), prepared from commercially available 3-fluoro-4-trifLuoromethyl-
acetophenone according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole
[CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg.
Med. Chem. Lett. 12 (2002) 3537 - 3541] (80 mg, 0.5 mmol) according to general
procedure B yielded the title compound as a yellow solid (92 mg, 43%). MS (ISP) 427.0
20 [(M+H)+];mp2620C.
Example 4.18
5-(3-Ruoro-4-trifluorometiyl-p a] pyrimidine
Reaction of l-(3-fluoro-4-1xifluoromethyl-phenyl)-44>4-trifluoro-butane-l,3-dione (151
25 mg, 0.5 mmol), prepared from commercially available 3-fluoro-4-trifluoromethyl-
acetophenone according to general procedure A, and 3-ammo-4-(3-pyridmyl)-pyrazole
[CAS No. 40545-68-2; prepared from 3-cyanomethyl-pyridine as described in Bioorg.
Med. Chem. Lett 12 (2002) 3537 - 3541] (80 mg, 0.5 mmol) according to general
procedure B yielded the title compound as a yellow solid (135 mg, 63%). MS (ISP) 427.0
30 [(M+H)+];mpl62°C.
Example 4.19
5-(4-CUoro-phen7l)-3-(2,6-dime a] pyrimidine
Reaction of l-(4-chloro-phenyl)-4,4,4-trifLuoro-butane-l?3-dione (125 ing, 0.5 mmol), 35 prepared from commercially available 4-chloro-acetophenone according to general

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procedure A, and 3-aTTiino-4-(2,6-dimet^yl-4-pyridiiiyl)-p]T:azole [prepared from 4-q'anomethyl-2,6-dimethyl-pyridine, CAS KTo. 130138-46-4, see part synthesis of amino-pyrazole derivatives] (94 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (95 mg> 47%). MS (ISP) 403.2 [(M+H)+]; mp 256°C.
5 Example 4.20
5-(4-Chloro-3-me:thyl-phenyl)-3-(2,6-dimet^^ pyrazolo[l,5-a]pyrimidine
Reaction of l-(4-cUoro-3-meth7i-phenyl)-4>4,4-t3iQuoro-b-utane-l>3-dione (132 rag, 0.5 mmol), prepared from commercially available 4-dJoro-3-methyl-acetophenone 10 according to general procedure A, and 3-ajmino-4-(236-dimetiiyl-4-p}rridinyl)-pyrazole [prepared from 4-cyanomethyl-2;6-drmeth.yl-p)aidine) see part synthesis of amino-pyrazole derivatives] (94 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (95 mg, 46%). MS (ISP) 417.2 [(M+H)+]; mp 254°C.
Example 4.21
15 5-(3-CHoro-4-fluoro-phenyI)-3-(2,6-dimethyl~^ pyr azolo [ 1,5 -a] pyrimidine
Reaction of l-(3-chloro-4-fluoro-phenyl)-4>434-trifluoro-butane-l>3-dione (134 mg, 0.5 minol), prepared from commercially available 3-chloro-4-fluoro-acetophenone according to general procedure A, and 3-arnino-4-(2?6-dimethyl-4-pyridinyl)-pyrazole 20 [prepared from 4-cyanomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, see part synthesis of amino-pyrazole derivatives] (94 mg? 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (97 mg, 46%). MS (ISP) 421.1 [(M+H)1; mp 271°C.
Example 4,22
25 5-(3,4-DicHoro-phenyl)-3-(2,6-dimet^^ a] pyrimidine
Reaction of l-(3,4-dichloro-phenyl)-4J434-txifluoro-butane-l>3*dione (143 mg, 0.5 rnmol), prepared from commercially available 3,4-dichloro-acetophenone according to general procedure A, and 3-ainino-4-(256-diinetiiyl-4-p3nridinyl)-p'5n:azole [prepared 30 from 4-cyanomethyl-256-dimethyl-pyridine, CAS No. 130138-46-4, see part synthesis of amino-pyrazole derivatives] (94 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (106 mg, 48%). MS (ISP) 437.1 [(M+H)"]; mp 281°C.

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Example 4.23
5-(4-TrifLuoromethyl-pheiiyl)^ pyrazolo[l,5-a]pyrimidine
Reaction of l-(4"txifluoromethyl«phen7i)-4J4,4-i3ifiuoro-butane-13-dioiie (142 mg, 0.5
5 mmol) > prepared from commercially available 4-trifLiioromethyl-acetophenone
according to general procedure A, and 3*amino-4-(2,6-diinethyl-4-pyridinyl)-pyrazole
[prepared from 4-cyanomeiiiyl-236-diinetiiyl-pyridine) CAS No. 130138-46-4, see part
synthesis of arnino-pyrazole derivatives] (94 mg, 0.5 mmol) according to general
procedure B yielded the title compound as a yellow solid (102 mg, 47%). MS (ISP) 437.2
10 [(M4-H)+];mp257°C.
Example 4.24
5-(3-Trifluororaethyl-phenyl)^^ pyrazolo[l?5-a}pyriTrndj-ne
Reaction of l-(3-trifIuoromethyl-phenyl)-434>4-trifluoro-butane-l,3-dione (142 mg, 0.5
15 mmol)> prepared from commercially available 3-trifluoromethyi-acetophenone
according to general procedure A, and 3-amino-4-(2s6-dimethyl-4-p*5nddinyl)-pyrazoIe
[prepared from 4-qranomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, see part
synthesis of amino-pyrazole derivatives] (94 mg, 0.5 mmol) according to general
procedure B yielded the title compound as a yellow solid (99 mg, 45%). MS (ISP) 437.2
20 [(M+H)+];mp236°C.
Example 4-25
5-(3-Fluoro-44rifluorometliyl-phen^ trifluoromeiiiyl-pyrazolo [l,5-a]pyrimidine
Reaction of l-(3-flnoro-4-trifluoromethyl-phen^ (151 -
25 mg, 0.5 mmol), prepared from commercially available 3-fluoro-4-trifiuoromethyl-acetophenone according to general procedure A, and 3-amino-4-(2,6-dimethyl~4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2,6-dimeth.yi-pyridine3 CAS No. 130138-46-4> see part synthesis of arnino-pyrazole derivatives] (94 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (46 mg, 30 20%). MS (ISP) 455.0 [(M+H)+]; mp 245°C.
Example 4.26 5- (4-Methyl-3-trifluoromethyl-ph.enyl) -3-pyridin-3-yl-7-trifluoromethyl-pyrazolo[l,5-
ajpyrimidine
Reaction of l-(4-methyl-3-trifluoromethyl-phenyl)-4,4,4-trifIuoro-butane-l,3-dione 35 (149 mg, 0.5 mmol), prepared from 4-niethyl-3-trifluoromethyl-acetoph.enone according

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to" general procedure A, and 3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from 3-q^anornetKyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537 - 3541] (-80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (160 mg, 76%). MS (ISP) 423.2 [(M+H)+]; mp 182°C.
5 Example 4.27
5-(4-Methyl-3-taifluorome& ajpyrimidine
Reaction of l-(4-methyl-3-trifluoromeiiyl-pH^
(149 ing, 0.5 mmol), prepared from 4-methyl-3-trifluoroinethyl-acetophenone according' 10 to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanometh.yi-pyridine as described in Bioorg. Med. Chem. Lett 12 (2002) 3537 — 3541] (80 mg? 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (122 mg, 58%). MS (ISP) 423.1 [(M+Hf]; mp 218°C.
Example 4.2 8 15 5-(4-Methyl-3-trifluoro:methyl-ph
trifluoromethyl-pyTazolo[l>5-a]pyrirriidine
Reaction of l-(4-metkyl-3-txifluorome^
(149 mg, 0.5 mmol), prepared from 4-iraethyl-3-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-20 amino^(2,6-dimethyi-4-pyridinyl)"pyrazole [prepared from 4-cyanomethyl-2,6-dimetliyl-pyridine, see part synthesis of amino-pyrazole derivatives] (94 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (114 mg, 51%). MS (ISP) 451.2 [(M+H)*]; mp 258°C.
Example 4,29
25 5-(4-CHoro-phenyl)-3-(2-meiiiyl-pyridin^ ajpyrimidine
Reaction of l-(4-chloro-phenyl)-4>4>4-trifluoro-bu.tane-l,3-dione (125 mg, 0.5 mrnol), prepared from commercially available 4-chloro-acetophenone according to general procedure A, and 3-amino-4-(2-methyl-4-pyridixLyl)-pyrazole [see part synthesis of 30 amino-pyxazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (84 mg, 43%). MS (ISP) 389.1 [(M+H)*]; mp 220°C.
Example 4.30
5- (4-Chloro-3-methyl-phenyi)-3- (2-metliyl-pyridiri-4-yi)-7-trifl-uorometiiyl-pyrazolo [ 1,5- a] pyrimidine

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Reaction of l-(4-cHoro-3-methyl-phenyl)-4,4,4-1xifluoro-butane-l3-dione (132 mg, 0.5 mmol), prepared from commercially available 4-chloro-3-methyl-acetophenone according to general procedure A, and 3-amLno-4-(2-met±iyi-4-pyridinyl)-pyra2;ole [see part synthesis of amino-pyrazole derivatives] (87 mg, 0.5 mmol) according to general 5 procedure B yielded the title compound as a yellow solid (97 mg, 48%). MS (ISP) 403.5 [(M+H)+];mp240°C.
Example 431
5-(3-CMoro-4~fluoro-phenyl)^ pyrazolo [ 1 >5~a] pyrimidine
10 Reaction of l-(3-chloro-4-fluoro-phenyl)-4,4,4-trifluoro-butane-l>3-dione (134 mg, 0.5 mmol), prepared from commercially available 3-cHloro-4-fhioro-acetophenone according to general procedure A, and 3-amino-4-(2-meth.yI-4-pyridinyl)-pyrazole [see part synthesis of amino-pyrazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (86 mg> 42%). MS (ISP) 407.3
15 [(M+H)+];mp292°C.
Example 4.32
5-(3,4-Dichloro-phenyl)-3-(2-metl^ ajpyrimidine
Reaction of l-(3>4-dichloro-phenyl)-4)4)4-trifluoro-butane-l,3-dione (143 mg, 0.5 20 mmol), prepared from commercially available 3,4-dichloro-acetophenone according to general procedure A, and 3-amino-4~(2-methyl-4-pyridinyl)-pyrazole [see part synthesis of amino-pyrazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (100 mg, 47%). MS (ISP) 423.0 [(M+H)*]; mp 275°C.
25 Example 433
5-(4-Trifluorometiyl-phenyi)-3-(2-^ pyrazolo[l>5-a]pyrimidine
Reaction of l-(4*trifluoromethyl-phenyl)-4,434-trifluoro-butane-l>3-dione (142 mg, 0.5 mmol), prepared from commercially available 4-trifluorometiiyl-acetophenone 30 according to general procedure A, and 3-amino-4-(2-inethyl-4-p}Tridinyl)-pyrazole [see part synthesis of amino-pyrazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (111 mg, 53%). MS (ISP) 423.0 [(M+H)+];mp243°C.

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Example 4.34
5-(3-Trifluoromethyl-phenyl)-3-(2-meth^^ pyrazolo [l75-a]pyrimidine
Reaction of l-(3-trifluoromettyl-phenyl)-4A4-trifLuoro-butane-l>3-dione (142 mg, 0.5 5 romol), prepared from commercially available 3-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(2-inetliyl-4-pyiidinyl)-pyrazole [see part synthesis of amino-pyrazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (108 mg, 51%). MS (ISP) 423.3 [(M+H)+];mp232°C
10 Example 4.35
5~(3-Fluoro-4-trifluoromethyl-ph^ pyrazolo [l,5-a]pyrimidirie
Reaction of l-(3-fLuoro-4-1xifluoromethyl-phenyl)-4>4>4-trifluoTO-butane-l>3-dioiie (151 mg, 0.5 mmol), prepared from commercially available 3-fluoro-4-txifluoromethyl-15 acetophenone according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [see part synthesis of amino-pyrazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (85 mg, 39%). MS (ISP) 441.5 [(M+H)+]; mp 250°C.
Example 4.36
20 5- (3-Methyl-4-trifluoromethyl-phenyl)-3-pyridin-:3-yl- 7-trifluoromethyl-pyrazoIo [ 1,5-ajpyrimidine
Reaction of l-(3-methyl^-trifluoromethyl-phenyl)-4,434-trifluoro-bu1^ne-l3-dione (149 mg? 0.5 mmol), prepared from 3-methyl-4-trifluoromethyl-acetophenone (synthsesis: see part acetophenone derivatives) according to general procedure A, and 3-25 amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from 3-qranomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537 - 3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as an orange solid (116 mg, 55%). MS (ISP) 423.3 [(M+H)+]; mp 177°C.
Example 4.37
30 5~(3-Methyl-4-1xifluoromethyl-^^ ajpyrimidine
Reaction of 1- (3-methyl-4-trifluoromethyl-phenyl) -4,4,4-trifhioro-butane-1,3-dione
(149 mg, 0.5 mmol), prepared from 3-methyl-4-trifluoromethyl-acetophenone
(synthsesis: see part acetophenone derivatives) according to general procedure A, and 3-
35 amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-

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pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537 - 3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (104 mg, 49%). MS (ISP) 423.3 [(M+H)*]; mp 227°C.
Example 4.38 5 5-(3-Metiiyl-4rtrifou>rom
trifluoromethyl-pyrazolollp-ajpyiimidiiie
Reaction of l-(3-metiyl-4-trifluoromet3^
(149 mg, 0.5 mmol), prepared from 3-methyl-4-trifl-u.orometiiyi-acetophenone (syntbsesis; see part acetophenone derivatives) according to general procedure A, and 3-10 aixiino-4-(2>6-dimethyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2,6-dimettiyl-pyridine, CAS No. 130138-46-4, see part synthesis of amino-pyrazole derivatives] (94 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (107 mg, 48%). MS (ISP) 451.5 [(M+H)*]; mp 253°C.
Example 439
15 5-(3-Metiyl-4-trifluorothyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile.
pyrazolo [l,5-a]pyrimidine
Reaction of l-(3-metliyl-4-trifluoromethyl-pH
(149 mg, 0.5 mmol)> prepared from 3-methyl-4-trifiixoromethyl-acetophenone (synthsesis: see part acetophenone derivatives) according to general procedure A, and 3-20 amino-4-(2-inethyl-4-pyridinyl)-pyrazole [see part synthesis of amino-pyrazole derivatives] (87 mg> 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (113 mg, 52%). MS (ISP) 437.5 [(M+H)+j; mp 237°C.
Example 4.40
5-(4-Etiio:xy-3-txifluoromet&y^ 25 a]p}Timidine
Reaction of l-(4^thoxy-3-trifluoromet^
(164 mg, 0.5 mmol), prepared from 4-ethoxy-3-trifluoromethyl-acetophenone (synthsesis: see part acetophenone derivatives) according to general procedure A, and 3-ammo-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from 3-cyanomethyl-30 pyridine as described in Bioorg. Med. Chem. Lett 12 (2002) 3537 - 3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (155 mg, 68%). MS (ISP) 453.5 [(M+H)+]; mp 178°C.
Example 4.41 5- (4-Ethoxy-3-txifluoromeththyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile.

35 a]pyrimidine

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Reaction of l-4(ethoxy-3-trifluoromethyl-phenyO^^^-trifiuoro-butane-l^-dione (1164 mg, 0.5. mmol), prepared from 4-ethosy-3Hxifluorometh}d-acetophenone (synthsesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-5 pyridine as described in Bioorg. Med. Chem. Lett 12 (2002) 3537 - 3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (128 ing, 57%), MS (ISP) 453.5 [(M+H)+]; mp 233°C.
Example 4.42
5-(4-Trifluoroetho3y-3-trifiuoromet 10 pyrazolo[l,5-a]pyrimidine
Reaction of l-(4-trifluoroeth.o:xy-3-1xifluorometh^ 1,3-
dione (191 mg, 0.5 mmol), prepared from 4-trifluoroethoxy-3-trifluoromethyl~ acetophenone (synthsesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(3-pyridinyI)-pyrazole [CAS No. 40545-68-2; prepared 15 from 3-cyanometh.yl-pyridine as described in Bioorg. Med. Chem. Lett 12 (2002) 3537 -3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (174 mg, 69%). MS (ISP) 507.5 [(M+H)+]; mp 181°C.
Example 4.43
5-[4-(2,2>2-Trifluorothox)0-3-trifluoromethyl-phenyl]-3-p}Tidin-4-yl-7-20 trifiuoromethyl-pyra^)lo[l,5-a]pyiiniidine
Reaction of l-[4-(2>2,2-trifluoroethox}0-3-1xifluoromethyl-phenyl]-4,4?4-trifluoro-butane-l,3-dione (191 mg, 0.5 mmol), prepared from 4-(2,2>2-trifluoroethoxy)-3-trifluoromethyl-acetoplienone (synthsesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; 25 prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537 - 3541] (80 mg, 0.51 mmol) according to general procedure B yielded the title compound as a yellow solid (139 mg, 55%). MS (ISP) 507.5 [(M+Hf]; mp 247°C.
Example 4.44
5-(4-Etho;^-3-trifluoromethyl-^ 30 pyrazolo [1,5-a]pyrimidine
Reaction of l-(4-ethox)r-3-txifluoromethyl-phenyl)-4>4>4-1xifLuoro-butane-l,3-dione (164 mg, 0.5 mmol), prepared from 4-ethoxy-3-trifluoromethyl-acetophenone(synthsesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazoIe [see part synthesis of 35 amino-pyrazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded

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the title compound as a yellow solid (145 mg, 62%). MS (ISP) 467.2 [(M+H)+]; mp 250°C.
Example 4.45
5- [4- (2>2>2-Tri£luoroet3ioxyr)-3-trifluoromethyl-plienyl] -3- (2,6-dimethyi-pyridin-4-yl)-5 7-trifluoromethyl-pyrazolo [1 p-ajpyrimidine
Reaction of l-[4-(2>2,2-trifluoroeiho:xy)-3-1ri^
butane-l>3-dione (191 ing, 0.5 mmol), prepared from 4-(2>2^-trifluoroethoxy)-3-iiifluoromethyl*-acetophenone (synthsesis: see part acetophenone derivatives) according to general procedure A5 and 3-aroiQO-4-(236-dimeth]4-4-pyridinyl)-pyrazole [prepared 10 from 4-cyanometiiyl-2,6-dimetliyl-pyridine> CAS No. 130138-46-4, see part synthesis of amino-pyrazole derivatives] (94 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (165 mg, 62%). MS (ISP) 535.5 [(M+H)*]; mp 229°C.
Example 4.46 15 5-[4-(2>2,2-Trifluoroethoxy)-3-txifl^^
trifluoromethyl-pyrazolo [1,5-ajpyrimidine
Reaction of l-[4-(2,2,2-trifluoroetio:xy)-3-triflu
butane-l?3-dione (191 mg> 0.5 mmol), prepared from 4-(2>2>2-trifluoroethoxy)-3-trifluoromethyl-acetophenone (synthsesis; see part acetophenone derivatives) according 20 to general procedure A, and 3-amino-4-(2-methyl-4"pyridinyl)-pyrazole [see part synthesis of amino-pyrazole derivatives] - (87 mg> 0.5 mxnol) according to general procedure B yielded the title compound as a yellow solid (176 mg, 68%). MS (ISP) 521.5 [(M+H)+];mp210DC
Example 4.47
25 5-(3-Ethoxy-4-trifluoromelhy^ a]pyrimidine
Reaction of l-(3-ethox)r-4-1xifluoroinethyl-phenyl)-454)4-trifluoro-butane-l?3-dione (164 mg> 0.5 mmol), prepared from S-ethoxj^-trifluoromethyl-acetophenone (synthsesis: see part acetophenone derivatives) according to general procedure A, and 3-30 arnino-4-(4-p))Tidinyl)-p)TTazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett 12 (2002) 3537 - 3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (108 mg, 48%). MS (ISP) 453.1 [(M+H)+]; mp 251°C.

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Esample 4.48
3-(2,6-Dimethyl-pyridin-4^ triiluoromethyl-pyrazolo [ 1 ,5-a]pyrimidine
Reaction of l-(3-etiioxy-4-txffluoromethyl-p^
5 (164 mg, 0.5 mmol), prepared from 3-ethox7-4-trifluoromethyl-acetophenone (synthsesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(2?6-dirnetfayl-4-p)rridin)7i)-pyrazole [prepared from 4-cyanometb)7i-2?6-dimethyl-pyridine, CAS No. 130138-46-4, as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537 — 3541] (94 mg, 0.5 mmol) according to general procedure B yielded the title 10 compound as a yellow solid (120 mg, 50%). MS (ISP) 481.4 [(M+H)*]; mp 257°C.
Example 4.49
5-(3-Etho:xy-4-tiifluoromethyl-phenyl)-3-(2-m pyrazolo [1,5-aJpyrimidine
Reaction of l-(3-et±iox7-4-trifluoromethyl-phenyl)-44>4-trifluoro-butane-l?3-dione
15 (164 mg, 0.5 mmoT), prepared from 3-ethoxy-4-trifluorometiiyl-
acetophenone(synthsesis: see part acetophenone derivatives) according to general
procedure A, and 3-amino-4-(2-methyl-4-pyridinyI)-pyrazole [prepared from 4-
cyanomethyl-2-methyl-pyridine, as described in Bioorg. Med. Chem. Lett. 12 (2002)
3537 - 3541] (87 mg, 03 mmol) according to general procedure B yielded the title
20 compound as a yellow solid (113 mg> 49%). MS (ISP) 467.4 [(M+H)+]; mp 226°C.
Example 4.50
3-Pyridin-4-yl-5- [3-(2>2,2-txifluoro-ethoxy)-4-trifluorometbiyl-plienyl] -7-trifluorometliyl-pyrazolo [ 1,5-ajpyrimidine
Reaction of l-[3-(2>272-trifluoroet±ioxy)-4-trifluoroinethyl-phenyl] -4,4,4-trifluoro-
25 butane-1,3-dione (191 ing, 0.5 mmol), prepared from 4-(2A2-txifluoroethoxy)-3~
trifluoromethyl-acetophenone (synthsesis: see part acetophenone derivatives) according
to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9;
prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Ckem. Lett 12
(2002) 3537 - 3541] (30 mg, 0.5 mmol) according to general procedure B yielded the title
30 compound as a yellow solid (127 mg, 50%). MS (ISP) 507.4 [(M+H)+]; mp 251°C.
Example 4,51 3-(2,6-Dime1iiyl-pyiidm-4-yi)-5-[3-(2>2>2-trifluoro-eth
7-trifluoromethyl-pyrazolo [1,5-a]pyrimidine
Reaction of l-[3-(2>2)2-trifIuoroethox7)-4-tri£luoromethyl--phenyl]-4J434-trifluoro-35 butane-l^-dione (191 mg, 0.5 mmol), prepared from 4-(2>2,2-triftuoroetho:xy)-3-

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trifluoromethyl-acetophenone (synthsesis: see part acetophenone derivatives) according to general procedure A, and 3-ajiiiQO-4-(2J6-dimetiiyl-4-pyridin7l)-pyrazole [prepared from 4-cyanomeiiiyl-2,6-diinetliyl-pyTidine? CAS No. 130138-46-4, as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537 - 3541] (94 mg, 0.5 mmol) according to 5 general procedure B yielded the title compound as a yellow solid (139 mg, 52%). MS (ISP) 535.4 [(M+H)+]; mp 245DC
Example 4.52
3-(2-Methyl-p7ridin-4-7i)-5-[3-(2,2>2-trifluoro-ethoxy^ trifluoromethyl-pyrazolo [1,5-a] pyrimidine
10 Reaction of l-[3-(232,2"trifluoroetiioxy)-4-tiiQuorometii)d-plLenyl] -4,4,4-trifluoro-butane-l,3-dione (191 mg, 0.5 mmol), prepared from 4-(2,2>2-trifluoroethoxy)-3-trifiuoromethyl-acetophenone (synthsesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2-methyl-pyridine, as described in Bioorg. Med. Chem. Lett 12 (2002)
15 3537 - 3541] (87 mg> 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (140 mg, 54%). MS (ISP) 521.4 [(M+H)*]; mp 201°C.
Example 4,53
5- (3,4-Bis-txifluoromethyl-phenyl)-3-p}Tidin-4-yl-7-1xifluoromethyl-pyrazolo [ 1 >5-a]pyximidine
20 Reaction of l-(3>4-bis-trifluoronaethyl-phenyl)-4?4,4-trifluoro-butane-l>3-dione (176 mg, 0.5 mmol), prepared from commercially available 3,4-bis-trifluorometbyl-acetophenone [CAS No. 129604-25-7] according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med Chem. Lett. 12 (2002) 3537 - 3541] (SO mg, 0.5 mmol)
25 according to general procedure B yielded the title compound as a yellow solid (83 mg, 35%). Yellow solid MS (ISP) 477.2 [(M+H)+]; mp 209°C.
Example 4.54
5-(3,4-Bis-trifluoromethyl-phenyl)-3-(2-m pyxazolo [l,5-a]pyrimidme
30 Reaction of ^(S^-bis-txifLuoromethyl-phenyy^^^-trifluoro-butane-l^-dione (176 mg> 0.5 mmol), prepared from commercially available 3,4-bis-trifluoromethyl-acetophenone [CAS No. 129604-25-7] according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [prepared from 4-cyanometh)3-2-methyl-pyridine, as described in Bioorg. Med Chem. Lett. 12 (2002) 3537 - 3541] (87 mg, 0.5 mmol)
35 according to general procedure B yielded the title compound as a yellow solid (93 mg, 38%). MS (ISP) 491.3 [(M+H)+]; mp 223°C.

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Example 4.55 5-(4-Bromo-phenyl)-3-pyridin-4-yl-^^
Reaction of ^(^bxomo-phenylj^^^trifluoro-butane-l^-dione (148 mg, 0.5 mmol), prepared from commercially available 4-bromo-acetophenone according to general 5 procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyi-pyridine as described in Bioorg. Med. Chem. Lett 12 (2002) 3537 — 3541] (80 nag, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (79 mg, 38%). MS (ISP) 421.2 [(M+H)+]; mp 289°C.
Example 4.56
10 5-(4-Bromo-phenyl)-3-(2-methyl-pyridto-4-yl)-7-1xifluoromeAyl-pyrazolo[l>5-ajpyrimidine
Reaction of l-(4-broino-phenyl)-43434-trifluoro-butane-l>3-dione (148 mg, 0.5 mmol), prepared from commercially available 4-bromo-acetophenone according to general procedure A, and 3-amino-4-(2-meth.yl-4-p)aJdinyl)-pyrazole [prepared from 4-15 cyanomethyl-2-methyl-p)7ridine, as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537 - 3541] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (94 mg, 43%). MS (ISP) 433.3 [(M+H)+]; mp 226°C
Example 4.57
5- (4-Bromo-phenyl)-3-(2,6-dimethyl-pyridin-4-yl) -7-txifluoromethyl-pyrazolo [ 1,5-20 ajpyrimidine
Reaction of l-(4-bromo-plienyl)-4,4)4-trifluoro-butane-l>3-dione (148 mg, 0.5 mmol), prepared from commercially available 4-bromo-acetophenone according to general procedure A> and 3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from 4-q^anomethyl-236-dimethyl-pyridine? CAS No. 130138-46-4, as described in Bioorg. Med 25 Chem. Lett 12 (2002) 3537 - 3541] (94 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (93 mg, 42%). MS (ISP) 447.2 [(M+H)+]; mp 25S°C
Example 4.58 5-(4-Metiioxy-phenyl)-3-pyTidin-4-yl-7-tri^^
30 Reaction of l-(4-methoxyTphenyl)-4,4,4-trifluoro-butane-l>3-dione (123 mg, 0.5 mmol), prepared from commercially available 4-methoxy-acetophenone according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS .No. 216661-87-9; prepared from 4-q7ranomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537 -3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as
35 a yellow solid (110 mg, 59%). MS (ISP) 371.2 [(M+H)+h mp 244°C.

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Example 5: Preparation of phenyI-4-trifluoromethyl-iinidazo [ 1,5* a] pyri mi din e-8 -
carbonitriles and pyridmyl-4-txifluoromethyl^ 8-carbonitriles
5 A stirred mixture of commercially available 4-amino-5-cyano-lH-imidazole (1 eq.) and a l-phen7i-4,4,4-trifluoro-butane-l^-dione or l-pyridin-2-yI-4,4,4-trifluoro-butane-l>3-dione (1 eq.)> prepared according to general procedure A, in acetic acid was heated under reflux conditions for 3.5 h. The reaction mixture was evaporated and the product was isolated by column chromatography (heptane/ethyl acetate) and further purified by 10 crystallization. If the product precipitates during the reaction it can be isolated by filtration and further purified by crystallization.




Example 5.1 2-Phenyl-4-txifluorometiiyi-iinidazo [ 1,5- a] pyriirudine-8 -carbonitrile
Reaction of l-plienyl^^^-trifLuoro-butane-l^-dione (216 mg, 1.0 rnmol)> prepared 5 from commercially available acetophenone according to general procedure A, and 4-amino-S-q^ano-lH-iinidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (107 mg, 37%). MS (ISP) 289.0 [(M+H)*]; mp 202°C.
Example 5.2 . L0 2~(4-CHoro-phenyl)-4-trifluoromethyl~ii^
Reaction of l-(4-chloro-ph.enyl)-4>4>4-trifLuoro-butane-l?3-dione (251 mg, 1.0 mmol), prepared from commercially available 4-chloro-acetopbenone according to general procedure A, and 4-amino-5-cyano-lH-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (124 ing, 38%). MS 15 (ISP) 323.1 [(M+H)*]; mp 205°G
Example 53 2-(3-CHoro-phenyl)-4-trifluorom
Reaction of l-(3-chloro-phenyl)-4>434-trifluoro-butane-l>3-dione (251 mg, 1.0 mmol), prepared from commercially available 3-chloro-acetophenone according to general 20 procedure A, and 4-amino-5-q^ano-lH-imidazole (108 mg> 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (133 mg, 41%). MS (ISP) 323.1 [(M+H)+]; mp 221°C
Example 5,4 2-(4-MetlLyl-phenyI)-4rti±ft^
25 Reaction of l-(4-meiiyl-phenyl)-434?4-trifluoro-butane-l>3-dione (230 mg, 1.0 mmol), prepared from commercially available 4-mettiyUacetoph.enone according to general procedure A, and 4-anuno-5-q>-ano-lH-iimdazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (133 mg> 44%). MS (ISP) 303.1 [(M+H)+]; mp 197°C.

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Esample 5.5 2-(4-Metho;xy-phenyI)Hl-i2ifLuorom
Reaction of l-(4-inetihox7"-phenyl)^,4>4-ti±&uoro-butane-l,3-dione (246 mg, 1.0 mmol), prepared from commercially available 4-methoxy-acetoplienone according to general 5 procedure A, and 4-amino-5-cyano-lH-imidazole (108 mg> 1.0 mmol) according to general procedure B yielded tie title compound as a yellow solid (125 ing, 39%). MS (ISP) 319.1 [(M+H)*]; mp 192°C.
Example 5-6 2-(2-CUoro-phenyl)-4-1xiiluoromethyl-
10 Reaction of l-(2-chloro-phenyl)-4>4>4-trifluoro-biitane-l>3-dione (251 mg, 1.0 mmol), prepared from commercially available 2-chloro-acetophenone according to general procedure A, and 4-arnino-5-cyaiio-lH-iinidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (55 mg,17%). MS (ISP) 323.1 [(M+H)+];mpl80°C.
15 Example 5.7
2-(2,4rDicHoro-phenyl)-4-txifluoromet^^
Reaction of l-(2>4-dichloro-phenyl)-4)434-trifluoro-butane-l>3-dione (285 mg, 1.0 mmol), prepared from commercially available 2,4-dichloro-acetophenone according to general procedure A, and 4-amino-5-cyano-lH-imidazole (108 mg, 1.0 mmol) 20 according to general procedure B yielded the title compound as a yellow solid (43 mg, 12%). MS (ISP) 357.0 [(M+H)+j; mp 139°C.
Example 5.8 2- (2-Methyl-phenyl)-4-trifluorome^
Reaction of l-(2-methyl-phenyl)-4,4,4-trifluoro-butane-l,3-dione (230 mg, 1.0 mmol), 25 prepared from commercially available 2-methyl-acetophenone according to general procedure A, and 4-amino-5-cyano-lH-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (19 mg, 6%). MS (ISP) 303.0 [(M+H)+];mpl51°C.
Example 5.9 30 2-(3-Methyl-phenyl)-4-trifluorom
Reaction of l-(3-methyl-phenyl)-4,4,4-trifLuoro-butane-l>3-dione (230 mg, 1.0 mmol)> prepared from commercially available 3-methyl-acetoph.enone according to general procedure A, and 4-amino-5-q'rano-lH-imida2ole (108 mg, 1.0 mmol) according to

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general procedure B yielded the title compound as a yellow solid (161 mg, 53%). MS (ISP) 302.9 [(M+H)*]; mp 202°C.
Example 5.10 2-(4-Trifluororaetiiyl-pLenyl)»4-trifl
5 carbonitrile
Reaction of l-(4-trifluoromettyl-phenyi)-4^4-trifluoro-butaBe-l,3-dione (284 mg> 1.0 mmol), prepared from commercially available 4-trifluorometfcyI-acetophenone according to general procedure A5 and 4~amino-5-cyano-lH-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid 10 (151 mg, 42%). MS (ISP) 357.0 [(M+H)"1]; mp 236°C.
Example 5.11
2- (3-Trifluoromethyl-phenyl)-4-trifluoroniethyl-ixnidazo [ 1,5-a]pyrimidine-8-carbonitrile
Reaction of l-(3-Mfluoromethyl-phenyl)-4>454-trifluoro-butane-l>3-dione (284 rag, 1.0 15 mrnol), prepared from commercially available 3-trifluoromethyI-acetophenone according to general procedure A, and 4-amino-5-cyano-lH-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (125 mg, 35%). MS (ISP) 357.0 [(M+H)*]; mp 202°C.
Example 5.12 20 5-(3-Fluoro-phenyl)-7-txiiluoromet3^
Reaction of l-(3-fluoro-plienyl)-4J4J4-trifluoro-butane-l)3-dione (234 mg, 1.0 mmol), prepared from commercially available 3-fluoro-acetophenone according to general procedure A, and 4-amino-5-cyano-lH-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (128 mg, 42%). MS 25 (ISP) 307.0 [(M+H)*]; mp 210°C.
Example 5.13 5- (4-Fluoro-phenyl)-7-trifluoromethyl-irnidazo [ 1,5-aj pyriimdine-8-carbomtrile
Reaction of l-(4-fluoro-phenyl)-4,4,4-trifluoro-butane-l,3-dione (234 mg, 1.0 mmol), prepared from commercially available 4-fluoro-acetophenone according to general 30 procedure A, and 4-amino-5-cyano-lH-imida2ole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (119 mg, 39%). MS (ISP) 307.0 [(M+H)+]; mp 206°C.
Example 5.14 5- (2,4-Difluoro-phenyl)-7-trifluoromethyl-imidazo [ 1 >5-a] pyrimidine-S-carbonitrile

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Reaction of l-(254-difluoro-phenyl)-4?434r-trifltioro-butaiie-13-dione (252 mg, 1.0 mmol), prepared from commercially available 2,4-difluoro-acetophenone according to general procedure A, and^amiao-S-cyano-lH-imidazole (108 mg, 1.0 ixrmol) according to general procedure B yielded the title compound as a yellow solid (75 mg, 23%). MS-5 (ISP) 325.2 [(M+H)+]; mp 169°C.
Example 5.15 5-(2-Fluoro-phenyl)-7-1riiiuorometfcyl-i^
Reaction of l-(2-fiuoro-plienyl)-4>4)4-trifluoro-butane-l?3-dione (234 mg, 1.0 mrnol), prepared from commercially available 2-fluorq-acetophenone according to general 10 procedure A> and 4-amino-5-cyano-lH-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (99 mg, 32%). MS (ISP) 307.1 [(M+H)+];mpl47°C.
Example 5.16 5-(3,4-Difluoro~phenyl)-7-trifLuorom
15 Reaction of l-(3,4-difluoro~phenyl)-4,4,4-trifluoro-butane-l,3-dione (252 mg, 1.0 mmol), prepared from commercially available 3,4-difhioro-acetophenone according to general procedure A, and 4-amino-5-cyano-lH-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (107 mg, 33%). MS (ISP) 325.2 [(M+H)+]; mp 187°C.
20 Example 5.17
5-(4-Fluoro-3-trifluoromethyl-phen^ carbonitrile
Reaction of l-(4-fluoro-3-1xifluoromethyl-phenyl)-4>4,4-trifluoro-butane-l>3-dione (302 mg, 1.0 mmol), prepared from commercially available 4-fluoro-3-trifluoromethyl-25 acetophenone according to general procedure A, and 4-amino-5-cyano- lH-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (141 mg, 38%). MS (ISP) 375.3 [(M+H)+]; mp 207°C.
Example 5.18
5-(3-CUoro-4-fluoro-phenyl)-7-trifluoro 30 carbonitrile
Reaction of l-(3-chloro-4-fluoro-phenyl)-4,4,4-trifluoro-butane-l,3-dione (269 mg, 1.0 mmol), prepared from commercially available 3-chloro-4-fLuoro-acetophenone according to general procedure A, and 4-amino-5-cyano-lH-imidazole (108 mg, 1.0

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mmol) according to general procedure B yielded the title compound as a yellow solid (L20 mg, 35%). MS (ISP) 341.1 [(M+H)+j; mp 195°C.
Example 5,19
5-(4-Chloro-3-methyl-phenyl)-7^ 5 carbonitrile
Reaction of l-(4-cHoro-3-metliyl-phenyi)-4,454"trifluoro-butane-13-dione (265 mg, 1.0 mmol) , prepared from commercially available 4-cHoro-3-methyl-acetophenone according to general procedure A, and 4-amino-5-cyano-lH-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid 10 (171 mg, 51%). MS (ISP) 337.1 [(M+H)+]; mp 238°C.
Example 5.20 5-(3,4~DicHoro-phenyI)-7-trifluorom
Reaction of l-(3>4-dichloro-phenyl)-4)4>4-trifluoro-butane-l>3-dione (285 ing, 1.0 mmol), prepared from commercially available 3,4-dichloro-acetophenone according to 15 general procedure A, and 4-amino-5-cyrano-lH-imidazole (108 mg, L0 mmol) according to general procedure B yielded the title compound as a yellow solid (161 mg, 45%). MS (ISP) 357.2 [(M+H)*]; mp 219°C
Example 5.21
5-(3-Huoro-4-txifluorometiyl~phen 20 carbonitrile
Reaction of l-(3-fluoro-4-trifluoroinethyI-ph.enyI)-4>4,4-trifluoro-butane-l>3-dione (302 mg, 1.0 mmol), prepared from commercially available 3-fluoro-4-trif.uoromethyl-acetophenone according to general procedure A, and 4-amino-5-cyano-lH-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a 25 yellow solid (110 mg, 29%). MS (ISP) 375.0 [(M+H)+]; mp 210°C.
Example 5.22
2-(4~Methyl-3-txifluorometliyl-p^ carbonitrile
Reaction of l-(4-methyl-3-trifluoromethyl~phenyl)-4,4,4-trifluoro-butane-13-dione 30 (298 mg, 1.0 mmol), prepared from 4-rDethyl-3-trifluoromethyl-acetophenone (synthsesis: see part acetophenone derivatives) according to general procedure A, and 4-amino-S-cyano-lH-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (143 mg, 39%). MS (ISP) 371.1 [(M+H)"]; mp 220°C.

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Example 5.23
2- (3-Methyl-4-txifLuGromethyl-pheny^^^ [ 1 >5-a]pyrimi(iine- 8-
carbonitrile
Reaction of l-(3-metkyI-4-trifluorome^
5 (224 mg, 0.75 xnmol), prepared from 3-mettyl-4-trifluorometh7l-acetophenoiie (synthsesis: see part acetophenone derivatives) according to general procedure A, and 4-amino-5-cyano-lH-iinidazole (81 mg, 0.75 mmol) according to general procedure B yielded the title compound as a yellow solid (131 mg, 47%). MS (ISP) 371.1 [(M+H)*]; mp 217°C
10 Example 5.24
2-(4-Trifluoroethoxy-3-t^ [ 1,5-
a] pyrimidine-8-carbonitrile
Reaction of l-(4-1xifiuoroet±ioxy~3-trifluorometh^
dione (382 mg, 1.0 mmol), prepared from 4-trifluoroetlioxy-3-trifluoromethyl-15 acetophenone (synthsesis: see part acetophenone derivatives) according to general procedure A, and 4-amino-5-cyano-lH-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (182 mg, 40%). MS (ISP) 453.0 [M*]; mp 189°C.
Example 5,25
20 2- Pyridin-2-yl-4-trifluoromethyl-iiaidazo [ 1,5-a] pyrimidine- S-caxbonitrile
i., Reaction of l-pyridin-2-yl-4>4?4-trifluoro-butane- 1,3-dione (217 mg, 1.0 mmol),
prepared from commercially available 2-acetylpyri'dine according to general procedure A, and 4-amino-5-cyano-lH-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (135 mg, 47%). MS (ISP) 289.9 25 [(M+H)+];mp205°C
Example 5,26 2-Pyridin- 3 -yl-4-trifl.uoromethyl-imidazo [ 1 >5-a] pyriiriidine-8-carbonitrile
Reaction of l-pyridin-3"yi-4,4?4-trifluoro-butane-l,3-dione (217 mg, 1.0 mmol), prepared from commercially available 3-acetylpyridine according to general procedure A> 30 and 4-amino-5-cyano-lH-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (37 mg, 13%). MS (ISP) 290.1 [(M+H)*];mp222°C.
Example 5.27 2 ~Pyridm~4-yl-4-trifluthyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile.
oromeiiy

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Reaction of l-pyridin-4-yi-4>4,4-txifliioro--butane'lJ3-dione (217 mg, 1.0 mmol), prepared from commercially available 4-acetyJpyridine according to general procedure A, and 4r-amino-5-cyano-lH-imidazole (108 mg> 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (77 mg, 27%). MS (ISP) 289.8 5 [(M+H)^; mp 254°C.
Example 6: 5-plienyl)-3-(2-hydro:xymetliyl-p}Ti(^
pyrazolo[l,5-a]pyrimidines (General procedure C)
General procedure C:
10 a) To a stirred solution of a 5-phenyl-3-(2-metiiyl-pyridin-4-yl)-7-trifluorometiiyl-pyrazolo[l35-a]pyrinoidine prepared according to general procedure B (example 4) in dichloromethane MeOH and 3-chloro-perbenzoic add are added at RT. The solution is stirred at RT for about 17h, sat. NaHCO3 solution and dichloromethane is added and the mixture was stirred for about 30 min. The organic layer is separated, washed with a
15 Na2S2C>3 solution, sat. NaHCCh solution, brine and dried (Mg^SOj. Evaporation of the solvent yields a crude 5-phenyl-3-(2-methyl-l-oxo-p)rridin-4-yl)-7-trifluoromethyl-pyrazolo[l,5-a]pyrimidine compound as a solid, which can be used without further purification.
b) A stirred, mixture of a 5-phenyi-3-(2-methyl-l-oxo-pyridin-4-yl)-7-trifluoromethyl-
20 p^azolotl^-ajpyrimidine compound and acetic acid anhydride is reftuxed for about 30
min, poured into sat NaHCC>3 solution and extracted with dichloromethane (e.g. 3 times 20 ml). The combined organic layers is washed with brine and dried (MgSO4). Purification of the crude product by column chromatography on silica gel (ethyl acetate/ hexane 1:1) yields a 4-[5-phenyl-7-trifluorometiiyl-pyrazolo[13-a]pyrimidin-3-yl]-25 pyridm-2-yknethyl acetate compound as a solid.
c) To a stirred solution of said 4-[5-phenyl-7-1xifluorometliyl-pyra2X)lo[l,5-a]pyrimidin-
3-yl]-pyridin-2-ylmethyI acetate compound in MeOH is added at RT NaOMcThe
reaction mixture is stirred for about 17h5 poured into water and extracted with,
dichloromethane (e.g. 3 times 40 ml). The combined organic layers is washed with brine,
30 dried (MgSO^) and evaporated. The crude product can be further purified by column chromatography on silica gel (e.g. ethyl acetate) to yield the title compounds as a solid.



Example 6.1
5-(4-TrifluoromethyI-phenyI^ 5 pyrazolo[l,5-a]pyrimidine
a) To a stirred solution of 5-(4-1xifluoroinetb7l-phenyl)-3-(2-metii7l-pyridiQ-4-yl)-7-
trijBLuorometh)4-pyra2olo[l,5-a]pyrimidine (0.15 g, 0.36 mmol, synthesis: see example
89) in dichloromethane (3.5 ml) was added at room temperature MeOH (1 ml) and 3-
cHoro-perbenzoic acid (70%, 0.10 ing, 0,41 mmol). The yellow solution was stirred at
10 RT for 17h, sat NaHCC>3 solution (10 ml) and dichloromethane (10 ml) was added and
the mixture was stirred for 30 min. The organic layer was separated, washed with 10%
Na2S2O3 solution (10 ml), sat NaHCC>3 solution (20 ml), brine (30 ml) and dried
(Mg2SO4). Evaporation of the solvent yielded crude 5-(4-1rifluoromethyl-phenyl)-3-(2-
methyi-l-oxo-pyridin^yi)-7-trifluoromethyi-pyrkzolo[ as an orange
15 solid (0.16 g), which was used without farther purification.
b) A stirred mixture of 5-(4-trifluoromethyl-phenyl)-3-(2-methyl-l-os:o-pyridiQ-4-yl)-7-
1xiiluoromethyl-pyra2olo[U5-a]pyrimidine (0.15 g, 0.33 mmol) and acetic add
anhydride (1 ml) was refluxed for 30 min, poured into sat NaHCC>3 solution (20 ml) and
extracted with, dichloromethane (3 times 20 ml). The combined organic layers were
20 washed with brine (50 ml) and dried (MgSO^. Purification of the crude product by column chromatography on silica gel (ethyl acetate/ hexane 1:1) yielded 4-[5-(4-

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txifiuoromethyl-phenyl)~7-txiflu^
ylmethyl acetate (0.16 g, 99%) as a brown solid.
c) To a stirred solution of 4-[5-(4-1xifluorometiLyl-phenyl)-7-trifiuorometiyi-pyrazoIo[l,5-a]pyrinudin-3-yl]-pyridin-2-ylmetliyl acetate (0.16 g, 0.33 mmol) in MeOH 5 (1 ml) was added at room temperature NaOMe (5.4M in MeOH, 02 ml).Tlie reaction mixture was stirred for 17h5 poured into water (40 ml) and extracted with, dichloromethane (3 times 40 ml). The combined organic layers were washed with brine (100 mL)> dried (MgSO^ and evaporated. The crude product was further purified by column chromatography on silica gel (ethyl acetate) to yield the title compound (112 mg, 10 ' 78%) as an orange solid. MS (ISP) 4393 [(M+H)+]; mp 2102°C
Example 6.2 5- (3-Metliyl-4-trifluoromethyl-phenyl)-3- (2-hydroxymethyl»pyridin-4-yl)-7-
trifluoromethyl-pyrazolo [ 1,5- a] pyrimidine
15 Transformation of 5-(3-methyi-4-triiluorome^
trifluoromethyl-pyrazolofl^-ajpyrimidine (0.34 g, 0.78 mmol, synthesis: see example 96) according to the general method of example 108 yielded the title compound (80 mg, 23%) as an orange solid. MS (ISP) 453.4 [(M+H)*]; mp 231°C.
Example 6.3 20 {4- [5- (4-Chloro- 3-methyi-phenyl)- 7-trifluoromethyl-pyrazolo [ 1 ,5-a] pyriirudin-3-yl] -
pyridin-2-yl}-methanol
Transformation of 5-(4-chlor-3-methyl-phenyl)-3-(2-methyl-p"5nridin-4-yl)-7-txifiuoromethyl-pyrazolofljS-ajp^Timidine (0.40 g, 1.0 mmol, synthesis: see example 86) according to the general method of example 108 yielded the title compound (140 mg, 25 33%) as an orange solid. MS (ISP) 419.3 [(M+H)+j; mp 220°C.
Example 6.4 {4-[5-(3,4-DicHoro-phenyi)-7-txfflu^
2-yl}-methanol
Transformation of 5-(3,4-dichloro-phenyl)-3-(2-methyl-pyridin-4-yl)-7-30 tafluoromethyl-pyrazolo[l?5-a]pyrimidin.e (0.43 g, 1.0 mmol, synthesis: see example 88) according to the general method of example 108 yielded the title compound (73 mg, 17%) as an orange solid. MS (ISP) 439.2 [(M+H)+j; mp 233°C.

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Example 7: 5-(4-CHoro-3-mettyl-pheny^
trif!uoroineti7l-pyrazolo[l55-a]p^Tiimdine (compound no. 7.1)
To a stirred solution of 5-(4-chloro-3-methyl^
1rLfluoromethyl-pyra2olo[l,5-a]pyriinidine (0.50 g, 1.24 mmol) in dichloromethane (12 5 ml) was added at RT MeOH (3 ml) and 3-dbloro-pefbenzoic add (70%, 0.36 mg> 1.44 mmol). The orange solution was stirred at RT for 17h> sat. NaHCO3 solution (75 ml) and dichloromethane (50 ml) was added and the mixture was stirred for 30 min. The organic layer was separated, washed "with 10% Na2S2O3 solution (60 ml), sat NaHCC>3 solution (60 ml), brine (100 ml) and dried (Mg^SO^. Evaporation of the solvent and 10 crystallization yielded the title compound (0.51 g, 99%) as an orange solid. MS (ISP) 418.1 [M+];mp279°C.
Oxidation of 5-(3,4-dicMoro-phenyl)-3-(2-metiyl-pyridin-4-yl)-7-1xifluoTomethyl-pyrazolo[l,5-a]pyrimidine (0.63 g, 1.49 mmol) according to the above procedure yielded 5-(3,4-dicUoro-phenyl)0-(2-meth^
15 pyrazolo[l>5~a]pyrimidine compound no. 7.2 (0.63 g, 96%) as an orange solid. MS (ISP) 438.0 [M+];mp287°C.
Example 8: Preparation of 5-phenyl-3-pyridinyl-7-trifi.uoromethyl-imidazol[l,5-ajpyrimidines (General Procedure B)








Example 8.1 2-(4-Chloro-3-methyl-phenyl)-8-pYrid^
ajpyriinidine
5 Reaction of l-(4-cHoro-3-methyl-phenyi)-4J4>4-1xifluoio-bu1^ne-l?3-dione (132 mg, 0.5 mmol), prepared from commercially available 4-chloro-3-methyl-acetophenone according to general procedure A, and 2-amino-3*(3-pyridinyi)-lH-iinidazole dihydrochloride [synthesis: see part axnino-imidazole derivatives] (117 mg, 0.5 mmol) according to general procedure B yielded the title compound as a red solid (43 mg, 22%).
10 MS (ISP) 289.3 [(M+H)*]; mp 210°C.

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Example 8.2 2-(4-CMoro-phenyI)-8-pyridin-3-yl-4-trifluoromethyl-imidazo[1,5-a]pyrimidine
Reaction of l-(4-cUoxo-phenyl)-4A4--tiifluoro-butaiie-l,3-dione (125 mg, 0.5 inmol), prepared from commercially available 4-chloro-acetophenone according to general 5 procedure A, and 2-amino-3-(3-pyridinyl)-lH-iirudazole dihydrochloride [synthesis: see part amino-imidazole derivatives] (117 mg, 0.5 mmol) according to general procedure B yidded the title compound as an orange solid (43 mg> 23%). MS (ISP) 375.5 [(M+H)*]; mp 206°C.
Example 8,3 10 2-(3-CHoro-4-fluoro-phenyl)-8-pyridino^
ajpyrimidiae
Reaction of l-(3-cHoro^fluoro-phenyl)»4)4>4-trifluoro--butane-l>3-dione (134 mg> 0.5 mmol)> prepared from commercially available 3-chloro-4-fhioro-acetophenone according to general procedure A, and 2-ainino-3-(3-pyridinyi)-lH-imidazole 15 dihydrochloride [synthesis: see part amino-imidazole derivatives] (117 mg, 0.5 nunol) according to general procedure B yielded the title compound as an orange solid (62 mg, 32%). Orange solid. MS (ISP) 393.1 [(M+H)+]; mp 188°C.
Example 8*4 2-(4-DicHoro-phenyl)-8-pyridin-3-yl-4~txthyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile.
if
20 Reaction of l-(3>4-dicbloro-phenyl)-4J4,4-trifluoro-butane- 1,3-dione (143 mg, 0.5 mmol), prepared from commercially available 3>4-dichloro-acetophenone according to general procedure A, and 2-am-Jno-3-(3-pyridinyl)-lH-imidazole dihydrochloride [synthesis: see part amino-imidazole derivatives] (117 mg, 0.5 mmol) according to general procedure B yidded the title compound as an orange solid (66 mg, 32%).
25 Red solid MS (ISP) 409.4 [(M+H)+]; mp 226°C.
Example 8.5 8-Pyxidin-3-yl-4-trifluoromethyl-^^
a]pyrimidine
Reaction of l-(3-trifluoromethyl-phenyI)-4J454-trif[uoro-butane-l}3-dione (284 mg, 1.0 30 mmol), prepared from commercially available 3-trifluoromethyl-acetophenone according to general procedure A, and 2-amino-3-(3-pyridinyl)-lH-imidazole dihydrochloride [synthesis: see part amino-imidazole derivatives] (233 mg, 1.0 mmol) according to general procedure B yielded the title compound as a red solid (54 mg, 13%). MS (ISP) 409.4 [(M+H)+]; mp 194°C.

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Example 8.6 8-Pyridin-3-yl-4-trifluorthyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile.
o
ajpyrimidine
Reaction of l-(4-trifluoromethyl-phenyl)-4,4>4-trifiuoro-butane-l,3-dione (284 mg, 1.0 5 rnmol), prepared from commercially available 4-txifluorometiiyl-acetophenone according to general procedure A, and 2-amino-3-(3-p}Tidinyl)-lH-iinidazole diliydrocMoride [synthesis: see part ainino-imidazole derivatives] (233 mg, 1.0 mmol) according to general procedure B yielded the title compound as an orange solid (73 mg, 18%). MS (ISP) 409.4 [(M+H)+]; mp 231°C
10 Example 8.7
2-(4-Methyl-3-txifLuoromethyl-ph^
ajpyrimidine
Reaction of l-(4-methyl-3-txifluoromethyl-^^
(149 mg, 0.5 mmol)3 prepared from 4-methyI-3-trifluoromet&yl-acetophenone 15 (synthesis: see part acetophenone derivatives) according to general procedure A, and 2-amino-3-(3-pyridinyl)-IH-imidazole dihydrochloride [synthesis; see part amino* imidazole derivatives] (117 mg, 0.5 mmol) according to general procedure B yielded the title compound as a red solid (84 mg, 40%). MS (ISP) 423.1 [(M+H)*); mp 236°C.
Example 8.8 20 2-(3-Metliyl-4-txifluorometi^^
a]pyrlmidine
Reaction of l-(3-methyl-4-tiifIuoromethyl--phenyl)-4)454-trifluoro-butane-l73-dione (149 mg, 0.5 mmol), prepared from 3-methyl-4-trifluoTomethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 2-25 amino-3-(3-pyridinyl)-lH-iinidazole dihydrochloride [synthesis: see part amino-imidazole derivatives] (117 mg, 0.5 mmol) according to general procedure B yielded the title compound as an orange solid (103 mg, 49%). MS (ISP) 423.3 [(M+H)4]; mp 173°C.
Example 8.9 2-(4-CUoro-phenyl)-S-pyridm-4-yl-4-t^
30 Reaction of l-(4-chloro-phenyl)-4,4,4-trifluoro-butane-l,3-dione (125 mg, 0.5 mmol), prepared from commercially available 4-chloro-acetophenone according to general procedure A, and 2-amino-3-(4-pyridinyl)-lH-imidazole [synthesis: see part amino-imidazole derivatives] (SO mg, 0.5 mmol) according to general procedure B yielded the title compound as an orange solid (44 mg, 23%). MS (ISP) 375.5 [(M+H)+]; mp 290°C.

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Example 8.10
2-(4-CHoro-3-methyl-phenyl)-S-pyridin
a]pyrimidiae
Reaction of l-(4-cUoro-3-methyl-piien7l)-4>4J4-trifiuoro-'butane-l33-dione (132 mg> 0.5 5 mmol), prepared from commercially available 4-chloro-3-meth.yl-acetophenone according to general procedure A, and 2-amino-3-(4-p37ridinyl)-lH-imida2ole [synthesis: see part amino-imidazole derivatives] (80 mgs 0.5 mmol) according to general procedure B yielded the title compound as an orange solid (98 mg, 50%). MS (ISP) 389.3 [(M+H)+];mp254°C.
10 Example 8.11
2- (3- CHoro-4-fluoro-phenyl)-8-pyridin-4-yl-4-txifluoromeiiyl-imidaz^ [ 1,5-
ajpyrimidine
Reaction of l-(3-chloro-4-fl'uoro-plienyl)-4J4>4-trifl.-uoro-butane-l>3-dione (134 ing, 0.5 mmol), prepared from commercially available 3-chIoro~4-fluoro-acetophenone 15 according to general procedure A, and 2-amino-3-(4-pyridinyl)-lH-imidazole [synthesis: see part amino-imidazole derivatives] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as an orange solid (84 mg, 43%). MS (ISP) 393.1 [(M+H)+];mp266°C.
Example 8*12 20 2-(4-DicHoro-phenyl)-8-pyridm-4-y^
Reaction of l-(3,4-dichloro-phen)Tl)-4,4>4-trifluoro-butane-l)3-dione (143 mg, 0.5 mmol), prepared from commercially available 3,4-dichloro-acetophenone according to general procedure A, and 2-ajnino-3-(4-pyridinyl)-lH-iniidazole [synthesis: see part amino-imidazole derivatives] (SO mg, 0.5 mmol) according to general procedure B 25 yielded the title compound as an orange solid (95 mg, 46%). MS (ISP) 4093 [(M+H)+]j mp 262°C.
Example 8.13 8-Pyridia-4-yl-4~txiftuoro^
ajpyrimidine
30 Reaction of l-(3-1rifluorornethyl--phenyl)-434,4-txifIuoro-butane-l,3-dione (142 mg, 0.5 mmol), prepared from commercially available 3-trifluoromethyl-acetophenone according to general procedure A, and 2-amino-3-(4-pyridinyl)-lH-iinidazole [synthesis: see part amino-imidazole derivatives] (SO mg, 0.5 mmol) according to general procedure B yielded the title compound as an orange solid (100 mg> 49%). MS (ISP) 409.4
35 [(M+H)*]; mp 258°C

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Example8.14 8-Pyridin-4-yl-4-triflu^
ajpyrimidine
Reaction of l-(4-trifluoromethyl-phenyl)-4,4,4-triJiuoro«butane-l,3-dione (142 mg, 0.5 5 mmol), prepared from commercially available 4-trifluorornethyUacetophenone according to general procedure A, and 2-ainiiio-3-(4-pyridinyl)'lH-iinidazole [synthesis: see part ammo-iinidazole derivatives] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as an orange solid (88 mg, 43%). MS (ISP) 409.4 [(M+H)+];mp240°C.
10 Example 8.15
2-(3-Fluoro-4-trifluorome1±Lyl-phen^
ajpyrimidrne
Reaction of l-(3-fluoro-4-txifluorometiyl-plienyl)-454,4-1xifluoro-^but^ne-l3-dione (151 mg, 0.5 mmol), prepared from commercially available 3-fluoro-4-trifluoromethyl-15 acetophenone according to general procedure A, and 2-airrino-3-(4-pyridinyl)~lH-imidazole [synthesis: see part amino-ixnidazole derivatives] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as an orange solid (116 mg> 54%). MS (ISP) 427.4.0 [(M+H)*]; mp 267°C.
Example 8.16 20 2-(4-Methyl-3-trifiuoromethyl-ph^
ajpyrinridine
Reaction of 1- (4-metiiyl-3-trifluoromethyi-phenyl) -4,4,4-trifluoro-hutane-1,3-dione (149 mg, 0.5 mmol), prepared from 4-methyl-3-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 2-25 amino-3-(4-pyridinyl)-lH-imidazole [synthesis: see part amino-imidazole derivatives] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as an orange solid (101 mg, 48%). MS (ISP) 4233 [(M+H)*]; mp 222°C.
Example 8.17
2- (4-Etho:xy-3-tri£luoromethyl-phe [ 1,5-
30 ajpyrimidine
Reaction of l-(4-ethoxy-3-1xifluoromethyl-phenyl)-4J4?4-trifluoro-butane-l?3~dione (164 mg, 0.5 mmol), prepared from 4-ethoxy-3-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 2-amino-3"(4-pyridinyl)-lH-imidasole [synthesis: see part amino-imidazole derivatives]
35 (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as an orange solid (98 mg, 43%). MS (ISP) 453.5.0 [(M+H)+]; mp 244°C.

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Example8,18 8-Pyridm-4-yl-2-[4-(2,2,2-trrfluoro^
trifhioromethyl-imidazo [1,5-ajpyriinidine
Reaction of l-[4-(2A2,-trifluoro-ethoxy)-3-1ri^
5 butane-1,3-dione (191 mg> 0.5 mmol), prepared from 4-(2,2>2-trifluoro-ethoxy)-3-trifluoromethyl-acetophenone (syntiiesis: see part acetophenone derivatives) according to general procedure A, and 2-amino-3-(4-pyridinyI)-lH-imidazole [syntiiesis: see part amino-imidazole derivatives] (80 nag, 0.5 mmol) according to general procedure B yielded the title compound as an orange solid (111 mg, 44%). MS (ISP) 507.5 [(M+H)*]; 10 mp 269°C.
Example 8.19
2- (3-Methyl-4-trifluorometh^ [ 1,5-
ajpyrimidine
Reaction of l-fS-metiyM-trifluorometli^-plieny^^^^-trifluoro-butane-l^-dione 15 (149 mg, 0.5 mmol), prepared from 3-methyl-4-trifluorometLyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 2-amino-3-(4-pyridinyl)-lH-iinidazole [synthesis: see part amino-imidazole derivatives] (80 xng, 0-5 mmol) according to general procedure B yielded the title compound as an orange solid (93 mg, 44%). MS (ISP) 422.1 [(M+H)*]; mp 225°C.
20 Example 8.20
2-(4-CHoro-phenyl)-8-(2-metfayl-pyri
a] pyrimidine
Reaction of l-(4-chloro-phenyl)-4J4)4-trifluoro-butane-l>3-dione (125 mg, 0.5 mmol)3 prepared from commercially available 4-chloro-acetophenone according to general 25 procedure A, and 2-amino-3-(2-meAyl-4-pyridinyl)-lH-imidazole [synthesis: see part amino-imidazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as an orange-solid (46 mg, 24%). MS (ISP) 389.2 [(M+H)+]; mp 232°C.
Example 8>21 30 2-(4-Cbloro-3-methyi-phen^
imidazo [ 1 ,5-a] pyrimidine
Reaction of l-(4-choro-3-methyl-phenyl)-4,4?4-trifluoro-butane-l>3-dione (132 mg, 0.5
mmol), prepared from commercially available 4-chloro-3-methyl-acetophenone
according to general procedure A, and 2-ainino-3-(2-methyl-4-pyridinyl)-lH-iinidazole
35 [synthesis: see part amino-imidazole derivatives] (87 mg, 0.5 mmol) according to general

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procedure B yielded the title compound as an orange solid (49 mg> 24%). MS (ISP) 403.4 [(M+H)+];mp246°C.
Example 8.22 2-(3-CHoro-4-fluoro-phenyl)-8-(2-meii^^^
5 imidazo[l,5-a]pyriinidiiie
Reaction of l-(3-chloro^fiuoro-phenyi)-4>4,4-trifluorO"butane-l,3-dione (134 mg> 0.5 mmol), prepared from coxnmeTcially available 3-chloro-4-fluoro-acetophenone according to general procedure A> and 2-axnino-3-(2-mettyl-4-pyridinyl)-lH-imidazole [synthesis: see part amino-imidazole derivatives] (87 mg, 0.5 mmol) according to general 10 procedure B yielded the tide compound as an orange solid (52 mg, 26%). MS (ISP) 407.3 [(M+H)+];mp255°C.
Example 8,23 2-(4-DicHoro-phenyl)-8-(2-meth^
a] pyrimidine
15 Reaction of l-(3,4-dicMorO"phenyl)-4,4>4-trifluoro-butane-l,3«dione (143 mg, 0.5 mmol), prepared from commercially available 3,4-dichloro-acetoph.enone according to general procedure A, and 2-amino-3-(2-methyI-4-pyridinyl)-lH-imidazole [synthesis: see part amino-imidazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as an orange solid (57 mg, 27%)- MS (ISP) 423.2
20 [(M+H)+];mp271°C.
Example 8.24
8-(2-Metkyl-pyridin-4-yl)-4-tri£ta^
a]pyrimidine
Reaction of l-(4-1xifluorometiiyl-phenyl)-4J4,4-trifluoro-butane-l,3-dione (142 mg> 0.5 25 mmol), prepared from commercially available 4-trifl.uoromethyl-acetophenone according to general procedure A, and 2-ajxdno-3-(2-metiiyl-4-pyridinyi)-lH-imida2ole [synthesis: see part amino-imidazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as an orange solid (46 mg, 22%). MS (ISP) 423.2 [(M+H)+];mp257°C
30 Example 8.25
8-(2-Metkyl-pyridm-4-yl)-4-1^^
a] pyrimidine
Reaction of 1-(S-ixifluoromettyl-phenyl)-4,4,4-trifiuoro-butane-ljS-dione (142 mg, 0.5
rnmol), prepared from commercially available 3-trifluoromethyl-acetophenone
35 according to general procedure A, and 2-amino-3-(2-methyi-4-pyridinyl)-lH-imidazole

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[ synthesis: see part amino-imickzole derivatives] (87 ing, 0.5 mmol) according to general procedure B yielded the title compound as an orange solid (59 mg> 28%). MS (ISP) 423.2 [(M+H)+];mp234°C.
Example 8.26 5 2-(3-Huoro-4-txifiuoromethYl-ph^
umdazo[l,5-a]pyrimidine
Reaction of l-(3-fluoro-4-1xiftaorometh]^ (151
mg, 0.5 mmol), prepared from commercially available 3-fluoro-4-trifluoromethyl-acetoptenone according to general procedure A, and 2-amino-3-(2-metiLyl-4-pyridinyl)~ 10 lH-imidazole [synthesis: see part arrun o-imidazole derivatives] (87 mg> 0.5 mmol) according to general procedure B yielded the title compound as a red solid (59 mg, 27%). MS (ISP) 441.2 [(M+H)+]; mp 252°C.
Example 8.27 2- (4-Etfaoxy-3-trifiuorometiiyl-phenyl)- 8- (2-methyl-pyridin-4-yl-4-trifluoromethyl-
15 imida2o[l)5-a]p"57rimidine
Reaction of l-(4-ethoxy-3-trifluorometiiyi-phenyl)-4)434-trifiuoro-butane-l,3-dione (164 mg, 0.5 mmol), prepared from 4-ethox}r-3-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A> and 2-amino-3-(2-methyl-4-pyridin')d)- lH-imidazole [synthesis: see part amino-imidazole
20 derivatives] (87 mg, 03 mmol) according to general procedure B yielded the title compound as an orange solid (41 mg, 18%). MS (ISP) 467.4 [(M+H)+]; mp 249°C:
Example 8.28 8 - (2-Metiyl-pyridm~4-yl-2-[4^
trifluorometiyl-iinidazo[ly5-a]pyrimidiiie
25 Reaction of l-[4-(2,2,2,-trifluoro-etiLoxy)-3-^
butane- 1,3-dione (191 mg, 0.5 mmol), prepared from 4-(2>2?2-trifluoro-ethox)r)-3-trifluorometh}4-acetopheaone (s^oithesis: see part acetophenone derivatives) according to general procedure A, and2-aniino-3-(2-rnethyl-4-p"5oddinyl)-lH--irQidazole [synthesis: see part amino-imidazole derivatives] (87 mg, 0.5 mmol) according to general procedure
30 B yielded the title compound as an orange solid (51 mg, 20%). Orange solid. MS (ISP) 521.4 [(M+H)+];mp219°C.
Example 8.29 2-(3-Me1i)d-4-trifluorome^^
imidazo[I,5-a]pyrimidine

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Reaction of l-(3-methyl-4-tafluoromethyl-ph^^
(149 mg, 0.5 mmol), prepared from 3-methyl-4-trifluoromethyl-acetophenone
(synthesis: see part acetophenone derivatives) according to general procedure A, and 2-
' amino-3-(2-metiyl-4-pyridinyl)-lH-inndazoIe [synthesis: see part amino-imidazole
5 derivatives] (87 ing, 0.5 mmol) according to general procediire B yielded the title
compound as an orange solid (44 mg, 20%). Orange solid. MS (ISP) 437.4 [(M+H)+]->
mp 243°C.
Example 8,30 2- (3-Ethoxy-4-trifluoromethyl-phm
10 a]pyrimidine
Reaction of l-(3-ethoxy^trifluoromet^^
(164 mg5 0.5 mmol), prepared from 3-ethoxy-4-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 2-ainmo-3-(4-pyridinyl)-lH-irnidazole [synthesis: see part amino-imidazole derivatives]
15 (80 ing, 0.5 mmol) according to general procedure B yielded the title compound as an orange solid (70 mg, 31%). MS (ISP) 453.4 [(M+H)*]; mp 212°C.
Example 8.31
2-(3-Ethoxy-4-txi&uorQmetk^
imidazoflyS-ajpyrimidine
20 Reaction of l-(3-ethoxy-4-trifluoromethyl-phenyl)-4)4>4-trifluoro-butane-l)3-dione (164 mg, 0.5 mmol), prepared from 3-ethoxy-4-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 2-amino-3-(4-p}Tidinyl)-lH'imida2ole [synthesis: see part amino-imidazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as an
25 orange solid (30 mg, 13%). MS (ISP) 467.2 [(M+H)+]; mp 177°C.
Example 832-8-Pyridin-4-yl-2-[3-(2,2>2"1xifluoro-ethoxy)-4-trifluoromethyl-phenyl]-4-
trifluoromethyl-imidazo [ 1,5-a] pyximidine
Reaction of 1- [3-(2?2^?-trifLuoro-ethox)'-)-4-trifluoromethyl-pheiiyl] -4,4,4-trifluoro-
30 butane-1,3-dione (191 mg, 0.5 mmol), prepared from 3-(2,2?2-trifluoro-ethoxy)-4-trifLuoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 2-amino-3-(4-pyridinyl)-lH-imidazole [synthesis: see part amino-imidazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as an orange solid (84 mg, 33%). MS (ISP) 507.4 [(M+H)+];
35 mp 233°C.

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Example 8.33 8-(2-Methyl-pyridin-4-yl)-2-[3-(2,2>2-fr^
trifluoromethyl-imidazo [l,5-a]pyrirnidine Reaction of l-[3-(2?2,2?-trifiuoro-ethoxy)-4-tri^^
5 butane-l,3-dione (191 mg, 0.5 nunol), prepared from 3-(2>2)2-trifluoro-ethox}0-4-txifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 2-amino-3-(2-methyl-4-pyridinyl)-lH-imidazole [synthesis: see part amino-imidazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as an orange solid (140 mg, 54%). MS (ISP) 521.3 10 [(M+H)+];mpl89°C
Example 8,34
2-(3,4-Bis-txifluoromethyl-phe^ [1,5-
a] pyrimidine
Reaction of l-(3>4-bis-trifluoromethyl-phenyl)-4,4?4-trifluoro-butane-l,3-dione (176 15 mg, 0-5 mmol), prepared from 3>4-bis-trifluoromethyl-acetophenone [CAS No. 129604-25-7] according to general procedure A, and 2-amino-3-(4-pyridinyl)-lH-imidazole [synthesis: see part amino-imidazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as an orange solid (80 mg, 34%). MS (ISP) 477.2 [(M-hH)+];mp2irC
20 Example 8.35
2-(3,4-Bis-txifluoromethyi-phen^
imidazo [ 1 ,5- a] pyrimidine
Reaction of l-(3>4-bis-trifluoromethyi-phenyl)-4,434-trifluoro-butane-l>3-dione (200 mg, 0.57 mmol), prepared from 3,4-bis-trifluoromethyl-acetophenone [CAS No. 25 129604-25-7] according to general procedure A, and 2-amino-3-(2-methyl-4-pyridiayl)-lH-imidazole [synthesis: see part amino-imidazole derivatives] (99 mg, 0.57 mmol) according to general procedure B yielded the title compound as an orange solid (28 ing, 10%). Orange solid. MS (ISP) 491.3 [(M+H)+]; mp 218°C.
Example 8.36 30 2- (4-Bromo~phenyl)-8- (2-inethyl-pyridin-4-yl)-4-trifluoromethyl-iinidazo [ 1,5-
a]pyrimidine
Reaction of l-(4-bromo-phenyi)-4,4,4-trifluoro-butane-lJ3-dione (148 mg, 0.5 mmol),
prepared from commercially available 4-bromo-acetophenone according to general
procedure A, and 2»anoino-3-(2-metiiyl-4-pyridinyl)-lH*imidazole [synthesis: see part
35 amino-imidazole derivatives] (87 mg, 0.5 mmol) according to general procedure B

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yielded the title compound as an orange solid (42 mg? 19%). MS (ISP) 435.3 [(M+H)+]; mp 249°C.
Example 9: Preparation of 5-phenyl-3-p7ridmyi-7*difluoromethyl-pyrazolo[l,5-
a]pyrimidines (General Procedure B)
5 A stirred mixture of a 3-amino-4-pyridinyl-pyrazole (1 eq.) and a l-phenyl-4,434-
difluoro-butane-l,3-dione (1 eq.), prepared according to general procedure A, in acetic acid was heated under reflux conditions for about 3.5 h. The reaction mixture was evaporated and the product was isolated by column chromatography (e.g. heptane/ethyl acetate) and further purified by crystallization. If the product precipitates during the 10 reaction it can be isolated by filtration and further purified by crystallization.

Example 9.1 7-Difluoromeiiyl-3-pyridin-4-yl-5-(4-trifluorometHyl-phenyl)-pyra:azolo[l?5-
15 ajpyrimidine
Reaction of 4,4-difluoro-l-(4-trifluoromethyl-pheiiyl)-butane-l>3-dione (133 mg> 0.5 mmol), prepared from commercially available 4-trifluoromethyl-acetophenone

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according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med.* Chem. Lett. 12 (2002) 3537 - 3541] (80 ing, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (130 mg, 67%). US (ISP) 391.2 [(M+H)*]; 5 mp 222°C.
Example 9.2 7-Difluoromethyl-3-(2-methy^
pyrazolo [ 1,5-aJpyrimidine
Reaction of 4,4-difluoro-l-(4-trifluoxometliyl-plienyl)-butane-13-dione (133 mg, 0.5
10 mmol), prepared from commercially available 4-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyi-2-methyl-pyridine, as described in Bioorg. Med. Chem. Lett 12' (2002) 3537 — 3541] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (159- mg, 79%). MS (ISP) 405.4 [(M+H)*]; mp
15 213°C.
Example 9.3 7-Difluoromet3iyl-5-(3-meth^
ajpyrimidine
Reaction of 4,4-difluoro-l-(3-metliyl-4-tiifluorometiiyi-phenyl)-butane-l>3-dione (140
20 mg, 0.5 mmol), prepared from 3-methyl-4-trifluorometiyl-acetophenone (synthsesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No; 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett 12 (2002) 3537 - 3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (140 mg,
25 69%). MS (ISP) 405.4 [(M+H)*]; mp 236°C.
Example 9.4 7-Difluordmethyl-3-(2-methyl-py^
pyrazolo [ 1,5-a] pyrimidine
Reaction of 4>4-difluoro-l-(3-methyl-4-trifluoromethyl-phenyl)-butane-l,3-dione (140
so mg, 0.5 mmol), prepared from 3-methyl-4-trifluoromethyl-acetophenone (synthsesis: see
part acetophenone derivatives) according to general procedure A, and 3-amino-4-(2-
methyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2-methyl-pyridine3 CAS
No. 130138-46-4, as described in Bioorg. Med. Chem. Lett 12 (2002) 3537 - 3541] (87
mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow
15 solid (164 mg, 78%). MS (ISP) 419.3 [(M+H)+]; mp 221°C.

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Example 9.5 7-Difluoromethyl-5-(4-methox^
Reaction of 454-diflTioro-l-(4-metiiox7-phen7l)-butane-l?3-dione (114 mg, 0.5 mmol), prepared from commercially available 4-methoxy-acetophenone according to general 5 procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett 12 (2002) 3537 -3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (120 mg, 68%). MS (ISP) 353.2 [(M+H)+]; mp 206°C.
10 Compounds of formula I and their phannaceutically acceptable salts (hereinafter: Pharmaceutical Compound) have pharmacological activity and are useful as Pharmaceuticals. In particular, Pharmaceutical Compounds exhibit metabotropic glutamate receptor antagonist activity In particular, Pharmaceutical Compounds are active at the mGluR2 receptor.
15 The mGluR interaction of the Pharmaceutical Compounds maybe demonstrated, e.g. in an in vitro binding assay, e.g. as follows:
[ H]-LY354740 binding on mGlu2 transfected CHO cell membranes. Transfection and cell culture: cDNA encoding the rat mGlu2 receptor protein in pBluescript II was subcloned into the eukaryotic expression vector pcDNA I-amp from
20 Invitrogen (NV Leek, The Netherlands). This vector construct (pcDlmGR2) was co-
transfected with a psvNeo plasmid encoding the gene for neomycin resistance, into CHO cells by a modified calcium phosphate method described by Chen & Okayama (1988). The cells were maintained in Dulbecco's Modified Eagle medium with reduced L-glutamine (2 mM final concentration) and 10 % dialysed foetal calf serum from Gibco
25 BRL (Basel, Switzerland). Selection was made in the presence of G-418 (1000 fig/ml
final). Clones were identified by reverse transcription of 5 |ig total RNA, followed by PCR using mGlu2 receptor specific primers 55-atcactgcttgggtttctggcactg-3? and 5'-agcatcactgtgggtggcataggagc-3' in 60 mM Tris HC1 (pH 10), 15 mM (NH4)2SO4, 2 mM MgCk, 25 units/ml Taq Polymerase with 30 q^cles annealing at 60°C for 1 min.,
30 extention at 72°C for 30 s, and 1 min. 95°C denaturation.
Membrane preparation: Cells, cultured as above, were harvested and washed three times ■with cold PBS and frozen at -S0°C. The pellet was resuspended in cold 20 mM HEPES-NaOH buffer containing 10 mM EDTA (pH 7.4), and homogenised with a polytron (Kinematica, AG> Littau, Switzerland) for 10 s at 10 000 rpm. After centrifiigation for 30
35 min. at 4°C, the pellet was washed once with the same buffer, and once with cold 20 mM

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HEPES-NaOH buffer containing 0.1 niM EDTA3 (pH 7.4)- Protein content was measured using the Pierce method (Socochim, Lausanne) Switzerland) using bovine serum albumin as standard.
[ H] -LY354740 binding: After thawing, the membranes were resuspended in cold 50mM 5 Tris-HCl buffer containing 2 mM MgCl2 and 2 mM CaCl2, (pH 7) (binding buffer). The final concentration of the membranes in the assays was 25 jig protein/mL Inhibition experiments were performed with membranes incubated with 10 nM [ H]-LY354740 at room temperature, for 1 hour, in the presence of various concentrations of the compound to be tested. Following the incubations, membranes were filtered onto
10 Whatmann GF/C glass fiber filters and washed 5 times with cold binding buffer. Non specific binding was measured in the presence of 10 JIM DCGIV. After transfer of the filters into plastic vials containing 10 ml of Ultima-gold scintillation fluid (Packard, Zurich, Switzerland), the radioactivity was measured by liquid scintillation in a Tri-Carb 2500 TR counter (Packard, Zurich, Switzerland).
15 Data analysis: The inhibition curves were fitted with a four parameter logistic equation giving IC50 values, and Hill coefficients.
The compounds show activities, as measured in the above assay, of 5 pM or less, typically 0.5 pM or less, and ideally of 0.1 JJM OX less. The below table shows exemplary Ki values;

20 Activity specifically as medicament in Alzheimer's disease maybe demonstrated in accordance with standard test methods, e.g. an asymptotic performance in an operant delayed match to position (DMTP) task, modified from the procedure originally publishedbyDunnett>Psychopharmacology(Berl) 87:357-63 (1985) [Higgins et alo Europ. J. Neurosdence 15:1827-1840 (2002); Higgins et aL, Europ. J. Neuroscience
25 15:911-922 (2002); Higgins et al, Neuropharmacology44:324-241 (2003)],
Pharmaceutical Compounds and prodrugs thereof, e.g. esters, N-oxides> phosphate esters, glycoaraide esters and glyceride conjugates, are accordingly useful as mGluR

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antagonists, e.g. in the treatment or prevention of diseases and conditions in which activation of mGliiR plays a role or is implicated. Such conditions include in particular acute and/or chronic neurological disorders.
At present, eight different members of these mGluRs are known and of these some even 5 have sub-types. On the basis of structural parameters, the different influences on the synthesis of secondary metabolites and the different affinity to low-molecular weight chemical compounds, these eight receptors can be sub-divided into three sub-groups: mGluRl and mGluR5 belong to group I3 mGhiR2 and mGluR3 belong to group II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group HI.
10 Ligands of metabotropic glutarnate receptors belonging to the group II can be used for the treatment or prevention of acute and/or chronic neurological disorders.
Acute and/or chronic neurological disorders include psychosis, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits like mild cognitive impairment, age-related cognitive decline, vascular dementia, Parkinsons's disease,
15 memory impairment associated with depression or anxiety, Down's syndrome, stroke, traumatic brain injury, and attention deficit disorder. Other treatable indications are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are acute and chronic pain,
20 Huntington's chorea, amyotrophic lateral sderosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficient functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, psychotic episodes, opiate addiction, anxiety, vomiting, dyskinesia and depression.
25 In one embodiment, the acute and/or chronic neurological disorder is Alzheimer's
disease. In another embodiment, the acute and/or chronic neurological disorder is mild cognitive impairment
As used herein, a mammal in need of treatment of an acute and/or chronic neurological disorder means a mammal, e.g. a human that is suffering from, or is at risk of suffering 30 from, an acute and/or chronic neurological disorder.
As used herein, the terms "treat35, treating "and treatment", and the like, as applied to an acute and/or chronic neurological disorder, refer to methods that slow, ameliorate, reduce or reverse such a disorder or any symptoms associated with said disorder, as

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currently afflicting the subject, as well as methods that prevent such a disorder or any symptoms thereof, from occurring.
Pharmaceutical Compounds can be used as medicaments, e.g. in the form of pharmaceutical compositions. The pharmaceutical compositions can be administered 5 orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the administration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
Pharmaceutical Compounds can be processed with pharmaceutically inert, inorganic or 10 organic carriers for the production of pharmaceutical compositions. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, e.g., as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, e.g., vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance no carriers are, however, 15 usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, e.g., water, polyols, sucrose, invert sugar, glucose and the like. Adjuvants, such as alcohols, polyols, glycerol, vegetable oils and the like, can be used for aqueous injection solutions of water-soluble salts of compounds of formula I, but as a rule are not necessary. Suitable carriers for suppositories are, e.g., natural or hardened 20 oils, waxes, fats, semi-liquid or liquid polyols and the like.
In addition, the pharmaceutical compositions may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain still other therapeutically valuable substances.
25 As mentioned earlier, medicaments containing Pharmaceutical Compound and a
therapeutically inert excipient are also an object of the present invention, as is a process for the production of such medicaments which comprises bringing one or more Pharmaceutical Compound and, if desired, one or more other therapeutically valuable substances into a galenical dosage form together with one or more therapeutically inert
30 carriers.
The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, the effective dosage for oral or parenteral administration is between 0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/ kg/day being

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preferred for all of the indications described. The daily dosage for an adult human being weighing 70 kg accordingly lies between 0.7-1400 mg per day, preferably between 7 and 700 mg per day.
In accordance with the foregoing the present invention also provides:
5 (a) A pharmaceutical compound for use as a metabotropic glutamate receptor
antagonist, for example for use in any of the particular indications as hereinbefore set forth;
("b) A pharmaceutical composition comprising a pharmaceutical compound as under (a) as active ingredient together with a phannaceutically acceptable diluent or carrier
10 therefor;
i
(c) A pharmaceutical composition for the treatment or prevention of a disease or condition in which metabotropic glutamate receptor activation plays a role or is implicated comprising a pharmaceutical compound as under (a) and a carrier;
(d.) Use of a pharmaceutical compound as under (a) for the manufacture of a 15 medicament for the treatment or prevention of a disease or condition in which naetabotropic glutamate receptQr activation plays a role or is implicated;
(e) A process for the preparation of a compound as under (a).

Claims;
1. A process for reducing an exocyclic double bond at the 5-position of a
thiazolidinedione moiety of a thiazolidinedione precursor comprising the steps of:
a) preparing a solution or suspension of the thiazolidinedione precursor in a non-ether
solvent medium with a base, and
b) combining the solution or suspension with a dithionite source.

2. A process as claimed in claim 1, wherein the solvent medium comprises an aqueous
medium which comprises water or a mixture of water with one or more organic
solvents.
3. A process as dakned in claim 2, wherein the organic solvent comprises an alcohol, an
alkyl ester, an aromatic hydrocarbon, a halogenated hydrocarbon, an amide or a urea,
or a mixture thereof.
4. A process as claimed in claim 2 or 3, wherein the organic solvent comprises methanol,
ethanol, isopropanol, ethyl acetate, toluene, xylene, methylene chloride, N,N-dimethyl-
formamide, or a mixture thereof.
5. A process as claimed in any preceding claim, wherein the dithionite source comprises
sodium-, lithium-, potassium-, calcium-, magnesium-, a tetraalkylammonium- or a
guanidinium-dithionite.
6. A process as claimed in any preceding claim, wherein the dithionite source is sodium
dithionite.
7. A process as claimed in claim 1, wherein the base comprises an alkaline or alkaline
earth carbonate, an alkaline hydrogen carbonate, an organic secondary or tertiary
amine or an amidine.
8. A process as claimed in claim 7, wherein the base comprises sodium carbonate or
potassium carbonate.
9. A process as claimed in any preceding claim, which process takes place in the presence
of a phase-transfer catalyst.

10. A process as claimed in claim 9, wherein the phase-transfer catalyst comprises a
tetrabutylammonium halide, a tetraethylammonium halide or a benzyl
tributylainmoniuin halide.
11. A process as claimed in any preceding claim, wherein the thiazolidinedione precursor is
5-[4-[2-(5-ethyI-2-pyridinyl)ethoxy]phenyl]methenyl-2,4-thiazolidinedioneor5-[4-[2-
(methyl-2-pyridinylamino)ethoxy]phenyl]methenyl-2,4-thiazolidinedione.
12. A process as claimed in any preceding claim, wherein the thiazolidinedione precursor is
5-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-l-benzopyran-2-yl)methoxy]
phenyl]methenyl-2,4- thiazolidinedione.
13. A process as claimed in any preceding claim, wherein the solution or suspension of the
thiazolidinedione precursor in the solvent medium with the base is combined with the
dithionite source at elevated temperatures.
14. A process as claimed in any preceding claim, further comprising the step of isolation of
the reduced thiazolidinedione precursor.
15. A process for preparing a thiazolidinedione antihyperglycemic compound comprising
reduction of the exocyclic double bond at the 5-position of the thiazolidinedione moiety
of the corresponding thiazolidinedione precursor which process comprises the steps of:

a) preparing a solution or suspension of the thiazolidinedione precursor in a non-
ether solvent medium with a base, and heating the solution or suspension to a
temperature of about 40°C to 100°C,
b) combining the solution or suspension with a dithionite source selected from the
group of sodium-, lithium-, potassium-, calcium-, magnesium-, a tetraalkyl-
ammonium- or a guanidinium-dithionite, to provide a reaction mixture,
c) maintaining the reaction mixture at a temperature of about 40°C to 100°C for
about 1 to 10 hours, and
d) isolating the resulting thiazolidinedione antihyperglycemic compound as free
base.
16. A process as claimed in claim 15, wherein the thiazolidinedione antihyperglycemic
compound is pioglitazone, rosiglitazone or troglitazone.

17. A process for preparing pioglitazone, which process comprises the following steps:
a) preparing a solution or suspension of 5-[4-[2-(5-ethyI-2-pyridinyl) ethoxy]
phenyl]methenyl-2,4-thiazolidinedione in a non-ether solvent medium with a
base, and heating the solution or suspension to a temperature of about 60°C to
80°C,
b) combining the solution or suspension with sodium dithionite to provide a
reaction mixture,
c) maintaining the reaction mixture at a temperature of about 60°C to 80°C for
about 1 to 3 hours, and
d) isolating pioglitazone as free base.
18. A process for preparing rosiglitazone, which process comprises the following steps:
a) preparing a solution or suspension of 5-[4-[N-(2-pyridinyl)-N-
methyl)ethoxy]phenyl]methenyl-2,4-thiazolidinedione in a non-ether solvent
medium with a base, and heating the solution or suspension to a temperature of
about 60°C to 80°C,
b) combining the solution or suspension with sodium dithionite to provide a
reaction mixture,
c) maintaining the reaction mixture at a temperature of about 60°C to 80°C for
about 1 to 3 hours, and
d) isolating rosiglitazone as free base.

19. A process as claimed in any of claims 15 to 18, wherein the reaction mixture is cooled
to about 0°C to 30°C before isolation of the thiazolidinedione antihyperglycemic
compound.
20. Use of pioglitazone free base as obtained by a process as claimed in any one of claims 1
to 11 and 13 to 17, for conversion to the hydrochloride or other pharmaceutically
acceptable salt form of pioglitazone.
21. Use of a thiazolidinedione antihyperglycemic compound, as obtained according to a
process as claimed in any of claims 1 to 19, for the manufacture of a medicament for
the administration to a mammal in need thereof.
22. Use of pioglitazone as free base or as hydrochloride, as obtained by a process claimed in
any of claims 1 to 11 and 13 to 17, for the manufacture of a medicament for the
administration to a mammal in need thereof.

23. Use of rosiglitazone free base as obtained by a process as daimed in any one of claims 1
to 11, claims 13 to 16, or claim 18 for conversion to the maleate or other
pharmaceutically acceptable salt form of rosiglitazone.
24. Use of a dithionite source in the presence of a non-ether solvent medium to reduce
selectively an exocyclic double bond at the 5-position of a thiazolidinedione moiety of a
thiazolidinedione precursor to obtain the corresponding thiazolidinedione compound.


Documents:

1135-CHENP-2006 AMENDED CLAIMS 25-02-2011.pdf

1135-CHENP-2006 AMENDED PAGES OF SPECIFICATION 25-02-2011.pdf

1135-CHENP-2006 CORRESPONDENCE OTHERS 24-08-2010.pdf

1135-CHENP-2006 EXAMINATION REPORT REPLY RECIEVED 25-02-2011.pdf

1135-chenp-2006 form-3 25-02-2011.pdf

1135-CHENP-2006 OTHER PATENT DOCUMENT 25-02-2011.pdf

1135-CHENP-2006 POWER OF ATTORNEY 25-02-2011.pdf

1135-chenp-2006-abstract.pdf

1135-chenp-2006-claims.pdf

1135-chenp-2006-correspondence others.pdf

1135-chenp-2006-description complete.pdf

1135-chenp-2006-form 1.pdf

1135-chenp-2006-form 3.pdf

1135-chenp-2006-form 5.pdf


Patent Number 248395
Indian Patent Application Number 1135/CHENP/2006
PG Journal Number 28/2011
Publication Date 15-Jul-2011
Grant Date 12-Jul-2011
Date of Filing 03-Apr-2006
Name of Patentee F. HOFFMANN-LA ROCHE AG
Applicant Address Grenzacherstrasse 124, CH-4070 Basel
Inventors:
# Inventor's Name Inventor's Address
1 WOLTERING, Thomas, Johannes In den Abtsmatten 6, D-79639 Grenzach-wyhlen
2 WICHMANN, Juergen Birkenweg 25, 79585 Steinen
PCT International Classification Number C07D487/04
PCT International Application Number PCT/EP2004/010807
PCT International Filing date 2004-09-27
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 03078075.3 2003-10-03 EUROPEAN UNION