Background of the Invention Field of the Invention
The present invention relates to a method of treating or inhibiting the growth of cancerous tumour cells and associated diseases in a mammal by administering an effective amount of a substituted-triazolopyrimidine derivative and pharmaceutically acceptable salts thereof. Further, the present invention relates to a method for the treatment or prevention of (MDR) multiple drug resistance in a mammal in need thereof which method comprises adminstering to said mammal an effective amount of a substituted triazolopyrimidine derivative or a pharmaceutically acceptable salt thereof. More specifically, the present invention relates to a method of treating or inhibiting the growth of cancerous tumour cells and associated diseases in a mammal by interacting with tubulin and microtubules and promotion of microtubule polymerization which comprises administering to said mammal an effective amount of a substituted-triazolopyrimidine derivative and pharmaceutically acceptable salts thereof.
This application is divided out of Indian Patent Application No. 1/KOLNP/2003, filed on 1st January, 2003 (hereinafter referred to as "parent application"),
b) Description of the Prior Art
Most of the cytostatics in use today either inhibit the formation of. essential precursors for biosynthesis of DNA or block DNA polymerases or interfere with the template function of DNA because DNA was the primary target for developing therapeutic drugs for chemotherapy. Unfortunately,
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WO 02/02563 PCT/US01/20672
Inhibition of the formation of essential precursors for biosynthesis of DNA or blocking DNA polymerases or interference with the template function of DNA also affects normal tissues.
Microtubules are among the cellular structures necessary for cell growth. Tubulin is the biochemical target for several anticancer drugs, which include the vinca alkaloids vincristine and vinblastine. The interaction of vincristine and vinblastine by binding to the alpha and beta-tubulin subunits interfere with the growing and shortening of the microtubules and prevents the formation of microtubules necessary for cell functions. While these compounds have efficacy in cancer chemotherapy, they also have a destabilizing effect on the microtubules which also affects rapidly proliferating normal tissues and leads to toxicity.
Paditaxel and its semisynthetic derivative docetaxel (Taxotere®) also interfere with microtubule formation and stabilise microtubules. Paditaxel (Taxol®),is a diterpene isolated from the bark of the Western (Pacific) yew, Taxus brevifolia and is representative of a new class of therapeutic agent having a taxane ring system. It was additionally found in other members of the Taxacae family including the yew of Canada (Taxus canadensis) found in Gaspesia, eastern Canada and Taxus baccata found in Europe whose needles contain pacihaxel and analogs and hence provide a renewable source of paditaxel and derivatives. The crude extract was tested for the first time during the 1960s and its active prindple was isolated in 1971 and the chemical structure identified (M.C. Wani et al, J.Am.Chem.Soc, 93, 2325 (1971)). Further, a wide range of activity over melanoma cells, leukemia, various cardnomas, sarcomas and non-Hodgkin lymphomas as well as a number of solid tumors in animals was shown through additional testing. Paclitaxel and its analogs have been produced by partial synthesis from 10-deacetylbaccatin III, a precursor obtained from yew needles and twigs, and by total synthesis (Holton, et al., J. Am. Chem. Soc. 116:1597-1601 (1994) and
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WO 02/02563 PCT/US01/23672
Nicolaou, et al., Nature 367:630-634 (1994)). Paclitaxel has been demonstrated to possess antineoplastic activity. More recently, It was shown that the antitumor activity of paclitaxel is due to a promotion of microtubule polymerization (Kumar, N., J. Biol. Chem. 256:10435-10441 (1981); Rowinsky, et al., J. Natl.Cancer Inst, 82:1247-1259 (1990); and Schrff, et al., Nature, 277:665-667 (1979)). Paclitaxel has now demonstrated efficacy in several human tumors in clinical trials (McGuire, et al., Ann. Int. Med., 111:273-279 (1989); Holmes, et al., J. Natl. Cancer Inst, 83:1797-1805 (1991); Kohn et al., J. Natl. Cancer Inst, 86:18-24 (1994); and A. Bicker et al., Anti-Cancer Drugs, 4,141-148 (1993)
Paclitaxel is a microtubule blocker, inhibiting mitosis by interaction with microtubules. Paclitaxel does not prevent tubulin assembly but rather accelerates tubulin polymerization and stabilizes the assembled microtubules. Paclitaxel acts in a unique way which consists in binding to microtubules, preventing their depolymerization under conditions where usually depolymerization occurred(dilution, calcium, cold and microtubules disrupting drugs). Paclitaxel blocks the cell cycle at prophase which results in an accumulation of cells in G2+M.
Accordingly, there is still a need in the art for cytotoxic agents for use in cancer therapy. In particular, there is a need for drugs which inhibit or treat the growth of tumors which have an effect similar to paclitaxel and interfere with the process of microtubule formation. Additionally, there is a need in the art for agents which accelerate tubulin polymerization and stabilize the assembled microtubules.
Accordingly, it would be advantageous to provide a method of treating or inhibiting cell proliferation, neoplastic growth and malignant tumor growth in mammals by administering compounds which have paclitaxel like anticancer activity.
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Additionally, it would be advantageous to provide a method for treating or inhibiting multiple drug resistance (MDR).
Substituted triazolopyrimidine compounds of this invention are known to the art and have found use in agriculture as fungicides. The preparation of compounds of this invention and methods of preparation are disclosed in the following United States Patent Numbers: 5,593,996; 5,756,509;5,948,783; 5,981,534; 5,612,345; 5,994,360; 6,020,338; 5,985,883; 5,854,252; 5,808,066; 5,817,663; 5,955,252; 5,965,561; 5,986,135 ; and 5,750,766.
Compounds of this invention are also prepared according to procedures described in the following International Publication Numbers: WO98/46607; WO98/46608; WO99/48893; WO99/41255; EPO 834513A2; EPO 782997A2; EPO 550113B1; EPO 613900B1; FR2784381A1; EPO 989130A1; WO98/41496; WO94/20501; EPO 945453A1; EPO 562615A1 and EPO 562615B1.
Summary of the Invention
The invention provides a use of a substituted triazolopyrimidine derivative to make a medicament for
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treating or inhibiting the growth of cancerous tumour cells and associated diseases in a mammal in need thereof wherein the substituted triazolopyrimidine derivative is a compound of Formula (I):

wherein:
R1 is selected from the group consisting of halogen, an optionally substituted alkyl of 1 to 12 carbon atoms, optionally substituted alkenyl of 2 to 12 carbon atoms, optionally substituted alkynyl of 2 to 12 carbon atoms, optionally substituted alkadienyl of 4 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, optionally substituted aryl of 6, 10 or 14 carbon atoms, -CN, hydroxy, halogen, carbamoyl, carboxy, alkoxycarbonyl of 2 to 12 carbon atoms, heterocyclyl, optionally substituted bicycloalkyl of 5 to 10 carbon atoms, optionally substituted cycloalkyl of 3 to 8 carbon atoms in which one -CH2-may also be replaced by -O-, -S-, or-NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, thiophene, optionally substituted cycloalkenyl of 5 to 10 carbon atoms in which one -CH2- may also be replaced by -O-, -S-, or -NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, -S-aryl of 6, 10 or 14 carbon atoms, -S-alkyl of 1 to 12 carbon atoms, -S-cycloalkyl of 3 to 8
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WO 02/02563 PCT/US01/20672
carbon atoms, -S-alkenyl of 2 to 12 carbon atoms, -SO2aryl of 6,10 or 14 carbon atoms, -SO2cycloalkyl of 3 to 8 carbon atoms, -SO2alkyl of 1 to 12 carbon atoms, -O-aryl of 6,10 or 14 carbon atoms, and the moiety -NRaRb;
Ra is H, optionally substituted alkyl of 1 to 12 carbon atoms, optionally substituted alkenyl of 2 to 12 carbon atoms, optionally substituted alkynyl of 2 to 12 carbon atoms.optionally substituted alkadienyl of 4 to 12 carbon atoms, optionally substituted cycloalkyl of 3 to 8 carbon atoms, in which one -CH2- may also be replaced by-O-, -S-, or-NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, optionally substituted cydoalkenyl of 5 to 10 carbon atoms, in which one -CH2- may also be replaced by -O-, -S-, or-NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, optionally substituted bicycloalkyl of 5 to 10 carbon atoms, optionally substituted tricydoalkyi, haloalkyl of 1 to 10 carbon atoms, aryl of 6,10 or 14 carbon atoms, heterocydyl, benzyl, optionally substituted benzyl, cydoalkyt of 3 to 8 carbon atoms or a 3- to 6-membered heterocydyl ring, optionally ortho-fused with an optionally substituted phenyl ring;
Rb is H, an optionally substituted alkyl of 1 to 12 carbon atoms, optionally substituted alkenyl of 2 to 12 carbon atoms, optionally substituted alkynyl of 2 to 12 carbon atoms, optionally substituted alkadienyl of 4 to 12 carbon atoms, optionally substituted aryl of 6,10 or 14 carbon atoms, optionally substituted bicycloalkyl of 5 to 10 carbon atoms, optionally substituted cycloalkyl of 3 to 10 carbon atoms in which one -CHr may also be replaced by-O, -S-, or
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-NR' where R' is H or an alky! group of 1 to 12 carbon atoms, optionally substituted cycloalkenyl of 5 to 10 carbon atoms in which one -CH2- may also be replaced by-O-, -S-, or-NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, -S-aryl of 6, 10 or 14 carbon atoms, -S-alkyl, -S-alkenyl, -SO2aryl of 6, 10 or 14 carbon atoms, -S02cycloalkyl, -SO2alkyl, -O-aryl of 6, 10 or 14 carbon atoms, heterocyclyl, benzyl, optionally substituted benzyl, cycloalkyl of 3 to 8 carbon atoms or a 3- to 6-membered heterocyclyl ring, optionally ortho-fused with an optionally substituted phenyl ring ;
RaRb together with the nitrogen atom to which each is attached represent an optionally substituted saturated or unsaturated heterocyclyl ring from 3 to 12 ring atoms in which optionally, at least one -CH2- may optionally be replaced by -O-, -S-, or -NR where R is H or an alkyl group of 1 to 12 carbon atoms, said saturated or unsaturated heterocyclyl ring may optionally be aryl or cycloalkyl fused;
R2 is optionally substituted phenyl or optionally substituted thienyl;R3 is H, halogen, alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, aryloxy, -NRcRd, benzyloxy, aralkyloxy, haloalkoxy of 1 to 12 carbon atoms, alkylthio of 1 to 12 carbon atoms, heterocyclyl, aryl, hydroxy, carbamoyl, carboxy, alkoxycarbonyl of 2 to 12 carbon atoms, cyano, amino, alkylarnino of 1 to 12 carbon atoms, dialkylamino of 1 to 12 carbon atoms, or -N3;
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Rc is H, amino, optionally substituted alkyl of 1 to 12 carbon atoms, haloalkyl of 1 to 10 carbon atoms, optionally substituted alkenyl of 2 to 12 carbon atoms, optionally substituted alkynyl of 2 to 12 carbon atoms, optionally substituted alkadienyl of 4 to 12 carbon atoms, optionally substituted cycloalkyl of 3 to 10 carbon atoms, in which one -CH2- may also be replaced by-O-, -S-, or-NR' where R' is H or an alkyl group of 1 to 12 carbon atoms optionally substituted cycloalkenyl of 5 to 10 carbon atoms, in which one -CH2- may also be replaced by -O-, -S-, or -NR where R is H or an alkyl group of 1 to 12 carbon atoms, optionally substituted bicycloalkyl of 5 to 10 carbon atoms, aryl of 6,10 or 14 carbon atoms, benzyl, optionally substituted benzyl, or heterocyclyl;
Rd is H, amino, optionally substituted alky! of 1 to 12 carbon atoms, haloalkyl of 1 to 10 carbon atoms, optionally substituted alkenyl of 2 to 12 carbon atoms, optionally substituted alkynyi of 2 to 12 carbon atoms, optionally substituted alkadienyl of 4 to 12 carbon atoms, optionally substituted cycloalkyl of 3 to 10 carbon atoms, in which one -CH2- may also be replaced by -O-, -S-, or -NR where R is H or an alkyl group of 1 to 12 carbon atoms optionally substituted cydoalkenyl of 5 to 10 carbon atoms, in which one -CH2- may also be replaced by -O-, -S-, or-NR where R is H or an alkyl group of 1 to 12 carbon atoms optionally substituted bicycloalkyl of 5 to 10 carbon atoms, aryl of 6,10 or 14 carbon atoms, benzyl, optionally substituted benzyl, or heterocyclyl;
RcRd together with the nitrogen atom to which each is attached represent an optionally substituted heterocyclyl ring from 3 to 8 ring atoms optionally substituted in which one -CH2- may also be replaced by-O-, -S-, or-NR' where R' is H or alkyl of 1 to 12 carbon atoms;
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R4 is H, optionally substituted alkyl of 1 to 12 carbon atoms, optionally substituted alkoxy of 1 to 12 carbon atoms, amino, alkyl amino of 1 to 12 carbon atoms, dialkylamino of 1 to 12 carbon atoms, alkylthio of 1 to 12 carbon atoms, halogen, cyano, carboxy, aikoxycarbonyi of 2 to 12 carbon atoms, heterocyclyl, halogen, carbamoyl, optionally substituted aryl of 6, 10 or 14 carbon atoms, or -CF3;
provided that when: a) R1 is diethylamino, R3is chloro, R4is hydrogen, R2is
not 4-trifluoromethylphenyl, 3,4-dichlorophenyl, 4-chlorophenyl, 3-chloro-4-
methoxyphenyl; b) R1 is diethylamino, R3is bromo, R4is hydrogen, R2is not
4-trifluoromethylphenyl; c) R1 is isopropylamino, R3is chloro, R4 is hydrogen,
R2 is not 2-benzyloxyphenyi or 3,4,5-trimethoxyphenyl; d) R1 is
cyclopentylamino, R3 is chloro, R4 is hydrogen, R2 is not
3,4,5-trimethoxyphenyl, 2-napthyl or 2-stilbene; e) R1 is 2-amino-
bicyclo(2.2.1.)heptyl, R3 is chloro, R4 is hydrogen, R2is not 3,4,5-
trimethoxyphenyl and f) R1 is diethylamino, R3 is chloro, R4 is hydrogen, R2 is
not 4-trifluoromethylphenyl and g) R1 is 1,1,1-trifluoroethoxy, R3is chloro, R4
is hydrogen, R2is not 2-chloro-6-fluorophenyl h) R1 is -SO2ethyl or
-SO2cyclopentyl, R3is chloro, R4is hydrogen, R2is not 2-chloro-6-
fluorophenyl; i) R4is hydrogen, R2is 2-chloro-6-fluorophenyl, R1 and R3are
not 1,2,4-triazole; j) R' is cyclohexyl, R4is hydrogen, R2 is 2,4,6-
trifluorophenyl, and R3 is not -OCH2O2C(CH3)3; k) R1 is 2-thienyl, R4
is ethyl, R3 is hydrogen and R2 is not 2-methoxyphenyl, 4-methoxyphenyl, and 4-trifluorophenyl; I) R2 is phenyl, R3 is chloro, R4 is hydrogen, R1 is not (2E)-,7-dimethyl-2,6-octadienyl or a pharmaceutically acceptable salt thereof.
The invention provides a use of a substituted triazolopyrimidine derivative to make a medicament for treating or inhibiting the growth of cancerous tumour cells and associated diseases in a mammal in need thereof by interacting with tubulin and microtubules by promotion of
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microtubule polymerization, wherein the substituted triazolopyrimidine is a compound of Formula (I):

wherein:
R1 is selected from the group consisting of halogen, an optionally substituted alkyl of 1 to 12 carbon atoms, optionally substituted alkenyl of 2 to 12 carbon atoms, optionally substituted alkynyl of 2 to 12 carbon atoms, optionally substituted alkadienyl of 4 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, optionally substituted aryl of 6, 10 or 14 carbon atoms, -CN, hydroxy, halogen, carbamoyl, carboxy, alkoxycarbonyl of 2 to 12 carbon atoms, heterocyclyl, optionally substituted bicycloalkyl of 5 to 10 carbon atoms, optionally substituted cycloalkyl of 3 to 8 carbon atoms in which one -CH2-may also be replaced by -O-, -S-, or -NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, thiophene, optionally substituted cycloalkenyl of 5 to 10 carbon atoms in which one -CH2- may also be replaced by -O-, -S-, or -NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, -S-aryl of 6, 10 or 14 carbon atoms, -S-alkyl of 1 to 12 carbon atoms, -S-cycloalkyl of 3 to 8 carbon atoms, -S-aikenyl of 2 to 12 carbon atoms, -SO2aryl of 6, 10 or 14 carbon atoms, -SO2cyc!oalkyl of 3 to 8 carbon atoms, -SO2alkyl of 1 to 12 carbon atoms, -O-aryl of 6, 10 or 14 carbon atoms, and the moiety -NRaRb;
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WO 02/02563 PCT/US01/20672
Ra is H, optionally substituted alkyl of 1 to 12 carbon atoms, optionally substituted alkenyl of 2 to 12 carbon atoms, optionally substituted alkynyl of 2 to 12 carbon atoms.optionally substituted alkadienyi of 4 to 12 carbon atoms, optionally substituted cycloalkyl of 3 to 8 carbon atoms, in which one -CH2- may also be replaced by -O-, -S-, or-NR1 where R" is H or an alkyl group of 1 to 12 carbon atoms, optionally substituted cycloalkeny! of 5 to 10 carbon atoms, in which one -CH2- may also be replaced by -O-, -S-, or —NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, optionally substituted bicydoalkyf of 5 to 10 carbon atoms, optionally substituted tricycloalkyl, haloalkyl of 1 to 10 carbon atoms, aryl of 6,10 or 14 carbon atoms, heterocyclyl, benzyl, optionally substituted benzyl, cycloalkyl of 3 to 8 carbon atoms or a 3- to 6-membered heterocyclyl ring, optionally ortho-fused with an optionally substituted phenyl ring;
Rb is H, an optionally substituted alkyl of 1 to 12 carbon atoms, optionally substituted alkenyl of 2 to 12 carbon atoms, optionally substituted alkynyl of 2 to 12 carbon atoms, optionally substituted alkadienyi of 4 to 12 carbon atoms, optionally substituted aryl of 6,10 or 14 carbon atoms, optionally substituted bicycloalkyl of 5 to 10 carbon atoms, optionally substituted cycloalkyl of 3 to 10 carbon atoms in which one -CH2- may also be replaced by-O-, -S-, or -NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, optionally substituted cycloalkenyl of 5 to 10 carbon atoms in which one -CH2- may also
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be replaced by -0-, -S-, or -NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, -S-aryl of 6, 10 or 14 carbon atoms, -S-alkyl, -S-alkenyl, -SO2aryl of 6, 10 or 14 carbon atoms, -S02cycloalkyl; -SO2alkyl, -O-aryl of 6, 10 or 14 carbon atoms, heterocyclyl, benzyl, optionally substituted benzyl, cycloalkyl of 3 to 8 carbon atoms or a 3- to 6-membered heterocyclyl ring, optionally ortho-fused with an optionally substituted phenyl ring ;
RaRb together with the nitrogen atom to which each is attached represent an optionally substituted saturated or unsaturated heterocyciy! ring from 3 to 12 ring atoms in which optionally, at least one -CH2- may optionally be replaced by -O-, -S-, or -NR where R is H or an alkyl group of 1 to 12 carbon atoms, said saturated or unsaturated heterocyclyl ring may optionally be aryl or cycloalkyl fused;
R2 is optionally substituted phenyl or optionally substituted thienyl;
R3 is H, halogen, alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, aryloxy, -NRcRd, benzyloxy, aralkyloxy, haloalkoxy of 1 to 12 carbon atoms, alkylthio of 1 to 12 carbon atoms, heterocyclyl, aryl, hydroxy, carbamoyl, carboxy, alkoxycarbonyl of 2 to 12 carbon atoms, cyano, amino, alkylamino of 1 to 12 carbon atoms, diaikylamino of 1 to 12 carbon atoms, or -N3;
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WO 02/02563 PCT/US01/20672
Rc is H, amino, optionally substituted alkyl of 1 to 12 carbon atoms, haloalkyl of 1 to 10 carbon atoms, optionally substituted alkenyl of 2 to 12 carbon atoms, optionally substituted alkynyl of 2 to 12 carbon atoms, optionally substituted alkadienyl of 4 to 12 carbon atoms, optionally substituted cycloalkyl of 3 to 10 carbon atoms, in which one -CH2- may also be replaced by -O-, -S-, or -NR where R is H or an alkyl group of 1 to 12 carbon atoms optionally substituted cycloalkenyl of 5 to 10 carbon atoms, in which one -CH2- may also be replaced by -O-, -S-, or -NR where R is H or an alkyl group of 1 to 12 carbon atoms optionally substituted bicycioalkyl of 5 to 10 carbon atoms, aryl of 6,10 or 14 carbon atoms, benzyl, optionally substituted benzyl, heterocyclyl;
Rd is H, amino, optionally substituted alkyl of 1 to 12 carbon atoms, haloalkyl of 1 to 10 carbon atoms, optionally substituted alkenyl of 2 to 12 carbon atoms, optionally substituted alkynyl of 2 to 12 carbon atoms, optionally substituted alkadienyl of 4 to 12 carbon atoms, optionally substituted cycloalkyl of 3 to 10 carbon atoms, in which one -CHr rnay also be replaced by -O-, -S-, or -NR where R' is H or an alkyl group of 1 to 12 carbon atoms optionally substituted cycloalkenyl of 5 to 10 carbon atoms, in which one -CH2- may also be replaced by -O-, -S-, or -NR where R' is H or an alkyi group of 1 to 12 carbon atoms optionally substituted bicycloalkyl of 5 to 10 carbon atoms, aryl of 6,10 or 14 carbon atoms, benzyl, optionally substituted benzyl, or heterocyclyl;
RcRd together with the nitrogen atom to which each is attached represent an optionally substituted heterocyclyl ring from 3 to 8 ring atoms optionally substituted in which one -CH2- may also be replaced by -O-, -S-, or-NR1 where R' is H or alkylof 1 to 12 carbon atoms;
R4 is H, optionally substituted alkyl of 1 to 12 carbon atoms, optionally substituted alkoxy of 1 to 12 carbon atoms, amino, alkyl amino of 1 to 12
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carbon atoms, dialkylamino of 1 to 12 carbon atoms, alkylthio of 1 to 12 carbon atoms, halogen, cyano, carboxy, alkoxycarbonyl of 2 to 12 carbon atoms, heterocyclyl, halogen, carbamoyl, optionally substituted aryl of 6, 10 or 14 carbon atoms, or -CF3;
provided that when: a) R1 is diethylamino, R3is chloro, R4is hydrogen, R2is
not 4-trifluoromethylphenyl, 3,4-dichlorophenyl, 4-chlorophenyl, 3-chloro-4-
methoxyphenyl; b) R1 is diethylamino, R3is bromo, R4is hydrogen, R2is not
4-trifluoromethylphenyl; c) R1 is isopropylamino, R3is chloro, R4is hydrogen,
R2 is not 2-benzyloxyphenyl or 3,4,5-trimethoxyphenyl; d) R1 is
cyclopentylamino, R3is chloro, R4is hydrogen, R2is not 3,4,5-
trimethoxyphenyl, 2-napthyl or 2-stilbene; e) R1 is 2-amino-
bicyclo(2.2.1.)heptyl, R3is chloro, R4is hydrogen, R2is not 3,4,5-
trimethoxyphenyl and f) R1 is diethylamino, R3 is chloro, R4 is hydrogen, R2 is
not 4-trifluoromethylphenyl and g) R1 is 1,1,1-trifluoroethoxy, R3is chloro, R4
is hydrogen, R2 is not 2-chloro-6-fluorophenyl h) R1 is -SO2ethyl or
-SO2cyclopentyl, R3is chloro, R4is hydrogen, R2is not 2-chloro-6-
fluorophenyl; i) R4 is hydrogen, R2is 2-chloro-6-fluorophenyl, R1 and R3are
not 1,2,4-triazoIe; j) R1 is cyclohexyl, R4 is hydrogen, R2 is 2,4,6-
trifluorophenyl, and R3 is not -OCH2O2C(CH3)3 ; k) R1 is 2-thienyl, R4
is ethyl, R3 is hydrogen and R2 is not 2-methoxyphenyl, 4-methoxyphenyl, and 4-trifluorophenyl; I) R2 is phenyl, R3 is chloro, R4 is hydrogen R1 is not (2E)-,7-dimethyl-2,6-octadienyl or a pharmaceutically acceptable salt thereof.
The present invention provides a use of a substituted triazolopyrimidine to make a medicament for the treatment or prevention of multiple drug resistance (MDR) in a mammal in need thereof. In particular the multiple drug resistance (MDR) is mediated by p-glycoprotein or MXR.
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The substituted triazolopyrimidine used is a compound of Formula (I):

wherein:
R1 is selected from the group consisting of halogen, an optionally substituted alkyl of 1 to 12 carbon atoms, optionally substituted alkenyl of 2 to 12 carbon atoms, optionally substituted alkynyl of 2 to 12 carbon atoms, optionally substituted alkadienyl of 4 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, optionally substituted aryl of 6, 10 or 14 carbon atoms, -CN, hydroxy, halogen, carbamoyl, carboxy, alkoxycarbonyl of 2 to 12 carbon atoms, heterocyclyl, optionally substituted bicycloalkyl of 5 to 10 carbon atoms, optionally substituted cycloalkyl of 3 to 8 carbon atoms in which one -CH2-may also be replaced by -O-, -S-, or-NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, thiophene, optionally substituted cycloalkenyl of 5 to 10 carbon atoms in which one -CH2- may also be replaced by -O-, -S-, or -NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, -S-aryl of 6, 10 or 14 carbon atoms, -S-alkyl of 1 to 12 carbon atoms, -S-cycloalkyl of 3 to 8
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WO 02/02563 PCT/US01/20672
carbon atoms, -S-alkenyl of 2 to 12 carbon atoms, -SO2aryl of 6,10 or 14 carbon atoms, -SO2cycloalkyi of 3 to 8 carbon atoms, -SO2alkyl of 1 to 12 carbon atoms, -O-aryl of 6,10 or 14 carbon atoms, and the moiety -NRaRb;
R3 is H, optionally substituted alky! of 1 to 12 carbon atoms, optionally substituted alkenyl of 2 to 12 carbon atoms, optionally substituted alkynyl of 2 to 12 carbon atoms.optionally substituted alkadienyl of 4 to 12 carbon atoms, optionally substituted cycloalkyl of 3 to 8 carbon atoms, in which one -CH2- may also be replaced by-O-, -S-, or-NR' where R' is H or an alkyi group of 1 to 12 carbon atoms, optionally substituted cycloalkenyl of 5 to 10 carbon atoms, in which one -CHr may also be replaced by -O-, -S-, or -NR' where R' is H or an alkyi group of 1 to 12 carbon atoms, optionally substituted bicycloalkyl of 5 to 10 carbon atoms, optionally substituted tricycloalkyl, haloalkyl of 1 to 10 carbon atoms, aryl of 6,10 or 14 carbon atoms, heterocyclyl, benzyl, optionally substituted benzyl, cycloalkyl of 3 to 8 carbon atoms or a 3- to 6-membered heterocydyl ring, optionally ortho-fused with an optionally substituted phenyf ring;
Rb is H, an optionally substituted alkyi of 1 to 12 carbon atoms, optionally substituted alkenyl of 2 to 12 carbon atoms, optionally substituted alkynyl of 2 to 12 carbon atoms, optionally substituted alkadienyl of 4 to 12 carbon atoms, optionally substituted aryl of 6,10 or 14 carbon atoms, optionally substituted bicycloalkyl of 5 to 10 carbon atoms, optionally substituted cycloalkyl of 3 to 10 carbon atoms in which one -CH2- may also be replaced by-O-, -S-, or
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-NR1 where R' is H or an alkyl group of 1 to 12 carbon atoms, optionally substituted cycloalkenyl of 5 to 10 carbon atoms in which one -CH2- may also be replaced by -O-, -S-, or -NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, -S-aryl of 6, 10 or 14 carbon atoms, -S-alkyl, -S-alkenyl, -SO2aryl of 6, 10 or 14 carbon atoms, -SO2cycloalkyl, -SO2alkyl, -O-aryl of 6, 10 or 14 carbon atoms, heterocyclyl, benzyl, optionally substituted benzyl, cycloalkyl of 3 to 8 carbon atoms or a 3- to 6-membered heterocyclyl ring, optionally ortho-fused with an optionally substituted phenyl ring ;
RaRb together with the nitrogen atom to which each is attached represent an optionally substituted saturated or unsaturated heterocyclyl ring from 3 to 12 ring atoms in which optionally, at least one -CH2- may optionally be replaced by-O-, -S-, or-NR where R is H or an alkyl group of 1 to 12 carbon atoms, said saturated or unsaturated heterocyclyl ring may optionally be aryl or cycloalkyl fused;
R2 is optionally substituted phenyl or optionally substituted thienyl;
R3 is H, halogen, alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, aryloxy, -NRcRd , benzyloxy, aralkyloxy, haloalkoxy of 1 to 12 carbon atoms, alkylthio of 1 to 12 carbon atoms, heterocyclyl, aryl, hydroxy, carbamoyl, carboxy, alkoxycarbonyl of 2 to 12 carbon atoms, cyano, amino, alkylamino of 1 to 12 carbon atoms, dialkylamino of 1 to 12 carbon atoms, or -N3;
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WO 02/02563 PCT/US01/20672
Rc is H, amino, optionally substituted alkyl of 1 to 12 carbon atoms, haloalkyl of 1 to 10 carbon atoms, optionally substituted alkenyl of 2 to 12 carbon atoms, optionally substituted alkynyi of 2 to 12 carbon atoms, optionally substituted alkadienyl of 4 to 12 carbon atoms, optionally substituted cycloalkyl of 3 to 10 carbon atoms, in which one -CH2- may also be replaced by-O-, -S-, or -NR where R* is H or an alkyl group of 1 to 12 carbon atoms optionally substituted cycloalkenyl of 5 to 10 carbon atoms, in which one —CH2- may also be replaced by -O-, -S-, or -NR where R is H or an alkyl group of 1 to 12 carbon atoms, optionally substituted bicydoalkyi of 5 to 10 carbon atoms, aryl of 6,10 or 14 carbon atoms, benzyl, optionally substituted benzyl, or heterocydyl;
Rd is H, amino, optionally substituted alkyl of 1 to 12 carbon atoms, haloalkyl of 1 to 10 carbon atoms, optionally substituted alkenyl of 2 to 12 carbon atoms, optionally substituted alkynyi of 2 to 12 carbon atoms, optionally substituted alkadienyl of 4 to 12 carbon atoms, optionally substituted cydoalkylof 3 to 10 carbon atoms, in which one -CH2- may also be replaced by -O-, -S-, or -NR where R' is H or an alkyl group of 1 to 12 carbon atoms optionally substituted cycloalkenyl of 5 to 10 carbon atoms, in which one -CH2- may also be replaced by -O-, -S-, or -NR where R* is H or an alkyl group of 1 to 12 carbon atoms optionally substituted bicydoalkyi of 5 to 10 carbon atoms, aryl of 6, 10 or 14 carbon atoms, benzyl, optionally substituted benzyl, or heterocydyl;
RcRd together with the nitrogen atom to which each is attached represent an optionally substituted heterocydyl ring from 3 to 8 ring atoms optionally substituted in which one -CH2- may also be replaced by -O-, -S-, or -NR' where R' is H or alkyt of 1 to 12 carbon atoms;
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WO 02/02563 PCT/US01/20672
R4 is H, optionally substituted alkyi of 1 to 12 carbon atoms, optionally substituted alkoxy of 1 to 12 carbon atoms, amino, alkyl amino of 1 to 12 carbon atoms, dialkylamino of 1 to 12 carbon atoms, alkylthio of 1 to 12 carbon atoms, halogen, cyano, carboxy, alkoxycarbonyi of 2 to 12 carbon atoms, heterocyclyl, halogen, carbamoyt, optionally substituted aryl of 6,10 or 14 carbon atoms, or-CF3;
provided that when: a) R1 is diethylamino, R3 is chloro, R4 is hydrogen, R2 is
not 4-trifluoromethyiphenyl, 3,4-dichlorophenyl, 4-chlorophenyi, 3-chk>ro-4-
methoxyphenyl; b) R1 is diethylamino, R3is bromo, R4is hydrogen, R2 js not
4-trifluoromethylphenyt; c) R1 is isopropylamino, R3 is chloro, R4is hydrogen,
R2 is not 2-benzyloxyphenyl or 3,4,5-trimethoxyphenyi; d) R1 is
cyclopentyJamino, R3 is chloro, R4 is hydrogen, R2 is not
3,4,5-trimethoxyphenyl, 2-napthyl or 2-stilbene; e) R1 is 2-amino-
bicydo(2.2.1 .)heptyt, R3 is chloro, R4 is hydrogen, R2 is not 3,4,5-
trimethoxyphenyl and f) R1 is diethylamino, R3 is chloro, R4 is hydrogen, R2 is
not 4-trifluoromethylphenyi and g) R1 is 1,1,1-trifluoroethoxy, R3 is chloro, R4
is hydrogen, R2 is not 2-chloro-6-fluorophenyl h) R1 is -S02ethyl or
-SO2cyclopentyl, R3 is chloro, R4 is hydrogen, R2 is not 2-chloro-6-
fluorophenyl; i) R4 is hydrogen, R2 is 2-chloro-6-fluoropheny1, R1 and R3are
not 1 ,2,4-triazole; j) R1 Is cydohexyl, R4 is hydrogen, R2 is 2,4,6-
trifluorophenyl, and R3 is not -OCH2O2C(CH3)3 ; k) R1 Is 2-thtenyl, R4
is ethyl, R3 is hydrogen and R2 is not 2-methoxyphenyl, 4-methoxyphenyl, and 4-trifluorophenyl; I) R2 is phenyl, R3 is chloro, R4 is hydrogen, R1 Is not (2E)-,7-dimethyl-2,6-octadienyl or a pharmaceutically acceptable salt thereof.
Among the preferred groups of compounds of Formula (I) including pharmaceutically acceptable salts thereof useful for the methods of this invention are those in the subgroups below wherein the other variables of Formula (I) in the subgroups are as defined above wherein:
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a) R1 is selected from the group consisting of an optionally substituted alkyl of
1 to 12 carbon atoms, optionally substituted alkenyl of 2 to 12 carbon atoms,
optionally substituted alkynyl of 2 to 12 carbon atoms, optionally substituted
aikaciienyi of 4 to 12 carbon atoms, optionally substituted aryl of 6, 10 or 14
carbon atoms, optionally substituted bicycloalkyl of 5 to 10 carbon atoms,
optionally substituted cycloalkyl of 3 to 8 carbon atoms in which one -CH2-
may also be replaced by-O-, -S-, or-NR' where R' is H or an alkyl group of 1
to 12 carbon atoms, optionally substituted cycloalkenyl of 5 to 10 carbon
atoms in which one -CH2- may also be replaced by -O-, -S-, or -NR' where
R' is H or an alkyl group of 1 to 12 carbon atoms, -S-aryl of 6, 10 or 14 carbon
atoms, -S-aikyl of 1 to 12 carbon atoms, -S-alkenyl of 2 to 12 carbon atoms,
-SO2aryl of 6, 10 or 14 carbon atoms, -SO2cycloalkyl of 3 to 8 carbon atoms,
-SO2alkyl of 1 to 12 carbon atoms, -O-aryl of 6, 10 or 14 carbon atoms, and
the moiety -NRaRb;
b) Raand Rb each independently represent the moiety -C*H(Re)(Rf) where Re
and Rf independently represent an optionally halo-substituted alkyl group of 1
to 12 carbon atoms where C* represents the (R) or (S) isomer;
c) Rz is optionally substituted phenyl;
d) R3 is halogen, alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon
atoms, aryloxy, -NRcRd, benzyloxy, aralkyloxy, haloalkoxy of 1 to 12 carbon
atoms,
alkylthio of 1 to 12 carbon atoms, hydroxy, cyano, amino, alkylamino of 1 to
12 carbon atoms, dialkylamino of 1 to 12 carbon atoms, or -N3;
e) R4 is H, optionally substituted alkyl of 1 to 12 carbon atoms, optionally substituted alkoxy of 1 to 12 carbon atoms, amino, alkyl amino of 1 to 12 carbon atoms, dialkylamino of 1 to 12 carbon atoms, -CF3;
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Among the additionally preferred groups of compounds of this invention according to general Formula (1) including pharmaceutically acceptable salts thereof useful for the methods of this invention are those in the subgroups beiow, wherein the other variables of Formula (i) in the subgroups are as defined above wherein:
a) R1 is selected from the group consisting of an optionally substituted alkyl of 1 to 12 carbon atoms, optionally substituted alkenyl of 2 to 12 carbon atoms, optionally substituted alkynyl of 2 to 12 carbon atoms, optionally substituted alkadienyl of 4 to 12 carbon atoms, optionally substituted aryl of 6, 10 or 14 carbon atoms, optionally substituted bicycioaikyl of 5 to 10 carbon atoms, optionally substituted cycloalkyl of 3 to 8 carbon atoms in which one -CH2-may also be replaced by-O-, -S-, or-NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, optionally substituted cycloalkenyl of 5 to 10 carbon atoms in which one -CH2- may also be replaced by -O-, -S-, or -NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, -S-aryl of 6, 10 or 14 carbon atoms, -S-alkyl of 1 to 12 carbon atoms, -S-alkenyl of 2 to 12 carbon atoms, -SO2aryl of 6, 10 or 14 carbon atoms, -SC^cycloalkyl of 3 to 8 carbon atoms, -SO2alkyl of 1 to 12 carbon atoms, -O-aryl of 6, 10 or 14 carbon atoms, and the moiety -NRaRb wherein RaRb are optionally taken together with the nitrogen to which each is attached;
b) R2 is optionally substituted phenyl;
c) R3 is halogen, alkoxy of 1 to 12 carbon atoms, -NRcRd , haloalkoxy of 1 to
12 carbon atoms, alkylthio of 1 to 12 carbon atoms, cyano, amino, alkylamino
of 1 to 12 carbon atoms, dialkylamino of 1 to 12 carbon atoms, or -N3;
d) R4 is H, optionally substituted alkyl of 1 to 12 carbon atoms, amino, alkyl
amino of 1 to 12 carbon atoms, dialkylamino of 1 to 12 carbon atoms, -CF3;
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Among the more preferred groups of compounds of Formula (I) including pharmaceuticaily acceptable salts thereof useful for the methods of this invention are those in the subgroups below including the pharmaceuticaily acceptable salts thereof wherein the other variables of Formula (I) in the subgroups are as defined above wherein:
a) R1 is selected from the group consisting of an optionally substituted alkyl of 1 to 12 carbon atoms, optionally substituted cycloalkyl of 3 to 8 carbon atoms in which one -CH2- may also be replaced by -O-, -S-, or -NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, optionally substituted cycloalkenyl of 5 to 10 carbon atoms in which one -CH2- may also be replaced by-O-, -S-, or-NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, -S-aryl of 6, 10 or 14 carbon atoms, -S-alkyl of 1 to 12 carbon atoms, -S-alkenyl of 2 to 12 carbon atoms, -SO2aryl of 6, 10 or 14 carbon atoms, -SO2cycloalkyl of 5 to 10 carbon atoms, -SO2alkyl of 1 to 12 carbon atoms, and the moiety -NRaRb wherein RaRb are optionally taken together with the nitrogen to which each is attached;
b) R2 is optionally substituted phenyl;
c) R3 is halogen, alkoxy of 1 to 12 carbon atoms, -NRcRd, haloalkoxy of 1 to 12 carbon atoms, alkylthio of 1 to 12 carbon atoms, cyano, or -N3;
d) R4 is H;
Among the most preferred groups of compounds of Formula (I) including pharmaceuticaily acceptable salts thereof useful for the methods of this invention are those in the subgroups below including the pharmaceuticaily acceptable salts thereof wherein the other variables of Formula (I) in the subgroups are as defined above wherein:
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a)R1 is selected from the group consisting of an optionally substituted cycloalkyl of 3 to 8 carbon atoms in which one -CH2- may also be replaced by -O-, -S-, or -NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, optionally substituted cycloalkenyl of 5 to 10 carbon atoms in which one -CH2- may also be replaced by -O-, -S-, or -NR1 where R' is H or an alkyl group of 1 to 12 carbon atoms, -S-aryl of 6,10 or 14 carbon atoms, -S-alkyl of 1 to 12 carbon atoms, -S-alkenyl of 2 to 12 carbon atoms, -SO2aryl of 6,10 or 14 carbon atoms, -SO2cycloalkylof 3 to 8 carbon atoms, -SO2alkyl of 1 to 12 carbon atoms, and the moiety ~NRaRb wherein RaRb are optionally taken together with the nitrogen to which each is attached; R2 is optionally substituted phenyl; R3 is halogen, alkoxy of 1 to 12 carbon atoms, -NRcRd, haloalkoxy of 1 to 12 carbon atoms, alkylthio of 1 to 12 carbon atoms, cyario, or-N3; R4isH;
b) R1 is the moiety -NRaRb wherein RaRb are optionally taken together with
the- nitrogen to which each is attached; R2 is optionally substituted phenyl; R3
is halogen, alkoxy of 1 to 12 carbon atoms, -NRcRd, haloalkoxy of 1 to 12
carbon atoms, alkylthio of 1 to 12 carbon atoms, cyano, or -N3; R4 is H;
c) R1 is the moiety -NRaRb wherein RaRb are optionally taken together with
the nitrogen to which each is attached;
R2 is optionally substituted phenyl;
R3 is halogen, alkoxy, -NRcRd , haloalkoxy of 1 to 12 carbon atoms, alkylthio of 1 to 12 carbon atoms, cyano, or-Na; R4 is H;
Ra is H, optionally substituted alkyl of 1 to 12 carbon atoms, optionally substituted alkenyl of 2 to 12 carbon atoms, optionally substituted alkadienyl
of 4 to 12 carbon atoms, optionally substituted cycloalkyl of 3 to 8 carbon
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atoms, in which one -CHr may also be replaced by-O-, -S-, or-NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, optionally substituted cycloalkenyi of 5 to 10 carbon atoms, in which one -CHr may also be replaced by-O-, -S-, or-NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, haloalkyl of 1 to 10 carbon atoms, aryj of 6,10 or 14 carbon atoms, heterocyclyl, benzyl, optionally substituted benzyl; Rb is H, an optionally substituted alkyl of 1 to 12 carbon atoms, optionally substituted alkenyl of 2 to 12 carbon atoms, optionally substituted alkadienyl of 4 to 12 carbon atoms, optionally substituted aryl of 6,10 or 14 carbon atoms, optionally substituted cycloalkyl of 3 to 8 carbon atoms in which one -CH2-may also be replaced by-O-, -S-, or-NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, optionally substituted cycloalkenyi of 5 to 10 carbon atoms in which one -CH2- may also be replaced by-O-, -S-, or-NR' where R* is H or an alkyl group of 1 to 12 carbon atoms, -S-aryl of 6,10 or 14 carbon atoms, -S-alkyl of 1 to 12 carbon atoms, -S-alkenyl of 2 to 12 carbon atoms, -SO2aryl of 6,10 or 14 carbon atoms, -SO2cycloalkyl of 3 to8 carbon atoms, -SO2alkylof 1 to 12 carbon atoms, -O-aryl of 6,10 or 14 carbon atoms;
RaRb together with the nitrogen atom to which each is attached represent an optionally substituted saturated or unsaturated heterocyclyl ring from 3 to 12 ring atoms in which optionally, at least one -CH2- may also be replaced by _O-, -S-, or-NR where R is H or an alkyl group of 2 to 12 carbon atoms, said saturated or unsaturated heterocyclyl ring may optionally be aryl or cycloalkyl fused;
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Rc is H, amino, optionally substituted alkylof 1 to 12 carbon atoms, haloalkyi of 1 to 10 carbon atoms, optionally substituted alkenyl of 2 to 12 carbon atoms, optionally substituted alkadienyl of 4 to 12 carbon atoms, optionally substituted cycloalkyl of 3 to 8 carbon atoms, in which one -CHr rnay also be replaced by -O-,-S-, or-NR where R is H or an alkylgroup of 1 to 12 carbon atoms optionally substituted cycloalkenyl of 5 to 10 carbon atoms, in which one -CHr may also be replaced by -O-, -S-, or -NR where R is H or an alkyl group of 1 to 12 carbon atoms optionally substituted bicycloalkyl of 5 to 10 carbon atoms, aryl of 6,10 or 14 carbon atoms, benzyl, optionally substituted benzyl, or heterocycfyl;
Rd is H, amino, optionally substituted alkyl of 1 to 12 carbon atoms, haloalkyi of 1 to 10 carbon atoms, optionally substituted alkenyl of 2 to 12 carbon atoms, optionally substituted alkadienyl of 4 to 12 carbon atoms, optionally substituted cycloalkyl of 3 to 10 carbon atoms, in which one -CH2- may also be replaced by -O-, -S-, or-NR where R is H or an alkyl group of 1 to 12 carbon atoms optionally substituted cycloalkenyl of 5 to 10 carbon atoms, in which one -CHr rnay also be replaced by -O-, -S-, or -NR where R is H or an alkyl group of 1 to 12 carbon atoms optionally substituted bicycloalkyl of 5 to 10 carbon atoms, aryl of 6,10 or 14 carbon atoms, benzyl, optionally substituted benzyl, or heterocyclyj;
RcRd together with the nitrogen atom to which each is attached represent an optionally substituted heterocyclyl ring from 3 to 8 ring atoms optionally substituted in which one -CH2- may also be replaced by-O-, -S-, or-NR1 where Rf is H or alkyl of 2 to 20 carbon atoms;
d) R1 is the moiety -NRaRb wherein RaRb are optionally taken together with the nitrogen to which each is attached;
R2 is selected from
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R3 is halogen, alkoxy, -NR°Rd, haloalkoxy of 1 to 12 carbon atoms, alkylthio
of 1 to12 carbon atoms, cyano, or-N3;
R4 is H;
e) R1 Is the moiety -NRaRb wherein RaRb are optionally taken together with the nitrogen to which each is attached and wherein R1 is selected from
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R2 is optionally substituted phenyl;
R3 is halogen, alkoxy of 1 to 12 carbon atoms, -NRcRd , haloalkoxy of 1 to 12
carbon atoms, alkylthio of 1 to 12 carbon atoms, cyano, or-N3;
R4 is H;
f) R1 is the moiety -NRaRb wherein RaRb are optionally taken together with the nitrogen to which each is attached and wherein R1 is selected from
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R2 Is optionally substituted thienyl;
R3 is halogen, alkoxy of 1 to 12 carbon atoms, -NRcRd , haloalkoxy of 1 to 12
carbon atoms, alkyithio of 1 to 12 carbon atoms, cyano, or -N3;
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WO 02/02563 PCT/US01/20672
R4 is H;
Also, among the most particularly preferred compounds for the methods of this invention according to Formula (I) are the following compounds or a pharmaceutically acceptable salt thereof: 7-{1 -azepanyl)-5-chloro-6-pheny1[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2,6-difluorophenyI)-7-{4-methyl-1 -piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(4-methoxyphenyl)-7-(1 -piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyI)-7-(4-methyl-1-piperidinyl)[1,2,4}triazolo[1,5-a]pyrimidine;
7-(1-azepanyl)-5-chloro-6-(2-chloro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-(2-methyl-1 -piperidinyf )[1,2,4]triazolo[1 t5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-(4-tlhiornorpholinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
methyl [[5^hloro-6-(2-chloro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-yl](methyl)amino]acetate;
5-chloro-6-(2-chloro-6-fluorophenyl)-N-(1,1,3,3-tetramethylbutyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
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WO 02/02563 PCT/US01/20672
7-(1 -azepanyl)-5-chloro-6-(4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidine; 7-(1 -azepany!)-6-(4-bromophenyl)-5-chloro[1,2,4Jtriazolo[1,5-a]pyrimidine;
5-chIoro-7-(1-piperidinyl)-6-[2-(trrfluoromethiyl)phenyri[1,2,4]triazolo[1,5-a]pyrimidine;
6-(4-tert-butyiphenyl)-5-chloro-7-(4-methyI-1 -piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(4-methoxyphenyl)-7-(4-methyl-1-piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-{4-methoxyphenyl)-7-(3-methyl-1-piperidinyl)[1,2,4]triazolo[1,6-a]pyrimidine;
6-(4-bromophenyl)-5-chloro-7-(3-methyl-1-piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(3,4-drfluorophenyl)-7-(4-methyl-1 -piperidinyl)[1,2f4ltriazolo[1,5-a]pyrimidine;
5-chloro-6-(2,6-dichlorophenyl)-7-(2-methyl-1-pyrrolidiny{)[1 f2f4]triazDlo[1,5-a]pyrimidine;
5-chIoro-6-(2-chIorophenyI)-7-(2--methyl-1-pyrrolidinyl)j;i ,2,4]triazolo[1,5-a]pyrimidine;
7-(1-azepanyl)-5-chloro-6-(3-chloro-4-methoxyphenyl}[1,2,4]triazolo[1,5-a]pyrimidine;
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WO 02/02563 PCT/US01/20672
5-chloro-6-(3-chloro-4-methoxyphenyl)-7-(4-methyl-1-piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(3-chloro-4-methoxyphenyl)-7-(2-methyl-1-piperid inyl)[1,2,4]triazolo[1,5-a]pyrimidine;
6-(4-tert-butylphenyl)-5-chloro-7-(2-methyl-1 -piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-7-(2-methyl-1 -piperidinyl)-6-[3-(trifluoromethyl)phenyl][1,2,4]triazolo[1,5-a]pyrimidine;
Diethyl 2-[6-(2,6-difluorophenyI)-5-ethoxy|;i ,2,4]triazolo[1,5-a]pyrimidin-7-yflmaionate;
7-(azepanyl)-5-chloro-6-{2-chloro-6-nitrophenyl}[1,2,4}triazolo[1,5-a]pyrimidine;
5K^loro^2<^lort>6-fluorophenyl)-N-ethyl-N-(2-methyl-2-propenyl)[1,2,4Jtriazolo[1,5-a]pyrimidin-7-amine;
5-chlono-6-(2-chlon>6-fluorophenyl)-N-(2,2^- trifluoroethyl)[1 ^,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chIoro-6-(2-chloro-6-fluorophenyl)-N-[(2,2-dichlorocyclopropyl)methyl]-N-methyl[1,2,4}triazoio[1,5-a]pyrimidin-7-amine;
1 -[5-chloro-6-(2-chloro-6-fluorophenyl)[1,2,4Jtriazolo[1,5-aJpyrimidin-7-yl]-3-piperidinol;
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N-bicyclo[2.2.1]hept-2-yl-5-chloro-6-(3-chloro-4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-{2,5-d{fluorophenyl)-N-dodecyl[1,2,4]triazolo[1,6-a]pyrimiclin-7-
amine;
5-chloro-7-(4-methy-1-piperidinyl)-6-(2,3,6- trifluoropheny))[1,2,4]triazolo[1,5-
a]pyrimidine;
N-[5-chloro-6-(2,3,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]-N-isopropylamine;
5-chloro-N-ethyl-N-(2-methyJ-2-propenyJ)-6-(2t3,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
N-alIyl-5-chloro-6-(2-chloro-6-fluorophenyl)-N-(2-methyl-2-propenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-anriine;
5-chloro-6-(2-chloro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(3-choloro-4-methoxyphenyl)-N-cyclloheptyl[1,2,4]triazolo{1,5-a]pyrimidin-7-amine;
5-chloro-6-(3-chloro-4-methoxyphenyl)-7-(3,3-dimethyl-1-piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-N-(3-chloropropyl)-N-methyl-6-(2,3,6-trifluorophenyi)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
7-(1 -azocanyl)-5-chloro-6-(2>3,6-trifluorophenyi)[1,2,4]triazolo[1,5-a]pyrimidine;
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5-chloro-6-(2,6-difIuorophenyl)-7-(3,6-dihydro-1(2H)-pyridinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
7-(1 -azocanyl)-5-chloro-6-(2,6-difluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-methoxy-6-(2-chJoro-6-fluorophenyl)-7-(4-methyl-1-piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
[5-chIoro-6-(2-chloro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]methanol;
1 -[5-chloro-6-(2,6-dlfluoropheny()[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-4-piperidinol;
5-chloro-7-{4-chloro-1-piperidinyl)-6-(2I6-drfluorophenyl)[1,2,4]triazolo[1,5-ajpyrimidine;
5-chloro-7-(4-thiomorpholinyl)-6-(2,3,6-trifluorophenyi)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2,6-difluorophenyl)-7-(2,4-dimethyl-1 -piperidinyl)[1,2,4]triazoio[1,5-a]pyrimidine;
7-{4-methyl-1-piperidinyl)-5-amino-6-{2-chioro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2,6-difIuorophenyl}-7-(2,5-dihydro-1H-pyrrol-1-yl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyl)-(2,5-dimethyl-2,5-dihydro-1H-pyrrol-1-
yl)[1,2,4]triazolof 1,5-a]pyrimidine;
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5-chloro-6-(2-chloro-6-fluorophenyl)-7-{2-ethyl-1H-imidazol-1 -yl)[ 1,2,4]triazolo[1,5-a]pyrimidine;
7-(4-bromo-1-piperidinyl)-5-chloro-6-(2-chloro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chIoro-6-(2-methyiphenyl)-7-(4-thiomorpholinyl)[1,2,4]triazolo[1,5-
a]pyrimidine;
6-(2-bromophenyl)-N-(sec-butyl}-5-chloro[1,2,4}triazolo[1,5-a]pyrimidin-7-
amine;
5-chloro-N-ethyl-6-(4-methoxypheny!)-N-(2-methyl-2-propenyl)[1,2,4]triazolo[1,5- a]pyrimidin-7-amine;
5-chloro-6-(4-methoxyphenyl)-7-(4-thiomorphoIinylX1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-7-(4-chloro-1 -piperidinyl)-6-j2-(trifluoromethyl)phenyl][1,2,4]triazolo[1,5-a]pyrimidine;
5<:hlorcH6^2^lorCH6-fluorophenyl)7-{4-{trifluorornethyl)-1-piperidinyl][1,2,4]triazolo[1,5-a]pyrimidine;
7-(4-bromo-1 -piperidinyl)-5-chloro-6-(2,6-difluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
7-(4-bromo-1 -piperidinyl)5-chIoro-6-(2-chlorophenyI)[1,2,4]triazolo[1,5-a]pyrimidine;
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5-chloro-N-ethyl-N-(2-methyl-2-propenyI)-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N-isopropyl-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5- a]pyrimidin-7-amine;
5-chloro-7-{4-thiomorpholinyl)-6-(2,4,6-trifiuorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
7-(1 -azepanyl)-5-chloro-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-[2-(1 -pyrrolidinyl)-1 -cyclopenten-1 -yl][1,2,4]triazoio[1,5-a]pyrimidine;
5-chloro-7-(4-isopropyl-1 -piperidinyl)-6-{4~methoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-7-(2,4-dimethyl-1-piperidinyf)-6-(4-rnethoxyphenyl)[1 ,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-7-fethyl(2-methyl-2-propenyl)amino}-6-{4-nitrophenyl}[1,2,4]triazolo[1,5-a]pyrimidine;
7-(1 -azepanyl)-5-chlorio-6-{4-nltrophenyl}[1,2,4]triazolo[1,5-a]pyrimidine;
N-bicyclo[2.2.1]hept-2-yl-5-chloro-6-(2,4,6-trifiuorophenyI)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2,6-difluorophenyl)-N-(2,2,2-trifluorethy!)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
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5-chloro-6-(2-chlorophenyl)-N-(2,2,2-trifluoroethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2-ch!oro-6-fluorobenzyf)-7-tetrahydro-2-furanyl[1,2,4]tria2olo[1,5-a]pyrimidine;
7-(allylsulfanyl)-5-chIoro-6-(2-chlono-6-fiuorophenyl)[1,2,4]triazolo[1,5-ajpyrirnidine;
5-chloro-N-ethyl-6-mes{tyl-N-(2-methyl-2-propenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N-ethyl-6-(2-methoxyphenyI}-N-(2-methyl-2-propenyl)[1,2,4Jtriazolo[1,5-a]pyrimidin-7-amine,-
5-chloro-6-(2-chIoro-6-fluorophenyl)-N-hexyl|[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-7-(4-methyl-1 -piperidinyl)-6-[4-(methylsulfany!)phenyl][1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-N-ethyl-N-(2-methyl-2-propenyl)-6-[4-(methylsulfanyl)phenyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
N-(sec-butyl)-5-chIorlo-6-[4-(methylsuIfanyl)phenyl][1,2,43triazolo[1,5-a]pyrimidin-7-amine;
S-chloro6-[4-(methytsulfanyl)phenyl]-7-(4-thiomorpholinyl)[1,2,4}tria2olo[1,5-a]pyrimidine;
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5-chloro-6-[2,6-dichloro-4-(trifluoromethyl)phenyl]-7-(4-methyI-1-piperidinyl)[1,2,4Jtriazolo[1,5-a]pyrimidine;
7-(1-azepanyl)-5-chloro-6-[2,6-clichloro-4-(trifluoromethyl)phenylj[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-[(2,2,2-trifluoroethyl)sulfanyl][1,2,4]triazo)o[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyi)-7-(4,4r-dimethyl-1-piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5^hloro^[2,6^ichlorcH4Ktrifluoromethyl)phenyl]-N-ethyl-N-(2-methyl-2-propenyl)[1,2,4]tria2olo[1,5-a]pyrimidin-7-amine;
5-chloro-6-[2,6-dichloro-4-(trifluoromethyl)phenyI3-7-(4-thiomorpholinyl)[1 ^,4]tria2olo[1,5-a]pyrimidine;
5-chloro-6-(3f 5-difiuorophenyl)-7-(4-methyl-1 -plperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chlon>6-fluorophenyl)-7-{isopropylsulfanyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-tetrahydro-2-furanyl[1,2,4]tria2olo[1,5-a]pyrimidine;
4-[5-chloro-7-(4-methyl-1-piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]aniline:
N-{4-[5-chloro-7-(4-methyl-1 -piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidin-6-y!]phenyl}acetamide;
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[5-chloro-6-(2-chloro-6-fluorophenyl)[1,2,43triazoIo[1,5-a]py'rimidin-7-yl]methyl acetate;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-(chloromethyl)[1,2,4]triazolo[1,5-a]pyrimidine;
diethyl 2-[6-(2-chIoro6-fluorophenyl)-7-(4-methyl-1 -piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]maIonate;
7-(1 -azepanylmethyl)-5-chloro-6-{2-chloro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
N-allyl-5-chloro-6-(2-chloro-6-fluorophenyl)-N-hexyl[1,2,4)triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-7-(4-methyl-1 -piperidinyl}-6-[4-(trifluonomethoxy)phenyl)[1,2,4]triazolo[1,6-a]pyrimidine;
5-chloro-7-(4-methyl-1 -piperidinyl)-6-(4-phenoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5chloro-6-(2-chloro-6-fluorophenyl)-N-(cyclopropylmethyl)-N-propyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-7-(2-methyl-1 -piperidinyl)-6-(4-phenoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chIoro-6-{2-chloro-4-nitrophenyI}-7-(4-methyl-1 -piperidjnyl)[1,2,4]triazolo[1,5-a]pyrimidine;
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5-chloro-6-(4-chioro-2,3,5,6-tetrafiuorophenyl)-N-cyclopentyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
4-[5-chloro-2-methyl-7-(4-methyl-1 -piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]-N, N-dimethylaniline;
6-(2-chloro-6-fluorophenyl)-5-methyl-7-(4-methyl-1-piperidinyl)[1,2,4]triazoio[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fIuorophenyl)-7-[2-(1-pyrrolidiny[)-1-cyclohexen-1-yl][1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-(methoxymethyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-{2-chloro-4-nrtrophenyl}-7-[ethyI(2-methyl-2-propenyl)amino][1,2,4]triazolo[1,5-a]pyrimid[ne;
5-bromo-6-(2-chIoro-6-fluorophenyl)-7-{isopropylsulfanyl)[1,2,4]triazolo[1,5-ajpyrimidine;
5-chloro-N-cyclopentyl-6-(4-ethoxy-2,3,5,(5-tetrafluorophenyl)[1,2,4]triazolo[1,6-a]pyrimidin-7-amine;
5-chloro-N-methyl-N-(2-methyl-2-propenyI)-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7~amine;
4-bromo1 -[5-chloro-6-(2-chloro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]butyl acetate;
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diethyl 2-a!lyl-2-{[5-chloro-6-(2-chloro-6-fIuorophenyi)[1,2,4]triazolo[1,5-a]pyrimidin-7-yI]oxy}malonate;
6-(2-chloro6-fluorophenyl)-N-ethyl-5-methyl[1,2,4]triazolo[1 ,5-a]pyiimidin- 7-amine;
N-butyI-5-chloro-N-ethyl-6-(2,3,4,5,6-pentafluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
6-(2-chloro-6-fluorophenyl)-5-(difluoromethoxy)-7-{4-methyl--1-piperidinyl)[1,2,4Jtriazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-{(4-chlorophenyl)sulfanyl|[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-[(2-rnethoxyphenyl)sulfanyl][1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyl)-N-(1,2,2-trimethylpropyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2,3,4,5,6-pentafluorophenyl)-N-(1,2,2-trimethyipropyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chIoro-6-(2,4,6-trifluorophenyI)-N-(1,2,2-trimethylpropyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(4-fluorophenyl)-N-(1,2,2- trimethylpropyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
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5,7-bis(4-methyl-1-piperidinyl)-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-methylphenyl)-N-(1,2,2-trimethyIpropyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2,4,5-tiifluorophenyl)-N-(1,2,2-trimethylpropyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
6-(2-bromophenyl)-5-chloro-N-(1,2,2-trimethyipropyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N-isobutyl--N-{2,2,2-trifluoroethyl)-6-{2,4t6-trifluorophenyl)[1,2,4}triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N-isobutyl-6-(2-methylphenyl)-N-(2,2,2-trifluoroethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-diloro-6-(2-chloro-6-fluorophenyl)-N-(2f2,2-trifiuoro-1-methylethyl)[1,2,4Jtriazolo[1,6-a]pyrimidin-7-amine;
5-chloro-6-(2,6-difluorophenyl)-N-(2,2,2-trifluoro-1-methylethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N-(2,2,2-trifluoro-1-methylethyl)-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
N-allyl-5-chloro-N-isobutyl-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
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5-chloro-N-(1,2-dimethylpropyl)-6-(2,4,6-trifluorophenyI)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N-isopropyl-N-methyl-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N-isopropyl-N-(2,2,2-trifluoromethyl)-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
7-butyI-5-chlorio-6-(2f4,6-trifiuoropheny{)[1,2,4Jtriazolo[1,5-a]pyrimidine;
5-chloro-N-(1-phenylethyl)-6-(2l4,6-trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-{2-chloro)phenyI)-N-(2f2,2-trifluora-1-methylethyl)[1,2,4]triazo!o[1,5-a]pyrimidin-7-amine;
5-chloro-N-ethyl-N-isobutyl-6-{2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-hexyl[1,2,4]triazolo[1,5-a]pyrimldine;
5-chloro-6-(2-methylphenyl)-N,N-bis(2,2,2-trifluoroethyI)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chIoro-N-cyclopentyl-N-methyl-6-(2,3,4,5,6-pentafluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
7-butyl-5-ch!oro-6-(2,6-d[fluorophenyI)[1,2,4]triazolo[1,5-a]pyrimidine;
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5-chloro-N-(1,2-dimethylpropyl)-N-methyl-6-(2,3,4,5,6-pentafluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2-chloro-6-fluorophenyI)-7-phenyl[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chIoro-6-fiuorophenyl)-7-(2-methyipropanyi)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-pentyl[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-N-(1,2-dimethyIpropyl)-N-methyl-6-(2,4,6-trifiuorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amJne;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-cycIohexyl[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-bromo-5-chlorophenyl)-N-(2,2,2-trifluoro-1-methyiethyl)[1 f2,4Jtriazolo[1,5-a]pyrimidin-7-amine;
5^hIoro-6-(2-chlon>6-fluorophenyl)-7-(3,3,3-trifluoropropyl)[1,2,4Jtriazofo[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluonophenyI)-7-(3-methylphenyt)[1,2,4]tria20lo[1,5-a]pyrimidine;
[5-chloro-6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]-{1-p-tolyl-ethyl)-amine;
5-choloro-6-(2,4,6-trifluro-phenyl)-7-cyclohexyl[1,2,4]triazolo[1,5-a]pyrimidine;
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5-chIoro-7-cyclohexyl-6-(2,3,4,5,6-pentafluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-(4,4-difluoro-1-piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
7^bicycio[2.2.1]hept-2-ylarnino)-5-chloro-6-{2-fluoro-4-nitrophenyl}[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-{2-fluoro-4-nltrDphenyJ}-7-(4-methyl-1 -piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-(methylsuffanyl)-6-(2-chloro-6-fluorophenyl>-7-cyclohexyl[1,2,4]triazolo[1,5-a]pyrimidine;
[5-chloro-6-(2,4,6-trifiuorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-ylJ (2,2,2-trifluoro-1 -phenylethy})-amine;
5-chloroN-{1 -(trifluorpmethyl)propyl3-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-bromo-6-(2-chloro-6-fluorophenyl)-7-cyclohexyl[1,2,4]triazolo[1,5-a]pyrimidine;
6-(2-chloro-6-fluorophenyl)-7-cyclohexyl[1,2,4]triazolo[1,5-a]pyrimidin-5-amine;
[5-chloro-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]-(2-methyl-1 -trifluoromethyl-propyl)amine;
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5-ch!oro-7-(3-cyelohexen-1 -yl)-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-ch!oro-7-(1-cyclohexen-1-yl)-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-N-[(1R)-2,2,2-trifluoro-1-methylethyl]-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
6-(2,4-difluorophenyl)-5-chloro-N-(2,2,2-trifluoro-1-methylethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2,6-difluoro-4-methoxyphenyl)-7-(4-methyl-1-piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2,6-difluoro-4-methoxyphenyl)-N-(2,2,2-trifluoro-1-methylethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-7-cyclohexyl-6-(2,6-difluoro-4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2,6-difluoro-4-methoxyphenyl)-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
7-cyclohexyl-6-(2,6-difluoro-4-methoxyphenyl)-5-methoxy[1,2,4]triazolo[1,5-a]pyrimidine;
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5-chloro-7-(4-fluorocyclohexyI)-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2,6-dichloro-4-fluorophenyl>7-(3,3,3-trifluoropropyl)[1,2,4Jtriazolo[1,5-a]pyrimidin-7-amine;
N-(sec-butyl)-5-chloro-6-(2,6-dichloro-4-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
4-{5-chloro-7-[(2,2,2-trifluoro-1 -methylethyj)amino][1,2,4}triazolo[1,5-a]pyrimidin-6-yl}-3,6-difluonophenol;
5-chloro-7-(3-cyciohexen-1-y})-6-(2,6-difluoro-4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2,6-difluoro-4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N-cyclopentyl-6-(2,6-difluoro-4-methoxyphenyI)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5^)oro-6-(2,6~dif)uoro-4-methoxyphenyl)-7-(3,6-dihydro-1(2H>-pyridinyi)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2,6-difluoro-4-methoxyphenyl)-7-{4-thiomorpholinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
7-(1 -azepanyl)-5-chloro-6-(2,6-difluoro-4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
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5-chloro-6-(2,6-difluoro-4-methoxyphenyl)-N-(1,2,2-trimethylpropyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2,6-difluoro-4-methoxyphenyl)-N-ethyl-N-(2-methyl-2-propenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2,6-difluoro-4-methoxyphenyl)-7-(4-fluorocyclohexyl)[1,2,4]triazolo[1,5-a]pyrimidine;
6-(4-{5-chloro)-7-[(2,2,2-trifluono-1-methylethyl)amino][1 f2,4]triazolo[1,5-a]pyrimidin-6-yl}-3,5-difluorophenoxy)hexanoicadd;
2,6-difluoro-4-(2-fluoroethoxy)phenyl]-N-(2,2,2-trifluoro-1-methylethyl)[1,2,4Jtriazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N-isopropyJ-6-{2-[(trifluofomethyl )sulfanyl]phenyl}[1,2,4Jtriazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N-[4-(trifluoromethy})phenyl]-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N-(4,4,4-trifluoro-2-methyIbutyl)-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2,6-difluoro-4-methoxyphenyl)-7-(3-methyl-3-butenyl)[1,2,4}tria2oio[1,5-a]pyrimidine;
5-chloro6-(2,6-dffluoro-4-methoxyphenyl)-7-isobutyl[1,2,4]triazolo[1,5-a]pyrimidine;
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7-cyclopentyi-6-{2,6-difluoro-4-methoxyphenyI)-5-methoxyI1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-thienyI)-N-[(1 R)-2,2,2-trifluoro-1 -methyiethyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
4-(5-chloro-7-(2,2,2-trifluoro-1 -methyl-ethylamino)[1,2,4]triazolo[1,5-a]pyrimidin-e-yl]-3,5-difluoro-phenol;
{5-chloro-6-[2,6-difluoro-4-(22,2-trifluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-(2,2,2-trifluoro-1-methyl-ethyl)amine;
5^hloro^^2,6^ifluoro-4-(methoxypheny1)-N-(2,2,2-tnfiuora-1-methylethy1)n ,2,4]triazolo[1,5-a3pyrimidin-7-amine;
(5-chloro-6-{4-f2-(2-ethoxyethoxy]-ethoxy3-2,6-dJfluorc>-phenyl}[1,2,4}triazolo[1 ,5-a]pyrimidin-7-yl-)-(2,2,2-trifluoro-1 -methylethyl)amine;
(5-chloro-6-{2,6-difluoro-4-[2-(2-methoxy-ethoxy)ethoxy]-phenyl]-[1,2,4]triazolo[1,5-a3pyrimidin-7-yl-)-{2,2,2-trifluoro-1-methylethyl)amine;
5-chloro-6-[2,6-difluoro-4-{3-furan-3-ylmethoxy)pheny1[1,2,4]triazolo[1,5-a]pyri midin-7-yl}-N-{2,2,2-trifiuoro-1-methylethyl)amine;
5-chloro-6-(2,5-difluoro-4-methoxyphenyl)-N-(1,2,2-trimethylpropyl)[1 r2,43triazolo[1,5-a3pyrimidin-7-annine;
7-cyclohexyl-6-[2,6-difluoro-4-(2-methoxyethoxy)phenyiJ-5-methoxy[1,2,4]triazolo[1,5-a]pyrimidine;
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5-chloro-6-(2-fluoro-4-methoxy-6-chlorophenyl)-N-(2,2,2-trifluoro-1-methylethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-[2,6-difluoro-4-(2-fluoroethoxy)phenyI]-N-ethyl-N-(2-methyl-2-propeny1)[1,2,4]triazolo[1,5~a]pyrimidin-7-amine;
2-[2-(4-{5-chloro-7-[(2,2,2-trifluoro-1 -methylethyl)amino][1,2,4]triazolo[1,5-a]pyrimidin-6-yl}-3,5-difluorophenoxy)ethoxy]ethanol;
5-chloro-6-(2,3-difluoro-4-methoxyphenyl)-N-(2,2,2-trifluoro-1-methylethyl)[1,2,4]triazolo[1,6-a]pyrimidin-7-amine;
5-chloro-6-{4-(2-fluoroethoxy)-2,6-dlfluorphenyl}-N-(2,2,2-trifluoro-1-methylethy!)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N-(4-chlorobenzyl)-6-(2-chloro-6-fluorophenyl)[1,2,4]triazolo[1,5-a3pyrimidin-7-amine;
5-chloro-6-(2-chloro-6-fIuorophenyl)-7-[4-(2-pyridinyl)-1-piperazinyl][1,2,4]triazolo[1 ,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyl)-N-(1 -ethylpentyl)[1,2,4]triazolo[1 ,5-a]pyrimidin-7-amine;
5-chIoro-6-(2-chloro-6-fluorophenyl)-7-t4-(2-chlorophenyI)-1-piperazinyl][1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-ch!oro-6-fluorophenyl)-7-[4-(4-methoxyphenyl)-3-methyl-1-piperazinyl][1,2,4]triazolo[1,5-a]pyrimidine;
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5-chloro-N-cyclopentyl-6-(2-chIoro-6-fluorophenyl)[1,2,4}triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-7-phenoxy-6-{4-methoxy-pheny!)[1,2,4JtriazoIo[1,5-a]pyrimidine;
5-chloro-N-cyclopentyl-6-(4-methylphenyl)[1,2,4Jtriazolo[1,5~a]pyrimidin-7-amine;
5,7-diphenoxy-6-(4-methoxyphenyl)[1,2,4}triazolo[1,5-a]pyrimidine;
5-chloro-N-cyclopentyl-6-(2-chlorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N,N-diethyl-6-[4-methoxyphenyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chiono-N,N-diethyl-6-[2,4-dichlorophenyl][1,2,43triazolo[1,5-a]pyrimidin-7-amine;
N-bicyclo[2.2.1]hept-2-yl-5-chloro-6-{2,4-dichIorophenyl(1,2,4)triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-(2-chloro-6-fluorophenyl)-7-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-cyano-7-(4-methyl-1-piperJdinyl)-6-(2-chloro-5-fluorophenyl)[1,2,4}triazolo[1,5-a]pyrimidine;
5-(methylsulfanyl)-7-(4-methy!-1-piperidinyl)-6-(2-ch!oro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
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5-(methylsulfanyl)-7-(4-methyl-1-piperidinyl)-6-(2-chloro-5-(methylsulfanyl)phenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-7-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)-6-(4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-N-ethyl-N-(2-methyl-2-propenyl)-6-(4-(methylsulfanyl)phenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
2-methyl-6,7-di-(4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
2-methyl-6-phenyl-7-(4-chlorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
2-trifluoromethyl-6-phenyl-7-(4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(3,4-difluorophenyl)-N-(isopropyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-bromo-6-(4-bromophenyl)-7-dimethylamino[1,2,4]triazolo[1,5-a]pyrimidine;
5-bromo-6-(4-trifluoromethylphenyl)-7-dimethylamino[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(3,4-difluorophenyl)-7-dimethylamino[1,2,4]triazolo[1,5-a]pyrimidine;
5-ch!oro-6-(4-trifluoromethylphenyl)-N-(ethyl)[1,2,4]triazolo[1)5-a]pyrimidin-7-amine;
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7-(1 -azepanyl)-5-chloro~6-(4-tert-butylphenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
ethyl {[5-ch!oro-6-(2-chloro-6-fiuoropheny!)[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]amino}acetate;
diethyl 5-ch!oro-6-(2,6-difluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-malonate;
5-chloro-6-(2,5-dlfiuorophenyl)-N-(3-methyi-2-butenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
[5-chloro-6-(2-chIoro-6-fluorophenyl)-[1,2,4}triazolo[1,5-a]pyrimidin-7-yl]acetic acid methyl ester;
5-chloro-6-(2,6-difluorophenyI)-7-(2-ethyl-1 H-imidazol-1-yl)[1,2,4]triazolo[1,5-
a]pyrimjdine;
5-chloro-N,N-diethyl-6-[4-(methylsulfanyl)phenyl][1,2,4]triazolo[1,5-
a3pyrimidin-7-amine;
ethyl [6-(2-chloro-6-fluorophenyl)-7-(4-methyl-1-piperldinyl)- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl]acetate;
5-chloro-N-ethyl-N-(2-methyl-2-propenyl)-6-(4-phenoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
dimethyl 2-[5-chloro-6-{2-chloro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]malonate;
diethyi 2-{[5-chioro-6-{2-chloro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]oxy}-2-isobutylma!onate;
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2-[5-chloro-6-(2-chloro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]-1,3-cyclohexanedione;
2-[5-chIoro-6-(2-chioro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-yljcydohexanone;
5-chloro-7-(3-nltro-4-methylanilino)-6-(2, 4, 6-trifiuorophenyl) [1,2,4]triazolo[1 ^a]pyrimidine;
7-cyclohexyl-6-[2,6-difluoro-4-{2-methoxyethoxy)phenyl]5-(2-methoxyethoxy)[1,2,4]triazolo[1,5-a]pyrimidine;
7-(3-bromophenyl)-2-ethyl-6-(4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
7-(3-bromophenyI)-6-(3-chlorophenyi)-2-ethyl[1,2,4]triazolo[1 t5-a]pyrimidine,'
7-(4-bromophenyl)-2-ethyl-6-r4-(trifluoromethyl)phenyl][1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyl)-N-(3,4,5-trimethoxybenzyl)[1,2,4]triazo)o[1 t5-a]pyrimidin-7-amine;
7-(2-benzyl-4,5-dihydro-1 H-imidazol-1 -yl)-5-chloro-6-(2-chloro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
N-4-[5-chloro-6-(2-chloro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-yI-N,N-1-diethyl-1,4-pentanediamine;
5-chloro-N-(3-methyI-2-butenyl}-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
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5-dimethylamino-6-phenyl-N-cyclopentyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-7-[(2-furylmethyl)sulfanyl]-6-(4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
6-[1,1 '-biphenyl]-4-yl-5-chloro-N-cyclopentyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
6-[4-(benzyloxy)phenyl]-5-chIoroN-isopropyl[1l2,4!|triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N-[(2,2-dichIorocyclopropyl)methyl]-6-(3,4,5-trimethoxyphenyl)[1,2,43triazolo[1,5-a]pyrimidin-7-amine;
N-cyclopentyl-6-(2-fluorophenyl)-5-hydrazino[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
6-chloro-N-ethyl-6-{2-methylphenyl)[1,2,4Jtriazolo[1,5-alpyrimidin-7-amine;
6-(4-tert-butylphenyl)-5-chloroN-isopropy)[1,2,43triazolo[1,5-a]pyrimidin~7-amine;
5-choloro-[2,6-difluoro-4-[(3-methyI-2-butenyl)oxy]phenyl]-N-(2,2,2-trifluont>1-methylethyl)~l[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-[2,6-difluoro-4-(1-propenyloxy)phenyl]-N(2,2,2-trifluoro-1-methylethyl)-l[1,2,43triazolo[1,5-a]pyrimidin-7-amine;
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5-chloro-N-(3-tricyclo[2.2.1.02,6]hept-1-yl)-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-azido-7-cyclohexyI-6-(2-fluoro-6-chlorophenyl) [1,2,4]triazolo[1,5-a]pyrimidine;
5-azido6-[2-chloro-6-fluorophenyl]-7-(4-methyl-1-piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
2,5-dichloro-7-(4-methyi-1-piperidinyl)-6-[2-chloro-6-fluorophenyl][1,2,4]triazolo[1,5-a]pyrimidine.
It Is understood that the definition of compounds of Formula (I), when R1, R2, R3, R4, Ra, Rb, Rc, Rd, or R contain asymmetric carbons, encompass all possible stereoisomers and mixtures thereof which possess the activity discussed below. In particular, the definition encompasses racemic modifications and any optical isomers, (R) and (S), which possess the indicated activity. Optical isomers may be obtained in pure form by standard separation techniques or enantiomer specific synthesis. It is understood that this invention encompasses all crystalline forms of compounds of Formula (I). The pharmaceuticaliy acceptable salts of the basic compounds of this invention are those derived from such organic and inorganic acids as: lactic, citric, acetic, tartaric, fumaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and similarly known acceptable acids. Where R1, R2, R3, R4, Ra, Rb, Rc, Rd, or R contains a carboxyl group, salts of the compounds in this invention may be formed with bases such as alkali metals (Na, K, Li) or alkaline earth metals (Ca or Mg).
For the compounds defined above and referred to herein, unless otherwise noted, the following terms are defined.
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The term halogen atom may denote a bromine, iodine, chlorine or fluorine atom, and is especially a bromine, chlorine or fluorine atom.
The terms alkyl, alkenyl, alkynyl, alkadienyl as used herein with respect to a radical or moiety refer to a straight or branched chain radical or moiety. As a rule, such radicals have up to 12, in particular up to 6 carbon atoms. Suitably an alkyl moiety has from 1 to 6 carbon atoms, preferably from 1 to 3 carbon atoms. A preferred alkyl moiety is an ethyl or especially a methyl group. Suitably an alkenyl moiety has from 2 to 12 carbon atoms. A preferred alkenyi moiety has from 2 to 6 carbon atoms. Most preferred is allyl or especially a 2-methylallyl group. Any of the alkyl, alkenyl, alkynyl, alkadienyl groups as used herein with respect to the radical or moiety may optionally be substituted with one or more of substituents which include for example, halogen atoms, nitro, cyano, thiocyanato, cyanato, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl, aryl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, carbamoyl, alkylamido, phenyl, phenoxy, benzyl, benzyloxy, heterocyclyl, especially furyl, and cydoalkyl, especially cydopropyl, groups. Typically, 0-3 substituents may be present.
Cycloalkyl or cycjoalkenyl as used herein with respect to a radical or moiety refer to a cycloalkyl or cycloalkenyl group having 3 to 8 carbon atoms preferably 3 to 6 carbon atoms or a cycloalkenyl group having 5 to 8 carbon atoms, preferably 5 to 7 carbon atoms, in particular cyclopentyl, cyclohexyl or cydohexenyl being optionally substituted by one or more of substituents which include for example, halogen atoms, nitro, cyano, thiocyanato, cyanato, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, aikylamino, dialkylamino, formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsulphinyl, alkyisulphonyi, carbamoyl, alkyiamido, phenyl, phenoxy, benzyl, benzyloxy, heterocydyi, especially furyl, and cycloalkyl, especially cydopropyl, groups. Typically, 0-3 substituents may be present. Optionally, -CH2- group of the
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cycloalkyl or cycloalkenyi radical or moiety may optionally be replaced with -O-, -S- or-NR' where R' is H or an alky! group of 2 to 12 carbon atoms.
A bicycloalkyl group may contain from 5 to 10 carbon atoms.
Aryl as used herein with respect to the radical or moiety refers to an aryi group having 6,10 or 14 carbon atoms, preferably 6 to 10 carbon atoms, in particular, phenyl, or naphthyl group being optionally substituted by one or more independently selected substituents which include, halogen atoms, nitro, cyano, alkenyl, thiocyanato, cyanato, hydroxyl, alkyl, haloalkyl, alkoxy, alkenyloxy, haloalkoxy, amino, alkyiamino, dialkylamino, formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, carbamoyt, alkylamido, phenyl, phenoxy, bersyl, benzyloxy, heterocyclyl, and cycloalkyl, groups. Typically, 0-5 substituents may be present.
Aralkyl as used herein means an aryl-alkyl group in which the aryi and alkyl group are previously defined. Exemplary aralkyl groups include benzyl and pbenethyl.
Aralkyloxy as used herein refers to an aryl-alkyl-O- group in which the alkyl group and aryl group are previously described.
Phenyl as used herein refers to a 6-membered aromatic ring.
Heterocydyl group may be a single ring, a bicyclic ring system or a system of annelated or spiro-fused rings as a saturated or unsaturated moiety or radical having 3 to 12 ring atoms with 5 to 8 ring atoms preferred with 5 or 6 ring atoms more preferred selected from carbon, oxygen, sulfur and nitrogen, one or more, typically one or two, of which being oxygen, nitrogen or sulfur, being optionally substituted by one or more of substituents which include for example, halogen atoms, preferably fluorine, nitro, cyano, thiocyanato,
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cyanato, hydroxyl, alkyl of 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms, haloalkyl, preferably haloalkyl of 1 to 6 carbon atoms, alkoxy, alkoxy of 1 to 12 carbon atoms, preferably alkoxy of 1 to 6 carbon atoms, haloalkoxy, amino, alkylamino, dialkylamino, formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyt, carbamoyl, alkylamido, phenyl, phenoxy, benzyl, benzyloxy, heterocyclyl, especially furyl, and cycloalkyl, especially cyclopropyl, groups. Typically, 0-3 substituents may be present Optionally substituted heterocyclyJ groups include pyrrolodinyl, pyrrazolidinyl, piperidinyl, piperazinyl or morpholin-4-yl, pyridinyl, 2,3-dehydropiperid-3-yl, tetrahydropyranyl, tetrahydrofuranyl or tetrahydrothienyl, N-methyl-2,3-dehydropiperid-3-yl. pyrimidinyl, pyrrolidinyi, furyl, pyranyl, morpholinyl, tetrahydropyridine, thienyl, pyrrolidinyl, piperidyl, dihydropiperidyl, dihydropyridinyl, thiazanyl, morpholinyl, thiazinyl, azepanyl, azocanyl and dioxa-aza- spiro-decyi.
When any of the foregoing substituents are designated as being optionally substituted, the substituent groups which are optionally present may be any one or more of substituents which include for example, halogen atoms, nitro, cyano, thiocyanato, cyanato, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkyternino, dialkylamino, formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, carbamoyl, alkylamido, phenyl, phenoxy, benzyl, benzyloxy, heterocyclyl, especially furyl, and cycloalkyl, especially cyclopropyl, groups. Typically, 0-3 substituents may be present When any of the foregoing substituents represents or contains an alkyl substituent group, this may be linear or branched and may contain up to 12, preferably up to 6, and especially up to 4, carbon atoms. When any of the foregoing substituents represents or contains an aryl or cycloalkyl moiety, the aryl or cycloalkyl moiety may itself be substituted by one or more halogen atoms, nitro, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy groups. In the case of cycloalkyl and heterocyclyl groups, optional substituents also include groups which together with two adjacent carbon atoms of the cycloalkyl or
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heterocyclyl group form a saturated or unsaturated hydrocarbyl ring. In other words, a saturated or unsaturated hydrocarbyl ring may be optionally fused with the cycloalkyl or heterocyclyl group.
When any of the foregoing substituents represents or contains an aryl or cycloalkyl moiety, the aryl or cycloalkyl moiety may itself be substituted by one or more halogen atoms, nitro, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy groups. In the case of cycloalkyl and heterocyclyl groups, optional substituents also include groups which together with two adjacent carbon atoms of the cycloalkyl or heterocyclyl group form a saturated or unsaturated hydrocarbyl ring. In other words, a saturated or unsaturated hydrocarbyl ring may be optionally fused with the cycloalkyl or heterocyclyl group.
Optionally substituted moieties may be unsubstituted or have from one up to the maximal possible number of substituents. Typically, 0 to 3 substituents are present.
The present invention accordingly provides a pharmaceutical composition which comprises a compound of this invention, preferably subject to the proviso that R2 is optionally substituted thienyl or to the proviso that R1 is other than optionally substituted alkyl or the moiety -NRa Rb or to the proviso that R1, R2, R3 and R4 are as defined in claim 14, in combination or association with a pharmaceutically acceptable carrier. In particular, the present invention provides a pharmaceutical composition which comprises an effective amount of a compound of this invention and a pharmaceutically acceptable carrier. As used in accordance with this invention, the term providing an effective amount of a compound means either directly administering such compound, or administering a prodrug derivative, or analog which will form an effective amount of the compound within the body.
DESCRIPTION OF THE INVENTION
Compounds of this invention are prepared according to the procedures described in U.S. Patent Nos. 5,593,996; 5,756,509;5,948,783; 5,981,534;
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5,612,345; 5,994,360; 6,020,338; 5,985,883; 5,854,252; 5,808,066; 5,817,663; 5,955,252; 5,965,561; 5,986,135 ; and 5,750,766 which are hereby incorporated herein by reference. For instance, the compounds of this invention include 5-chloro]-6-(2,4,6-trifluorophenyl)-7-N-[(S)-(1,1,1-trifluoroprop-2-ylamino) 1,2,4-triazolo[1,5a] pyrimidine prepared according to the procedure described in U.S. Patent No. 5,986,135. The compound may also be called 5-chloro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine.
Representative compounds of this invention were evaluated in several standard pharmacological test procedures that showed that the compounds of this invention possess significant activity as promoters of microtubule polymerization and are antineoplastic agents. Based on the activity shown in the standard pharmacological test procedures, the compounds of this invention are therefore useful as anticancer agents. Associated cancers are selected from the group consisting of breast, colon, lung, prostate, melanoma, epidermal, leukemia, kidney, bladder, mouth, larynx, esophagus, stomach, ovary, pancreas, liver, skin and brain. In particular the compounds of this invention possess an effect similar to Paclitaxel. The test procedures used and results obtained are shown below.
CYTOTOXICITY STANDARD PHARMACOLOGICAL TEST PROCEDURE USING
MTS AS DETECTION REAGENT
This standard pharmacological test procedure identifies representative examples of substituted triazolopyrimidine compounds of the invention, which further includes compounds of Formula (I), which kill various human cancer cell lines. The test is based on the conversion by viable cells, but not by dead cells, of the tetrazolium salt, MTS, into a water-soluble colored formazan which is detected by spectrophotometry. The test procedure was used to identify the most potent compounds within a series of related structures which were known or suspected to have a microtubule mechanism of action. The most potent compounds were then taken forward into other test procedures which specifically analyzed effects on microtubules.
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Part 1. Cytotoxicity with HeLa Cells
In the first cytotoxicity test, representative compounds of the invention were tested with the HeLa human cervical carcinoma ceil line at a single concentration. HeLa cells (ATCC CCL2.2) were routinely maintained by twice-weekly subculture in fresh medium. Medium was RPMI-1640 with L-glutamine, supplemented with 10% heat-inactivated fetal calf serum, 100 units/ml penicillin, and 100 µg/ml streptomycin.
For assay, HeLa cells were harvested by trypsinization, washed, counted and distributed to wells of 96-well flat-bottom microtiter plates at 1000 cells per well in 100 µl of medium. The plates were incubated at 37° in humidified 5% CO2 in air for about 24 hr.
On day 2, compounds for test were diluted and added to wells. Compounds were dissolved in dimethyl sulfoxide (DMSO) at 10 mg/ml. These solutions were diluted into medium to give solutions of 20 µg/ml, and then 100 ul was added in duplicate to wells already containing cells, to give final drug concentrations of 10 µg/ml and a final DMSO concentration of 0.1 %. Each plate also contained the following controls: cells with no drug (uninhibited cell growth = maximal MTS response = control response); cells plus 100 nM paclitaxel (all cells killed = minimal MTS response); and medium only (MTS reagent control). The plates were returned to the incubator for three days.
After three days of culture with test compounds (day 5 overall), the MTS assay was done on all wells of the plates. Twenty µl of the combined MTS/PMS reagent (Promega "CellTiter 96 Aqueous Non-Radioactive Cell Proliferation Assay," catalog no. G5421; see Technical Bulletin No. 169, Revised 9/96) were added to each well with a repeating pipettor, and the plates were returned to the 37° incubator for 2 hr before recording the absorbance of each well at 490 nm using an ELISA plate reader.
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The absorbance values of the duplicate sample wells were averaged and expressed as a percentage of the average value of the control wells. Percentages less than 100 indicated that the test compounds had exerted a
cytotoxic effect on the cells. The results of this pharmacological test
procedure are displayed in Table 1.

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Table 1
Evaluation of Representative Compounds of the invention in the MTS Cytotoxicity Standard Pharmacological Test Procedure with HeLa Cells
Ex No. Percent of Control at 10 µg/ml
1 -1.6
2 10.4
4 2.9
5 -0.8
6 -0.4
7 0.6
8 2
9 8.1
12 0.3
19 -1.3
24 3.7
27 2.2
28 3.4
30 -0.4
32 20.3
33 -1.3
35 17.6
37 -1.6
38 0.2
39 10.6
41 7.1
42 -0.1
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Table 1 (cont)
Ex No. Percent of Control at 10µg/ml
43 5.8
47 0
48 13.9
49 12
54 -0.1
59 0.9
60 4.9
61 -12
62 -0.7
63 10.6
64 -2
65 -0.6
66 -0.7
70 1.4
72 -1.8
73 15.6
79 7.1
82 -1.5
87 -0.2
99 1.8
102 1.1
103 -0.7
105 0
113 -0.3
116 -1.3
117 -0.1
121 -0.8
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Table 1 (cont)
Ex No. Percent of Control at 10 µg/ml
122 2.1
123 -2.2
124 -1.6
127 -0.9
128 -0.3
130 5.4
132 3.4
133 10.7
135 -1.1
140 -0.9
141 10.8
143 92.8
144 2.3
145 16.2
146 16.1
149 7.8
150 3.4
151 9.6
157 -2.7
158 -0.4
159 -1
160 1.1
163 27.2
167 -2.5
168 8.7
169 23.8
170 22.6
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Table 1 (cont)
Ex No. Percent of Control at 10µg/ml
172 -0.9
173 -0.6
174 0.6
175 1.9
176 -0.6
177 8.5
180 -0.3
181 -1.5
182 -1.7
183 -0.1
184 1.3
185 1.5
186 1
187 -1.4
188 8.8
189 2.2
213 10.2
216 5.8
217 -0.5
225 -1
Part 2. Cytotoxicity with COLO 205 Cells
In the second cytotoxicity standard pharmacological test procedure, representative compounds of the invention were tested with the COLO 205 human colon adenocarcinoma cell line at six concentrations, in order to determine IC50 values. COLO 205 cells (ATCC CCL 222) were routinely
maintained by thrice-weekly subculture in fresh medium. Medium was RPMJ-
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1640 with L-glutamine, supplemented with 10% heat-inactivated fetal calf serum, 20 mM HEPES, 100 units/ml penicillin, and 100 µg/ml streptomycin.
For the test procedure, COLO 205 cells were harvested by trypsinization, washed, counted and distributed to wells of 96-well flat-bottom microtiter plates at 1000 cells per well in 100 µl of medium. In addition, one row of wells on an additional plate received cells as above ("time 0" plate). AH plates were incubated at 37° in humidified 5% CO2 in air for about 24 hr.
On day 2, compounds for test were diluted and added to wells. Compounds were dissolved in DMSO at 10 mg/ml. For each compound, six serial 3-fold dilutions were prepared in medium. The highest drug concentration with cells was 5 µg/ml and the highest DMSO concentration was 0.05%. Drugs were added in duplicate to wells in 100 µl volume. Each plate also contained the following controls: cells with no drug (uninhibited cell growth = maximal MTS response); cells plus 100 nM paclitaxel (all cells killed = minimal MTS response); and medium only (MTS reagent control). The plates were returned to the incubator for three days.
At the time of drug addition to the experimental plates, the MTS assay was run on the "time 0" plate. This produced the "time 0 MTS value" which was related to the number of viable cells per well at the time of drug addition. The MTS values of the wells of the experimental plates were lower than, higher than, or the same as the time 0 value, depending on whether a drug killed the cells, did not inhibit cell growth, or was cytostatic, respectively.
After three days of culture with test compounds (day 5 overall), the MTS assay was done on all wells of the experimental plates. The results for each plate were calculated separately, using its own controls. The absorbance values of the duplicate sample wells were averaged and divided by the average of the "time 0" values. The average of the control wells without drug, divided by the average "time 0" value, gave the maximal relative increase in MTS color yield due to cell growth during the final three days of culture. The average of the control wells with paclitaxel, divided by the "time 0"
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value, gave the minimal relative color yield for cells that were completely killed. The six values for each compound were plotted against concentration, and the concentration that produced a relative color yield half way between the maximum and minimum was taken as the IC50 value. The most potent compounds had the lowest IC50 values. Test results of representative compounds of the invention are displayed in Table 2.
In addition, some compounds of the invention were tested in duplicate at 25 and 50 µg/ml with COLO 205 cells in the MTS cytotoxicity pharmacological test procedure. Results were expressed as a percent of the average value of the control wells. Percentages less than 100 indicated that the test compounds had exerted a cytotoxic effect on the cells. These test results are also displayed in Table 2. .
I
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Table 2
Evaluation of Representative Compounds of the invention in the WITS Cytotoxicity Standard Pharmacological Test Procedure with COLO 205
Cells
Ex No. IC50 (µg/ml) n % of Control At
25 µg/ml 50 µg/ml
1 0.84
2 0.092
3 0.82
4 0.082
5 0.057
6 0.16
7 0.12
8 3.3
9 0.86
10 0.35
11 2.5
12 0.32 2
13 4.3
14 0.22
15 1.2
16 4.8
17 0.91
18 0.33
19 0.25
20 1
21 2.8
22 4.6
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Table 2 (cont)
Ex No. IC50(µg/mL) n % of Control At
25 µg/ml 50 µg/ml
23 ' 3.7
24 >5
25 >5a
26 0.33
27 0.033
28 0.08
29 0.29
30 0.31 2
31 2.8
32 >5
33 0.062
34 0.44
35 0.026 3
36 0.1
37 >5
38 2.5
39 2.2
40 0.31
41 0.062
42 0.33
43 0.084
44 0.64
45 4.8
46 0.31
47 0.11
48 0.13
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Table 2 (cont)
Ex No. rC50 (µg/ml) n % of Control At
25 µg/ml 50 µg/ml
49 0.15
50 2.1
51 0.86
52 0.7
53 1.3
54 0.094
55 0.59
56 0.86
57 0.64
58 1
59 0.18
60 0.19
61 0.095
62 0.13
63 0.16
64 0.68 2
65 0.18
66 0.11
67 0.34
68 1.7 2
69 0.36
70 0.22
71 0.87 2
72 0.22
73 0.13
74 0.31
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Table 2 (cont)
Ex No. IC50 (µg/ml) n % of Control At
25 µg/ml 50 µg/ml
75. 4.3
76 0.37 2
T7 0.66 2
78 2.4
79 0.27
80 2.6 2
81 2.5 2
82 0.038
83 3 2
84 2.8
85 2.8 2
86 0.26 2
87 0.24
88 2.8 2
89 2.9 2
90 1
91 0.39 2
92 1.8
93 2.7 2
94 3.5 2
95 3.8
96 0.79 2
97 >5 a
98 2 2
99 0.064
100 >5 a
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Table 2 (cont)
Ex No. IC50 (µg/ml) n % of Control At
25 µg/ml 50 µg/ml
101 4.4
102 2.3
103 0.27
104 0.25 2
105 0.12 2
106 >5 a
107 0.11 2
108 0.63 2
109 3.5
110 0.32 2
111 0.39 2
112 0.34
113 0.91
114 3.7
115 >5 a
116 >5
117 0.26 -
118 1.2 2
119 0.75 2
120 1.4 2
121 2.7
122 0.73
123 >5
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Table 2 (cont)
Ex No. IC50 (µg/ml) n % of Control At
25 µg/ml 50 µg/ml
124 0.12
125 4.7 2
126 0.14
. 127 0.056
128 2.6
129 0.31 2
130 0.91
131 0.1 2
132 0.084
133 0.092 2
134 0.33 2
135 0.16
136 0.55 2
137 1.2
138 0.34 2
139 0.96
140 0.075
141 0.28.
142 0.29 2
143 0.097
144 0.084
145 2.5
146 0.099
147 1.2 2
148 0.36
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Table 2 (cont)
Ex No. IC50 (µg/ml) n % of Control At
25 µg/ml 50 µg/ml
149 0.056
150 0.28 .
151 0.099
152 1
153 0.42
154 1.2
155 1.1
156 0.11
157 >5
158 0.19
159 0.38
160 0.27
161 2.6
162 0.78
163 0.27
164 0.17
165 0.96
166 0.32
167 0.1
168 0.11
169 0.31 4
170 0.074 11
171 0.29
172 0.3
173 0.3
174 0.13
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Table 2 (cont)
Ex No. IC50 (µg/ml) n % of Control At
25 µg/ml 50 µg/ml
175 0.038 3
176 0.1
177 0.13
178 0.099 3
179 0.36
180 0.81
181 0.043
182 1.3
183 0.078
184 0.25
185 0.04
186 0.034
187 0.035
188 0.012 2
189 0.055
190 0.33
191 0.032
192 >5 a
193 0.95
194 0.58
195 0.1
196 0.15
197 0.3
198 0.091 3
199 0.38
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Table 2 (cont)
Ex No. IC50 (µg/ml) n % of Control At
25 µg/ml 50 µg/ml
200 0.27
201 0.39
202 0.25
203 0.17
204 0.12
205 0.036
206 0.12
207 0.035
208 0.014 2
209 0.11
210 0.31
211 0.049 3
212 0.88
213 0.47
214 0.79
215 3.5
216 0.63
217 0.2
218 >5 a
219 0.89
220 4.9
221 2.8
222 5 2
223 2.1
224 0.3
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Table 2 (cont)
Ex No. IC50 (µg/ml) n % of Control At
25 µg/ml 50 µg/m
225 0.086
226 0.095
227 4.3
228 >5 a
229 0.95 2
230 2.5
231 44.3 6.6
232 67.5 15.0
233 27.3 20.4
234 0.13
235 80.6 14.7
236 28.4 10.9
237 24.1 -3.5
238 100.4 41.5
239 58.8 25.5
240 -0.9 -4.0
241 2.3 2.4
242 13.1 -4.8
243 12.7 -3.0
244 9.2 21.0
245 100.3 72.5
246 4.0 -4.8
247 63.6 46.4
248 15.5 -3.9
249 47.4 20.3
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Table 2 (cont)
Ex No. IC50 (µg/ml) n % of Control At
25 µg/ml 50 µg/ml
250 16.4 4.6
251 103.9 28.1
252 94.8 69.6
253 120.0 74.1
254 39.6 15.6
255 58.3 86.1
256 20.2 14.8
257 27.3 -3.5
258 74.6 44.1
259 32.6 0.7
260 87.8 53.5
261 7.4 -3.9
262 23.7 -5.1
263 -1.5 2.0
264 34.5 -4.2
265 8.1 -1.6
266 84.9 72.4
267 17.8 32.1
268 -0.8 4.2
269 3.5 11.9
270 0.095
271 0.32
272 0.91
273 1
274 1.9
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Notes to Table 2:
1. n = number of independent assays (n = 1 unless stated otherwise)
2. a means that at 5 ng/ml the inhibition was between 30 and 50%
Part 3. Cytotoxicity with H157, U87MG, PC-3 MM2, and DLD1 Cells
The cytotoxicity standard pharmacological test procedure with MTS detection was applied to representative compounds of the invention with four additional human cancer cell lines in order to characterize the range of tumor types against which the compounds were active. The cell lines used were H157 human non-small cell lung carcinoma, U87MG human glioblastoma, PC-3 MM2 human prostate carcinoma, and DLD1 human colon adenocarcinoma. The procedure of the test and the method of data calculation were the same as described above in Part 2 with COLO 205 cells. The results are displayed in Table 3.
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Table 3
Evaluation of Representative Compounds of the Invention and Standard
Cytotoxic Agents in the MTS Cytotoxicity Standard Pharmacological Test
Procedure with Four Human Cancer Cell Lines

Example IC50 (nM)
H157 U87MG PC-3 MM2 DLD1
35 31 390 220 105
169 >1000 >1000
170 310 200 140 560
175 180 240 215
178 . 480 550
186 38
187 86
188 16 48 73 48
198 640 580
205 83
208 10 120 140 69
211 370 400
Camptothectn 10
Colchicine 13 6.5 10 25
Doxorubicin 17 170
Mitoxantrone 13
Nocodazole 33 34 43 40
Paclitaxel 0.17 1.4
Vincristine 0.28 0.30 3.0
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Part 4. Cytotoxicity with KB Cells and Drug-Resistant Lines Derived from KB
The cytotoxicity standard pharmacological test procedure with MTS detection was applied to representative compounds of the invention with the KB human epidermoid carcinoma cell line and two multidrug resistant lines derived from it. These derived lines were colchicine-resistant KB 8.5, which expresses a moderate level of the multidrug transporter P-glycoprotein, and vinblastine-resistant KB VI, which expresses a high level of P-glycoprotein. The purpose of these experiments was to determine if the compounds were able to overcome drug resistance mediated by P-glycoprotein. If the IC50's of the compounds are essentially the same on all three lines, then the compounds are not substrates of P-glycoprotein. If on the other hand, the compounds have much higher IC50's on KB 8.5 and KB VI compared to KB (as do paclitaxel, vincristine, and many other standard anti-cancer drugs) then they would be substrates of P-glycoprotein.
The procedure of the cytotoxicity test and the method of data calculation were the same as described above in Part 2 with COLO 205 cells. The results are displayed in Table 4. The results show that the compounds of this invention have essentially the same IC50's on all three cell lines, indicating that they would not be subject to multidrug resistance mediated by P-glycoprotein.
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Table 4 Evaluation of Representative Compounds of the Invention and Standard
Cytotoxic Agents in the MTS Cytotoxicity Standard Pharmacological Test
Procedure with Human Cancer Cell Lines that Overexpress the
P-alvcoDrotein Transnorter

Example IC50 (nM) Relative Resistance
KB KB 8.5 KB VI KB KB 8.5 KB VI
35 19 31 16 1 1.6 0.8
186 30 48 33 1 1.6 1.1
187 45 76 56 1 1.7 1.2
188 10 18 11 1 1.8 1.1
Taxol <0.03 19 3,325 1 >630 >111,000
Vincrisfine <0.06 29 3,150 1 >480 >52,500
Colchicine 12. 51 1,330 1 7.1 185
Nocodazole 21 24 33 1 1.1 1.6
Doxorubicin 34 101 4,400 1 3.0 130
Part 5. Cytotoxicity with S1 Cells and a Drug-Resistant Line Derived fromS1
The cytotoxidty standard pharmacological test procedure with MTS detection was applied to representative compounds of the invention with the S1 human colon carcinoma cell line and a multidrug resistant line derived from ft. The derived line was mttoxantrone-resistant S1-M1, which expresses the muftidrug transporter MXR. The purpose of these experiments was to determine representative compounds of the invention able to overcome drug resistance mediated by MXR. If the IC50's of the compounds are essentially the same on both lines, then the compounds are not substrates of MXR. If on the other hand, the compounds have much higher IC50's on S1-M1 compared
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to S1 (as do many standard anti-cancer drugs) then they would be substrates of MXR.
The procedure of the cytotoxicity test and the method of data calculation were the same as described above in Part 2 with COLO 205 cells. The results are displayed in Table 5. The results show that the compounds of this invention have essentially the same IC50's on both cell lines, indicating that they would not be subject to multidrug resistance mediated by MXR.
Table 5
Evaluation of Representative Compounds of the Invention and Standard Cytotoxic Agents in the MTS Cytotoxicity Pharmacological Test Procedure with a Human Cancer Cell Line that Overexpresses the MXR Transporter
Protein

Example IC50 (nM) Relative Resistance
S1 S1-M1 S1 S1-M1
35 73 94 1 1.3
186 99 102 1 1.0
187 99 124 1 1.3
188 33 74 1 2.2
Coichicine 11 47 1 4.3
Nocodazole 43 146 1 3.4
Doxorubicin 19 10,700 1 565
Mitoxantrone <4 >10,000 1 >2,500
Camptothecin 6.8 21 1 3.1
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INHIBITION OF CELLULAR PROLIERATION STANDARD PHARMACOLOGICAL TEST PROCEDURE USING SULFORHODAMINE B
AS DETECTION REAGENT
This standard pharmacological test procedure measures the ability of compounds to inhibit cellular proliferation. Sulforhodamine B staining was used to estimate total cellular protein in each culture after exposure to compounds. A decrease in staining compared to untreated control cultures indicated an inhibition of proliferation.
Two cell lines were used in these experiments: Reh human acute lymphocytic leukemia, and CCRF-CEM human acute lymphoblastic leukemia, both obtained from ATCC. Two types of experiments were done on each of the two cell lines. In the first, cells were cultured with Example 170 at several concentrations for either 24 or 72 hr, and the effect on cellular proliferation was determined. In the second, cells were cultured with Example 170 at several concentrations for 24 hr, the compound was removed and replaced with fresh medium without compound, culture was continued for another 48 hr, and the effect on cellular proliferation was determined. This second experiment determined the ability of cells to recover from the damage inflicted by compound during the first 24 hr of culture. At the end of the incubation periods, cells were fixed with trichloroacetic acid and stained with sulforhodamine B using the in vitro Toxicology Assay Kit (Sigma). Actinomycin D was used as a positive control in all experiments. Bound dye was measured spectrophotometrically at 565 nm with a reference wavelength of 690 nm. Cultures were done in 96-well assay plates with five replicates of each concentration. The absorbance values of the replicates were averaged and expressed as a percent of the vehicle control. Each experiment was repeated once, and the percent of control for a given concentration in each experiment were averaged to calculate the results displayed in Table 6.
The results showed that Example 170 inhibited the proliferation of both cell lines, with a greater effect observed after 72 hr compared with 24 hr. In
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addition, the recovery experiment showed that neither cell line could recover from the toxicity induced by 24 hr of culture with Example 170.
An additional experiment was done with HL-60 human promyelocytic leukemia in which the inhibition of cellular proliferation by several concentrations of Example 170 were determined after 24 or 72 hrs of culture using the Sulforhodamine B test procedure as described above. Concentrations of Example 170 ranged from 0.005-100 µg/ml. The calculated EC50 value at 24 hr was 2.3 µg/ml, and the EC50 value at 72 hr was 0.1 µg/ml.
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Table6
Evaluation of Example 170 in the Sulforhodamine B Standard Pharmacological Test Procedure with Two Human Leukemia Cell Lines

Percent of Contro
Reh Cells CCRF-CEM Cells

Conc. (µg/ml) 24 hr. Treatment 72 hr Treatment 24 hr Treatment 48 hr Recovery 24 hr Treatment 72 hr Treatment 24 hr Treatment 48 hr Recovery
0.005 120.15 88.57 105.29 104.86 94.88 152.66
0.01 110.83 89.43 103.98 111.05 88.98 143.58
0.05 81.50 71.31 81.23 67.31 19.73 57.05
0.1 68.67 65.87 84.68 65.48 24.04 38.99
0.5 67.70 66.24 74.13 65.72 11.59 50.17
1 83.94 52.91 66.81 51.41 20.74 29.42
5 66.21 41.86 61.34 30.04 22.24 28.90
10 71.46 44.70 34.10 42.05. 8.17 18.19
50 55.07 35.40 36.36 47.10 24.84 27.16
100 84.35 51.62 35.76 113.70 54.07 39.47

0.2* 66.99 50.54 39.75 52.44 • 45.71 20.26
* Actinomycin-D
CELL CYCLE ANALYSIS STANDARD PHAMACOLOGICAL TEST
PROCEDURE
This standard pharmacological test procedure measures the percentages of cells in a population that are in the G1, S and G2/M phases of the cell cycle. It utilizes staining of fixed cells with propidium iodide and analysis of these cells by flow cytometry. The procedure also gives an estimate of apoptosis induction caused by drug treatment by measurement of the appearance of particles with sub-G1 amounts of DNA. Microtubule-active
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drugs characteristically arrest cells in the G2/M phase of the cell cycle because of disruption of the function of the microtubules that comprise the mitotic spindle.
HeLa cells were maintained in RPMI-1640 medium with L-glutamine, supplemented with 10% heat-inactivated fetal calf serum, 100 units/ml penicillin, and 100 µg/ml streptomycin. For assay, cells were harvested by trypsinization, washed, counted and distributed to wells of a 6-well plate at 50,000 cells per well in 3 ml of medium. Cells were cultured overnight at 37° in humidified 5% CO2 in air.
On day 2, compounds for test were diluted and added to wells at the final concentrations given in the tables. Twenty hours after drug addition, cells from each well were harvested, fixed with cold 80% ethanol, treated with 100 µg/ml RNAse and stained with propidium iodide before analysis by flow cytometry. The percentages of total cells in G1, S, G2/M, and apoptosis (sub-G1 population) were estimated from the fluorescence histograms, and compared with those determined using untreated control cells in the same assay.
Table 7 displays results for representative compounds of this invention tested at a low concentration and at a five-fold higher concentration. Table 8 displays results of a second experiment in which representative compounds were tested at six concentration levels each. In both experiments the compounds caused a profound increase in the percentage of cells in the G2/M phase of the cell cycle and induced substantial apoptosis.
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Table 7
Evaluation of Representative Compounds of the Invention in the Cell Cycle Analysis Standard Pharmacological Test Procedure with HeLa Cells

Example Cone. (µg/mL) Percent Cell Cycle Phase
Apop G1 S G2/M
None - 3 64 18 16
- 2 63 18 17
1 0.84 8 3 10 79
42 13 7 12 68
5 0.057 44 10 22 25
0.285 9 1 5 85
7 0.12 8 2 6 84
0.6 9 3 8 81
9 0.86 10 2 7 81
4.3 16 28 21 35
12 0.27 46 10 18 26
1.35 7 1 7 85
27 0.033 28 4 13 55
0.165 8 1 5 86
35 0.022 28 5 14 54
0.11 - - -
39 2.19 26 4 15 55
10.95 19 17 20 45
41 0.062. 9 58 20 13
0.31 34 18 17 30
42 0.33 47 14 20 19
1.65 6 1 10 83
47 0.11 8 2 8 83
0.55 7 1 10 81
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Table 7 continued

Example Conc. (µg/mL) Percent Cell Cycle Phase
Apop G1 S G2/M
59 0.18 43 8 24 26
0.9 8 2 6 84
61 0.08 7 1 9 83
0.4 7 2 8 83
105 0.08 12 3 11 74
0.4 6 2 8 84
127 0.08 8 2 12 79
0.4 6 3 6 84
151 0.08 15 4 14 67
0.4 9 6 8 76
186 0.08 7 2 8 82
0.4 7 . 2 10 80
187 0.08 6 4 9 81
0.4 7 2 9 81
188 0.08 9 2 8 81
0.4 9 2 10 78
Note to Table 6: Apop = Apoptosis
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Table 8
Evaluation of Representative Compounds of the Invention in the Cell Cycle Analysis Standard Pharmacological Test Procedure with HeLa Cells

Example Cone. (µglml) Percent Cell Cycle Phase
Apop G1 S G2/M
None - 4 55 23 18
- 3 49 25 20
- 1 56 20 20
35 0.001 1 57 22 20
0.003 1 58 22 18
0.01 2 57 20 21
0.03 29 20 25 25
0.1 26 9 13 50
0.3 4 4 3 89
133 0.01 4 54 19 23
0.03 28 25 21 25
0.1 34 9 26 29
0.3 15 5 8 73
1 3 4 3 90
3 3 4 3 89
169 0.01 2 51 23 24
0.03 14 41 21 24
0.1 33 17 23 25
0.3 34 8 24 32
1 3 5 3 88
3 4 5 2 68
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Example Conc.(µg/mL) Percent Cell Cycle Phase
Apop G1 S G2/M
170 0.01 13 42 21 24
0.03 33 17 20 28
0.1 27 3 18 50
0.3 5 5 4 85
1 3 4 4 88
3 3 4 4 88
188 0.001 1 55 21 23
0.003 2 56 18 23
0.01 18 35 19 27
0.03 27 7 14 52
0.1 4 4 3 88
0.3 3 3 3 90
208 0.001 2 59 20 20
0.003 2 57 20 21
0.01 14 43 20 23
0.03 33 8 21 36
0.1 3 2 3 90
0.3 3 3 2 91
Note to Table 7: Apop = Apoptosis
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TUBULIN POLYMERIZATION STANDARD PHARMACOLOGICAL TEST PROCEDURE USING HIGHLY PURIFIED TUBULIN
This standard pharmacological test procedure determines the activity of representative compounds of this invention in promoting the polymerization of ?/? tubulin heterodimers. The tubulin preparation used was over 99% pure so that any effects of test compounds on polymerization must be due to direct binding of the test compounds to tubulin protein. It is well known that in this assay paclitaxel promotes polymerization compared to the control reaction without drug, and that vincristine and colchicine inhibit polymerization. Highly purified tubulin does not exhibit substantial spontaneous polymerization at protein concentrations between 1 and 2 mg/ml. Therefore an agent such as glycerol is added to the reactions to lower the critical concentration for polymerization and yield a higher spontaneous control polymerization. In some experiments described below, either glycerol or guanosine 5-triphosphate (the energy source of polymerization) was left out of the reaction mixtures in order to better compare the effects of paclitaxel and representative compounds of this invention.
Part 1. Polymerization of Purified Tubulin in the Presence of Guanosine 5'-triphosphate and Glycerol
Bovine brain tubulin, purchased from Cytoskeleton, Inc., was greater than 99% pure by polyacrylamide gel electrophoresis. The protein was dissolved at 1.5 mg/ml in ice-cold GPEM buffer (80 mM piperazine-N,N'-bisf2-ethanesulfonic acid], pH 6.9,1 mM ethylene glycol-bis(?-aminoethyl ether)-N,N,N',N'-tetraacetic acid, 1 mM magnesium chloride, 1 mM guanosine 5'-triphosphate, GTP) containing 10% (w/w) glycerol. The solution was centrifuged at top speed in an Eppendorf model 5415C microfuge for 10 min at 4° immediately before use. The tubulin solution was added to wells of a 1/2 area 96-well plate (Costar No. 3696) already containing the compounds of
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interest. Each compound was assayed at three concentrations as indicated. Final volume per well was 110 µl. Each sample was done in duplicate, and the control reaction, which received drug solvent only, was done in quadruplicate. The highest concentration of DMSO in any reaction was 1%. The plate was put in a Molecular Devices SpectraMax plate reader thermostated at 35° and the absorbance of each well at 340 nm was determined every minute for 60 minutes. The absorbance at time 0 for each well was subtracted from each of the subsequent absorbance readings for that well, and then the duplicates were averaged.
The results of this standard pharmacological test procedure with representative compounds of this invention and with standard microtubule-active drugs are displayed in Tables 9 to 14. Compounds that-enhanced the rate and/or extent of purified tubulin polymerization compared to the control (as does paclitaxel) were judged to be promoters of polymerization; compounds that reduced the rate or extent of polymerization (e.g., vincristine, colchicine) were judged to be inhibitors.

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Table 9 Evaluation of Examples 35 and 188 in the Tubulin Polymerization
Standard Pharmacological Test Procedure

AA340
Example 35 Example 188 8 Control
Time (min) 10 µM 0.1 µM 10µM 1 µM 0.1 µM
0 0 0 0 0 0 0 0
5 0.0434 0.0003 0.0004 0.0179 -0.0007 -0.0006 -0.0009
10 0.0972 0.0015 0.0010 0.0469 0.0001 -0.0005 -0.0008
15 0.1219 0.0028 0.0012 0.0667 0.0016 -0.0001 0.0001
20 0.1316 0.0058 0.0024 0.0813 0.0040 0.0009 0.0019
25 0.1364 0.0079 0.0041 0.0919 0.0063 0.0026 0.0051
30 0.1387 0.0106 0.0061 0.0988 0.0110 0.0052 0.0087
35 0.1397 0.0139 0.0079 0.1032 0.0141 0.0079 0.0132
40 0.1401 0.0177 0.0099 0.1064 0.0179 0.0119 0.0198
45 0.1392 0.0232 0.0133 0.1100 0.0229 0.0142 0.0221
50 0.1396 0.0278 0.0167 0.1149 0.0288 0.0203 0.0245
55 0.1399 0.0311 0.0193 0.1165 0.0337 0.0262 0.0282
60 0.1398 0.0350 0.0224 0.1176 0.0372 0.0304 0.0340

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Table 10
Evaluation of Example 170 and Paclitaxel in the Tubulin Polymerization Standard Pharmacological Test Procedure

AA340
Example 170 Paclitaxel Control
Time (min) 10 µM 1µM 0.1 µM 10 µM 1 µM 0.1 µM
0 0 0 0 0 0 0 0
5 0.0103 -0.0001 -0.0005 0.0136 0.0044 -0.0012 -0.0009
10 0.0555 0.0008 -0.0010 0.0416 0.0167 -0.0010 -0.0008
15 0.0923 0.0028 -0.0005 0.0704 0.0336 0.0001 0.0001
20 0.1100 0.0056 0.0002 0.0931 0.0500 0.0025 0,0019
25 0.1199 0.0093 0.0018 0.1075 0.0638 0.0060 0.0051
30 0.1257 0.0143 0.0041 0.1162 0.0748 0.0100 0.0087
35 0.1289 0.0198 0.0053 0.1216 0.0835 0.0123 0.0132
40 0.1330 0.0246 0.0088 0.1245 0.0903 0.0168 0.0198
45 0.1353 0.0291 0.0124 0.1269 0.0957 0.0229 0.0221
50 0.1353 0.0338 0.0155 0.1279 0.0997 0.0257 0.0245
55 0.1363 0.0380 0.0192 0.1279 0.1027 0.0293 0.0282
60 0.1364 0.0419 0.0241 0.1282 0.1053 0.0314 0.0340
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Table 11
Evaluation of Examples 169 and 175 in the Tubulin Polymerization Standard Pharmacological Test Procedure

#A340
Example 169 Example 175 Control
Time (min) 10 µM 1 µM 0.1 µM 10 µM 1 µM 0.1 µM
0 0 0 0 0 0 0 0
5 0.0239 0.0005 -0.0014 0.0073 0.0001 -0.0012 -0.0012
10 0.1172 0.0011 -0.0009 0.0199 0.0014 -0.0005 -0.0011
15 0.1435 0.0024 0.0001 0.0309 0.0037 0.0011 0.0000
20 0.1509 0.0045 0.0020 . 0.0399 0.0067 0.0025 0.0024
25 0.1532 0.0073 0.0042 0.0488 0.0102 0.0057 0.0051
30 0.1548 0.0106 0.0057 0.0566 0.0160 0.0088 0.0108
35 0.1554 0.0154 0.0105 0.0638 0.0217 0.0116 0.0157
40 0.1555 0.0197 0.0136 0.0704 0.0294 0.0177 0.0203
45 0.1552 0.0246 0.0186 0.0761 0.0349 0.0233 0.0246
50 0.1545 0.0331 0.0234 0.0817 0.0416 0.0261 0.0329
55 0.1561 0.0414 0.0282 0.0872 0.0450 0.0309 0X369
60 0.1552 0.0456 0.0322 0.0919 0.0485 0.0373 0.0392
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Table 12
Evaluation of Example 178 and Paclitaxel in the Tubulin Polymerization Standard Pharmacological Test Procedure

AA340
Example 178 Paclitaxel Control
Time (min) 10µM 0.1 µM 10 µM 1µM 0.1 µM
0 0 0 0 0 0 0 0
5 0.0182 -0.0029 -0.0001 0.0200 0.0024 -0.0008 -0.0012
10 0.0304 -0.0021 0.0000 0.0587 0.0144 0.0005 -0.0011
15 0.0448 -0.0007 0.0002 0.0939 0.0315 0.0031 0.0000
20 0.0602 0.0006 0.0009 0.1199 0.0484 0.0070 0.0024
25 0.0770 0.0039 0.0030 0.1369 0.0626 0.0103 0.0051
30 0.0951 0.0064 0.0055 0.1470 0.0746 0.0159 0.0108
35 0.1099 0.0110 0.0080 0.1522 0.0838 0.0197 0.0157
40 0.1250 0.0152 0.0134 0.1557 0.0913 0.0256 0.0203
45 0.1360 0.0202 0.0216 0.1583 0.0969 0.0304 0.0246
50 0.1424 0.0242 0.0218 0.1584 0.1014 0.0336 0.0329
55 0.1488 0.0273 0.0229 0.1588 0.1050 0.0368 0.0369
60 0.1538 0.0316 0.0299 0.1586 0.1076 0.0399 0.0392
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Table 13
Evaluation of Examples 198 and 211 and Paclitaxel in the Tubulin Polymerization Standard Pharmacological Test Procedure

#A340
Example 198 Example 211 Paclitaxel **
* 10 µM 1 µM 0.1 µM 10 µM 1µM 0.1 µM 10 µM 1 µM 0.1 µM
0 0 0 0 0 0 0 0 0 0 0
5 0.0011 0.0001 0.0021 -0.0008 -0.0019 -0.0001 0.0145 0.0037 -0.0014 -0.0012
10 0.0025 0.0006 0.0053 ¦0.0006 -0.0017 .0.0014 0.0496 0.0173 0.0032 -0.0014
15 0.0057 0.0017 0.0096 0.0009 0.0000 0.0043 0.0857 0.0381 0.0056 -0.0001
20 0.0117 0.0046 0.0143 0.0029 0.0027 0.0080 0.1119 0.0572 0.0098 0.0031
25 0.0206 0.0071 0.0200 0.0055 0.0060 0.0129 0.1280 0.0731 0.0160 0.0077
30 0.0303 0.0106 0.0239 0.0085 0.0107 0.0173 0.1370 0.0860 0.0217 0.0124
35 0.0407 0.0153 0.0292 0.0121 0.0138 0.0228 0.1427 0.0961 0.0289 0.0193
40 0.0489 0.0214 0.0367 0.0165 0.0195 0.0287 0.1462 0.1041 0.0360 0.0223
45 0.0572 0.0258 0.0393 0.0211 0.0251 0.0321 0.1483 0.1102 0.0431 0.0288
50 0.0661 0.0320 0.0495 0.0263 0.0279 0.0397 0.1495 0.1148 0.0488 0.0345
55 0.0729 0.0360 0.0556 0.0320 0.0339 0.0458 0.1505 0.1185 0.0544 0.0389
60 0.0763 0.0413 0.0607 0.0383 0.0393 0.0512 0.1508 0.1211 0.0596 0.0440
* Time (min) ** Control
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Table 14
Evaluation of Vincristine, Colchicine, and Paclitaxel in the Tubulin Polymerization Standard Pharmacological Test Procedure

AA340
Vincristine Colchicine Paclitaxel **
* 10 µM 1 µM 0.1 µM 10 µM 1µM 0.1 µM 10 µM 1µM 0.1 µM
0 0" 0 0 0 0 0 0 0 0 0
5 0.0011 ¦0.0008 0.0016 0.0005 -0.0003 0.0011 0.0104 0.0023 -0.0008 -0.0016
10 0.0001 ¦0.0007 0.0012 0.0011 0.0000 O.0012 0.0372 0.0128 0.0020 -0.0013
15 -0.0001 -0.0007 0.0018 0.0006 0.0002 0.0008 0.0658 0.0288 0.0084 0.0007
20 -0.0006 -0.0001 0.0031 -0.0001 0.0009 0.0003 0.0885 0.0434 0.0107 0.0027
25 -0.0012 0.0003 0.0044 -0.0003 0.0019 0.0024 0.1040 0.0568 3.0160 0.0054
30 -0.0015 0.0012 0.0074 -0.0008 0.0029 0.0058 0.1149 3.0682 0.0251 0.0103
35 -0.0018 0.0019 0.0119 -0.0008 0.0039 0.0086 0.1218 0.0779 0.0321 0.0181
40 -0.0017 0.0029 0.0154 -0.0012 0.0044 0.0119 0.1261 0.0857 0.0366 0.0232
45 -0.0020 0.0041 0.0189 -0.0016 0.0057 0.0159 0.1299 0.0920 0.0423 0.0272
30 -0.0025 0.0057 0.0253 -0.0020 0.0067 0.0209 0.1313 0.0975 0.0480 0.0300
55 -0.0026 0.0067 0.0298 -0.0020 0.0079 0.0243 0.1325 0.1015 0.0517. 0.0362
60 -0.0026 0.0079 0.0322 -0.0021 0.0090 0.0274 0.1335 0.1049 0.0550 0.0399
* Time(min) ** Control
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Part 2. Polymerization of Purified Tubulin in the Absence of Either Guanosing 5'-triphosphate or Glycerol
This standard pharmacological test procedure measures the ability of a representative example of the invention to induce polymerization of purified tubulin in the absence of glycerol or guanosine 5'-triphosphate (GTP). All other conditions and data calculation were as given above in Part 1.
In the first experiment, the polymerization reaction mixture did not contain glycerol. In the absence of glycerol, highly purified tubulin undergoes very little spontaneous polymerization but paclitaxel is known to induce polymerization under these conditions. The data displayed in Table 15 show that Example 170 also induced polymerization in the absence of glycerol.
In the second experiment, GTP was absent from the reaction mixture. Normal tubulin polymerization requires energy released from GTP hydrolysis to drive subunit assembly, but paclitaxel is able to induce polymer formation even in the absence of GTP. The data displayed in Table 16 show that Example 170 also induced polymerization in the absence of GTP.
The results of both these experiments are consistent with the conclusion that Example 170 has a paclitaxel-like mechanism of action on tubulin polymerization.
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Table 15
Evaluation of Example 170 and Paclitaxel in the Tubulin Polymerization Standard Pharmacological Test Procedure in the absence of glycerol

Time (min) AA340
Example 170 Paclitaxel Control

10 µM 1µM 10 µM 1 µM
0 0 0 0 0 0
5 0.0019 0.0005 0.0056 0.0014 0.0002
10 0.0049 0.0014 0.0279 0.0091 0.0007
15 0.0095 0.0024 0.0546 0.0198 0.0011
20 0.0153 0.0039 0.0801 0.0310 0.0018
25 0.0215 0.0054 0.1016 0.0412 0.0024
30 0.0280 0.0074 0.1188 0.0500 0.0033
35 0.0347 0.0097 0.1070 0.0576 0.0043
40 0.0422 0.0121 0.1142 0.0638 0.0048
45 0.0504 0.0149 0.1192 0.0691 0.0058
50 0.0595 0.0188 0.1238 0.0737 0.0069
55 0.0687 0.0222 0.1262 0.0773 0.0077
60 0.0783 0.0264 0.1293 0.0805 - 0.0094
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Table 16
Evaluation of Example 170 and Paclitaxel in the Tubulin Polymerization Standard Pharmacological Test Procedure in the absence of GTP

Time (min) AA340
Example 170 Paclitaxel Control

20 µM 5 µM 20 µM 5 µM
. 0 0. 0 0 0 0
5 0.0364 0.0000 0.0204 0.0032 -0.0010
10 0.0582 0.0009 0.0592 0.0160 -0.0004
15 0.0735 0.0028 0.0933 0.0305 0.0019
20 0.0830 0.0046 0.1159 0.0445 0.0035
25 0.0921 0.0078 0.1288 0.0570 0.0078
30 0.1022 0.0107 0.1365 0.0674 0.0121
35 0.1086 0.0142 0.1409 0.0764 0.0167
40 0.1125 0.0180 0.1435 0.0843. 0.0198
45 0.1192 0.0220 0.1449 0.0908 0.0241
50 0.1225 0.0265 0.1457 0.0962 0.0276
55 0.1264 0.0310 0.1456 0.1008 0.0333
60 0.1277 0.0357 0.1455 0.1046 0.0387
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IMMUNOFLUORESCENCE STANDARD TEST PROCEDURE FOR ANALYSIS OF EFFECTS OF COMPOUNDS ON MORPHOLOGY OF MITOTIC SPINDLE MICROTUBULES IN CELLS
Compounds that bind to tubulin or microtubules typically have profound and characteristic effects on the structure of the microtubules which comprise the mitotic spindle of dividing cells. Compounds such as vincristine and colchicine that inhibit normal tubulin polymerization cause a severe disruption and even disappearance of spindle microtubules. On the other hand, compounds such as palitaxel that promote tubulin polymerization and stabilize microtubules cause the appearance of dense tubulin bundles or aggregates. These effects of compounds can be visualized by immunofluorescent staining of fixed cells.
PC-3 MM2 human prostate carcinoma cells were plated at 5 x 104 cells/chamber in 8-chamber microscope slides that had been treated with poly-D-lysine (Biocoat 8-well CultureSlide, Becton Dickinson). The cells were allowed to attach and grow for 24 hr before addition of compounds at the indicated concentrations. After an additional 18-20 hr of culture with compounds, cells were fixed directly on the slides with methanol at minus 20°, rehydrated in phosphate-buffered saline, and stained with a mouse monoclonal antibody to ?-tubulin (clone DM 1A, Sigma) followed by F(ab')2 fragments of goat anti-mouse IgG, FITC conjugate (Jackson immunoresearch). Cells were also stained with Hoescht 33258 to visualize DNA. Cells were viewed with a Zeiss fluorescence microscope under epi-illumination, and digital images were captured with a MTl Model DC330 video camera using Optimas V software. Images were processed using Corel PhotoPaint
As displayed in Table 17, representative compounds or this invention produced marked bundling or aggregation of spindle microtubules in dividing
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cells. The patterns of microtubule bundling were similar to that produced by paclitaxel. When tested at equi-potent concentrations (i.e., at a concentration of each compound equal to eight times its IC50 value in the 3-day MTS cytotoxicity assay), paclitaxel produced predominantly bipolar structures in which the microtubules appeared to be shortened and condensed. The compounds of this invention typically produced two, three, or four dense, circular bundles with intense fluorescence. The microtubule disrupting agents, vincristine and colchicine, produced patterns that were quite distinct from the compounds described here. These results are consistent with the conclusion that the compounds of this invention promote tubulin polymerization, as does paclitaxel.
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Table 17
Evaluation of Representative Compounds of this Invention on Morphology of
Mitotic Spindle Microtubules in PC-3 MM2 Cells Determined by the
Immunofluorescence Standard Pharmacological Test Procedure

Ex. Concentration (µM) Appearance of Mitotic Spindle Microtubules
35 0.54 Less tightly condensed, greater variety of abnormal structures, including "tangled spaghetti""
169 6.41 Dense, compact, highly fluorescent bundles, roughly circular in shape, 2-4 per cell
170 1.74 Dense, compact, highly fluorescent bundles, roughly circular in shape, 2-4 per cell
175 0.74 Dense, compact, highly fluorescent bundles, roughly circular in shape, 2-4 per cell
178 1.91 Rigid spikes emanating from a central core: "sea urchin" appearance
188 0.24 Dense, compact, highly fluorescent bundles, roughly circular in shape, 2-4 per cell
198 2.10 Dense, compact, highly fluorescent bundles, roughly circular in shape, 2-4 per cell
208 0.26 Dense, compact, highly fluorescent bundles, roughly circular in shape, up to 8 per cell
211 0.89 Dense, compact, highly fluorescent bundles, roughly circular in shape, 2-4 per cell
Paclitaxel 0.016 Dense, compact, highly fluorescent bundles, typically bipolar
Vincristine 0.008 Multiple abnormal structures, many resembling partially disrupted spindles
Colchicine 0.064 Almost completely depolymerized microtubules, sometimes with multiple small flecks of brighter fluorescence
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STANDARD PHARMACOLOGICAL TEST PROCEDURE OF ANTITUMOR ACTIVITY IN ATHYIMIC MICE BEARING HUMAN TUMOR XENOGRAFTS
The tumors used were H157 human non-small cell lung carcinoma, U87MG human glioblastoma, LOX human melanoma, and DLD1 human colon adenocarcinoma. Cells were cultured in RPMI-1640 medium with L-glutamine, supplemented with 10% heat-inactivated fetal calf serum, 100 units/ml penicillin and 100 µg/ml streptomycin. Cells were injected subcutaneously into the flank of outbred nu/nu mice. About 5 days later tumors were staged and those around 100 mg were selected for use. Tumor weights were calculated from measurements of length in two dimensions.
Compounds for test were prepared in Klucel and administered to mice by intraperitoneal injection (0.5 mJ volume) or by oral gavage (0.2 ml volume). Typically, the compounds of this invention were given twice per day for 14 days at-the doses indicated in the tables. Each experimental group contained 10 animals unless otherwise indicated. The control group (also 10 animals) received Klucel only. Tumor weights were estimated every 3 to 5 days in most experiments (every 7 days in one experiment).
Individual experiments are displayed in Tables 18-28.
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Table 18
Evaluation of Example 170 on Growth of Human H157 Non-small
Cell Lung Carcinoma in Athymic Mice: Comparison of
Intraperitoneal and Oral Dosing

Treatment Parameter DayO Day 7 Day10 Day 14 Day 16 Day 18 Day 21
Klucel MTW 121 509 756 1298 1583 1752 2879


Ex 170 MTW 128 221 287 567 755 1163 2467
25mg/kg bid, ip
T/C 1.05 0.43 0.38 0.44 0.48 0.66 0.86
P 0.001 0.001 0.001 0.009 0.062 .0.282.
Ex.170 • MTW 125 191 235 489 591 816 1835
25mg/kg bid.po
T/C 1.03 0.37 0.31 0.38 0.37 0.47 0.64
P 0.0005 0.0003 0.0003 0.0025 0.0065 0.052
Notes:
1. MTW = mean tumor weight = mean weight of tumors in all animals of the group.
Each group had 10 animals.
2. Animals were staged on day 0 and dosed on days 1-14.
3 7/c = MTW of treated animals on day n/MTW of control animals on day n.
4. p = p value, Student's T-test
5. No deaths in experimental groups.
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Table 19 Evaluation of Example 170 on Growth of Human H157 Non-small
Cell Lung Carcinoma in Athymic Mice: Comparison of Oral Dosing at Three Levels

Treatment Parameter DayO Day 4 Day 8 Day 12 Day 14 Day 17
Klucel MTW 117 270 549 1066 1632 2314


Ex.170 25mg/kg bid, po MTW ' 127 142 194 428 602 839
T/C 1.08 0.53 0.35 0.40 0.37 0.36
P . 0.002 0.001 0.003 0.001 0.001
Ex 170 12.5mg/kg bid, po MTW 126 188 275 464 748 965
T/C 1.08 0.70 0.50 0.44 0.46 0.42
P 0.018 0.005 0.004 0.004 0.002
Ex.170 6.3 mg/kg bkJ.po MTW 121 221 377 643 1030 1147
T/C 1.03 0.82 0.69 0.60 0.63 0.50.
P 0.130 0.044 0.023 0.024 0.003
Notes:
1. MTW = mean tumor weight = mean weight of tumors in all animals of the group.
Each group had 10 animals. .
2. Animals were staged on day 0 and dosed on days 1-14.
3. T/C = MTW of treated animals on day n/MTW of control animals on day n.
4. p = p value, Student's T-test.
5. One death each in 25 and 12.5 groups.
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Table 20
Evaluation of Example 170 on Growth of Human H157 Non-small Cell
Lung Carcinoma in Athymic Mice: Comparison of Oral Dosing Once or Twice Per Day

Treatment Parameter DayO Day 4 Day 9 Day 12 Day 14 Day 18
Kiucel MTW 111 334 577 1037 2237 3782


Ex.170 25mg/kg qd. po MTW 126 219 287 431 766 1550
T/C 1.14 0.65 0.50 0.42 (U4 0.41
P 0.03 0.01 0.0006 0.0006 0.005
Ex 170 25mg/kg bid. po MTW 115 1223 158 176 413 817
T/C 1.04 0.37 0.27 0.17 0.18 0.22
P 4E-05 5E-05 2E-06 9E-06 2£E-05
Notes:
1. MTW = mean tumor weight = mean weight of tumors in all animals of the group.
Each group had 10 animals.
2. Animals were staged on day 0 and dosed on days 1-14.
3. T/C = MTW of treated animals on day n/MTW of control animals on day n.
4. p = p value, Student's T-test.
5. No deaths in experimental groups.
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Table 21
Evaluation of Example 170, Example 169, and Example 133 on Growth of Human H157 Non-smalJ Cell Lung Carcinoma in Athymic
Mice:

Treatment Parameter DayO Day 5 Day 7 Day 10 Day 14 Day 17
Klucel MTW 119 300 425 638 1385 1940


Ex.170 25mg/kg bid, ip MTW 136 215 253 345 540 1203
T/C 1.14 0.72 0.60 0.54 0.39 0.62
P 0.07 0.05 0.07 0.03 0.10
Ex.169 25 mg/kg bid, Ip MTW 136 277 425 716 1641 1869
T/C 1.14 0.92 1.00 1.12 1.18 0.96

Ex.133 25mg/kg bid, ip MTW 139 262 367 558 1103 1888
T/C 1.17 0.87 0.86 0.87 0.80 0.97
Notes:
1. MTW » mean tumor weight - mean weight of tumors in all animals of the group.
Each group had 10 animals.
2. Animals were staged on day 0 and dosed on days 1-14.
3. T/C = MTW of treated animals on day n/MTW of control animals on day n.
4. p = p value, Student's T-test
5. One death in Example 170 group.
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Table 22
Evaluation of Example 170 and Example 208 on Growth of Human H157 Non-small Cell Lung Carcinoma in Athymic Mice

Treatment Parameter DayO Day 3 Day 7 Day 10 Day 14 Day 17 Day 21
Klucel MTW 138 213 580 1028 194B 3041 3453


Ex.170 MTW 159 123 162 236 391 562 1335
50mg/kg bid, then qd, ip
T/C 1.15 0.58 0.28 023 0.20 0.18 0.39
P 0.002 0.0005 0.001 0.001 0.0005 0.006
Ex.208 50mg/kg bid, then qd,ip MTW 158 187 287 367 See note 5 See note 5 See note 5
Notes:
1. MTW = mean tumor weight = mean weight of tumors in all animals of the group.
Each group had 10 animals.
2. Animals were staged on day 0 and dosed on days 1-14. Dosing was bid days 1-
6, then qd days 7-14.
3. T/C = MTW of treated animals on day n/MTW of control animals on day n.
4. p ~ p value, Student*s T-test
5. Dosing of Example 208 was stopped after 10 days because of toxicity.
6. 1 death in Example 170 group.
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Table 23
Evaluation of Example 35 on Growth of Human H157 Non-small Cell Lung Carcinoma in Athymic Mice

Treatment Parameter DayO Day 6 Day 10 Day 14 Day 18 Day 21 Day 25
Kluce! MTW 87 255 334 721 1212 1148 2076


Ex 35 50mg/kg bid,ip MTW 91 305 514 1372 2192 2296 2154
T/C 1.05 1J20 1.54 1.90 1.81 2.00 1.04
P
Notes:

10

1. MTW = mean tumor weight = mean weight of tumors in all animals of the group.
Each group had 10 animals.
2. Animals were staged on day 0 and dosed on days 1-14
3. T/C = MTW of treated animals on day n/MTW of control animals on day n.
4. p = p value, Students T-test
5. No deaths in experimental group.

C£s
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Table 24
Evaluation of Example 188 on Growth of Human H157 Non-small Cell Lung Carcinoma in Athymic Mice

Treatment Parameter DayO Day 4 Day 7 Day 10
Kiucel MTW 139' 325 516 942


Ex. 188 50mg/kg bid, ip MTW 154 385 560 1037
T/C 1.11 1.18 1.08 1.10
P 0.15 0.33 0.31
Notes:
1. MTW = mean tumor weight = mean weight of tumors in all animals of the group.
Each group had 10 animals.
2. Animals were staged on day 0 and dosed on days 1-10.
3. T/C = MTW of treated animals on day n/MTW of control animals on day n.
4. p s= p value, Student's T-test
5. Dosing of Example 188 was stopped after 10 days because of toxicity.
&
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Table 25
Evaluation of Example 170 on Growth of Human U87MG
Glioblastoma in Athymic Mice: Comparison of Intraperitoneal
Dosing at Three Levels

Treatment Parameter DayO Day 4 Day 7 Day 10 Day 14 Day 17 Day 19
Klucel MTW 160 258 406 504 1025 1656 2257


Ex.170 25mg/kg bid, ip MTW 156 134 145 111 144 200 296
T/C 0.98 0.52 0.36 0.22 0.14 0.12 0.13
P 2E-07 8.8E-O7 1.5E-08 6.9E-O9 3.3E-09 2.8E-06
Ex.170 10mgAg bid, ip MTW 156 190 232 314 664 1155 1896
T/C 0.98 0.74 0.57 0.62 0.65 0.70 0.84
P 0.0010 0.0001 0.00O5 0.0027 D.00fl4 0.174
Ex.170 5mg/kg bid, ip MTW 161 213 320 414 849 1631 2567
T/C 1.01 0.83 0.79 . 0.82 0.83 059 1.14
P 0.028 0.052 0.100 0.157 0.462 0259
Notes:
1. MTW = mean tumor weight = mean weight of tumors in all animals of the group.
Each group had 10 animals.
2. Animate were staged on day 0 and dosed on days 1-14.
3. T/C = MTW of treated animals on day n/MTW of control animals on day n.
4. p - p value, Student's T-test
5. No deaths in experimental groups.
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Table 26
Evaluation of Representative Compounds of this Invention on Growth of Human U87MG Glioblastoma in Athymic Mice

Treatment Parameter DayO Day 3 Day 7 Day 9
Klucei MTW 128 213 363 537


Ex.170 25mg/kg bid, ip MTW 128 138 120 112
T/C 1.00 0.65 0.33 0.21

Ex.211 25mg/kg bid, ip MTW 130 171 266 374
T/C 1.02 0.80 0.73 0.70

Ex.198 25mg/kg bid, ip MTW 127 198 305 659
T/C 0.99 0.93 0.84 1.04
*
Ex.178 ' 25 mg/kg bid, ip MTW 124 112 See note 4 See note4
T/C 0.97 0.53
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Table 26 Continued
Evaluation of Representative Compounds of this Invention on Growth of Human U87MG Glioblastoma in Athymic Mice

Treatment Parameter DayO Day 3 Day 7 Day 9
Klucei MTW 128 213 363 537


Ex.175 25mg/kg bid, ip MTW 138 176 239 433
T/C 1.08 0.83 0.66 0.81

Ex.35 25mg/kg bid, ip MTW 135 180 226 427
T/C 1.05 0.85 0.62 0.80

Ex, 169 25mg/kg bid, ip MTW 136 187 254 464
T/C 1.06 0.88 0.70 0.86
Notes:

10

1. MTW = mean tumor weight = mean weight of tumors in all animals of the group.
Each group had 10 animals.
2. Animals were staged on day 0 and dosed on days 1-9.
3. T/C = MTW of treated animals on day n/MTW of control animals on day n.
4. Dosing of Example 178 was stopped after 4 days because of toxicity.

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Table 27
Evaluation of Example 170 on Growth of Human LOX Melanoma in Athymic Mice: Comparison of Intraperitoneal and Oral Dosing

Treatment Parameter DayO Day 7 Day 14
Klucel RT6 1 11.51 40.53


Ex.170 25mg/kg bid, ip RTG 1 4.91 14.77
T/C 1 0.43 0.36
p 0.05 0.08
Ex.170 10mg/kg bid, ip RTG 1 8.06 35.55
T/C 0.70 0.88
P 0.38 0.53
Ex.170 25mg/kg bid, po RTG 1 10.17 40.49
T/C 0.88 1.00
P 0.61 0.53
Notes:
1. RTG = relative tumor growth = mean tumor weight on day n/mean tumor weight
of same group on day 0. 10 animals in control group, 5 in CL 376894 groups.
2. Animals were staged on day 0 and dosed on days 1-14.
3. T/C = RTG of treated animals on day n/RTG of control animals on day n.
4. p = p value, Student's T-test.
5. No deatns in experimental groups.
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Table 28
Evaluation of Example 170 on Growth of Human DLD1 Colon Carcinoma in Athymic Mice: Comparison of Intraperitoneal and
Oral Dosing

Treatment Parameter DayO Day 7 Day 14 Day 21
Kluce! RTG 1 3.17 9.62 18.11


Ex.170 25mg/kg bid, ip RTG 1 3.60 8.08 14.58
T/C 1.14 0.84 0.81
P 0.87 020 0.31
Ex.170 25mg/kg bid, po RTG 1 3.95 9.64 17.32
T/C 125 1.00 0.96
P 0.96 0.56 0.48
Notes:
1. RTG = relative tumor growth = mean tumor weight on day n/mean tumor weight
of same group on day 0. Each group had 10 animals.
2. Animals were staged on day 0 and dosed on days 1-14.
3. T/C = RTG of treated animals on day n/RTG of control animals on day n.
4. p = p value, Student's T-test
5. No deaths in experimental groups.
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Based on the results of these standard pharmacological test procedures, the compounds of this invention are useful as agents for treating, inhibiting or controlling the growth of cancerous tumor cells and associated diseases in a mammal in need thereof by interacting with tubulin and microtubules and promotion of microtubule polymerization. The compounds of the invention are also useful for the treaatment or prevention of multiple drug resistant (MDR). The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and severity of the condition being treated. However, in general satisfactory results are obtained when the compounds of the invention are administered in amounts ranging from about 0.10 to about 100 mg/kg of body weight per day. A preferred regimen for optimum results would be from about 1 mg to about 20 mg/kg of body weight per day and such dosage units are employed that a total of from about 70 mg to about 1400 mg of the active compound for a subject of about 70 kg of body weight are administered in a 24 hour period.
The dosage regimen for treating mammals may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A decidedly practical advantage is that these active compounds may be administered in any convenient manner such as by the oral, intravenous, intramuscular or subcutaneous routes. The active compounds may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft shell gelatin capsules, or they may be compressed into tablets or they may be incorporated directly with the food of the diet. For oral therapeutic administration, these active compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like. Such compositions and preparations should contain at least 0.1 % of active compound. The percentage of the compositions and preparations may, of course, be varied
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WO 02/02563 PCT/US01/20672
and may conveniently be between about 2% to about 60% of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained. Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between 10 and 1000 mg of active compound.
The tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, com starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as com starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose,vlactose, or saccharin may be added or a flavoring agnet such as peppermint, oil of wintergreen or cherry flavoring. When the dosage unit form is a capsule, ft may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit For instance, tablets, pills or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose, as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts used. In addition, these active compounds may be incorporated into sustained-release preparations and formulations.
These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth or microorganisms.
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The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and starage and must be prepared against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glyeol and liquid poly-ethylene glyeol), suitable mixtures thereof, and vegetable oils.
The following examples are representative compounds of this invention which are useful as promoters of microtubule polymerization and as anticancer agents.
Example 1
7-(1-azepanvl>-5-chloro-6-phenviri .2.4Ttriazolof1,5-aipyrimidine
Example 2
5-chloro-6-/'2.6-difluorophenvl>-7-f4-methyH-piperidinvl)f 1.2.4TtriazotoH .5-
a")pvrimid'»ne
Example 3 5-nhloro-6-f4-methoxvphenvlV7-(1-P»peridinviyi ,2.4Ttriazolon .5-alpvrimidine
Example 4
5-chloro-6-(2-chloro-6-ftuorophenvl V-7-(4-methy|-1 -pjperidinvOH .2.4TtriazoloP1,5-aipvrimidine
Example 5
7-(1-azepanvl>-5-chloro-6-(2~chlofo-6-fluorophenvl)ri ,2,4TtriazoloH ,5-
alpyrimidine
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WO 02/02563 PCT/US01/20672
Example 6
5-chloro-6-f2-chloro-6-fluorophenviV-7-(2-rnethvl-1-piperidinvOM .2.4ltriazolof1.5-aiDvrimidine
Example 7
5-chloro-6-(2-chloro-6-fluorophenvtV7-(4-thiomorpholinvlU1.2,4ltriazolo[115-
alpyrimidine
Example 8
methyl fr5-chloro-6-(2-chloro-6-fluorophenv0ri .2.4ftriazolof1 .5-atovrimidin-7-
vfUmethvlteminolacetate
Example 9
5-chloro-6-(2~chloro-6-fluorDPhenvlVN-(1.1.3.3-tetramethvibirtvOf 1.2.4Ttriazolof 1,5-a1pyrimidin-7-amine
Example 10 7-f 1 -azepanylV5-chlorp-6-(4-methoxvphenvl)ri .2.41triazolori .5-aipyrimldine
Example 11 7-(1 -azepanviV6-/4-bromophenvl>-5-chlorori ,2,4ftriazoloH .5-aipyrimidine
Example 12
5-chloro-7-(1-piperidinvtV6-f2--(trifluoromethvibhenvr|ri .2.41triazolori .5-
alpyrimidine
Example 13
6-(4-tert-butylphenvlV5-chloro-7-(4-methvi-1 -ptperidinvn[1.2.41triazolof1.5-
alpyrimidine
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WO 02/02563 PCT/US01/20672
Example 14
5-chloro-6-(4-methoxvDhenvt)-7-/4-methyl-1-piperidin^)f1,2,4Ttriazolof1.5-
afovrimidine
Example 15
5-chioro6-^4-methoxvphenvl)-7-/3-fnethv1-1-piperidinvl)ri .2.4TtriazotoH T5-
a]pvrimidine
Example 16
6-(4--bromophenvi>-5-chloro-7-<>3-methvt-1-piperidinvl)ri .2.4Ttriazolori ,5-
alpyrimidine
Example 17
fi-chloro-6-(3.4-dtfluorophenvlV7-(4-methvl-1-piperidinv<)ri .2.4^tria2oton .5-
alpyrimidine
Example 18
5-chloro-6-(2.6-dichlorDPhenvl)-7-(2--metiivl'1-pvrrolidinvt)ri .2.41tria2:otori .5-
alpyrimidine
Example 19
fi-chloro-6-/2'Chlofophenvl V-7-(2-methvl-1 -pynrolidinvlHI .2.4Ttriazolof 1.5-
alpvrimidine
Example 20
7-(1-azepanvt)-5-chloro-6~C3-chloro-4-methoxvphenvl)ri .2.4TtriazoloTi .5-
alpyrimtdine
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WO 02/02563 PCT/US01/20672
Example 21
5-chloro-6-(3-chloro-4-methoxyphenvl)-7-(4-methv<-1-piperidinvOH .2.4Ttriazolori ,5-aipyrimidine
Example 22
5-chlono-6-(r3-chlono-4-methoxyphenvl)-7-(2-methv{-1-piperidinvDf 1.2,4]triazolof1,5-aipyrimidine
Example 23
6-f4-tert-buMphenylV5-chloro7-(2-methvt-1 -piperidinylKI .2.4]triazolori .5-
alpyrimidine
Example 24
5-chloro-7-(2-methvi-1 -piperidinvl V6-F3-(trifluoromethvl)phenvnM ,2.41triazolon .5-aipvrimidine
Example 25
Diethvi 2-r6-f2.6-difluorophenvl)-5-ethoxv^1.2.4Ttriazolon .5-a1pvrimidin-7-
vf]malonate
Example 26 7-Tazepanvi>-5-chloro-6-l2-chloro-6-nitrophenvt)ri .2.4)triazolon .5-aipyrimidine
Example 27
5<^iloro-6-(2-chloro-6-fluorophenvi>-N-ethvl-N-(2-methvt-2-propenvOfi ^^Ttriazolon ,5-a1pyrimidin-7-amine
Example 28
5-chloro-6-f2-chloro-6-fluorophenvi>-N-(2,2,2- trifluoroethvDn ,2,41triazobri .5-
aipvrimidin-7-amine
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WO 02/02563 PCT/US01/20672
Example 29
5-chloro-6-(2-chloro-6-fluorophenvl)-N-^2.2-dichlorocvclopropvnmethvn-N-methv/n .2,47triazolof1,5-alpyrimidin-7-amine
Example 30
1 -r5-chloro6-(2-chloro-6-fluorophenvl)n ,2,41triazolof 1,5-aipyrimidin-7-vn-3-
piperidinol
Example 31
N-bicvdof2.2. nhept-2'Vi-5-chloro-6-(3-chloro-4-methoxyphenyl)f1,2.4]tria2olon ,5-a)Dvrimid'm-7-amtne
Example 32
5-chloro-6-f2.5-difluorophenvtVN-cloclecvtf 1.2.41triazoton .5-alDvrimtdin-7-
amine
Example 33
5-chlor»7-f4-methvl-1-piperidinv< V6-(2.3.6- trifluorophenvPfi .2.4Ttriazoton .5-
alpvrimidine
Example 34
N-f5-chtoro-6-(2.3.6-trffluorophenv»f1.2.4ttriazotoH .5-a1pvrimtdin-7-vn-^
isopropyiamine
Example 35
5-chloro-N-ethvl-N-(2-methv1-2-propenvlV6-(2.3.6-trifluorophenvDn ,2.4]triazoton .5-aipvrimidin-7-amine
Example 36
N-allv)-5-chloro-6-(r2-chloro-6-fluorophenvi>-N-f2-methvl-2-propenvDH ,2Altriazolof1,5-a1pyrimfdm-7-amine
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WO 02/02563 PCT/USO1/20672
Example 37 5-chloro-6-f2-chloro-6-fluorophenvl)ri,2,4Ttriazolori.5-a]pvrimidin-7-amine
Example 38
S-chloro-e-fS-chloro-^methoxvphenvfVN-cvcloheptvin ,2.41triazolo|"1,5-
a|pyrimidin-7-amine
Example 39
5^hlorD-6-f3-chlorp-4-methoxvphenvl)-7-(3.3-dirnethvl-1-piperidinyDfi ,2.41triazolof 1 ,5-aipvrimidine
Example 40
5-chloro-N-(3-chlon3propv<)-N-methvl-6-f2.3.6-trifluorophenvOH .2.4Hriazolof1.5-aiPvrimidin-7-amine
Example 41 7-(1-azocanvl>-5-chloro-6-(2.3.6-trifluorophenvl)ri .2,41triazolori .5-aipyrimidine
Example 42
5-chloro-6-(2.6-d(fluorophenvl>-7-(3.6-dihvdrt)-1f2H>-pyridinvDn .2.4Ttriazolon .5-aipvrimidine
Example 43 7-(1-azocanvl)-5-chloro-6-f2.&-dtfluorophenvl)n .2,41triazolon .5-alpvrimidine
Example 44
5-methoxv-6-(2-chloro-6-fluorophenvl)-7-(4-methvl-1-pjperidinvDn .2,4]triazolon ,5-aipyrimidine
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WO 02/02563 PCT/USOI/20672
Example 45
f5-chloro-6-C2-chlono-6-fluoroDhenvt)f1,2,41triazolori ,5-alpvrimidin-7-
vl]methanol
Example 46
1 -r5-chloro-6-(2,6-difluorophenv0f 1.2,41triazolof 1,5-a1pvrimidin-7-vfl-4-
piperidinol
Example 47
5-chloro-7-(4-chlorD-1-piperidinvlV6-(2,6-difluorophenvi¥1.2.41triazolori .5-
a)pyrimidine
Example 48
5-chloro-7-(4-thiomorpholinvt)-6-(2,3,6-trifluorophenvi)ri ^!.41tria2olori .5-
alpvrimidine
Example 49
5-chtofD-6-f2.6-dffluorophenvt>-7-(2.4-dimethvt-1-pjperidinvlVI ,2.4ltria2olo[1.5-aipvrimidine
Example 50
7-(4-methvl-1-piperidinvt>-5-amino-6-(2-chloro-6-fluorophen^^i .2,4Ttriazoiof 1.5-alPVrimidine
Example 51
5-chloro-6-(2.6-d jfluorophenvlV7-f 2,5-dihvdn>1 H-pyrrol-1 -vOn .2.4Ttriazoton .5-aipyrimidine
Example 52
5-chloro^-f2H:hloro-6-fluorDPhenvlV7"f2.5-dimethvl-2,5-dihvdro-1H-pvrrol-1-
vl)f1.2,41tria2olofi ,5-a)pyrimidine
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WO 02/02563 PCT/USO1/20672
Example 53
S-chloro-S-^-chloro-S-fluorophenvD-y-^-ethvl-IH-imidazol-i-vWI ,2,41triazolon ,5-aipyrimidine
Example 54
7-(4-bromo-1-piperidinvi)-5-chloro-6-(2-chloro-6-fluorophenvDfi ,2,41triazolof 1,5-aipyrirnidine
Example 55
5-chloro-6-(2-methvlphenviV7-(4-thiomorpholinvl)ri ,2.41triazolof 1 .5-
a]pvrimidine
Example 56
6-(2-bromophenyl)-N-(sec-butvl)-5-chlorof 1,2T41triazolof 1,5-a1pvrimidin-7-
arnine
Example 57
5-chlorD-N-ethv4-6-f4-methoxyphenyl)-N-(2-methv1-2-propenvl)f 1.2,4Ttriazolon .5- aiPvrimidin-7-amine
Example 58
5-chloro-6-(4-methoxyphenvl>-7-(4-thiomorpholinvi)f 1.2.41triazolon .5-
alpyrimidine
Example 59
5-chloro-7-(4-chloro-1 -piperidinvD-6-r2-(trifluoromethyl)phenvliri t2,4")triazolo|i 1,5-aipyrimldine
Example 60
5-chloro-6-f2-chloro-6-fluorophenvl)-7-f4-(trifluoromethvl)-1-piperidinyHf 1,2Altriazo\oJ 1.5-afovrimidine
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WO 02/02563 PCT/US01/2067:
Example 61
7-(4-bromo-1 -piperidinvl>-5-chloro-6-(2,6-difluorophenvt)ri .2,4Ttriazolof 1 ,5-
alpyrimidine
Example 62
7-(4-bnomo-1 -piperidinvi)-5-chloro-6-^2-chlorophenvl)ri .2.4Ttriazotof1,5-
alpyrimidine
Example 63
5-chioro-N-ethvt-N-(2-methv)-2-prDPenvl>-6-f2.4.6-trifluorophenvi¥1,2,41tria2olof1.5-alpvrimidin-7~amine
Example 64
5-chloroN-isopropyi-6-(2.4.6-trifluorophenvl)n .2,4Ttriazo)on .5- aipyrimidin-7-
amine
Example 65
5-chloro-7-(4-thiomorpholinv})-6-(2,4.6-trtfluorDPhenvl)ri .2.41triaaQtof 1.5-
alpvrimidine
Example 66
7-f 1-azepanvl>-5-chloro-6-(2,4.6-trifluorophenvl)ri ,2.4Ttriazolon .5-
alpytimidine
Example 67
5^htoro-^--('2-chioro-6-fluorophenviV7-{2-(1-pviTolidinvlV1-cvdopenten-1-
vfin .2.4]tria2olori .5-aipvrimidine
Example 68
5-chlQro-7-r4-isopropvl-1 -piperidinvf V-6-(4-methoxvphen vlW 1.2.4]triaz6lof 1.5-
a]pyrimidine
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WO 02/02563 PCT/US01/20672
Example 69
5-chloro-7-(2.4rdimethvl-1-piperidinvl)-6-(4-methoxvphenvl)ri.2.4]tria2olof115-
alpyrimidine
Example 70
5-chloro-7-fethvl(2-methvl-2-propenv<)amino1-644-nrtrophenvMI ,2,41triazolof1,5-aipyrimidine
Example 71 7-(1 -azepanvl)-5-chloro-6-(4-n}trophenvt>ri ,2.41triazolon .5-afovrimidine
Example 72
N-bicvdor2.2.nhept-2-vl-5-chloro-6-(2,4.6-trifiuorophenvl)ri .2.4Ttriazolof1.5-
aipyrimidin-7-amine
Example 73
5-chlorD-6-(2.6-difluorophenvt>-N-(2.2.2-trifluoroethvl)ri .2.41triazolori .5-
aiPvrimidin-7-amine
Example 74
5-chlorD-6-(2-chlorophenvl)-N-r2,2.2-trifluoroethvl)ri .2.41tria2olori ,5-
aipvrimidin-7-amine
Example 75
5-chloro-6-(2-chloro-6-fluorobenzvl>-7-tetrahvdro-2-furanviri ,2,41triazoloM .5-
a"|pyrimidine
Example 76
7--N-f2-methv<-2-propenvDf 1.2.47triazolof 1,5-aipyrimidin-7-amine
Example 79
5-chtQro-6-(2-chioro6-fluorophenvlVN-hexviri .2.4"ltriazolof1 .5-afovrimidin-7-
amine
Example 80
5-chloro-7-(4-methvt-1-piperidinvi>-6-f4-(methvlsulfanvi)phenvnri .2.4TtriazoloH .5-aipyrimidine
Example 81
5-chloro-N-ethvl-N-(2-methv(-2-propenvt>-6-f4-f methvlsulfanvOphenynri .2.4Ttriazolof1.5-aipyrimidin-7-amine
Example 82
N-(sec-butv»-5-chlorD-6-r4-(methvlsuifanvibhenvnri .2.4Ttriazplon .5-
aipvrimidin-7-amine
Example 83
5-chloro-6-r4-(methvlsulfanvi)phenvn-7-(4-thiomorpholinvl)ri.2,4]triazolori.5-
alpyrimidine
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WO 02/02563 PCT/US01/20672
Example 84
5-ch{oro-6-f2,6-dichloro-4-ftrifluoromethvlbhenvi1-7-(4-methvl-1-piperidinvPH T2.4]triazotof1.5-alpyrimidine
Example 85
7-(1 -azepanvl)-5-chloro-6-[2,6-dichloro-4-(trifluoromethyt)phenvnri ,2,4]triazolof 1,5-alpyrimtdine
Example 86
5-chloro-6-(2-chtoro-6-fluorophenv4)-7-IY2.2.2-trifluoroethvDsulfanvnfi .2,41tria2olof 1,5-aipvrimidine
Example 87
5-chloro-6-(2-chloro-6-fluorophenviV-7-(4,4-dimethvt-1-piperidlnvDf 1,2.4Ttriazolori ,5-aipyrimidine
Example 88 5^hlorcH642.6Klicfrloro-4^trifluoroi^
propenvOH ,2,41triazolon .5-a1pvrimidin-7-amine
Example 89
5K?hloro-642.6^ichloro-4-(trifluoromethv!)phenvlT-7-(4-thiomorohollnvDn ,2,41triazolof1.5-aipvrimidine
Example 90
5-chioro-6-(3.5-d}fluorophenvl)-7-(4-methv(-1-piperidinvl)ri ,2,41triazolon ,5-
alpyrimldine
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WO 02/02563 PCT/US01/20672
Example 91
5-chloro-6-f2-chloro-6-fluorophenv))-7-fisopropvlsulfanvl)f1,2.41triazolori.5-
alpyrimidine
Example 92
5-chloro-6-(2-chloro-6-fluorophenyl>-7-tetrahvdro-2-furanviri,2.4]triazolof1.5-
alpyrimidine
Example 93
4-f5^hloro-7^4-methW-1-piperidinvt)ri,2,4]triazotori,5-alpvrirTi»din-6-vnaniline
Example 94
N-{4-r5-chloro-7-f4>methvi-1-piperidin\^>)f1,2,41triazotof1 .5-a1pvrimidin-6-
vnphenvDacetamide
Example 95
f5-chloro-6-(2-chloro-6-f}uorophenvl¥1 ^.4Ttriazoton ,5-a1lDVrimidin-7-vnmethvt
acetate
Example 96
5-^k3rp-6^2^hlon>6-fluoit>phenv1>-7-(chtort>methvf )f1.2.47triazotof1.5-
alpvrimidine
Example 97
diethvf 2>r6-(2-chloro-6-fluorophenv1 V7-(4-methvl-1 -pjperidinvOH .2.41triazolol1.5-alpyrimidin-5-vflma?onate
Example 98
7-(1-azepanv1meth\4V5-chloro-6-(2-chloro-6-fluorpphenvl)f1.2,4ttriazolof1,5-
alpvrimidme
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WO 02/02563 PCT/US01/20672
Example 99
N-allyl-5-chloro-6-(2-chloro-6-fluorophenvi)-N-hexviri .2.41triazolori 15-
aipyrimidin-7-amine
Example 100
5-chloro-7-(4-methyl-1 -piperidinvi)-6-[4-(trffluoromethoxv)phenvflfi .2,41tria2olof1,5-aipvrimidine
Example 101
5-chloro-7-(4-methvi-1-piperidinvlV6-(4-phenoxvphenvl)f1,2.41triazolon .5-
alpyrimidine
Example 102
5-chloro-6-(2-chlorc)-6-fluorophenvi>-N-(cvclopropvimethviV-N-propvlfi .2,41triazolon .5-a1pyrimidin-7-amine
Example 103
5-chloro-7-f2-methvt-1-piperidinvlV6-f4-phenoxvphenvl')ri .2.4Ttriazolof1.5-
alpyrimidine
Example 104
5<^>loro-6-(2-chloro-4-nitrophenvl)-7-(4-methvl-1 -pjperidinvt¥1.2,41triazolof1.5-aipvrimidine
Example 105
5-chloro-6-(4-chloro-2.3.5,6-tetrafluorophenvlVN-cvclopentviri .2,4Ttriazolon .5-a1pyrimidin-7-amine
Example 106
4-[5-chloro-2-methvl-7-(4-methvl-1 -piperidinvDH .2.41triazolon .5-aipyrimidin-
6-vn-N,N-dimethylaniline -150-

WO 02/02563 PCT/US01/2067Z
Example 107
6-f2-chloro-6-fluorophenvl)-5-methvl-7-(4-methvl-1-piperidinvDn ,2.41triazolof1,5-aipyrimidine
Example 108
5-chlorD-6-(2-chloro-6-fluorophenv<)-7-r2-(1-PVrrol(clinv{>-1-cvclohexen-1-vfin .2.4ltriazolof1,5-a]pvrimidine
Example 109
5-chloro-6-(2-chloro-6-fluorophenvt)-7-(methoxvmethvl)ri ,2,4Ttriazolof1 ,5-
alpvrimidine
Example 110
5^hloro-6-(2-chloro-4-nttrophenvl>-7-fethvl(2-mefr>vi-2-propenvDaminoif 1,2,4)triazolori .5-a1pvrim!dine
Example 111
54jrorno-6-(2-chlorD-6-fluorophenvl)-7-(isopropvlsutfanvi)ri .2.41triazotoH .5-
a^pyrimidine
Example 112
5-chloro-N-cvclopentvl-6-(4-ethoxv-2.3.5.6-tetrafluorophenvDIf 1,2,4ttriazolon .5-a1pyrimidin-7-amine
Example 113
5-ch[oro-N-methvi-N-(2-methvl-2-pn3penviV6-(2,4.6-trifluorophenW)ri ,2,4Ttria2olon .5-a]pyrimidin-7-amine
Example 114
4-bromo-1-r5-chloro-6-(2-ch(oro-6-fluorophenv{)f1,2.4'ltriazolori,5-a1pvrimid}n-
7-vf|buwl acetate
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WO 02/02563 PCTYUS01/20672
Example 115
diethvl 2-allvl-2-(r5-chloro-6-(2-chloro-6-fluorophenvl)ri ,2,41triazolo[1 T5-
a]pyrimidin-7-ylloxv>malonate
Example 116
6-^2-chloro-6-fluorophenvl)-N-ethvl-5-methvi[1,2,41triazolon .5-aipvrimtdin- 7-
amine
EExample117
N-butvl-5-ch{oro-N-ethvl-6-f2.3.4.5.6-pentafluorophenvt)f1.2.4]triazotori .5-
aipvrimidin-7-amine
Example 118
6-f2-chloro-6-f)uorophenv1>-5-(difluoromethoxv)-7-(4-methvt-1-piperidinvWI .2.4Ttriazolon .5-aipvrimidine
Example 119
5-6--fluorophenviV7--f(2-methoxvphenvOsutfanvnfi ,2,41tria2olof 1.5-aipyrimidine
Example 121
5-chlorp-6-f2-ch>oro-6-fluorpphenvt)-N-<1,2.2-trimethylpropvDn .2.4Ttriazolof1.5-aipyrimidin-7-amine
Example 122
5-chloro-6-(2,3,4,5,6-pentafluoropheny(VN-(1,2.2-trimethvlpropvl)[1,2,4ltriazolof1.5-a]Pvrimidin-7-amine
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Example 123
5-ch(or<>6-f2,4.6-trifluorophenvl)-N-( 1.2.2-trimethvlpropvl)ri ,2,4Ttriazolon .5-
aipyrimidin-7-amine
Example 124
5-chloro-6-(4-fluorophenyl)-N-(1.2.2- trimethvlpropvOri ,2,41triazolon .5-
aipvrimidin-7-amine
Example 125
5.7-bts(4-methvl-1-piperidinvl)-6-(2.4.6-trifluorophenvl)ri ,2.41triazolon .5-
alpyrimidine
Example 126
5-chloro-6-(2-methvlphenvlVN-(1.2.2-trimethylpropvi)ri .2.4Ttriazolon .5-
aipvrimidin-7-amine
Exampie 127
5-chloro-6-(2.4.5-trifluorpphenvlVN-('1.2.2-trimethvlpropvOri .2.4Ttriazoton .5-
aipyrimidin-7-amine
Example 128
6-f2-bromophenyiy5-chloro-N-(1.2.2-trimethylpropvt)n .2.4]triazoloM .5-
aipyrimidin-7-amine
Example 129
5-chloro-N-ispbutvl-N-f2.2.2-trifluoroethvlV6-f2.4,6-trifluprophen\^)f1.2.41triazolon .5-a1pyrimidin-7-amine
Example 130
5-chloro-N-isobutvl-6-(2-methvlphenv))-N-(2,2,2-trifluoroethvOH .2.41triazolon .5-a1pyrimidin-7-amine
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Example 131
5-chloro-6-(2-chloro-6-fiuorophenvl>-N-(2,2,2-tr1fluoro-1-methvlethvDH ,2.41l:riazolof1,5-aipyrimidin-7-amine
Example 132
5-chloro-6-(2,6-diflLiorophenvtV-N-(2,2,2-trifluoro-1-methvlethvMI,2,4ttriazolori ,5-aipyrinaidin-7-amine
EExample 133
5-chloro-N-(2,2,2-trifluoro-1-methvlethvl>-6-(2.4.6-trifluorophenvDn .2.4Ttriazolo|i1 .5-a1pvrimidin-7-amine
Example 134
N-al)vl-5-chloro-N-isobutvl-6-f2.4.6-trifluorpphenvl)F1,2.41tria2olon .5-
aipyrimidin-7-amine
Example 135
5-chloro-N-(1.2-dimethvipropvlV-6-(2.4.6-trifluorophenvl^1.2.41triazolon .5-
aipyrimidin-7-amine
Example 136
5-chloro-N-isopropyl-N-methv<-6~(2.4.6-trifluorophenvl)ri .2.4TtriazoloF1.5-
a|pyrimidin-7-a mine
Example 137
5-chloro-N-isopropyl-N-(2,2,2-trifluoroethvlV6-(2.4,6-trifluorophenvl)I1J2,4ltriazolori .5-aipyrimidin-7-amine
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WO 02/02563 PCT/DS0I/2s)672
Example 138 7-butvl-5-chloro-6-f2.4.6-trifluorophenvl)f1,2.41triazolon,5-a]pvrimidine
Example 139
5-chloroN-(1-phenvlethvl)-6-(2,4,6-trifluorophenvt)ri ,2,41triazolon .5-
a]pyrimidin-7-amine
Example 140
5-chloro-6-(2>chlofophenvl>-N-(2,2.2-trifluoro-1-methvlethvt)ri .2.4Ttriazolon .5-
alpyrimidin-7-amine
Example 141
5-chloro-N-ethvi-N-isobLrtvl-6-(2,4.6-trifluorophenvl)ri .2,4Ttriazo»on .5-
aipvrirnidin-7-amine
Example 142 5-chloro-6-(2-chloiT>-6-fluorophenvl)-7-hexviri ,2.41triazolof 1,5-aipvrimidine
Example 143
5-chlorp-6-f2-methvlphenvl)-N.N-bis(2.2.2-trifluoft)ethvl)ri ,2.4Ttria2olon .5-
aiPvrimidin-7-amine
Example 144
5-chloro-N-cvclopentvi-N-methvi-6-(2.3.4,5,6-pentafluorophenvDn .2.4Ttriazolori ,5-a1pvrimidin-7-amine
Example 145 7-butyl-5-chloro-6-f2,6-dif)uorDphenvl)ri ,2,41triazolori ,5-aipvrimidine
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WO 02/02563 PCT/US01/20672
Example 146
5-chloro-N^1,2-dimethvlpropylVN-methvl-6-f2,3,4.5.6-pentafluorophenvMI .2,41triazolof1,5-atovrimidiiv7-amine
Example 147 5^hloro^(2-chloro-6-fluorophenvl)-7-phenvlf1,2,41triazolori,5-a1pvrimidine
Example 148
5n;hlonD-^2-chloro-6-fluorophenvi>-7-(2--methvlpropanvl)ri .2,41triazoloH .5-
alpyrimidine
Example 149 5-chloro-6-(2-chloro-6-fluoropher»vl)-7-pentvlf1.2.4ttriazolon ,5-aiPvrimidine
Example 150
5-chloro-N-(1.2-dimethviprDPVt)-N-methvl-6-f 2.4.6-trifluorophenvOH ,2.4TtriazochlorophenvlVN-(2.2,2-trifiuoro-1-methylethvDn .2.4Ttriazolori .5-alpyrimidin-7-amine
Example 153
5-chloro-6-(2-chloro-6-fluoropheny{)-7-(3.3.3-trifluoroprQpvl)ri.2.4]triazolori,5-
alpyrimidine
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WO 02/02563 PCT/USO1/20&72
Example 154
S-chloro-e-^-chloro-e-fluoroDhenvlVT-fS-methvlphenvDri^^Ttriazolon.S-
alpyrimidine
Example 155
r5-chloro-6-(2,4,6-trifluorophenvlMi ,2,41triazolon ,5-a1pyrimidin-7-vn-(1 -p-toM-
ettivlVamine
Example 156 5-chloro-6-(2.4,6-trifluorp-phenvl>-7-cvclohexviri .2,41triazolon .5-aipyrimidine
Example 157
5-chloro-7-cvdohexv<-6-(2.3.4.5,6-pentafluorophenv<)ri ,2.41triazolon .5-
alpyrimidine
Example 158
5^hloro-6^2-chloro-6-fluorophenvi)-7-f4.4-difluorD-1-piperidinvl)f1.2.4]triazoloM .5-aipyrimidine
Example 159
7-(bicvclor2.2.11hept-2-via mino>-5-chlofD-6-(2-fluoro-4-nitrophenvDfi .2.4Ttriazolon .5-aipyrimidine
Example 160
5-chloro-6-f2-fluon>4-nitrophenvt)-7-(4-mettivl-1--piperidinvl)ri .2.4^triazoton .5-
alpyrimidine
Example 161
5-(fmethvisulfanvl)-6-C2-chloro-6-fluorophenvlV-7-cvclohexviri ,2,4]triazoloH .5-
alpyrimidine
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Example 162
f5-chloro-6-(2,4,6-trifluorophenvl)ri ,2.41triazo!on ,5-alpyrimidin-7-vn (2.2,2-
trifluoro-1 -phenvlethvD-amine
Example 163
5-chlofD-N-ri-(tnfluoromethvl)propvn-6-(2,4,6-trifluorophenvOfi ,2,41triazolof1,5-a1pyrimidin-7-amine
Example 164
5-bromo-6"(2-chloro-6~fluorophenvl>-7-cvclohexviri ,2,4Ttriazolof1.5-
alpvrimidine
Example 165 6-(2-chloro-6-fluorophenvlV-7-cvdohexviri .2.41tria2olof1.5-a1pyrimidin-5-amine
Example 166
r5-chloro-6-(2 A6-trffluorophenv»)ri .2.4ltria2Olof1.5-a1pyrimidin-7-vn-(2-methvl-
1 -trifluoromethvl-propvl)amine
Example 167
5-chloro-7-f3-cvclohexen-1-vl)-6-(2,4.6-trifluorophenvl)H .2.4Ttriazolon .5-
alpyn'midine
Example 168
5-chloro-7-(1-cvclohexen-1-vl)-6-(2,4.6-trifluorophenvl)f1,2,4Ttriazolon ,5-
alpyrimidine
Example 169
5-chloro-N-r(1R)-2,2,2-trifluoro-1-methvlethvn-6-(2,4.6-trifluorophenvDn .2.47triazolof1,5-a1pyrimidin-7-amine
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Example 170
5-chloroN-Ki RV2.2,2-trifluoro-1 -methylethvl1-6-(2,4,6-trifluorophenyQf 1,2,4)triazolon ,5-alpyrirnidin-7-amine
Example 171
6-f2,4-difluorophenv1V5-chloro-N-(2,2,2-trifluoro-1-methvfethvOn .2.4ftriazolori ,5-aipyrimidin-7-amine
Example 172
5^hloro-6^2.6-dffluoro-4-methoxvphenvi)-7-(4-methv}-1-piperidinvDf 1,2,4]triazolof1,5-aipyrimidine
Example 173
5-chloro-6-(2,6-difluoro-4-methoxvphenvl)-N-f2,2,2-trifluon>1-metfivtethvDf 1.2,4Ttriazotof 1 t5-a]pyrimidtn-7-amine
Example 174
5^hloro-7K;vdohexv1^f2.6^if}uoro-4-methoxvphenv{)ri .2.41triazolof 1,5-
alpyrimidine
Example 175
5-chloro-6-f2,6-difluoro-4-methoxvphenvl)-N-f(1 $V-2,2,2-trifluoro-1 -methyiethyflfi .2.4Ttriazotof 1,5-a]pvrimidin-7-amine
Example 176
7-^vdohexvl-6-(2,6-difluoro-4-methoxvphenvl>-5-methoxvri ,2,4Ttriazolof1.5-
a)pvrimidine
Example 177
5-chloro-7--6-(2,4,6-trifluorophenv{)ri,2,41tria2olori.5-
alpyrimidine
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WO 02/02563 PCT/US01/20672
Example 178
5-chloro-6-(2.6-dichloro-4-fluoropheny[V7-(3,3,3-trifluoropropvPfi .2.41triazolori .5-a1pyrimidin-7-amine
Example 179
N-(rsec-buty{)-5-chloro-6-(r2,6-dich7-r(2.2.2-trifluorp-1-methvlethvl)amino7ri ,2.41tria2olof1.5-alpvrimidin-6-vtV-3.6-difluorophenol
Example 181
5-chlonD-7-f3-cvdohexen-1 -vD-6-(2.6~difluoro-4-methoxvphenvDf 1.2,4Ttriazolof 1,5-aipyrimidine
' Example 182
5-chtoro-6-(2.6-dffluoro-4-methoxvphenv1)ri ^^Uriazolori .5-aipyrimidin-7-
amine
Example 183
5-chlon>N-cvclopentvl-6-(2.6-difluoro-4-methoxvphenvl)ri .2.41triazolof 1.5-
aipyrimidin-7-amine
Example 184
5K;hloro^(2,6^j}fluorc>-4-methoxvphenvl)-7-(3,6-dlhvdrD-1f2HV pvridinvDn ,2.4ltriazo{of1.5-aipyrimidine
Example 185
5-chloro-6-f2,6-difiuoro-4-methoxvphenvl)-7-(4-thiomorpholinvDf 1,2,41triazolon ,5-alpyrimidine
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WO 02/02563 PCT/US0I/2O67?.
Example 186
7-n-a2epanvl)-5-chloro-6-('2.6-difluoro-4-methoxvDhenvt)ri .2,4ttriazolof1,5-
a"|pyrimidine
Example 187
5-chloro-6-(2.6-difluoro-4-methoxvphenvl>-N-(1.2.2-trimethylpropvOn .2.41triazolof1.5-a1pvrimidin-7-afnine
Example 188
5^hlorcH6^2.6HJifluoiXH4^T>ethoxvphenvl)-N-ethvi-N-(2-fTiethvl-2-propenvi^n .2.4)triazolof1.5-a1pyrimidin-7-amine
Example 189
5-chloro-6-f2.6-difluoro-4-methoxvDhenvlV-7-(4-fluorocvdohexvOH ,2,4]triazoiof1,5-alpyrimidine
Example 190
6~T4-f5-chlofx>-7-ff2.2,2-trifluoro1-methv)ethv»)aminoiri .2,4Ttria2o>on .5-a1pvrimidin'6-vfV-3.5-drfluorophenoxv)hexanoicacid
Example 191
2.6-dffluoro-4-(2-fluoroethoxv)phenvn-N-(2.2,2-trifluorD-1-methviethvDn .2.4Ttria2olori ,5-a1pyrimiditv7-amine
Example 192
5-chloro-N-isoprop\i-642-r(trifluoromethvl)sulfanvnphenv{>ri ,2.4Ttriazblof1.5-
alpvrimidin-7-amine
Example 193
5-chloro-N-r4-(trifluoromethvl)phenvn-6-(2,4.6-trifluorophenvl)f1 T2,41triazolon ,5-alpyrimidin-7-amine
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WO 02/02563 PCT/US01/2©£72
Example 194
5-chloro-N-(4,4,4-trifluoro-2-methvlbutvl>-6-(2,4.6-trifluorophenvDfi ,2,41triazolori ,5-alpvrimidin-7-amine
Example 195
5-chioro-6-f2.6-difluon>4-methoxvphenvl>-7-(3-methvl-3-butenvlMi.2.41triazoiori .5-aipyrimidine
Example 196
5-chloro-6-^2,6-dffiuorD-4-methoxvphenv()-7'-isobutvfri .2,47triazotof 1.5-
alpyrimidine
Example 197
7-cvclopentvi-6-(2.6-difluoro-4-methoxvphenvi>-5-methoxvf 1.2,4Ttriazolon .5-
alpyrimidine
Example 198
5-chloro-6-f2-thienvi)-N-r(1 RV-2.2.2-trifluoro-1-methviethviri .2,4Ttriazolon .5-
a]pyrimidin-7-amine
Example 199
4-f5-chloro-7-(2.2.2"trifluort>1-methvl-ethviamino)ri ,2,4]triazolori .5-a1pvrimidin-6-^T-3,5-dlfluort>-phenol
Example 200
r5-chloro-6-r2,6-dffluoro-4-(2,2,2-trifluoro-ethoxvV-phenvn-ri ,2,4ttriazolon ,5-a]pvrimidin-7-vl>-(2,2.24rifluoro-1-methvi-ethvl)amine
Example 201
5-chloro-6-f2.6-difluoro-4-fmethoxvphenvl)-N-(2,2,2-trifluorQ-1-methylethvOri ,2,41triazolon ,5-a1pyrimidin-7-amine
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WO 02/02563 PCT/US01/20672
Example 202
r5-chloro-6-(4-r2-(2-ethoxvethoxv1-ethoxv1-2.6-dffluoro-phenvDH .2AWiazoioI1,5-alpyrimidin-7'Vl->-f2,2.2-trifluoro-1-
methvlethvDamine
Example 203
(5-chloro-6-f2.6-difluoro-4-r2-(2-methoxv-ethoxv)ethoxvT-phenv()-n .2,4Ttriazolon ,5-a1pyrimidin-7-vi-W2.2.2-trifluoro-1-nr>ethviethvl)amine
Example 204
5-chiorp-6~r2.6-difluoro-4-C3-furan-3-vlmethoxv)phenviri .2.4]tria2olon .5-a1pvrimidin-7-vt>-N-(2.2.2-trifluoro-1-methvlethvt)amine
Example 205
5-chlon>6-f2.5-difluorD-4-methoxvphenvl)-N-(1.2.2-trimethvipropvl)f1.2.4Ttria2oton ^S-aipyrimidin-y-amine
Example 206
7-cvdohexvl-6-r2.6-difluorc>-4-(2-methoxvethoxv)phenvn-5-methoxvn .2.4Ttria2olon .5-aipyrimidine
Example 207
5^h>oro-6^2>fluoro^methoxv-^-chtorophenvf>-N-(r2,2.2-trffluoft>-1-methylethvDn .2,41triazolon ,5-a1pyrimidin-7-amine
Example 208
5^hloro-6~r2.6-dffiuoro-4-f2-fluorpethoxv)phenvn-N-ethvl-N-(2-methv<'2-propenv})n ,2,41triazolon ,5-a1pyrimidin-7-amine
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WO 02/02563 PCT/US01/20672
Example 209
2-f2-(4-(5-chloro-7-r(2,2,2-trifluoro1 -methyiethvQaminoif 1,2,4]triazolon .5-a1pvrimidin-6-yl}-3,5-difluorophenoxv)ethoxv1ethanol
Example 210
5-chloro-6-(2.3-difluoro-4-methoxvphenvl)-N-f2,2,2--trifluoro-1-methvlethvl)f1,2.41triazolo[1.5-a1pyrimidin-7-amine
Example 211
5-chloix)-6-f4--(2-fluoroethoxvV2.6-difluorphenvlV-N-(2.2.2-trifluorp-1-methyiethvl)[1.2,4]triazolof 1,5-afovrimiclin-7-amine
Example 212
5<:hloro-N-(4-chlorobenzvlV-6--(2-chlorc>-6-fluorophenvl)ri .2.4Ttriazolon .5-
aipyrimidin-7-amine
Example 213
5^lorD-6-/2-chlorD-6-fluorophenvl)-7-r4-f2-Pvridinvt>-1-piperazinvf|n .2,4Ttriazolof1,5-aipvrimidine
Example 214
5-chloro-6-(2-chloro-6-fluorophenvl)--N-n-ethvlpentvl)ri .2,41triazolon .5-
aipyrimidin-7-amine
Example 215
5-chloro-6-f2-chloro-6-fluorophenvl)-7-r4-(2-chlorDPhenvl)-1-piperazinvflM ,2,4Ttriazolof 1,5-aipyrimidine
Example 216
5-chloro-6-(2-chloro-6-fIuorophenvl>-744-(4-methoxvphenvl>-3-methvl-1-piperazinvlin ,2.4ltriazoloi"1,5-aipvrimidine
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WO 02/02563 PCT/USOl/20672
Example 217
5-chloro-N-cvclopentyl-6-(2-chloro-6-fluorophenvl)f1.2,41triazolof1.5-
aipvrimidin-7-amine
Example 218 5-chloro-7-phenoxv-6-(4-methoxv-phenvi)ri ,2,41triazolof1.5-aipvrimidine
Example 219
5-chtoroN-cvdopentvi-6-(4-methvtphenvi)ri .2,41triazolori .5-a1pvrimidin-7-
amine
Example 220 5.7-diphenoxv-6-/4-methoxvpheny{)f 1,2,4ltriazolof 1,5-aipvrimidine
Example 221
5-chlofQ-N-cvclopentvl-6-l'2-chtorophenvl)ri .2.4Ttriazolof 1.5-aipvrimidjn-7-
amine
Example 222
5-chIorD-N.N-diethvJ-6-f4-methoxvphenvflf1.2.41triazoloT1.5-a1pvrimidin-7-
amine
Example 223
5-chloro-N.N-diethyl-6-r2.4-dichlorophenvnn .2,4Ttriazolon .5-a1pvrimidin-7-
amine
Example 224
N-bicvclor2.2.1lhept-2-vl-5-chloro-6-(2,4-dichlofDPhenvl)ri,2,4]triazolori.5-
aipyrimidin-7-amine
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WO 02/02563 PCT/US01/20672
Example 225
5-chloro-6-(2-chloro-6-fluorophenvl)-7-(1,4-dioxa-8-azaspiror4.51dec-8-yl)ri.2,41triazolon ,5-aipyrimidine
Example 226
5-cvano-7-(4-methv<-1-piperidinvlV6-(2-chloro-5-fluorophenvOd ,2,41triazolori ,5-alpyrimidine
Example 227
5-(methvisutfanvlV7-(4-methvl-1-piperidinvi>-6-(2-chloro-6-fluorophenvDfi ,2,4]triazolori ,5-aipyrimidine
Example 228
54methvisulfanvlV-7-(4-niethvi-1-pipendinvl)-6-(2-chtorD-5-(methvisulfanvlbhenvl)f 1.2.4Ttiiazolon .5-aipvrimidine
Example 229
5-chloro-7-(1,4-dioxa-8-azaspirof4.51dec-8-vlV^-(4-methoxvphenvOli .2.4Ttriazolon .5-aipvrimkline
Example 230
5-chloro-N-emvl-N-(2-methvi-2-propenviV-6-(4-(metfivtsutfanvt)phenv()ri .2,4]triazolon .5-aipyrimidin-7-amine
Example 231 2-methvf-6.7-di-(4-methoxvphenv{)f1,2.4Kriazolon .5-alpyrimidine
Example 232 2-methvl-6-phenv<-7-(4-chlorophenvl)ri ,2,41triazolof1.5-alpvrimidine
-166,

Example 233 2-trifluoromethvl-6-phenvl-7-(4-methoxvphenyl)[1,2,41triazolof1,5-a1pvrimidine
Example 234
2,5-dichloro-7-(4-methyl-1-piperidinvl)-6-f2-chloro-6-fluorophenyliM,2,41triazolo[1,5-aipvrimidine
Example 235
5-chloro-6-(3,4-difluorophenvl)-N-(isopropvnf1.2,41triazolof115-a|pyrimidin-7-
amine
Example 236 5-bromo-6-(4-bromophenvl)-7-dimethvlaminon,2,4ltriazolo[1,5-aipyrimidine
Example 237
5-bromo-6-(4-tnfluoromethvlphenyl)-7-dimethvlamino|"1,2,41triazolo|'1,5-
a]pvrimidine
Example 238 5-chloro-6-(3,4-difluorophenyl)-7-dimethvlamino[1,2,41triazolon,5-a1pyrimidine
Example 239
5-chloro-6-(4-trifluoromethviphenvl)-N-(ethvl)ni2t41triazolo[1,5-a1pyrimidin-7-
amine
Example 240 7-(1-azepanvl)-5-chloro-6-(4-tert-butvlphenvl)ri,2,41triazolon,5-a1pvrimidine
Example 241
ethyl {[5-chloro-6-(2-chloro-6-fluorophenyl)n ,2,41triazolori ,5-a1pyrimidin-7-
yliaminolacetate
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WO 02/02563 PCT/US01/20672
Example 242
diethv) 5-chloro-6-(2.6-difluorophenyl)ri ,2,41triazolori .5-aipyrimidin-7-
malonate
Example 243
5-chloro-6-r2,5-dlfluorophenvl)-N-(3-methvl-2-butenvl)ri .2,41triazploH .5-
aipyrimidin-7-amine
Example 244
r5-chloro-6-(2-chloro-6-fluorophenvlVri ,2.4ttriazoloH ,5-a1pvrimidin-7-vnacetic
acid methyl ester
Example 245
5-chforo-6-(2,6-difluorophenvt V7-f2-ethvt-1 H-imidazol-1 -v\)\1.2.4Ttriazolof 1.5-
alpvrimidine
Example 246
5-chloro-N.N-diethvl-6-r4-(methvlsulfanvl)phenvflri .2.4Ttiiazo»on .5-
aiPVrimidin-7-am»ne
Example 247
ethvl r6-(2-chtoro-6-fluorophenvl>-7-(4-methvl-1-piperidinvi>- M .2.4Ttriazolori .5-
aipvrimidin-5-vnacetate
Example 248
5-chloro-N-ethvl-N-(2-methvl-2-prppenvlV6-f4~ phenoxvphenvOH .2.4]triazolof 1.5-a1pvrimidin-7-arnine
Example 249
dimethyl 2-r5-ch[oro-6-(2-chloro-6-fluorophenv0n .2,41triazofon .5-aipyrimidin-
7-vlimalonate
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WO 02/02563 PCT/US01/2067J
Example 250
diethvl 24r5-chloro6-f2-ch[oro6-fluorophenvl)f1,2,41triazolon .5-a1pyrimidin-7-
vrioxvl-2-isobutylmalonate
Example 251
2-f5-chloro-6-f2-chloro-6-fluorophenvi)ri .2,41triazolon ,5-a1pyrimidin-7-vfl-1,3-
cyclohexanedione
Example 252
2-r5-chloro-6-(2-ch>oro-6-fluorophenvl)ri .2,4Ttriazolon ,5-alpyrimtdin-7-
vncyclohexanone
Example 253
5-chioro-7-(3-nitro-4-methvlaniIinoV6-(2,4. 6-trifluorophenvl) f1 >2.4]tria2olo|'1.5-a|pyrimidine
Example 254
7^^dohexy{-6-f2,6-dtfluoro-4-(2-methoxvethoxv)phenvn5-f2-methoxvethoxv)ri.2.4Ttriazoion,5-aiPvrimidine
Example 255 7-f3-bromophenvl)-2-ethv(-6-(4-methoxvphenv{)ri ,2.4ltriazolori .5-aiPvrimidine
Example 256 7-(3-brpmophenvi>-6-(3-chlorDPhenvl)-2-ethviri .2,4Ttria2olon ,5-aipyrimidine
Example 257
7-(4-bromophenvlV-2-ethvl-6-f4-ftrifiuorometh'\4)phenvnri ,2,4Ttria2olon .5-
alpyrimidine
-169-

WO 02/02563 FCT/US01/20672
Example 258
5-chloro-6-(2-chloro-6-fluorophenvlVN-f3,4,5-trimethoxvbenzvOH .2,4]triazolof1,5-a1pvrimidin-7-amine
Example 259
7-(2-benzyi-4.5-dihvdro-1 H-imidazol-1 -vlV5-chloro-6-(2-chloro-6-fluorophenvDf 1,2,4ltriazolo[1,5-aipyrimidine
Example 260
N-4-f5-chloro-6-(2-chloro-6-fluorophenvl)ri .2.4ltriazoloM .5-a1pyrimidin-7-vi-
N.N-1-diethv1-1,4-pentanediamine
Example 261
5-chloro-N-(3-methvl-2-butenvl)-6-phenviri ,2,41triazolori .5-aipvrimidin-7-
amine
Example 262
5-dimethvlamino-6-phenv^N-cvclopentviri .2.41triazolon .5-a1pvrimidin-7-
amine
Example 263
5-chloro-7-f(2-furvlmethvt)sutfanvn-6-(4-methoxvphenvi)ri .2,4]tria2olon .5-
a]pyrimidine
Example 264
6-11.1 '-biphenWl-4-v}-5-chloro-N-cvclopentvtn ,2,4Ttriazolon ,5-aTpyrimldin-7-
amine
Example 265
6-r4-(benzvloxy)phenvil-5-ch)oro-N-isopropviri2,41triazolof1,5-a1pvrimidin-7-
amine
-170-

WO 02/02563 PCT/US01/20672
Example 266
5-chloro-N-r(2,2-dichlorocvcloproD\4)rr)eth\i1-6-(3.4,5-trimethoxvphenvDH ,2,4]triazolof1.5-alpyrimidin-7-amine
Example 267
NH^cfopenty(-6-(2-fJuorophenv))-5-hvdraanori,2,4]triazolori.5-a)pvrimidin-7-
amine
Example 268 5-chloro-N-ethvl-6-f2-methvlphenvl)C1.2.4ttriazoloH .5-a1pvrimidin-7-amine
Example 269
6-(4-tert-butvlphenvl)-5-chloro-N-»soprDpvtri .2,41triazolon .5-aipyrimidin-7-
amine
Example 270
5^h(oro-6-r2,6KJifluoro-44f3HTieth\4-2-butenvi)oxv1phenvn>N42^.2-trifluoft^ methvlethvf V-in ,2.41triazolori .5-aipyrimidtn-7-amine
Example 271
S^htoro-6-f2.6HJifluoix>-4^iH3fDpenv(oxv)phenv(|-N^2.2.2-trifluoro-1-methvdethvt>-iri .2.41triazolof1.5-aipyrimidin-7-amine
Example 272
5-chloro-N-f3-tricvdor2.2,1.02'61hept-1-vl>-6-(2.4,6-trifluorophenvl>f1,2,41triazolof 1,5-aipyrimidin-7-amine
Example 273
5-azido-7-cvclohexy{-6-f2-fluoro-6-chlorophenyi) f 1,2,41triazoton .5-
a]pvrimidine
-171-

Example 274
5-azido-6-[2-chloro-6-fluorophenvll-7-(4-methvl-1-piperidinyl)[1,2,41triazolo[1,5-aipyrimidine
-172-

We claim:
1. A pharmaceutical composition useful for treating or inhibiting the growth of cancerous tumour cells and associated diseases in a mammal in need thereof comprising an effective amount of a substituted triazolopyrimidine derivative, wherein the substituted triazolopyrimidine derivative is a compound selected from those of the formula:

wherein:
R1 is selected from the group consisting of halogen, an optionally substituted alkyl of 1 to 12 carbon atoms, optionally substituted alkenyl of 2 to 12 carbon atoms, optionally substituted alkynyl of 2 to 12 carbon atoms, optionally substituted alkadienyl of 4 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, optionally substituted aryl of 6, 10 or 14 carbon atoms, -CN, hydroxy, halogen, carbamoyl, carboxy, alkoxycarbonyl of 2 to 12 carbon atoms, heterocyclyl, optionally substituted bicycloalkyl of 5 to 10 carbon atoms, optionally substituted cycloalkyl of 3 to 8 carbon atoms in which one -CH2-may also be replaced by -O-, -S-, or -NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, thiophene, optionally substituted cycloalkenyl of 5 to 10 carbon atoms in which one -CH2- may also be replaced by -O-, -S-, or
-173-

-NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, -S-aryi of 6, 10 or 14 carbon atoms, -S-alkyl of 1 to 12 carbon atoms, -S-cycloalkyl of 3 to 8 carbon atoms, -S-alkenyl of 2 to 12 carbon atoms, -SO2aryl of 6,10 or 14 carbon atoms, -SC>2cycloalkyl of 3 to 8 carbon atoms, -SO2alkyl of 1 to 12 carbon atoms, -O-aryl of 6,10 or 14 carbon atoms, and the moiety -NRaRb;
Ra is H, optionally substituted alkyl of 1 to 12 carbon atoms, optionally substituted alkenyl of 2 to 12 carbon atoms, optionally substituted alkynyl of 2 to 12 carbon atoms.optionally substituted alkadienyl of 4 to 12 carbon atoms, optionally substituted cycloalkyl of 3 to 8 carbon atoms, in which one -CH2- may also be replaced by -O-, -S-, or-NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, optionally substituted cycloalkenyl of 5 to 10 carbon atoms, in which one -CH2- may also be replaced by -O-, -S-, or -NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, optionally substituted bicycloalkyl of 5 to 10 carbon atoms, optionally substituted tricycloalkyl, haloalkyl of 1 to 10 carbon atoms, aryl of 6, 10 or 14 carbon atoms, heterocyclyl, benzyl, optionally substituted benzyl, cycloalkyl of 3 to 8 carbon atoms or a 3- to 6-membered heterocyclyl ring, optionally ortho-fused with an optionally substituted phenyl ring ;
Rb is H, an optionally substituted alkyl of 1 to 12 carbon atoms, optionally substituted alkenyl of 2 to 12 carbon atoms, optionally substituted alkynyl of 2 to 12 carbon atoms, optionally substituted alkadienyl of 4 to 12 carbon atoms, optionally substituted aryl of 6, 10 or 14 carbon atoms, optionally substituted bicycloalkyl of 5 to 10 carbon atoms, optionally substituted cycloalkyl of 3 to 10 carbon atoms in which one -CH2- may also be replaced by -O-, -S-, or -NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, optionally substituted cycloalkenyl of 5 to 10 carbon atoms in which one -CH2- may also be replaced by -O-, -S-, or-NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, -S-aryl of 6, 10 or 14 carbon atoms, -S-alkyl, -S-alkenyl,
-174-

-S02aryl of 6, 10 or 14 carbon atoms, -SO2cycloalkyl, -SO2alkyl, -O-aryl of 6, 10 or 14 carbon atoms, heterocyclyl, benzyl, optionally substituted benzyl, cycloalkyl of 3 to 8 carbon atoms or a 3- to 6-membered heterocyclyl ring, optionally ortho-fused with an optionally substituted phenyl ring ;
5
RaRb together with the nitrogen atom to which each is attached represent an optionally substituted saturated or unsaturated heterocyclyl ring from 3 to 12 ring atoms in which optionally, at least one -CH2- may optionally be replaced by-O-, -S-, or-NR where R is H or an alkyl group of 1 to 12 carbon 10 atoms, said saturated or unsaturated heterocyclyl ring may optionally be aryl or cycloalkyl fused;
R2 is optionally substituted phenyl or optionally substituted thienyl;
R3 is H, halogen, alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, aryloxy, -NRcRd, benzyloxy, aralkyloxy, haloalkoxyof 1 to 12 carbon atoms, alkylthio of 1 to 12 carbon atoms, heterocyclyl, aryl, hydroxy, carbamoyl, carboxy, alkoxycarbonyl of 2 to 12 carbon atoms, cyano, amino, alkylamino of 1 to 12 carbon atoms, dialkylamino of 1 to 12 carbon atoms, or -N3;
Rc is H, amino, optionally substituted alkyl of 1 to 12 carbon atoms, haloalkyl of 1 to 10 carbon atoms, optionally substituted alkenyl of 2 to 12 carbon atoms, optionally substituted alkynyl of 2 to 12 carbon atoms, optionally substituted alkadienyl of 4 to 12 carbon atoms, optionally substituted cycloalkyl of 3 to 10 carbon atoms, in which one -CH2- may also be replaced by -O-, -S-, or-NR where R is H or an alkyl group of 1 to 12 carbon atoms optionally substituted cycloalkenyl of 5 to 10 carbon atoms, in which one -CH2- may also be replaced by -O-, -S-, or -NR where R is H or an alkyl group of 1 to 12 carbon atoms optionally substituted bicycloalkyl of 5 to
-175-

10 carbon atoms, aryl of 6,10 or 14 carbon atoms, benzyl, optionally substituted benzyl, or heterocyclyl;
Rd is H, amino, optionally substituted alkyl of 1 to 12 carbon atoms, haloalkyl of 1 to 10 carbon atoms, optionally substituted alkenyl of 2 to 12 carbon atoms, optionally substituted alkynyl of 2 to 12 carbon atoms, optionally substituted alkadienyl of 4 to 12 carbon atoms, optionally substituted cycloalkyl of 3 to 10 carbon atoms, in which one -CH2- may also be replaced by-O-, -S-, or-NR where R is H or an alkyl group of 1 to 12 carbon atoms optionally substituted cycloalkenyl of 5 to 10 carbon atoms, in which one -CH2- may also be replaced by -O-, -S-, or -NR where R is H or an alkyl group of 1 to 12 carbon atoms optionally substituted bicycloalkyl of 5 to 10 carbon atoms, aryl of 6, 10 or 14 carbon atoms, benzyl , optionally substituted benzyl, or heterocyclyl;
RcRd together with the nitrogen atom to which each is attached represent an optionally substituted heterocyclyl ring from 3 to 8 ring atoms optionally substituted in which one -Chfe- may also be replaced by -O-, -S-, or-NR' where R1 is H or alkyl of 1 to 12 carbon atoms;
R4 is H, optionally substituted alkyl of 1 to 12 carbon atoms, optionally substituted alkoxy of 1 to 12 carbon atoms, amino, alkyl amino of 1 to 12 carbon atoms, dialkylamino of 1 to 12 carbon atoms, alkylthio of 1 to 12 carbon atoms, halogen, cyano, carboxy, alkoxycarbonyl of 2 to 12 carbon atoms, heterocyclyl, halogen, carbamoyl, optionally substituted aryl of 6, 10 or 14 carbon atoms, or-CF3;
provided that when: a) R1 is diethylamino, R3 is chloro, R4 is hydrogen, R2 is not 4-trifluoromethylphenyl, 3,4-dichlorophenyl, 4-chlorophenyl, 3-chloro-4-methoxyphenyl; b) R1 is diethylamino, R3is bromo, R4is hydrogen, R2is not 4-trifluoromethylphenyl; c) R1 is isopropylamino, R3 is chloro, R4 is hydrogen, R2 is not 2-benzyloxyphenyl or 3,4,5-trimethoxyphenyl; d) R1 is
-176-

cyclopentylamino, R3is chloro, R4is hydrogen, R2is not 3,4,5-
trimethoxyphenyl, 2-napthyl or 2-stilbene; e) R1 is 2-amino-
bicyclo(2.2.1.)heptyl, R3is chloro, R4is hydrogen, R2is not 3,4,5-
trimethoxyphenyl and f) R1 is diethylamino, R3 is chloro, R4 is hydrogen, R2 is
not 4-trifluoromethylphenyl and g) R1 is 1,1,1-trifluoroethoxy, R3 is chloro, R4
is hydrogen, R2 is not 2-chloro-6-fluorophenyl h) R1 is -SO2ethyl or
-SO2cyclopentyl, R3 is chloro, R4 is hydrogen, R2 is not 2-chloro-6-
fluorophenyl; i) R4is hydrogen, R2is 2-chloro-6-fluorophenyl, R1 and R3are
not 1,2,4-triazole; j) R1 is cyclohexyl, R4 is hydrogen, R2 is 2,4,6-
trifluorophenyl, and R3 is not -OCH2O2C(CH3)3; k) R1 is 2-thienyl, R4
is ethyl, R3 is hydrogen and R2 is not 2-methoxyphenyl, 4-methoxyphenyl, and 4-trifluorophenyl; I) R2 is phenyl, R3 is chloro, R4 is hydrogen R1 is not (2E)-3,7-dimethyl-2,6-octadienyl
or a pharmaceutically acceptable salt thereof; in association with a pharmaceutically acceptable carrier.
2. A pharmaceutical composition as claimed in claim 1, subject to the proviso
that R2 is optionally substituted thienyl or to the proviso that R1 is other than
optionally substituted alkyl or the moiety -NRaRb or to the proviso that R1 is
the moiety -NRaRb wherein RaRb are optionally taken together with the
nitrogen to which each is attached; R2 is optionally substituted phenyl; R3 is
halogen, alkoxy of 1 to 12 carbon atoms, -NRcRd , haloalkoxy of 1 to 12
carbon atoms, alkylthio of 1 to 12 carbon atoms, cyano, or -N3; and R4 is H.
3. A pharmaceutical composition according to claim 1 or 2 wherein R1 is the
moiety -NRaRb wherein RaRb are optionally taken together with the nitrogen
to which each is attached; R2 is optionally substituted phenyl; R3 is halogen,
alkoxy of 1 to 12 carbon atoms, -NRcRd, haloalkoxy of 1 to 12 carbon atoms,
alkylthio of 1 to 12 carbon atoms, cyano, or-N3; and R4 is H.
-177-

4. A pharmaceutical composition according to any preceding claim, wherein
R1 is selected from the group consisting of an optionally substituted alkyl of 1
to 12 carbon atoms, optionally substituted alkenyl of 2 to 12 carbon atoms,
optionally substituted alkynyl of 2 to 12 carbon atoms, optionally substituted
alkadienyl of 4 to 12 carbon atoms, optionally substituted aryl of 6, 10 or 14
carbon atoms, optionally substituted bicycloalkyl of 5 to 10 carbon atoms,
optionally substituted cycloalkyl of 3 to 8 carbon atoms in which one -CH2-
may also be replaced by -O-, -S-, or -NR' where R' is H or an alkyl group of 1
to 12 carbon atoms, optionally substituted cycloalkenyl of 5 to 10 carbon
atoms in which one -CH2- may also be replaced by-O-, -S-, or-NR' where
R' is H or an alkyl group of 1 to 12 carbon atoms, -S-aryl of 6, 10 or 14 carbon
atoms, -S-alkyl of 1 to 12 carbon atoms, -S-alkenyl of 2 to 12 carbon atoms,
-SO2aryl of 6, 10 or 14 carbon atoms, -SO2cycloalkyl of 3 to 8 carbon atoms,
-SO2alkyl of 1 to 12 carbon atoms, -O-aryl of 6, 10 or 14 carbon atoms, and
the moiety -NRaRb or a pharmaceutically acceptable salt thereof.
5. A pharmaceutical composition according to any preceding claim, wherein
Ra and Rb each independently represent the moiety -C*H(Re)(Rf) where Re
and Rf independently represent an optionally halo-substituted alkyl group of 1
to 12 carbon atoms where C* represents the (R) or (S) isomer or a
pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition according to any preceding claim, wherein
R3 is halogen, alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms,
aryloxy, -NRcRd, benzyloxy, aralkyloxy, haloalkoxy of 1 to 12 carbon atoms,
alkylthio of 1 to 12 carbon atoms, hydroxy, cyano, amino, alkylamino of 1 to
12 carbon atoms, dialkylamino of 1 to 12 carbon atoms, or-N3 or a
pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition according to any preceding claim, wherein
R4 is H, optionally substituted alkyl of 1 to 12 carbon atoms, optionally
-178-

substituted alkoxy of 1 to 12 carbon atoms, amino, alkyl amino of 1 to 12 carbon atoms, dialkylamino of 1 to 12 carbon atoms, -CF3 or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition according to any preceding claim, R1 is selected from the group consisting of an optionally substituted alkyl of 1 to 12 carbon atoms, optionally substituted alkenyl of 2 to 12 carbon atoms, optionally substituted alkynyl of 2 to 12 carbon atoms, optionally substituted alkadienyl of 4 to 12 carbon atoms, optionally substituted aryl of 6, 10 or 14 carbon atoms, optionally substituted bicycloalkyl of 5 to 10 carbon atoms, optionally substituted cycloalkyl of 3 to 8 carbon atoms in which one -CH2-may also be replaced by -O-, -S-, or -NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, optionally substituted cycloalkenyl of 5 to 10 carbon atoms in which one -CH2- may also be replaced by -O-, -S-, or -NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, -S-aryl of 6, 10 or 14 carbon atoms, -S-alkyl of 1 to 12 carbon atoms, -S-alkenyl of 2 to 12 carbon atoms, -SO2aryl of 6, 10 or 14 carbon atoms, -SC^cycloalkyl of 3 to 8 carbon atoms, -SO2alkyl of 1 to 12 carbon atoms, -O-aryl of 6, 10 or 14 carbon atoms, and the moiety -NRaRb wherein RaRb are optionally taken together with the nitrogen to which each is attached or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition according to any preceding claim, wherein
R3 is halogen, alkoxy of 1 to 12 carbon atoms, -NRcRd, haloalkoxy of 1 to 12
carbon atoms, alkylthio of 1 to 12 carbon atoms, cyano, amino, alkylamino of
1 to 12 carbon atoms, dialkylamino of 1 to 12 carbon atoms, or-N3.
10. A pharmaceutical composition according to any preceding claim, wherein
R4 is H, optionally substituted alkyl of 1 to 12 carbon atoms, amino, alkyl
-179-

12. A pharmaceutical composition according to any preceding claim, wherein R2 is optionally substituted phenyl or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition according to any preceding claim, wherein
R3 is halogen, alkoxy of 1 to 12 carbon atoms, -NRcRd, haloalkoxy of 1 to 12
carbon atoms, alkylthio of 1 to 12 carbon atoms, cyano, or -N3 or a
pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition according to any preceding claim, wherein
R4 is H or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition according to any preceding claim, wherein
R1 is selected from the group consisting of an optionally substituted cycloalkyl
of 3 to 8 carbon atoms in which one -CH2- may also be replaced by -O-, -S-,
-180-

or-NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, optionally substituted cycloalkenyl of 5 to 10 carbon atoms in which one -CH2- may also be replaced by -O-, -S-, or -NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, -S-aryl of 6, 10 or 14 carbon atoms, -S-alkyl of 1 to 12 carbon atoms, -S-alkenyl of 2 to 12 carbon atoms, -SO2aryl of 6, 10 or 14 carbon atoms, -SOacycloalkyI of 3 to 8 carbon atoms, -SO2alkyl of 1 to 12 carbon atoms, and the moiety -NRaRb wherein RaRb are optionally taken together with the nitrogen to which each is attached; R2 is optionally substituted phenyl; R3 is halogen, alkoxy of 1 to 12 carbon atoms, -NRcRd, haloalkoxy of 1 to 12 carbon atoms, alkylthio of 1 to 12 carbon atoms, cyano, or -N3; R4 is H or a pharmaceutically acceptable salt thereof.
16. A pharmaceutical composition according to any preceding claim, wherein R1 is the moiety -NRaRb wherein RaRb are optionally taken together with the nitrogen to which each is attached; R2 is optionally substituted phenyl;
R3 is halogen, alkoxy, -NRcRd, haloalkoxy of 1 to 12 carbon atoms, alkylthio of 1 to 12 carbon atoms, cyano, or-N3; R4 is H;
Ra is H, optionally substituted alkyl of 1 to 12 carbon atoms, optionally substituted alkenyl of 2 to 12 carbon atoms, optionally substituted alkadienyl of 4 to 12 carbon atoms, optionally substituted cycloalkyl of 3 to 8 carbon atoms, in which one -CH2- may also be replaced by -O-, -S-, or-NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, optionally substituted cycloalkenyl of 5 to 10 carbon atoms, in which one -CH2- may also be replaced by-O-, -S-, or-NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, haloalkyl of 1 to 10 carbon atoms, aryl of 6, 10 or 14 carbon atoms, heterocyclyl, benzyl, optionally substituted benzyl; Rb is H, an optionally substituted alkyl of 1 to 12 carbon atoms, optionally substituted alkenyl of 2 to 12 carbon atoms, optionally substituted alkadienyl of 4 to 12 carbon atoms, optionally substituted aryl of 6, 10 or 14 carbon atoms,
-181-

optionally substituted cycloalkyl of 3 to 8 carbon atoms in which one -CH2-may also be replaced by-O-, -S-, or-NR' where R' is H or an alky! group of 1 to 12 carbon atoms, optionally substituted cycloalkenyl of 5 to 10 carbon atoms in which one -CH2- may also be replaced by-O-, -S-, or-NR' where R' is H or an alkyl group of 1 to 12 carbon atoms, -S-aryl of 6,10 or 14 carbon atoms, -S-alkyl of 1 to 12 carbon atoms, -S-alkenyl of 2 to 12 carbon atoms, -SO2aryl of 6,10 or 14 carbon atoms, -SO2cycloalkyl of 3 to8 carbon atoms, -SO2alkyl of 1 to 12 carbon atoms, -O-aryl of 6, 10 or 14 carbon atoms; RaRb together with the nitrogen atom to which each is attached represent an optionally substituted saturated or unsaturated heterocyclyl ring from 3 to 12 ring atoms in which optionally, at least one -CH2- may also be replaced by -O-, -S-, or-NR where R is H or an alkyl group of 2 to 12 carbon atoms, said saturated or unsaturated heterocyclyl ring may optionally be aryl or cycloalkyl fused;
Rc is H, amino, optionally substituted alkyl of 1 to 12 carbon atoms, haloalkyl of 1 to 10 carbon atoms, optionally substituted alkenyl of 2 to 12 carbon atoms, optionally substituted alkadienyl of 4 to 12 carbon atoms, optionally substituted cycloalkyl of 3 to 8 carbon atoms, in which one -CH2- may also be replaced by -O-, -S-, or -NR where R is H or an alkyl group of 1 to 12 carbon atoms optionally substituted cycloalkenyl of 5 to 10 carbon atoms, in which one -CH2- may also be replaced by -O-, -S-, or -NR where R is H or an alkyl group of 1 to 12 carbon atoms optionally substituted bicycloalkyl of 5 to 10 carbon atoms, aryl of 6, 10 or 14 carbon atoms, benzyl, optionally substituted benzyl, or heterocyclyl;
Rd is H, amino, optionally substituted alkyl of 1 to 12 carbon atoms, haloalkyl of 1 to 10 carbon atoms, optionally substituted alkenyl of 2 to 12 carbon atoms, optionally substituted alkadienyl of 4 to 12 carbon atoms, optionally substituted cycloalkyl of 3 to 10 carbon atoms, in which one -CH2- may also be replaced by -O-, -S-, or-NR where R is H or an alkyl group of 1 to 12
-182-

carbon atoms optionally substituted cycloalkenyl of 5 to 10 carbon atoms, in which one -CH2- may also be replaced by -O-, -S-, or -NR where R is H or an alkyl group of 1 to 12 carbon atoms optionally substituted bicycloalkyl of 5 to 10 carbon atoms, aryl of 6, 10 or 14 carbon atoms, benzyl, optionally substituted benzyl, heterocyclyl;
RcRd together with the nitrogen atom to which each is attached represent an optionally substituted heterocyclyl ring from 3 to 8 ring atoms optionally substituted in which one -CH2- may also be replaced by-O-, -S-, or-NR' where R' is H or alkyl of 2 to 20 carbon atoms or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition according to any preceding claim, wherein R1 is the moiety -NRaRb wherein RaRb are optionally taken together with the nitrogen to which each is attached;
R2 is selected from

-183-


-184-


-185-


-186-


-187-


-188-


R3 is halogen, alkoxy, -NRcRd, haloalkoxy of 1 to 12 carbon atoms, alkylthio of 1 to12 carbon atoms, cyano, or -N3; R4 is H or a pharmaceutically acceptable salt thereof
18. A pharmaceutical composition according to any preceding claim, wherein R1 is the moiety -NRaRb wherein RaRb are optionally taken together with the nitrogen to which each is attached and wherein R1 is selected from
-189-


-190-


-191-


-192-


-193-


-194-

R2 is optionally substituted phenyl;
R3 is halogen, alkoxy of 1 to 12 carbon atoms, -NRcRd, haloalkoxy of 1 to 12 carbon atoms, alkylthio of 1 to 12 carbon atoms, cyano, or -N3; R4 is H or a pharmaceutically acceptable salt thereof.
-195-
19. A pharmaceutical composition according to any preceding claim, wherein R1 is the moiety -NRaRb wherein RaRb are optionally taken together with the nitrogen to which each is attached and wherein R1 is selected from



-196-


-197-


-198-


-199-

R2 is optionally substituted thienyl;
R3 is halogen, alkoxy of 1 to 12 carbon atoms, -NRcRd, haloalkoxy of 1 to 12 carbon atoms, alkylthio of 1 to 12 carbon atoms, cyano, or-N3; R4 is H or a pharmaceutically acceptable salt thereof.
20. A pharmaceutical composition according to any preceding claim, wherein said substituted triazolopyrimidine derivative is selected from:
7-(1-azepanyl)-5-chloro-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2,6-difluorophenyl)-7-(4-methyl-1-piperidinyl)[1,2,4]triazolo[1,5-ajpyrimidine;
5-chloro-6-(4-methoxyphenyl)-7-(1 -piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-(4-methyl-1-piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
7-(1 -azepanyl)-5-chloro-6-(2-chloro-6-fluorophenyl)[1,2,4]triazolo[1,5-ajpyrimidine;
5-chloro-6-(2-ch!oro-6-fluorophenyl)-7-(2-methyl-1-piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chioro-6-fluorophenyl)-7-(4-thiomorpholinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
methyl [[5-chloro-6-(2-chloro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-yl](methyl)amino]acetate;
-200-

5-chloro-6-(2-chloro-6-fluorophenyl)-N-(1,1,3,3-tetramethylbutyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
7-(1-azepanyI)-5-chloro-6-(4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
7-(1 -azepanyl)-6-(4-bromophenyl)-5-chloro[1,2,4]triazolo[1,5-a]pyrimidine; 5-chloro-7-(1 -piperidinyl)-6-[2-(trifluoromethyl)phenyl][1,2,4]triazolo[1,5-a]pyrimidine;
6-(4-tert-butylphenyl)-5-chloro-7-(4-methyl-1-piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(4-methoxyphenyl)-7-(4-methyl-1-piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(4-methoxyphenyl)-7-(3-methyl-1 -piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
6-(4-bromophenyl)-5-chloro-7-(3-methyl-1 -piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(3,4-difIuorophenyl)-7-(4-methyl-1-piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2,6-dichlorophenyl)-7-(2-methyl-1-pyrrolidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chlorophenyl)-7-(2-methyl-1 -pyrrolidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
-201-

7-(1-azepanyl)-5-chloro-6-(3-chloro-4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(3-chloro-4-methoxyphenyl)-7-(4-methyl-1-piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(3-chloro-4-methoxyphenyl)-7-(2-methyl-1-piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
6-(4-tert-butylphenyl)-5-chloro-7-(2-methyl-1 -piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-7-(2-methyl-1-piperidinyl)-6-[3-(trifluoromethyl)phenyl][1,2,4]triazolo[1,5-a]pyrimidine;
Diethyl 2-[6-(2,6-difluorophenyl)-5-ethoxy[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]malonate;
7-(azepanyl)-5-chloro-6-{2-chloro-6-nitrophenyl}[1,2,4}triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyl)-N-ethyi-N-(2-methyl-2-propenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2-chloro-6-fluorophenyl)-N-(2,2,2- trifluoroethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2-chloro-6-fluorophenyl)-N-[(2,2-dichlorocyclopropyl)methyl]-N-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
1 -[5-chloro-6-(2-chloro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]-3-piperidinol;
-202-

N-bicyclo[2.2.1]hept-2-yl-5-chloro-6-(3-chloro-4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2,5-difluorophenyl)-N-dodecyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-7-(4-methyl-1-piperidinyl)-6-(2,3,6- trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
N-[5-chIoro-6-(2,3,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]-N-isopropylamine;
5-chloro-N-ethyl-N-(2-methyi-2-propenyl)-6-(2,3,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
N-allyl-5-chloro-6-(2-chloro-6-fluorophenyl)-N-(2-methyl-2-propenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2-chloro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(3-chloro-4-methoxyphenyl)-N-cycloheptyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(3-chloro-4-methoxyphenyl)-7-(3,3-dimethyl-1-piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-N-(3-chloropropyl)-N-methyl-6-(2,3,6-trif!uorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
7-(1 -azocanyl)-5-chloro-6-(2,3,6-trif!uorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
-203-

5-chloro-6-(2,6-difluorophenyl)-7-(3,6-dihydro-1(2H)-pyridinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
7-(1-azocanyl)-5-chloro-6-(2!6-difluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-methoxy-6-(2-chloro-6-fluorophenyl)-7-(4-methyl-1-piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
[5-chloro-6-(2-chloro-6-fluorophenyl)[1,2,4]triazo!o[1,5-a]pyrimidin-7-yljmethanol;
1 -[5-chloro-6-(2,6-difluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]-4-piperidinol;
5-chloro-7-(4-chloro-1 -piperidinyl)-6-(2,6-difluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-7-(4-thiomorpholinyl)-6-(2,3,6-trifluorophenyl)[1I2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2,6-difluorophenyl)-7-(2,4-dimethyl-1-piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
7-(4-rnethyl-1-piperidinyl)-5-amino-6-(2-chloro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chioro-6-(2,6-difluorophenyl)-7-(2,5-dihydro-1H-pyrrol-1-yl)[1,2,4]triazolo[1,5-a]pyrimidine;
-204-

5-ch!oro-6-(2-chloro-6-fluorophenyl)-7-(2,5-dimethyl-2,5-dihydro-1H-pyrrol-1-yl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-(2-ethyl-1H-imidazol-1-yl)[1,2,4]triazolo[1,5-a]pyrimidine;
7-(4-bromo-1-piperidinyl)-5-chloro-6-(2-chloro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-methylphenyl)-7-(4-thiomorpholinyl)[1,2l4]triazolo[1,5-a]pyrimidine;
6-(2-bromophenyl)-N-(sec-butyl)-5-chloro[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N-ethyl-6-(4-methoxyphenyl)-N-(2-methyl-2-propenyl)[1,2,4]triazolo[1,5- a]pyrimidin-7-amine;
5-chloro-6-(4-methoxyphenyl)-7-(4-thiomorpholinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-7-(4-chloro-1-piperidinyl)-6-[2-(trifluoromethyl)phenyl][1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-[4-(trifluoromethyl)-1-piperidinyl][1,2,4]triazolo[1,5-a]pyrimidine;
7-(4-bromo-1 -piperidinyl)-5-chloro-6-(2,6-difluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
-205-

7-(4-bromo-1 -piperidinyl)-5-chloro-6-(2-ch!orophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-ch!oro-N-ethyl-N-(2-methyi-2-propenyl)-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N-isopropyl-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5- a]pyrimidin-7-amine;
5-chloro-7-(4-thiomorpholinyl)-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
7-(1 -azepanyl)-5-chloro-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-[2-(1 -pyrrolidinyl)-1 -cyclopenten-1 -yl][1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-7-(4-isopropyl-1 -piperidinyl)-6-(4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-7-(2,4-dimethyl-1 -piperidinyl)-6-(4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-7-[ethyl(2-methyl-2-propenyl)amino]-6-{4-nitrophenyi}[1,2,4]triazolo[1,5-a]pyrimidine;
7-(1 -azepanyl)-5-chloro-6-{4-nitrophenyl}[1,2,4]triazolo[1,5-a]pyrimidine;
N-bicyclo[2.2.1]hept-2-yl-5-chloro-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-
a]pyrimidin-7-amine;
-206-

5-chloro-6-(2,6-difluorophenyl)-N-(2,2,2-trifluoroethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2-chlorophenyl)-N-(2,2,2-trifluoroethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2-chloro-6-fluorobenzyl)-7-tetrahydro-2-furanyl[1,2,4]triazolo[1,5-a]pyrimidine;
7-(allylsuifanyl)-5-chloro-6-(2-chloro-6-f!uorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-N-ethyl-6-mesityl-N-(2methyl-2-propenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N-ethyl-6-(2-methoxyphenyl)-N-(2-methyl-2-propenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2-chloro-6-fluorophenyl)-N-hexyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-7-(4-methy!-1-piperidinyl)-6-[4-(methylsulfanyl)phenyl][1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-N-ethyl-N-(2-methyl-2-propenyl)-6-[4-(methylsulfanyl)phenyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
N-(sec-butyl)-5-chloro-6-[4-(methylsulfanyl)phenyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
-207-

5-chloro-6-[4-(methylsulfanyl)phenyl]-7-(4-thiomorpho!inyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-[2,6-dichloro-4-trifluoromethyl)phenyl]-7-(4-methyl-1-piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
7-(1-azepanyl)-5-chloro-6-[2,6-dich!oro-4-(trifluoromethyl)pheny!][1,2,4]triazo!o[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-[(2,2,2-trifluoroethyl)suifanyl][1,2,4]triazoio[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-(4,4-dimethyi-1-piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-[2,6-dichloro-4-(trifluoromethyl)phenyl]-N-ethyl-N-(2-methyl-2-propenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-[2,6-dichloro-4-(trifluoromethyl)phenyl]-7-(4-thiomorpholinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(3,5-difluorophenyl)-7-(4-methyl-1 -piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-(isopropylsulfanyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-tetrahydro-2-furanyl[1,2,4]triazolo[1,5-a]pyrimidine;
4-[5-chloro-7-(4-methyl-1-piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]aniline;
-208-

N-{4-[5-chloro-7-(4-methyl-1 -piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]phenyl}acetamide;
[5-chloro-6-(2-chloro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]methyl acetate;
5-chloro-6-(2-ch!oro-6-fluorophenyl)-7-(chloromethyl)[1,2)4]triazolo[1,5-a]pyrimidine;
diethyl 2-[6-(2-chloro-6-fluorophenyl)-7-(4-methyl-1 -piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]malonate;
7-(1 -azepanylmethyl)-5-chloro-6~(2-chloro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
N-allyl-5-chloro-6-(2-chloro-6-fluoropheny!)-N-hexyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-7-(4-methyl-1-piperidinyl)-6-[4-(trifluoromethoxy)phenyl][1,2,4]triazolo[1,5-a]pyrimidine; 5-chloro-7-(4-methyl-1 -piperidinyl)-6-(4-phenoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chioro-6-fluorophenyi)-N-(cyciopropylmethyl)-N-propyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-7-(2-methyl-1 -piperidinyl)-6-(4-phenoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-{2-chloro-4-nitrophenyl}-7-(4-methyl-1-piperidinyl)[1,2,4]triazo!o[1,5-a]pyrimidine;
-209-

5-chloro-6-(4-ch!oro-2,3,5,6-tetrafluorophenyl)-N-cyclopentyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
4-[5-chloro-2-methyl-7-(4-methyl-1-piperidinyl)[1,2,4]triazolo[1,5-a]pyrirnidin-6-yl]-N,N-dimethylaniline;
6-(2-chloro-6-fluorophenyl)-5-methyl-7-(4-methyl-1-piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-[2-(1 -pyrrolidinyl)-1 -cyclohexen-1 -yl][1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-(methoxymethyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-{2-chloro-4-nitrophenyl}-7-[ethyl(2-methyl-2-propenyl)amino][1,2,4]triazolo[1,5-a]pyrimidine;
5-bromo-6-(2-chloro-6-fluorophenyl)-7-(isopropylsu!fanyl)[1,2,4]triazo!o[1,5-a]pyrimidine;
5-chloro-N-cyclopentyl-6-(4-ethoxy-2,3,5,6-tetrafluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N-methyl-N-(2-methyl-2-propenyl)-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
4-bromo-1-[5-chloro-6-(2-chloro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]butyl acetate;
-210-

diethyl 2-allyl-2-{[5-chloro-6-(2-chloro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]oxy}malonate;
6-(2-chloro-6-fluorophenyl)-N-ethyl-5-methyl[1,2,4]triazoio[1,5-a]pyrimidin- 7-amine;
N-butyl-5-chloro-N-ethyl-6-(2,3,4,5,6-pentafluoraphenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
6-(2-chloro-6-fluorophenyl)-5-(difluoromethoxy)-7-(4-methyl-1-piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-[(4-chlorophenyl)sulfanyl][1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-[(2-methoxyphenyl)sulfanyl][1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-ch!oro-6-fluorophenyl)-N-(1,2,2-trimethylpropyl)[1,2,4]triazo!o[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2,3,4,5,6-pentafluorophenyl)-N-(1,2,2-trimethylpropyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2,4,6-trifluorophenyl)-N-(1,2,2-trimethylpropyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(4-fluoropheny!)-N-(1,2,2- trimethylpropyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
-211-

5,7~bis(4-methyl-1 -piperidinyl)-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-methylphenyl)-N-(1,2,2-trimethylpropyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2,4,5-trifluorophenyl)-N-(1,2,2-trimethylpropyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
6-(2-bromophenyl)-5-chloro-N-(1,2,2-trimethylpropyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N-isobutyl-N-(2,2,2-trifluoroethyl)-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N-isobutyl-6-(2-methylphenyl)-N-(2,2,2-trifluoroethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2-chloro-6-fluorophenyl)-N-(2,2,2-trifluoro-1-methylethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2,6-difluorophenyl)-N-(2,2,2-trifluoro-1-methylethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N-(2,2,2-trifluoro-1-methylethyl)-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
N-allyl-5-chloro-N-isobutyl-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
-212-

5-chloro-N-(1,2-dimethylpropyl)-6-(2,4,6-trifluorophenyI)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N-isopropyl-N-methyl-6-(2,4,6-trif!uorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N-isopropyl-N-(2)2,2-trif!uoroethyl)-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
7-butyl-5-chloro-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-N-(1 -phenylethyl)-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2-chlorophenyl)-N-(2,2,2-trifluoro-1-methylethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N-ethyl-N-isobutyl-6-(2,4,6-trif!uorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2-chloro-6-fluorophenyi)-7-hexyl[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-methylphenyl)-N,N-bis(2,2)2-trifluoroethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N-cyclopentyl-N-methyl-6-(2,3,4,5,6-pentafluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
7-butyl-5-chloro-6-(2,6-difluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
-213-

5-chloro-N-(1,2-dimethylpropyl)-N-methyl-6-(2,3,4,5,6-pentafluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-phenyl[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-(2-methylpropanyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-pentyl[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-N-(1,2-dimethylpropyl)-N-methyl-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2-ch!oro-6-fluorophenyl)-7-cyclohexyl[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-bromo-5-chlorophenyl)-N-(2l2,2-trifluoro-1-methylethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-(3,3,3-trifluoropropyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-ch!oro-6-fluorophenyl)-7-(3-methylphenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
[5-chloro-6-(2l4,6-trifluorophenyl)-[1,2,4jtriazolo[1,5-a]pyrimidin-7-yl]-(1 -p-tolyl-ethyl)-amine;
5-chloro-6-(2,4,6-trifluoro-phenyl)-7-cyclohexyl[1,2,4]triazolo[1,5-a]pyrimidine;
-214-

5-chloro-7-cyclohexyl-6-(2,3,4,5,6-pentafluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-(4,4-difluoro-1-piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
7-(bicyclo[2.2.1]hept-2-ylamino)-5-chloro-6-{2-fluoro-4-nitrophenyl}[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-{2-fluoro-4-nitrophenyl}-7-(4-methyl-1-piperidinyi)[1,2,4]triazolo[1,5-a]pyrimidine;
5-(methylsulfanyi)-6-(2-chloro-6-fluorophenyl)-7-cyclohexyl[1,2,4]triazolo[115-a]pyrimidine;
[5-chloro-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-yl] (2,2,2-trifluoro-1-phenylethyl)-amine;
5-chloro-N-[1-(trifluoromethyl)propyl]-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-bromo-6-(2-chloro-6-fluorophenyl)-7-cyclohexyl[1,2,4]triazolo[1,5-a]pyrimidine;
6-(2-chloro-6-fluorophenyl)-7-cyclohexyl[1,2,4]triazolo[1,5-a]pyrimidin-5-amine;
[5-chloro-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]-(2-methyl-1-trifluoromethyl-propyl)amine;
-215-

5-chloro-7-(3-cyclohexen-1 -yl)-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-7-(1 -cyclohexen-1 -yl)-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
6-(2,4-difluorophenyl)-5-chloro-N-(2,2,2-trifluoro-1-methylethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2,6-difluoro-4-methoxyphenyl)-7-(4-methyl-1-piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2,6-difluoro-4-methoxyphenyl)-N-(2,2,2-trifluoro-1-methylethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-7-cyclohexyl-6-(2,6-difluoro-4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2,6-difluoro-4-methoxyphenyl)-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
7-cyclohexyl-6-(2,6-difluoro-4-methoxyphenyl)-5-methoxy[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-7-(4-fluorocyclohexyi)-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2,6-dichloro-4-fluorophenyl)-7-(3,3,3-trifluoropropyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
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N-(sec-butyl)-5-chloro-6-(2,6-dichloro-4-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
4-{5-chloro-7-[(2,2,2-trifluoro-1 -methylethyl)amino][1,2,4]triazolo[1,5-a]pyrimidin-6-yl]-3,6-difluorophenol;
5-chloro-7-(3-cyclohexen-1-yl)-6-(2,6-difluoro-4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2,6-difluoro-4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N-cyclopentyl-6-(2,6-difluoro-4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2,6-difluoro-4-methoxyphenyl)-7-(3,6-dihydro-1(2H)-pyridinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2,6-difluoro-4-methoxyphenyl)-7-(4-thiomorpholinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
7-(1 -azepanyl)-5-chloro-6-(2,6-difluoro-4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2,6-difluoro-4-methoxyphenyl)-N-(1,2,2-trimethylpropyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2,6-difluoro-4-methoxyphenyl)-N-ethyl-N-(2-methyl-2-propenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
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5-chloro-6-(2,6-difluoro-4-methoxyphenyl)-7-(4-fluorocyclohexyl)[1,2,4]triazolo[1,5-a]pyrimidine;
6-(4-{5-chloro-7-[(2,2,2-trifluoro-1 -methylethyl)amino][1,2,4]triazolo[1,5-a]pyrimidin-6-yl}-3,5-difluorophenoxy)hexanoicacid;
2,6-difluoro-4-(2-fluoroethoxy)phenyl]-N-(2,2,2-trifluoro-1-methylethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N-isopropyl-6-{2-[(trifluoronnethyl)sulfanyl]phenyl}[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N-[4-(trifluoromethyl)phenyl]-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N-(4,4,4-trifluoro-2-methylbutyl)-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2,6-difluoro-4-methoxyphenyl)-7-(3-methyl-3-butenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2,6-difluoro-4-methoxyphenyl)-7-isobutyl[1,2,4]triazolo[1J5-a]pyrimidine;
7-cyclopentyl-6-(2,6-difluoro-4-methoxyphenyl)-5-methoxy[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-thienyl)-N-[(1 R)-2,2,2-trifluoro-1-methylethyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
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4-(5-chloro-7-(2,2,2-trifluoro-1 -methyl-ethylamino)[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]-3,5-difluoro-phenol;
{5-chloro-6-[2,6-difluoro-4-(2,2,2-trifluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-(2,2,2-trifluoro-1-methyl-ethyl)amine;
5-chloro-6-{2,6-difluoro-4-(methoxyphenyl)-N-(2,2,2-trifluoro-1-methylethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
(5-chloro-6-{4-[2-(2-ethoxyethoxy]-ethoxy]-2,6-difluoro-phenyl}[1,2,4]triazolo[1,5-a]pyrimidin-7-yl-)-(2,2,2-trifluoro-1 -methylethyl)amine;
(5-chloro-6-{2,6-difluoro-4-[2-(2-methoxy-ethoxy)ethoxy]-phenyl}-
[1,2,4]triazolo[1,5-a]pyrimidin-7-yl-)-(2,2,2-trifluoro-1 -methylethyl)amine;
5-chioro-6-[2,6-difluoro-4-(3-furan-3-ylmethoxy)phenyl[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-N-(2,2,2-trifluoro-1-methylethyl)amine;
5-chloro-6-(2,5-difluoro-4-methoxyphenyl)-N-(1,2,2-trimethylpropyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
7-cyclohexyl-6-[2,6-difluoro-4-(2-methoxyethoxy)phenyl]-5-methoxy[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-fluoro-4-methoxy-6-chlorophenyl)-N-(2>2,2-trifluoro-1-methylethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-[2,6-difluoro-4-(2-fluoroethoxy)phenyl]-N-ethyl-N-(2-methyl-2-propenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
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2-[2-(4-{5-chloro-7-[(2,2,2-trifluoro-1 -methylethyl)amino][1,2,4]triazolo[1,5-a]pyrimidin-6-yl}-3,5-difluorophenoxy)ethoxy]ethanol;
5-chloro-6-(2,3-difluoro-4-methoxyphenyl)-N-(2,2,2-trifluoro-1-methylethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-{4-(2-fluoroethoxy)-2,6-difluorphenyl}-N-(2,2,2-trifluoro-1-methylethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N-(4-chlorobenzyl)-6-(2-chloro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-[4-(2-pyridinyl)-1-piperazinyl][1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyl)-N-(1 -ethylpentyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-[4-(2-chlorophenyl)-1-piperazinyl][1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-[4-(4-methoxyphenyl)-3-methyl-1-piperazinyl][1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-N-cyclopentyl-6-(2-chloro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-7-phenoxy-6-(4-methoxy-phenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-N-cyc!opentyi-6-(4-methylphenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
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5,7-diphenoxy-6-(4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-N-cyclopentyl-6-(2-chlorophenyl)[1!2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N,N-diethyl-6-[4-methoxyphenyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N,N-diethyl-6-[2,4-dich!orophenyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
N-bicyclo[2.2.1]hept-2-yl-5-chloro-6-(2,4-dichlorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-(2-chloro-6-fluorophenyl)-7-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-cyano-7-(4-methyl-1-piperidinyl)-6-(2-chloro-5-fluorophenyl)[1 !2,4]triazolo[1,5-a]pyrimidine;
5-(methylsulfanyl)-7-(4-methyl-1-piperidinyl)-6-(2-chloro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-(methylsulfanyl)-7-(4-methyl-1-piperidinyl)-6-(2-chloro-5-(methylsulfanyl)phenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-7-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)-6-(4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
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5-chloro-N-ethyl-N-(2-methyl-2-propenyl)-6-(4-(methylsulfanyl)phenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
2-methyl-6,7-di-(4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
2-methyl-6-phenyl-7-(4-chlorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
2-trifluoromethyl-6-phenyl-7-(4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(3,4-difluorophenyl)-N-(isopropyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-bromo-6-(4-bromophenyl)-7-dimethylamino[1,2,4]triazolo[1,5-a]pyrimidine;
5-bromo-6-(4-trifluoromethylphenyl)-7-dimethylamino[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(3,4-difluorophenyl)-7-dimethylamino[1,2,4]triazolo[1,5-a]pyrimidine;
5-chloro-6-(4-trifluoromethylphenyl)-N-(ethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
7-(1 -azepanyl)-5-chloro-6-(4-tert-butylphenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
ethyl {[5-chloro-6-(2-chloro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]amino}acetate;
diethyl 5-chloro-6-(2,6-difluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-malonate;
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5-chloro-6-(2,5-difluorophenyl)-N-(3-methyl-2-butenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
[5-chloro-6-(2-chloro-6-fluorophenyl)-[1,2,4]triazolo[1,5-a]pynmidin-7-yl]acetic
acid methyl ester;
5-chloro-6-(2,6-difluorophenyl)-7-(2-ethyl-1 H-imidazol-1 -yl)[1,2,4]triazolo[1,5-
a]pyrimidine;
5-chloro-N,N-diethyl-6-[4-(methylsulfanyl)phenyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
ethyl [6-(2-chloro-6-fluorophenyl)-7-(4-methyl-1-piperidinyl)- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl]acetate;
5-chloro-N-ethyl-N-(2-methyl-2-propenyl)-6-(4-phenoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
dimethyl 2-[5-chloro-6-(2-chloro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]malonate;
diethyl 2-{[5-chloro-6-(2-chloro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]oxy}-2-isobutylmalonate;
2-[5-chloro-6-(2-chloro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]-1,3-cyclohexanedione;
2-[5-chloro-6-(2-chloro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]cyclohexanone;
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5-chloro-7-(3-nitro-4-methylanilino)-6-(2, 4, 6-trifluorophenyl) [1,2,4]triazolo[1,5-a]pyrimidine;
7-cyclohexyl-6-[2,6-difluoro-4-(2-methoxyethoxy)phenyl]5-(2-methoxyethoxy)[1,2,4]triazolo[1,5-a]pyrimidine;
7-(3-bromophenyl)-2-ethyl-6-(4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
7-(3-bromophenyl)-6-(3-chlorophenyl)-2-ethyl[1,2,4]triazolo[1,5-a]pyrimidine;
7-(4-bromophenyl)-2-ethyl-6-[4-(trifluoromethyl)phenyl][1,2,4]triazolo[1,5-
a]pyrimidine;
5-chloro-6-(2-chloro-6-fluorophenyl)-N-(3,4,5-
trimethoxybenzyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
7-(2-benzyl-4,5-dihydro-1H-imidazol-1-yl)-5-chloro-6-(2-chloro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
N-4-[5-chloro-6-(2-chloro-6-fluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-yl-N,N-1-diethyl-1,4-pentanediamine;
5-chloro-N-(3-methyl-2-butenyl)-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-dimethylamino-6-phenyl-N-cyclopentyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-7-[(2-furylmethyl)suifanyl]-6-(4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidine;
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6-[1,1'-biphenyl]-4-yl-5-chloro-N-cyclopentyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
6-[4-(benzyloxy)phenyl]-5-chloro-N-isopropyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N-[(2,2-dichlorocyclopropyl)methyl]-6-(3,4,5-trimethoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
N-cyclopentyl-6-(2-fluorophenyl)-5-hydrazino[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N-ethyl-6-(2-methylphenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
6-(4-tert-butylphenyl)-5-chloro-N-isopropyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-[2,6-difluoro-4-[(3-methyl-2-butenyl)oxy]phenyl]-N-(2,2,2-trifluoro-1-methylethyl)-l[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-6-[2,6-difluoro-4-(1-propenyloxy)phenyl]-N-(2,2,2-trifluoro-1-methylethyl)-l[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-chloro-N-(3-tricyclo[2.2.1.02.6]hept-1-yl)-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine;
5-azido-7-cyclohexyl-6-(2-fluoro-6-chlorophenyl) [1,2,4]triazolo[1,5-a]pyrimidine;
5-azido-6-[2-chloro-6-fluorophenyl]-7-(4-methyl-1-piperidinyl)[1,2,4]triazolo[1,5-a]pyrimidine;
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2,5-dichloro-7-(4-methyl-1-piperidinyl)-6-[2-chloro-6-
fluorophenyl][1,2,4]triazolo[1,5-a]pyrimidine or a pharmaceutically acceptable
salt thereof.
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21. Pharmaceutical composition according to claim 21 wherein the 5-chloro-N-(2,2,2-trifluoro-1 -methylethyl)-6-(2,4,6- trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine is 5-chloro-N-[(1 R)-2,2,2-trifluoro-1 -methylethyl]-6-(2,4,6-rifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine or 5-chloro-N-[(1 S)-2,2,2-trifiuoro-1-methylethyl]-6-(2,4,6-rifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine.

The invention provides a method of treating of inhibiting the growth of cancerous tumour cells and associated diseases in a mammal in need thereof which comprises administering to said mammal an effective amount of a substituted triazolopyrimidine derivative or a pharmaceutically acceptable salt thereof and further provides a method of treating or inhibiting the growth of cancerous tumour cells and associated diseases in a mammal in need thereof by interacting with tubulin and microtubules and promoting microtubule polymerization which comprises administering to said mammal an effective amount of a substituted triazolopyrimidine derivative or a pharmaceutically acceptable salt thereof.