AU1161601A - Activators of soluble guanylate cyclase - Google Patents

Description

WO 01/32604 PCT/GBOO/04249 ACTIVATORS OF SOLUBLE GUANYLATE CYCLASE This invention relates to activators of soluble guanylate cyclase (sGC), to their preparation and to their use. Soluble guanylate cyclase is responsible for the enzymatic conversion of 5 guanosine-5'-triphosphate (GTP) to cyclic guanosine-3',5'-monophosphate (cGMP). The enzyme is stimulated by NO binding to the enzyme. sGC is responsible for numerous physiological processes including vascular and non-vascular smooth muscle relaxation, peripheral and central neurotransmission, platelet reactivity and phototransduction (Hobbs A.J., TiPS, 10 December 1997, Vol 18, p.484). Activators of sGC can therefore be expected to have valuable therapeutic properties. As explained above, NO is known as an activator of sGC. However, this compound has a number of different physiological effects and its use in activating sGC therefore suffers from a myriad of side effects. There is therefore a need for 15 selective activators of sGC. 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) is a known NO independent activator of sGC (Hobbs, A.J., TiPS, December 1997, Vol 18, p.484). However, the activation achieved is not high. Accordingly, the present invention provides the use of a compound of the 20 formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the activation of soluble guanylate cyclase Z P NR 1

R

2 25 wherein: - R, and R 2 are the same or different and each represent a CI-C 6 alkyl group, or R, and R 2 together form a C 3

-C

6 alkylene group; - Z is a C 1

-C

4 alkylene group; - P is a direct bond or a moiety -X-, -Y-, -W-, -XY-, -YW- or -XYW-, 30 wherein: - W is -0-, -S-, or -NR 3 , wherein R 3 is hydrogen or CI-C 6 alkyl; WO 01/32604 PCT/GBOO/04249 -2 - Y is a moiety -U-V- wherein V is a direct bond or a C 1

C

6 alkylene group and U is -CS-, -CO-, -S(0) 2 - or -C(=NR) wherein R is hydrogen, hydroxy or C 1

C

6 kyl; - X is -0- or -NR 6 - wherein R 6 is hydrogen, C 1

C

6 alkyl, C 2

-C

6 5 alkenyl, C 2

-C

6 alkynyl, aryl or heteroaryl; and - R 4 is C-C 6 alkyl, C 2

-C

6 alkenyl, C 2

-C

6 alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, a group -R-A wherein R is -(C-C 6 alkyl)-,

-(C

2

-C

6 alkenyl)- or -(C 2

-C

6 alkynyl)- and A is aryl, heteroaryl, carbocycyl or heterocyclyl, or R 4 is a group -COR", -CO 2 R", -S(O) 2 R" 10 or -CONR/R" wherein R' is hydrogen, C-C 6 alkyl, C 2

-C

6 alkenyl or

C

2

-C

6 alkynyl and R" is is aryl, heteroaryl, carbocyclyl or heterocyclyl. In the moiety P, the moiety -X-, when present, is attached to R 4 and the moiety W, when present, is attached to Z. In the moiety Y, the moiety V is attached 15 to W or, if W is not present, to Z, and the moiety U is attached to X or, if X is not present, to R 4 . As used herein, a C-C 6 alkyl group or moiety is a linear or branched alkyl group or moiety. Suitable alkyl groups and moieties include C-C 4 alkyl groups and moieties, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl. Methyl, 20 ethyl, n-propyl and t-butyl are preferred. A C 1

C

6 alkyl group or moiety can be substituted or unsubstituted at any position. Typically, it is unsubstituted or carries 1, 2 or 3 substituents. Suitable substituents include C-C 6 alkyl, C-C 6 alkylthio, C-C 6 alkoxy, C-C 6 haloalkyl, for example -CF 3 and -CC1 3 , C-C 6 haloalkoxy, for example -OCF 3 and -OCC1 3 , halogen, 25 hydroxy, cyano, nitro, aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, heterocyclythio, carbocyclyl, carbocyclyloxy, carbocyclylthio, oxo, -NR'R" wherein R' and R" are the same or different and are hydrogen or C 1

C

6 alkyl, =NR, -COR, -CONRR, -CO 2 R, -NRCOR,

-NRCO

2 R, -NRCONRIR, -S(O) 2 R and -S(0) 2 NRR wherein each R, can be the same 30 or different and represents hydrogen or C 1

C

6 alkyl and each R can be the same or different and represents C-C 6 alkyl, aryl, heteroaryl, heterocyclyl or carbocyclyl, and WO 01/32604 PCT/GBOO/04249 -3 -S-(Ci-C 6 alkyl)-R"'and -O-(CI-C 6 alkyl)-R" wherein each R"' can be the same or different and represents aryl, heteroaryl, heterocyclyl or carbocyclyl. Further, two substituents on the same atom can, together with the atom to which they are attached, form a carbocyclyl or heterocyclyl group. 5 Preferred substituents include oxo, halogen, CI-C 6 alkyl, aryl, arylthio, aryloxy, heteroaryl, heteroarylthio, heteroaryloxy and -NRR", =N-R, -CONHR and

-NHCO

2 R wherein R, R' and R" are as defined above. Further, two preferred substituents on the same carbon atom may, together with the atom to which they are attached, form a carbocyclyl group, preferably a C 3

-C

6 cycloalkyl group. 10 More preferred substituents are oxo, halogen, for example chlorine and fluorine, C-C 4 alkyl, for example methyl, ethyl or t-butyl, aryl, for example phenyl, -CONH-aryl, for example -CONH-phenyl, =N-aryl, for example =N-phenyl, -NH C0 2 -(Ci-C 4 alkyl), heteroarylthio, for example pyrimidinethio and -CO-aryl, for example -CO-phenyl. It is also preferred that two substituents on the same carbon 15 atom may, together with the atom to which they are attached, form a C3-C6 cycloalkyl group. As used herein, a C 2

-C

6 alkenyl group or moiety is a linear or branched alkenyl group or moiety. Suitable alkenyl groups and moieties include C 2

-C

4 alkenyl groups and moieties such as ethenyl, propenyl and butenyl groups and moieties. 20 Ethenyl and propenyl are preferred. A C 2

-C

6 alkenyl group or moiety may be substituted or unsubstituted at any position. A C 2

-C

6 alkenyl group is typically unsubstituted or carries 1, 2, 3 or 4 substituents. Preferably, it carries at least two substituents. Suitable substituents include oxo, CI-C 6 alkyl, CI-C 6 alkylthio, Ci-C 6 alkoxy, C 1

-C

6 haloalkyl, for example 25 -CF 3 and -CCl 3 , C 1

-C

6 haloalkoxy, for example -OCF 3 and -OCC1 3 , halogen, hydroxy, cyano, nitro, aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, heterocyclythio, carbocyclyl, carbocyclyloxy, carbocyclylthio, -NR/R" wherein R' and R" are the same or different and are hydrogen or CI-C 6 alkyl, =N-R, -COR, -CONRR, -CO 2 R, -NR/COR, 30 -NRCO 2 R, -NRCONRR, -S(O) 2 R and -S(O) 2 NRR wherein each R, can be the same or different and represents hydrogen or CI-C 6 alkyl and each R can be the same or WO 01/32604 PCT/GBOO/04249 -4 different and represents C 1

-C

6 alkyl, aryl, heteroaryl, heterocyclyl or carbocyclyl, and

-S-(CI-C

6 alkyl)-R"' and -O-(CI-C 6 alkyl)-R"' wherein each R' can be the same or different and represents aryl, heteroaryl, heterocyclyl or carbocyclyl. Further, two substituents on the same atom can, together with the atom to which they are attached, 5 form a carbocyclyl or heterocyclyl group. Preferred substituents include oxo, halogen, C 1

-C

6 alkyl, aryl, arylthio, aryloxy, heteroaryl, heteroarylthio, heteroaryloxy and -NR'R", =N-R, -CONHR and

-NHCO

2 R wherein R, R' and R" are as defined above. Further, two preferred substituents on the same carbon atom may, together with the atom to which they are 10 attached, form a carbocyclyl group, preferably a C 3

-C

8 cycloalkyl group. More preferred substituents are halogen, for example chlorine and fluorine,

C

1

-C

4 alkyl, for example methyl, ethyl or t-butyl, aryl, for example phenyl, heteroaryl, for example furanyl, -CONH-aryl, for example -CONH-phenyl, -NH C0 2

-(C

1

-C

4 alkyl), -NH-CO-(C 1

-C

4 alkyl), -NH-CO-aryl, for example -NH-CO 15 phenyl, heteroarylthio, for example pyrimidinethio and -CO-aryl, for example -CO phenyl. It is also preferred that two substituents on the same carbon atom may, together with the atom to which they are attached, form a C 3 -Cs cycloalkyl group. A C 2 r C 6 alkynyl group or moiety is typically an ethynyl, propynyl or butynyl group or moiety. It may be substituted or unsubstituted at any position. Typically, it 20 is unsubstituted or carries 1 or 2 substituents. Suitable substituents include C 1

-C

6 alkyl, C 1

-C

6 alkylthio, C 1

-C

6 alkoxy, C 1

-C

6 haloalkyl, for example -CF 3 and -CC1 3 ,

C

1

-C

6 haloalkoxy, for example -OCF 3 and -OCCl 3 , halogen, hydroxy, cyano, nitro, aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, heterocyclythio, carbocyclyl, carbocyclyloxy, carbocyclylthio, 25 -NR/R" wherein R' and R" are the same or different and are hydrogen or C 1

-C

6 alkyl, COR, -CONRR, -CO 2 R, -NRCOR, -NRCO 2 R, -NRCONR/R, -S(O) 2 R and

-S(O)

2 NR/R wherein each R, can be the same or different and represents hydrogen or

C

1

-C

6 alkyl and each R can be the same or different and represents C 1

-C

6 alkyl, aryl, heteroaryl, heterocyclyl or carbocyclyl, and -S-(Cl-C 6 alkyl)-R' and 30 -O-(CI-C 6 alkyl)-R"' wherein each R' can be the same or different and represents aryl, heteroaryl, heterocyclyl or carbocyclyl. Further, two substituents on the same WO 01/32604 PCT/GBOO/04249 -5 atom can, together with the atom to which they are attached, form a carbocyclyl or heterocyclyl group. Preferred substituents include halogen, C-C 6 alkyl, aryl, arylthio, aryloxy, heteroaryl, heteroarylthio, heteroaryloxy and -CONHR and -NHCO 2 R wherein R is 5 as defined above. Further, two preferred substituents on the same carbon atom may, together with the atom to which they are attached, form a carbocyclyl group, preferably a C 3

-C

6 cycloalkyl group. More preferred substituents are halogen, for example chlorine and fluorine,

C

1

-C

4 alkyl, for example methyl, ethyl or t-butyl, aryl, for example phenyl, 10 -CONH-aryl, for example -CONH-phenyl, -NH-C0 2

-(C-C

4 alkyl), heteroarylthio, for example pyrimidinethio and -CO-aryl, for example -CO-phenyl. It is also preferred that two substituents on the same carbon atom may, together with the atom to which they are attached, form a C 3

-C

6 cycloalkyl group. A C 1

-C

6 alkoxy group is typically a said C 1

-C

6 alkyl group attached to an 15 oxygen atom. A C 1

-C

6 alkylthio group is typically a said C 1

-C

6 alkyl group attached to a sulphur atom. As used herein, a said alkylene group is a divalent alkyl moiety. It may be unsubstituted or substituted at any position. Typically, it is unsubstituted or monosubstituted. Suitable substituents include halogen, for example chlorine and 20 flourine, hydroxy, C 1

-C

4 alkyl such as methyl and ethyl, C 1

-C

4 alkoxy, for example methoxy, C 1

-C

4 haloalkyl, for example -CF 3 and -CCl 3 and C 1

-C

4 haloalkoxy, for example -OCF 3 and -OCC1 3 . These substituents are typically themselves unsubstituted. A halogen is typically chlorine, fluorine, bromine or iodine. It is preferably 25 chlorine. A haloalkyl or haloalkoxy group is typically a said alkyl or alkoxy group substituted by one or more said halogen atoms. Typically, it is substituted by 1, 2 or 3 said halogen atoms. Preferred haloalkyl and haloalkoxy groups include perhaloalkyl and perhaloalkoxy groups such as -CX 3 and -OCX 3 wherein X is a said 30 halogen atom. Particularly preferred haloalkyl groups are CF 3 and CC1 3 . Particularly preferred haloalkoxy groups are -OCF 3 and -OCCl 3

.

WO 01/32604 PCT/GBOO/04249 -6 As used herein, an aryl group or moiety is typically a C 6

-C

20 aryl group or moiety. Suitable such aryl groups and moieties include phenyl, naphthyl and pyrenyl. Phenyl and pyrenyl are preferred. An aryl group or moiety may be substituted or unsubstituted at any position. 5 Typically, it is unsubstituted or carries 1, 2, 3 or 4 substituents. Suitable substituents include C-C 6 alkyl, C-C 6 alkylthio, C-C 6 alkoxy, C-C 6 haloalkyl, for example -CF 3 and -CCI 3 , CrC 6 haloalkoxy, for example -OCF 3 and -OCC1 3 , halogen, cyano, hydroxy, nitro, aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, heterocyclythio, carbocyclyl, carbocyclyloxy, 10 carbocyclylthio, -NR'R" wherein R' and R" are the same or different and are hydrogen or C 1

-C

6 alkyl, -COR, -CONRR, -CO 2 R, -NRCOR, -NRCO 2 R, -NRCONR, R, -S(O) 2 R and -S(O) 2 NRR wherein each R, can be the same or different and represents hydrogen or C-C 6 alkyl and each R can be the same or different and represents C-C 6 alkyl, aryl, heteroaryl, heterocyclyl or carbocyclyl, and -S-(C-C 6 15 alkyl)-R"'and -O-(C-C 6 alkyl)-R' wherein each R' can be the same or different and represents aryl, heteroaryl, heterocyclyl or carbocyclyl. Preferred substituents include C 1

-C

6 alkyl, for example methyl and ethyl,

CI-C

6 alkoxy, for example methoxy, C-C 6 alkylthio, for example methylthio, C-C 6 haloalkyl, for example -CF 3 and -CC1 3 , C-C 6 haloalkoxy, for example -OCF 3 and 20 -OCC1 3 , halogen, for example chlorine and fluorine, nitro, cyano, aryl, for example phenyl, aryloxy, for example phenyloxy, arylthio, for example phenylthio, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclyl, -NR'R" wherein R' and R" are the same or different and are hydrogen or C-C 6 alkyl, -CONH-(C-C 6 alkyl), -NHCONH-R wherein R is aryl, for example phenyl, or heteroaryl, -S(O) 2 NHR' 25 wherein R' is aryl, for example phenyl, or heteroaryl, -S-(C-C 6 alkyl)-R" wherein R" is aryl, for example phenyl, or heteroaryl and -COR' wherein R"' is heterocycyl, heteroaryl or aryl. Particularly preferred substituents are phenyl, in particular 4-phenyl, phenoxy, in particular 2-phenoxy, phenylthio, halogen, -CF 3 , -CCl 3 , nitro, cyano, 30 -OCF 3 , -OCCl 3

C-C

4 alkyl, C-C 4 alkoxy, C-C 4 alkylthio, -CONH-(C-C 4 alkyl), -CO-phenyl, -S(O) 2 NH-phenyl, -S-(C-C 4 alkyl)-phenyl, -S-(C-C 4 alkyl)-pyrazole, WO 01/32604 PCT/GBOO/04249 -7

-S-(C-C

4 alkyl)-pyrimidine, -(C 1 rC 4 alkyl)-NH-COr 2

(C

1 rC 4 alkyl), thiazole, -COR wherein R is benzothiophenyl or -carbolinyl and -NH-(CH 2 )nNR/R" wherein n is from 2~to 4 and R' and R" are the same or different and are C 1 rC 4 alkyl. An aryl group or moiety may be fused to a further said aryl group or to a 5 carbocyclic, heterocyclic or heteroaryl group. For example, an aryl group may be fused to a pyridine ring to form a quinoline or isoquinoline group, or to a furan ring. It may also, for example, be fused to a cyclopropyl or cyclohexyl group or to a tetrahydrofuryl group, a 1,4-dioxolane group or a pyrimidone ring, for example a 4 pyrimidone ring. 10 As used herein, a carbocyclic group or moiety is a non-aromatic, saturated or unsaturated carbocyclic group or moiety. Typically, it has from 3 to 10, for example from 3 to 8, carbon atoms. Preferably, it has from 3 to 8, for example 3 to 6, carbon atoms. Examples of suitable carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopetadienyl, cyclohexyl, cyclohexenyl and 15 cyclooctanyl groups. Preferred carbocyclic groups include cyclohexyl, cyclooctanyl and cyclohexenyl groups. A carbocyclic group or moiety may be unsubstituted or substituted at any position. Typically, it carries up to 3 substituents. Suitable substituents include oxo, Cr-C 6 alkyl, C-C 6 alkylthio, C-C 6 alkoxy, C 1

-C

6 haloalkyl, for example -CF 3 and 20 CCl 3 , CrC 6 haloalkoxy, for example -OCF 3 and -OCCl 3 , halogen, hydroxy, cyano, nitro, aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, heterocyclythio, carbocyclyl, carbocyclyloxy, carbocyclylthio, NR/R" wherein R' and R" are the same or different and are hydrogen or C 1

-C

6 alkyl, =NR, -COR, -CONRIR, -CO 2 R, -NRCOR, -NRCO 2 R, 25 -NR/CONRR, -S(O) 2 R and -S(0) 2 NRR wherein each R/ can be the same or different and represents hydrogen or C 1 rC 6 alkyl and each R can be the same or different and represents C 1

C

6 alkyl, aryl, heteroaryl, heterocyclyl or carbocyclyl, and -S-(Cr-C 6 alkyl)-R'"and -O-(C 1 rC 6 alkyl)-R' wherein each R" can be the same or different and represents aryl, heteroaryl, heterocyclyl or carbocyclyl. Further, two 30 substituents on the same atom can, together with the atom to which they are attached, form a carbocyclyl or heterocyclyl group.

WO 01/32604 PCT/GBOO/04249 -8 Preferred substituents include oxo, C-C 6 alkyl, for example methyl and ethyl,

C

1

-C

6 alkoxy, for example methoxy, C-C 6 alkylthio, for example methylthio, C-C 6 haloalkyl, for example -CF 3 and -CC 3 , C-C 6 haloalkoxy, for example -OCF 3 and -OCCl 3 , halogen, for example chlorine and fluorine, nitro, cyano, aryl, for example 5 phenyl, aryloxy, for example phenyloxy, arylthio, for example phenythio, heteroaryl, heteroarylthio, heterocyclyl, -CONH-(C-C 6 alkyl), -NHCONH-R wherein R is aryl, for example phenyl, or heteroaryl, =NR' wherein R' is aryl, for example phenyl, or heteroaryl, -S(0) 2 NIIR" wherein R" is aryl, for example phenyl, or heteroaryl,

-S-(C-C

6 alkyl)-R' wherein R"' is aryl, for example phenyl, or heteroaryl, and 10 -COR"" wherein R"" is heterocyclyl, heteroaryl or aryl. Particularly preferred substituents are oxo, =N-aryl, for example =N-phenyl, aryl, for example phenyl, and -CO-aryl, for example -CO-phenyl. A carbocyclic group or moiety may be fused to a further carbocyclic group or to an aryl, heteroaryl or heterocyclic group. 15 A heteroaryl group or moiety is typically a 5- to 10- membered aryl ring containing at least one heteroatom, for example 1, 2 or 3 heteroatoms, selected from 0, S and N. Preferably, the heteroaryl group or moiety is a 5- or 6- membered ring. Suitable heteroaryl groups and moieties include pyridyl, pyranyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, 20 imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, furazanyl, triazolyl and thiadiazolyl groups. Pyridyl, pyrrolyl, thienyl, thiazolyl, furanyl, pyrazinyl and 1, 2, 3-thiadiazolyl groups are preferred. A heteroaryl group or moiety may be unsubstituted or substituted at any position. Typically, it is unsubstituted or carries up to three substituents. Suitable 25 substituents include C-C 6 alkyl, C-C 6 alkylthio, C-C 6 alkoxy, C-C 6 haloalkyl, for example -CF 3 and -CCl 3 , C 1

-C

6 haloalkoxy, for example -OCF 3 and -OCC1 3 , halogen, hydroxy, cyano, nitro, aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, heterocyclythio, carbocyclyl, carbocyclyloxy, carbocyclylthio, -NR'R" wherein R' and R" are the same or different 30 and are hydrogen or C-C 6 alkyl, -COR, -CONRR, -CO 2 R, -NR/COR, -NR/CO 2 R, -NRCONRR, -S(0) 2 R and -S(0) 2 NR/R wherein each R/ can be the same or different WO 01/32604 PCT/GBOO/04249 -9 and represents hydrogen or CI-C 6 alkyl and each R can be the same or different and represents C 1

-C

6 alkyl, aryl, heteroaryl, heterocyclyl or carbocyclyl, and

-S-(CI-C

6 alkyl)-R"' and -O-(C 1

-C

6 alkyl)-R' wherein each R"' can be the same or different and represents aryl, heteroaryl, heterocyclyl or carbocyclyl. 5 Preferred substituents include CI-C 6 alkyl, for example methyl and ethyl,

CI-C

6 alkoxy, for example methoxy, CI-C 6 alkylthio, for example methylthio, CI-C 6 haloalkyl, for example -CF 3 and -CCl 3 , CI-C 6 haloalkoxy, for example -OCF 3 and -OCC1 3 , halogen, for example chlorine, cyano, nitro, aryl, for example phenyl, aryloxy, for example phenoxy, arylthio, for example phenylthio and 10 -O-(C 1

-C

6 alkyl)-R, -S-(C 1

-C

6 alkyl)-R, -S-(C 1

-C

6 alkyl)-CONH-R, -CO-R and -CO-NH-R, wherein R is an aryl group, for example a phenyl group. Particularly preferred substituents include phenyl, halogen, for example chlorine, C 1

-C

4 alkyl, for example methyl, -CF 3 , -CC1 3 , -OCF 3 , -OCC1 3 , phenylthio, phenoxy, -S-(CI-C 4 alkyl)-CONH-phenyl, -S-(CI-C 4 alkyl)-phenyl, 15 -O-(CI-C 4 alkyl)-phenyl, -CO-phenyl, cyano, C 1

-C

4 alkylthio, nitro, 2,3-dihydrobenzafuranyl and -CO-NH-(1, 2, 3, 4-tetrahydranaphthalen-8-yl). A heteroaryl group may be fused to a said aryl or carbocyclic group or to a further heteroaryl group or to a heterocyclic group. Examples of such fused heteroaryl groups include quinolyl, indolyl, isoindolyl, benzothiophenyl, 20 imidazo[1,2-a]pyridyl and p-carbolinyl groups. As used herein, a heterocyclic group or moiety is a non-aromatic, saturated or unsaturated cyclic group or moiety containing at least one, for example, one, two or three, heteroatoms selected from N, 0 and S. Typically, it is a 3- to 6- membered ring. Preferably, it is a 5- or 6- membered ring containing, as heteroatoms, one or 25 two nitrogen atoms. Suitable heterocyclic groups and moieties include pyrazolidinyl, piperidyl, piperazinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolinyl, 3,4-dihydro-2H-pyranyl, tetrahydropyrimidinyl (for example 1,2,3,4- or 1,4,5,6 tetrahydrapyrimidinyl), 2-hydropyridinyl, 2-hydrothiazolyl, tetrahydropyridinyl (for 30 example 1,2,5,6- or 2,3,4,5-tetrahydropyridinyl) and tetrahydropyridazinyl, for example 3,4,5,6-tetrahydropyridazinyl.

WO 01/32604 PCT/GBOO/04249 -10 A heterocyclic group or moiety may be substituted or unsubstituted at any position. Typically, it is unsubstituted or carries 1, 2, 3, 4 or 5 substituents. Suitable substituents include oxo, C 1

-C

6 alkyl, Ci-C 6 alkylthio, C 1

-C

6 alkoxy, CI-C 6 haloalkyl, for example -CF 3 and -CC1 3 , C 1

-C

6 haloalkoxy, for example -OCF 3 and -OCC 3 , 5 halogen, hydroxy, cyano, nitro, aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, heterocyclythio, carbocyclyl, carbocyclyloxy, carbocyclylthio, -NR'R" wherein R' and R" are the same or different and are hydrogen or CI-C 6 alkyl, =NR, -COR, -CONR/R, -CO 2 R, -NRCOR,

-NR/CO

2 R, -NRCONR/R, -S(O) 2 R and -S(O) 2 NR/R wherein each R, can be the same 10 or different and represents hydrogen or Ci-C 6 alkyl and each R can be the same or different and represents CI-C 6 alkyl, aryl, heteroaryl, heterocyclyl or carbocyclyl, and -S-(Ci-C 6 alkyl)-R"'and -O-(C 1

-C

6 alkyl)-R' wherein each R' can be the same or different and represents aryl, heteroaryl, heterocyclyl or carbocyclyl. Further, two substituents on the same atom can, together with the atom to which they are attached, 15 form a carbocyclyl or heterocyclyl group. Preferred substituents include oxo, CI-C 6 alkyl, for example methyl and ethyl,

CI-C

6 alkoxy, for example methoxy, Ci-C 6 alkylthio, for example methylthio, Ci-C 6 haloalkyl, for example -CF 3 and -CC13, C 1

-C

6 haloalkoxy, for example -OCF 3 and -OCCl 3 , halogen, for example chlorine and fluorine, nitro, cyano, aryl, for example 20 phenyl, aryloxy, for example phenyloxy, arylthio, for example phenythio, heteroaryl, heteroarylthio, heterocyclyl, -CONH-(CI-C 6 alkyl), -NHCONH-R wherein R is aryl, for example phenyl, or heteroaryl, =NR' wherein R' is aryl, for example phenyl, or heteroaryl, -S(O) 2 NHR" wherein R" is aryl, for example phenyl, or heteroaryl,

-S-(C

1

-C

6 alkyl)-R"' wherein R' is aryl, for example phenyl, or heteroaryl, and 25 -COR"" wherein R"" is heterocyclyl, heteroaryl or aryl. Particularly preferred substituents are oxo, =N-aryl, for example =N-Ph, aryl, for example phenyl, halogen, C 1

-C

4 alkyl, for example methyl and ethyl, C 1

-C

4 alkoxy, for example methoxy and ethoxy, Ci-C 4 haloalkyl, for example -CF 3 and -CC1 3 and Ci-C 4 haloalkoxy, for example -OCF 3 and -OCC1 3 . 30 Heterocyclic groups carrying one oxo substituent and up to 2, for example 0, 1 or 2, further substituents are particularly prefered.

WO 01/32604 PCT/GBOO/04249 -11 A heterocyclic group or moiety may be fused to a further said heterocyclic group or to a said carbocyclic, aryl or heteroaryl group. Typically, it is non-fused or is fused to a benzene ring or to an iodole group. Examples of such fused heterocyclic groups include chromanyl and chromonyl groups. 5 An aryloxy, heteroaryloxy, heterocyclyloxy or carbocyclyloxy group is typically a said aryl, heteroaryl, heterocyclyl or carbocyclyl group attached to an oxygen atom. An arylthio, heteroarylthio, heterocyclylthio or carbocyclylthio group is typically a said aryl, heteroaryl, heterocyclyl or carbocyclyl group attached to a sulphur atom. 10 Typically, R, and R 2 are the same or different and represent methyl, ethyl, propyl, n-butyl or t-butyl. Preferably the groups represented by R, and R 2 are unsubstituted or carry one or two substituents. Preferred substituents for R, and R 2 include CI-C 4 alkyl, for example methyl and ethyl, CI-C 4 alkoxy, for example methoxy and ethoxy, halogen, for example chlorine, Cl-C 4 haloalkyl, for example 15 -CF 3 and -CC1 3 and CI-C 4 haloalkoxy, for example -OCF 3 and -OCCl 3 Typically, these substituents are themselves unsubstituted. More preferably, R, and R 2 are methyl or R 1 and R 2 together form a n-butylene group. Z is methylene, ethylene, propylene or butylene and is preferably propylene. 20 Preferably Z is unsubstituted, monosubstituted or disubstituted. Preferred substituents for Z include CI-C 4 alkyl, for example methyl and ethyl, CI-C 4 alkoxy, for example methoxy and ethoxy, halogen, for example chlorine, Ci-C 4 haloalkyl, for example -CF 3 and -CC1 3 and C-C 4 haloalkoxy, for example -OCF 3 and -OCCl 3 Typically, these substituents are themselves unsubstituted. Particularly preferred 25 substituents for Z are CI-C 4 alkyl groups, in particular methyl groups. A preferred substituted alkylene group is 2,2-dimethylpropylene. Typically, the moiety P is -Y-, -XY-, -YW- or -XYW-. Preferably, the moiety P is -XYW- or -YW-. When P is -W- or is a direct bond, R 4 is typically an aryl, heteroaryl or heterocyclyl moiety and/or is typically substituted by an aryl, 30 heteroaryl, heterocyclyl or carbocyclyl substituent. Typically, W is -0- or -NR 3 . Typically, R 3 is hydrogen or is methyl, ethyl, WO 01/32604 PCT/GBOO/04249 -12 propyl, n-butyl or t-butyl. Preferably, R 3 is unsubstituted or carries one or two substituents. Preferred substituents for R 3 include CI-C 4 alkyl, for example methyl and ethyl, CI-C 4 alkoxy, for example methoxy and ethoxy, halogen, for example chlorine, CI-C 4 haloalkyl, for example -CF 3 and -CC1 3 and C 1

-C

4 haloalkoxy, for 5 example -OCF 3 and -OCCl 3 . Typically, these substituents are themselves unsubstituted. More preferably, R 3 is hydrogen or methyl, most preferably hydrogen. V is preferably a direct bond. U is preferably -CO-, -S(O) 2 -, -C(=NH)- or -C(=NOH)-, more preferably -CO-. 10 X is typically -NR 6 -. When X is a group -NR 6 -, R 6 is typically C 1

-C

4 alkyl, for example methyl, ethyl, propyl, n-butyl and t-butyl, aryl, for example phenyl, or heteroaryl, for example pyridyl. Preferably, R 6 is unsubstituted or carries 1, 2 or 3 substituents. Preferred substituents for R 6 include C 1

-C

4 alkyl, for example methyl and ethyl, Ci-C 4 alkoxy such as methoxy or ethoxy, halogen, for example fluorine or 15 chlorine, C 1

-C

4 haloalkyl, for example -CF 3 and -CCl 3 , CI-C 4 haloalkoxy, for example -OCF 3 and -OCC1 3 , cyano, nitro and -NR'R" wherein R' and R" are the same or different and are hydrogen or C 1

-C

4 alkyl. Typically, these substituents are themselves unsubstituted. Preferably, X is -NH-. 20 Typically, the group R 4 has up to 30 carbon atoms and up to 10 heteroatoms selected from N, 0 and S. Preferably, it has up to 25 carbon atoms and up to 7 heteroatoms. Typically, the group R 4 contains at least one, preferably at least two, aryl or heteroaryl rings. Preferably, R 4 is CI-C 6 alkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, 25 -(CI-C 6 alkyl)-aryl, -(CI-C 6 alkyl)-heteroaryl or -COR", -CO 2 R" or -CONR'R" wherein R' is hydrogen or C 1

-C

6 alkyl and R" is an aryl, heteroaryl, carbocyclyl or heteroaryl group. Suitable substituents for the group R 4 are oxo, CI-C 6 alkyl, C 1

-C

6 alkylthio,

CI-C

6 alkoxy, Ci-C 6 haloalkyl, for example -CF 3 and -CCl 3 , CI-C 6 haloalkoxy, for 30 example -OCF 3 and -OCCl 3 , halogen, hydroxy, cyano, nitro, aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, WO 01/32604 PCT/GBOO/04249 -13 heterocyclythio, carbocyclyl, carbocyclyloxy, carbocyclylthio, -NR/R" wherein R' and R" are the same or different and are hydrogen or C-C 6 alkyl, =NR, -COR, -CONRR, -CO 2 R, -NRCOR, -NRCO 2 R, -NRCONRR, -S(O) 2 R and -S(O) 2 NR/R wherein each R, can be the same or different and represents hydrogen or C-C 6 alkyl 5 and each R can be the same or different and represents C-C 6 alkyl, aryl, heteroaryl, heterocyclyl or carbocyclyl, and -S-(C-C 6 alkyl)-R'" and -O-(C-C 6 alkyl)-R' wherein each R"' can be the same or different and represents aryl, heteroaryl, heterocyclyl or carbocyclyl. Further, two substituents on the same atom can, together with the atom to which they are attached, form a carbocyclyl or heterocyclyl group. 10 Substituents on the group R 4 may be further substituted. Typically, when P is a direct bond, -0- or -NH-, R 4 is not a moiety (A) or (B). 15R'3 R'3 15 - -_ N (A) N (B)

R'

4 R' 4 N R' 1

R'

1 20 wherein: R', is: hydrogen, aryl, heteroaryl, 3- to 6- membered heterocyclyl, -(C-C 4 alkyl)-R wherein R is aryl, heteroaryl or 3- to 6- membered heterocyclyl, C-C 4 alkyl,

-CONA'

2 , -COA" or -SO 2 A" wherein each A' is the same or different and is 25 selected from H, C-C 4 alkyl and aryl and each A" is the same or different and is selected from CrC 4 alkyl and aryl; and

R'

3 and R' 4 are either: (a) the same or different and selected from -CO 2 A' wherein A' is as defined above, -CF 3 , -CC1 3 , halogen, C-C 4 alkoxy, -(C-C 4 alkyl) 30 aryl, -(C-C 4 alkyl)-heteroaryl, hydrogen, C-C 4 alkyl, C 3

-C

6 carbocyclyl, 3- to 6- membered heterocyclyl, -SO 2

NA'

2 wherein A' is WO 01/32604 PCT/GBOO/04249 -14 as defined above, and -CONZZ 2 wherein Z, and Z 2 , which are the same or different, represent H, Ci-C 4 alkyl, aryl, heteroaryl, C 3

-C

6 carbocyclyl, 3- to 6- membered heterocyclyl or -(Cl-C 4 alkyl)-R wherein R is aryl, heteroaryl, 3- to 6- membered heterocyclyl or C 3

-C

6 5 carbocyclyl, or Z, and Z 2 , together with the nitrogen atom to which they are attached, denote a 5- or 6- membered N-containing heterocyclic group; or (b) different, one of R' 3 and R' 4 being aryl or heteroaryl and the other being as defined above 10 or R', is as defined above and R' 3 and R' 4 together form the divalent group,

-(CH)

4 -, which group is optionally substituted. Preferably, R 4 is not a 3- or 5- pyrazole or a 3- indazole group when P is a direct bond, -0- or -NH-. More preferably R 4 is not a pyrazole or indazole group when P is a direct bond, -0- or -NH-. More typically, R 4 is not a 3- or 5- pyrazole or 15 a 3- indazole group or, more preferably, a pyrazole or indazole group when P does not contain the moiety U. More preferably, when P is a direct bond, -0- or -NH- and R 4 is a heteroaryl group, R 4 is a pyridyl, pyrimidyl, thiazolyl or thienyl group. R 4 is typically also a pyridyl, pyrimidyl, thiazolyl or thienyl group when P does not contain the moiety U 20 and R 4 is a heteroaryl group. Suitable pyridyl, pyrimidyl, thiazolyl and thienyl groups include groups fused to a said aryl or said carbocyclic group or to a said heteroaryl or said heterocyclic group. In such compounds, R 4 may be substituted by one or more of the groups mentioned above as appropriate substituents for R 4 . Preferred compounds of the invention are those in which X is -NR- wherein 25 R 6 is as defined above, and R 4 is aryl or heteroaryl. In these preferred compounds, P is typically -XYW-. Y is typically -CO-. W is typically -NR 3 - wherein R 3 is as defined above. X is preferably -NH- and/or R 4 is preferably phenyl, thienyl or pyrazolyl. In the above preferred compounds, when R 4 is phenyl it is typically 30 substituted by a phenoxy group or by a phenylthio group, in particular a 2-phenoxy or 2-phenylthio group, or by a further phenyl group, in particular a 4-phenyl group. When R 4 is thienyl or pyrazolyl, it is typically substituted by a phenyl or phenylthio group. These substituents may be unsubstituted or may be further substituted at any position. Typically, they are unsubstituted or carry one, two or three further WO 01/32604 PCT/GBOO/04249 -15 substituents. Preferred further substituents include halogen, for example chlorine and fluorine, C 1

-C

4 alkyl, for example methyl and ethyl, C 1

-C

4 alkoxy, for example methoxy and ethoxy, C 1

-C

4 haloalkyl, for example -CF 3 and -CC1 3 , and

-S(O)

2 NH-phenyl. These further substituents are typically themselves unsubstituted. 5 In the above preferred compounds of the invention, R 4 is preferably 2-phenoxyphenyl, 2-fluoro-diphen-4-yl, 5-(4-chlorophenylthio)-thien-3-yl, 4-(4-fluorophenyl)-thien-2-yl, 5-(4-chlorophenyl)-1-(3,4-dichlorophenyl)-pyrazol-3 yl or -(C 6

H

4

)-S-(C

6

H

4

)-S(O)

2

-NH-(C

6

H

4 ). Further preferred compounds of the invention are those in which P is -YW 10 and R 4 is an aryl, heterocyclyl or heteroaryl group. In these further preferred compounds, Y is typically -CO-. W is typically -NR 3 - wherein R 3 is as defined above. Further, R 4 is preferably an oxo-substituted heterocyclic group such as a chromonyl group or is a pyrazolyl, thienyl, phenyl or indolyl group. In the above further preferred compounds, R 4 is typically unsubstituted or 15 substituted by one or more, for example, one, two or three substituents selected from Cl-C 6 alkyl, for example t-butyl, phenyl, thiazolyl, phenylthio, cyano, nitro, C 1

-C

6 alkylthio, for example i-propylthio, Cl-C 6 alkoxy, halogen such as chlorine and

-S-(C

1

-C

4 alkyl)-phenyl. These substituents may be unsubstituted or may be substituted at any position. Typically, they are unsubstituted or carry one, two or 20 three further substituents. Preferred further substituents include halogen, for example chlorine, C 1

-C

4 haloalkyl, for example -CF 3 , phenyl and -S(0) 2 -NH-phenyl. These further substituents are typically themselves unsubstituted. Additional preferred compounds of the invention are those in which P is -W or -YW- wherein Y is -CO- and W is -0-. 25 Particularly preferred compounds of the invention are compounds of formula (I') and pharmaceutically acceptable salts thereof, R4 Y z X N NR 1

R

2

R

3 30 WO 01/32604 PCT/GBOO/04249 -16 wherein: - R 1 and R 2 are the same or different and each represent a C 1

-C

6 alkyl group, or R 1 and R 2 together form an alkylene group having from 3 to 5 . 6 carbon atoms; - Z is an alkylene group having from 2 to 4 carbon atoms; - R 3 is hydrogen or CI-C 6 alkyl; - Y is -CO- or-S(O)2 - X is a direct bond or -NR 6 - wherein R 6 is hydrogen, C 1

-C

6 alkyl, C 2

-C

6 10 alkenyl, C 2

-C

6 alkynyl, aryl or heteroaryl; and - R 4 is Cl-C 6 alkyl, C 2

-C

6 alkenyl, C 2

-C

6 alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, a group -R-A wherein R is -(CI-C 6 alkyl)-,

-(C

2

-C

6 alkenyl)- or -(C 2

-C

6 alkynyl)- and A is aryl, heteroaryl, carbocycyl or heterocyclyl, or R 4 is a group -COR' or -CO 2 R' wherein 15 R' is aryl, heteroaryl, carbocyclyl or heterocyclyl. Further particularly preferred compounds of the invention are compounds of formula (I"), and pharmaceutically acceptable salts thereof 0 20 X N NR 1

R

2 (I) R3 wherein R 1 and R 2 are methyl or together form a n-butylene group, R 3 is 25 hydrogen or methyl, R 4 is as defined in the formula (I) or in the formula (I') and X is a direct bond or is -NR 6 - wherein R 6 is as defined above. Preferably, when X in the formula (I") is -NR 6 -, R 4 is as defined as in the above preferred compounds of the invention. Preferably, when X in the formula (I") is a direct bond, R 4 is as defined in the above further preferred compounds of the invention. 30 The present invention includes pharmaceutically acceptable salts of the compounds of the invention. Suitable salts include salts with pharmaceutically WO 01/32604 PCT/GBOO/04249 -17 acceptable acids, both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succininc, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid. Salts may also be 5 formed with pharmaceutically acceptable bases such as alkali metal (eg sodium or potassium) and alkali earth metal (eg calcium or magnesium) hydroxides and organic bases such as alkyl amines, aralkyl amines or heterocyclic amines. Particularly preferred compounds of the invention are: 1-(3-Dimethylamino-propyl)-3-(2-phenoxy-phenyl)-urea 10 1-[2-(4-Chloro-phenoxy)-pyridin-3-yl]-3-(3-dimethylaminopropyl)-urea 1-(3-Dimethylamino-propyl)-3-pyren-1-ylmethyl-urea 1-(3-Dimethylamino-propyl)-3-[(1R,2R)-5-phenyl-2-(1-phenyl-methanoyl) cyclohexyl]-urea 1-(3-Dimethylamino-propyl)-3-[2-(4-phenoxy-phenyl)-ethyl]-urea 15 1-(3-Dimethylamino-propyl)-3-[3-methyl-5-(4-methyl-[1,2,3]thiadiazol-5 yl)-1-(4-trifluoromethoxy-phenyl)-1H-pyrazol-4-yl]-urea 2'-[3-(3-Dimethylamino-propyl)-ureido]-biphenyl-2-carboxylic acid (4 fluoro-phenyl)-amide N-(3-Chloro-4-methyl-phenyl)-4-[3-(3-dimethylamino-propyl)-ureido]-3 20 phenyl-butyramide 1-[4-(4-Chloro-phenylsulfanyl)-thiophen-3-yl]-3-(3-dimethylamino-propyl) urea 1-[2-(3,4-Dimethoxy-phenyl)-6-methyl-quinolin-4-yl]-3-(4-dimethylamino propyl)-urea 25 1-(6-Bromo-2-thiophen-3-yl-quinolin-4-yl)-3-(3-dimethylamino-propyl)-urea 1-[3-(4-Chloro-phenyl)-4-cyano-5-isobutylsulfanyl-thiophen-2-yl]-3-(3 dimethylamino-propyl)-urea 1-[6-(2,4-Dichloro-phenyl)-cyclohex-3-enyl]-3-(3-dimethylamino-propyl) urea 30 1-(2-Benzylsulfanyl-phenyl)-3-(3-dimethylamino-propyl)-urea 2- {2-[3-(3-Dimethylamino-propyl)-ureido]-phenylsulfanyl} -N-phenyl- WO 01/32604 PCT/GBOO/04249 -18 benzenesulfonamide 1-(3-Dimethylamino-propyl)-3-(2'-fluoro-biphenyl-4-yl)-urea N-(3,5-Dichloro-phenyl)-2- {3-[3-(3-dimethylamino-propyl)-ureido]-pyridin 2-ylsulfanyl} -acetamide 5 1-(3 -Dimethylamino-propyl)-3-{2- [1 -(1 -trifluoromethyl- 1,3,4,9-tetrahydro-b carbolin-2-yl)-methanoyl] -phenyl} -urea 8-{2-[3-(3-Dimethylamino-propyl)-ureido] -phenylsulfanyl} -naphthalene- 1 carboxylic acid methylamide 1-[1 -(3,4-Dichloro-benzyl)-6-oxo- 1,6-dihydro-pyridin-3 -yl]-3 -(3 10 dimethylamino-propyl)-urea 1-(3-Dimethylamino-propyl)-3-(3-oxo-1,2,3-triphenyl-propyl)-urea 1-[5-(4-Chloro-phenyl)- 1 -(3,4-dichloro-phenyl)- 1 H-pyrazol-3 -yl)-3 -(3 dimethylamino-propyl)-urea 1- {4-[4-(4-Chloro-phenyl)-thiazol-2-yl] -phenyl} -3-(3-dimethylamino 15 propyl)-urea 1-(3-Dimethylamino-propyl)-3-[5-(4-fluoro-phenyl)-thiophen-2-yl]-urea 1-[3-(4-tert-Butyl-benzyloxy)-thiophen-2-yl]-3-(3-dimethylamino-propyl) urea 1-(3-Dimethylamino-propyl)-3-[4-(4-phenyl-thiazol-2-yl)-phenyl]-urea 20 1-[3-(3,4-Dichloro-benzylsulfanyl)-thiophen-2-yl]-3-(3-dimethylamino propyl)-urea 1-[2-(5 -Chloro- 1 -methyl-3 -phenyl- 1H-pyrazol-4-ylmethylsulfanyl)-phenyl] 3-(3-dimethylamino-propyl)-urea 1-[2-(4-Chloro-benzylsulfanyl)-3-methyl-4-oxo-3,4-dihydro-quinazolin-7-yl] 25 3-(3-dimethylamino-propyl)-urea 1-(3-Dimethylamino-propyl)-3- {4-[4-(4-methoxy-phenyl)-pyrimidin- 2 ylsulfanylmethyl]-phenyl} -urea 1-(4-Bromophenyl)-3-(3-(1-pyrrolidinyl) propyl) urea 1-(4-Bromophenyl)-3-(3-dimethylamino propyl) urea 30 3-(4-Bromophenyl)-1-methyl-1-(3-dimethylamino propyl) urea 1-(3-Phenyl-5-methoxy phenyl)-3-(3-dimethylamino propyl) urea WO 01/32604 PCT/GBOO/04249 -19 3-(4-Chlorophenyl)-1-methyl-1-(3-dimethylamino propyl) urea 1-(3-Nitrophenyl)-1-benzyl-3-(3-dimethylamino propyl) urea 1-Benzyl-1-(4-methyl-3-pyridinyl)-3-(3-dimethylamino propyl) urea 1-Methyl-1-(3,5-bistrifluoromethylphenyl)-3-(3-dimethylaminopropyl)urea 5 1-(2-Phenacyl-4-chorophenyl)-1-methyl-3-(3-dimethylamino propyl) urea 1-(2-Chloro-4-trifluoromethylphenyl)-3-(3-dimethylaminopropyl) urea 1-(3-Fluoro-5-trifluoromethylphenyl)-3-(3-dimethylaminopropyl) urea 1-(3-N-tert-butoxycarbonyl-benzylamino)-3-(3-dimethylaminopropyl) urea N-(3-Dimethylamino-propyl)-2-[1-(4-fluorobenzoyl]-benzamide 10 2-[1-(4-Chlorobenzoyl]-N-(3-dimethylamino-propyl)-benzamide 5-(4-Chloro-phenyl)-1-phenyl-1H-pyrazole-3-carboxylic acid (3 dimethylamino-propyl)-amide 5-Chloro-3-phenyl-1H-indole-2-carboxylic acid (3-dimethylamino-propyl) amide 15 N-(3-Dimethylamino-propyl)-2-(2-phenylsulfamoyl-phenylsulfanyl) benzamide 2-Benzylsulfanyl-N-(3-dimethylamino-propyl)-benzamide 6,8-Di-tert-butyl-4-oxo-4H-chromene-2-carboxylic acid (3-dimethylamino -propyl)-amide 20 3-(4-Chloro-phenyl)-4-cyano-5-isobutylsulfanyl-thiophene-2-carboxylic acid (3-dimethylamino-propyl)-amide 4-(4-Chloro-phenoxy)-N-(3-dimethylamino-propyl)-3-nitro-benzamide N-(3-Dimethylamino-propyl)-4-(4-phenyl-thiazol-2-yl)-benzamide 1-(3-Dimethylamino-propyl)-3-(2-phenoxyphenyl)-urea 25 1-[4-(4-Chloro-phenylsulfanyl)-thiophen-3-yl]-3-(3-dimethylamino-propyl) -urea 1-(3-Dimethylamino-propyl)-3-(2'-fluoro-biphenyl-4-yl)-urea N-(3-Dimethylamino-propyl)-2-[I1-(4-fluorobenzoyl]-benzamide N-(3-Dimethylamino-propyl)-3-phenoxy-benzamide 30 N-(3-Dimethylamino-propyl)-2-phenoxy-benzamide 2-(4-Chloro-phenoxy)-N-(3-dimethylamino-propyl)-nicotinamide WO 01/32604 PCT/GBOO/04249 -20 4'-n-Propyl-biphenyl-4-carboxylic acid (3-dimethylamino-propyl)-amide 2-[1-(4-Bromo-phenyl)-methanoyl]-cyclohexanecarboxylic acid (3 dimethylamino-propyl)-amide 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid (3-dimethylamino 5 propyl)-amide 2-[1-(4-Chlorobenzoyl]-N-(3-dimethylamino-propyl)-benzamide 2-Phenyl-quinoline-4-carboxylic acid (3-dimethylamino-propyl)-amide 2-(l-(4-Chloro-3-nitrobenzoyl)]-N-(3-dimethylamino-propyl)-benzamide N-(3-Dimethylamino-propyl)-2-pyren-1-yl-acetamide 10 N-(3-Dimethylamino-propyl)-2-[1-(3-methyl-benzo[b]thiophen-2-yl) methanoyl]-benzamide 4-Chloro-N-(3-dimethylamino-propyl)-2-phenoxy-benzamide N-(3-Dimethylamino-propyl)-3-(4-phenoxy-phenyl)-propionamide N-(3-Dimethylamino-propyl)-2-[1-(1-trifluoromethyl-1,3,4,9-tetrahydro-b 15 carbolin-2-yl)-methanoyl]-benzamide 1-(4-Chloro-phenyl)-2,5-dimethyl-1-pyrrole-3-carboxylic acid (3 dimethylamino-propyl)-amide 2-{1-[(3-Dimethylamino-propylcarbamoyl)-methyl]-cyclopentyl} -N-(4 trifluoromethoxy-phenyl)-acetamide 20 8-[2-(3 -Dimethylamino-propylcarbamoyl)-phenylsulfanyl]-naphthalene- 1 carboxylic acid methylamide 3-Methyl-5-(4-methyl-[1,2,3]thiadiazol-5-yl)-l-(4-trifluoromethoxy-phenyl) 1H-pyrazole-4-carboxylic acid (3-dimethylamino-propyl)-amide 6,8-Di-tert-butyl-4-oxo-4H-chromene-2-carboxylic acid (3-dimethylamino 25 propyl)-amide 2-(Furan-2-yl)-quinoline-4-carboxylic acid (3-dimethylamino-propyl)-amide Biphenyl-2,2'-dicarboxylic acid 2'-[(3-dimethylamino-propyl)-amide]- 2

-[(

4 fluoro-phenyl)-amide] 3-Phenyl-pentanedioic acid (3-chloro-4-methyl-phenyl)-amide (3 30 dimethylamino-propyl)-amide 2-(3,4-Dimethoxy-phenyl)-6-methyl-quinoline-4-carboxylic acid (3- WO 01/32604 PCTIGBOOIO4249 -21 dimethylamino-propyl)-amnide 6-Bromo-(2-thiophen-3-yl)-quinoline-4-carboxylic acid (3-dirnethylamnino propyl)-amide 3-(4-Chloro-phenyl)-4-cyano-5-isobutysufal-thiophele-2-carboxyic acid 5 (3-dimethylamino-propyl)-amide 4-(4-Chloro-phenoxy)-N-(3 -dimethylamnino-propyl)-3 -nitro-benzamide 6-(2,4-Dichloro-phenyl)-cyclohex-3 -ene carboxylic acid (3-dimethylamino propyl)-amide N-(3-Dimethylamino-propyl)-2-(2-phenysufaoy-peflsulfaflyl) 10 benzamide 2'-Fluoro- [1,1'-biphenyl] -4-carboxylic acid (3 -dimethylamino-propyl)-amide 2-Benzylsulfanyl-N-(3 -dimethylamino-propyl)-benzamide Pyrazine-2 ,3 -dicarboxylic acid 2-[(3-dimethylamino-propyl)-amide] 3 [(5 ,6,7,8-tetrahydro-naphthalen- 1 -yl)-amide] 15 2- [(3,5 -Dichloro-phenylcarbamnoyl)-methylsulfanyl]-N-(3 -dimethylamino propyl)-nicotinamide 2-(3-Trifluoromethyl-phenyl)-thiazole-4-carboxylic acid (3 -dimethylamino propyl)-amide 2-(4-Chloro-phenyl)-thiazole-4-carboxylic acid (3-dimethylamino-propyl) 20 amide 5 -Chioro-l1-(2,4-dichloro-benzyl)-6-oxo- 1,6-dihydro-pyridine-3 -carboxylic acid (3 -dimethylamino-propyl)-amide 1 -(2,4-Dichloro-benzyl)-6-oxo- 1,6-dihydro-pyridine-3 -carboxylic acid (3 dimethylamino-propyl)-amide 25 5-Chioro-l1-(3 ,4-dichloro-benzyl)-6-oxo- 1,6-dihydro-pyridine-3 -carboxylic acid (3 -dimethylamnino-propyl)-amide 1 -(3 ,4-Dichloro-benzyl)-6-oxo- 1,6-dihydro-pyridine-3-carboxylic acid (3 dimethylamnino-propyl)-amide 5-Chioro-l1-(2,6-dichloro-benzyl)-6-oxo- 1,6-dihydro-pyridine-3-carboxylic 30 acid (3-dimethylamino-propyl)-amide 1,1 -Dimethyl-indan-4-carboxylic acid (3-dimethylamino-propyl)-amide WO 01/32604 PCTIGBOOIO4249 -22 N-(3-Dimethylamino-propyl)-2-[l1-(4-ethyl-phenyl)-methanoyl]-benzamide N-(3 -Dimethylamino-propyl)-3-(2,4,5 -trimethyl-pheriyl)-butyramide 2-[3 -(3 ,4-Dichloro-phenyl)-ureido]-N-(3-dimethylamino-propy1)-beflzamide N-(3 -Dimethylamino-propyl)-4-oxo-2,3 ,4-triphenyl-butyramide 5 5-(4-Chloro-phenylsulfanyl)-[ 1,2,3]thiadiazole-4-carboxylic acid (3 dimethylamino-propyl)-amide 2-(3-Chloro-5 -trifluoromethyl-pyridin-2-ylsulfanyl)-3 -methyl-3H-imidazole 4-carboxylic acid (3-dimethylamino-propyl)-amide 2-(2-Chloro-4-trifluoromethyl-phenyl)- [1,3] -thiazole-4-carboxyli c acid (3 10 dimethylamino-propyl)-amide -2-(2,3 -Dihydro-l1-benzofuran-5 -yl)-l ,3 -thiazole-4-carboxylic acid (3 dimethylamino-propyl)-amide 2-(2,3 -Dichioro-phenyl)- 1,3 -thiazole-4-carboxylic acid (3 -dimethylamino propyl)-amide 15 4-[4-(4-Chloro-phenyl)-thiazol-2-yl] -N-(3 -dimethylamino-propyl)-benzamide 5-(4-Fluoro-phenyl)-thiophene-2-carboxylic acid (3 -dimethylamino-propyl) amide 4-Methyl-2-(3 -trifluoromethyl-phenyl)-thiazole-5 -carboxylic acid (3 dimethylamino-propyl)-amide 20 3 -(4-tert-Butyl-benzyloxy)-thiophene-2-carboxylic acid (3 -dimethylamino propyl)-amide 4-Oxo-3-(3 -trifluoromethyl-phenyl)-3 ,4-dihydro-phthalazine-l1-carboxylic acid (3-dimethylamino-propyl)-amide 2-(4-Chloro-pheny1)-N-(3-dimethylamino-propy)-4-oxo-4-phelyl 25 butyramide 5-(4-Chloro-phenyl)-l1-phenyl- 1H-pyrazole-3 -carboxylic acid (3 dimethylamino-propyl)-amide N-(3 -Dimethylamino-propyl)-4-(4-phenyl-thiazol-2-y)-belzamide 1 -(2,4,5-Trichloro-phenylsulfonyl)-pyrrolidine-2-carboxylic acid (3 30 dimethylamnino-propyl)-am-ide 3-(3 ,4-Dichloro-benzylsulfanyl)-thiophene-2-carboxylic acid (3- WO 01/32604 PCTIGBOOIO4249 -23 dimethylamino-propyl)-amide 5 -Chloro-3 -phenyl- 1H-indole-2-carboxylic acid (3-dimethylamino-propyl) amide N-(3 -Dimethylamino-propyl)-2-[ 1-(4-fluoro-benzyl)- 1H-indol-3 -yl] 5 acetamide 2-Phenyl-imidazo[ 1,2-a]pyridine-3 -carboxylic acid (3 -dimethylamnino propyl)-amide N-(3-Dimethylamino-propyl)-2-(7-ethyl- 1H-indol-3-yl)-4-oxo-4-phenyl butyramide 10 Phenyl-trifluoromethyl-thieno[3 ,2-b]pyridine-2-carboxylic acid (3 dimethylamino-propyl)-amide 3-(4-Nitro-3 -trifluoromethyl-phenoxy)-thiophene-2-caboxylic acid (3 dimethylamino-propyl)-amide 2-(5-Chloro-l1-methyl-3-phenyl- 1H-pyrazol-4-ylmethylsulfanyl)-N-(3 15 dimethylamino-propyl)-benzamide 2-(4-Chloro-benzylsulfanyl)-3 -methyl-4-oxo-3 ,4-dihydro-quinazoline-7 -carboxylic acid (3-dimethylamino-propyl)-amide N-(3 -Dimethylamino-propyl)-4- [4-(4-methoxy-phenyl)-pyrimidifl-2 -ylsulfanylmethy1I-benzamide 20 1 -(4-chlorobenzyl)-3 -(2-N,N-dimethylethylamido)-6-pyridone 1 -(2,6-dichlorobenzyl)-3-(3 -N,N-dimethylpropylamido)-6-pyridofle 1 -(3 -trifluoromethylbenzyl)-3 -(2-N,N-dimethylethylamido)-2-pyridofle 1 -(2,6-dichlorobenzy1)-3-(2-N,N-dimethylethylamido)-2-pyridofle 1 -(3 ,4-dichlorobenzy1)-3-(N-[2,N,N-dimethyaminfoethylamido])- 2 -pyridone 25 1 -(2,6-dichlorobenzyl)-3 -(N-[2-N,N-dimethylaminoethylamido])-6-pyfldofle 5 -chloro-l1-(3 ,4-dichlorobenzyl)-3-(2-N,N-dimethylamiloethylamido)- 6 -pyridone 5-chloro-3 -(2-N,N-dimethylaminoethylamido)- 1-(3-trifluoromethylbenzyl)-6 pyridone 30 5 -chioro-l1-(3 ,4-dichlorobenzyl)-3-N-(2- [N',N'-dimethylaminoethylamido])-2 pyridone WO 01/32604 PCTIGBOOIO4249 -24 5 -chioro- 1 -(4-chlorobenzyl)-3 -N-(2-(N',N'-dimethylamino)ethyl)amido-2 pyridone 5-chioro- 1 -(3-trifluoromethylbenzyl)-3 -N-(2-(N',N'-dimethylamino)ethyl) amido-2-pyri done 5 1 -benzyl-5-chloro-3 -N-(2- [N',N'-dimethylamino] ethyl)carboxkamido-6 pyridone 5-chioro-l1-(4-chlorobenzyl)-3-N-(2- [N',N'-dimethylamino] ethyl)carboxamnido -6-pyridone 4-(2,4-dichlorobenzoyl)pyrrole-2-N-dimethyamilopropycarboxamide 10 4- (N-[3-(N,N?-dimethyamninopropy)]carboxamido] -2-phenyithiazole 4-(N-(3 -N',N'-dimethylaminopropy1)carboxamido)-2-(4-pyrdil)thiazole 2-[4-(N- [3-N',N'-dimethylaminopropyl]carboxamido)phenyl-4 (3-trifluoromethylphenyl)]thiazole 4-(4-chlorophenyl)-2-(4-[3 -N',N'-dimethylaminopropyl]carboxamido)phelyl) 15, thiazole 1 -(3,5 -bis(trifluoromethy1)benzy1)-3-[N-(2-dimethylamioethyl) carboxamnido]-2[1 H]-pyridone N-(3 -dimethylaminopropyl)-4-(3-chloro-5 -trifluoromethyl-2-pyridyloxy) phenylsulfonamide 20 Ni -[3-(dimethylamino)propyl] -3 -[3-chloro-5 -(trifluoromethyl)-2-pyridyll propanamide 3-(N-(2-dimethylaminoethyl)carboxamido]- 1 -(4-trifluoromethylbenzyl))-2 [1 H]-pyridone 1 -ethyl-3-(3-dimethylaminopropyl)urea 25 1 -(3-(dimethylamino)-propyl)-3-phenylurea NI -[2-(2,4-dichlorophenoxy)phenyl] -N2-[3 -(dimethylamino)propyl] ethanediamnide N4-[3-(dimethylamino)propyll-3 -(2,6-dichlorophenyl)-5 -methylisoxazole-4-c arboxamide 30 N- [[3 -(2,6-dichlorophenyl)-5-methylisoxazol-4-yljcarbonyl] -N'-[3 -(dimethyla mino)propyllurea WO 01/32604 PCT/GBOO/04249 -25 N-(4-chlorophenyl)-N'-[3-dimethylaminopropyl]urea N-(3,5-Dichloro-phenyl)-3-(3-dimethylamino-propylamino)-propionamide [3-(2-Ethyl-6-methyl-pyridin-3-yloxy)-propyl]-dimethyl-amine 8-(3-Dimethylamino-propoxy)- 1,3,7-trimethyl-3,7-dihydro-purine-2,6-dione 5 2-(3-Dimethylamino-propylamino)-isophthalonitrile Dimethylamino-(3-methyl-benzo[b]thiophen-2-yl)-propan-1-one (HCL) N-Benzo[1,3]dioxol-5-ylmethyl-N,N-dimethyl-propane-1,3-diamine N,N-Dimethyl-N-(5-nitro-quinolin-8-yl)-propane-1,3-diamine 1-(4-Chloro-phenyl)-3-(3-dimethylamino-propyl)-urea 10 2-Amino-N-(3-dimethylamino-propyl)-benzamide 3-Phenyl-acrylic acid 3-dimethylamino-propyl ester 3,5-Dinitro-benzoic acid 2-dimethylamino-ethyl ester [4-(4-Bromo-phenyl)-3-(3-dimethylamino-propyl)-3H-thiazol-2-ylidene] phenyl-amine 15 3-Methyl-benzofuran-2-carboxylic acid dimethylamino-dimethyl-propyl ester N'-(2-Chloro-4-nitro-phenyl)-N,N-dimethyl-propane-1,3-diamine [3-(3-Dimethylamino-propyl)-5-(4-nitro-phenyl)-3H-thiazol-2-ylidene] phenyl-amine [3-(10,11-Dihydro-dibenzo[a,d]cyclohepten-5-ylidene)-propyl]-dimethyl 20 amine 2,3-Dimethyl-1H-indole-5-carboxylic acid 2-dimethylamino-ethyl ester N'-(3,4-Dinitro-5-pyridin-2-yl-thiophen-2-yl)-N,N-dimethyl-propane-1,3 diamine Cyclooctyl-dithiocarbamic acid 2-dimethylamino-ethyl ester (HCl) 25 N-(2,6-Difluoro-phenyl)-C-dimethylamino-acetamide 2-Acetylamino-3-(4-chloro-phenyl)-N-(3-dimethylamino-propyl)-acrylamide N-[2-[5-(4-Bromo-phenyl)-furan-2-yl]-1-(3-dimethylamino-propyl carbamoyl)-vinyl]-4-methyl-benzamide 2,6-Bis-(3-dimethylamino-propylamino)-3-nitro-benzonitrile 30 N-[2-(2,4-Dichloro-phenoxy)-phenyl]-N'-(3-dimethylamino-propyl) oxalamide WO 01/32604 PCT/GBOO/04249 -26 3,5-Dichloro-N-(3-dimethylamino-propyl)-2,6-dimethoxy -benzamide 2-Dimethylaminomethyl-3,4-dihydro-2H-naphthalen- 1-one (HCl) 2-({1-[N-(3-Dimethylamino-propyl)-3-trifluoromethyl-phenyl] methanimidoyl)-amino)-6-fluoro-benzoic acid 5 2,4-Dichloro-N-(3-dimethylamino-propyl)-N'-hydroxy-benzaidine 3-(3-Methyl-ureido)-4-oxo-3,4-dihydro-quinazoline-2-carboxylic acid (3-dimethylamino-propyl)-amide 5-Bromo-N-(3-dimethylamino-propyl)-2-hydroxy-benzamide N-(2,4-Dichloro-phenyl)-6-(2-dimethylamino-ethylsulfanyl)-4 10 trifluoromethyl-nicotinamide 1-(2,6-Dichloro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (2-dimethylamino-ethyl)-amide 3-Amino-4-oxo-3,4-dihydro-quinazoline-2-carboxylic acid (3-dimethylamino-propyl)-amide 15 Certain compounds of the invention are novel. Thus, the present invention also provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof, in which R 1 , R 2 , Z, R 3 , Y, X and R 4 are as defined above except for: 2-Benzylsulfanyl-N-(3-dimethylamino-propyl)-benzamide N-(3-Dimethylamino-propyl)-3-phenoxy-benzamide 20 1-(4-chlorobenzyl)-3-(2-N,N-dimethylethylamido)-6-pyridone 1-(2,6-dichlorobenzyl)-3-(3-N,N-dimethylpropylamido)-6-pyridone 1-(3-trifluoromethylbenzyl)-3-(2-N,N-dimethylethylamido)-2-pyridone 1-(2,6-dichlorobenzyl)-3-(2-N,N-dimethylethylamido)-2-pyridone 1-(3,4-dichlorobenzyl)-3-(N-[2,N,N-dimethylaminoethylamido])-2-pyridone 25 1-(2,6-dichlorobenzyl)- 3-(N-[2-N,N-dimethylaminoethylamido])-6-pyri done 5-chloro-1-(3,4-dichlorobenzyl)-3-(2-N,N-dimethylaminoethylamido)-6 pyridone 5-chloro-3-(2-N,N-dimethylaminoethylamido)-1-(3-trifluoromethylbenzyl)- 6 pyridone 30 5-chloro-1-(3,4-dichlorobenzyl)-3-N-(2-[N',N'-dimethylaminoethylamfido])- 2 pyridone WO 01/32604 PCTIGBOOIO4249 -27 5-chioro- 1 -(4-chlorobenzyl)-3 -N-(2-(N',N'-dimethylamino)ethyl)amido-2 pyridone 5-chioro- 1 -(3-trifluoromethylbenzyl)-3 -N-(2-(N',N'.-dimethyiamino)ethyl) amido-2-pyridone 5 1 -benzyl-5 -chloro-3-N-(2-[N',N'-dimethylaminol ethyl)carboxamido-6 pyridone 5 -chioro- 1 -(4-chlorobenzyl)-3 -N-(2- [N',N'-dimethylamino] ethyl) carboxamido-6-pyridone 4-(2,4-dichlorobenzoyl)pyrrole-2-N-dimethylaminopropylcarboxamride 10 4- [(N-[3 -(N',N'-dimethylaminopropyl)] carboxamido]-2-phenylthiazole 4-(N-(3 -N' ,N'-dimethylaminopropyl)carboxamido)-2-(4-pyidinyl)thiazole 2- [4-(N- [3-N',N'-dimethylaminopropyl]carboxamido)phenyl-4 (3 -trifluoromethylphenyl]thiazole 4-(4-chlorophenyl)-2-(4- [3-N',N'-dimethylaminopropyl] carboxamido)phenyl) 15 thiazole 1 -(3,5 -bis(trofluoromethyl)benzyl)-3 -[N-(2-dimethylaminoethyl) carboxamido]-2[ 1H]-pyridone N-(3 -dim ethylaminopropyl)-4-(3 -chloro- 5 -trifluoromethyl-2 -pyri dyloxy) phenylsulfonamide 20 NI -[3-(dimethylamino)propyl] -3- [3-chloro-5-(tri fluoromethyl)-2-pyridyl] propanamide 3 -(N-(2-dimethylamninoethyl)carboxamido] -1 -(4-trifluoromethylbenzyl))-2 [11] -pyridone 1 -ethyl-3 -(3-dimethylaminopropyl)urea 25 1 -(3 -(dimethylamino)-propyl)-3-phenylurea Ni -[2-(2,4-dichlorophenoxy)phenyl] -N2-[3 -(dimethylamino)propyl] ethanediamide N4- [3 -(dim ethyiamino)propyll]-3 -(2,6-dichlorophenyl)-5 -methyli soxazole-4-c arboxamide 30 N-[[3 -(2,6-dichlorophenyl)-5 -methylisoxazol-4-yilcarbonyll-N'-[3 (dimethylamino)propyi]urea WO 01/32604 PCT/GBOO/04249 -28 N-(4-chlorophenyl)-N'-[3-dimethylaminopropyl]urea N-(3,5-Dichloro-phenyl)-3-(3-dimethylamino-propylamino)-propionamide [3-(2-Ethyl-6-methyl-pyridin-3-yloxy)-propyl]-dimethyl-amine 8-(3-Dimethylamino-propoxy)- 1,3,7-trimethyl-3,7-dihydro-purine-2,6-dione 5 2-(3-Dimethylamino-propylamino)-isophthalonitrile Dimethylamino-(3-methyl-benzo[b]thiophen-2-yl)-propan- 1-one (HCl) N-Benzo[1,3]dioxol-5-ylmethyl-N,N-dimethyl-propane-1,3-diamine N,N-Dimethyl-N-(5-nitro-quinolin-8-yl)-propane-1,3-diamine 1-(4-Chloro-phenyl)-3-(3-dimethylamino-propyl)-urea 10 2-Amino-N-(3-dimethylamino-propyl)-benzamide 3 -Phenyl -acrylic acid 3-dimethylamino-propyl ester 3,5-Dinitro-benzoic acid 2-dimethylamino-ethyl ester [4-(4-Bromo-phenyl)-3-(3-dimethylamino-propyl)-3H-thiazol-2-ylidene] phenyl-amine 15 3-Methyl-benzofuran-2-carboxylic acid dimethylamino-dimethyl-propyl ester N'-(2-Chloro-4-nitro-phenyl)-N,N-dimethyl-propane-1,3-diamine [3-(3-Dimethylamino-propyl)-5-(4-nitro-phenyl)-3H-thiazol-2-ylidene] phenyl-amine [3-(10,11 -Dihydro-dibenzo[a,d]cyclohepten-5-ylidene)-propyl]-dimethyl 20 amine 2,3-Dimethyl-1H-indole-5-carboxylic acid 2-dimethylamino-ethyl ester N'-(3,4-Dinitro-5-pyridin-2-yl-thiophen-2-yl)-N,N-dimethyl-propane-1,3 diamine Cyclooctyl-dithiocarbamic acid 2-dimethylamino-ethyl ester (HCl) 25 N-(2,6-Difluoro-phenyl)-C-dimethylamino-acetamide 2-Acetylamino-3-(4-chloro-phenyl)-N-(3-dimethylamino-propyl)-acrylamide N-[2-[5-(4-Bromo-phenyl)-furan-2-yl]-1-(3-dimethylamino propylcarbamoyl)-vinyl]-4-methyl-benzamide 2,6-Bis-(3-dimethylamino-propylamino)-3-nitro-benzonitrile 30 N-[2-(2,4-Dichloro-phenoxy)-phenyl]-N'-(3-dimethylamino-propyl) oxalamide OI I rIr I ITC tIIC T II" II WO 01/32604 PCT/GBOO/04249 -29 3,5-Dichloro-N-(3-dimethylamino-propyl)-2,6-dimethoxy-benzamide 2-Dimethylaminomethyl-3,4-dihydro-2H-naphthalen-1-one (HCl) 2-({1-[N-(3-Dimethylamino-propyl)-3-trifluoromethyl-phenyl] methanimidoyl}-amino)-6-fluoro-benzoic acid 5 2,4-Dichloro-N-(3-dimethylamino-propyl)-N'-hydroxy-benzamidine 3-(3-Methyl-ureido)-4-oxo-3,4-dihydro-quinazoline-2-carboxylic acid (3-dimethylamino-propyl)-amide 5-Bromo-N-(3-dimethylamino-propyl)-2-hydroxy-benzamide N-(2,4-Dichloro-phenyl)-6-(2-dimethylamino-ethylsulfanyl)-4 10 trifluoromethyl-nicotinamide 1-(2,6-Dichloro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (2-dimethylamino-ethyl)-amide 3-Amino-4-oxo-3,4-dihydro-quinazoline-2-carboxylic acid (3-dimethylamino-propyl)-amide 15 Compounds of the invention in which P is -U-W- may be prepared by reacting a compound of formula (II) z Wv NR 1

R

2 20 wherein Z, R, and R 2 are as defined above and W'is a group WH wherein W is as defined above, with a compound of formula (III) 25 R4 --- 11(III) 30 wherein R 4 is as defined above and U' is a group -UL wherein U is as defined above and L is a hydroxy group or a leaving group such as a halogen atom.

WO 01/32604 PCT/GBOO/04249 -30 Compounds of formulae (II) and (III) are known compounds, or may be prepared by analogy with known methods. Typically, the reaction takes place in the presence of a base such as diisopropylethylamine or the equivalent polymer bound resin NN 5 (diisopropyl)amino-methylpolystyrene resin (PS-DIEA), and a coupling agent such as O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU). The reaction typically takes place in a solvent such as acetonitrile at a temperature of from 0 to 100 'C, preferably from 20 to 80 'C. The work-up typically involves the use of a sequestration enabling reagent such as tetrafluorophthalic 10 anhydride and polymer bound scavenger resins to remove unwanted starting materials. Such techniques are described in Parlow et al Tetrahedron Lett., 1997, 38, 7959. Compounds of the invention wherein P is -NH-CO-W- can be prepared by reacting a compound of formula (1I) above with a compound of formula (IV) 15

R

4 -N=C=O (IV) 20 wherein R 4 is as defined above. Typically, the reaction takes place in a hydrocarbon solvent such as toluene at a temperature of from 0 to 100 *C. The work-up typically involves the use of a sequestration enabling reagent such as tetrafluorophthalic anhydride and polymer bound scavenger resins to remove unwanted starting materials. The amides thereby 25 prepared may be converted to the corresponding amidines by standard methods. The compounds of formula (IV) may be prepared by techniques known in the art. For example, they may be prepared by reacting a compound of formula (V) WO 01/32604 PCT/GBOO/04249 -31 0 14 kOH 5 wherein R 4 is as defined above, with diphenylphosphoryl azide (DPPA), in the presence of a base such as triethylamine. Typically, the reaction takes place under reflux, in a solvent such as toluene. Compounds of formula (V) are known 10 compounds or may be prepared by analogy with known methods. Compounds of the invention wherein P is -X-U-W- wherein X, U and W are as defined above can be prepared by reacting a compound of formula (II) above with a compound of formula (VI) 1R4 U 15 R(VI) X L 20 wherein R 4 , X and U are as defined above and L is a hydroxy group or leaving group such as a 4-nitro-phenoxy group. Typically, the reaction takes place in a hydrocarbon solvent such as tetrahydrofuran at a temperature of from 60 to 70 *C. The work-up typically involves the use of a sequestration enabling reagent such as tetrafluorophthalic anhydride and polymer bound scavenger resins to remove 25 unwanted starting material. The compounds of formula (VI) are known compounds or may be prepared by analogy with known methods. For example, compounds of formula (VI) in which U is -CO- can be prepared by reacting a compound of formula (VII)

R

4 XH (VII) 30 WO 01/32604 PCT/GBOO/04249 -32 wherein R 4 and X are as defined above, with a chloroformate, for example an aromatic chloroformate such as 4-nitrophenyl chloroformate. Typically, the reaction takes place under reflux, in a solvent such as anhydrous THF. Further, compounds of formula (VI) in which U is -C-(=NH)- can, for example, be prepared from the 5 corresponding nitrile of formula R 4 -X-C= N, for example by reaction with hydrochloric acid. Compounds of the invention in which P is -X-Y- or -X-Y-W- and R 4 is other than -COR", -CO 2 R", -S(O) 2 R" and -CONR'R" can be made by standard techniques, for example by reacting a compound of formula (VIII) 10

R

4 -X-H (VIII) wherein R 4 is other than -COR", -CO 2 R", S(O) 2 R" and -CONR/R' and X is as defined above, with a compound of formula (IX) 15

L-Y-ZNRR

2 (IX) wherein Y, Z, R 1 and R 2 are as defined above and L represents a hydroxy group or a leaving group such as a halogen. The reaction is typically conducted in 20 the presence of a base at from -78*C to the reflux temperature of the solvent. The compounds of formulae (VIII) and (IX) are known compounds or may be prepared by analogy with known methods. Compounds of the invention in which P is -X-U-W- and R 4 is -COR",

-CO

2 R", -S(O) 2 R" or -CONR'R" can be made in an analogous fashion by reacting a 25 compound of formula (X)

R

4 X-U-L (X) wherein R 4 , X and U are as defined above and L represents a hydroxy group 30 or a leaving group such as a halogen, with a compound of formula (XI) WO 01/32604 PCT/GBOO/04249 -33

HWZNRIR

2 (XI) wherein W, Z, R, and R 2 are as defined above. The compounds of formula (X) and (XI) are known compounds or may be 5 prepared by analogy with known methods. Compounds in which P is X or W and R 4 is other than -COR", -CO 2 R",

-S(O)

2 R" and -CONR'R" can be prepared, for example, by reacting a compound of formula (XII) 10

R

4 -AH (XII) wherein A is -X- or -W-, wherein X and W are as defined above and R 4 is other than -COR", -CO 2 R", -S(O) 2 R" and -CONR/R", with a compound of formula (XIII) 15

L-Z-NRR

2 (XIII) wherein Z, R, and R 2 are as defined above and L is a leaving group such as a triflate group or a halogen atom. The reaction can be conducted under standard 20 conditions. Typically, it takes place in the presence of a base in a solvent such as DMF. The compounds of formula (XII) are known compounds or may be prepared by analogy with known methods. The compounds of formula (XIII) are also known compounds or may be prepared by analogy with known methods. For example, they 25 can be prepared from a corresponding compound of formula HO-Z-NRIR 2 by reaction with triflic anhydride or with PCl 5 . Compounds of the invention in which P is X or W and R 4 is -COR", -CO 2 R", -S(O)2R" or CONR'R" can be prepared by reacting a compound of formula (IXV) 30 HA-Z-NRjR 2

(IXV)

WO 01/32604 PCT/GBOO/04249 -34 wherein A, Z, R 1 and R 2 are as defined above, with R 4 -L, wherein R 4 is as defined above and L is a hydroxy group or a leaving group, for example a halogen. The reaction can be conducted under standard conditions, such as those given above for the reaction of compounds of formulae (VIII) and (IX). 5 Compounds of formula (IXV) and compounds of formula R 4 -L are known compounds or may be prepared by analogy with known methods. Compounds of the invention in which P is Y, Y is -CO- and R 4 is aryl or heteroaryl may be prepared, for example, by a Friedel-Crafts reaction between a compound of formula (XV) 10

R

4 -H (XV) wherein R 4 is aryl or heteroaryl, and a compound of formula (XVI) 15 0 L 1VZNR 1

R

2 (XVI) 20 wherein L is a hydroxy group, a group OR wherein R is alkyl, or a halogen, for example chlorine, and Z, V, R 1 and R 2 are as defined above. The reaction can be performed under conventional conditions, in the presence of a catalyst such as AlCl 3 . Examples of such reactions are described in section 1-15 of "Advanced Organic Chemistry", 3 rd Edition, by Jerry March. 25 The compounds of formulae (XV) and (XVI) are known compounds or may be prepared by analogy with known methods. Compounds in which P is -Y- or -XY- and in which X, Y and R 4 are as defined above may be prepared, for example, by reacting a compound of formula

(XVII)

WO 01/32604 PCT/GBOO/04249 -35 R4 (XVII) L 5 wherein R 4 is as defined above, Y' is -U- or -X-U-, and L is a hydroxy group or a leaving group, for example a halogen atom, with an organometallic compound of formula (XVIII)

M-B-NRR

2 (XVIII) 10 wherein B is -V-Z- wherein V and Z are as defined above, R 1 and R 2 are as defined above and M is a metal-containing moiety such as Li or -MgX wherein X is a halogen atom such as bromine. The reaction can be carried out under conventional conditions. Preferably, M 15 in the formula (XVIII) is Li. When M in the formula (XVIII) is -MgX, it may be necessary to conduct the reaction at around -78 "C and to use a large excess of the compound of formula (XVII). The compounds of formula (XVII) are known compounds or may be prepared by analogy with known methods. The compounds of formula (XVIII) are also 20 known compounds or may be prepared by analogy with known methods. For example, compounds of formula (XVIII) in which M is Li can be prepared by reacting a corresponding compound of formula Br-B-NR 1

R

2 with lithium or with magnesium. In some cases, it may be necessary to protect the -NR 1

R

2 group during the 25 synthesis of the compounds of formula (XVIII) or during the reaction between the compounds of formulae (XVIII) and (XVII). This can be done by standard techniques. Compounds of the invention in which P is -Y-W- or -XYW-, wherein Y is UV- and -V- is -(CI-C 6 alkyl)-, can be made, for example, by reacting a compound of 30 formula (IXX)

R

4 -P-L (IXX) WO 01/32604 PCT/GBOO/04249 -36 wherein R 4 and P are as defined above and L is a leaving group such as a halogen atom or a triflate group, with a compound of formula (XX) 5 HW-ZNRIR 2 (XX) wherein W, Z, R, and R 2 are as defined above. The reaction can be conducted under conventional conditions. Typically, it is conducted in the presence of a base. If necessary, the NRIR 2 group can be protected during the reaction by conventional 10 means. The compounds of formulae (IXX) and (XX) are knowN compounds, or may be prepared by analogy with known methods. For example, the compounds of formula (IXX) can be prepared by reacting a corresponding compound of formula R-P-OH with triflic anhydride or PCI. 15 Compounds in which P is a direct bond can be prepared by conventional synthetic techniques. A compound of the invention can, of course, be converted to a different compound of the invention by standard functional group interconversions known to those of skill in the art. For example, a compound of the invention in which U is 20 -CO- can be converted to a compound of the invention in which U is -C(=NR)- by reaction with a compound of formula RNH 2 . Suitable such reactions are described in section 6-14 of "Advanced Organic Chemistry" 3 rd Edition, by Jerry March. Pharmaceutically acceptable salts of the compounds of formula (I) may be prepared by salifying a compound of formula (I) with an appropriate acid or base. 25 The compounds of the invention are activators of sGC. They can be used as selective sGC activators. A compound of the invention can therefore be used as a vasodilator or to inhibit platelet aggregation. It can be used for the treatment or prevention of peripheral vascular diseases such as hypertension, angina pectoris, arteriosclerosis, or for the treatment or prevention of glaucoma, preeclampsia, 30 Raynaud's Syndrome, stroke or erectile dysfunction. Further, the compounds of the invention are effective in improving ocular blood flow. They can therefore be used 0I 1-iOOTi ITC= QLICCT IOI II = Oa\- WO 01/32604 PCT/GBOO/04249 -37 in the treatment and prevention of age-related macular degeneration (AMD). For example, they can be used in the treatment and prevention of non-exudative or exudative AMD. They can also be used in the treatment and prevention of neovascular or non-neovascular AMD. 5 Conditions attributable to down regulation of sGC can thus be alleviated. Accordingly, the present invention also provides a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of the human or animal body, wherein RI, R 2 , Z, R 3 , Y, X and R 4 are as defined above. 10 The compounds of the invention may be administered in a variety of dosage forms. Thus, they can be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules. The compounds of the invention may also be administered parenterally, either subcutaneously, intravenously, intramuscularly, intrasternally, transdermally or by 15 infusion techniques. The compounds may also be administered as suppositories. A compound of the invention is typically formulated for administration with a pharmaceutically acceptable carrier or diluent. For example, solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic 20 acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g. starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and 25 pharmacologically inactive substances used in pharmaceutical formulations. Such pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film coating processes. Liquid dispersions for oral administration may be syrups, emulsions and suspensions. The syrups may contain as carriers, for example, saccharose or 30 saccharose with glycerine and/or mannitol and/or sorbitol. Suspensions and emulsions may contain as carrier, for example a natural SUBSTITUTE SHEET (RULE 261 WO 01/32604 PCT/GBOO/04249 -38 gum, agar, sodium alginte, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. The suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, 5 a suitable amount of lidocaine hydrochloride. Solutions for intravenous or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions. A therapeutically effective amount of a compound of the invention is 10 administered to a patient. A typical daily dose is from about 0.1 to 50 mg per kg of body weight, according to the activity of the specific compound, the age, weight and conditions of the subject to be treated , the type and severity of the disease and the frequency and route of administration. Preferably, daily dosage levels are from 5 mg to 2 g. 15 The Examples which follow illustrate the invention.

WO 01/32604 PCT/GBOO/04249 -39 EXAMPLES The synthesis of some of the compounds of the invention is detailed below. Examples I to 69 5 The aryl acid (different for each reaction) (0.1 mmol), 3-(dimethylamino) propylamine (10 mg, 0.1 mmol), N, N-(diisopropyl)amino-methylpolystyrene resin (PS-DIEA), (86.0 mg, 0.3 mmol, loading 3.5 mmol/g) and O-(7-azabenzotriazol-1 yl)-N, N, N, N-tetramethyluronium hexafluorophosphate (HATU) (38 mg, 0.1 mmol) were shaken under nitrogen in anhydrous acetonitrile (4 mL) and heated to 50 'C for 10 5 hours. After this time the reaction mixture was cooled to room temperature. Tetrafluorophthalic anhydride (65 mg, 0.3 mmol) was then added and the reaction mixture was shaken under nitrogen for 18 hours. Macroporous triethylammonium methylpolystyrene carbonate resin (MP-carbonate), (610 mg, 1.96 mmol, loading 3.18 mmol/g) was then added and the reaction mixture was shaken 15 under nitrogen for a further 48 hours. The reactions were then filtered through filter syringes into vials and washed with methanol. The solvent was removed on a vacuum concentrator and each product was weighed and analysed by LC-MS. This method was used to synthesise the following compounds. The molecular weight, purity and yield of the compounds synthesised is shown in Table 20 1. Example No. Compound 1 N-(3-Dimethylamino-propyl)-2-[1-(4-fluorobenzoyl]-benzamide (CFM2262) 2 N-(3-Dimethylamino-propyl)-3-phenoxy-benzamide (CFM2263) 25 3 N-(3-Dimethylamino-propyl)-2-phenoxy-benzamide (CFM2264) 4 2-(4-Chloro-phenoxy)-N-(3-dimethylamino-propyl)-nicotinamide (CFM2265) 5 4'-n-Propyl-biphenyl-4-carboxylic acid (3-dimethylamino propyl)-amide (CFM2266) WO 01/32604 PCT/GBOO/04249 -40 6 2-[l-(4-Bromo-phenyl)-methanoyl]-cyclohexanecarboxylic acid (3-dimethylamino-propyl)-amide(CFM2267) 7 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid (3 dimethylamino-propyl)-amide (CFM2268) 8 2-[1-(4-Chlorobenzoyl]-N-(3-dimethylamino-propyl)-benzamide (CFM2269) 9 2-Phenyl-quinoline-4-carboxylic acid (3-dimethylamino-propyl) amide (CFM2331) 5 10 2-[l-(4-Chloro-3-nitrobenzoyl)]-N-(3-dimethylamino-propyl) benzamide (CFM2332) 11 N-(3-Dimethylamino-propyl)-2-pyren-1-yl-acetamide (CFM2333) 12 N-(3-Dimethylamino-propyl)-2-[1-(3-methyl-benzo[b]thiophen 2-yl)-methanoyl]-benzamide (CFM2320) 13 4-Chloro-N-(3-dimethylamino-propyl)-2-phenoxy-benzamide (CFM2321) 14 N-(3-Dimethylamino-propyl)-3-(4-phenoxy-phenyl) propionamide (CFM2322) 10 15 N-(3-Dimethylamino-propyl)-2-[1-(1-trifluoromethyl-1,3,4,9 tetrahydro-b-carbolin-2-yl)-methanoyl]-benzamide (CFM2334) 16 1-(4-Chloro-phenyl)-2,5-dimethyl-1-pyrrole-3-carboxylic acid (3 dimethylamino-propyl)-amide (CFM2335) 17 2-{1-[(3-Dimethylanino-propylcarbamoyl)-methyl] cyclopentyl}-N-(4-trifluoromethoxy-phenyl)-acetamide (CFM2336) 18 8-E2-(3-Dimethylamino-propylcarbamoyl)-phenylsulfanyl] naphthalene- 1 -carboxylic acid methylamide (CFM2337) 19 3-Methyl-5-(4-methyl-[1,2,3]thiadiazol-5-yl)-1-(4 trifluoromethoxy-phenyl)-lH-pyrazole-4-carboxylic acid (3 dimethylamino-propyl)-amide (CFM2338) WO 01/32604 PCT/GBOO/04249 -41 20 6,8-Di-tert-butyl-4-oxo-4H-chromene-2-carboxylic acid (3 dimethylamino-propyl)-amide (CFM2339) 21 2-(Furan-2-yl)-quinoline-4-carboxylic acid (3-dimethylamino propyl)-amide (CFM2340) 22 Biphenyl-2,2'-dicarboxylic acid 2'-[(3-dimethylamino-propyl) amide]-2-[(4-fluoro-phenyl)-amide] (CFM2342) 23 3-Phenyl-pentanedioic acid (3-chloro-4-methyl-phenyl)-amide (3-dimethylamino-propyl)-amide (CFM2343) 5 24 2-(3,4-Dimethoxy-phenyl)-6-methyl-quinoline-4-carboxylic acid (3-dimethylamino-propyl)-amide (CFM2344) 25 6-Bromo-(2-thiophen-3-yl)-quinoline-4-carboxylic acid (3 dimethylamino-propyl)-amide (CFM2345) 26 3-(4-Chloro-phenyl)-4-cyano-5-isobutylsulfanyl-thiophene-2 carboxylic acid (3-dimethylamino-propyl)-amide (CFM2346) 27 4-(4-Chloro-phenoxy)-N-(3 -dimethylamino-propyl)-3-nitro benzamide (CFM2347) 28 6-(2,4-Dichloro-phenyl)-cyclohex-3-ene carboxylic acid (3 dimethylamino-propyl)-amide (CFM2348) 10 29 N-(3-Dimethylamino-propyl)-2-(2-phenylsulfamoyl phenylsulfanyl)-benzamide(CFM2349) 30 2'-Fluoro-[1,1'-biphenyl]-4-carboxylic acid (3-dimethylamino propyl)-amide (CFM2350) 31 2-Benzylsulfanyl-N-(3-dimethylamino-propyl)-benzamide (CFM235 1) 32 Pyrazine-2,3-dicarboxylic acid 2-[(3-dimethylamino-propyl) amide] 3-[(5,6,7,8-tetrahydro-naphthalen-1-yl)-amide] (CFM2352) 33 2-[(3,5-Dichloro-phenylcarbamoyl)-methylsulfanyl]-N-(3 dimethylamino-propyl)-nicotinamide (CFM2432) l IRRTITilTF q-FFT (Pill F 9A WO 01/32604 PCT/GBOO/04249 -42 34 2-(3-Trifluoromethyl-phenyl)-thiazole-4-carboxylic acid (3 dimethylamino-propyl)-amide (CFM2368) 35 2-(4-Chloro-phenyl)-thiazole-4-carboxylic acid (3 dimethylamino-propyl)-amide (CFM2369) 36 5-Chloro-1-(2,4-dichloro-benzyl)-6-oxo-1,6-dihydro-pyridine-3 carboxylic acid (3-dimethylamino-propyl)-amide (CFM2370) 37 1-(2,4-Dichloro-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (3-dimethylamino-propyl)-amide (CFM2371) 5 38 5-Chloro-1-(3,4-dichloro-benzyl)-6-oxo-1,6-dihydro-pyridine-3 carboxylic acid (3-dim ethylamino-propyl)-amide (CFM2372) 39 1-(3,4-Dichloro-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (3-dimethylamino-propyl)-amide (CFM2373) 40 5 -Chloro- 1 -(2,6-dichloro-benzyl)-6-oxo- 1,6-dihydro-pyridine-3 carboxylic acid (3-dimethylamino-propyl)-amide (CFM2388) 41 1,1 -Dimethyl-indan-4-carboxylic acid (3 -dimethylamino-propyl) amide (CFM2389) 42 N-(3-Dimethylamino-propyl)-2-[1-(4-ethyl-phenyl)-methanoyl] benzamide (CFM2390) 10 43 N-(3-Dimethylamino-propyl)-3-(2,4,5-trimethyl-phenyl) butyramide (CFM2391) 44 2-[3-(3,4-Dichloro-phenyl)-ureido]-N-(3-dimethylamino-propyl) benzamide (CFM2392) 45 N-(3-Dimethylamino-propyl)-4-oxo-2,3,4-triphenyl-butyramide (CFM2393) 46 5-(4-Chloro-phenylsulfanyl)-[1,2,3]thiadiazole-4-carboxylic acid (3-dimethylamino-propyl)-amide (CFM2394) 47 2-(3-Chloro-5-trifluoromethyl-pyridin-2-ylsulfanyl)-3-methyl 3H-imidazole-4-carboxylic acid (3-dimethylamino-propyl)-amide (CFM2395) WO 01/32604 PCT/GBOO/04249 -43 48 2-(2-Chloro-4-trifluoromethyl-phenyl)-[ 1,3]-thiazole-4 carboxylic acid (3-dimethylamino-propyl)-amide (CFM2396) 49 2-(2,3-Dihydro-1-benzofuran-5-yl)-1,3-thiazole-4-carboxylic acid (3-dimethylamino-propyl)-amide (CFM2397) 50 2-(2,3-Dichloro-phenyl)-1,3-thiazole-4-carboxylic acid (3 dimethylamino-propyl)-amide (CFM2398) 51 4-[4-(4-Chloro-phenyl)-thiazol-2-yl]-N-(3-dimethylamino propyl)-benzamide (CFM1899) 5 52 5-(4-Fluoro-phenyl)-thiophene-2-carboxylic acid (3 dimethylamino-propyl)-amide (CFM2399) 53 4-Methyl-2-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid (3-dinethylamino-propyl)-amide (CFM2400) 54 3-(4-tert-Butyl-benzyloxy)-thiophene-2-carboxylic acid (3 dimethylamino-propyl)-amide (CFM2401) 55 4-Oxo-3-(3-trifluoromethyl-phenyl)-3,4-dihydro-phthalazine-1 carboxylic acid (3-dimethylamino-propyl)-amide (CFM2402) 56 2-(4-Chloro-phenyl)-N-(3-dimethylamino-propyl)-4-oxo-4 phenyl-butyramide (CFM2403) 10 57 5 -(4-Chloro-phenyl)-1-phenyl-1H-pyrazole-3-carboxylic acid (3 dimethylamino-propyl)-amide (CFM2404) 58 N-(3-Dimethylamino-propyl)-4-(4-phenyl-thiazol-2-yl) benzamide (CFM2405) 59 1-(2,4,5-Trichloro-phenylsulfonyl)-pyrrolidine-2-carboxylic acid (3-dimethylamino-propyl)-amide (CFM2406) 60 3-(3,4-Dichloro-benzylsulfanyl)-thiophene-2-carboxylic acid (3 dimethylamino-propyl)-amide (CFM2407) 61 5-Chloro-3-phenyl-1H-indole-2-carboxylic acid (3 dimethylamino-propyl)-amide (CFM2408) WO 01/32604 PCT/GBOO/04249 -44 62 N-(3-Dimethylamino-propyl)-2-[1-(4-fluoro-benzyl)-1H-indol-3 yl]-acetamide (CFM2409) 63 2-Phenyl-imidazo[1,2-a]pyridine-3-carboxylic acid (3 dimethylamino-propyl)-amide (CFM2410) 64 N-(3-Dimethylamino-propyl)-2-(7-ethyl-1H-indol-3-yl)-4-oxo-4 phenyl-butyramide (CFM241 1) 65 Phenyl-trifluoromethyl-thieno[3,2-b]pyridine-2-carboxylic acid (3-dimethylamino-propyl)-ami de (CFM2412) 5 66 3-(4-Nitro-3-trifluoromethyl-phenoxy)-thiophene-2-carboxylic acid (3-dimethylamino-propyl)-amide (CFM2428) 67 2-(5-Chloro-1-methyl-3-phenyl-1H-pyrazol-4-ylmethylsulfanyl) N-(3-dimethylamino-propyl)-benzamide (CFM2429) 68 2-(4-Chloro-benzylsulfanyl)-3-methyl-4-oxo-3,4-dihydro quinazoline-7-carboxylic acid (3-dimethylamino-propyl)-amide (CFM2430) 69 N-(3-Dimethylamino-propyl)-4-[4-(4-methoxy-phenyl) pyrimidin-2-ylsulfanylmethyl]-benzamide (CFM243 1) WO 01/32604 PCT/GBOO/04249 -45 Table 1 Example Molecular Weight LC-MS Results % Purity Yield (mg) % Yield 1 328.22 62.1 25.5 40 5 2 298.22 86.6 23.7 41 3 298.22 86.1 32.1 55 4 333.64 96.6 33 51 5 324.3 100 35.1 55 6 395.17 60.1 33.5 43 10 7 340.18 95.7 14.2 21 8 344.68 58.5 25.2 37 12 380.35 90.5 32.2 43 13 332.67 73.8 24.5 38 14 326.28 96.1 21.2 33 15 9 333.27 94.0 22.6 35 10 389.68 94.4 43.8 57 11 344.3 44.0 46.1 68 15 472.35 96.2 50.9 >100 16 333.7 87.0 24.3 74 20 17 429.35 71.6 30.1 71 18 421.4 52.4 28.7 69 19 468.34 72.4 28.1 61 20 386.37 68.0 10.8 28 21 323.23 92.9 12.8 40 25 22 350.1 90.8 22.5 65 23 415.8 52.0 17 41 24 407.35 90.5 15.5 38 25 418.19 69.5 13.1 32 26 435.88 95.9 21.3 43 30 27 377.67 83.6 12.8 33 28 355.15 59.0 16.8 48 29 469.46 72.9 21.9 74 30 300.24 93.1 11.5 35 31 328.31 63.4 16 34 35 32 381.32 57.0 17.1 45 34 357.24 97.3 14.1 40 35 323.68 96.9 17.7 55 36 416.57 94.1 10.1 25 37 382.13 86.0 14 37 WO 01/32604 PCT/GBOO/04249 -46 38 416.57 88.9 12.8 31 39 382.13 64.5 10.3 27 40 416.57 100 22.6 55 41 274.24 97.4 12.3 45 5 42 338.28 89.0 16.7 50 43 290.28 81.6 15.7 55 44 409.15 91.9 12.1 30 45 414.38 41.0 18.8 47 46 356.73 86.6 20.3 58 10 47 421.71 79.9 14.3 34 48 391.68 90.9 25 72 49 331.27 91.2 24.5 20 50 358.13 34.2 16.3 75 52 306.24 96.4 18.3 44 15 53 371.26 97.4 27.6 60 54 374.38 94.8 75 55 418.26 96.7 26.2 71 56 372.73 34.4 21 51 57 382.73 100 19.9 54 20 58 365.34 100 26.3 69 59 442.63 96.6 16.2 45 60 403.23 100 27.8 63 61 355.71 100 19.9 50 62 367.71 100 8.9 25 25 63 322.25 54.6 26.2 66 64 405.38 97.8 21.2 53 65 407.3 100 11.5 50 66 417.24 79.5 19.7 48 67 442.85 59.7 5.1 12 30 68 444.82 32.7 18.9 43 69 436.41 86.3 23.6 55 33 441.22 40.3 18.2 42 Examples 70 to 99 35 The aryl acid (different for each reaction) (0.1 mmol) was stirred under nitrogen in anhydrous toluene (2 mL) and heated to 50 0 C. Triethylamine (10 mg, 0.1 mmol) dissolved in 1 mL of anhydrous toluene was then added. The temperature was raised to 80 'C and diphenylphosphorylazide (DPPA), (27.0 mg, 0.1 mmol) was added.

WO 01/32604 PCT/GBOO/04249 -47 The reaction was kept at this temperature for 1 hour then cooled to room temperature while still stirring under nitrogen. 3-(Dimethylamino)-propylamine (10 mg, 0.1 mmol) was added and the whole mixture was stirred at room temperature overnight. Tetrafluorophthalic anhydride 5 (64.7 mg, 0.3 mmol) was added and the reaction stirred for a further 18 hours. Following this 20 equivalents of macroporous triethylammonium methylpolystyrene carbonate resin (MP-carbonate), (610 mg, 1.96 mmol) was added and the reactions were stirred for another 24 hours. Each reaction was then filtered through filter syringes into vials and washed with methanol. The solvent was removed using a 10 vacuum concentrator and each product was weighed and analysed by LC-MS. This method was used to synthesise the following compounds. The molecular weight, purity and yield of the compounds synthesised is shown in Table 2. 15 Examples No. Compounds 70 1-( 3 -Dimethylamino-propyl)-3-(2-phenoxy-phenyl)-urea (CFM2260) 71 1-[2-(4-Chloro-phenoxy)-pyridin-3-yl]-3-(3 dimethylaminopropyl)-urea (CFM226 1) 72 1-(3-Dimethylamino-propyl)-3-pyren-1-ylmethyl-urea (CFM2317) 20 73 1-(3-Dimethylamino-propyl)-3-[(1R,2R)-5-phenyl-2-(1-phenyl methanoyl)-cyclohexyl]-urea (CFM2318) 74 1-(3-Dimethylamino-propyl)-3-[2-(4-phenoxy-phenyl)-ethyl] urea (CFM2319) 75 1-(3-Dimethylamino-propyl)-3-[3-methyl-5-(4-methyl [1,2,3]thiadiazol-5-yl)-1-(4-trifluoromethoxy-phenyl)-1H pyrazol-4-yl]-urea (CFM2353) 76 2'-[3-( 3 -Dimethylamino-propyl)-ureido]-biphenyl-2-carboxylic acid (4-fluoro-phenyl)-amide (CFM2354) 77 N-(3-Chloro-4-methyl-phenyl)-4-[3-(3-dimethylamino-propyl) ureido]-3-phenyl-butyrarnide (CFM2355) WO 01/32604 PCT/GBOO/04249 -48 78 1-[4-(4-Chloro-phenylsulfanyl)-thiophen-3-yl]-3-(3 dimethylamino-propyl)-urea (CFM2356) 79 1-[2-(3,4-Dimethoxy-phenyl)-6-methyl-quinolin-4-yl]-3-(4 dimethylamino-propyl)-urea (CFM2357) 80 1-(6-Bromo-2-thiophen-3-yl-quinolin-4-yl)-3-(3-dimethylamino propyl)-urea (CFM2358) 81 1-[3-(4-Chloro-phenyl)-4-cyano-5-isobutylsulfanyl-thiophen-2 yl]-3-(3-dimethylamino-propyl)-urea (CFM2359) 5 82 1-[6-(2,4-Dichloro-phenyl)-cyclohex-3-enyl]-3-(3 dimethylamino-propyl)-urea (CFM2360) 83 1-(2-Benzylsulfanyl-phenyl)-3-(3-dimethylamino-propyl)-urea (CFM2361) 84 2-{2-[3-(3-Dimethylamino-propyl)-ureido]-phenylsulfanyl}-N phenyl-benzenesulfonamide (CFM2362) 85 1-(3-Dimethylamino-propyl)-3-(2'-fluoro-biphenyl-4-yl)-urea (CFM2363) 86 N-(3,5-Dichloro-phenyl)-2- {3-[3-(3-dimethylamino-propyl) ureido]-pyridin-2-ylsulfanyl}-acetamide (CFM2364) 10 87 1-(3-Dimethylamino-propyl)-3-{2-[1-(1-trifluoromethyl-1,3,4,9 tetrahydro-b-carbolin-2-yl)-methanoyl]-phenyl}-urea (CFM2366) 88 8-{2-[3-(3-Dimethylamino-propyl)-ureido]-phenylsulfanyl} naphthalene- 1-carboxylic acid methylamide (CFM2367) 89 1-[1-(3,4-Dichloro-benzyl)-6-oxo-1,6-dihydro-pyridin-3-yl]-3-(3 dimethylamino-propyl)-urea (CFM2413) 90 1-(3-Dimethylamino-propyl)-3-(3-oxo-1,2,3-triphenyl-propyl) urea (CFM2414) 91 1-[5-(4-Chloro-phenyl)-1-(3,4-dichloro-phenyl)-1H-pyrazol-3 yl]-3-(3-dimethylamino-propyl)-urea (CFM2415) 15 92 1-{4-[4-(4-Chloro-phenyl)-thiazol-2-yl]-phenyl}-3-(3 dimethylamino-propyl)-urea (CFM2416) 93 1-(3-Dimethylamino-propyl)-3-[5-(4-fluoro-phenyl)-thiophen-2 yl]-urea (CFM2417) 94 1-[3-(4-tert-Butyl-benzyloxy)-thiophen-2-yl]-3-(3 dimethylamino-propyl)-urea (CFM2418) WO 01/32604 PCTGBOOIO4249 -49 95 1 -(3 -Dimethylamino-propyl)-3 -[4-(4-phenyl-thiazol-2-yl) phenyl]-urea (CFM241 9) 96 1- [3 -(3 ,4-Dichloro-benzylsulfanyl)-thiophen-2-yl] -3-(3 dimethylamnino-propyl)-urea (CFM2420) 97 1 -[2-(5-Chloro-lI-methyl-3-phenyl- lH-pyrazol-4 ylmethylsulfanyl)-phenyl]j-3-(3-dimethylamino-propyl)-urea __________(CFM2433) 98 1 -[2-(4-Chloro-benzylsulfanyl)-3 -methyl-4-oxo-3 ,4-dihydro ___________quinazolin-7-yl]-3-(3-dimethylamino-propyl)-urea (CFM2434) 5 99 1 -(3-Dimethylamino-propyl)-3- {4-[4-(4-methoxy-phenyl) ___________pyrimidin-2-ylsulfanylmethyl]-phenyl} -urea (CFM243 5) WO 01/32604 PCT/GBOO/04249 -50 Table 2 Example Molecular Weight of Product LC-MS Results % Product Yield (mg) % Yield 70 313.22 57.53 51 83.06 71 348.64 56.3 41.4 60.6 5 72 359.3 58.85 108.7 >100 73 407.38 42.59 75.1 94.1 74 341.28 54.28 52.1 77.9 87 487.35 53.05 29.4 61.44 88 436.4 53.98 63.6 >100 10 75 483.34 42 41.8 87.45 76 434.34 76.93 26 60.48 77 430.8 31.66 34.5 80.98 78 369.76 74.31 36.3 99.18 79 422.35 26.75 36.7 87.79 15 80 433.19 69.82 32.4 75.55 81 450.88 32 27.3 61.31 82 370.15 38.84 29.1 79.42 83 343.31 100 32.2 94.46 84 484.46 36.4 15.8 32.94 20 85 315.21 56.84 23.3 74.68 86 456.22 38.85 58.6 >100 89 397.13 32.11 46.1 >100 90 429.38 35.0 51.0 >100 91 466.62 51.18 45.7 98.6 25 92 414.78 70.68 65.8 >100 93 321.24 48.83 20.5 65.12 94 389.38 44.0 41.8 >100 95 380.34 49.46 33.5 89.88 96 418.23 27.0 32.8 80 30 97 457.85 52.98 47.1 >100 98 459.82 60.47 65.9 >100 99 451.41 55.72 19.9 44.53 Example 100 35 1-(4-Bromophenyl)-3-(3-(1-pyrrolidinyl) propyl) urea (CFM2138) 4-Nitrophenyl chloroformate (87.0 mg, 0.436 mmol), 4-bromoaniline (50.0 mg, 0.29 mmol) and triethylamine (44.0 mg, 0.436 mmol) were refluxed under nitrogen in WO 01/32604 PCT/GBOO/04249 -51 anhydrous THF (20 mL) for 18 hours. After this time 1-(3-aminopropyl) pyrrolidine (55.0 mg, 0.436 mmol) was added and the whole reaction mixture was refluxed for a further 2 hours. The reaction mixture was cooled to room temperature and tetrafluorophthalic 5 anhydride (191.0 mg, 0.87 mmol) was added. The reaction was stirred at room temperature under nitrogen for 1 hour, then 6 equivalents of tris-(2-aminoethyl)amine polystyrene resin (PS-trisamine), (500 mg, 1.74 mmol, loading 3.5 mmol/g) was added and the reaction stirred for 2 hours. Following this 20 equivalents of Dowex AGI resin (OH- form) (1.68 g, 5.8 mmol, loading 3.45 mmol/g) was added and the 10 mixture was stirred for 18 hours at room temperature. It should be noted that the Cl- form of the resin was converted to the OH form by washing with 20 volumes of IM NaOH solution, followed by distilled water until the washings are neutral. Another 20 equivalents of the resin was added after this time and the reaction was stirred for a further 2 hours. The reaction mixture was 15 then filtered and the solvent removed using a vacuum concentrator. Example 101 1-(4-Bromophenyl)-3-(3-dimethylamino propyl) urea (CFM2134) Prepared as in Example 100 using 4-nitrophenyl chloroformate (77.2 mg, 0.38 20 mmol), 4-bromoaniline (30.0 mg, 0.174 mmol) and triethylamine (38.8 mg, 0.38 mmol) to form the intermediate followed by 3-(dimethylamino)propylamine (26.6 mg, 0.26 mmol) to form the desired product. Work-up as in Example 100. The crude product was purified by flash chromatography using MeOH/CHCl 3 (40:60). 25 Example 102 3-(4-Bromophenyl)-1-methyl-1-(3-dimethylamino propyl) urea (CFM2139) Prepared as in Example 100 using 4-nitrophenyl chloroformate (87.0 mg, 0.436 mmol), 4-bromoaniline (50.0 mg, 0.29 mmol) and triethylamine (44.0 mg, 0.436 mmol) refluxed for 5 hours in anhydrous THF (20mL) to form the intermediate. 30 Then N,N,N'-trimethyl-1,3-propanediamine (50.5 mg, 0.436 mmol) was added and WO 01/32604 PCT/GBOO/04249 -52 the reaction mixture refluxed for 18 hours to form the title compound. Work-up as in Example 100. Example 103 5 1-(3-Phenyl-5-methoxy phenyl)-3-(3-dimethylamino propyl) urea (CFM2148) Prepared as in Example 100 using 4-nitrophenyl chloroformate (45.5 mg, 0.226 mmol), 5-phenyl-o-anisidine (30.0 mg, 0.151 mmol) and triethylamine (22.8 mg, 0.226 mmol) refluxed in anhydrous THF (20 mL) for 18 hours to form the intermediate followed by 3-(dimethylamino)-propylamine (23.1 mg, 0.226 mmol) 10 and refluxed for a further 5 hours to form the title compound. Work-up as in Example 100. Example 104 3-(4-Chlorophenyl)-1-methyl-1-(3-dimethylamino propyl) urea (CFM2200) 15 Prepared as in Example 100 using 4-nitrophenyl chloroformate (830 mg, 4.12 mmol), 4-chloroaniline (350 mg, 2.75 mmol) and triethylamine (416 mg, 4.12 mmol) refluxed for 7 hours in anhydrous THF (30mL) to form the intermediate. Then N,NNV-trimethyl-1,3-propanediamine (478 mg, 4.12 mmol) was added and the reaction mixture refluxed for 18 hours to form the title compound. Work-up as in 20 Example 100. Example 105 1-(3-Nitrophenyl)-1-benzyl-3-(3-dimethylamino propyl) urea (CFM2270) Prepared as in Example 100 using 4-nitrophenyl chloroformate (66.0 mg, 0.328 25 mmol), N-benzyl-3-nitroaniline (50.0 mg, 0.219 mmol) and triethylamine (33.0 mg, 0.328 mmol) refluxed in anhydrous THF (20 mL) for 6 hours to form the intermediate followed by 3-(dimethylamino)propylamine (44.6 mg, 0.438 mmol) and refluxed for a further 36 hours to form the title compound. Work-up as in Example 100. 30 Example 106 WO 01/32604 PCT/GBOO/04249 -53 1-Benzyl-1-(4-methyl-3-pyridinyl)-3-(3-dimethylamino propyl) urea (CFM2271) Prepared as in Example 100 using 4-nitrophenyl chloroformate (76.0 mg, 0.378 mmol), 2-benzylamino-4-methyl-pyridine (50.0 mg, 0.25 mmol) and triethylamine (38.0 mg, 0.378 mmol) refluxed in anhydrous THF (20 mL) for 5 hours to form the 5 intermediate followed by 3-(dimethylamino)propylamine (38.0 mg, 0.378 mmol) and refluxed for a further 18 hours to form the desired product. Work-up as in Example 100. The crude product was purified by flash chromatography using a gradient from 10 to 50 % MeOH (in CHCl 3 ) to give the title compound. 10 Example 107 1-Methyl-1-(3,5-bistrifluoromethylphenyl)-3-(3-dimethylaminopropyl)urea (CFM2311) Prepared as in Example 100 using 4-nitrophenyl chloroformate (62.0 mg, 0.308 mmol), N-methyl-3,5-bis(trifluoromethyl)aniline (50.0 mg, 0.206 mmol) and 15 triethylamine (31.0 mg, 0.308 mmol) refluxed in anhydrous THF (20 mL) for 5 hours to form the intermediate followed by 3-(dimethylamino)propylamine (31.5 mg, 0.308 mmol) and refluxed for a further 18 hours to form the desired product. Work-up as in Example 100. The crude product was purified by flash chromatography using a gradient from 10 to 40 % MeOH (in CHC1 3 ) to give the title compound. 20 Example 108 1-(2-Phenacyl-4-chorophenyl)-1-methyl-3-(3-dimethylamino propyl) urea (CFM231 0) 4-Nitrophenyl chloroformate (61.5 mg, 0.31 mmol), 5-chloro-2-(methylamino) 25 benzophenone (50.0 mg, 0.20 mmol) and triethylamine (30.80 mg, 0.31 mmol) were refluxed for 5 hours in anhydrous THF (20 mL) as in Example 100 to form the intermediate. Then 3-(dimethylamino)-propylamine (32.0 mg, 0.31 mmol) was added and the mixture was refluxed for a further 5 hours to form the desired product. Work-up as in Example 100. The crude product was purified by flash 30 chromatography using a gradient from 10 - 40% MeOH (in CHCl 3 ) to give the title compound.

WO 01/32604 PCT/GBOO/04249 -54 Example 109 1-(2-Chloro-4-trifluoromethylphenyl)-3-(3-dimethylaminopropyl) urea (CFM2421) 4-Nitrophenyl chloroformate (77.0 mg, 0.39 mmol), 4-amino-3-chloro 5 benzotrifluoride (50.0 mg, 0.26 mmol) and triethylamine (38.0 mg, 0.39 mmol) were refluxed for 18 hours in anhydrous THF (20 mL) as in Example 100 to form the intermediate. Then 3-(dimethylamino)-propylamine (38.0 mg, 0.39 mmol) was added and the mixture was refluxed for a further 5 hours to form the desired product. Work-up as in Example 100. The crude product was purified by flash 10 chromatography using a gradient from 10 - 40% MeOH (in CHCl 3 ) to give the title compound. Example 110 1-(3-Fluoro-5-trifluoromethylphenyl)-3-(3-dimethylaminopropyl) urea 15 (CFM2422) 4-Nitrophenyl chloroformate (84.0 mg, 4.19 mmol), 3-amino-5 fluorobenzotrifluoride (50.0 mg, 0.28 mmol) and triethylamine (42.0 mg, 4.19 mmol) were refluxed for 18 hours in anhydrous THF (20 mL) as in Example 100 to form the intermediate. Then 3-(dimethylamino)-propylamine (42.0 mg, 4.19 nmol) 20 was added and the mixture was refluxed for a further 5 hours to form the desired product. Work-up as in Example 100. The crude product was purified by flash chromatography using a gradient from 10 - 40% MeOH (in CHC1 3 ) to give the title compound. 25 Example 111 1-(3-N-tert-butoxycarbonyl-benzylamino)-3-(3-dimethylaminopropyl) urea CFM2374 4-Nitrophenyl chloroformate (3.13 g, 15.54 mmol), 3-amino-1-(N-tert-butoxy carbonyl)benzylamine (2.30 g, 10.36 mmol) and triethylamine (1.56 g, 15.54 mmol) 30 was refluxed for 18 hours in anhydrous THF (100 mL) as in Example 100 to form the intermediate. Then 3-(dimethylamino)propylamine (1.58 g, 15.54 mmol) was WO 01/32604 PCT/GBOO/04249 -55 added and the mixture was refluxed for a further 5 hours to form the desired product. Work-up same as in Example 100. The crude product was purified by flash chromatography using a gradient from 10 - 40% MeOH (in CHC1 3 ) to give the title compound. 5 Example 112 N-(3-Dimethylamino-propyl)- 2 -[1-(4-fluorobenzoyl]-benzamide (CFM2262) 2-(4-Fluorobenzoyl)benzoic acid (1.25 g, 5.12 mmol), NN-(diisopropyl)amino methylpolystyrene resin (PS-DIEA), (4.30 g, 15.36 mmol), and 0-(7-azabenzotriazol-1 yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU) (1.95 g, 5.12 mmol) 10 was stirred in anhydrous acetonitrile (50 mL) at room temperature under nitrogen for 5 minutes. Then 3-(dimethylamino)propylamine (0.52 g, 5.12 mmol) was added and the temperature was taken up to 50 *C and the mixture was left to stir at this temperature for 18 hours. The mixture was allowed to cool and tetrafluorophthalic anhydride (3.40 g, 15.36 mmol) was added and the mixture was allowed to stir for 5 hours. To the mixture 15 was added water (5 mL) and the solvent was removed on a vacuum concentrator. The crude product was purified by flash chromatography using a gradient from 5 to 10% MeOH (in CHCl 3 ) and the title compound was isolated as a white solid 0.36 g, 22 % yield (mp 84 - 85 *C). 20 Example 113 2-[1-(4-Chlorobenzoyl]-N-(3-dimethylamino-propyl)-benzamide (CFM 2269) 2-(4-Chlorobenzoyl)-benzoic acid (1.25 g, 4.80 mmol), N,N-(diisopropyl)amino methylpolystyrene resin (PS-DIEA), (4.00 g, 14.38 mmol), and 0-(7 azabenzotriazol- 1 -yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU) 25 (1.82 g, 4.80 mmol) was stirred in anhydrous acetonitrile (50 mL) at room temperature under nitrogen for 5 minutes. Then 3-(dimethylamino)propylamine (0.50 g, 4.80 mmol) was added and the temperature was taken up to 50 *C and the mixture was left to stir at this temperature for 18 hours. The mixture was allowed to cool and tetrafluorophthalic anhydride (3.20 g, 14.40 mmol) was added and the 30 mixture was left to stir for 5 hours. The workup and purification was the same as WO 01/32604 PCT/GBOO/04249 -56 described in Example 112. The title compound was isolated as a white solid 0.68g, 41 % yield (mp 108-110 C). Example 114 5 5-(4-Chloro-phenyl)-1-phenyl-1H-pyrazole-3-carboxylic acid (3-dimethylamino propyl)-amide (CFM2404) 5-(4-Chlorophenyl)-1-phenyl-lH-pyrazole-3-carboxylic acid (1.10 g, 4.09 mmol), N,N-(diisopropyl)amino-methylpolystyrene resin (PS-DIEA), (3.40g, 12.27 mmol), and 0-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate 10 (HATU) (1.56 g, 4.09 mmol) was stirred in anhydrous acetonitrile (50 mL) at room temperature under nitrogen for 5 minutes. Then 3-(dimethylamino)propylamine (0.42 g, 4.09 mmol) was added and the temperature was taken up to 50 IC and the mixture was left to stir at this temperature for 18 hours. The mixture was allowed to cool and tetrafluorophthalic anhydride (2.70 g, 12.27 mmol) was added and the 15 mixture was allowed to stir for 5 hours. The workup and purification was the same as described in Example 112. The title compound was isolated as a white solid 0.62g, 44 % yield (mp 165 *C). Example 115 20 5-Chloro-3-phenyl-1H-indole-2-carboxylic acid (3-dimethylamino-propyl) amide (CFM2408) 5-Chloro-3-phenyl-1H-indole-2-carboxylic acid (1.00 g, 3.68 mmol), NN (diisopropyl)amino-methylpolystyrene resin (PS-DIEA), (3.00 g, 11.04 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate 25 (HATU) (1.49 g, 3.68 mmol) was stirred in anhydrous acetonitrile (50 mL) at room temperature under nitrogen for 5 minutes. Then 3-(dimethylamino)propylamine (0.38 g, 3.68 mmol) was added and the temperature was taken up to 50 *C and the mixture was left to stir at this temperature for 18 hours. The mixture was allowed to cool and tetrafluorophthalic anhydride (2.43 g, 11.00 mmol) was added and the 30 mixture was allowed to stir for 5 hours. The workup and purification was the same WO 01/32604 PCT/GBOO/04249 -57 as described in Example 112. The title compound was isolated as a white solid 0.24 g, 18.5 % yield (mp 143-144 *C). Example 116 5 N-(3-Dimethylamino-propyl)-2-(2-phenylsulfamoyl-phenysulfanyl) benzamide(CFM2349) 2-(2-Phenylsulfamoyl-phenylsulfanyl)-benzoic acid (1.10 g, 2.60 mmol), NN (diisopropyl)amino-methylpolystyrene resin (PS-DIEA), (2.18g, 7.78 mmol), and 0 (7-azabenzotriazol- 1 -yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU) 10 (0.98 g, 2.6 mmol) was stirred in anhydrous acetonitrile (50 mL) at room temperature under nitrogen for 5 minutes. Then 3-(dimethylamino)propylamine (0.26 g, 2.60 mmol) was added and the temperature was taken up to 50 *C and the mixture was left to stir at this temperature for 18 hours. The mixture was allowed to cool and tetrafluorophthalic anhydride (1.70 g, 7.78 mmol) was added and the mixture was 15 allowed to stir for 5 hours. The workup and purification was the same as described in Example 112. The title compound was isolated as a white solid (0.1 g, 9 %), (mp 75-76 *C). Example 117 20 2-Benzylsulfanyl-N-(3-dimethylamino-propyl)-benzamide (CFM2351) 2-Benzylsulfanyl-benzoic acid (1.00 g, 4.09 mmol), NN-(diisopropyl)amino methylpolystyrene resin (PS-DIEA), (3.40 g, 12.27 mmol), and 0-(7 azabenzotriazol- 1 -yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU) (1.55 g, 4.09 mmol) was stirred in anhydrous acetonitrile (50 mL) at room 25 temperature under nitrogen for 5 minutes. Then 3-(dimethylamino)propylamine (0.42 g, 4.09 mmol) was added and the temperature was taken up to 50 *C and the mixture was left to stir at this temperature for 18 hours. The mixture was allowed to cool and tetrafluorophthalic anhydride (2.60 g, 12.27 mmol) was added and the mixture was allowed to stir for 5 hours. The workup and purification was the same WO 01/32604 PCT/GBOO/04249 -58 as described in Example 112. The title compound was isolated as a white solid 0.41g, 30.5 % yield (mp 85-86 *C). Example 118 5 6,8-Di-tert-butyl-4-oxo-4H-chromene-2-carboxylic acid (3-dimethylamino propyl)-amide (CFM2339) 6,8-Di-tert-butyl-4-oxo-4H-chromene-2-carboxylic acid (1.00 g, 3.31 mmol), NN (diisopropyl)amino-methylpolystyrene resin (PS-DIEA), (2.78 g, 9.93 mmol), and 0-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate 10 (HATU) (1.25 g, 3.31 mmol) was stirred in anhydrous acetonitrile (50 mL) at room temperature under nitrogen for 5 minutes. Then 3-(dimethylamino)propylamine (0.34 g, 3.31 mmol) was added and the temperature was taken up to 50 *C and the mixture was left to stir at this temperature for 18 hours. The mixture was allowed to cool and tetrafluorophthalic anhydride (2.18 g, 9.93 mmol) was added and the 15 mixture was allowed to stir for 5 hours. The workup and purification was the same as described in Example 112. The title compound was isolated as a white solid (0.26g) in 20 % yield (mp 135-136 *C). Example 119 20 3-(4-Chloro-phenyl)-4-cyano-5-isobutylsulfanyl-thiophene-2-carboxylic acid (3 dimethylamino-propyl)-amide (CFM2346) 3-(4-Chlorophenyl)-4-cyano-5-isobutylsulfanyl-thiophene-2-carboxylic acid (1.00 g, 2.84 mmol), NN-(diisopropyl)amino-methylpolystyrene resin (PS-DIEA), (2.37 g, 8.53 mmol), and 0-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium 25 hexafluorophosphate (HATU) (1.08g, 2.84 mmol) was stirred in anhydrous acetonitrile (50 mL) at room temperature under nitrogen for 5 minutes. Then 3 (dimethylamino)propylamine (0.3 g, 2.84 mmol) was added and the temperature was taken up to 50 *C and the mixture was left to stir at this temperature for 18 hours. The mixture was allowed to cool and tetrafluorophthalic anhydride (1.87 g, 8.52 30 mmol) was added and the mixture was allowed to stir for 5 hours. The workup and WO 01/32604 PCT/GBOO/04249 -59 purification was the same as described in Example 112. The title compound was isolated as a white oil/solid 0.3 g, 24 % yield. Example 120 5 4-(4-Chloro-phenoxy)-N-(3-dimethylamino-propyl)-3-nitro-benzamide (CFM2347) 4--(4-Chlorophenoxy)-3-nitro-benzoic acid (1.00 g, 3.40 mmol), N, N (diisopropyl)amino-methylpolystyrene resin (PS-DIEA), (2.84 g, 10.20 mmol), and O-(7-azabenzotriazol- 1 -yl)-N,N,N,N-tetramethyluronium hexafluorophosphate 10 (HATU) (1.29 g, 3.40 mmol) was stirred in anhydrous acetonitrile (50 mL) at room temperature under nitrogen for 5 minutes. Then 3-(dimethylamino)propylamine (0.35 g, 3.40 mmol) was added and the temperature was taken up to 50 *C and the mixture was left to stir at this temperature for 18 hours. The mixture was allowed to cool and tetrafluorophthalic anhydride (2.24 g, 10.20 mmol) was added and the 15 mixture was allowed to stir for 5 hours. The workup and purification was the same as described in Example 112. The title compound was isolated as a yellow solid (0.6 g) in 46.5% yield (mp 165-167 'C. Example 121 20 N-(3-Dimethylamino-propyl)-4-(4-phenyl-thiazol-2-yl)-benzamide (CFM2405) 4-(4-Phenyl-thiazol-2-yl)-benzoic acid (1.38 g, 4.91 mmol), NN-(diisopropyl)amino methylpolystyrene resin (PS-DIEA), (3.84 g, 14.70 mmol), and 0-(7 azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU) (1.87 g, 4.91 mmol) was stirred in anhydrous acetonitrile (50 mL) at room 25 temperature under nitrogen for 5 minutes. Then 3-(dimethylamino)propylamine (0.50 g, 4.91 mmol) was added and the temperature was taken up to 50 *C and the mixture was left to stir at this temperature for 18 hours. The mixture was allowed to cool and tetrafluorophthalic anhydride (3.24 g, 14.70 mmol) was added and the mixture was allowed to stir for 5 hours. The workup and purification was the same 30 as described in Example 112. The title compound was isolated as a white solid (1.18 g) in 66% yield (mp 204-205 *C).

WO 01/32604 PCT/GBOO/04249 -60 Example 122 1-(3-Dimethylamino-propyl)-3-(2-phenoxyphenyl)-urea (CFM2260) 2-Phenoxybenzoic acid (1.50 g, 7.00 mmol) was stirred in anhydrous toluene (50 5 mL) at 50 *C under nitrogen. To this mixture was added triethylamine (0.71 g, 7.00 mmol) and the temperature was increased to 80 'C at which stage diphenylphosphorylazide (DPPA) (1.92 g, 7.00 mmol) was added and the mixture was left to stir at this temperature for 5 hours. After this period 3 (dimethylamino)propylamine (0.71 g, 7.00 mmol) was added and the mixture was 10 left to stir at 80 *C overnight under nitrogen. The solvent was removed on a vacuum concentrator The residue was taken up in chloroform (100 mL) and washed with 1M sodium hydroxide (2 x 50 mL). The organic fraction was washed with saturated sodium chloride solution and then dried (Na 2 S0 4 ). The solvent was removed on a vacuum concentrator. The crude product was purified by flash chromatography 15 using a gradient from 5 to 10% MeOH (in CHCl 3 ) and the title compound was isolated as a white solid (1.00 g ) in 46% yield (mp 126- 128 *C). Example 123 1-[4-(4-Chloro-phenylsulfanyl)-thiophen-3-yl]-3-(3-dimethylamino-propyl)-urea 20 (CFM2356) 4-(4-Chlorophenylsulfanyl)-thiophene-3-carboxylic acid (1.30 g, 4.80 mmol) was stirred in anhydrous toluene (50 mL) at 50 *C under nitrogen. To this mixture was added triethylamine (0.48 g, 4.80 mmol) and the temperature was increased to 80 'C at which stage diphenylphosphorylazide (DPPA) (1.32 g, 4.80 mmol) was added and 25 the mixture was left to stir at this temperature for 5 hours. After this period 3 (dimethylamino)propylamine (0.48 g, 4.80 mmol) was added and the mixture was left to stir at 80 'C overnight under nitrogen. The solvent was removed on a vacuum concentrator. The residue was taken up in chloroform (100 mL) and washed with 1M sodium hydroxide (2 x 50 mL). The organic fraction was washed with saturated 30 sodium chloride solution and then dried (Na 2 S0 4 ). The solvent was removed on a WO 01/32604 PCT/GBOO/04249 -61 vacuum concentrator. The crude product was purified by flash chromatography using a gradient from 5 to 10% MeOH (in CHCl3) and the title compound was isolated as a white solid (0.50 g ) in 28% yield (mp 125-126 *C). 5 Example 124 1-(3-Dimethylamino-propyl)-3-(2'-fluoro-biphenyl-4-yl)-urea (CFM2363) 2-Fluoro-biphenyl-4-carboxylic acid (1.00 g, 4.63 mmol) was stirred in anhydrous toluene (50 mL) at 50 *C under nitrogen. To this mixture was added triethylamine (0.47 g, 4.63 mmol) and the temperature was increased to 80 *C at which stage 10 diphenylphosphorylazide (DPPA) (1.27 g, 4.63 mmol) was added and the mixture was left to stir at this temperature for 5 hours. After this period 3 (dimethylamino)propylamine (0.48 g, 4.63 mmol) was added and the mixture was left to stir at 80 *C overnight under nitrogen. The solvent was removed on a vacuum concentrator. The residue was taken up in chloroform (100 mL) and washed with 15 1M sodium hydroxide (2 x 50 mL). The organic fraction was washed with saturated sodium chloride solution and then dried (Na 2

SO

4 ). The solvent was removed on a vacuum concentrator. The crude product was purified by flash chromatography using a gradient from 5 to 10% MeOH (in CHCl 3 ) and the title compound was isolated as a orange oil (0.50 g ) in 34% yield. 20 Physical data for some of the compounds synthesised in the Examples is given in Table 3.

WO 01/32604 PCT/GBOO/04249 -62 TABLE 3: Physical Data Example 1H NMR 8, CDC1 3 , 300 MHz MS mp yield 101 7.28 (d, 2H, J = 8.7 Hz), 7.17 (d, 2H, J= 9.0 Hz), (APCI) 302 73% 3.22 (q, 2H, J= 5.9 Hz), 2.31 (t, 2H, J= 6.2 Hz), [M+2H]* 2.12 (s, 6H), 1.58 (quintet, 2H, J= 6.2 Hz) 5 100 7.31 - 7.27 (m., 2H), 7.16 - 7.19 (m, 2H), 3.26 (q, (APCI) 328 69% 2H, J = 6.0 Hz), 2.52 (t, 2H, J = 6.4 Hz), 2.46 - [M+2H]* 2.44 (m, 4H), 1.72 - 1.68 (m, 4H), 1.64 (t, 2H, J = 6.2 Hz) 102 CD 3 OD 7.37 (d, 2H, J= 9.0 Hz), 7.29 (d, 2H, J= (FAB) 314 M* 85% 8.7 Hz), 3.41 (t, 2H, J = 6.4 Hz), 2.95 (s, 3H), 2.37 (t, 2H, J = 6.9 Hz), 2.29 (s, 6H), 1.81 (quintet, 2H, 1= 6.7 Hz) 103 8.31 (d, 1H, J= 2.26 Hz), 7.62, (t, 2H, J= 7.16 (FAB) 328 85% Hz), 7.41 (t, 2H, J= 6.41 Hz), 7.33 - 7.29 (m, [M+1H]* 1H), 7.25 (dd, 1H, J= 2.5 Hz, J= 8.5 Hz), 6.94 (d, 1H, J= 8.67 Hz), 3.92 (s, 3H), 3.40 (q, 2H, J = 5.9 Hz), 2.39 (q, 2H, J= 6.7 Hz), 2.18 (s, 6H), 1.74 - 1.65 (m, 2H) 104 9.86 (br s, 1H), 7.26 (d, 2H, J= 9.0 Hz), 7.12 (d, (FAB) 270 31% 2H, J= 9.0 Hz), 3.31 (t, 2H, J= 5.8 Hz), 2.83 (s, [M+1H] 3H), 2.32 (t, 2H, J= 5.8 Hz), 2.22 (s, 611), 1.69 (quintet, 2H, J= 5.8 Hz) 105 8.04 - 8.00 (m, 1H), 7.95 - 7.91 (m, 1H), 7.45 - (EI) 356 M* 26% 7.35 (m, 2H), 7.25 - 7.14 (m, 5H), 6.49 (br s, IH), 4.85 (s, 2H), 3.29 (m, 2H), 2.24 (t, 2H, J= 5.7 Hz), 1.81 (s, 6H), 1.54 (q, 2H, J= 5.7 Hz) 10 106 acetone-d 6 8.42 (d, IH, J= 4.9 Hz), 7.53 - 7.41 (APCI) 327 37% (mn, 5H), 7.16 (s, 1H), 7.06 (d, 1H, J= 5.3 Hz), [M+1H]* 5.48 (s, 2H), 3.68 (m, 2H), 3.04 (brs, 2H), 2.76 (s, 6H), 2.45 (s, 3H), 2.19 (m, 2H) 108 7.43 (d, 1H, J= 2.26 Hz), 7.31 - 7.15 (m, 7H), (APCI) 374 30% 6.72 (d, 11H, J= 9.05 Hz), 3.76 - 3.69 (m, 1H), [M+1H]* 3.32 (s, 3H), 3.33 - 3.30 (m, 1H), 2.60 - 2.40 (m, 2H), 2.19 (brs, 6H), 1.78 - 1.63 (m, 2H) 107 7.68 (s, 2H), 7.63 (s, 1H), 6.77 (br s, 1H), 3.35 - (APCI) 372 33% 3.31 (m, 2H), 3.28 (s, 311), 2.64 - 2.52 (m, 2H), [M+1H]* 2.23 (br s, 6H), 1.80 - 1.68 (m, 2H) 111 7.47 - 7.43 (m,2H), 7.35 (t, 1H, J= 7.9Hz), 7.06 (FAB) 351 83% (d, 1H, J= 7.53 Hz), 4.38 (d, 2H, J= 5.27 Hz), [M+1H]* 4.05 - 3.85 (br s, 3H), 3.50 - 3.40 (m, 2H), 2.80 (t, 2H, J= 6.6 Hz), 2.56 (s, 6H), 1.92 (t, 2H, J= 6.2 Hz), 1.59 (s, 9H) 109 8.36 (d, 1H, J= 8.67 Hz), 7.69 (s, 1H), 7.53 (d, (EI) 323 M* 24% 1H, J= 8.29 Hz), 3.08 (t, 2H, J= 7.73 Hz), 2.80 (s, 6H), 1.94 (2H, t, J= 7.35 Hz), 1.31 (t, 211, J= 7.16 Hz) 15 110 7.56 (br s, 1H), 7.51 (br s, 1H), 6.97 (br d, 1H, J (FAB) 308 35% = 8.29 Hz), 3.26 (t, 2H, J= 6.78 Hz), 2.62 (t, [M+1H]' 2H, J= 7.73 Hz), 2.44 (s, 6H), 1.79 (t, 2H, J 7.53 Hz) WO 01/32604 PCT/GBOO/04249 -63 112 7.81 (d, IH, J = 6.41 Hz), 7.64 - 7.52 (m, 2H), EI 328 [M]* 84- 44% 7.48 - 7.39 (m, 2H), 7.29 (d, 1H, J = 6.78 Hz), 85 0 C 7.10 (t, 2H, J= 8.86 Hz), 3.65 - 3.56 (m, 1H), 3.21 - 3.11(m, IH), 2.92 (t, 2H, J= 7.54 Hz), 2.69(s, 6H), 1.93 - 1.76 (m, 2H) 113 7.81 (d, 1H, J= 6.78 Hz), 7.63 - 7.52 (m, 2H), (APCI) 345 108- 41% 7.38 (s, 4H), 7.29 (d, 1H, J=6.78 Hz), 3.65 - 3.56 [M]* 1100C (quintet, 1H, J = 7.06 Hz), 3.20 - 3.10 (quintet, 1H, J = 7.06 Hz), 2.92 (t, 2H, J = 7.35 Hz), 2.68 (s, 6H), 1.93 - 1.77 (m, 2H) 114 7.45 - 7.43 (m, 3H), 7.37 - 7.32 (m, 3H), 7.23 (d, (APCI) 383 M' 1650C 44% 2H, J= 8.67, Hz), 7.02 (s, 1H), 3.50 (t, 2H, J= 6.40 Hz), 3.20 (t, 2H, J= 7.73, Hz), 2.91 (s, 6H), 2.08 - 1.99 (quintet, 2H, J= 7.25 Hz) 115 7.57 - 7.38 (m, 7H), 7.22 (dd, 1H, J= 8.67 Hz, J (FAB) 356 143- 18.5 = 1.89 Hz), 3.29 (t, 2H, J= 6.78 Hz), 2.19 (t, 2H, [M]* 144 C % J= 7.53 Hz), 2.16 (s, 6H), 1.60 (quintet, 2H, J= 7.25 Hz) 5 116 8.02 (dd, IH, J= 7.73 Hz, J= 1.7 Hz), 7.50 (dd, (APCI) 470 75- 9% 1H, J= 7.54 Hz, J= 1.51 Hz), 7.41 - 7.11 (m, [M]* 760C 9H), 7.01 (t, 2H, J = 6.97 Hz), 3.36 (t, 2H, J = 6.78 Hz), 2.42 (t, 2H, J = 7.91 Hz), 2.21 (s, 6H), 1.74 (quintet, 2H, J= 7.25 Hz) 117 7.43 - 7.20 (m, 9H), 4.16 (s, 2H), 3.36 (t, 2H, J= (APCI) 329 M' 85- 30.5 6.78 Hz), 2.45 (t, 2H, J = 7.73 Hz), 2.23 (s, 6H), 86 0 C % 1.79 (quintet, 2H, J= 7.35 Hz) 118 8.05 (d, 1H, J= 2.64 Hz), 7.89 (d, 1H, J= 2.26 (APCI) 387 135- 20% Hz), 7.88 (s, 1H), 3.47 (t, 2H, J= 6.78 Hz), 2.44 [M]* 1360C (t, 2H, J= 7.72 Hz), 2.27 (s, 6H), 1.84 (quintet, 2H, J = 7.34 Hz), 1.57 (s, 9H), 1.39 (s, 9H) 119 7.54 (d, 2H, J = 8.66 Hz), 7.45 (d, 2H, J = 8.67 (APCI) 436 24% Hz), 3.20 (t, 2H, J = 6.79 Hz), 3.07 (d, 2H, J = [M]* 7.15 Hz), 2.17 (s, 3H), 2..14 (t, 2H, J= 7.92 Hz), 2.05 - 1.92 (m, 1H), 1.56 (quintet, 2H, J= 7.44 Hz), 1.09 (d, 6H, J= 6.78 Hz) 120 (CDCl 3 ) 8.50 (d, 1H, J = 2.26 Hz), 8.08 (dd, J (APCI) 378 MP 46.5 = 8.66 Hz, J = 2.26 Hz), 7.31 (d, 2H, J= 9.04 tM]+ 165- % Hz), 6.96 (d, 2H, J= 8.66 Hz), 6.91 (s, 1H), 16700 3.56 (q, 2H, J= 5.91 Hz), 3.07 (t, 2H, J= 6.60 Hz), 2.79 (s, 6H), 2.11 (quintet, 2H, J= 6.03 Hz) 10 121 8.16 (d, 2H, J= 8.67 Hz), 8.04 (d, 2H, J= 7.16 (APCI) 366 mp 66% Hz ), 7.97 (d, 2H, J= 8.67 Hz), 7.90 (s, 1H), [M] 204 7.46 (t, 2H, J= 7.35 Hz), 7.37 (d, 1H, J= 7.53 2050C Hz), 3.50 (t, 2H, J= 6.78 Hz), 3.03 (t, 2H, J= 7.54 Hz), 2,77 (s, 6H), 2.00 (quintet, 2H, J= 7.07 Hz) 122 8.06 (dd, 1H, J= 8.11 Hz, J= 1.7 Hz), 7.34 (t, (FAB) 314 (M mp 44% 2H, J= 8.11 Hz), 7.12 - 7.05 (m, 2H), 6.98 - + H)* 126 6.91 (m, 3H), 6.82 (dd, 1H, J= 8.29 Hz, J = 1280C 1.51 Hz), 3.19 (t, 2H, J= 6.78 Hz), 2.26 (s, 6H), 1.73 - 1.63 (quintet, 2H, J = 7.25 Hz) WO 01/32604 PCT/GBOO/04249 -64 123 7.72 (d, 2H, J= 3.39 Hz), 7.57 (d, 2H, J= 3.76 (FAB) 370 M* mp 28% Hz), 7.24 (d, 2H, J= 8.66 Hz), 6.99 (d, 2H, J= 125 8.67 Hz), 3.16 (t, 2H, J= 6.59 Hz), 2.32 (t, 2H, 126 0 C J= 7.72 Hz), 2.22 (s, 6H), 1.64 (quintet, 2H, J= 7.25 Hz) 124 7.44 (bs, 4H), 7.31 - 7.11 (m, 4H), 3.25 (t, 2H, J (APCI) 316 35 = 6.78 Hz), 2.44 (t, 2H, J= 7.72 Hz), 2.29 (s, [M+1H] 4% 6H), 1.79 - 1.69 (quintet, 2H, J= 7.25 Hz) Activity Example 1 5 Compounds of the invention were assayed to determine their ability to activate sGC. The assay employed was an enzyme immunoassay to measure changes in cGMP. To perform the assay recombinant soluble Guanylate cyclase was added to 1.1 mg/mI IBMX, 2.6 mg/ml GTP, 667 nM DeaNO and the test compound (10 M). The mixture was then incubated at room temperature for 10 minutes. Compounds 10 were formulated in DMSO diluted in Tris HCI (pH 7.4) buffer and with a final DMSO concentration of <0.5%. To determine the amount of cGMP produced, the BiotrakTM cGMP enzyme immunoassay system commercially available from AmershamiM was used. The assay is based on the competition between unlabelled cGMP and a fixed 15 quantity of peroxidase labelled cGMP for a limited amount of cGMP specific antibody. The peroxidase ligand that is bound to the antibody is immobilised on precoated microtitre wells. The amount of labelled cGMP is determind using a one pot stabilised substrate. The concentration of unlabelled cGMP in a sample is determined by interpolation from a standard curve. 20 The results are shown in Tables 4 to 7. The results shown in Tables 6 and 7 relate to commercially available compounds. Activity Example 2 The ability of the compounds of the invention to inhibit platelet aggregation 25 was also determined. IC 5 0 values were measured as set out below. Materials WO 01/32604 PCT/GBOO/04249 -65 Prostacyclin (PGI 2 ; ICN Pharmaceuticals, Oxford) in Tris (0.05M, pH 9), Sodium citrate solution, Tyrodes solution without calcium (140mM NaCl; 3mM KCl; 12mM NaHCO 3 ; 0.4mM NaH 2

PO

4

.H

2 0; 2mM MgC1 2 .6H 2 0; 0.1% Glucose) contains 0.05M Hepes, pH7.4. Collagen (collagenreagent Horm, Nycomed 5 Arzneimittel GmbH, Munchen).

PGI

2 dissolved in Tris buffer (0.05M, pH9). Test compounds dissolved in DMSO (at 10mM) and subsequent dilutions made in Tyrodes; final assay concentration of DMSO did not exceed 0.1% (which is without effect on platelet reactivity). 10 Platelet Preparation Platelets prepared according to Vagas, J.R., Radomski, M. and Moncada, S. The use ofprostacyclin in the separation from plasma and washing of human 15 platelets. PROSTAGLANDINS 1982; 23:6:929-945. Briefly, fresh human blood was collected into tubes containing 1:9 sodium citrate (3.15%) and centrifuged immediately at 260g for 20 minutes to separate the red cells from the platelet rich plasma (PRP). The PRP was decanted and PGI 2 (0.3 g/ml) was added. The PRP was then centrifuged at 180g for 1Omins to sediment 20 the remaining red and white cells. The resulting PRP was decanted into new tubes,

PGI

2 (0.15p.ig/ml) added and centrifuged at 950 g for 10 mins to sediment the platelets. The resultant platelet poor plasma (PPP) was discarded and the platelet pellet was resuspended in an equal volume of Tyrodes buffer by gently pipetting up and down. The suspension was centrifuged at 870 g for 1 Omins at 4 *C. The 25 supernatant was discarded and the platelet pellet was resuspended in an equal volume of Tyrodes buffer as before. The platelets were counted (using a Coulter Counter model T540 (address)) and normalised to 250,000cells/g1 using Tyrodes. The resultant suspension was placed on ice for approximately 1 hour until use. 30 Platelet Assays WO 01/32604 PCT/GBOO/04249 -66 Platelet aggregation was monitored using either a Chrono-Log model 560-CA dual channel ormodel 570-4S four channel aggregometer (Chrono-Log Corp., Havertown, PA). Aggregation was analysed by using 0.5 mL aliquots of the platelet suspension at 37 *C using % light transmittance. 5 For each sample, baseline reading was established for a 3 min period, followed by addition of test compound or buffer. An EC 50 dose of collagen was added I min later and the response measured 3 min after addition of collagen. Data Analysis 10 The amplitude of each aggregatory response, normalised to the collagen control, was used to plot dose-response curves. The concentration of drug that inhibited collagen-induced platelet aggregation by 50% (IC,) was calculated from the dose-response curves. 15 The results are shown in Tables 4 to 7. The results shown in Tables 6 and 7 relate to commercially available compounds.

WO 01/32604 PCT/GBOO/04249 -67 Table 4

IC

50 for Inhibition of 1st Test cGMP Change with 1 M cpd (NO Platelet Aggregation Example Donor Present), % of DEANO response ( tM) 70 153.79 4 5 71 136.37 10+ 72 135.49 73 143.35 74 158.0 75 163.88 10+ 10 76 303.25 6 77 284.9 8 78 303.77 4 79 218.24 10+ 80 244.87 6.5 15 81 230.49 4.5 82 224.57 83 314.64 6 84 408.17 3.5 85 358.65 2 20 86 358.65 10+ 87 336.16 10+ 88 377.13 10+ 89 10+ 90 6 25 91 2.5 92 5 93 4 94 10+ 95 10+ 30 96 10+ 97 9.5 98 10+ 99 5 101 199.21 35 100 135.7 102 273.17 103 8 WO 01/32604 PCT/GBOO/04249 -68

IC

50 for Inhibition of 1st Test cGMP Change with 1 pM cpd (NO Platelet Aggregation Example Donor Present), % of DEANO response (pM) 104 10 105 181.53 106 137.91 108 129.29 5 107 125.26 111 476.39 10+ 109 7 110 10+ WO 01/32604 PCT/GBOO/04249 -69 Table 5

IC

5 0 for Inhibition 1st Test cGMP Change with 1mM cpd (NO of Platelet Example Donor Present), % of DEANO response Aggregation (pM) 1 93.33 3.5 5 2 145.84 6 3 132.77 10+ 4 184.86 7 5 134.99 5 6 131.66 8 10 7 178.03 8 125.15 2 12 128.76 13 169.14 14 166.45 15 9 153.88 10+ 10 157.53 6 11 174.75 6 15 201.95 6 16 282.88 6.5 20 17 173.64 6 18 201.95 10+ 19 209.14 10+ 20 459.96 5 21 250.98 10+ 25 22 186.32 23 225.46 24 249.76 25 142.96 26 299.44 1.5 30 27 338.6 6 28 144.71 29 256.76 3.5 30 201.33 31 353.4 1.5 WO 01/32604 PCT/GBOO/04249 -70

IC

50 for Inhibition 1st Test cGMP Change with 1mM cpd (NO of Platelet Example Donor Present), % of DEANO response Aggregation (ptM) 32 151.68 10+ 34 322.81 6 35 363.36 10+ 36 296.59 10+ 5 37 337.89 10+ 38 295.16 10+ 39 312.4 10+ 40 418.37 10+ 41 455.13 10+ 10 42 181.88 8 43 215.41 10+ 44 457.39 10+ 45 218.66 5 46 10+ 15 47 10+ 48 10+ 49 10+ 50 10+ 52 10+ 20 53 9 54 5 55 7 56 6.5 57 3 25 58 3 59 10+ 60 7.5 61 1.5 62 7 30 63 9.5 64 10+ 65 10+ 33 7 WO 01/32604 PCT/GBOO/04249 -71 Table 6 Compound 1st Test cGMP IC 50 for Change with 1 tM Inhibition of cpd (NO Donor Platelet Present), % of Aggregation DEANO response (gM) 1-(4-chlorobenzyl)-3-(2-N,N- 156.75 dimethylethylamido)-6-pyridone (CFMI882) 5 1-(2,6-dichlorobenzyl)-3-(3-N,N- 421.09 20 dimethylpropylamido)-6-pyridone (CFM1883) 1-(3-trifluoromethylbenzyl)-3-(2-N,N- 207.03 dimethylethylamido)-2-pyridone (CFM1884) 1-(2,6-dichlorobenzyl)-3-(2-N,N- 194.38 10 dimethylethylamido)-2-pyridone (CFM1885) 1-(3,4-dichlorobenzyl)-3-(N-[2,N,N- 204.61 dimethylaminoethylamido])-2-pyridone (CFM1886) 1-(2,6-dichlorobenzyl)-3-(N-[2-N,N- 154.78 15 dimethylaminoethylamido])-6-pyridone (CFM1887) 5-chloro-1-(3,4-dichlorobenzyl)-3-(2-N,N- 140.94 dimethylaminoethylamido)-6-pyridone (CFM1888) 20 5-chloro-3-(2-N,N-dimethylaminoethylamido)- 1- 135.6 (3 -trifluoromethylbenzyl)-6-pyridone (CFM1889) 5-chloro-1-(3,4-dichlorobenzyl)-3-N-(2-[N',N'- 202.02 dimethylaninoethylamido])-2-pyridone (CFM1890) 25 5-chloro- 1 -(4-chlorobenzyl)-3-N-(2-(N',N'- 170.53 dimethylamino)ethyl)amido-2-pyridone (CFM1891) 5-chloro- 1 -(3 -trifluoromethylbenzyl)-3 -N- 164.85 (2-(N',N'-dimethylamino)ethyl)amido-2-pyridone 30 (CFM1892) WO 01/32604 PCT/GBOO/04249 -72 Compound 1st Test cGMP IC 5 0 for Change with 1p [M Inhibition of cpd (NO Donor Platelet Present), % of Aggregation DEANO response (pM) 1-benzyl-5-chloro-3-N-(2-[N',N'-dimethylamino) 148.43 ethyl)carboxamido-6-pyridone (CFM1893) 5-chloro-1-(4-chlorobenzyl)-3-N-(2-[N',N'- 144.32 dimethylamino]ethyl)carboxamido-6-pyridone 5 (CFM1894) 4-(2,4-dichlorobenzoyl)pyrrole-2-N- 360.01 dimethylaminopropylcarboxamide (CFM1985) 4-[(N-[3-(N',N'-dimethylaminopropyl)] 334.25 10 carboxamido]-2-phenylthiazole (CFM1896) 10 4-(N-(3-N',N'-dimethylaminopropyl) 296.23 carboxamido)-2-(4-pyridinyl)thiazole (CFM1897) 2-[4-(N-[3-N',N'-dimethylaminopropyl] 269.18 1.5 carboxamido)phenyl-4-(3-trifluoromethylphenyl] thiazole (CF1898) 15 4-(4-chlorophenyl)-2-(4-[3-N',N'- 233.13 1.5 dimethylaminopropyl]carboxamido)phenyl) 1-(3,5-bis(trifluoromethyl)benzyl)-3-[N-(2- 149.33 dimethylaminoethyl)carboxamido]-2[1H] pyridone (CFM1900) 20 N-(3-dimethylaminopropyl)-4-(3-chloro-5- 191.9 trifluoromethyl-2-pyridyloxy)phenylsulfonamide (CFM1901) Ni-[3-(dimethylamino)propyl]-3-[3-chloro-5- 309.73 (trifluoromethyl)-2-pyridyl]propanamide 25 (CFM1902) 3-(N-(2-dimethylaminoethyl)carboxamido]-1- 169.35 (4-trifluoromethylbenzyl))-2[1H]-pyridone (CFM1905) 1-ethyl-3-(3-dimethylaminopropyl)urea 266.6 30 (CFM1917) WO 01/32604 PCT/GBOO/04249 -73 Compound 1st Test cGMP IC 50 for Change with 1 pIM Inhibition of cpd (NO Donor Platelet Present), % of Aggregation _____________________________DEANO response (VtM) 1-( 3 -(dimethylamino)-propyl)-3-phenylurea 281.16 (CFM1918)

NI-[

2 -(2,4-dichlorophenoxy)phenyl]-N2-[3- 207.01 (dimethylamino)propyl]ethanediamide 5 (CFM1935)

N

4 -[3-(dimethylamino)propyl]-3-(2,6- 142.14 dichlorophenyl)-5-methylisoxazole-4 carboxamide (CFM1936) N-[[3-(2,6-dichlorophenyl)-5-methylisoxazol-4 334.47 10 -yl]carbonyl]-N'-[3-(dimethylamino)propyl]urea (CFM1937) N-(4-chlorophenyl)-N'-[3-dimethylaminopropyl] 299.26 urea (CFM1938) WO 01/32604 PCT/GBOO/04249 -74 Table 7 1st Test cGMP Change with 1mM Compound cpd (NO Donor Present), % of DEANO response 5 N-( 3 ,5-Dichloro-phenyl)-3-(3-dimethylamino-propylamino)p 174.42 ropionamide [3-(2-Ethyl-6-methyl-pyridin-3-yloxy)-propyl]-dimethyl 188.03 -amine 8-(3-Dimethylamino-propoxy)-1,3,7-trimethyl-3,7-dihydro 191.65 10 -purine-2,6-dione 2

-(

3 -Dimethylamino-propylamino)-isophthalonitrile 213.04 Dimethylamino-(3-methyl-benzo[b]thiophen-2-yl)-propan-1 279.33 -one (HCl) N-Benzo[1,3]dioxol-5-ylmethyl-N,N-dimethyl-propane-1,3 184.90 15 -diamine N,N-Dimethyl-N-(5-nitro-quinolin-8-yl)-propane-1,3 219.03 -diamine 1-(4-Chloro-phenyl)-3-(3-dimethylamino-propyl)-urea 421.21 2 -Amino-N-(3-dimethylamino-propyl)-benzamide 363.98 20 3-Phenyl-acrylic acid 3-dimethylamino-propyl ester 298.89 3,5-Dinitro-benzoic acid 2-dimethylamino-ethyl ester 141.22 [4-(4-Bromo-phenyl)-3-(3-dimethylanino-propyl)-3H-thiazol 204.10 -2-ylidene]-phenyl-amine 3-Methyl-benzofuran-2-carboxylic acid dimethylamino 197.46 25 -dimethyl-propyl ester WO 01/32604 PCT/GBOO/04249 -75

N'-(

2 -Chloro-4-nitro-phenyl)-N,N-dimethyl-propane- 1,3 161.70 -diamine [3-( 3 -Dimethylamino-propyl)-5-(4-nitro-phenyl)-3H-thiazol 157.02

-

2 -ylidene]-phenyl-amine 5 [3-(10,11-Dihydro-dibenzo[a,d]cyclohepten-5-ylidene) 150.39 -propyl]-dimethyl-amine 2,3 -Dimethyl- 1 H-indole-5-carboxylic acid 2-dimethylamino 217.3 -ethyl ester N'-(3, 4 -Dinitro-5-pyridin-2-yl-thiophen-2-yl)-N,N-dimethyl 282.12 10 -propane-1,3-diamine Cyclooctyl-dithiocarbamic acid 2-dimethylamino-ethyl ester 185.31 (HCI)

N-(

2 ,6-Difluoro-phenyl)-C-dimethylamino-acetamide 168.99 2-Acetylamino-3-(4-chloro-phenyl)-N-(3-dimethylamino 142.31 15 -propyl)-acrylamide N-[2-[5-(4-Bromo-phenyl)-furan-2-yl]- 1 -(3-dimethylamino 163.49 -propylcarbamoyl)-vinyl]-4-methyl-benzamide 2,6-Bis-(3-dimethylamino-propylamino)-3-nitro-benzonitrile 167.75 N-[2-(2,4-Dichloro-phenoxy)-phenyl]-N'-(3-dimethylamino 328.31 20 -propyl)-oxalamide 3,5-Dichloro-N-(3-dimethylamino-propyl)-2,6-dimethoxy 193.93 -benzamide 2-Dimethylaminomethyl-3,4-dihydro-2H-naphthalen- 1 175.73 -one (HC) 25 2-({ 1 -[N-(3-Dimethylamino-propyl)-3-trifluoromethy 231.40 -phenyl]-methanimidoyl}-amino)-6-fluoro-benzoic acid WO 01/32604 PCT/GBOO/04249 -76 2,4-Dichloro-N-(3-dimethylamino-propyl)-N'-hydroxy 212.83 -benzamidine 3-(3-Methyl-ureido)-4-oxo-3,4-dihydro-quinazoline-2 305.22 -carboxylic acid (3-dimethylamino-propyl)-amide 5 5-Bromo-N-(3-dimethylamino-propyl)-2-hydroxy-benzamide 258.28 N-(2,4-Dichloro-phenyl)-6-(2-dimethylamino-ethylsulfanyl) 162.85 -4-trifluoromethyl-nicotinamide 1-(2,6-Dichloro-benzyl)-2-oxo-1,2-dihydro-pyridine-3 149.44 -carboxylic acid (2-dimethylamino-ethyl)-amide 10 3-Amino-4-oxo-3,4-dihydro-quinazoline-2-carboxylic acid 230.76 (3-dimethylamino-propyl)-amide 15 20 25

Claims (16)

1. Use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the activation of 5 soluble guanylate cyclase z P NRiR 2 wherein: 10 - R, and R 2 are the same or different and each represent a Ci-C 6 alkyl group, or R, and R 2 together form a C 3 -C 6 alkylene group; - Z is a C 1 -C 4 alkylene group; - P is a direct bond or a moiety -X-, -Y-, -W-, -XY-, -YW- or -XYW-, wherein: 15 - W is -0-, -S-, or -NR 3 , wherein R 3 is hydrogen or CI-C 6 alkyl; - Y is a moiety -U-V- wherein V is a direct bond or a C-C alkylene group and U is -CS-, -CO-, -S(O) 2 - or -C(=NR) wherein R is hydrogen, hydroxy or CI-C 6 alkyl; - X is -0- or -NR 6 - wherein R 6 is hydrogen, C 1 -C 6 alkyl, C 2 C 6 20 alkenyl, C 2 C 6 alkynyl, aryl or heteroaryl; and - R 4 is CI-C 6 alkyl, C 2 C 6 alkenyl, C 2 C 6 alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, a group -R-A wherein R is -(Ci-C 6 alkyl)-, -(C 2 C 6 alkenyl)- or -(C 2 C 6 alkynyl)- and A is aryl, heteroaryl, carbocycyl or heterocyclyl, or R 4 is a group -COR", -CO 2 R", -S(0) 2 R" 25 or -CONR'R" wherein R' is hydrogen, CI-C 6 alkyl, C 2 C 6 alkenyl or C 2 C 6 alkynyl and R" is is aryl, heteroaryl, carbocyclyl or heterocyclyl.

2. Use according to claim 1, wherein R, and/or R 2 are methyl. WO 01/32604 PCT/GBOO/04249 -78

3. Use according to claim I or 2, wherein Z is propylene.

4. Use according to any one of the preceding claims, wherein P is -XYW- or -YW-. 5

5. Use according to any one of the preceding claims, wherein W is -0- or -NR 3 wherein R 3 is as defined in claim 1.

6. Use according to any one of the preceding claims, wherein Y is -CO-. 10

7. Use according to any one, of the preceding claims wherein X is -NH-.

8. Use according to any one of the preceding claims wherein R 4 is CrC 6 alkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, -(C-C 6 alkyl)-aryl, -(C-C 6 alkyl) 15 heteroaryl or -COR", -CO 2 R" or -CONR'R" wherein R' is hydrogen or CrC6 alkyl and R" is an aryl, heteroaryl, carbocyclyl or heterocyclyl group.

9. Use according to any one of the preceding claims, wherein P is -XYW-, X is NH- and R 4 is phenyl, thienyl or pyrazolyl. 20

10. Use according to any one of claims I to 8, wherein P is -YW- and R 4 is a chromonyl, pyrazolyl, thienyl, phenyl or indolyl group.

11. Use according to claim 1, wherein the compound of formula (I) is 25 1-( 3 -Dimethylamino-propyl)-3-(2-phenoxy-phenyl)-urea 1-[2-(4-Chloro-phenoxy)-pyridin-3-yl]-3-(3-dimethylaminopropyl)-urea 1-(3-Dimethylamino-propyi)-3-pyren-1-ylmethyl-urea 1-(3-Dimethylamino-propyl)-3-[(1R,2R)-5-phenyl-2-(I-phenyl-methanoyl) cyclohexyl]-urea WO 01/32604 PCT/GBOO/04249 -79 1-(3-Dimethylamino-propyl)-3-[2-(4-phenoxy-phenyl)-ethyl]-urea 1-(3-Dimethylamino-propyl)-3-[3-methyl-5-(4-methyl-[1,2,3]thiadiazol-5 yl)- 1 -(4-trifluoromethoxy-phenyl)- 1H-pyrazol-4-yl]-urea 2'-[3-( 3 -Dimethylamino-propyl)-ureido]-biphenyl-2-carboxylic acid (4 5 fluoro-phenyl)-amide N-(3-Chloro-4-methyl-phenyl)-4-[3-(3-dimethylamino-propyl)-ureido]-3 phenyl-butyramide 1-[4-(4-Chloro-phenylsulfanyl)-thiophen-3-yl]-3-(3-dimethylamino-propyl) urea 10 1-[ 2 -( 3 , 4 -Dimethoxy-phenyl)-6-methyl-quinolin-4-yl]-3-(4-dimethylamino propyl)-urea 1-(6-Bromo-2-thiophen-3-yl-quinolin-4-yl)-3-( 3 -dimethylamino-propyl)-urea 1-[3-( 4 -Chloro-phenyl)-4-cyano-5-isobutylsulfanyl-thiophen-2-yl]-3-(3 dimethylamino-propyl)-urea 15 1-[ 6 -(2,4-Dichloro-phenyl)-cyclohex-3-enyl]-3-(3-dimethylamino-propyl) urea 1-(2-Benzylsulfanyl-phenyl)-3-(3-dimethylamino-propyl)-urea 2-{2-[3-(3-Dimethylamino-propyl)-ureido]-phenylsulfanyl}-N-phenyl benzenesulfonamide 20 1-(3-Dimethylamino-propyl)-3-( 2 '-fluoro-biphenyl-4-yl)-urea N-(3,5-Dichloro-phenyl)-2-{3-[3-(3-dimethylamino-propyl)-ureido]-pyridin 2-ylsulfanyl}-acetamide 1-(3-Dimethylamino-propyl)-3-{2-[1-(1-trifluoromethyl-1,3,4,9-tetrahydro-b carbolin-2-yl)-methanoyl]-phenyl } -urea 25 8- { 2 -[3-(3-Dimethylamino-propyl)-ureido]-phenylsulfanyl} -naphthalene- 1 carboxylic acid methylamide 1-[1-(3,4-Dichloro-benzyl)-6-oxo-1,6-dihydro-pyridin-3-yl]-3-(3 dimethylamino-propyl)-urea 1-(3 -Dimethylamino-propyl)-3 -(3 -oxo- 1,2,3 -triphenyl-propyl)-urea WO 01/32604 PCT/GBOO/04249 -80 1-[5-(4-Chloro-phenyl)- 1 -(3,4-dichloro-phenyl)- 1H-pyrazol-3-yl]- 3 -( 3 dimethylamino-propyl)-urea 1- {4-[4-(4-Chloro-phenyl)-thiazol-2-yl]-phenyl} -3-(3-dimethylamino propyl)-urea 5 1-(3-Dimethylamino-propyl)-3-[5-(4-fluoro-phenyl)-thiophen-2-yl]-urea 1-[3-(4-tert-Butyl-benzyloxy)-thiophen-2-yl]-3-(3-dimethylamino-propyl) urea 1-(3-Dimethylamino-propyl)-3-[4-(4-phenyl-thiazol-2-yl)-phenyl]-urea 1-[3-(3,4-Dichloro-benzylsulfanyl)-thiophen-2-yl]-3-(3-dimethylamino 10 propyl)-urea 1-[2-(5-Chloro-1-methyl-3-phenyl-IH-pyrazol-4-ylmethylsulfanyl)-phenyl] 3-(3-dimethylamino-propyl)-urea 1-[2-(4-Chloro-benzylsulfanyl)-3-methyl-4-oxo-3,4-dihydro-quinazolin-7-yl] 3-(3-dimethylamino-propyl)-urea 15 1-(3-Dimethylamino-propyl)- 3 - {4-[4-(4-methoxy-phenyl)-pyrimidin-2 ylsulfanylmethyl] -phenyl} -urea 1-(4-Bromophenyl)-3-(3-(1-pyrrolidinyl) propyl) urea 1-(4-Bromophenyl)-3-(3-dimethylamino propyl) urea 3-(4-Bromophenyl)-1-methyl-1-(3-dimethylamino propyl) urea 20 1-(3-Phenyl-5-methoxy phenyl)-3-(3-dimethylamino propyl) urea 3-(4-Chlorophenyl)-1-methyl-1-(3-dimethylamino propyl) urea 1-(3-Nitrophenyl)-1-benzyl-3-(3-dimethylamino propyl) urea 1-Benzyl-1-(4-methyl-3-pyridinyl)-3-(3-dimethylamino propyl) urea 1-Methyl-1-(3,5-bistrifluoromethylphenyl)-3-(3-dimethylaminopropyl)urea 25 1-(2-Phenacyl-4-chorophenyl)-1-methyl-3-(3-dimethylamino propyl) urea 1-(2-Chloro-4-trifluoromethylphenyl)-3-(3-dimethylaminopropyl) urea 1-(3-Fluoro-5-trifluoromethylphenyl)-3-(3-dimethylaminopropyl) urea 1-(3-N-tert-butoxycarbonyl-benzylamfino)- 3 -( 3 -dimethylaminopropyl) urea N-(3-Dimethylamino-propyl)-2-[1-(4-fluorobenzoyl]-benzamide WO 01/32604 PCTIGBOOIO4249 -81 2- [1-(4-Chlorobenzoyl]-N-(3-dimethylamino-propyl)-benzamide 5-(4-Chloro-phenyl)-l1-phenyl- 1H-pyrazole-3-carboxylic acid (3 dimethylamino-propyl)-amnide 5-Chloro-3 -phenyl- 1H-indole-2-carboxylic acid (3-dimethylamino-propyl) 5 amide N-(3 -Dimethylamino-propy)-2-(2-phenysufamoy1-phellsulfanyl) benzamnide 2-Benzylsulfanyl-N-(3 -dimethylamino-propyl)-benzamide 6,8-Di-tert-buty-4-oxo-4H-chromele-2-carboxylic acid (3-dimethylamino 10 -propyl)-amide 3-4Clr-hnl--yn--sbtlufnltipee2croyi acid (3-dimethylamino-propyl)-amide 4-(4-Chloro-phenoxy)-N-(3 -dimethylamino-propyl)-3-nitro-beflzamide N-(3 -Dimethylamino-propy)-4-(4-phel-thiazo1-2-y)-belzamide 15 1.(3-Dimethylamino-propyl)-3-(2-pheoxyphelyl)-urea 1 -[4-(4-Chloro-phenylsulfanyl)-thiophel-3-y1]-3 -(3 -dimethylamino-propyl) -urea 1 -(3 -Dimethylamino-propyl)-3-(2'-fluoro-biphel- 4 -yl)-urea N-(3 -Dimethylaxmno-propyl)-2- [1-(4-fluorobenzoyl]-benzamide 20 N-(3 -Dimethylamino-propyl)- 3 -phenoxy-benzamide N-(3 -Dimethylamino-propy1)-2-phenoxy-beflzamide 2-(4-Chloro-phenoxy)-N-(3-dimethyamTiflo-propy1)-flicotifamide 4 '-n-Propyl-biphenyl-4-carboxylic acid (3 -dimethylamino-propyl)-amide 2-[ 1-(4-Bromo-phenyl)-methanoyl]-cyclohexalecarboxylic acid (3 25 dimethylamino-propyl)-amide 5 -(3 -Trifluoromethyl-phenyl)-furan-2-carboxylic acid (3-dimethylamino propyl)-amide 2-[ 1 (4-Chlorobenzoy1]-N-(3-dimethylamino-propy)-belzamTide 2-Phenyl-quinoline-4-carboxylic acid (3-dimethylamino-propyl)-amide WO 01/32604 PCTGBOOIO4249 -82 2-[ 1-(4-Chloro-3 -nitrobenzoyl)] -N-(3 -dimethylamino-propyl)-benzamide N-(3 -Dimethylamino-propyl)-2-pyrel- 1 -yl-acetamide N-(3 -Dimethylamino-propyl)-2-[ 1-(3-methyl-benzo [b]thiophen-2-yl) methanoyl]-benzamide 5 4-Chloro-N-(3-dimethylamino-propyl)-2-pheloxy-beflzamide N-(3 -Dimethylamino-propy)-3-(4-pheloxy-phel)-propiofl3.fde N-(3 -Dimethylamino-propyl)- 2 -[ 1 -(1 -trifluoromethyl- 1,3 ,4,9-tetrahydro-b carbolin-2-yl)-methanoyl-belzamlide 1 -(4-Chloro-phenyl)-2, 5-dimethyl-lI-pyrrole-3 -carboxylic acid (3 10 dimethylamino-propyl)-amide 2- {1- [(3-Dimethylamino-propycarbamoy)-methyl-cyclopeltyl}-N-(4 trifluoromethoxy-phenyl)-acetamide 8 -[2-(3 -Dimethylamino-propycarbamoyl)-phelsulfanlF-naphthalene- 1 carboxylic acid methylamide 15 3-Methyl-5 -(4-methyl-[ 1,2,3]thiadiazol-5-yl)-l1-(4-trifluoromethoxy-phenyl) IH-pyrazole-4-carboxylic acid (3 -dimethylamino-propyl)-amide 6,8-itr-uy -x-H-hoee2croyi acid (3 -dimethylamino propyl)-amide 2-(Furan-2-yl)-quinoline-4-carboxylic acid (3-dimethylamino-propyl)-amide 20 Biphenyl-2 ,2 '-dicarboxylic acid 2 '-[(3-dimethylamino-propyl)-amide]- 2 -[( 4 fluoro-phenyl)-amide] 3-Phenyl-pentanedioic acid (3-chloro-4-methyl-phenyl)-amide (3 dimethylamnino-propyl)-amide 2-34Dmtoypey)6mehlqioie4croyi acid (3 25 dimethylamino-propyl)-amnide 6-rm-2tipe--l)qioie4croyi acid (3-dimethylamino propyl)-amide 3-4Clr-hnl--yn--sbtlufnltipee2croyi acid (3 -dimethylamnino-propyl)-amide WO 01/32604 PCTGBOOIO4249 -83 4-(4-Chloro-phenoxy)-N-(3-dimethylaio-propy1)-3 -nitro-benzamide 6-(2,4-Dichloro-phenyl)-cyclohex-3-ene carboxylic acid (3 -dimethylamino propyl)-amide N-(3 -Dimethylamino-propy)-2-(2-phelsufamoy1-phellsulfalyl) 5 benzamide 2'-Fluoro-[ 1,1'-biphenylll-4-carboxylic acid (3 -dimethylamino-propyl)-amide 2-Benzylsulfanyl-N-(3-dimethylarlilo-propy1>-belzamide Pyrazine-2,3-dicarboxylic acid 2-[(3-dimethylamino-propyl)-amidel 3 [(5,6,7,8-tetrahydro-naphthalen- 1-yl)-amnide] 10 2-[(3 ,5-Dichloro-phenylcarbamoyl)-methylsulfalI-N-( 3 -dimethylamino propyl)-nicotinamide 2-(3-Trifluoromethy-pheny)-thiazole-4-carboxylic acid (3-dimnethylamnino propyl)-amide 2-(4-Chloro-phenyl)-thiazole-4-carboxylic acid (3-dimethylamino-propyl) 15 amide 5 -Chioro-l1-(2,4-dichloro-benzyl)-6-oxo- 1,6-dihydro-pyridine-3.-carboxylic acid (3-dimethylamino-propyl)-amnide 1 -(2,4-Dichloro-benzyl)-6-oxo- 1,6-dihydro-pyridine-3-carboxylic acid (3 dimethylamino-propyl)-amnide 20 5 -Chioro-l1-(3 ,4-dichloro-benzyl)-6-oxo- 1,6-dihydro-pyridine-3 -carboxylic acid (3-dimethylamino-propyl)-amnide 1 -(3 ,4-Dichloro-benzyl)-6-oxo- 1,6-dihydro-pyridine-3 -carboxylic acid (3 dimethylamino-propyl)-amide 5-Chioro-l1-(2,6-dichloro-benzyl)-6-oxo- 1,6-dihydro-pyridine-3-carboxylic 25 acid (3-dimethylamino-propyl)-amide 1,1 -Dimethyl-indan-4-carboxylic acid (3 -dimethylamino-propyl)-amide N-(3 -Dimethylamnino-propyl)- 2 -[ 1 (4-ethy1-pheny1)-methanoy1Ij-beflzamide N-(3-Dimethylamino-propyl)-3 -(2 ,4,5-trimethyl-phenyl)-butyramide 2- [3-(3 ,4-Dichloro-phenyl)-ureido]-N-(3 -dimethylamnino-propyl)-benzamide WO 01/32604 PCTIGBOOIO4249 -84 N-(3-Dimethylamino-propyl)- 4 -oxo- 2 , 3 ,4-triphenyl-butyramnide 5 -(4-Chloro-phenylsulfanyl)-[ 1,2,3 ]thiadiazole-4-carboxylic acid (3 dimethylamino-propyl)-amide 2-(3-Chloro-5-trifluoromethy-pyn'dil-2-y1sulfal} 3 -methyl-3H-imidazole 5 4-carboxylic acid (3-dimethylamino-propyl)-alcide 2-(2-Chloro-4-trifluoromethyl-pheflyl)-[ 1,3 ]-thiazole-4-carboxylic acid (3 dimethylamino-propyl)-amide 2-(2,3 -Dihydro-l1-benzofuran-5 -yl)-l ,3-thiazole-4-carboxylic acid (3 dimethylamino-propyl)-amide 10 2-(2,3 -Dichioro-phenyl)-1I,3-thiazole-4-carboxylic acid (3-dimethylamino propyl)-amide 4-[4-(4-Chloro-pheny)-thiazol-2-y1F-N(3 -dimethylamino-propyl)-benzamide 5-(4-Fluoro-pheny1)-thiophefle-2-carboxylic acid (3-dimethylamino-propyl) amide 15 4-ehl2(-rfurmty-hnl-haoe5croyi acid (3 dimethylamino-propyl)-amide 3-(4-tert-Buty1-benzyloxy)-thiophele-2-carboxylic acid (3-dimethylamino propyl)-amide 4-Oxo-3 -(3-trifluoromethyl-phenyl)-3 ,4-dihydro-phthalazine-l1-carboxylic 20 acid (3-dimethylamino-propyl)-almde 2-(4-Chloro-phenyl)-N-(3 -dimethylamino-propyl)-4-oxo-4-phelyl butyramide 5 -(4-Chioro-phenyl)-l1-phenyl- 1H-pyrazole-3 -carboxylic acid (3 dimethylamino-propyl)-ariTde 25 N-(3 -Dimethylamnino-propy1)-4-(4-phel-thiazoI-2-y1>-beflzamide I -(2,4,5-Trichloro-phenylsulfony)-pyrrolidifle-2-carboxylic acid (3 dimethylamino-propyl)-armde 3 -(3 ,4-Dichloro-benzylsulfany1)-thIOPhefle-2-carboxylic acid (3 dimethylamino-propyl)-amnide WO 01/32604 PCT/GBOO/04249 -85 5-Chloro-3-phenyl-1H-indole-2-carboxylic acid (3-dimethylamino-propyl) amide N-(3-Dimethylamino-propyl)- 2 -[1-(4-fluoro-benzyl)-1H-indol-3-yl] acetamide 5 2-Phenyl-imidazo[1,2-a]pyridine-3-carboxylic acid (3-dimethylamino propyl)-amide N-(3-Dimethylamino-propyl)-2-(7-ethyl- 1H-indol-3-yl)-4-oxo-4-phenyl butyramide Phenyl-trifluoromethyl-thieno[ 3 ,2-b]pyridine-2-carboxylic acid (3 10 dimethylamino-propyl)-amide 3-(4-Nitro-3-trifluoromethyl-phenoxy)-thiophene-2-carboxylic acid (3 dimethylamino-propyl)-amide 2-(5-Chloro-1-methyl-3-phenyl-1H-pyrazol-4-ylmethylsulfanyl)-N-( 3 dimethylamino-propyl)-benzamide 15 2-(4-Chloro-benzylsulfanyl)-3-methyl- 4 -oxo- 3 ,4-dihydro-quinazoline-7 -carboxylic acid (3-dimethylamino-propyl)-amide N-(3-Dimethylamino-propyl)-4-[4-(4-methoxy-phenyl)-pyrimidin-2 -ylsulfanylmethyl]-benzamide 1-(4-chlorobenzyl)-3-(2-N,N-dimethylethylamido)-6-pyridone 20 1-(2,6-dichlorobenzyl)-3-(3-N,N-dimethylpropylamido)-6-pyridone 1-(3-trifluoromethylbenzyl)-3-(2-N,N-dimethylethylamido)-2-pyridone 1-(2,6-dichlorobenzyl)-3-(2-N,N-dimethylethylamido)-2-pyridone 1-(3,4-dichlorobenzyl)-3-(N-[2,N,N-dimethylaminoethylamido])-2-pyridone 1-(2,6-dichlorobenzyl)-3-(N-[2-N,N-dimethylaminoethylamido])-6-pyridone 25 5-chloro-1-(3,4-dichlorobenzyl)-3-(2-N,N-dimethylaminoethylamido)-6 -pyridone 5-chloro-3-(2-N,N-dimethylaminoethylamido)-1-(3-trifluoromethylbenzyl)-6 pyridone WO 01/32604 PCTIGBOOIO4249 -86 5 -chioro- 1 -(3 ,4-dichlorobenzy1)-3-N-(2-[N',N'-dimethylamTifloethyiamido]- 2 pyridone 5 -chioro- 1 -(4-chlorobenzyl)-3-N-(2-(N',N'-dimethylaflllfo)ethyl)aimido- 2 pyridone 5 5 -chioro- 1 -(3 -trifluoromethylbenzyl)-3 -N-(2-(N',N'-dimethylamino)ethyl) amnido-2-pyridone I -benzyl-5 -chioro-3 -N-(2-[N',N'-dimethylamnino] ethyl)carboxamido-6 pyridone 5 -chioro-l1-(4-chlorobenzyl)-3 -N-(2- [N',N'-dimethylamino] ethyl)carboxamido 10 -6-pyridone 4-24dclrbnolproe2Ndmtyaiorplabxmd 4-[(N-[3 -(TNIdimethylaminopropyi)]carboxamido-2-pheflylthiazole 4-N(-'N-iehlmnpoy~aroaio--4prdnltizl 2-[4-(N-[3 -N',N'-dimethylaminopropyI1carboxamido)phefll 4 15 (3 -trifluoromethylphenyl)]thiazole 4-(4-chlorophenyl)-2-(4-[3 -N',N'-dimethylaminopropyi]carboxamido)phelyl) thiazole 1 -(3,5 -bis(trifluoromethyl)benzyl)-3 -[N-(2-dimethylaminoethyl) carboxamidol-2[1 H]-pyridone 20 N-3dmtyaiorpl--3clr--rfurmty--yiyoy phenylsulfonamide Ni -[3-(dimethylamnino)propyl] -3- [3-chloro-5-(trifluoromethyl)-2-pyridylI propanamide 3-(N-(2-dimethylainoethy)carboxamhdoI1-(4-trifluoromethylbenzyl))- 2 25 [1H]-pyridone 1 -ethyl-3-(3-dimethyaminopropy1)urea 1 -(3 -(dimethylamino)-propyl)- 3 -phenyiurea Ni -[2-(2,4-dichlorophenoxy)phenyll-N2-[3 -(dimethylamino)propyl] ethanediamide WO 01/32604 PCT/GBOO/04249 -87 N4-[3-(dimethylamino)propyl]- 3 -(2,6-dichlorophenyl)-5-methylisoxazole- 4 -c arboxamide N-[[3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl]carbonyll-N'-[3-(dimethyla mino)propyl]urea 5 N-(4-chlorophenyl)-N'-[3-dimethylaminopropyl]urea N-(3,5-Dichloro-phenyl)-3-(3-dimethylamino-propylamino)-propionamide [3-(2-Ethyl-6-methyl-pyridin-3-yloxy)-propyl]-dimethyl-amine 8-(3-Dimethylamino-propoxy)-1,3,7-trimethyl-3,7-dihydro-purine-2,6-dione 2-(3-Dimethylamino-propylamino)-isophthalonitrile 10 Dimethylamino-(3-methyl-benzo[b]thiophen-2-yl)-propan-1-one (HCl) N-Benzo[1,3]dioxol-5-ylmethyl-N,N-dimethyl-propane-1,3-diamine N,N-Dimethyl-N-(5-nitro-quinolin-8-yl)-propane-1,3-diamine 1-(4-Chloro-phenyl)-3-(3-dimethylamino-propyl)-urea 2-Amino-N-(3-dimethylamino-propyl)-benzamide 15 3-Phenyl-acrylic acid 3-dimethylamino-propyl ester 3,5-Dinitro-benzoic acid 2-dimethylamino-ethyl ester [4-(4-Bromo-phenyl)-3-(3-dimethylamino-propyl)-3H-thiazol-2-ylidene] phenyl-amine 3-Methyl-benzofuran-2-carboxylic acid dimethylamino-dimethyl-propyl ester 20 N'-(2-Chloro-4-nitro-phenyl)-N,N-dimethy1-propane- 1 ,3-diamine [3-(3-Dimethylamino-propyl)-5-(4-nitro-phenyl)-3H-thiazol-2-ylidene] phenyl-amine [3-(10,11-Dihydro-dibenzo[a,d]cyclohepten-5-ylidene)-propyl]-dimethyl amine 25 2,3-Dimethyl-1H-indole-5-carboxylic acid 2-dimethylamino-ethyl ester N'-(3,4-Dinitro-5-pyridin-2-yl-thiophen-2-yl)-N,N-dimethyl-propane-1,3 diamine Cyclooctyl-dithiocarbamic acid 2-dimethylamino-ethyl ester (HCl) N-(2,6-Difluoro-phenyl)-C-dimethylamino-acetamide WO 01/32604 PCT/GBOO/04249 -88 2-Acetylamino-3-(4-chloro-phenyl)-N-(3-dimethylamino-propyl)-acrylamide N-[2-[5-(4-Bromo-phenyl)-furan-2-yl]-1 -(3-dimethylamino-propyl carbamoyl)-vinyl]-4-methyl-benzamide 2,6-Bis-(3-dimethylamino-propylamino)- 3 -nitro-benzonitrile 5 N-[2-(2,4-Dichloro-phenoxy)-phenyl]-N'-(3-dimethylamino-propyl) oxalamide 3,5-Dichloro-N-(3-dimethylamino-propyl)- 2 ,6-dimethoxy-benzamide 2-Dimethylaminomethyl-3,4-dihydro-2H-naphthalen- 1-one (HCl) 2-({1 -[N-(3-Dimethylamino-propyl)-3-trifluoromethyl-phenyl] 10 methanimidoyl}-amino)-6-fluoro-benzoic acid 2,4-Dichloro-N-(3-dimethylamino-propyl)-N'-hydroxy-benzamidine 3-(3-Methyl-ureido)-4-oxo-3,4-dihydro-quinazoline-2-carboxylic acid (3-dimethylamino-propyl)-amide 5-Bromo-N-(3-dimethylamino-propyl)-2-hydroxy-benzamide 15 N-(2,4-Dichloro-phenyl)-6-(2-dimethylamino-ethylsulfanyl)- 4 trifluoromethyl-nicotinamide 1-(2,6-Dichloro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (2-dimethylamino-ethyl)-amide 3-Amino-4-oxo-3,4-dihydro-quinazoline-2-carboxylic acid 20 (3-dimethylamino-propyl)-amide

12. Use according to any one of the preceding claims, wherein the medicament is for use as a vasodilator or to inhibit platelet aggregation. 25

13. Use according to claim 12, wherein the medicament is for use in the treatment or prevention of a peripheral vascular disease, glaucoma, age related macular degeneration, preeclampsia, Raynaud's Syndrome, stroke or erectile dysfunction. WO 01/32604 PCT/GBOO/04249 -89

14. A method of treating a patient in need of an activator of soluble guanylate cyclase, which method comprises administering to said patient an effective amount of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof. 5

15. A compound of the formula (I), as defined in any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, for use in the treatment of the human or animal body by therapy. 10

16. A compound of the formula (I), as defined in any one of claims I to 11, or a pharmaceutically acceptable salt thereof, excluding the following compounds: 2-Benzylsulfanyl-N-(3-dimethylamino-propyl)-benzamide N-(3-Dimethylamino-propyl)-3-phenoxy-benzamide 1-(4-chlorobenzyl)-3-(2-N,N-dimethylethylamido)-6-pyridone 15 1-(2,6-dichlorobenzyl)-3-(3-N,N-dimethylpropylamido)-6-pyridone 1-(3-trifluoromethylbenzyl)-3-(2-N,N-dimethylethylamido)-2-pyridone 1-(2,6-dichlorobenzyl)-3-(2-N,N-dimethylethylamido)-2-pyridone 1-(3,4-dichlorobenzyl)-3-(N-[2,N,N-dimethylaminoethylamido])-2-pyridone 1-(2,6-dichlorobenzyl)-3-(N-[2-N,N-dimethylaminoethylamido])-6-pyridone 20 5-chloro-1 -(3,4-dichlorobenzyl)-3-(2-N,N-dimethylaminoethylamido)-6 pyridone 5-chloro-3-(2-N,N-dimethylaminoethylamido)- 1-(3-trifluoromethylbenzyl)-6 pyridone 5-chloro-1 -(3,4-dichlorobenzyl)-3-N-(2-[N',N'-dimethylaminoethylamido])- 2 25 pyridone 5-chloro- 1-(4-chlorobenzyl)-3-N-(2-(N',N'-dimethylamino)ethyl)amido-2 pyridone 5-chloro-1-(3-trifluoromethylbenzyl)-3-N-(2-(N',N'-dimethylamino)ethyl) amido-2-pyridone WO 01/32604 PCTGBOOIO4249 -90 I -benzyl-5-chloro-3-N-(2- [N',Nl-dimethylamino]ethyl)carboxamido-6 pyridone 5 -chioro- 1 -(4-chlorobenzyl)-3 -N-(2- [N',N t -dimethylamino] ethyl) carboxamido-6-pyridone 5 4-24dclrbnolproe2Ndmtyaiorp~abxmd 4-[(N-[3 -(N',N'-dimethylaminopropyl)]carboxamido]-2-phelylthiazole 4-N(-'N-iehlmnpoy~aroaio--4prdnltizl 2-[4-(N-[3-N',N'-dimethylamiopropylIIcarboxamido)phenll 4 (3-trifluoromethylphenyl]thiazole 10 4-4clrpey)2(-3N,'dmehlmnpoy~abxmd~hnl thiazole 1 -(3,5 -bis(trofluoromethyl)benzyl)-3- [N-(2-dimethylamninoethyl) carboxaniido]-2[1 H]-pyridone N-(3-dimethylaminopropyl)-4-( 3 -chloro-5-trifluoromethyl-2-pyridyIoxy) 15 phenylsulfonamnide NI -[3 -(dimethylamino)propyl]-3 -[3-chloro-5 -(trifluoromethyl)-2-pyridyl] propanamnide 3 -(N-(2-dimethylaminoethyl)carboxamfido]- 1 -(4-trifluoromethylbenzyl))-2 [IH]-pyridone 20 1 -ethyl-3 -(3 -dimethylaminopropyl)urea I -(3-(dimethylamino)-propyl)- 3 -phenylurea NI -[2-(2,4-dichlorophenoxy)phenylI-N2-[3 -(dimethylamino)propyl] ethanediamide N4- [3 -(dimethylamino)propylI-3-(2,6-dichlorophelyl)-S -methylisoxazole-4-c 25 arboxamide N- [[3 -(2,6-dichlorophenyl)-5-methylisoxazol-4-y1]Carboflyl]-N'[ 3 (dimethylamino)propyl]urea N-(4-chlorophenyl)-N'-[3 -dimethylamninopropyl]urea N-(3 ,5 -Dichloro-phenyl)-3-(3 -dimethylamino-propylamino)-propioflam~ide WO 01/32604 PCT/GBOO/04249 -91 [3-(2-Ethyl-6-methyl-pyridin-3-yloxy)-propyl]-dimethyl-amine 8-(3-Dimethylamino-propoxy)-1,3,7-trimethyl-3,7-dihydro-purine-2,6-dione 2-(3-Dimethylamino-propylamino)-isophthalonitrile Dimethylamino-(3-methyl-benzo[b]thiophen-2-yl)-propan- 1-one (HCl) 5 N-Benzo[1,3]dioxol-5-ylmethyl-N,N-dimethyl-propane-1,3-diamine N,N-Dimethyl-N-(5-nitro-quinolin-8-yl)-propane-1,3-diamine 1-(4-Chloro-phenyl)-3-(3-dimethylamino-propyl)-urea 2-Amino-N-(3-dimethylamino-propyl)-benzaTide 3-Phenyl-acrylic acid 3-dimethylamino-propyl ester 10 3,5-Dinitro-benzoic acid 2-dimethylamino-ethyl ester [4-(4-Bromo-phenyl)-3-(3-dimethylamino-propyl)-3H-thiazol-2-ylidene] phenyl-amine 3-Methyl-benzofuran-2-carboxylic acid dimethylamino-dimethyl-propyl ester N'-(2-Chloro-4-nitro-phenyl)-N,N-dimethyl-propane-1,3-diamine 15 [3-(3-Dimethylamino-propyl)-5-(4-nitro-phenyl)-3H-thiazol-2-ylidene] phenyl-amine [3-(10,11 -Dihydro-dibenzo[a,d]cyclohepten-5-ylidene)-propyl]-dimethyl amine 2,3-Dimethyl-1H-indole-5-carboxylic acid 2-dimethylamino-ethyl ester 20 N'-(3,4-Dinitro-5-pyridin-2-yl-thiophen-2-yl)-N,N-dimethyl-propane-1,3 diamine Cyclooctyl-dithiocarbamic acid 2-dimethylamino-ethyl ester (HCl) N-(2,6-Difluoro-phenyl)-C-dimethylamnino-acetamide 2-Acetylamino-3-(4-chloro-phenyl)-N-( 3 -dinethylamino-propyl)-acrylamide 25 N-[2-[5-(4-Bromo-phenyl)-furan-2-yl]-1-(3-dimethylamino propylcarbamoyl)-vinyl]-4-methyl-benzamide 2,6-Bis-(3-dimethylamino-propylamino)-3-nitro-benzonitrile N-[2-(2,4-Dichloro-phenoxy)-phenyl]-N'-(3-dimethylamino-propyl) oxalamide WO 01/32604 PCTIGBOOIO4249 -92 3 ,5-Dichloro-N-(3-dimethylamino-propy1)-2,6-dimethoxy-beflzamide 2-Dimethylaminomethyl-3 ,4-dihydro-2H-naphthalen- i-one (HC1) 2-( { 1-[N-(3 -Dimethylamnino-propyl)-3 -trifluoromethyl-phenyl] methanimidoyl} -amino)-6-fluoro-benzoic acid 5 2,4-Dichloro-N-(3 -dimethylamino-propyl)-N'-hydroxy-belzamidifle 3-(3-Methyl-ureido)-4-oxo-3 ,4-dihydro-quinazoline-2-carboxylic acid (3-dimethylamnino-propyl)-amide 5-Bromo-N-(3-dimethylamiflo-propy)-2-hydroxy-beflzamide N-(2,4-Dichloro-pheny)-6-(2-dimethyamio-ethylsulfanl)> 4 10 trifluoromethyl-nicotinamide 1 -(2,6-Dichloro-benzyl)-2-oxo- 1,2-dihydro-pyridine-3-carboxylic acid (2-dimethylamino-ethyl)-amfide 3-Amino-4-oxo-3 ,4-dihydro-quinazoline-2-carboxylic acid (3-dimethylamino-propyl)-aimide