Pyrrole derivatives as PLK1 inhibitors

Abstract

The invention provides compounds of the formula (3): ##STR00001##
or a pharmaceutically acceptable salt or tautomer thereof, wherein:
Z is a 5-membered heteroaryl ring containing one or two nitrogen ring members and optionally one further heteroatom ring member selected from N and O;
ring X is a benzene or pyridine ring;
ring Y is a benzene, pyridine, thiophene or furan ring;
Ar.sup.1 is an optionally substituted benzene, pyridine, thiophene or furan ring;
m is 0, 1 or 2;
n is 0, 1 or 2;
R.sup.1 is selected from various substituents:
R.sup.2 is selected from hydrogen and a C.sub.1-4 hydrocarbon group;
R.sup.3 is selected from hydrogen and a C.sub.1-4 hydrocarbon group;
R.sup.4 is selected from various substituents;
R.sup.5 is selected from various substituents;
Ar.sup.2 is an optionally substituted phenyl, pyridyl or pyridone group;
R.sup.6 is a group Q.sup.1-R.sup.a—R.sup.b;
Q.sup.1 is absent or is a C.sub.1-3 saturated hydrocarbon linker;
R.sup.a is selected from O; C(O); C(O)O; CONR.sup.c; N(R.sup.c)CO; N(R.sup.c)CONR.sup.c, NR.sup.c; and SO.sub.2NR.sup.c;
R.sup.b is selected from hydrogen and various substituents;
and R.sup.7 is selected from R.sup.4. The compounds are useful in the treatment of cancers.

Claims

1. A compound of formula (3): ##STR00178## or a pharmaceutically acceptable salt or tautomer thereof, wherein: Z is selected from a pyrrole, pyrazole or isoxazole ring; ring X is a benzene or pyridine ring; ring Y is a benzene, pyridine, thiophene or furan ring; Ar.sup.1 is a benzene, pyridine, thiophene or furan ring optionally substituted with one or more substituent R.sup.5; m is 0, 1 or 2; n is 0, 1 or 2; R.sup.1 is CF.sub.3; Hyd.sup.1 and Hyd.sup.2 are the same or different and are C.sub.1-4 hydrocarbon groups; R.sup.2 is selected from hydrogen and a C.sub.1-4 hydrocarbon group; R.sup.3 is selected from hydrogen and a C.sub.1-4 hydrocarbon group; R.sup.4 is selected from: fluorine; chlorine; bromine; hydroxyl; cyano; carboxyl; C(O)O(Hyd.sup.1); amino; (Hyd.sup.2)NH; (Hyd.sup.2).sub.2N; and a C.sub.1-5 hydrocarbon group where 0, 1 or 2 of the carbons in the hydrocarbon group are replaced with a heteroatom selected from N, O and S, the hydrocarbon group being optionally substituted with one or more fluorine atoms; R.sup.5 is selected from halogen; O-Ar.sup.2; cyano, hydroxy; amino; Hyd.sup.1-SO.sub.2- and a non-aromatic C.sub.1-8 hydrocarbon group where 0, 1 or 2 but not all of the carbons in the hydrocarbon group are optionally replaced with a heteroatom selected from N, O and S and where the hydrocarbon group is optionally substituted with one or more fluorine atoms; Ar.sup.2 is a phenyl, pyridyl or pyridone group optionally substituted with 1 or 2 substituents selected from halogen; cyano and a C.sub.1-4 hydrocarbon group optionally substituted with one or more fluorine atoms; R.sup.6 is a group Q.sup.1-R.sup.a—R.sup.b; Q.sup.1 is absent or is a C.sub.1-3 saturated hydrocarbon linker; R.sup.a is selected from O; C(O); C(O)O; CONR.sup.c; N(R.sup.c)CO; N(R.sup.c)CONR.sup.c, NR.sup.c; and SO.sub.2NR.sup.c; R.sup.b is selected from: hydrogen; a C.sub.1-8 non-aromatic hydrocarbon group where 0, 1 or 2 of the carbon atoms in the hydrocarbon group are replaced with a heteroatom selected from N and O, the C.sub.1-8 non-aromatic hydrocarbon group being optionally substituted with one or more substituents selected from fluorine and a group Cyc.sup.1; and a group Cyc.sup.1; Cyc.sup.1 is a non-aromatic 4-7 membered carbocyclic or heterocyclic ring group containing 0, 1 or 2 heteroatom ring members selected from N, O and S and being optionally substituted with one or more substituents selected from hydroxyl; amino; (Hyd.sup.2)NH; (Hyd.sup.2).sub.2N; and a C.sub.1-5 hydrocarbon group where 0, 1 or 2 of the carbons in the hydrocarbon group are replaced with a heteroatom selected from N, O and S, the hydrocarbon group being optionally substituted with one or more fluorine atoms or by a 5- or 6-membered heteroaryl group containing 1 or 2 heteroatom ring members selected from N and O; R.sup.c is selected from hydrogen and a C.sub.1-4 non-aromatic hydrocarbon group; R.sup.7 is selected from R.sup.4; with the proviso that when n is 2 and both occurrences of R.sup.7 are —OCH.sub.3, R.sup.6 is not —NH.sub.2 or —NHCH.sub.3; and provided that the compound is other than: (i) a compound wherein R.sup.6 is hydroxy, methoxymethyl or unsubstituted or fluoro-substituted C.sub.1-8 alkoxy; (ii) a compound wherein the ring Z is an isoxazole ring and Ar.sup.1 is an unsubstituted 4-pyridyl group attached to the isoxazole 3-position; and R.sup.2 and R.sup.3 are both absent; or (iii) a compound wherein Z is an isoxazole ring and R.sup.4 is an azetidin-4-yloxy group.

2. A compound according to claim 1 wherein ring Z is a pyrrole ring.

3. A compound according to claim 2 wherein ring X is attached to the nitrogen atom of the pyrrole ring.

4. A compound according to claim 1 wherein: Q.sup.1 is absent or is a CH.sub.2, CH.sub.2(CH.sub.3) or C(CH.sub.3).sub.2 linker; R.sup.a is selected from O; C(O); C(O)O; CONR.sup.c; N(R.sup.c)CO; N(R.sup.c)CONR.sup.c, NR.sup.c; and SO.sub.2NR.sup.c; R.sup.b is selected from: hydrogen; a C.sub.1-8 non-aromatic hydrocarbon group where 0, 1 or 2 of the carbon atoms in the hydrocarbon group are replaced with a heteroatom selected from N and O, the C.sub.1-8 non-aromatic hydrocarbon group being optionally substituted with a substituent Cyc.sup.1; and a group Cyc.sup.1; Cyc.sup.1 is a non-aromatic 5-6 membered carbocyclic or heterocyclic ring group containing 0, 1 or 2 heteroatom ring members selected from N and O and being optionally substituted with one or more substituents selected from methyl and (dimethyl)amino; and R.sup.c is selected from hydrogen and methyl.

5. A compound according to claim 1 wherein R.sup.6 is selected from groups A to AM in the table below: TABLE-US-00018 embedded image A B C D E F G H I J K L M N O P Q R S T U CO.sub.2H V —SO.sub.2NH.sub.2 W X Y Z AA AB AC AD AE AF AG AH AI AJ embedded image AK AL AM

6. A compound according to claim 1 wherein R.sup.a is CONR.sup.c.

7. A compound according to claim 1 wherein R.sup.6 is a group: ##STR00216##

8. A compound according to claim 1 wherein ring X is a benzene ring.

9. A compound according to claim 1 wherein ring Y is a benzene ring.

10. A compound according to claim 1 wherein Ar.sup.1 is an optionally substituted benzene ring.

11. A compound according to claim 10 wherein the benzene ring is monosubstituted with a bromine or chlorine atom.

12. A compound according to claim 1 wherein R.sup.2 and R.sup.3 are both hydrogen.

13. A compound according to claim 1 wherein m is 0.

14. A compound according to claim 1 wherein n is 0.

15. A pharmaceutical composition comprising a compound as defined in claim 1 and a pharmaceutically acceptable excipient.

16. A compound selected from: 3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]benzoic acid; 3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino) ethyl]benzamide; N-[2-(dimethylamino)ethyl]-3-[5-phenyl-1-[2-(trifluoromethyl) phenyl]pyrrol-2-yl]benzamide; 3-[5-(4-bromophenyl)-1-[4-chloro-2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino) ethyl]benzamide; N-[2-(dimethylamino)ethyl]-3-[5-(4-fluorophenyl)-1-[2-(trifluoromethyl) phenyl]pyrrol-2-yl]benzamide; 3-[5-(4-bromophenyl)-1-[4-(trifluoromethyl)-3-pyridyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]benzamide; 1-[3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]-N,N-dimethyl-methanamine; 4-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]benzamide; 3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[(1-methyl-4-piperidyl)methyl]benzamide; 3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-(1-methyl-4-piperidyl)benzamide; 3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]-N-methyl-benzamide; 3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]benzamide; 3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[(3 S)-1-methylpyrrolidin-3-yl]benzamide; 3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-4-chloro-N-[2-(dimethylamino)-ethyl]benzamide; N-[3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]-N′,N′-dimethyl-propane-1,3-diamine; 3-[3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenoxy]-N,N-dimethyl-propan-1-amine; N-[[3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]methyl]-N′,N′-dimethyl-ethane-1,2-diamine; N-[[3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]methyl]-2-(dimethylamino)acetamide; N-[2-(dimethylamino)ethyl]-3-[5-(4-isopropylphenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]benzamide; 3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(methylamino)ethyl]benzamide; 3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[3-(dimethylamino)propyl]benzamide; 3-[5-(4-bromophenyl)-1-(2-hydroxyphenyl)pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]benzamide; N-[2-(dimethylamino)ethyl]-4-[5-phenyl-1-[2-(trifluoromethyl) phenyl]pyrrol-2-yl]benzamide; 4-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]benzoic acid 5-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]pyridine-2-carboxamide; 6-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]pyridine-3-carboxamide; 6-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]pyridine-3-carboxylic acid; 4-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[3-(dimethylamino)propyl]-2-methoxy-benzamide; 4-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]-3-methoxy-benzamide; 4-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]benzamide; 4-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[3-(dimethylamino)propyl]benzamide; 3-[4-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenoxy]-N,N-dimethyl-propan-1-amine; 4-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-3-chloro-N-[2-(dimethylamino) ethyl]benzamide; 3-chloro-N-[2-(dimethylamino)ethyl]-4-[5-phenyl-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]benzamide; 4-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-2-chloro-N-[2-(dimethylamino)ethyl]benzamide; 2-chloro-N-[2-(dimethylamino)ethyl]-4-[5-phenyl-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]benzamide; 4-[5-(4-bromophenyl)-1-[4-(trifluoromethyl)-3-pyridyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]benzamide; N-[2-(dimethylamino)ethyl]-4-[5-(6-fluoro-3-pyridyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]benzamide; 4-[5-(2,4-difluorophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]benzamide; 4-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]-benzenesulfonamide; 2-[[4-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]methoxy]-N,N-dimethyl-ethanamine; N-[4-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]-3-(dimethylamino) propanamide; 2-[4-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]acetic acid; 1-[[4-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]methyl]-4-methyl-piperazine; 4-[5-(4-chlorophenyl)-1-[4-(trifluoromethyl)-3-pyridyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]-benzamide; 4-[5-(4-bromophenyl)-1-[2-(methoxymethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]benzamide; 4-[5-(4-chlorophenyl)-1-[4-(trifluoromethyl)-3-pyridyl]pyrrol-2-yl]-N-[3-(dimethylamino)-propyl]benzamide; 3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]-4-methoxy-benzamide; 5-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]-2-methoxy-benzamide; [3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]-[(3R)-3-(dimethylamino) pyrrolidin-1-yl]methanone; [3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]-[(3S)-3-(dimethylamino) pyrrolidin-1-yl]methanone; 4-[5-(4-cyanophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]benzamide; 4-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[3-(dimethylamino)propyl]benzamide; N-[2-(dimethylamino)ethyl]-4-[5-(4-fluorophenyl)-1-[2-(trifluoromethyl) phenyl]pyrrol-2-yl]benzamide; N-[3-(dimethylamino)propyl]-4-[5-(4-fluorophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]benzamide; 6-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]pyridine-3-carboxamide; 6-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[3-(dimethylamino)propyl]-pyridine-3-carboxamide; 4-[5-(4-chlorophenyl)-1-[5-isobutyl-2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]-benzamide; 4-[5-(4-chlorophenyl)-1-[5-isobutyl-2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[3-(dimethylamino)propyl]-benzamide; 4-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]benzenesulfonamide; 4-[5-(6-cyano-3-pyridyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]-benzamide; 3-chloro-N-[2-(dimethylamino)-ethyl]-4-[5-phenyl-1-[4-(trifluoromethyl)-3-pyridyl]pyrrol-2-yl]benzamide; 3-chloro-N-[3-(dimethylamino)-propyl]-4-[5-phenyl-1-[4-(trifluoromethyl)-3-pyridyl]pyrrol-2-yl]benzamide; 6-[5-(4-chlorophenyl)-1-[4-(trifluoromethyl)-3-pyridyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]-pyridine-3-carboxamide; 4-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]benzamide; 4-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[(3 S)-1-methylpyrrolidin-3-yl]benzamide; 4-[5-(3-chlorophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]-benzamide; 4-[5-(4-chlorophenyl)-1-[4-(trifluoromethyl)-3-pyridyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]-3-methoxy-benzamide; 4-[5-(4-chlorophenyl)-1-[4-(trifluoromethyl)-3-pyridyl]pyrrol-2-yl]-N-[3-(dimethylamino)propyl]-3-methoxy-benzamide; 4-[5-(5-chloro-2-pyridyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]-benzamide; 4-[5-(5-chloro-2-pyridyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[3-(dimethylamino)propyl]-benzamide; 4-[5-(4-chlorophenyl)-1-[3-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]-benzamide; 4-[5-(4-chlorophenyl)-1-[3-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[3-(dimethylamino)propyl]-benzamide; 4-[5-(4-chlorophenyl)-1-[3-(trifluoromethyl)-2-pyridyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]-benzamide; 4-[5-(4-chlorophenyl)-1-[3-(trifluoromethyl)-2-pyridyl]pyrrol-2-yl]-N-[3-(dimethylamino)propyl]-benzamide; 4-[5-(4-chlorophenyl)-1-[4-(trifluoromethyl)-3-pyridyl]pyrrol-2-yl]-N-(2-morpholinoethyl)-benzamide; 4-[4-(4-chlorophenyl)-5-[2-(trifluoromethyl)phenyl]pyrazol-1-yl]-N-[2-(dimethylamino)ethyl]-benzamide; 4-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]-N-methyl-benzamide; 4-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]-piperazin-1-yl-methanone; [4-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]-(4-methylpiperazin-1-yl)methanone; 4-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-(2-methoxyethyl)benzamide; 4-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-(2-piperazin-1-ylethyl)benzamide; 4-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(4-methylpiperazin-1-yl)ethyl]benzamide; 4-[5-(4-chlorophenyl)-1-[4-(trifluoromethyl)-3-pyridyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]-3-fluoro-benzamide; 1-[4-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]-3-[2-(dimethylamino)-ethyl]urea; 2-[4-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]-N-[2-(dimethylamino)-ethyl]acetamide; 4-[3-(4-chlorophenyl)-4-[2-(trifluoromethyl)phenyl]isoxazol-5-yl]-N-[2-(dimethylamino)ethyl]-benzamide; 4-[3-(4-chlorophenyl)-4-[2-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl]-N-[2-(dimethylamino)ethyl]benzamide; N-(2-aminoethyl)-4-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)-phenyl]pyrrol-2-yl]benzamide; 4-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-(2-morpholinoethyl)benzamide; 4-[5-(4-chlorophenyl)-1-[4-fluoro-2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]-benzamide; 4-[5-(4-chlorophenyl)-1-[4-chloro-2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]-benzamide; 5-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]-thiophene-2-carboxamide; 2-[4-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]-N-(2-morpholinoethyl)-acetamide; 2-[4-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]-N-(2-piperazin-1-ylethyl)acetamide; [3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]-[4-(3-pyridylmethyl)-1-piperidyl]methanone; 4-[4-(4-chlorophenyl)-5-[2-(trifluoromethyl)phenyl]pyrazol-1-yl]-N-(2-morpholinoethyl)-benzamide; 4-[4-(4-chlorophenyl)-5-[2-(trifluoromethyl)phenyl]pyrazol-1-yl]-N-[3-(dimethylamino)propyl]-benzamide; N-[2-(dimethylamino)ethyl]-4-[4-(4-fluorophenyl)-5-[2-(trifluoromethyl)phenyl]pyrazol-1-yl]benzamide; 2-[4-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]-N-[2-(dimethylamino)ethyl]-2-methyl-propanamide; 4-[5-(4-chlorophenyl)-1-(4-trifluoromethyl-3-pyridyl)pyrrol-2-yl]-N-[2-[[(3S)-tetrahydrofuran-3-yl]amino]ethyl]-benzamide; and 4-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[(2S)-2-(dimethylamino)propyl]benzamide, or a pharmaceutically acceptable salt or tautomer thereof.

17. A compound which is 4-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)-phenyl]pyrrol-2-yl]-N-[2(dimethylamino)ethyl]benzamide or a pharmaceutically acceptable salt thereof.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is a plot of blood plasma concentrations against time following oral and i.v. dosing to mice of the compound of Example 33. The lower line, extending as far as 40 hours, is the line for the 2 mg/kg I.V. dose. The other line is for the 10 mg/kg P.O. dose.

(2) FIG. 2 is a plot of blood plasma and brain concentrations against time following oral dosing to mice of the compound of Example 33. The upper line shows the brain concentrations while the lower line shows the plasma concentrations.

(3) FIG. 3 is a plot of tumour volume against time following the oral dosing of the compound of Example 33 (identified as “Poloppin II” in the Figure) to mice bearing HCT116 tumours. The top line is the vehicle control, the middle line is the 50 mg/kg dose and the lower line is the 200 mg/kg dose.

EXAMPLES

(4) The invention will now be illustrated, but not limited, by reference to the specific embodiments described in the following examples.

(5) In the examples, the following abbreviations are used. AcCl acetyl chloride aq aqueous Boc.sub.2O di-tert-butyl dicarbonate DCM dichloromethane DIPEA N,N-diisopropylethylamine DMA N,N-dimethylacetamide DME dimethoxyethane DMF dimethylformamide DMSO dimethylsulfoxide Et.sub.3N triethylamine Et.sub.2O diethyl ether EtOAc ethyl acetate EtOH ethanol HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxid hexafluorophosphate) HCl hydrogen chloride HPLC high performance liquid chromatography LC liquid chromatography LCMS liquid chromatography-mass spectrometry LiOH lithium hydroxide MeCN acetonitrile MeOH methanol MsCl mesyl chloride NaBH(AcO).sub.3 sodium triacetoxyborohydride NaH sodium hydride NaHCO.sub.3 sodium hydrogen carbonate NaOH sodium hydroxide Na.sub.2SO.sub.4 sodium sulfate NBS N-bromosuccinimide NCS N-chlorosuccinimide NH.sub.3 ammonia NH.sub.4Cl ammonium chloride NMR nuclear magnetic resonance Pd(dba).sub.2 bis(dibenzylideneacetone)palladium(0) PhMe toluene PTSA p-toluenesulfonic acid TFA trifluroacetic acid THF tetrahydrofuran UV ultraviolet

(6) Proton magnetic resonance (.sup.1H NMR) spectra were recorded on a Bruker 400 instrument operating at 400 MHz, in DMSO-d.sub.6 or MeOH-d.sub.4 (as indicated) at 27° C., unless otherwise stated and are reported as follows: chemical shift δ/ppm (multiplicity where s=singlet, d=doublet, dd=double coublet, dt—double triplet, t=triplet, q=quartet, m=multiplet, br=broad, number of protons). The residual protic solvent was used as the internal reference.

(7) Liquid chromatography and mass spectroscopy analyses were carried out using the system and operating conditions set out below. Where atoms with different isotopes are present and a single mass quoted, the mass quoted for the compound is the monoisotopic mass (i.e. .sup.35Cl; .sup.79Br etc.)

(8) LCMS Conditions

(9) The LCMS data given in the following examples were obtained using one of Methods B, C or, where stated, Method A below

(10) LCMS Method A

(11) Samples were analysed by reverse phase HPLC-MS using a Waters 2795 Alliance HT HPLC, a Micromass ZQ mass spectrometer and a Waters 996 photodiode array UV detector. The LCMS used electrospray ionisation and the chromatography system, as follows:

(12) TABLE-US-00002 Mass Spectrometer: Ionization mode: Positive Negative Capillary Voltage: 3.20 kV −3.00 kV Cone Voltage: 30 V −30 V Source Temperature: 110° C. 110° C. Desolvation Temperature: 350° C. 350° C. Cone Gas Flow: 30 L/Hr 30 L/Hr Desolvation Gas Flow: 400 L/Hr 400 L/Hr Scan duration: 0.50 seconds 0.50 seconds Interscan delay: 0.20 seconds 0.20 seconds Mass range: 80 to 1000 AMU 80 to 1000 AMU

(13) LCMS was carried using a X-BRIDGE C18 100×4.6 mm, 5 micron column. Column flow was 1.0 mL/min and the mobile phase used were 0.1% formic acid in water (A) and methanol (B), with an injection volume of 10 μL.

(14) The gradient was as described below.

(15) TABLE-US-00003 Time (min) % A % B 0.01 90 10 3.00 10 90 6.00 0 100 7.00 0 100 7.01 90 10 10.00 90 10

(16) LCMS Method B

(17) Samples were analysed by reverse phase HPLC-MS using a Waters 2795 Alliance HT HPLC, a Micromass ZQ mass spectrometer and a Waters 996 photodiode array UV detector. The LCMS used electrospray ionisation and the chromatography system, as follows:

(18) TABLE-US-00004 Mass Spectrometer: Ionization mode: Positive Negative Capillary Voltage: 3.20 kV −3.00 kV Cone Voltage: 30 V −30 V Source Temperature: 110° C. 110° C. Desolvation Temperature: 350° C. 350° C. Cone Gas Flow: 30 L/Hr 30 L/Hr Desolvation Gas Flow: 400 L/Hr 400 L/Hr Scan duration: 0.50 seconds 0.50 seconds Interscan delay: 0.20 seconds 0.20 seconds Mass range: 80 to 1000 AMU 80 to 1000 AMU

(19) LC-MS was carried out on BEH C18 50*2.1 mm 1.7 micron. Column flow was 0.55 mL/min and mobile phase used were: (A) 5 mM ammonium acetate and 0.1% formic acid in water; and (B) 0.1% formic acid in acetonitrile. The injection volume was 2 uL.

(20) The gradient was as described below.

(21) TABLE-US-00005 Time (min) % A % B 0.01 50 50 0.4 50 50 0.8 65 35 1.2 45 55 2.5 0 100 3.3 0 100 3.31 50 50 4.0 50 50

(22) LCMS Method C

(23) Samples were analysed by reverse phase HPLC-MS using a Waters 2795 Alliance HT HPLC, a Micromass ZQ mass spectrometer and a Waters 996 photodiode array UV detector. The LCMS used electrospray ionisation and the chromatography system, as follows:

(24) TABLE-US-00006 Mass Spectrometer: Ionization mode: Positive Negative Capillary Voltage: 3.20 kV −3.00 kV Cone Voltage: 30 V −30 V Source Temperature: 110° C. 110° C. Desolvation Temperature: 350° C. 350° C. Cone Gas Flow: 30 L/Hr 30 L/Hr Desolvation Gas Flow: 400 L/Hr 400 L/Hr Scan duration: 0.50 seconds 0.50 seconds Interscan delay: 0.20 seconds 0.20 seconds Mass range: 80 to 1000 AMU 80 to 1000 AMU

(25) LC-MS was Carried Out on X-BRIDGE, C18, 5 Micron 4.6×100 mm Column. Flow was 1.2 mL/Min and Mobile Phase Used were: (A) 0.1% Ammonia in Water; and (B) 100% Methanol. The Injection Volume was 10 uL.

(26) Following Gradient was Used for the Elution.

(27) TABLE-US-00007 Time (min) % A % B 0.0 90 10 1.00 90 10 5.00 0 100 7.00 0 100 7.50 90 10 8.00 90 10

Examples 1 to 107

(28) The compounds of Examples 1 to 107 shown in Table 2 below have been prepared. Their NMR and LCMS properties are set out in Table 3.

(29) TABLE-US-00008 TABLE 2 embedded image Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 0 Example 7 Example 8 Example 9 Example 10 Example 11 Example 12 Example 13 Example 14 Example 15 Example 16 0 Example 17 Example 18 Example 19 Example 20 Example 21 Example 22 Example 23 Example 24 Example 25 embedded image Example 26 0 Example 27 Example 28 Example 29 Example 30 Example 31 Example 32 Example 33 Example 34 Example 35 Example 36 0 Example 37 Example 38 Example 39 Example 40 Example 41 Example 42 Example 43 Example 44 Example 45 Example 46 00 Example 47 01 Example 48 02 Example 49 03 embedded image Example 50 04 Example 51 05 Example 52 06 Example 53 07 Example 54 08 Example 55 09 Example 56 0 Example 57 Example 58 Example 59 Example 60 Example 61 Example 62 Example 63 Example 64 Example 65 Example 66 0 Example 67 Example 68 Example 69 Example 70 Example 71 Example 72 embedded image Example 73 Example 74 Example 75 Example 76 0 Example 77 Example 78 Example 79 Example 80 Example 81 Example 82 Example 83 Example 84 Example 85 Example 86 0 Example 87 Example 88 Example 89 Example 90 Example 91 Example 92 Example 93 Example 94 Example 95 Example 96 0 embedded image Example 97 Example 98 Example 99 Example 100 Example 101 Example 102 Example 103 Example 104 Example 105 Example 106 0 Example 107

(30) TABLE-US-00009 TABLE 3 Ex. Synthetic LC MS LCMS No. Name Method .sup.1H NMR (RT) (MH.sup.+) Method 1 3-[5-(4-bromophenyl)-1-[2- A (DMSO-d.sub.6) δ 12.91 (s, 1H), 7.79 (m, 3H), 7.70 (m, 2H), 7.61 2.88 486 A (trifluoromethyl)phenyl]pyrrol-2- (s, 1H), 7.39 (d, 2H), 7.32 (m, 2H), 7.01 (d, 2H) and 6.62 (m, yl]benzoic acid 2H). 2 3-[5-(4-bromophenyl)-1-[2- A (DMSO-d.sub.6) δ 8.82 (br s, 1H), 7.79 (m, 4H), 7.68 (s, 2H), 2.10 558 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 7.41 (d, 2H), 7.24 (m, 1H), 7.00 (m, 3H), 6.65 (m, 2H), N-[2-(dimethylamino) 3.58 (s, 2H), 3.20 (s, 2H) and 2.74 (s, 6H). ethyl]benzamide hydrochloride 3 N-[2-(dimethylamino)ethyl]-3-[5- A (DMSO-d.sub.6) δ 8.75 (t, 1H), 7.85 (s, 1H), 7.70-7.56 (m, 5H), 4.70 478 A phenyl-1-[2-(trifluoromethyl) 7.24-7.08 (m, 7H), 6.62 (d, 1H), 6.52 (d, 1H), 3.75 (t, 2H), phenyl]pyrrol-2-yl]benzamide 3.38 (t, 2H) and 2.99 (s, 6H). hydrochloride 4 3-[5-(4-bromophenyl)-1-[4-chloro-2- A (DMSO-d.sub.6) δ 7.82 (t, 1H), 7.76-7.74 (m, 2H), 7.72-7.69 (m, 5.30 592 A (trifluoromethyl)phenyl] pyrrol-2-yl]- 2H), 7.66-7.63 (m, 1H), 7.37 (d, 2H), 7.30 (t, 1H), 7.18- N-[2-(dimethylamino) 7.16 (m, 1H), 7.03 (d, 2H), 6.63 (d, 1H), 6.57 (d, 1H), 3.77 ethyl]benzamide hydrochloride (t, 2H), 3.40 (t, 2H) and 2.99 (s, 6H). 5 N-[2-(dimethylamino)ethyl]-3-[5-(4- A (DMSO-d.sub.6) δ 10.29 (br s, 1H), 8.87 (t, 1H), 7.80-7.74 (m, 5.11 496 A fluorophenyl)-1-[2-(trifluoromethyl) 4H), 7.71-7.64 (m, 2H), 7.24 (t, 1H), 7.11-7.02 (m, 5H), phenyl]pyrrol-2-yl]benzamide 6.67 (d, 1H), 6.55 (d, 1H), 3.61 (q, 2H), 3.24 (br s, 2H) and hydrochloride 2.81 (br s, 6H). 6 3-[5-(4-bromophenyl)-1-[4- A (DMSO-d.sub.6) δ 10.27 (br s, 1H), 9.20 (s, 1H), 8.90-8.89 (m, 4.85 559 A (trifluoromethyl)-3-pyridyl]pyrrol-2- 2H), 7.81-7.74 (m, 3H), 7.46-7.44 (m, 2H), 7.39-7.26 (m, yl]-N-[2-(dimethylamino)ethyl] 2H), 7.14-7.12 (m, 1H), 7.04-7.02 (m, 1H), 6.72-6.71 (d, benzamide hydrochloride 1H), 6.65 (d, 1H), 3.61 (br s, 2H), 3.25 (q, 2H) and 2.82 (d, 6H). 7 1-[3-[5-(4-bromophenyl)-1-[2- B (DMSO-d.sub.6) δ 7.74-7.72 (m, 2H), 7.64 (t, 2H), 7.35-7.29 (m, 5.06 499 A (trifluoromethyl)phenyl]pyrrol-2- 5H), 7.14 (dt, 1H), 6.99 (d, 2H), 6.61 (d, 1H), 6.57 (d, 1H), yl]phenyl]-N,N-dimethyl- 4.22 (s, 2H) and 2.74 (d, 6H). methanamine hydrochloride 8 N-[2-(dimethylamino)ethyl]-3-[1-(4- A (DMSO-d.sub.6) δ 9.55 (br s, 1H), 8.73 (t, 1H), 7.79 (s, 1H), 5.17 520 A fluorophenyl)-5-(4- 7.67 (d, 1H), 7.40 (q, 2H), 7.30 (t, 1H), 7.22-7.14 (m, 5H), phenoxyphenyl)pyrrol-2- 7.09-7.05 (m, 3H), 7.00 (d, 2H), 6.86 (d, 2H), 6.57 (d, 1H), yl]benzamide hydrochloride 6.49 (d, 1H), 3.60 (q, 2H), 3.25 (br d, 2H) and 2.84 (d, 6H). 9 4-[5-(4-bromophenyl)-1-[2- C (DMSO-d.sub.6) δ 9.60 (br s, 1H), 8.68 (t, 1H), 7.82-7.77 (m, 4.96 556 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 3H), 7.70-7.68 (m, 3H), 7.39 (d, 2H), 7.12 (d, 2H), 6.99 (d, N-[2-(dimethylamino)ethyl] 2H), 6.69 (d, 1H), 6.61 (d, 1H), 3.56-3.54 (m, 2H), 3.22- benzamide hydrochloride 3.16 (m, 2H) and 2.80 (s, 6H). 10 3-[5-(4-bromophenyl)-1-[2- A (DMSO-d.sub.6) δ 9.72 (br s, 1H), 8.54 (t, 1H), 7.79-7.76 (m, 5.09 596 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 3H), 7.68-7.66 (m, 2H), 7.61 (d, 1H), 7.41-7.39 (m, 2H), N-[(1-methyl-4-piperidyl)methyl] 7.24 (t, 1H), 7.06 (d, 1H), 7.00-6.98 (m, 2H), 6.65-6.61 (m, benzamide hydrochloride 2H), 3.41 (d, 2H), 3.17-3.11 (m, 2H), 2.93-2.87 (m, 2H), 2.73 (d, 3H), 1.83-1.74 (m, 3H) and 1.45-1.36 (m, 2H). 11 3-[5-(4-bromophenyl)-1-[2- A (DMSO-d.sub.6) δ 9.75 (br s, 1H), 8.42 (d, 1H), 7.79-7.76 (m, 5.09 582 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 3H), 7.70-7.62 (m, 3H), 7.42-7.38 (m, 2H), 7.25 (t, 1H), N-(1-methyl-4-piperidyl)benzamide 7.08 (d, 1H), 7.01-6.98 (m, 2H), 6.62 (dd, 2H), 3.97-3.95 hydrochloride (m, 1H), 3.46-3.43 (m, 2H), 3.06-3.02 (m, 2H), 2.76 (s, 3H), 2.00-1.97 (m, 2H) and 1.83-1.74 (m, 2H). 12 3-[5-(4-bromophenyl)-1-[2- A (DMSO-d.sub.6) δ 9.95 (br s, 1H), 7.83-7.77 (m, 3H), 7.69 (t, 5.01 570 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 1H), 7.40 (d, 2H), 7.27 (d, 2H), 7.18 (s, 1H), 7.07 (br s, N-[2-(dimethylamino)ethyl]-N- 1H), 6.99 (d, 2H), 6.61 (t, 2H), 3.76 (q, 2H), 3.30 (t, 2H), methyl-benzamide hydrochloride 2.84 (s, 6H) and 2.74 (s, 3H). 13 3-[5-(4-bromophenyl)-1-[2- A (DMSO-d.sub.6) δ 10.80 (br s, 1H), 8.83 (d, 1H), 7.81-7.76 (m, 4.98 568 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 4H), 7.70-7.68 (m, 2H), 7.40 (d, 2H), 7.25 (t, 1H), 7.06 (s, N-[(3R)-1-methylpyrrolidin-3- 1H), 6.99 (d, 2H), 6.69 (s, 1H), 6.62 (d, 1H), 4.65-4.62 (m, yl]benzamide hydrochloride 1H), 3.97-3.57 (m, 1H), 3.51-3.48 (m, 1H), 3.06-3.03 (m, 2H), 2.85 (s, 3H), 2.24-2.33 (m, 1H) and 2.02-1.99 (m, 1H). 14 3-[5-(4-bromophenyl)-1-[2- A (DMSO-d.sub.6) δ 8.79 (br s, 1H), 7.81-7.58 (m, 6H), 7.33-7.31 4.99 568 A (trifluoromethyl)phenyl]pyrrol-2-yl]- (d, 2H), 7.16 (dt, 2H), 7.00 (d, 2H), 6.63 (d, 1H), 6.57 (d, N-[(3S)-1-methylpyrrolidin-3- 1H), 4.61-4.57 (m, 1H), 4.05-3.91 (m, 1H), 3.77 (d, 1H), yl]benzamide hydrochloride 3.47-3.42 (m, 1H), 3.24-3.12 (m, 1H), 3.02 (d, 3H), 2.68- 2.42 (m, 1H) and 2.29-2.24 (m, 1H). 15 3-[5-(4-bromophenyl)-1-[2- A (DMSO-d.sub.6) δ 10.00 (br s, 1H), 8.81 (t, 1H), 7.80-7.77 (m, 5.10 590 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 1H), 7.71-7.66 (m, 4H), 7.58 (d, 2H), 7.41 (d, 2H), 6.99- 4-chloro-N-[2-(dimethylamino)- 6.97 (m, 2H), 6.65 (d, 1H), 6.51 (d, 1H), 3.55 (q, 2H), 3.21 ethyl]benzamide hydrochloride (t, 2H) and 2.79 (s, 6H). 16 N-[3-[5-(4-bromophenyl)-1-[2- D (DMSO-d.sub.6) δ 10.26 (br s, 2H), 7.81-7.76 (m, 3H), 7.70- 5.12 542 A (trifluoromethyl)phenyl]pyrrol-2- 7.66 (m, 1H), 7.38 (d, 2H), 7.02-6.96 (m, 3H), 6.66 (d, 1H), yl]phenyl]-N′,N′-dimethyl-propane- 6.59 (s, 1H), 6.57 (d, 1H), 6.51 (d, 1H), 6.45 (d, 1H), 3.10- 1,3-diamine hydrochloride 3.06 (m, 2H), 2.97 (t, 2H), 2.73 (s, 6H) and 1.84-1.79 (m, 2H). 17 3-[3-[5-(4-bromophenyl)-1-[2- E (DMSO-d.sub.6) δ 10.37 (br s, 1H), 7.81-7.77 (m, 3H), 7.71- 5.22 543 A (trifluoromethyl)phenyl]pyrrol-2- 7.67 (m, 1H), 7.39 (d, 2H), 7.10 (t, 1H), 6.98 (d, 2H), 6.74- yl]phenoxy]-N,N-dimethyl-propan- 6.72 (m, 1H), 6.63-6.56 (m, 4H), 3.89-3.83 (m, 2H), 3.15- 1-amine hydrochloride 3.12 (m, 2H), 2.76 (s, 6H) and 2.10-2.03 (m, 2H). 18 N-[[3-[5-(4-bromophenyl)-1-[2- B (DMSO-d.sub.6) δ 7.73 (t, 2H), 7.64-7.60 (m, 3H), 7.37 (d, 1H), 4.75 542 A (trifluoromethyl)phenyl]pyrrol-2- 7.32 (d, 2H), 7.20 (t, 1H), 6.99 (d, 2H), 6.93 (d, 1H), 6.65 yl]phenyl]methyl]-N′,N′-dimethyl- (d, 1H), 6.56 (d, 1H), 4.24 (d, 2H), 3.57 (s, 4H) and 3.00 (s, ethane-1,2-diamine hydrochloride 6H). 19 3-[5-(4-bromophenyl)-1-phenyl- A (DMSO-d.sub.6) δ 10.11 (br s, 1H), 8.89 (t, 1H), 7.92 (d, 1H), 5.15 522 A pyrrol-2-yl]-4-chloro-N-[2- 7.83 (dd, 1H), 7.49 (d, 1H), 7.42 (d, 2H), 7.26-7.23 (m, (dimethylamino)ethyl]benzamide 3H), 7.05-6.98 (m, 4H), 6.60 (d, 1H), 6.42 (d, 1H), 3.60 (q, hydrochloride 2H), 3.24 (t, 2H) and 2.81 (s, 6H). 20 3-[5-(4-bromophenyl)-1-phenyl- A (DMSO-d.sub.6) δ 9.64 (br s, 1H), 8.64 (t, 1H), 7.85-7.81 (m, 4.95 518 A pyrrol-2-yl]-N-[2-(dimethylamino) 2H), 7.39 (d, 2H), 7.23-7.21 (m, 3H), 6.98-6.87 (m, 5H), ethyl]-4-methoxy-benzamide 6.52 (d, 1H), 6.32 (d, 1H), 3.59 (q, 2H), 3.33 (s, 3H), 3.25 hydrochloride (t, 2H) and 2.83 (s, 6H). 21 N-[[3-[5-(4-bromophenyl)-1-[2- F (DMSO-d.sub.6) δ 9.76 (br s, 1H), 8.99 (t, 1H), 7.79-7.75 (m, 5.02 556 A (trifluoromethyl)phenyl]pyrrol-2- 3H), 7.70-7.67 (m, 1H), 7.39 (d, 2H), 7.14-7.06 (m, 3H), yl]phenyl]methyl]-2- 6.98 (d, 2H), 6.80 (d, 1H), 6.59 (d, 1H), 6.53 (d, 1H), 4.24 (dimethylamino)acetamide (d, 2H), 3.92 (s, 2H) and 2.79 (s, 6H). hydrochloride 22 N-[2-(dimethylamino)ethyl]-3-[5-(4- A (DMSO-d.sub.6) δ 10.25 (br s, 1H), 8.85 (br s, 1H), 7.79-7.65 5.15 520 A isopropylphenyl)-1-[2- (m, 6H), 7.23 (t, 1H), 7.08-6.97 (m, 5H), 6.65 (d, 1H), 6.52 (trifluoromethyl)phenyl]pyrrol-2- (d, 1H), 3.61 (br d, 2H), 3.24 (br d, 2H), 2.82 (d, 6H), 2.79- yl]benzamide hydrochloride 2.77 (m, 1H) and 1.13 (d, 6H). 23 3-[5-(4-bromophenyl)-1-[2- A (DMSO-d.sub.6) δ 9.88 (br s, 1H), 8.83 (t, 1H), 7.80-7.77 (m, 5.06 542 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 4H), 7.71-7.67 (m, 2H), 7.40 (d, 2H), 7.24 (t, 1H), 7.04- N-[2-(methylamino)ethyl] 6.98 (m, 3H), 6.68 (d, 1H), 6.62 (d, 1H), 3.54 (q, 2H), 3.07 benzamide hydrochloride (s, 2H) and 2.57 (s, 3H). 24 3-[5-(4-bromophenyl)-1-[2- A (DMSO-d.sub.6) δ 10.09 (br s, 1H), 8.67 (t, 1H), 7.80-7.63 (m, 5.12 570 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 6H), 7.40 (d, 2H), 7.24 (t, 1H), 7.04 (d, 1H), 6.99 (d, 2H), N-[3-(dimethylamino)propyl] 6.65 (d, 1H), 6.62 (d, 1H), 3.31-3.29 (m, 2H), 3.07-3.03 benzamide hydrochloride (m, 2H), 2.75 (s, 6H) and 1.92-1.85 (m, 2H). 25 3-[5-(4-bromophenyl)-1-(2- A (DMSO-d.sub.6) δ 10.05 (s, 2H), 8.80 (t, 1H), 7.90 (s, 1H), 7.66 4.79 506 A hydroxyphenyl)pyrrol-2-yl]-N-[2- (d, 1H), 7.39 (d, 2H), 7.25-7.09 (m, 5H), 6.93-6.90 (m, 2H), (dimethylamino)ethyl]benzamide 6.74-6.71 (m, 1H), 6.58 (d, 1H), 6.53 (d, 1H), 3.62-3.59 (m, hydrochloride 2H), 3.25-3.24 (m, 2H) and 2.82 (d, 6H). 26 N-[2-(dimethylamino)ethyl]-4-[5- C (DMSO-d.sub.6) δ 9.59 (br s, 1H), 8.67 (t, 1H), 7.82-7.76 (m, 4.80 478 A phenyl-1-[2-(trifluoromethyl) 3H), 7.69 (d, 2H), 7.22-7.05 (m, 6H), 6.68 (d, 1H), 6.57 (d, phenyl]pyrrol-2-yl]benzamide 1H), 3.65 (t, 2H), 3.23-3.16 (m, 2H) and 2.80 (s, 6H). hydrochloride 27 4-[5-(4-bromophenyl)-1-[2- C (DMSO-d.sub.6) δ 7.81-7.78 (m, 3H), 7.73-7.69 (m, 3H), 7.40 5.93 486 A (trifluoromethyl)phenyl]pyrrol-2- (d, 2H), 7.14-7.12 (m, 2H), 7.00 (d, 2H), 6.71 (d, 1H) and yl]benzoic acid 6.62 (d, 1H). 28 5-[5-(4-bromophenyl)-1-[2- G (DMSO-d.sub.6) δ 9.87 (br s, 1H), 9.02 (t, 1H), 8.21 (s, 1H), 4.88 557 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 7.94-7.83 (m, 4H), 7.76-7.67 (m, 2H), 7.43 (d, 2H), 7.02 (d, N-[2-(dimethylamino)ethyl] 2H), 6.88 (d, 1H), 6.69 (d, 1H), 3.60 (d, 2H), 3.23 (d, 2H) pyridine-2-carboxamide and 2.79 (d, 6H). hydrochloride 29 6-[5-(4-bromophenyl)-1-[2- G (DMSO-d.sub.6) δ 10.10 (br s, 1H), 8.88 (t, 1H), 8.52 (d, 1H), 4.92 557 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 8.14 (dd, 1H), 7.78-7.72 (m, 2H), 7.69-7.62 (m, 3H), 7.41- N-[2-(dimethylamino)ethyl] 7.40 (d, 2H), 7.17 (d, 1H), 7.02 (d, 2H), 6.65 (d, 1H), 3.58 pyridine-3-carboxamide (q, 2H), 3.22 (q, 2H) and 2.79 (d, 6H). hydrochloride 30 6-[5-(4-bromophenyl)-1-[2- G (DMSO-d.sub.6) δ 13.16 (s, 1H), 8.47 (d, 1H), 8.07 (dd, 1H), 5.82 487 A (trifluoromethyl)phenyl]pyrrol-2- 7.77-7.72 (m, 2H), 7.68-7.60 (m, 3H), 7.42 (d, 2H), 7.18 (d, yl]pyridine-3-carboxylic acid 1H), 7.03 (d, 2H) and 6.66 (d, 1H). 31 4-[5-(4-bromophenyl)-1-[2- A (DMSO-d.sub.6) δ 9.69 (br s, 1H), 8.25 (t, 1H), 7.89-7.81 (m, 5.09 599 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 3H), 7.72 (t, 1H), 7.59 (d, 1H), 7.41 (d, 2H), 7.01 (d, 2H), N-[3-(dimethylamino)propyl]-2- 6.84 (d, 1H), 6.73 (d, 1H), 6.62 (d, 1H), 6.60 (s, 1H), 3.56 methoxy-benzamide hydrochloride (s, 3H), 3.30 (q, 2H), 3.03 (t, 2H), 2.75 (s, 6H) and 1.87- 1.83 (m, 2H). 32 4-[5-(4-bromophenyl)-1-[2- A (DMSO-d.sub.6) δ 10.12 (br s, 1H), 8.85 (t, 1H), 7.70-7.55 (m, 2.31 586 B (trifluoromethyl)phenyl]pyrrol-2-yl]- 4H), 7.41-7.36 (m, 4H), 7.10 (d, 1H), 6.96 (dd, 2H), 6.58 N-[2-(dimethylamino)ethyl]-3- (d, 1H), 6.39 (d, 1H), 3.65 (s, 3H), 3.60 (q, 2H), 3.24 (t, 2H) methoxy-benzamide hydrochloride and 2.80 (s, 6H). 33 4-[5-(4-chlorophenyl)-1-[2- C (DMSO-d.sub.6) δ 10.09 (br s, 1H), 8.76 (t, 1H), 7.86-7.78 (m, 2.26 512 B (trifluoromethyl)phenyl]pyrrol-2-yl]- 3H), 7.74-7.69 (m, 3H), 7.28 (d, 2H), 7.12 (d, 2H), 7.07 (d, N-[2-(dimethylamino)ethyl] 2H), 6.69 (d, 1H), 6.62 (d, 1H), 3.61-3.56 (m, 2H), 3.22 (br benzamide hydrochloride s, 2H) and 2.80 (s, 6H). 34 4-[5-(4-bromophenyl)-1-[2- C (DMSO-d.sub.6) δ 9.85 (br s, 1H), 8.58 (t, 1H), 7.84-7.78 (m, 5.02 571 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 3H), 7.72-7.70 (m, 1H), 7.66 (d, 2H), 7.40 (d, 2H), 7.11 (d, N-[3-(dimethylamino)propyl] 2H), 6.99 (d, 2H), 6.68 (d, 1H), 6.61 (d, 1H), 3.30-3.26 (m, benzamide hydrochloride 2H), 3.06-3.02 (m, 2H), 2.73 (s, 6H) and 1.87-1.83 (m, 2H). 35 3-[4-[5-(4-bromophenyl)-1-[2- E (DMSO-d.sub.6) δ 10.14 (br s, 1H), 7.80-7.75 (m, 3H), 7.68- 5.17 543 A (trifluoromethyl)phenyl]pyrrol-2- 7.65 (m, 1H), 7.38 (d, 2H), 7.03-6.95 (m, 4H), 6.77 (d, yl]phenoxy]-N,N-dimethyl-propan- 2H), 6.56 (d, 1H), 6.43 (d, 1H), 3.97 (t, 2H), 3.15 (t, 2H), 1-amine hydrochloride 2.76 (s, 6H) and 2.11-2.04 (m, 2H). 36 4-[5-(4-bromophenyl)-1-[2- A (DMSO-d.sub.6) δ 9.89 (br s, 1H), 8.91 (t, 1H), 7.98 (s, 1H), 5.13 590 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 7.74-7.69 (m, 3H), 7.62-7.60 (m, 2H), 7.41-7.39 (m, 2H), 3-chloro-N-[2-(dimethylamino) 7.14-7.12 (d, 1H), 6.99 (d, 2H), 6.65 (d, 1H), 6.58 (d, 1H), ethyl]benzamide hydrochloride 3.58 (t, 2H), 3.23 (t, 2H) and 2.80 (s, 6H). 37 3-chloro-N-[2-(dimethylamino) A (DMSO-d.sub.6) δ 9.65 (br s, 1H), 8.85 (t, 1H), 7.96 (d, 1H), 4.90 512 A ethyl]-4-[5-phenyl-1-[2- 7.74-7.67 (m, 3H), 7.60-7.56 (m, 2H), 7.21-7.11 (m, 4H), (trifluoromethyl)phenyl]pyrrol-2- 7.05 (d, 2H), 6.58 (dd, 2H), 3.56 (t, 2H), 3.23 (t, 2H) and yl]benzamide hydrochloride 2.80 (s, 6H). 38 4-[5-(4-bromophenyl)-1-[2- A (DMSO-d.sub.6) δ 9.96 (br s, 1H), 8.64 (t, 1H), 7.92-7.90 (m, 5.03 590 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 1H), 7.86-7.82 (m, 2H), 7.73 (t, 1H), 7.40 (t, 3H), 7.11 (d, 2-chloro-N-[2-(dimethylamino)ethyl] 1H), 7.05 (dd, 1H), 7.01 (d, 2H), 6.75 (d, 1H), 6.63 (d, 1H), benzamide hydrochloride 3.54 (t, 2H), 3.19 (t, 2H) and 2.80 (s, 6H). 39 2-chloro-N-[2-(dimethylamino) A (DMSO-d.sub.6) δ 10.14 (br s, 1H), 8.66 (t, 1H), 7.90-7.80 (m, 4.80 512 A ethyl]-4-[5-phenyl-1-[2- 3H), 7.73-7.69 (m, 1H), 7.40 (d, 1H), 7.21-7.16 (m, 3H), (trifluoromethyl)phenyl]pyrrol-2- 7.10-7.04 (m, 4H), 6.74 (d, 1H), 6.58 (d, 1H), 3.56-3.54 (m, yl]benzamide hydrochloride 2H), 3.19-3.15 (m, 2H) and 2.80 (s, 6H). 40 4-[5-(4-bromophenyl)-1-[2- C (DMSO-d.sub.6) δ 11.22 (br s, 1H), 10.33 (br s, 1H), 8.84 (t, 4.12 545 A [(dimethylamino)methyl]phenyl]pyrrol- 1H), 8.06 (s, 1H), 7.78-7.77 (m, 3H), 7.57-7.56 (m, 2H), 2-yl]-N-[2-(dimethylamino) 7.43 (d, 2H), 7.23 (d, 2H), 7.10 (d, 2H), 6.76 (d, 1H), 6.70 ethyl]benzamide hydrochloride (d, 1H), 3.60-3.58 (m, 2H), 3.51 (d, 1H), 3.44 (d, 1H), 3.23- 3.22 (m, 2H), 2.79 (d, 6H) and 2.37 (d, 6H). 41 4-[5-(4-bromophenyl)-1-[4- C (DMSO-d.sub.6) δ 9.82 (br s, 1H), 9.24 (s, 1H), 8.92 (d, 1H), 4.84 557 A (trifluoromethyl)-3-pyridyl]pyrrol-2- 8.72 (t, 1H), 7.81 (d, 1H), 7.75 (d, 2H), 7.46 (d, 2H), 7.17 yl]-N-[2-(dimethylamino)ethyl] (d, 2H), 7.04 (d, 2H), 6.72 (d, 1H), 6.66 (d, 1H), 3.57-3.54 benzamide hydrochloride (m, 2H), 3.24-3.20 (m, 2H) and 2.80 (s, 6H). 42 N-[2-(dimethylamino)ethyl]-4-[5-(6- G (DMSO-d.sub.6) δ 10.03 (br s, 1H), 8.76 (t, 1H), 7.96-7.92 (m, 4.43 497 A fluoro-3-pyridyl)-1-[2- 2H), 7.86-7.80 (m, 2H), 7.75-7.70 (m, 3H), 7.61 (td, 1H), (trifluoromethyl)phenyl]pyrrol-2- 7.15 (d, 2H), 7.09 (dd, 1H), 6.74 (d, 1H), 6.71-6.70 (d, 1H), yl]benzamide hydrochloride 3.58 (q, 2H), 3.22 (t, 2H) and 2.79 (s, 6H). 43 4-[5-(2,4-difluorophenyl)-1-[2- C (DMSO-d.sub.6) δ 10.48 (br s, 1H), 7.88 (br s, 1H), 7.68 (br s, 4.78 514 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 2H), 7.59-7.54 (m, 2H), 7.49-7.45 (m, 2H), 7.11 (d, 2H), N-[2-(dimethylamino)ethyl] 7.03-6.97 (m, 1H), 6.76-6.68 (m, 2H), 6.63 (d, 1H), 6.49 (d, benzamide hydrochloride 1H), 3.77 (br s, 2H), 3.34 (br s, 2H) and 2.91 (br s, 6H). 44 4-[5-(4-bromophenyl)-1-[2- K (DMSO-d.sub.6) δ 10.49 (br s, 1H), 8.05 (br s, 1H), 7.84-7.81 4.91 592 A (trifluoromethyl)phenyl]pyrrol-2-yl]- (m, 3H), 7.75-7.72 (m, 1H), 7.64 (d, 2H), 7.42 (d, 2H), 7.23 N-[2-(dimethylamino)ethyl]- (d, 2H), 7.01 (d, 2H), 6.78 (d, 1H), 6.65 (d, 1H), 3.09 (br s, benzenesulfonamide hydrochloride 4H) and 2.72 (s, 6H). 45 2-[[4-[5-(4-bromophenyl)-1-[2- H (DMSO-d.sub.6) δ 9.69 (br s, 1H), 7.80-7.76 (m, 3H), 7.69-7.68 5.03 545 A (trifluoromethyl)phenyl]pyrrol-2- (m, 2H), 7.39 (d, 2H), 7.19 (d, 2H), 7.05 (d, 2H), 6.98 (d, yl]phenyl]methoxy]-N,N-dimethyl- 2H), 6.57 (d, 2H), 4.45 (s, 2H), 3.69 (s, 2H), 3.27 (s, 2H) ethanamine hydrochloride and 2.74 (s, 6H). 46 N-[4-[5-(4-bromophenyl)-1-[2- I (DMSO-d.sub.6) δ 10.30 (s, 1H), 9.87 (br s, 1H), 7.78-7.66 (m, 4.97 556 A (trifluoromethyl)phenyl]pyrrol-2- 4H), 7.42-7.37 (m, 4H), 6.70-6.96 (m, 4H), 6.57 (d, 1H), yl]phenyl]-3-(dimethylamino) 6.49 (d, 1H), 3.32 (q, 2H), 2.82 (t, 2H) and 2.76 (s, 6H). propanamide hydrochloride 47 2-[4-[5-(4-bromophenyl)-1-[2- J (DMSO-d.sub.6) δ 12.29 (s, 1H), 7.82-7.75 (m, 3H), 7.67 (t, 1H), 5.87 500 A (trifluoromethyl)phenyl]pyrrol-2- 7.38 (d, 2H), 7.08 (d, 2H), 7.01-6.97 (m, 4H), 6.58 (d, 1H), yl]phenyl]acetic acid 6.52 (d, 1H) and 3.48 (s, 2H). 48 1-[[4-[5-(4-bromophenyl)-1-[2- B (DMSO-d.sub.6) δ 12.23 (br s, 1H), 11.82 (br s, 1H), 7.82-7.78 5.02 556 A (trifluoromethyl)phenyl]pyrrol-2- (m, 3H), 7.72-7.68 (m, 1H), 7.45-7.38 (m, 4H), 7.09 (d, yl]phenyl]methyl]-4-methyl- 2H), 6.99 (d, 2H), 6.62 (dd, 2H), 4.19 (s, 2H), 3.37 (br m, piperazine hydrochloride 8H) and 2.78 (s, 3H). 49 4-[5-(4-chlorophenyl)-1-[4- C (DMSO-d.sub.6) δ 9.57 (br s, 1H), 9.25 (s, 1H), 8.92 (d, 1H), 4.85 513 A (trifluoromethyl)-3-pyridyl]pyrrol-2- 8.67 (t, 1H), 7.81 (d, 1H), 7.74 (d, 2H), 7.33 (d, 2H), 7.18 yl]-N-[2-(dimethylamino)ethyl]- (d, 2H), 7.11 (d, 2H), 6.72 (d, 1H), 6.65 (d, 1H), 3.57 (q, benzamide hydrochloride 2H), 3.22 (br s, 2H) and 2.81 (s, 6H). 50 4-[5-(4-bromophenyl)-1-[2- C (DMSO-d.sub.6) δ 9.99 (br s, 1H), 8.73 (t, 1H), 8.72 (d, 2H), 5.03 532 A (methoxymethyl)phenyl]pyrrol-2-yl]- 7.46-7.44 (m, 2H), 7.41-7.38 (m, 4H), 7.17 (d, 2H), 7.04 (d, N-[2-(dimethylamino)ethyl] 2H), 6.69 (d, 1H), 6.62 (d, 1H), 3.76 (s, 2H), 3.58 (q, 2H), benzamide hydrochloride 3.22 (q, 2H), 3.01 (s, 3H) and 2.80 (s, 6H). 51 4-[5-(4-chlorophenyl)-1-[4- C (DMSO-d.sub.6) δ 10.12 (br s, 1H), 9.22 (s, 1H), 8.91 (1H, d), 4.84 527 A (trifluoromethyl)-3-pyridyl]pyrrol-2- 8.62 (br s, 1H), 7.81 (d, 1H), 7.72 (d, 2H), 7.32 (d, 2H), yl]-N-[3-(dimethylamino)- 7.16 (d, 2H), 7.11 (d, 2H), 6.67 (d, 2H), 3.29 (br d, 2H), propyl]benzamide hydrochloride 3.05 (br s, 2H), 2.73 (d, 6H) and 1.88 (br s, 2H). 52 3-[5-(4-bromophenyl)-1-[2- C (DMSO-d.sub.6) δ 8.67 (br s, 1H), 7.82-7.79 (m, 2H), 7.59-7.56 4.92 588 A (trifluoromethyl)phenyl]pyrrol-2-yl]- (m, 2H), 7.50 (t, 2H), 7.30 (d, 2H), 6.97 (d, 2H), 6.90 (d, N-[2-(dimethylamino)ethyl]-4- 1H), 6.54 (d, 1H), 6.36 (d, 1H), 3.74 (q, 2H), 3.63 (s, 3H), methoxy-benzamide hydrochloride 3.37 (t, 2H) and 2.99 (s, 6H). 53 5-[5-(4-bromophenyl)-1-[2- A (DMSO-d.sub.6) δ 9.71 (br s, 1H), 8.43 (t, 1H), 7.78-7.75 (m, 5.01 586 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 3H), 7.69-7.65 (m, 1H), 7.62 (d, 1H), 7.39-7.37 (m, 2H), N-[2-(dimethylamino)ethyl]-2- 7.10 (dd, 1H), 6.99-6.96 (m, 3H), 6.57 (d, 1H), 6.47 (d, methoxy-benzamide hydrochloride 1H), 3.82 (s, 3H), 3.62-3.57 (m, 2H), 3.20 (t, 2H) and 2.81 (s, 6H). 54 [3-[5-(4-bromophenyl)-1-[2- A (DMSO-d.sub.6) δ 10.68 (br s, 1H), 7.79 (m, 3H), 7.71-7.70 (m, 4.95 582 A (trifluoromethyl)phenyl]pyrrol-2- 1H), 7.39 (d, 2H), 7.29 (s, 2H), 7.18-7.14 (m, 2H), 6.98 (d, yl]phenyl]-[(3R)-3-(dimethylamino) 2H), 6.60 (s, 2H), 3.86-3.82 (m, 1H), 3.64-3.61 (m, 2H), pyrrolidin-1-yl]methanone 3.25-3.22 (m, 1H), 2.79-2.69 (m, 6H) and 2.22-2.16 (m, hydrochloride 2H). 55 [3-[5-(4-bromophenyl)-1-[2- A (DMSO-d.sub.6) δ 10.89 (br s, 1H), 7.81-7.77 (m, 3H), 7.72- 4.91 582 A (trifluoromethyl)phenyl]pyrrol-2- 7.70 (m, 1H), 7.39 (d, 2H), 7.29-7.14 (m, 4H), 6.98 (d, 2H), yl]phenyl]-[(3S)-3-(dimethylamino) 6.61 (s, 2H), 3.85-3.81 (m, 2H), 3.66-3.62 (m, 2H), 3.25- pyrrolidin-1-yl]methanone 3.18 (m, 1H), 2.80-2.70 (m, 6H) and 2.33-1.99 (m, 2H). hydrochloride 56 3-[1-(2-aminophenyl)-5-(4- A (DMSO-d.sub.6) δ 10.19 (br s, 1H), 8.84 (t, 1H), 7.95 (s, 1H), 4.83 505 A bromophenyl)pyrrol-2-yl]-N-[2- 7.68 (dt, 1H), 7.40 (d, 2H), 7.26-7.15 (m, 4H), 7.08 (td, (dimethylamino)ethyl]benzamide 1H), 6.91 (dd, 1H), 6.71 (dd, 1H), 6.68 (d, 1H), 6.62 (d, hydrochloride 1H), 6.52 (td, 1H), 3.65-3.60 (m, 2H), 3.27-3.23 (m, 2H) and 2.84 (d, 6H, —CH.sub.3). 57 4-[5-(4-cyanophenyl)-1-[2- C (DMSO-d.sub.6) δ 10.15 (br s, 1H), 8.78 (d, 1H), 7.89-7.82 (m, 4.56 503 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 3H), 7.76-7.74 (m, 3H), 7.66 (d, 2H), 7.20 (d, 2H), 7.14 (d, N-[2-(dimethylamino)ethyl] 2H), 6.83 (d, 1H), 6.74 (d, 1H), 3.60-3.57 (m, 2H), 3.23 (s, benzamide hydrochloride 2H) and 2.80 (s, 6H). 58 4-[5-(4-chlorophenyl)-1-[2- C (DMSO-d.sub.6) δ 9.73 (br s, 1H), 8.55 (t, 1H), 7.85-7.79 (m, 4.95 526 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 3H), 7.72-7.65 (m, 3H), 7.28 (d, 2H), 7.12 (d, 2H), 7.06 (d, N-[3-(dimethylamino)propyl] 2H), 6.69 (d, 1H), 6.62 (d, 1H), 3.31-3.26 (m, 2H), 3.07- benzamide hydrochloride 3.03 (m, 2H), 2.74 (s, 6H) and 1.90-1.82 (m, 2H). 59 N-[2-(dimethylamino)ethyl]-4-[5-(4- A (DMSO-d.sub.6) δ 9.52 (br s, 1H), 8.63 (t, 1H), 7.86-7.77 (m, 4.79 496 A fluorophenyl)-1-[2-(trifluoromethyl) 3H), 7.69 (d, 3H), 7.14-7.04 (m, 6H), 6.69 (d, 1H), 6.56 (d, phenyl]pyrrol-2-yl]benzamide 1H), 3.59-3.54 (m, 2H), 3.23-3.21 (m, 2H) and 2.81 (d, hydrochloride 6H). 60 N-[3-(dimethylamino)propyl]-4-[5- A (DMSO-d.sub.6) δ 9.65 (br s, 1H), 8.54 (t, 1H), 7.85-7.77 (m, 4.79 510 A (4-fluorophenyl)-1-[2- 3H), 7.71-7.65 (m, 3H), 7.13-7.04 (m, 6H), 6.67 (d, 1H), (trifluoromethyl)phenyl]pyrrol-2- 6.55 (d, 1H), 3.29 (q, 2H), 3.08-3.03 (m, 2H), 2.75 (d, 6H) yl]benzamide hydrochloride and 1.88-1.81 (m, 2H). 61 6-[5-(4-chlorophenyl)-1-[2- G (DMSO-d.sub.6) δ 9.71 (br s, 1H), 8.77 (t, 1H), 8.50 (d, 1H), 4.85 513 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 8.10 (dd, 1H), 7.77-7.72 (m, 2H), 7.68-7.62 (m, 3H), 7.28 N-[2-(dimethylamino)ethyl]pyridine- (d, 2H), 7.16 (d, 1H), 7.09 (d, 2H), 6.64 (d, 1H), 3.57 (br d, 3-carboxamide hydrochloride 2H), 3.22 (br d, 2H) and 2.80 (d, 6H). 62 6-[5-(4-chlorophenyl)-1-[2- G (DMSO-d.sub.6) δ 10.09 (br s, 1H), 8.69 (t, 1H), 8.49 (d, 1H), 4.88 527 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 8.08 (dd, 1H), 7.78-7.72 (m, 2H), 7.68-7.61 (m, 3H), 7.29- N-[3-(dimethylamino)propyl]- 7.27 (m, 2H), 7.16 (d, 1H), 7.09 (d, 2H), 6.64 (d, 1H), 3.28 pyridine-3-carboxamide (q, 2H), 3.07-3.02 (m, 2H), 2.72 (d, 6H) and 1.90-1.83 (m, hydrochloride 2H). 63 4-[5-(4-chlorophenyl)-1-[5-isobutyl- C (DMSO-d.sub.6) δ 10.01 (br s, 1H), 8.72 (t, 1H), 7.72-7.63 (m, 5.17 568 A 2-(trifluoromethyl)phenyl]pyrrol-2- 4H), 7.47 (d, 1H), 7.26 (d, 2H), 7.15 (d, 2H), 7.09 (d, 2H), yl]-N-[2-(dimethylamino)ethyl]- 6.68 (d, 1H), 6.60 (d, 1H), 3.58 (q, 2H), 3.22 (q, 2H), 2.80 benzamide hydrochloride (s, 6H), 2.57 (d, 2H), 1.84-1.81 (m, 1H) and 0.76 (q, 6H). 64 4-[5-(4-chlorophenyl)-1-[5-isobutyl- C (DMSO-d.sub.6) δ 9.47 (br s, 1H), 8.52 (t, 1H), 7.69-7.62 (m, 5.28 582 A 2-(trifluoromethyl)phenyl]pyrrol-2- 4H), 7.47 (d, 1H), 7.26 (d, 2H), 7.15-7.07 (m, 4H), 6.68 (d, yl]-N-[3-(dimethylamino)propyl]- 1H), 6.60 (d, 1H), 3.28 (t, 2H), 3.05 (t, 2H), 2.76 (s, 6H), benzamide hydrochloride 2.58 (d, 2H), 1.84-1.79 (m, 3H) and 0.76 (d, 6H). 65 4-[5-(4-bromophenyl)-1-[2- K (DMSO-d.sub.6) δ 7.89-7.79 (m, 3H), 7.73-7.69 (m, 1H), 7.62 5.46 521 A (trifluoromethyl)phenyl]pyrrol-2- (d, 2H), 7.41 (d, 2H), 7.31 (s, 2H), 7.21 (d, 2H), 7.01 (d, yl]benzenesulfonamide 2H), 6.72 (d, 1H), 6.63 (d, 1H). 66 4-[5-(6-cyano-3-pyridyl)-1-[2- A (DMSO-d.sub.6) δ 9.94 (br s, 1H), 8.76 (t, 1H), 8.50 (s, 1H), 4.37 504 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 7.96 (d, 1H), 7.90-7.85 (m, 3H), 7.80-7.74 (m, 3H), 7.46 N-[2-(dimethylamino)ethyl]- (dd, 1H), 7.17 (d, 2H), 7.03 (d, 1H), 6.80 (d, 1H), 3.58 (br benzamide hydrochloride d, 2H), 3.22 (br s, 2H) and 2.80 (s, 6H). 67 3-chloro-N-[2-(dimethylamino)- A (DMSO-d.sub.6) δ 9.90 (br s, 1H), 9.07 (s, 1H), 8.91 (t, 1H), 5.00 513 A ethyl]-4-[5-phenyl-1-[4- 8.81 (d, 1H), 7.99 (d, 1H), 7.73 (d, 1H), 7.68 (dd, 1H), (trifluoromethyl)-3-pyridyl]pyrrol-2- 7.27-7.18 (m, 4H), 7.10-7.08 (m, 2H), 6.65-6.63 (m, 2H), yl]benzamide hydrochloride 3.61-3.57 (m, 2H), 3.23 (q, 2H) and 2.81 (d, 6H). 68 3-chloro-N-[3-(dimethylamino)- A (DMSO-d.sub.6) δ 9.79 (br s, 1H), 9.06 (s, 1H), 8.81 (d, 1H), 5.00 527 A propyl]-4-[5-phenyl-1-[4- 8.75 (t, 1H), 7.92 (d, 1H), 7.73 (d, 1H), 7.63 (dd, 1H), 7.30- (trifluoromethyl)-3-pyridyl]pyrrol-2- 7.18 (m, 4H), 7.10-7.08 (m, 2H), 6.64-6.62 (m, 2H), 3.31- yl]benzamide hydrochloride 3.27 (q, 2H), 3.09-3.03 (m, 2H), 2.75 (d, 6H) and 1.90-1.82 (m, 2H). 69 6-[5-(4-chlorophenyl)-1-[4- G (DMSO-d.sub.6) δ 9.94 (br s, 1H), 8.98 (s, 1H) 8.88-8.82 (m, 4.70 514 A (trifluoromethyl)-3-pyridyl]pyrrol-2- 2H), 8.44 (d, 1H), 8.18 (dd, 1H), 7.90 (d, 1H), 7.79 (d, 1H), yl]-N-[2-(dimethylamino)ethyl]- 7.33 (d, 2H), 7.25 (d, 1H), 7.14 (d, 2H), 6.68 (d, 1H), 3.60- pyridine-3-carboxamide 3.56 (m, 2H), 3.22 (q, 2H) and 2.79 (d, 6H). hydrochloride 70 4-[5-(4-chlorophenyl)-1-[2- C (DMSO-d.sub.6) δ 10.71 (br s, 1H), 8.72 (d, 1H), 7.85-7.79 (m, 4.88 524 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 3H), 7.69 (q, 3H), 7.28 (d, 2H), 7.12 (d, 2H), 7.06 (d, 2H), N-[(3R)-1-methylpyrrolidin-3- 6.70 (d, 1H), 6.62 (d, 1H), 4.62-4.50 (br d, 1H), 3.82-3.66 yl]benzamide hydrochloride (br d, 1H), 3.30-3.20 (br d, 1H), 3.03 (br d, 1H), 2.83 (br s, 3H), 2.33 (br s, 1H), 2.19 (br d, 1H) and 2.05 (br d, 1H). 71 4-[5-(4-chlorophenyl)-1-[2- C (DMSO-d.sub.6) δ 10.84 (br s, 1H), 8.74 (d, 1H), 7.84-7.78 (m, 4.89 524 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 3H), 7.75-7.69 (m, 3H), 7.27 (d, 2H), 7.12 (d, 2H), 7.06 (d, N-[(3S)-1-methylpyrrolidin-3- 2H), 6.70 (d, 1H), 6.62 (d, 1H), 4.64-4.52 (br d, 1H), 3.82- yl]benzamide hydrochloride 3.67 (br d, 1H), 3.51 (br s, 1H), 3.31 (br d, 1H), 3.06 (br s, 1H), 2.83 (br s, 3H), 2.44 (s, 1H) and 2.00 (d, 1H). 72 4-[5-(3-chlorophenyl)-1-[2- C (DMSO-d.sub.6) δ 10.01 (br s, 1H), 8.75 (t, 1H), 7.89-7.80 (m, 5.73 512 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 3H), 7.74-7.72 (m, 3H), 7.23-7.22 (m, 2H), 7.15-7.13 (m, N-[2-(dimethylamino)ethyl]- 2H), 7.06-7.01 (m, 2H), 6.70 (d, 2H), 3.59-3.56 (m, 2H), benzamide hydrochloride 3.22 (t, 2H) and 2.80 (s, 6H). 73 4-[5-(4-chlorophenyl)-1-[4- A (DMSO-d.sub.6) δ 9.93 (s, 1H), 8.85 (d, 2H), 8.77 (d, 1H), 7.70 5.79 543 A (trifluoromethyl)-3-pyridyl]pyrrol-2- (d, 1H), 7.45 (dd, 1H), 7.36 (d, 1H), 7.28 (d, 3H), 7.07 (d, yl]-N-[2-(dimethylamino)ethyl]-3- 1H), 6.61 (d, 1H), 6.44 (d, 1H), 3.63-3.59 (m, 2H), 3.56 (s, methoxy-benzamide hydrochloride 3H), 3.24 (br d, 2H) and 2.82 (d, 6H). 74 4-[5-(4-chlorophenyl)-1-[4- A (DMSO-d.sub.6) δ 9.90 (s, 1H), 8.85 (s, 1H), 8.77 (d, 1H), 8.68 5.81 557 A (trifluoromethyl)-3-pyridyl]pyrrol-2- (br s, 1H), 7.70 (d, 1H), 7.41-7.39 (d, 1H), 7.32-7.24 (m, yl]-N-[3-(dimethylamino)propyl]-3- 4H), 7.06 (d, 2H), 6.61 (d, 1H), 6.43 (d, 1H), 3.56 (s, 3H), methoxy-benzamide hydrochloride 3.30 (d, 2H), 3.06 (t, 2H), 2.75 (s, 6H) and 1.88 (t , 2H). 75 4-[5-(5-chloro-2-pyridyl)-1-[2- G (DMSO-d.sub.6) δ 9.85 (br s, 1H), 8.72 (t, 1H), 8.08 (d, 1H), 5.13 513 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 7.81-7.64 (m, 7H), 7.52 (d, 1H), 7.16 (d, 2H), 7.06 (d, 1H), N-[2-(dimethylamino)ethyl]- 6.71 (d, 1H), 3.60 (q, 2H), 3.21 (q, 2H) and 2.80 (d, 6H). benzamide hydrochloride 76 4-[5-(5-chloro-2-pyridyl)-1-[2- G (DMSO-d.sub.6) δ 9.99 (br s, 1H), 8.60 (t, 1H), 8.08 (d, 1H), 5.16 527 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 7.81-7.73 (m, 3H), 7.66 (t, 4H), 7.52 (d, 1H), 7.14 (d, 2H), N-[3-(dimethylamino)propyl]- 7.06 (d, 1H), 6.70 (d, 1H), 3.28 (q, 2H), 3.07-3.02 (m, 2H), benzamide hydrochloride 2.73 (d, 6H) and 1.89-1.82 (m, 2H). 77 4-[5-(4-chlorophenyl)-1-[3- C (DMSO-d.sub.6) δ 10.11 (s, 1H), 8.78 (t, 1H), 7.78-7.74 (m, 3H), 4.93 512 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 7.60 (t, 1H), 7.52 (s, 1H), 7.42 (s, 1H), 7.31 (d, 2H), 7.14 N-[2-(dimethylamino)ethyl]- (d, 2H), 7.08 (d, 2H), 6.67 (d, 1H), 6.60 (d, 1H), 3.60 (q, benzamide hydrochloride 2H), 3.23 (t, 2H) and 2.80 (s, 6H). 78 4-[5-(4-chlorophenyl)-1-[3- C (DMSO-d.sub.6) δ 10.26 (s, 1H), 8.63 (t, 1H), 7.76-7.71 (m, 3H), 4.93 526 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 7.60 (t, 1H), 7.51 (s, 1H), 7.42 (d, 1H), 7.32-7.30 (d, 2H), N-[3-(dimethylamino)propyl]- 7.13 (d, 2H), 7.07 (d, 2H), 6.65 (d, 1H), 6.59 (d, 1H), 3.30 benzamide hydrochloride (q, 2H), 3.05 (t, 2H), 2.73 (s, 6H) and 1.92-1.87 (m, 2H). 79 4-[5-(4-chlorophenyl)-1-[3- C (DMSO-d.sub.6) δ 11.77 (s, 1H), 10.00 (br s, 1H), 8.83 (d, 2H), 4.85 513 A (trifluoromethyl)-2-pyridyl]pyrrol-2- 8.30 (d, 1H), 7.95 (q, 4H), 7.62 (q, 1H), 7.34 (d, 2H), 7.22 yl]-N-[2-(dimethylamino)ethyl]- (d, 2H), 6.86 (s, 1H), 3.65 (q, 2H), 3.28 (q, 2H) and 2.85 benzamide hydrochloride (d, 6H). 80 4-[5-(4-chlorophenyl)-1-[3- C (DMSO-d.sub.6) δ 11.77 (s, 1H), 10.32 (br s, 1H), 8.83 (d, 1H), 4.92 527 A (trifluoromethyl)-2-pyridyl]pyrrol-2- 8.72 (t, 1H), 8.30 (d, 1H), 7.92 (s, 4H), 7.63 (q, 1H), 7.34 yl]-N-[3-(dimethylamino)propyl]- (d, 2H), 7.22 (d, 2H), 6.85 (s, 1H), 3.36 (q, 2H), 3.12-3.07 benzamide hydrochloride (m, 2H), 2.76 (d, 6H) and 1.98-1.91 (m, 2H). 81 4-[5-(4-chlorophenyl)-1-[4- C (DMSO-d.sub.6) δ 10.82 (br s, 1H), 9.24 (s, 1H), 8.92 (d, 1H), 5.79 555 A (trifluoromethyl)-3-pyridyl]pyrrol-2- 8.86 (t, 1H), 7.82-7.77 (m, 3H), 7.33-7.31 (m, 2H), 7.17 (d, yl]-N-(2-morpholinoethyl)- 2H), 7.12-7.10 (m, 2H), 6.72 (d, 1H), 6.65 (d, 1H), 3.97 (d, benzamide hydrochloride 2H), 3.80 (t, 2H), 3.66-3.64 (m, 2H), 3.53 (d, 2H), 3.28- 3.26 (m, 2H) and 3.13-3.06 (m, 2H). 82 4-[4-(4-chlorophenyl)-5-[2- L (DMSO-d.sub.6) δ 9.79 (br s, 1H), 8.81 (s, 1H), 8.31 (s, 1H), 5.04 513 A (trifluoromethyl)phenyl]pyrazol-1- 7.85-7.83 (m, 5H), 7.78-7.77 (m, 1H), 7.33 (d, 2H), 7.31 (d, yl]-N-[2-(dimethylamino)ethyl]- 2H), 7.15 (d, 2H), 3.58 (br d, 2H), 3.23 (br s, 2H) and 2.81 benzamide hydrochloride (s, 6H). 83 4-[5-(4-chlorophenyl)-1-[2- C (DMSO-d.sub.6) δ 9.79 (br s, 1H), 8.81 (s, 1H), 8.31 (s, 1H), 5.48 526 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 7.85-7.83 (m, 5H), 7.78-7.77 (m, 1H), 7.33 (d, 2H), 7.31 (d, N-[2-(dimethylamino)ethyl]-N- 2H), 7.15 (d, 2H), 3.58 (br d, 2H), 3.23 (br s, 2H) and 2.81 methyl-benzamide hydrochloride (s, 6H). 84 [4-[5-(4-chlorophenyl)-1-[2- C (DMSO-d.sub.6) δ 9.36 (br s, 2H), 7.81-7.79 (m, 3H), 7.73-7.70 5.29 510 A (trifluoromethyl)phenyl]pyrrol-2- (m, 1H), 7.31-7.26 (m, 4H), 7.10 (d, 2H), 7.06 (d, 2H), 6.66 yl]phenyl]-piperazin-1-yl- (d, 1H), 6.61 (d, 1H), 3.65 (br s, 4H) and 3.11 (br s, 4H). methanone hydrochloride 85 [4-[5-(4-chlorophenyl)-1-[2- C (DMSO-d.sub.6) δ 7.75-7.59 (m, 4H), 7.33 (d, 2H), 7.22-7.17 5.41 524 A (trifluoromethyl)phenyl]pyrrol-2- (m, 4H), 7.06 (d, 2H), 6.64 (d, 1H), 6.56 (d, 1H), 3.37 (br s, yl]phenyl]-(4-methylpiperazin-1- 4H), 3.06 (br s, 4H) and 2.74 (s, 3H). yl)methanone hydrochloride 86 4-[5-(4-chlorophenyl)-1-[2- C (DMSO-d.sub.6) δ 8.42 (t, 1H), 7.82-7.78 (m, 3H), 7.72-7.64 (m, 6.12 499 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 3H), 7.27 (d, 2H), 7.11-7.05 (m, 4H), 6.68 (d, 1H), 6.61 (d, N-(2-methoxyethyl)benzamide 1H), 3.41-3.34 (m, 4H) and 3.24 (s, 3H). 87 4-[5-(4-chlorophenyl)-1-[2- C (DMSO-d.sub.6) δ 11.34 (br s, 1H), 9.61 (br s, 2H), 8.73 (s, 1H), 5.28 553 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 7.83-7.77 (m, 3H), 7.74-7.72 (m, 3H), 7.28 (d, 2H), 7.12 (d, N-(2-piperazin-1-ylethyl)benzamide 2H), 7.06 (d, 2H), 6.70 (d, 1H), 6.62 (d, 1H), 3.60 (br s, hydrochloride 3H), 3.41-3.28 (m, 6H) and 3.16 (br s, 3H). 88 4-[5-(4-chlorophenyl)-1-[2- C (DMSO-d.sub.6) δ 10.85 (br s, 2H), 8.66 (br s, 1H), 7.86-7.79 5.34 567 A (trifluoromethyl)phenyl]pyrrol-2-yl]- (m, 3H), 7.73-7.69 (m, 3H), 7.28 (d, 2H), 7.13 (d, 2H), 7.06 N-[2-(4-methylpiperazin-1- (d, 2H), 6.70 (d, 1H), 6.62 (d, 1H), 3.77 (t, 2H), 3.52-3.50 yl)ethyl]benzamide hydrochloride (m, 4H), 3.24 (br s, 6H) and 2.83 (s, 3H). 89 4-[5-(4-chlorophenyl)-1-[4- C (DMSO-d.sub.6) δ 9.88 (br s, 1H), 9.08 (s, 1H), 8.88 (s, 1H), 5.04 531 A (trifluoromethyl)-3-pyridyl]pyrrol-2- 8.86 (d, 1H), 7.78 (d, 1H), 7.67-7.61 (m, 2H), 7.33 (d, 2H), yl]-N-[2-(dimethylamino)ethyl]-3- 7.27 (t, 1H), 7.10 (d, 2H), 6.67 (dd, 2H), 3.64-3.57 (m, 2H), fluoro-benzamide hydrochloride 3.24-3.22 (m, 2H) and 2.80 (s, 6H). 90 1-[4-[5-(4-chlorophenyl)-1-[2- N (DMSO-d.sub.6) δ 10.85 (br s, 2H), 8.66 (br s, 1H), 7.86-7.79 5.29 527 A (trifluoromethyl)phenyl]pyrrol-2- (m, 3H), 7.73-7.69 (m, 3H), 7.28 (d, 2H), 7.14-7.12 (d, 2H), yl]phenyl]-3-[2-(dimethylamino)- 7.06 (d, 2H), 6.70 (d, 1H), 6.62 (d, 1H), 3.77 (t, 2H), 3.52- ethyl]urea hydrochloride 3.50 (m, 4H), 3.24 (br s, 6H) and 2.83 (s, 3H). 91 2-[4-[5-(4-chlorophenyl)-1-[2- A (DMSO-d.sub.6) δ 9.80 (br s, 1H), 8.35 (t, 1H), 7.83-7.76 (m, 5.36 526 A (trifluoromethyl)phenyl]pyrrol-2- 3H), 7.68 (t, 1H), 7.26 (d, 2H), 7.10-7.03 (m, 4H), 6.69 (d, yl]phenyl]-N-[2-(dimethylamino)- 2H), 6.57 (d, 1H), 6.51 (d, 1H), 3.57 (s, 2H), 3.37 (d, 2H), ethyl]acetamide hydrochloride 3.10 (t, 2H) and 2.51 (d, 6H). 92 4-[3-(4-chlorophenyl)-4-[2- O (DMSO-d.sub.6) δ 10.06-9.94 (br d, 2H), 8.96 (dt, 2H), 8.13 (d, 4.96 514 A (trifluoromethyl)phenyl]isoxazol-5- 1H), 8.06 (d, 1H), 8.01 (d, 1H), 7.96-7.88 (m, 5H), 7.84- yl]-N-[2-(dimethylamino)ethyl]- 7.76 (m, 4H), 7.67 (t, 1H), 7.54-7.45 (m, 6H), 7.37 (d, 2H), benzamide hydrochloride 3.68-3.57 (br m, 4H), 3.30-3.24 (br d, 4H) and 2.83 (br d, 6H). 93 4-[3-(4-chlorophenyl)-4-[2- M (DMSO-d.sub.6) δ 10.03 (br s, 1H), 8.79 (t, 1H), 7.87-7.86 (m, 4.81 513 A (trifluoromethyl)phenyl]-1H-pyrazol- 1H), 7.81-7.77 (m, 3H), 7.72-7.68 (m, 1H), 7.60-7.58 (m, 5-yl]-N-[2-(dimethylamino)ethyl] 1H), 7.38-7.32 (m, 4H), 7.29-7.27 (m, 2H), 3.59 (q, 2H), benzamide hydrochloride 3.23 (q, 2H) and 2.80 (d, 6H). 94 N-(2-aminoethyl)-4-[5-(4- C (DMSO-d.sub.6) δ 8.69 (br s, 1H), 8.07 (br s, 3H), 7.83-7.72 (m, 5.40 484 A chlorophenyl)-1-[2-(trifluoromethyl)- 6H), 7.28 (d, 2H), 7.12-7.05 (m, 4H), 6.65 (dd, 2H), 3.47 phenyl]pyrrol-2-yl]benzamide (br s, 2H) and 2.95 (br s, 2H). hydrochloride 95 4-[5-(4-chlorophenyl)-1-[2- C (DMSO-d.sub.6) δ 10.63 (br s, 1H), 8.79 (s, 1H), 7.86-7.79 (m, 5.30 554 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 3H), 7.74-7.69 (m, 3H), 7.27 (d, 2H), 7.13 (d, 2H), 7.07 (s, N-(2-morpholinoethyl)benzamide 2H), 6.71 (d, 1H), 6.62 (d, 1H), 3.97 (d, 2H), 3.77 (t, 2H), hydrochloride 3.63 (d, 2H), 3.52 (d, 2H), 3.26 (br s, 2H) and 3.09 (d, 2H). 96 4-[5-(4-chlorophenyl)-1-(4-methyl- C (DMSO-d.sub.6) δ 9.25 (s, 1H), 9.04 (br s, 2H), 8.92 (d, 1H), 5.11 555 A 3-pyridyl)pyrrol-2-yl]-N-[2-[[(3S)- 8.70 (br s, 1H), 7.81 (d, 1H), 7.76 (d, 2H), 7.32 (d, 2H), tetrahydrofuran-3-yl]amino]ethyl]- 7.17 (d, 2H), 7.11 (d, 2H), 6.72 (d, 1H), 6.65 (d, 1H), 3.91- benzamide hydrochloride 3.84 (br m, 3H), 3.78-3.76 (br m, 1H), 3.65-3.63 (br m, 1H), 3.55-3.54 (br m, 2H), 3.08 (br s, 2H) and 2.21-2.18 (br m, 2H). 97 4-[5-(4-chlorophenyl)-1-[4-fluoro-2- C (DMSO-d.sub.6) δ 10.03 (br s, 1H), 8.77 (t, 1H), 8.02-7.99 (m, 5.04 530 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 1H), 7.77-7.70 (m, 4H), 7.31 (dd, 2H), 7.15 (d, 2H), 7.09 N-[2-(dimethylamino)ethyl]- (dd, 2H), 6.69 (d, 1H), 6.22 (d, 1H), 3.61-3.57 (m, 2H), benzamide hydrochloride 3.22 (t, 2H) and 2.80 (s, 6H). 98 4-[5-(4-chlorophenyl)-1-[4-chloro-2- C (DMSO-d.sub.6) δ 9.97 (br s, 1H), 8.82 (t, 1H), 7.90-7.82 (m, 5.29 546 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 4H), 7.64 (d, 1H), 7.27 (d, 2H), 7.09 (d, 2H), 6.82 (d, 1H), N-[2-(dimethylamino)ethyl]- 6.76 (d, 1H), 6.63 (d, 1H), 3.53-3.50 (m, 2H), 3.20 (t, 2H) benzamide hydrochloride and 2.78 (s, 6H). 99 5-[5-(4-chlorophenyl)-1-[2- A (DMSO-d.sub.6) δ 9.97 (br s, 1H), 8.82 (t, 1H), 7.90-7.82 (m, 4.96 518 A (trifluoromethyl)phenyl]pyrrol-2-yl]- 4H), 7.64 (d, 1H), 7.27 (d, 2H), 7.09 (d, 2H), 6.82 (d, 1H), N-[2-(dimethylamino)ethyl]- 6.77 (d, 1H), 6.63 (d, 1H), 3.53-3.50 (m, 2H), 3.20 (t, 2H) thiophene-2-carboxamide and 2.78 (s, 6H). hydrochloride 100 2-[4-[5-(4-chlorophenyl)-1-[2- A (DMSO-d.sub.6) δ 9.97 (br s, 1H), 8.82 (t, 1H), 7.90-7.82 (m, 8.18 568 A (trifluoromethyl)phenyl]pyrrol-2- 4H), 7.64 (d, 1H), 7.27 (d, 2H), 7.09 (d, 2H), 6.82 (d, 1H), yl]phenyl]-N-(2-morpholinoethyl)- 6.76 (d, 1H), 6.63 (d, 1H), 3.53-3.50 (m, 2H), 3.19 (t, 2H) acetamide hydrochloride and 2.78 (s, 6H). 101 2-[4-[5-(4-chlorophenyl)-1-[2- A (DMSO-d.sub.6) δ 11.58 (br s, 1H), 9.59 (br s, 2H), 8.38 (s, 1H), 5.78 567 A (trifluoromethyl)phenyl]pyrrol-2- 7.83-7.76 (m, 3H), 7.68 (t, 1H), 7.25 (dd, 2H), 7.09 (d, 2H), yl]phenyl]-N-(2-piperazin-1- 7.04 (dd, 2H), 6.99 (d, 2H), 6.57 (d, 1H), 6.51 (d, 1H), 3.73 ylethyl)acetamide hydrochloride (br s, 2H), 3.57 (br s, 4H), 3.41 (br s, 2H), 3.38 (br s, 2H) and 3.21 (br s, 4H). 102 [3-[5-(4-bromophenyl)-1-[2- A (DMSO-d.sub.6) δ 8.79-8.76 (m, 2H), 8.37 (d, 1H), 7.96-7.93 5.75 644 A (trifluoromethyl)phenyl]pyrrol-2- (m, 1H), 7.81-7.76 (m, 3H), 7.70-7.66 (m, 1H), 7.40 (d, yl]phenyl]-[4-(3-pyridylmethyl)-1- 2H), 7.27 (t, 1H), 7.13 (d, 2H), 6.70-6.96 (m, 3H), 6.61 (s, piperidyl]methanone hydrochloride 2H), 4.34 (br s, 1H), 3.18 (br s, 1H), 2.75-2.73 (m, 3H), 1.89-1.82 (m, 1H), 1.59-1.53 (m, 1H), 1.44 (br s, 2H), 1.10 (br s, 1H) and 1.01 (br s, 1H). 103 4-[5-(4-chlorophenyl)-1-(o- C (DMSO-d.sub.6) 8.22 (t, 1H), 7.84-7.78 (m, 3H), 7.72-7.70 (m, 4.61 526 A tolyl)pyrrol-2-yl]-N-[(2S)-2- 1H), 7.63 (d, 2H), 7.27 (d, 2H), 7.11 (d, 2H), 7.06 (d, 2H), (dimethylamino)propyl]benzamide 6.68 (d, 1H), 6.61 (d, 1H), 3.30-3.25 (m, 1H), 3.15-3.08 (m, 1H), 2.75-2.73 (m, 1H), 2.18 (s, 6H) and 0.88 (d, 3H). 104 4-[4-(4-chlorophenyl)-5-[2- L (DMSO-d.sub.6) 10.64 (s, 1H), 8.92 (t, 1H), 8.31 (s, 1H), 7.88- 4.14 555 A (trifluoromethyl)phenyl]pyrazol-1- 7.84 (m, 5H), 7.78-7.75 (m, 1H), 7.33 (d, 2H), 7.31 (d, 2H), yl]-N-(2-morpholinoethyl)- 7.15 (d, 2H), 3.97 (br d, 2H), 3.77 (br t, 2H), 3.65-3.62 (m, benzamide hydrochloride 2H), 3.53 (br d, 2H), 3.28 (br d, 2H) and 3.13-3.08 (m, 2H). 105 4-[4-(4-chlorophenyl)-5-[2- L (DMSO-d.sub.6) 9.91 (s, 1H), 8.68 (t, 1H), 8.30 (s, 1H), 7.87- 4.39 527 A (trifluoromethyl)phenyl]pyrazol-1- 7.81 (m, 3H), 7.79-7.74 (m, 3H), 7.33-7.30 (m, 4H), 7.15 yl]-N-[3-(dimethylamino)propyl]- (dd, 2H), 3.29 (q, 2H), 3.09-3.03 (m, 2H), 2.74 (d, 6H) and benzamide hydrochloride 1.91-1.83 (m, 2H). 106 N-[2-(dimethylamino)ethyl]-4-[4-(4- L (DMSO-d.sub.6) 9.80 (br s, 1H), 8.82 (t, 1H), 8.27 (s, 1H), 7.85- 3.97 497 C fluorophenyl)-5-[2- 7.83 (m, 5H), 7.78-7.74 (m, 1H), 7.32 (d, 2H), 7.19-7.08 (trifluoromethyl)phenyl]pyrazol-1- (m, 4H), 3.60-3.56 (m, 2H), 3.23 (d, 2H) and 2.81 (s, 6H). yl]benzamide hydrochloride 107 2-[4-[5-(4-chlorophenyl)-1-[2- J (DMSO-d.sub.6) 10.23 (br s, 1H), 7.81-7.79 (m, 3H), 7.77-7.74 5.90 544 C (trifluoromethyl)phenyl]pyrrol-2- (m, 1H), 7.72-7.69 (m, 1H), 7.25 (dd, 2H), 7.14 (d, 2H), yl]phenyl]-N-[2- 7.03 (dd, 2H), 7.00 (d, 4H), 6.57 (d, 1H), 6.53 (d, 1H), 3.36 (dimethylamino)ethyl]-2-methyl- (t, 2H), 3.05 (q, 2H), 2.69 (d, 6H) and 1.40 (s, 6H). propanamide hydrochloride

(31) Synthetic Route A

(32) (Illustrated with reference to Example 2)

Example 2

3-[5-(4-Bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]benzamide Hydrochloride)

(33) ##STR00161##

2A. Methyl 3-[4-(4-bromophenyl)-4-oxo-butanoyl]benzoate

(34) Zinc chloride (1.98 g, 14.5 mmol) was heated to melting under vacuum and then allowed to cool to room temperature. Benzene (7 mL), t-butanol (0.83 g, 11.2 mmol) and triethylamine (1.13 g, 11.2 mmol) were added and the mixture stirred at room temperature for 2 hours under a nitrogen atmosphere at which point the zinc chloride had fully dissolved. Methyl 3-acetylbenzoate (2.0 g, 11.2 mmol) and 2-bromo-1-(4-bromophenyl)ethanone (1.87 g, 6.73 mmol) were added and the mixture stirred for 48 hours at room temperature. The reaction mixture was diluted with water (100 ml) and extracted with EtOAc (3×100 mL). The combined organic extracts were dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on silica gel (60-120 mesh) using 10% EtOAc/hexanes as the eluent to give the title compound (1.3 g, 48%) as a colourless oil.

2B. Methyl 3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]benzoate

(35) A stirred solution of methyl 3-[4-(4-bromophenyl)-4-oxo-butanoyl]benzoate (0.1 g, 0.26 mmol), 2-(trifluoromethyl)aniline (0.043 g, 0.26 mmol) and PTSA (5 mg, 0.02 mmol) in dioxane (1 mL) was heated to 150° C. under microwave irradiation for one hour. The mixture was allowed to cool to room temperature and the solvents evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (60-120 mesh) using 8% EtOAc/hexanes as the eluent to give the title compound (50 mg, 38%) as an off-white solid.

2C. 3-[5-(4-Bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]benzoic Acid

(36) A mixture of methyl 3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]benzoate (50 mg, 0.09 mmol) and lithium hydroxide monohydrate (8 mg, 0.18 mmol) in THF (1 mL) and water (1 mL) was stirred at room temperature for 16 hours. The pH of the mixture was adjusted to 4 with 1N HCl and then extracted with EtOAc (2×50 mL). The combined organic extracts were dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave a solid that was triturated with pentane (3×2 mL) and dried to give the title compound (27 mg, 56%) as a beige solid.

2D. 3-[5-(4-Bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]benzamide hydrochloride)

(37) HATU (0.175 g, 0.46 mmol) was added to a stirred solution of 3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]benzoic acid (0.15 g, 0.30 mmol) in DMF (1 mL) at 0° C. under a nitrogen atmosphere. After stirring for 30 minutes DIPEA (0.16 mL, 0.92 mmol) and N′,N′-dimethylethane-1,2-diamine (29 mg, 0.33 mmol) were added and stirring continued for 30 minutes. The mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine (20 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on silica gel (60-120 mesh) using 1% MeOH/DCM as the eluent. The resulting solid was dissolved in dioxane (1 mL) and a 4N HCl solution in dioxane (0.3 mL) was added and the mixture stirred for 16 hours at room temperature. The solvents were evaporated under reduced pressure to leave a solid that was triturated with pentane (3×2 mL) and Et.sub.2O (2×2 mL) and then dried to give the title compound (71 mg, 40%) as an off-white solid.

(38) Synthetic Route B

(39) (Illustrated with reference to Example 7)

Example 7

1-[3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]-N,N-dimethyl-methanamine Hydrochloride)

(40) ##STR00162##

7A. [3-[5-(4-Bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]methanol

(41) Isobutyl chloroformate (0.6 mL, 4.95 mmol) was added dropwise over 20 minutes to a stirred solution of 3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]benzoic acid (Example 2C) (1.5 g, 3.09 mmol) and triethylamine (0.7 mL, 4.95 mmol) in THF (40 mL) at −78° C. under a nitrogen atmosphere. The solution was stirred for one hour then allowed to slowly warm to 0° C. and sodium borohydride (1.3 g, 34 mmol) was added in portions over 10 minutes. Water (20 mL) was added dropwise maintaining the internal temperature at 0° C. and the resulting mixture stirred for 20 minutes. The mixture was filtered, diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine (20 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave the title compound (3.0 g, 100%) which was used without further purification.

7B. 3-[5-(4-Bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]benzaldehyde

(42) Dess-Martin periodinane (5.4 g, 12.7 mmol) was added to a solution of [3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]methanol (3.0 g, 6.4 mmol) in DCM (30 mL) at 0° C. The mixture was stirred for 30 minutes then filtered through celite and the filtrate evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (60-120 mesh) using 1% MeOH/DCM as the eluent to give the title compound (0.64 g, 21% over two steps).

7C. 1-[3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]-N,N-dimethyl-methanamine Hydrochloride

(43) Dimethylamine (2M in THF, 1.3 mL, 1.92 mmol) was added dropwise to a stirred solution of 3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]benzaldehyde (0.3 g, 0.64 mmol) in MeOH (6 mL) at 0° C. under a nitrogen atmosphere. The solution was stirred for 20 minutes then sodium borohydride (0.05 g, 1.28 mmol) was added in portions over 10 minutes maintaining the internal temperature at 0° C. The mixture was allowed to warm to room temperature and stirred for a further 20 minutes then poured into ice-water (50 mL) and extracted with EtOAc (4×30 mL). The combined organic extracts were dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on silica gel (60-120 mesh) using 3% MeOH/CHCl.sub.3 as the eluent. The resulting solid was dissolved in THF (2 mL) and 4N HCl solution in dioxane (0.3 ml) was added and the mixture stirred for 30 minutes at room temperature. The solvents were evaporated under reduced pressure to leave a solid that was triturated with pentane (3×2 mL) and then dried to give the title compound (40 mg, 12%) as an off-white solid.

(44) Synthetic Route C

(45) (Illustrated with reference to Example 9)

Example 9

4-[5-(4-Bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]benzamide Hydrochloride)

(46) ##STR00163##

9A. 4-[4-(4-Bromophenyl)-4-oxo-butanoyl]benzonitrile

(47) Zinc chloride (24.4 g, 179 mmol) was heated to melting under vacuum and then allowed to cool to room temperature. Toluene (80 mL), t-butanol (13.2 mL, 138 mmol) and triethylamine (19.3 mL, 138 mmol) were added and the mixture stirred at room temperature for 2 hours under a nitrogen atmosphere at which point the zinc chloride had fully dissolved. 4-Cyanoacetophenone (20.0 g, 138 mmol) and 2-bromo-1-(4-bromophenyl)ethanone (38.1 g, 6.73 mmol) were added and the mixture stirred for 48 hours at room temperature. The reaction mixture was diluted with water (100 ml) and extracted with EtOAc (3×200 mL). The combined organic extracts were dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on silica gel (60-120 mesh) using 8% EtOAc/hexanes as the eluent to give the title compound (8.0 g, 17%) as a colourless oil.

9B. 4-[5-(4-Bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]benzonitrile

(48) A stirred solution of 4-[4-(4-bromophenyl)-4-oxo-butanoyl]benzonitrile (6.0 g, 17.6 mmol), 2-(trifluoromethyl)aniline (8.5 g, 52.8 mmol) and PTSA (0.33 g, 1.76 mmol) in dioxane (60 mL) was heated to 150° C. under microwave irradiation for 6 hours. The mixture was allowed to cool to room temperature and the solvents evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (60-120 mesh) using 4% EtOAc/hexanes as the eluent to give the title compound (4.0 g, 49%) as an off-white solid.

9C. 4-[5-(4-Bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]benzoic Acid

(49) A mixture of 4-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]benzonitrile (3.44 g, 8.60 mmol) and sodium hydroxide (3.44 g, 86.0 mmol) in methanol (40 mL) and water (4 mL) was stirred at 90° C. for 18 hours. The pH of the mixture was adjusted to 4 with 1N HCl and then extracted with EtOAc (3×50 mL). The combined organic extracts were dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave a solid that was triturated with pentane (3×2 mL) and dried to give the title compound (3.5 g, 84%) as a white solid.

9D. 4-[5-(4-Bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]benzamide Hydrochloride

(50) HATU (3.53 g, 9.30 mmol) was added to a stirred solution of 4-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]benzoic acid (3.0 g, 6.2 mmol) in DMF (30 mL) at 0° C. under a nitrogen atmosphere. After stirring for 30 minutes DIPEA (3.3 mL, 18.6 mmol) and N′,N′-dimethylethane-1,2-diamine (0.6 g, 6.8 mmol) were added and stirring continued for 30 minutes. The mixture was diluted with water (300 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (50 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on silica gel (60-120 mesh) using 4% MeOH/CHCl.sub.3 as the eluent. The resulting solid was dissolved in THF (30 mL) and 4N HCl solution in dioxane (1 mL) was added and the mixture stirred for 30 minutes at room temperature. The solvents were evaporated under reduced pressure to leave a solid that was triturated with Et.sub.2O (3×10 mL) and then dried to give the title compound (2.7 g, 84%) as an off-white solid.

(51) Synthetic Route D

(52) (Illustrated with reference to Example 16)

Example 16

N-[3-[5-(4-Bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]-N′,N′-dimethyl-propane-1,3-diamine Hydrochloride)

(53) ##STR00164##

16A. 1-(4-Bromophenyl)-4-(3-nitrophenyl)butane-1,4-dione

(54) Zinc chloride (5.37 g, 39.4 mmol) was heated to melting under vacuum and then allowed to cool to room temperature. Toluene (20 mL), t-butanol (2.9 mL, 30.3 mmol) and triethylamine (4.2 mL, 30.3 mmol) were added and the mixture stirred at room temperature for 2 hours under a nitrogen atmosphere at which point the zinc chloride had fully dissolved. 3-Nitroacetophenone (5.0 g, 30.3 mmol) and 2-bromo-1-(4-bromophenyl)ethanone (8.35 g, 14.0 mmol) were added and the mixture stirred for 24 hours at room temperature. The reaction mixture was diluted with water (50 mL), filtered through celite and extracted with EtOAc (3×100 mL). The combined organic extracts were dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on silica gel (60-120 mesh) using 8% EtOAc/hexanes as the eluent to give the title compound (2.1 g, 19%) as a yellow solid.

16B. 2-(4-Bromophenyl)-5-(3-nitrophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrole

(55) A stirred solution of 1-(4-bromophenyl)-4-(3-nitrophenyl)butane-1,4-dione (2.0 g, 5.50 mmol), 2-(trifluoromethyl)aniline (2.66 g, 16.5 mmol) and PTSA (0.11 g, 5.50 mmol) in dioxane (20 mL) was heated to 150° C. under microwave irradiation for 6 hours. The mixture was allowed to cool to room temperature and the solvents evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (60-120 mesh) using 10% EtOAc/hexanes as the eluent to give the title compound (2.2 g, 82%) as an off-white solid.

16C. 3-[5-(4-Bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]aniline

(56) Sodium borohydride (2.04 g, 5.4 mmol) was added in portions over 30 minutes to a stirred solution of 2-(4-bromophenyl)-5-(3-nitrophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrole (2.2 g, 4.50 mmol) and copper (II) acetate (82 mg, 0.45 mmol) in methanol (20 mL) at 0° C. The mixture was allowed to warm to room temperature and stirring continued for one hour. The solvents were evaporated under reduced pressure to leave a residue which was purified by column chromatography on silica gel (60-120 mesh) using 15% EtOAc/hexanes as the eluent to give the title compound (2.0 g, 97%) as an off-white solid.

16D. N-[3-[5-(4-Bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]-N′,N′-dimethyl-propane-1,3-diamine Hydrochloride

(57) A solution of 3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]aniline (2.0 g, 4.4 mmol) in DMF (10 mL) was added dropwise to a stirred slurry of sodium hydride (60% in oil, 0.53 g, 13.2 mmol) in DMF (10 mL) at room temperature under a nitrogen atmosphere. After stirring for 30 minutes 3-chloro-N,N-dimethylpropan-1-amine hydrochloride (0.75 g, 4.8 mmol) was added and the mixture heated to 80° C. for 3 hours. The solution was allowed to cool to room temperature and then carefully poured into ice-water (100 mL) and extracted with EtOAc (4×50 mL). The combined organic extracts were washed with brine (50 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on silica gel (60-120 mesh) using 6% MeOH/CHCl.sub.3 as the eluent. The resulting solid was dissolved in THF (30 mL) and 4N HCl solution in dioxane (1 ml) was added and the mixture stirred for 30 minutes at room temperature. The solvents were evaporated under reduced pressure to leave a solid that was triturated with Et.sub.2O (3×10 mL) and then dried to give the title compound (120 mg, 5%) as an off-white solid.

(58) Synthetic Route E

(59) (Illustrated with reference to Example 17)

Example 17

3-[3-[5-(4-Bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenoxy]-N,N-dimethyl-propan-1-amine Hydrochloride)

(60) ##STR00165##

17A. (3-Acetylphenyl) Acetate

(61) Acetyl chloride (3.9 mL, 55.0 mmol) was added dropwise to a stirred solution of 3-hydroxyacetophenone (5.0 g, 36.7 mmol) and TFA (1.1 mL, 14.7 mmol) in chloroform (50 mL) under a nitrogen atmosphere. The resulting solution was heated to 80° C. for 20 hours then allowed to cool to room temperature and poured into saturated NaHCO.sub.3 solution (50 mL). The mixture was extracted with EtOAc (3×50 mL) then the combined organic extracts were washed with brine (20 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave the title compound (2.8 g, 43%) which was used without further purification.

17B. [3-[4-(4-Bromophenyl)-4-oxo-butanoyl]phenyl] Acetate

(62) Zinc chloride (2.48 g, 18.2 mmol) was heated to melting under vacuum and then allowed to cool to room temperature. Toluene (10 mL), t-butanol (1.4 mL, 14.0 mmol) and triethylamine (2.0 mL, 14.0 mmol) were added and the mixture stirred at room temperature for 2 hours under a nitrogen atmosphere at which point the zinc chloride had fully dissolved. (3-Acetylphenyl) acetate (2.5 g, 14.0 mmol) and 2-bromo-1-(4-bromophenyl)ethanone (3.90 g, 14.0 mmol) were added and the mixture stirred for 18 hours at room temperature. The reaction mixture was diluted with water (50 ml), filtered through celite and extracted with EtOAc (3×50 mL). The combined organic extracts were dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave a solid that was triturated with pentane (3×10 mL) to give the title compound (2.1 g, 40%) as a beige solid.

17C. 1-(4-Bromophenyl)-4-(3-hydroxyphenyl)butane-1,4-dione

(63) A mixture of methyl [3-[4-(4-bromophenyl)-4-oxo-butanoyl]phenyl] acetate (2.0 mg, 5.40 mmol) and lithium hydroxide monohydrate (0.90 g, 21.6 mmol) in THF (20 mL) and water (20 mL) was stirred at room temperature for 10 minutes. The pH of the mixture was adjusted to 4 with 1N HCl and then extracted with EtOAc (3×50 mL). The combined organic extracts were dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave a solid that was triturated with pentane (3×2 mL) and dried to give the title compound (1.50 g, 85%) as a beige solid.

17D. 3-[5-(4-Bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenol

(64) A stirred solution of 1-(4-bromophenyl)-4-(3-hydroxyphenyl)butane-1,4-dione (1.0 g, 3.0 mmol), 2-(trifluoromethyl)aniline (1.45 g, 9.0 mmol) and PTSA (0.057 g, 0.30 mmol) in dioxane (10 mL) was heated to 150° C. under microwave irradiation for 2 hours. The mixture was allowed to cool to room temperature and the solvents evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (60-120 mesh) using 10% EtOAc/hexanes as the eluent to give the title compound (0.25 g, 18%) as an off-white solid.

17E. 3-[3-[5-(4-Bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenoxy]-N,N-dimethyl-propan-1-amine Hydrochloride

(65) A solution of 3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenol (0.20 g, 0.44 mmol) in DMF (1 mL) was added dropwise to a stirred slurry of sodium hydride (60% in oil, 0.53 g, 13.2 mmol) in DMF (1 mL) at room temperature under a nitrogen atmosphere. After stirring for 30 minutes 3-chloro-N,N-dimethylpropan-1-amine hydrochloride (0.076 g, 0.48 mmol) was added and the mixture heated to 70° C. for one hour. The solution was allowed to cool to room temperature and then carefully poured into ice-water (20 mL) and extracted with EtOAc (4×30 mL). The combined organic extracts were washed with brine (50 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on silica gel (60-120 mesh) using 8% MeOH/CHCl.sub.3 as the eluent. The resulting solid was dissolved in THF (5 mL) and 4N HCl solution in dioxane (0.1 ml) was added and the mixture stirred for 30 minutes at room temperature. The solvents were evaporated under reduced pressure to leave a solid that was triturated with Et.sub.2O (3×10 mL) and then dried to give the title compound (150 mg, 64%) as an off-white solid.

(66) Synthetic Route F

(67) (Illustrated with reference to Example 21)

Example 21

N-[[3-[5-(4-Bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]methyl]-2-(dimethylamino)acetamide Hydrochloride)

(68) ##STR00166##

21A. [3-[5-(4-Bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]methyl Methanesulfonate

(69) Methane sulfonyl chloride (0.11 g, 0.96 mmol) was added dropwise to a stirred solution of [3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]methanol (Example 7B) (0.3 g, 0.64 mmol) and triethylamine (0.13 mL, 0.96 mmol) in THF (3 mL) at 0° C. under a nitrogen atmosphere. The mixture was stirred for 30 minutes then partitioned between saturated NaHCO.sub.3 solution (30 mL) and EtOAc (30 mL). The separated aqueous phase was extracted with EtOAc (3×30 mL) and then the combined organic extracts were washed with brine (10 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to give the title compound (0.62 g, quantitative) which was used without further purification.

21B. [3-[5-(4-Bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]methanamine

(70) A 9M ammonia in MeOH solution (2 mL) was added to a stirred solution of [3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]methyl methanesulfonate (0.62 g, 1.1 mmol) in ethanol (6 mL) at −5° C. under a nitrogen atmosphere. The solution was stirred at −5° C. for 2 hours then the solvents were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (60-120 mesh) using 6% MeOH/CHCl.sub.3 as the eluent to give the title compound (0.32 g, 60%) as an off-white solid.

21C. N-[[3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]methyl]-2-(dimethylamino)acetamide Hydrochloride

(71) HATU (0.52 g, 1.36 mmol) was added to a stirred solution of N,N-dimethylglycine (70 mg, 0.68 mmol) in DMF (3 mL) at 0° C. under a nitrogen atmosphere. After stirring for 30 minutes DIPEA (0.35 mL, 2.04 mmol) and [3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]methanamine (0.32 g, 0.68 mmol) were added and stirring continued for 30 minutes. The mixture was diluted with water (30 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (10 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on silica gel (60-120 mesh) using 4% MeOH/CHCl.sub.3 as the eluent. The resulting solid was dissolved in THF (30 mL) and 4N HCl solution in dioxane (1 mL) was added and the mixture stirred for 30 minutes at room temperature. The solvents were evaporated under reduced pressure to leave a solid that was triturated with Et.sub.2O (3×10 mL) and then dried to give the title compound (19 mg, 5%) as an off-white solid.

(72) Synthetic Route G

(73) (Illustrated with reference to Example 29)

Example 29

6-[5-(4-Bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]pyridine-3-carboxamide Hydrochloride)

(74) ##STR00167## ##STR00168##

29A. 1-(4-Bromophenyl)-3-(dimethylamino)propan-1-one Hydrochloride

(75) A stirred solution of 4-bromoacetophenone (1.0 g, 5.0 mmol), paraformaldehyde (0.15 g, 5.0 mol), N,N-dimethylamine hydrochloride (0.41 g, 5.0 mmol) and concentrated hydrochloric acid (0.5 mL) in absolute ethanol (15 mL) were heated to 90° C. for 4 hours. The solution was allowed to cool to room temperature and the solvents were evaporated under reduced pressure. The residue was triturated with n-pentane (3×20 mL), Et.sub.2O (3×10 mL) and dried to give the title compound (1.26 g, 86%) as a white solid.

29B. Diethyl pyridine-2,5-dicarboxylate

(76) Concentrated sulfuric acid (3.9 mL, 71.6 mmol) was added dropwise over 15 minutes to a stirred suspension of 2,5-pyridinedicarboxylic acid (3.0 g, 17.9 mol) in absolute ethanol (10 mL) and the resulting mixture heated to reflux for 18 hours. The solution was allowed to cool to room temperature and the solvents evaporated under reduced pressure. Saturated NaHCO.sub.3 solution was added to the residue to adjust the pH to ˜8 then the aqueous phase was extracted with EtOAc (4×50 mL). The combined organic extracts were washed with brine (30 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave the title compound (3.0 g, 75%) which was used without further purification.

29C. Ethyl 6-(hydroxymethyl)pyridine-3-carboxylate

(77) Sodium borohydride (1.27 g, 33.5 mmol) and anhydrous calcium chloride (2.35 g, 21.2 mmol) was added in several portions over 30 minutes to a stirred solution of diethyl pyridine-2,5-dicarboxylate (3.0 g, 13.4 mmol) in ethanol (12 mL) and THF (6 mL) at 0° C. under a nitrogen atmosphere. The mixture was allowed to warm to room temperature and stirring continued for one hour then poured into saturated NH.sub.4Cl solution (150 mL) and extracted with EtOAc (5×50 mL). The combined organic extracts were dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on silica gel (60-120 mesh) using 36% EtOAc/hexanes as the eluent to give the title compound (1.5 g, 62%) as an off-white solid.

29D. Ethyl 6-formylpyridine-3-carboxylate

(78) Dess-Martin periodinane (4.24 g, 10.0 mmol) was added to a solution of ethyl 6-(hydroxymethyl)pyridine-3-carboxylate (1.5 g, 8.3 mmol) in DCM (30 mL) at 0° C. The mixture was stirred for 30 minutes then filtered through celite and the filtrate evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (60-120 mesh) using 9% EtOAc/hexanes as the eluent to give the title compound (0.83 g, 56%).

29E. Ethyl 6-[4-(4-bromophenyl)-4-oxo-butanoyl]pyridine-3-carboxylate

(79) Ethyl 6-formylpyridine-3-carboxylate (0.61 g, 3.4 mmol) and 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazoliumbromide (0.18 g, 0.70 mmol) were added to a stirred solution of 1-(4-bromophenyl)-3-(dimethylamino)propan-1-one hydrochloride (1.0 g, 3.4 mmol) and triethylamine (0.95 mL, 6.8 mmol) in 1,2-dimethoxyethane (15 mL). The resulting solution was heated to 100° C. for 5 hours then allowed to cool to room temperature and diluted with EtOAc (150 mL). The solution was washed with water (3×50 mL), brine (20 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave a residue that was purified by column chromatography on silica gel (60-120 mesh) using 12% EtOAc/hexane as the eluent to give the title compound (0.67 g, 44%) as a beige solid.

29F. Ethyl 6-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]pyridine-3-carboxylate

(80) A stirred solution of ethyl 6-[4-(4-bromophenyl)-4-oxo-butanoyl]pyridine-3-carboxylate (0.67 g, 1.7 mmol), 2-(trifluoromethyl)aniline (0.82 g, 5.1 mmol) and PTSA (0.040 g, 0.20 mmol) in dioxane (15 mL) was heated to 170° C. under microwave irradiation for 5 hours. The mixture was allowed to cool to room temperature and the solvents evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (60-120 mesh) using 10% EtOAc/hexanes as the eluent to give the title compound (0.63 g, 71%) as an off-white solid.

29G. 6-[5-(4-Bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]pyridine-3-carboxylic Acid

(81) A mixture of methyl ethyl 6-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]pyridine-3-carboxylate (0.63 g, 1.20 mmol) and lithium hydroxide monohydrate (0.20 g, 4.8 mmol) in THF (6 mL) and water (6 mL) was stirred at 90° C. for 3 hours. The cooled solution was diluted with water (60 mL), neutralized with 10% KHSO.sub.4 solution and then extracted with EtOAc (3×30 mL). The combined organic extracts were dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave a solid that was purified by column chromatography on silica gel (60-120 mesh) using 45% EtOAc/hexane as the eluent to give the title compound (0.48 g, 81%) as a white solid.

29H. 6-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]pyridine-3-carboxamide Hydrochloride

(82) HATU (0.21 g, 2.40 mmol) was added to a stirred solution of 6-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]pyridine-3-carboxylic acid (0.41 g, 0.8 mmol) in DMF (1 mL) at 0° C. under a nitrogen atmosphere. After stirring for 30 minutes DIPEA (0.40 mL, 2.4 mmol) and N′,N′-dimethylethane-1,2-diamine (0.21 g, 2.40 mmol) were added and stirring continued for 40 minutes. The mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine (20 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on silica gel (60-120 mesh) using 5% MeOH/CHCl.sub.3 as the eluent. The resulting solid was dissolved in dioxane (5 mL) and a 4N HCl solution in dioxane (1.5 mL) was added and the mixture stirred for 30 minutes at room temperature. The solvents were evaporated under reduced pressure to leave a solid that was triturated with pentane (3×2 mL) and Et.sub.2O (2×2 mL) and then dried to give the title compound (0.30 g, 72%) as an off-white solid.

(83) Experimental Procedure for Example 33

(84) The compound of Example 33 was made by route C involving the following sequence of reactions:

(85) ##STR00169##

Step 1

4-[4-(4-chlorophenyl)-4-oxo-butanoyl]benzonitrile

(86) Zinc chloride (30.5 g, 0.223 mol) was heated up to melting temperature in a reaction flask in vacuo followed by cooling to room temperature (RT) in vacuo. To this mixture was added toluene (100 mL), tert-butanol (16.5 mL, 0.172 mol) and triethylamine (24 mL, 0.172 mol) under a nitrogen atmosphere. The reaction mixture (RM) was then stirred at the same temperature for 2 h until all the zinc chloride had dissolved. After this, 4-cyanoacetophenone (25 g, 0.172 mol) and 4-chlorophenacylbromide (40.2 g, 0.172 mol) were added at RT and the reaction mixture was stirred at the same temperature for 48 h.

(87) The reaction mixture was diluted with ethyl acetate (1 L) and then washed with water (4×250 mL) followed by brine solution (1×300 mL). The organic layer was separated off and dried over sodium sulphate then filtered. The filtrate was concentrated in vacuo to afford crude title product, which was further purified by triturating with methyl tert-butyl ether to afford the title product. Yield: 31.0 g (61%).

Step 2

4-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]benzonitrile

(88) To a solution of 4-[4-(4-chlorophenyl)-4-oxo-butanoyl]benzonitrile (30.0 g, 0.1 mol) and 2-trifluoromethyl aniline (40.64 mL, 0.323 mol) in dioxane (300 mL) was added p-toluene sulfonic acid monohydrate (1.92 g, 0.010 mol) at RT. The reaction mixture was then heated at 150° C. for 16 h.

(89) The reaction mixture was concentrated in vacuo to afford crude product, which was further purified by column chromatography using neutral silica gel. Elution at 5-7% ethyl acetate in hexane afforded the title product. Yield: 19.0 g (45%).

Step 3

4-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]benzoic Acid

(90) To a solution of 4-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]benzonitrile (19 g, 0.045 mol) in methanol (190 mL) was added a solution of sodium hydroxide (18 g, 0.45 mol) in water (95 mL) at RT. The resulting reaction mixture was stirred at 90° C. for 18 h.

(91) The reaction mixture was concentrated in vacuo at 40° C. to afford crude product, which was then acidified using a saturated solution of potassium hydrogen sulphate. The aqueous was extracted with ethyl acetate (3×200 mL). The organics were separated off, combined and washed with brine solution (1×100 mL). The organics were again separated off, dried over sodium sulphate, filtered and then concentrated in vacuo. Further purification by trituration with n-pentane afforded title product. Yield: 15.0 g (75%).

Step 4

4-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]benzamide

(92) To a solution of 4-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]benzoic acid (15 g, 0.034 mol) in DMF (150 mL) was added N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU, 19.38 g, 0.051 mol) at 0° C. and the reaction mixture was stirred for 30 minutes at the same temperature. After 30 minutes, N,N′-dimethyl ethylenediamine (4.09 mL, 0.038 mol) and DIPEA (18.26 mL, 0.105 mol) were added at 0° C. and the resulting reaction mixture was stirred at the same temperature for 30 minutes.

(93) The reaction mixture was diluted with ethyl acetate (500 mL), washed with ice-cold water (5×100 mL), followed by brine solution (100 mL) then dried over sodium sulphate. The organics were filtered and concentrated in vacuo. The crude product was further purified by column chromatography using basic alumina (˜100-300 uM), eluting with dichloromethane. Yield: 11.0 g (63%).

Step 5

4-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]benzamide Hydrochloride

(94) To a solution of 4-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]benzamide (10.5 g, 0.0205 mol) in tetrahydrofuran (100 mL) was added 4N HCl in dioxane (5 mL) at RT. The resulting reaction mixture was then stirred for 30 minutes at RT.

(95) The reaction mixture was concentrated in vacuo then further purified by trituration in n-pentane to afford title product. Yield: 10.5 g (93%).

(96) Synthetic Route H

(97) (Illustrated with reference to Example 45)

Example 45

2-[[4-[5-(4-Bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]methoxy]-N,N-dimethyl-ethanamine Hydrochloride)

(98) ##STR00170##

(99) 45A. [4-[5-(4-Bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]methanol

(100) Isobutyl chloroformate (0.6 mL, 4.95 mmol) was added dropwise over 20 minutes to a stirred solution of 4-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]benzoic acid (Example 9C) (1.5 g, 3.09 mmol) and triethylamine (0.7 mL, 4.95 mmol) in THF (40 mL) at −78° C. under a nitrogen atmosphere. The solution was stirred for one hour then allowed to slowly warm to 0° C. and sodium borohydride (1.3 g, 34 mmol) was added in portions over 10 minutes. Water (20 mL) was added dropwise maintaining in the internal temperature at 0° C. and the resulting mixture stirred for 20 minutes. The mixture was filtered, diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine (20 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave a residue that was purified by column chromatography on silica gel (60-120 mesh) using 17% EtOAc/hexane as the eluent to give the title compound (1.30 g, 89%) as a solid.

45B. 2-[[4-[5-(4-Bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]methoxy]-N,N-dimethyl-ethanamine Hydrochloride

(101) A solution of 3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenol (0.30 g, 0.64 mmol) in DMF (0.7 mL) was added dropwise to a stirred slurry of sodium hydride (60% in oil, 0.68 g, 0.96 mmol) in DMF (0.5 mL) at room temperature under a nitrogen atmosphere. After stirring for 30 minutes 2-bromo-N,N-dimethyl-ethanamine hydrobromide (0.15 g, 0.64 mmol) was added and the mixture heated to 90° C. for 18 hours. The solution was allowed to cool to room temperature and then carefully poured into ice-water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (20 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on silica gel (60-120 mesh) using 8% MeOH/CHCl.sub.3 as the eluent. The resulting solid was dissolved in THF (5 mL) and 4N HCl solution in dioxane (0.1 mL) was added and the mixture stirred for 30 minutes at room temperature. The solvents were evaporated under reduced pressure to leave a solid that was triturated with Et.sub.2O (3×10 mL) and then dried to give the title compound (58 mg, 16%) as an off-white solid.

(102) Synthetic Route I

(103) (Illustrated with reference to Example 46)

Example 46

N-[4-[5-(4-Bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]-3-(dimethylamino) propanamide Hydrochloride)

(104) ##STR00171##

46A. N-[4-[5-(4-Bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]-3-(dimethylamino) propanamide Hydrochloride

(105) HATU (0.67 g, 1.8 mmol) was added to a stirred solution of 3-(dimethylamino)propanoic acid (0.14 g, 0.87 mmol) in DMF (5 mL) at 0° C. under a nitrogen atmosphere. After stirring for 30 minutes DIPEA (0.46 mL, 2.6 mmol) and 3-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]aniline (prepared in an analogous manner to Example 16C) (0.40 g, 0.87 mmol) were added and stirring continued for 30 minutes. The mixture was diluted with water (30 mL) and extracted with EtOAc (3×40 mL). The combined organic extracts were washed with brine (20 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on silica gel (60-120 mesh) using 5% MeOH/CHCl.sub.3 as the eluent. The resulting solid was dissolved in dioxane (5 mL) and a 4N HCl solution in dioxane (1.5 mL) was added and the mixture stirred for 30 minutes at room temperature. The solvents were evaporated under reduced pressure to leave a solid that was triturated with pentane (3×2 mL) and Et.sub.2O (2×2 mL) and then dried to give the title compound (0.058 g, 11%) as an off-white solid.

(106) Synthetic Route J

(107) (Illustrated with reference to Example 47)

Example 47

2-[4-[5-(4-Bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]acetic Acid)

(108) ##STR00172##

47A. Methyl 2-(4-bromophenyl)acetate

(109) Concentrated sulfuric acid (1.0 mL, 18.4 mmol) was added dropwise over 15 minutes to a stirred solution of 2-(4-bromophenyl)acetic acid (4.0 g, 18.6 mol) in methanol (40 mL) and the resulting mixture heated to reflux for 4 hours. The solution was allowed to cool to room temperature and the solvents evaporated under reduced pressure. Saturated NaHCO.sub.3 solution was added to the residue to adjust the pH to ˜8, then the aqueous phase was extracted with EtOAc (4×50 mL). The combined organic extracts were washed with brine (30 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave the title compound (3.0 g, 70%) which was used without further purification.

47B. Methyl 2-(4-acetylphenyl)acetate

(110) Nitrogen was bubbled through a solution of methyl 2-(4-bromophenyl)acetate (3.0 g, 13.1 mmol) and tributyl(1-ethoxylvinyl)tin (5.67 g, 15.7 mmol) in toluene (30 mL) for 20 minutes then tetrakis(triphenylphosphine)palladium(0) (0.91 g, 7.9 mmol) was added and the resulting stirred mixture heated to 80° C. for 20 hours. The reaction mixture was allowed to cool to room temperature and 18% aqueous HCl (5 mL) was added and stirring continued for 30 minutes. The mixture was then diluted with water (50 mL), filtered through celite and the filtrate extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine (20 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on silica gel (60-120 mesh) using 20% EtOAc/hexane as the eluent to give the title compound (2.0 g, 79%) as a colourless oil.

47C. Methyl 2-[4-[4-(4-bromophenyl)-4-oxo-butanoyl]phenyl]acetate

(111) Zinc chloride (0.53 g, 3.9 mmol) was heated to melting under vacuum and then allowed to cool to room temperature. Toluene (4 mL), t-butanol (0.25 mL, 2.6 mmol) and triethylamine (0.35 mL, 2.6 mmol) were added and the mixture stirred at room temperature for 2 hours under a nitrogen atmosphere at which point the zinc chloride had fully dissolved. Methyl 2-(4-acetylphenyl)acetate (0.5 g, 2.6 mmol) and 2-bromo-1-(4-bromophenyl)ethanone (0.72 g, 2.6 mmol) were added and the mixture stirred for 18 hours at room temperature. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave a residue which was purified by trituration with n-pentane (3×10 mL) to give the title compound (0.4 g, 40%) as an off-white solid.

47D. Methyl 2-[4-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]acetate

(112) A stirred solution of methyl 2-[4-[4-(4-bromophenyl)-4-oxo-butanoyl]phenyl]acetate (0.40 g, 1.0 mmol), 2-(trifluoromethyl)aniline (0.48 g, 3.0 mmol) and PTSA (0.019 g, 0.10 mmol) in dioxane (4 mL) was heated to 150° C. under microwave irradiation for 4 hours. The mixture was allowed to cool to room temperature and the solvents evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (60-120 mesh) using 7% EtOAc/hexanes as the eluent to give the title compound (0.08 g, 15%) as an off-white solid.

47E. 2-[4-[5-(4-Bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]acetic Acid

(113) A mixture of methyl 2-[4-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]acetate (0.08 g, 0.16 mmol) and lithium hydroxide monohydrate (0.026 g, 0.62 mmol) in THF (1 mL) and water (1 mL) was stirred at 70° C. for 4 hours. The cooled solution was diluted with water (60 mL), neutralized with 10% KHSO.sub.4 solution and then extracted with EtOAc (3×10 mL). The combined organic extracts were dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave a solid that was purified by triturating with Et.sub.2O (3×2 mL), n-pentane (2×5 mL) and dried to give the title compound (0.05 g, 64%) as a white solid.

(114) Synthetic Route K

(115) (Illustrated with reference to Example 44)

Example 44

4-[5-(4-Bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]benzenesulfonamide Hydrochloride)

(116) ##STR00173##

44A. 4-Bromobenzenesulfonamide

(117) Concentrated ammonia solution (12 mL) was added dropwise over 15 minutes to a stirred solution of 4-bromobenzenesulfonyl chloride (6.0 g, 23.6 mmol) in MeOH (60 mL) at room temperature. The mixture was stirred for one hour then concentrated under reduced pressure to leave a solid which was taken up in cold water (50 mL). The solid was collected by filtration, washed with water (2×10 mL) and dried to give the title compound (5.0 g, 85%) as a white solid.

44B. 4-Acetylbenzenesulfonamide

(118) Nitrogen was bubbled through a stirred solution of 4-bromobenzenesulfonamide (4.0 g, 16.0 mmol) and tributyl(1-ethoxylvinyl)tin (6.93 g, 19.2 mmol) in toluene (40 mL) for 20 minutes then tetrakis(triphenylphosphine)palladium(0) (1.1 g, 6.0 mmol) was added and the resulting mixture heated to 100° C. for 5 hours. The reaction mixture was allowed to cool to room temperature and 18% aqueous HCl (5 mL) was added and stirring continued for 30 minutes. The mixture was then diluted with water (50 mL), filtered through celite and the filtrate extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine (20 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on silica gel (60-120 mesh) using 85% EtOAc/hexane as the eluent to give the title compound (2.5 g, 79%) as a white solid.

44C. 4-[4-(4-Bromophenyl)-4-oxo-butanoyl]benzenesulfonamide

(119) Zinc chloride (2.21 g, 16.2 mmol) was heated to melting under vacuum and then allowed to cool to room temperature. THF (25 mL), t-butanol (1.2 mL, 12.5 mmol) and triethylamine (0.35 mL, 12.5 mmol) were added and the mixture stirred at room temperature for 2 hours under a nitrogen atmosphere at which point the zinc chloride had fully dissolved. 4-Acetylbenzenesulfonamide (2.5 g, 12.5 mmol) and 2-bromo-1-(4-bromophenyl)ethanone (3.44 g, 12.5 mmol) were added and the mixture stirred for 48 hours at room temperature. The reaction mixture was diluted with water (50 ml) and extracted with EtOAc (3×80 mL). The combined organic extracts were dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on silica gel (60-120 mesh) using 2% MeOH/CHCl.sub.3 as the eluent to give the title compound (1.2 g, 24%) as a white solid.

44D. 4-[5-(4-Bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]benzenesulfonamide

(120) A stirred solution of 4-[4-(4-bromophenyl)-4-oxo-butanoyl]benzenesulfonamide (1.20 g, 3.0 mmol), 2-(trifluoromethyl)aniline (1.45 g, 9.0 mmol) and PTSA (0.057 g, 0.30 mmol) in dioxane (5 mL) was heated to 150° C. for 8 hours. The mixture was allowed to cool to room temperature and the solvents evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (60-120 mesh) using 50% EtOAc/hexanes as the eluent to give the title compound (0.80 g, 51%) as an off-white solid.

44E. 4-[5-(4-Bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]-N-[2-(dimethylamino)ethyl]benzenesulfonamide Hydrochloride

(121) A stirred mixture of 4-[5-(4-bromophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]benzenesulfonamide (0.43 g, 0.82 mmol), potassium carbonate (0.34 g, 2.48 mmol) and 2-chloro-N,N-dimethylethanamine hydrochloride (0.13 g, 0.90 mmoL) in anhydrous DMF (5 mL) was heated to 70° C. for 4 hours. The mixture was allowed to cool to room temperature and then poured in to water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with water (2×15 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on silica gel (60-120 mesh) using 4% MeOH/CHCl.sub.3 as the eluent. The resulting solid was dissolved in THF (10 mL) and a 4N HCl solution in dioxane (0.1 mL) was added and the mixture stirred for 30 minutes at room temperature. The solvents were evaporated under reduced pressure to leave a solid that was triturated with pentane (3×2 mL) and Et.sub.2O (2×2 mL) and then dried to give the title compound (0.13 g, 34%) as an off-white solid.

(122) Synthetic Route L

(123) (Illustrated with reference to Example 82)

Example 82

4-[4-(4-Chlorophenyl)-5-[2-(trifluoromethyl)phenyl]pyrazol-1-yl]-N-[2-(dimethylamino)ethyl]-benzamide Hydrochloride)

(124) ##STR00174##

82A. 2-(4-Chlorophenyl)-1-[2-(trifluoromethyl)phenyl]ethanol

(125) A solution of 1-bromo-2-(trifluoromethyl)benzene (2.9 g, 12.9 mmol) in anhydrous THF (5 mL) was added to activated magnesium metal (0.31 g, 12.9 mmol) in a sealed tube under a nitrogen atmosphere. The resulting mixture was stirred vigorously for 3 hours at room temperature. The resulting solution was added to a stirred solution of 2-(4-chlorophenyl)acetaldehyde (1.0 g, 6.4 mmol) in anhydrous THF (25 mL) at 0° C. under a nitrogen atmosphere. The resulting mixture was allowed to warm slowly to room temperature and then heated to reflux for 2 hours. The mixture was allowed to cool to room temperature and then poured in to saturated NH.sub.4Cl solution (100 mL) and extracted with EtOAc (3×200 mL). The combined organic extracts were washed with brine (2×25 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on silica gel (60-120 mesh) using 4% EtOAc/hexanes as the eluent to give the title compound (0.6 g, 31%) as a colourless oil.

82B. 2-(4-Chlorophenyl)-1-[2-(trifluoromethyl)phenyl]ethanone

(126) Dess-Martin periodinane (1.0 g, 2.3 mmol) was added in portions over 10 minutes to a stirred solution of 2-(4-chlorophenyl)-1-[2-(trifluoromethyl)phenyl]ethanol (0.6 g, 1.9 mmol) in DCM (50 mL) and the resulting mixture stirred at room temperature for 3 hours. The mixture was filtered through celite and the filtrate evaporated under reduced pressure to leave a residue which was purified by column chromatography on silica gel (60-120 mesh) using 1% EtOAc/hexanes as the eluent to give the title compound (0.4 g, 67%) as a colourless oil.

82C. (E)-2-(4-Chlorophenyl)-3-(dimethylamino)-1-[2-(trifluoromethyl)phenyl]prop-2-en-1-one

(127) A solution of N,N-dimethylformamide dimethyl acetal (0.32 g, 2.68 mmol) in DMF (1 mL) was added dropwise to a stirred solution of 2-(4-chlorophenyl)-1-[2-(trifluoromethyl)phenyl]ethanone (0.4 g, 1.34 mmol) in DMF (4 mL) at room temperature under a nitrogen atmosphere. The mixture was heated to 90° C. for 3 hours then allowed to cool to room temperature and poured in to water (50 mL) and extracted with EtOAc (3×150 mL). The combined organic extracts were washed with brine (2×10 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on silica gel (60-120 mesh) using 25% EtOAc/hexanes as the eluent to give the title compound (0.39 g, 82%) as a white solid.

82D. 4-[4-(4-Chlorophenyl)-5-[2-(trifluoromethyl)phenyl]pyrazol-1-yl]benzonitrile

(128) A mixture of (E)-2-(4-chlorophenyl)-3-(dimethylamino)-1-[2-(trifluoromethyl)phenyl]prop-2-en-1-one (0.39 g, 1.1 mmol), 4-cyanophenylhydrazine hydrochloride (0.21 g, 1.21 mmol) and sodium carbonate (82 mg, 0.77 mmol) in MeOH (40 mL) and water (80 mL) was stirred at room temperature for 15 minutes. Acetic acid (8 mL) was added dropwise over 10 minutes then the resulting mixture was heated to 140° C. for 8 hours. The cooled solution was neutralized with saturated Na.sub.2CO.sub.3 solution and extracted with EtOAc (3×150 mL). The combined organic extracts were washed with brine (2×25 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave a residue which was triturated with Et.sub.2O (3×10 mL) and pentane (3×10 mL) to give the title compound (0.4 g, 79%) as a white solid.

82E. 4-[4-(4-Chlorophenyl)-5-[2-(trifluoromethyl)phenyl]pyrazol-1-yl]benzoic Acid

(129) A mixture of 4-[4-(4-chlorophenyl)-5-[2-(trifluoromethyl)phenyl]pyrazol-1-yl]benzonitrile (0.40 g, 0.94 mmol) and sodium hydroxide (0.38 g, 9.44 mmol) in methanol (5 mL) and water (5 mL) was stirred at 80° C. for 3 hours. The pH of the mixture was adjusted to 4 with 1N HCl and the resulting solid collected by filtration. The collected solid was washed with water (2×5 mL) and hexane (2×5 mL) and dried to give the title compound (0.30 g, 77%) as a white solid.

82F. 4-[4-(4-Chlorophenyl)-5-[2-(trifluoromethyl)phenyl]pyrazol-1-yl]-N-[2-(dimethylamino)ethyl]benzamide Hydrochloride

(130) HATU (0.20 g, 0.53 mmol) was added to a stirred solution of 4-[4-(4-chlorophenyl)-5-[2-(trifluoromethyl)phenyl]pyrazol-1-yl]benzoic acid (0.15 g, 0.35 mmol) in DMF (2 mL) at 0° C. under a nitrogen atmosphere. After stirring for 30 minutes, DIPEA (0.2 mL, 1.01 mmol) and N′,N′-dimethylethane-1,2-diamine (37 mg, 0.42 mmol) were added and stirring continued for 90 minutes. The mixture was diluted with water (50 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (50 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on silica gel (60-120 mesh) using 4% MeOH/CHCl.sub.3 as the eluent. The resulting solid was dissolved in THF (2 mL) and 4N HCl solution in dioxane (0.1 ml) was added and the mixture stirred for 30 minutes at room temperature. The solvents were evaporated under reduced pressure to leave a solid that was triturated with Et.sub.2O (3×10 mL) and then dried to give the title compound (75 mg, 40%) as an off-white solid.

(131) Synthetic Route M

(132) (Illustrated with reference to Example 93)

Example 93

4-[3-(4-chlorophenyl)-4-[2-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl]-N-[2-(dimethylamino)ethyl] Benzamide Hydrochloride)

(133) ##STR00175##

93A. 4-(2,2-Dibromovinyl)benzonitrile

(134) Triphenylphosphine (16.0 g, 60.8 mmol) was added in portions over 15 minutes to a stirred solution of 4-formylbenzonitrile (2.0 g, 15.2 mmol) and carbon tetrabromide (10.1 g, 30.4 mmol) in DCM (50 mL) at 0° C. under a nitrogen atmosphere. The resulting brown coloured solution was stirred at 0° C. for 2 hours then diluted with EtOAc (100 mL) and poured into water (100 mL). After filtering through a pad of celite the separated aqueous phase was extracted with EtOAc (3×200 mL). The combined organic extracts were washed with brine (2×10 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on silica gel (60-120 mesh) using 4% EtOAc/hexanes as the eluent to give the title compound (3.5 g, 81%) as a white solid.

93B. N—[(E)-(4-Chlorophenyl)methyleneamino]-4-methyl-benzenesulfonamide

(135) A stirred solution of 4-chlorobenzaldehyde (3.0 g, 16.1 mmol) and p-toluenesulfonyl hydrazide (2.37 g, 16.9 mmol) in MeOH (20 mL) was heated to 60° C. for two hours. The solution was allowed to cool to room temperature and then the solvents were evaporated under reduced pressure. The resulting solid was recrystallised from MeOH/H.sub.2O to give the title compound (3.5 g, 71%) as a white solid.

93C. 4-[4-Bromo-3-(4-chlorophenyl)-1H-pyrazol-5-yl]benzonitrile

(136) A stirred solution of N-[(E)-(4-chlorophenyl)methyleneamino]-4-methyl-benzenesulfonamide (2.0 g, 6.5 mmol), 4-(2,2-dibromovinyl)benzonitrile (1.85 g, 6.5 mmol) and NaOH (0.78 g, 19.5 mmol) in 1,4-dioxane (60 mL) was heated to 70° C. for 17 hours. The cooled reaction mixture was partitioned between saturated potassium bisulfate solution (100 mL) and EtOAc (50 mL). The separated aqueous phase was extracted with EtOAc (3×50 mL) then the combined organic extracts were washed with brine (2×25 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (60-120 mesh) using 7% EtOAc/hexanes as the eluent to give the title compound (0.5 g, 22%) as an off-white solid.

93D. tert-Butyl 4-bromo-3-(4-chlorophenyl)-5-(4-cyanophenyl)pyrazole-1-carboxylate

(137) (Boc).sub.2O was added to a stirred solution of 4-[4-bromo-3-(4-chlorophenyl)-1H-pyrazol-5-yl]benzonitrile (0.50 g, 1.4 mmol) and triethylamine (0.3 mL, 2.1 mmol) in THF (5 mL) under a nitrogen atmosphere. The solution was stirred for 30 minutes at room temperature then partitioned between saturated potassium bisulfate solution (20 mL) and EtOAc (30 mL). The separated aqueous phase was extracted with EtOAc (3×30 mL) then the combined organic extracts were washed with brine (2×25 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (60-120 mesh) using 7% EtOAc/hexanes as the eluent to give the title compound (0.45 g, 70%) as an off-white solid.

93E. 4-[3-(4-Chlorophenyl)-4-[2-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl]benzonitrile

(138) A stirred mixture of tert-butyl 4-bromo-3-(4-chlorophenyl)-5-(4-cyanophenyl)pyrazole-1-carboxylate (0.45 g, 0.97 mmol), (2-(trifluoromethyl)phenyl)boronic acid (0.28 g, 1.46 mmol), tripotassium phosphate (0.62 g, 2.9 mmol) and tricyclohexylphosphine tetrafluoroborate (43 mg, 0.12 mmol) in 1,4-dioxane (13 mL) was degassed with nitrogen for 20 minutes. Bis(dibenzylideneacetone)palladium(0) (55 mg, 0.097 mmol) was added to the solution and the resulting mixture heated to 90° C. for 36 hours under a nitrogen atmosphere. The cooled reaction mixture was partitioned between water (20 mL) and EtOAc (30 mL). The separated aqueous phase was extracted with EtOAc (3×30 mL) then the combined organic extracts were washed with brine (2×25 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (60-120 mesh) using 12% EtOAc/hexanes as the eluent to give the title compound (0.16 g, 39%) as an off-white solid.

93F. 4-[3-(4-Chlorophenyl)-4-[2-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl]benzoic Acid

(139) A mixture of 4-[3-(4-chlorophenyl)-4-[2-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl]benzonitrile (0.16 g, 0.38 mmol) and sodium hydroxide (0.15 g, 3.78 mmol) in methanol (1.6 mL) and water (0.7 mL) was stirred at 90° C. for 18 hours. The cooled reaction mixture was partitioned between saturated potassium bisulfate solution (10 mL) and EtOAc (10 mL). The separated aqueous phase was extracted with EtOAc (3×10 mL) then the combined organic extracts were washed with brine (2×10 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to give the title compound (0.14 g, 84%) as an off-white solid.

93G. 4-[3-(4-Chlorophenyl)-4-[2-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl]-N-[2-(dimethylamino)ethyl] Benzamide Hydrochloride

(140) HATU (0.17 g, 0.44 mmol) was added to a stirred solution of 4-[3-(4-chlorophenyl)-4-[2-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl]benzoic acid (0.13 g, 0.29 mmol) in DMF (1.3 mL) at 0° C. under a nitrogen atmosphere. After stirring for 30 minutes, DIPEA (0.15 mL, 0.88 mmol) and N′,N′-dimethylethane-1,2-diamine (31 mg, 0.35 mmol) were added and stirring continued for 30 minutes. The mixture was diluted with water (20 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine (20 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on silica gel (60-120 mesh) using 4% MeOH/CHCl.sub.3 as the eluent. The resulting solid was dissolved in THF (2 mL) and 4N HCl solution in dioxane (0.1 mL) was added and the mixture stirred for 30 minutes at room temperature. The solvents were evaporated under reduced pressure to leave a solid that was triturated with n-pentane (3×10 mL) and then dried to give the title compound (33 mg, 25%) as an off-white solid.

(141) Synthetic Route N

(142) (Illustrated with reference to Example 90)

Example 90

1-[4-[5-(4-Chlorophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]-3-[2-(dimethylamino)-ethyl]urea Hydrochloride)

(143) ##STR00176##

90A. 1-[4-[5-(4-Chlorophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]phenyl]-3-[2-(dimethylamino)-ethyl]urea Hydrochloride

(144) A solution of 4-nitrophenylchloroformate (0.16 g, 0.8 mmol) in DCM (5 mL) was added dropwise to a stirred solution of 4-[5-(4-chlorophenyl)-1-[2-(trifluoromethyl)phenyl]pyrrol-2-yl]aniline (0.3 g, 0.72 mmol) (prepared using Method D) and pyridine (63 mg, 0.8 mmol) in DCM (10 mL) at 0° C. under a nitrogen atmosphere. The mixture was stirred at 0° C. for 2 hours then DIPEA (0.18 g, 1.44 mmol) and N,N′-dimethylethelenediamine (63 mg, 0.72 mmol) were added and the mixture allowed to warm to room temperature. Stirring was continued for a further 2 hours then the solvents were evaporated under reduced pressure to leave a residue which was purified by preparative HPLC using (A) 0.1% HCl in water and (B) 100% acetonitrile as mobile phase, using Denali C18 (250×25 mm) 5 um column with the flow rate of 25.0 mL/min and with the following gradient:

(145) TABLE-US-00010 Time (min) A B 0.01 60 40 14.00 55 45 14.01 0 100 19.00 0 100 19.01 60 40 20.00 60 40

(146) The title compound (0.07 g, 17%) was obtained as a white solid.

(147) Synthetic Route O

(148) (Illustrated with reference to Example 92)

Example 92

4-[3-(4-Chlorophenyl)-4-[2-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl]-N-[2-(dimethylamino)ethyl] Benzamide Hydrochloride)

(149) ##STR00177##

92A. (1E)-4-Chlorobenzaldehyde Oxime

(150) Sodium hydroxide (4.4 g, 110 mmol) was added in portions over 10 minutes to a stirred solution of 4-chlorobenzaldehyde (10 g, 71.1 mmol) and hydroxylamine hydrochloride (10 g, 144 mmol) in EtOH (50 mL) and water (50 mL) and the resulting mixture stirred at room temperature for 18 hours. The solution was neutralized with 2N HCl solution and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (50 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to give the title compound (10.0 g, 91%) as a white solid.

92B. (1Z)-4-Chloro-N-hydroxy-benzimidoyl Chloride

(151) N-Chlorosuccinimide (1.73 g, 12.9 mmol) was added in three portions over 15 minutes to a stirred solution of (1E)-4-chlorobenzaldehyde oxime (2.0 g, 12.9 mmol) in DMF (10 mL) at 0° C. under a nitrogen atmosphere. The solution was allowed to warm to room temperature and stirring continued for 18 hours before partitioning between water (100 mL) and EtOAc (50 mL). The separated aqueous phase was extracted with EtOAc (3×50 mL) then the combined organic extracts were washed with brine (2×25 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to give the title compound (0.16 g, 39%) as a beige solid.

92C. Methyl 4-[3-(4-chlorophenyl)isoxazol-5-yl]benzoate

(152) A mixture of (1Z)-4-chloro-N-hydroxy-benzimidoyl chloride (1.75 g, 9.2 mmol), methyl 4-ethynylbenzoate (1.47 g, 9.2 mmol) and Et.sub.3N (1.4 mL, 10.1 mmol) in Et.sub.2O (25 mL) was stirred at room temperature under a nitrogen atmosphere for 18 hours. The reaction mixture was partitioned between water (20 mL) and EtOAc (30 mL). The separated aqueous phase was extracted with EtOAc (3×30 mL) then the combined organic extracts were washed with brine (2×25 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (60-120 mesh) using 85% EtOAc/hexanes as the eluent to give the title compound (1.55 g, 54%) as an off-white solid.

92D. Methyl 4-[4-bromo-3-(4-chlorophenyl)isoxazol-5-yl]benzoate

(153) N-Bromosuccinimide (1.02 g, 5.7 mmol) was added to a stirred solution of methyl 4-[3-(4-chlorophenyl)isoxazol-5-yl]benzoate (1.50 g, 4.7 mmol) in glacial acetic acid (10 mL) and the resulting mixture heated to 110° C. for 3 hours. The cooled reaction mixture was diluted with water (100 mL) and the resulting solid collected by filtration. The obtained solid was further purified by column chromatography on silica gel (60-120 mesh) using 4% EtOAc/hexanes as the eluent to give the title compound (0.84 g, 45%) as a yellow solid.

92E. Methyl 4-[3-(4-chlorophenyl)-4-[2-(trifluoromethyl)phenyl]isoxazol-5-yl]benzoate

(154) A stirred mixture of methyl 4-[4-bromo-3-(4-chlorophenyl)isoxazol-5-yl]benzoate (0.80 g, 2.0 mmol), (2-(trifluoromethyl)phenyl)boronic acid (1.92 g, 10.1 mmol), tripotassium phosphate (1.29 g, 6.0 mmol) and tricyclohexylphosphine tetrafluoroborate (75 mg, 0.20 mmol) in 1,4-dioxane (30 mL) was degassed with nitrogen for 30 minutes at room temperature.

(155) Bis(dibenzylideneacetone)palladium(0) (60 mg, 0.10 mmol) was added to the solution and the resulting mixture heated to 110° C. for 18 hours under a nitrogen atmosphere. The cooled reaction mixture was partitioned between water (50 mL) and EtOAc (50 mL). The separated aqueous phase was extracted with EtOAc (4×50 mL) then the combined organic extracts were washed with brine (2×25 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (60-120 mesh) using 5% EtOAc/hexanes as the eluent to give the title compound (0.18 g, 19%) as an off-white solid.

92F. 4-[3-(4-Chlorophenyl)-4-[2-(trifluoromethyl)phenyl]isoxazol-5-yl]benzoic Acid

(156) A stirred solution of methyl 4-[3-(4-chlorophenyl)-4-[2-(trifluoromethyl)phenyl]isoxazol-5-yl]benzoate (0.17 g, 0.40 mmol) and lithium hydroxide monohydrate (67 mg, 0.16 mmol) in THF (2 mL) and water (2 mL) was heated at 90° C. for 16 hours. The cooled reaction mixture was partitioned between saturated potassium bisulfate solution (20 mL) and EtOAc (30 mL). The separated aqueous phase was extracted with EtOAc (3×30 mL) then the combined organic extracts were washed with brine (2×25 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to give the title compound (0.16 g, 98%) as an off-white solid.

92G. 4-[3-(4-Chlorophenyl)-4-[2-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl]-N-[2-(dimethylamino)ethyl] Benzamide Hydrochloride

(157) HATU (0.21 g, 0.54 mmol) was added to a stirred solution of 4-[3-(4-chlorophenyl)-4-[2-(trifluoromethyl)phenyl]isoxazol-5-yl]benzoic acid (0.16 g, 0.36 mmol) in DMF (2 mL) at 0° C. under a nitrogen atmosphere. After stirring for 30 minutes, DIPEA (0.2 mL, 1.01 mmol) and N′,N′-dimethylethane-1,2-diamine (38 mg, 0.43 mmol) were added and stirring continued for 2 hours. The mixture was diluted with water (50 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (50 mL), dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on silica gel (60-120 mesh) using 4% MeOH/CHCl.sub.3 as the eluent. The resulting solid was dissolved in THF (2 mL) and 4N HCl solution in dioxane (0.1 mL) was added and the mixture stirred for 30 minutes at room temperature. The solvents were evaporated under reduced pressure to leave a solid that was triturated with n-pentane (3×10 mL) and then dried to give the title compound (35 mg, 18%) as a white solid.

Biological Activity

Example A

(158) Assay to Measure the Effects of Compounds of the Invention on HCT116 Colorectal Cancer Cell Viability

(159) The following protocol was used to measure the effects of compounds of the invention on HCT116 cell viability.

(160) 1. HCT116 cells were grown in RPM11640 media supplemented with Glutamax and 10% FBS in a 37° C./5% CO2 incubator.

(161) 2. Growing culture of HCT116 cells were trypsinised, counted and diluted to give 10,000 cells/mL in an appropriate volume, allowing at least 6 mL of cells per plate.

(162) 3. 200 μL of PBS were added to all the outer wells of a flat-bottomed (8×12) 96-well TC plate. 100 μL of media were added only to wells in column 11 of the plates (these wells provided a blank for the cell titre blue assay). Two compounds were assayed on each plate.

(163) 4. 100 ul of 10,000 cells/mL HCT116s were plated in rows B-G of each plate.

(164) 5. The cells were incubated (37° C. 5% CO.sub.2) for 24 hours before treating with compounds.

(165) 6. An 8 mM compound stock in DMSO was prepared for all compounds to be tested. 2.5 μL of the compound stock was added to 1000 μL growth medium in a 96-well deep well block and serial dilutions were prepared across the plate by transferring 500 μL into wells containing 500 μL growth medium+0.25% DMSO to give eight concentrations of compound (this ensured a constant amount of DMSO at all concentrations of compound). When making up growth medium+DMSO, an amount of 5 ml was allowed per compound to be diluted.

(166) 7. 3 rows of cells were treated with 100 μL/well from each row on the dilution plate so that each cell plate is treated with a single compound. This gave a final volume in all wells of 200 μL and a titration of compound from a final concentration of 10 uM down to 78 nM.

(167) 8. The cells were incubated (37° C. 5% CO.sub.2) for 72 hours.

(168) 9. 5 ul cell titre blue reagent (Promega) were added to all wells except the edge wells (which contain PBS only) and incubated (37° C. 5% CO.sub.2) for 2.5-3 hours.

(169) 10. Fluorescence was measured on a suitable plate reader using a 530-570 nm filter set for excitation and a 580-620 nm filter set for fluorescence emission.

(170) 11. Data were analysed using an appropriate graphing package (such as GraphPad Prism). Data were expressed as the concentration of compound causing a 50% inhibition of cell viability or GI.sub.50.

(171) From the results obtained by following the above protocol, the GI.sub.50 values against the HCT116 cell line of each of the compounds of the Examples were determined as shown in Table 4.

(172) TABLE-US-00011 TABLE 4 Example GI.sub.50 (μM) Example GI.sub.50 (μM) Example GI.sub.50 (μM) 1 nd 2 nd 3 nd 4 nd 5 0.56 6 0.20 7 1.06 8 1.85 9 0.03 10 0.34 11 0.36 12 0.29 13 0.66 14 nd 15 2.18 16 2.72 17 nd 18 nd 19 4.21 20 3.94 21 1.06 22 2.75 23 0.39 24 0.49 25 3.89 26 0.12 27 4.74 28 nd 29 0.06 30 8.44 31 1.45 32 0.06 33 0.01 34 0.08 35 0.22 36 0.03 37 0.02 38 0.19 39 0.35 40 1.03 41 0.05 42 0.38 43 0.20 44 0.51 45 0.35 46 0.16 47 1.38 48 0.41 49 0.05 50 2.18 51 0.10 52 0.35 53 0.56 54 1.38 55 2.25 56 2.71 57 0.06 58 0.03 59 0.05 60 0.06 61 0.06 62 0.12 63 1.64 64 1.70 65 1.96 66 0.89 67 0.07 68 0.11 69 0.05 70 0.02 71 0.02 72 1.73 73 0.09 74 0.13 75 0.15 76 0.24 77 3.63 78 2.13 79 3.83 80 3.92 81 0.08 82 0.04 83 0.06 84 0.19 85 0.49 86 0.34 87 0.06 88 0.25 89 1.36 90 0.50 91 0.01 92 0.03 93 0.26 94 0.05 95 0.08 96 0.03 97 0.02 98 0.02 99 0.04 100 0.13 101 0.06 102 0.38 103 0.04 104 0.15 105 0.10 106 0.08 107 0.16

Example B

(173) Assay to Measure the Effects of Compounds of the Invention on Arresting Cells in Mitosis

(174) Inhibiting the ability of PLK1 to bind to its phosphopeptide binding partners through the PBD causes cells to arrest in mitosis. Experimentally, this is measured by assessing the number of cells which are in mitosis at a certain time after treatment with a PLK1-PBD inhibitor by immunofluorescent detection of phosphorylated Histone H3 (pH3), a marker which is only present in mitotic cells. PLK1-PBD inhibitors are expected to cause a dose-dependent increase in pH3-positive cells, which is reported as Mitotic Index (MI)—the percentage of cells which, at a given time, are positive for this mitotic mark. The following protocol has been used to measure MI: 1. Plate HeLa cells at 10,000/well in 100 μL/well in clear flat-bottom 96-well plates and incubate overnight. 2. Immediately prior to treatment, dilute compounds in medium in a 96-well round-bottom plate. Make up all compounds at 5 times final desired concentration on cells, and serially dilute 1:2 across the plate ensuring that there is 100 μL of each concentration (start with 200 μl of the top concentration on the left of the plate). Do not exceed a final concentration on cells of 1% DMSO (i.e. not greater than 5% in the dilution plate), and preferably remain below 0.5%. 3. Treat cells by adding 25 μL from the compound dilution plate to triplicate wells. 4. Incubate cells with compound for 24 hours. 5. After 24 hours, fixation and staining is carried out as follows: 6. Dilute 37% formaldehyde in PBS to give a 12.95% solution by adding 3.5 mL formaldehyde to 6.5 mL of PBS. 7. Add 50 μL of formaldehyde fixation solution directly to each well of cells (which already contain 125 μL medium). 8. Incubate at room temp for 10 minutes. 9. Remove fixative and add 100 μL/well PBS+0.1% Triton X-100 for 10 minutes. 10. Aspirate and add 100 μL/well PBS+1% BSA. 11. Aspirate and add 50 μL/well of primary antibody (anti-PH3 [1:2000]/anti-MPM2 [1:1000]) diluted in PBS+1% BSA. Incubate for 1 hour. 12. Wash×2 with 100 μL/well PBS+1% BSA. 13. Add 50 μL/well of secondary antibody plus Hoechst stain (anti-rabbit Alexafluor 488 [1:500]; anti-mouse Alexafluor 546 [1:500]+Hoechst 33342 [1:2500 final concentration=4 μg/mL])diluted in PBS+1% BSA. Incubate for 1 hour. 14. Wash twice with 100 μL/well PBS+1% BSA. 15. Aspirate and add 100 μL/well PBS. Plates can be stored at 4° C. in PBS for several weeks before scanning on the Cellomics Arrayscan. Ensure that plates do not dry out. 16. Scan on Cellomics using Target Activation Bioapplication. 17. MI data emerging from the Cellomic Bioapplication can be used to plot MI versus compound concentration, and subsequently used to generate an EC50 value for each compound using an appropriate graphing/curve-fitting package such as GraphPad Prism.

(175) From the results obtained by following the above protocol, the EC.sub.50 values and the percentage of cells in mitosis against the HeLa cell line was obtained for each of the compounds of the Examples were determined as shown in Table 5.

(176) TABLE-US-00012 TABLE 5 % mitotic % mitotic Example EC.sub.50 (μM) cells Example EC.sub.50 (μM) cells 2 0.86 86 3 1.58 65 4 0.55 65 6 0.66 86 7 2.2 75 9 0.19 89 10 0.78 62 11 0.80 54 12 0.79 62 13 0.75 71 14 0.83 68 17 1.45 65 18 1.64 67 22 >10 5 23 0.74 79 24 0.62 77

(177) In a separate experiment, the compound of Example 33 was tested in the mitotic arrest assay and was found to have an EC.sub.50 in the assay of 0.061±0.01 μM.

Example C

(178) Assay to Measure the Effects of Compounds of the Invention on Wild-Type Versus KRAS HeLa Cell Viability

(179) Identifying synthetic lethal interactions between targeted small molecule therapies and characterised oncogenic mutations is a goal of modern oncology drug discovery efforts. To this end, PLK1-PBD inhibitors were tested on HeLa cells engineered to inducibly express wild-type or oncogenic KrasG12V transgenes using the FLP-in/T-Rex system (Invitrogen). Cells were plated, and then treated with or without Doxycycline to induce transgene expression, and then treated with serially-diluted PBD inhibitors. After 72 hours of incubation, cell viability was assessed using the Cell Titre Blue reagent (Promega) and a BMG Pherastar plate reader. The effect of PBD inhibition on cell viability with either wild-type or oncogenic G12V KRAS was assessed using the graphing/curve-fitting packages in GraphPad Prism.

(180) From the results obtained by following the above protocol, the GI.sub.50 values against the wild-type and KRAS G12V HeLa cell line of each of the compounds of the Examples were determined as shown in Table 6.

(181) TABLE-US-00013 TABLE 6 Exam- WT GI.sub.50 G12V GI.sub.50 Exam- WT GI.sub.50 G12V GI.sub.50 ple (μM) (μM) ple (μM) (μM) 2 0.18 0.05 9 0.05 0.02 15 0.65 0.38 23 0.24 0.08 24 0.26 0.08 25 2.51 3.58 26 0.12 0.07 28 0.06 0.03 33 0.02 0.01 34 0.13 0.09 35 0.21 0.14 36 0.12 0.06 37 0.05 0.02 41 0.04 0.02 42 0.13 0.05 53 0.34 0.22 56 2.19 2.52 57 0.05 0.03 58 0.03 0.02 59 0.01 0.008 60 0.03 0.01 61 0.02 0.005 62 0.02 0.008 70 0.005 0.003 71 0.01 0.005 82 0.03 0.01 87 0.02 0.008 91 0.01 0.005

Example D

(182) Assay to Measure the Effects of Compounds of the Invention on Glioblastoma Cancer Cell Viability

(183) The compound of Example 33 was tested for inhibitory activity against the glioblastoma cell lines in Table 7 below.

(184) TABLE-US-00014 TABLE 7 Cell line # IC.sub.50(μM) 907042 0.071 908145 0.223 905984 0.241 906868 0.252 909905 0.276 906871 0.283 1240170 0.363 906746 0.430 687586 0.489 949094 0.709 909750 0.929 907313 1.109 909745 1.367 946368 1.397 946370 1.671 907271 2.059 908144 2.423 907279 27.821

Example E

(185) Kinase Selectivity Assay

(186) Compounds of the invention bind to the PBD domain of PLK1 but not to the catalytic domain and should exhibit good selectivity over other kinases. The compound of Example 33 was tested for off-target activity against a panel of fifty five kinases bearing functional or structural similarity to PLK1 at a concentration of 5 μM using the DiscoverX KinomeScreen assay. The results are shown in Table 8 below.

(187) TABLE-US-00015 TABLE 8 Gene Symbol % Control AAK1 100 AURKA 83 AURKB 95 AURKC 85 BMP2K 85 BUB1 90 CAMKK1 91 CAMKK2 97 CDK2 89 CSNK2A1 96 CSNK2A2 92 EIF2AK1 98 ERN1 74 GAK 100 EIF2AK4 97 GSG2 77 CHUK 100 IKBKB 100 IKBKE 75 NEK1 100 NEK10 94 NEK11 100 NEK2 94 NEK3 74 NEK4 100 NEK5 99 NEK6 99 NEK7 79 NEK9 92 PKMYT1 100 PLK1 100 PLK2 85 PLK3 74 PLK4 90 EIF2AK2 90 DSTYK 75 ROCK2 100 SBK1 61 SgK110 100 STK16 92 STK35 71 STK36 91 TBK1 80 TLK1 99 TLK2 94 TTK 83 ULK1 84 ULK2 100 ULK3 88 WEE1 98 WEE2 92 WNK1 97 WNK2 100 WNK3 100 WNK4 91

(188) The results demonstrate a lack of activity against the other kinases and hence the specificity of the compound of Example 33 for PLK1-PBD over other kinases.

Example F

(189) Determination of Oral Bioavailability

(190) The oral bioavailability of the compound of Example 33 was determined in mice and compared with the bioavailability following intravenous injection using the following protocol. Male CD-1 mice were dosed with the compound of Example 33, either by i.v. administration (2 mg/kg) or by peroral administration (10 mg/kg) and samples were taken for analysis at 2, 5, 10, 15, 30 min, 1, 2, 4, 8, 16, 24 and 40 hrs (for i.v.) and at 5, 15, 30 min, 1, 2, 4, 8, 16, 24, 48 and 72 hrs. The compound of Example 33 was formulated in 5% DMSO/95% hydroxypropyl-beta-cyclodextrin (20% w/v aqueous) for i.v. and 10% DMSO/90% hydroxypropyl-beta-cyclodextrin (20% w/v aqueous) for p.o. N=3 mice per time point with 15 ul plasma per aliquot. Quantitative bioanalysis was performed and the results are shown in FIG. 1 and in Table 9 below.

(191) TABLE-US-00016 TABLE 9 Parameter 2 mg/kg IV Parameter 10 mg/Kg PO T½ 13 hours T½ 15 hours CI 16 ml/min/kg Vz 23 l/kg Vss 17 l/kg Cmax 415 ng/ml Cmax 873 ng/ml AUCinf 9796 ng .Math. hr/ml AUCinf 2096 ng .Math. hour/ml F 93%

(192) The results demonstrate that the compound of Example 33 is highly absorbed following oral dosing in mice.

(193) Measurements of other pharmacokinetic parameters of the compound of Example 33 demonstrated that it has a kinetic solubility of 32 μM, exhibits negligible (>25 μM) binding to the hERG ion channel, and is stable in human hepatocytes (C.sub.Lint 10 μl/min/million cells). It also demonstrates negligible cytochrome P450 inhibition ((1A, 2D6, 2C9, 2C19, 3A4) all >10 uM).

Example G

(194) Determination of Brain Exposure Following Oral Dosing in Mice

(195) An experiment was carried out on the compound of Example 33 to determine the extent of its brain penetration following oral dosing in mice. The following protocol was used. 15 male CD-1 mice (n=3/time point) were dosed perorally with the compound of Example 33 (10 mg/kg; dose concentration 1 mg/ml; dose volume 10 mL/kg). The compound of Example 33 was formulated in 10% DMSO/90% hydroxypropyl-β-cyclodextrin (20% w/v aqueous). Animals were housed in pre-assigned housing cages until sampling. Appropriate samples were taken at 1, 4, 8 & 24 hour time points and stored immediately at −20° C. Homogenisation and protein precipitation with acetonitrile was carried out for plasma and brain. Analysis was carried out with tandem mass spectrometry using electrospray ionisation. The results of the experiment are shown in FIG. 2 and in Table 10 below.

(196) TABLE-US-00017 TABLE 10 Parameter 10 mg/Kg PO Tmax (Plasma) 8.0 hours Tmax (Brain) 24 hours AUClast (Plasma) 5031 ng .Math. hr/ml AUClast (Brain) 31920 ng .Math. hr/ml

Example H

(197) In Vivo Anti-Cancer Activity in Mice Bearing HCT116 Tumours

(198) Mice bearing HCT116 xenograft tumours were give oral dosages of either 50 mg/kg or 200 m/kg on days 1, 3, 7, 10 and 13 and the tumour volumes measured at days 1, 3, 5, 8, 10, 12 and 15. Tumour volumes in a control group of tumour-bearing mice, who had received vehicle only at the same time points were also measured. The results, shown in FIG. 3, demonstrate a pronounced effect on tumour growth (48% T/C).

(199) In a separate experiment, eight mice with established tumours were treated with the compound of Example 33 and euthanised 24 hours after administration of a single dose. The tumours were removed and analysed by Western blotting to reveal a clear induction of phospho-histone H3, indicating a block in mitosis.

Example I

(200) Drug Resistance Studies

(201) The compound 4-[[(7R)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6-oxo-2-pteridinyl]amino]-3-methoxy-N-(1-methyl-4-piperidinyl)benzamide, known by the code name B12536, is a PLK1 inhibitor which inhibits the catalytic activity of PLK1 and shows potent anticancer activity. B12536 has progressed into clinical studies in humans with locally advanced or metastatic cancers (Steegmaier et al., Current Biology, 17, 316-322, 2007).

(202) HCT116 cells (a mutant KRAS G-13D expressing cell line) were treated with five times the half maximal growth inhibiting amount of either B12536 or the compound of Example 33. After twenty two days, it was observed that drug-resistant colonies were formed with B12536 but not with the compound of Example 33. This result suggests that inhibiting the C-terminal polo box domain of PLK1, rather than the N-terminal catalytic domain, is less likely to result in the development of drug resistant strains of the cancer.

(203) Pharmaceutical Formulations

(204) (i) Tablet Formulation

(205) A tablet composition containing a compound of the formula (1) is prepared by mixing 50 mg of the compound with 197 mg of lactose (BP) as diluent, and 3 mg magnesium stearate as a lubricant and compressing to form a tablet in known manner.

(206) (ii) Capsule Formulation

(207) A capsule formulation is prepared by mixing 100 mg of a compound of the formula (1) with 100 mg lactose and filling the resulting mixture into standard opaque hard gelatin capsules.

(208) (iii) Injectable Formulation I

(209) A parenteral composition for administration by injection can be prepared by dissolving a compound of the formula (1) (e.g. in a salt form) in water containing 10% propylene glycol to give a concentration of active compound of 1.5% by weight. The solution is then sterilised by filtration, filled into an ampoule and sealed.

(210) (iv) Injectable Formulation II

(211) A parenteral composition for injection is prepared by dissolving in water a compound of the formula (1) (e.g. in salt form) (2 mg/ml) and mannitol (50 mg/ml), sterile filtering the solution and filling into sealable 1 ml vials or ampoules.

(212) v) Injectable formulation III

(213) A formulation for i.v. delivery by injection or infusion can be prepared by dissolving the compound of formula (1) (e.g. in a salt form) in water at 20 mg/ml. The vial is then sealed and sterilised by autoclaving.

(214) vi) Injectable formulation IV

(215) A formulation for i.v. delivery by injection or infusion can be prepared by dissolving the compound of formula (1) (e.g. in a salt form) in water containing a buffer (e.g. 0.2 M acetate pH 4.6) at 20 mg/ml. The vial is then sealed and sterilised by autoclaving.

(216) (vii) Subcutaneous Injection Formulation

(217) A composition for sub-cutaneous administration is prepared by mixing a compound of the formula (1) with pharmaceutical grade corn oil to give a concentration of 5 mg/ml. The composition is sterilised and filled into a suitable container.

(218) viii) Lyophilised formulation

(219) Aliquots of formulated compound of formula (1) are put into 50 ml vials and lyophilized. During lyophilisation, the compositions are frozen using a one-step freezing protocol at (−45° C.). The temperature is raised to −10° C. for annealing, then lowered to freezing at −45° C., followed by primary drying at +25° C. for approximately 3400 minutes, followed by a secondary drying with increased steps if temperature to 50° C. The pressure during primary and secondary drying is set at 80 millitor.

EQUIVALENTS

(220) The foregoing examples are presented for the purpose of illustrating the invention and should not be construed as imposing any limitation on the scope of the invention. It will readily be apparent that numerous modifications and alterations may be made to the specific embodiments of the invention described above and illustrated in the examples without departing from the principles underlying the invention. All such modifications and alterations are intended to be embraced by this application.

Pyrrole derivatives as PLK1 inhibitors

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