AU732863B2 - Indole derivatives having combined 5HT1A, 5HT1B and 5HT1D receptor antagonist activity - Google Patents
Indole derivatives having combined 5HT1A, 5HT1B and 5HT1D receptor antagonist activity Download PDFInfo
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- AU732863B2 AU732863B2 AU74310/98A AU7431098A AU732863B2 AU 732863 B2 AU732863 B2 AU 732863B2 AU 74310/98 A AU74310/98 A AU 74310/98A AU 7431098 A AU7431098 A AU 7431098A AU 732863 B2 AU732863 B2 AU 732863B2
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- indole
- dihydro
- methylpiperazin
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- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
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- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Description
C (i WO 98/50358 PCT/EP98/02262 INDOLE DERIVATIVES HAVING COMBINED 5HTIA, 5HT1B AND 5HTID RECEPTOR ANTAGONIST ACTIVITY The present invention relates to novel piperazine derivatives, processes for their preparation, and pharmaceutical compositions containing them.
WO 95/06637, WO 95/06044 and WO 95/04729 disclose a series of piperazine derivatives which are said to possess 5HT 1D receptor antagonist activity. These compounds are alleged to be of use in the treatment of various CNS disorders such as depression. EPA 0533266/7/8 disclose a series ofbenzanilide derivatives which are said to possess 5-HT1D receptor antagonist activity.
A structurally distinct class of compounds have now been found to exhibit combined 5HT 1A 5HT 1 B and 5HT 1 D receptor antagonist activity. It is expected that such compounds will be useful for the treatment and prophylaxis of various CNS disorders with the advantage of a relatively fast onset of action. In a first aspect, the present invention therefore provides a compound of formula or a salt thereof: N,
R
c
X
Ra D- SRb in which R a is a group of formula (i)
R'
(R2a (i) in which P1 is phenyl, bicyclic aryl, a 5 to 7 membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, or a bicyclic heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur;
R
1 is hydrogen, halogen, C 1 -6alkyl, C3.6cycloalkyl, COC 1 6 alkyl, Cl-6alkoxy, hydroxy, hydroxyC 1-6alkyl, hydroxyC 1-6alkoxy, C -6alkoxyC 1-6alkoxy, C -6alkanoyl, nitro, trifluoromethyl, cyano, SR 9
SOR
9 S0 2
R
9 S0 2
NR
1 0
R
1 1, C0 2
R
10 k WO 98/50358 WO 9850358PCT/EP98/02262
CONR
1 0
R
1 1, C0 2 NRl 0
R
1 1, CONRIO(CH 2 )cCO 2 RI I, (CH2)cNRiOR Ii, (CH2)cCONRi 0
R
1 1
(CH
2 )cNRi 0 C0RI I, (CH2)cCO 2 CI-6.alkyl, C02(CH 2 )coRl 0, NRlORll,NRlOCO 2 Rl, NROCONRIOR11, CRIO=NORl I, NROCOOR11, CNR I =NOR 1 1, where R 9 R 10 and R I are independently hydrogen or C I -alkyl and c isl1to 4;
R
2 is hydrogen, halogen, CI-6alkyl, C3-6cYcloalkyl, C3-6cycloalkeny1, CI-6alkoxy, Cp..
6alkanoyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, C0 2 RI 0, CONRI ORI 1, NRIORI 1 where RIO and RI 1 are as defined for Rl; a is 1, 2or 3; or R~a is a group of formula (ii)
(R
2 )a
(R
3 )b
R
1 -(p 3 -A p 2 wherein p 2 and p 3 are independently phenyl, bicyclic aryl, a 5- to 7- membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, or a bicyclic heterocyclic group containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur; A is a bond or oxygen, S(O)m where mn is 0 to 2, carbonyl, CH 2
-CH
2
-CH
2 or NR 4 where R 4 is hydrogen or C 1 I .6alkyl; RI is as defined above for formula or RI is a 5 to 7-membered heterocyclic ring, containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur, optionally substituted by C 1 6 alkyl, halogen or C 1 6 alkanoyl;
R
2 and R 3 are independently hydrogen, halogen, C 1 6 alkyl, C3-6cycloalky1, C3-6.cYcloalkenyl, CI-6.alkoxy, CI-6alkanoyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, C0 2
R
1 0 CONRIORI 1, NR 1 0
R
1 1 where RIO and RI I are as defined for RI; and a and b are independently 0, 1, 2 or 3; Y is -NR 5 where R 5 is C I 6 alkyl, or Y is -CF1 2 or V is oxygen or sulphur; WO 98/50358 PCT/EP98/02262 D is nitrogen, carbon or a CH group; W is (CR1 6
R
1 7 )t where t is 2, 3 or 4 and R 16 and
R
17 are independently hydrogen or Cl_ 6 alkyl or W is (CR1 6 R1 7 )u-J where u is 0, 1, 2 or 3 and J is oxygen, sulphur, CR 16
=CR
1 7
CR
16
=CR
1 6 0, =CR 16 S or =CR 16 -NR1 7 X is nitrogen or carbon; Rb is hydrogen, halogen, hydroxy, C 1 6 alkyl, trifluoromethyl, C1-6alkoxy, C2-6alkenyl, C3.7cycloalkyl optionally substituted by C1-4alkyl, or aryl;
R
e is hydrogen or Cl-6alkyl; and is a single bond when X is nitrogen or a single or double bond when X is carbon.
C -6alkyl groups whether alone or as part of another group may be straight chain or branched. The term 'acyloxy' is used herein to describe a group -OC(O)C 1 -6alkyl. The term 'aryl' is used herein to describe, unless otherwise stated, a group such as phenyl. The term 'aralkyl' is used herein to describe, unless otherwise stated, a group such as benzyl.
The bicyclic aryl group represented by pi, p 2 and/or P 3 which may be partially saturated, is preferably naphthyl.
Examples of bicyclic heterocyclic rings containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur include isoquinoline, indole, benzofuran, benzothiophene and preferably quinoline.
Examples of 5 to 7 membered heterocyclic rings containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur represented by Pl, p 2 and/or P 3 include thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrimidyl, pyridazinyl and pyrazinyl, and preferably pyridyl.
The heterocyclic rings as described above can be linked to the remainder of the molecule via a carbon atom or, when present, a suitable nitrogen atom. Such rings can also be saturated or partially saturated. Examples of saturated or partially saturated 5 to 7 membered heterocyclic rings include piperidine, pyrrolidine and morpholine. Examples of partially saturated bicyclic heterocyclic rings include dihydrobenzofuran, dihydrobenzothiophene, tetrahydroquinioline and tetrahydroisoquinoline
R
1 is preferably a halogen atom for example, fluorine, chlorine or bromine, and
R
2 and/or R 3 are each preferably hydrogen, halogen for example a chloro group, or a C 1 6alkyl group for example a methyl group. When R 1 is 5 to 7-membered heterocyclic rings suitable optional substituents include C1- 6 alkyl, C 1 -6 alkanoyl and halogen.
-3- WO 98/50358 WO 9850358PCT/EP98/02262 a and b are each preferably 1 or 2.
A is preferably a bond or oxygen, most preferably a bond.
is preferably -NH-.
V is preferably oxygen.
D is preferably nitrogen and the group W is preferably a (CRI 6
R
1 7 )t group where R 16 and R 17 are each advantageously hydrogen and t is suitably 2.
Rb is preferably hydrogen or a halogen atom for example chlorine, a Cl...6alkoxy group for example methoxy or a C 1 6 alkyl group such as methyl or ethyl.
X is preferably nitrogen.
RC is preferably a C I 6 alkyl group for example methyl.
Particularly preferred compounds according to the invention include:- 1-[(-rm--ehlhnl mncroy]5mtox--4mtypprzn I 1 Hindole, 4 -bromo- 3 -methylpheny)aminocarbonyl23.dihydro...smethoxy6(4methylpiperazin- 1 1H-indole, 2 3 -dichlorophenyl)ainocarbonyl]2,3dihydro5metoxy6(4-methylpiperazi- 1yl)- 1 H-indole, 2,3-Dihydro-5 -methoxy-6-(4-methylpiperazin- 1 -yl)-1I -[4-(pyridin-4-yl)naphth- 1 ylaminocarbonyl]- 1H-indole, 2 3 -Dihydro-5-methoxy-6-(4-methylpiperazin- 1 -yl)-1I -[5-(pyridin-4-yl)naphth- 1ylaminocarbonyl]- 1H-indole, 1-23Dclr--prdn4y~hnlmioabnl-,-iyr--ehx--4 methylpiperazin- 1-yl)- 1H-indole, 2 3 -Dihydro-5-methoxy-6-(4-methylpiperazin- 1 1 -(quinolin-5-ylamninocarbonyl)- 1 Hindole, 2 ,3-Dihydro-6-(4-methylpiperazin- 1 1 -[4-(pyridin-4-yl)naphth- 1 -ylaminocarbonyl]- 1 H-indole, -Chloro-2,3-dihydro-6-(4-methylpiperazin. 1 1 -[4-(pyridin-4-yl)naphth- 1 ylamninocarbonyl]- 1H-indole, 5-Bromo-2,3 -dihydro-6-(4-methylpiperazin- I 1 [4-(pyridin-4-yl)naphth- 1ylaminocarbonyl]- 1H-indole -4ki WO 98/50358 WO 9850358PCT/EP98/02262 5-Bromo-2,3-dihydro-6-(4-methylpiperazin- 1 1 (pyridin-4yl)phenylaminocarbonyl]- IH-indole, 1 3 -chloro- 4 -(pyridin-4-yI)phenyaminocarbony]23dihydro-6-(4methylpiperazin- I1-yl)-l H-indole, 2 ,3-Dihydro-5-methyl-6-(4-methylpiperazin- Il-yl)-1I 4 -(pyridin-4-yl)naphth- 1 ylaminocarbonyl]- 1H-indole, 1-3Clr--prdn4y~hnlmncroy]23dhdo5mty--4 methylpiperazin- 1-yl)-lil-indole, 2 ,3-Dihydro-6-(4-methylpiperazin- 1 -yl)-1I -[4-(pyridin-4-yl)naphth- 1 vinyl- I H-indole, 2,3-Dihydro-5-ethyl-6-(4-methylpiperazin. I -yl)-1I 4 -(pyridin-4-y1)naphth- 1ylaminocarbonyl]- 1H-indole, 1-3Clr--prdn4y~hnlmnoabnl-,-iyr--ty--4 methylpiperazin- l-yl)-l H-indole, 2,3-Dihydro-6-(4-methylpiperazin- 1-yl)-1 -!4-(pyridin-4-yl)naphth- 1-ylaminocarbonyl] trifluoromethyl- 1H-mndole, l-[ 3 -Chloro- 4 -(pyridin- 4 -yl)phenylaminocarbonyl]..2,3-dihydro-6-4methylpiperazin- 1 1H-indole, 2 ,3-Dihydro-5-mefioxy-6-(4-methylpiperazin- 1 -yl)-1I -[4-(pyridin-4-yl)naphth- 1 ylacetyl]- 1 H-indole;.
2 3 -Dihydro-5-methoxy-6-(4-methylpiperazin- I-yl)-lI -[5-(pyridin-4-yl)-naphth- 1 ylacetyl]- IH-indole, 2 ,3-Dihydro-6-(4-methylpiperazin- 1l-yl)- 1-[4-(pyridin-4-yl)naphth- 1 -ylacetyl]- 1 H-indole 5-Chloro-2,3-dihydro-6-(4-methylpiperazin. 1 -yl)-1I -[4-(pyridin-4-yl)naphth- 1 -ylacetyl]- 1H-indole, 5-Bromo-2,3-dihydro-6-(4-methylpiperazin- 1 -yl)-1I -[4-(pyridin-4-yl)naphth- I -ylacetyl]- 1 H-indole, 2,3-Dihydro-6-(4-methylpiperazin- 1 1 -[4-(pyridin-4-yl)naphth- 1 -ylacetyl] -5 -vinyl- 1 H-indole, 5-Bromo-2,3-dihydro-6-( I -methylpiperidin-4-yl)- 1 -[4-(pyridin-4-yl)naphth- 1 -ylaminocarbonyl] -1H-indole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin. I-yl)-lI -[5-(pyridin-4-yl)naphth- 1ylaminocarbonyl]- 1H-indole, *WO 98/50358 PCT/EP98/02262 5-Bromo-2,3-dihydro-6-(4-methylpiperazin. l-yI)-1 -II5-(pyridin-4-y1)naphth ylaminocarbonyJ- 1H-indole, 2 3 -Dihydro-5-methoxy-6-(4-methylpiperazin-l-yl)-l -(quinolin-6-ylaminocarbonyl). 1Hindole, 2,3-Dihydro- 1 4 -(t-butoxycarbonylamino)phenylaminocarbonyl]s..chloro-6-(4methylpiperazin- Il-yl)-l1 H-indole, 5-Bromo-2,3 -dihydro-6-(4-methylpiperazin. I-yI)-l1 -(quinolin-6-ylaminocarbonyl). 1 Hindole, 6 -Bromo-7-(4-methylpiperazin- 1 -yl)-1I [4-(pyridin-4-yl)naphth- 1 -ylaminocarbonyl] 1, 2 ,3,4-tetrahydroquinoline, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin- 1 -yI)-1I 4 -phenoxyphenylaminocarbonyl).
1H-indole 5-Chloro-2,3-dihydro- 1 4 4 -chlorophenoxy)phenylan-inocarbonyl]p6-(4methylpiperazin- Il-yl)-lI H-indole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin- I-yl)-1I -(quinolin-6-ylaminocarbonyl)- 1 Hindole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin- 1 1 3 -phenoxyphenylaminocarbony)- 1 H-indole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin- I-yl)-l1 4 -(pyrimidin-2-y1)phenylaminocarbonyl]-l1H-indole, 1 3 -Benzoylphenylaminocarbonyl)-5-chloro-2,3.-dihydro.-6-(4-methylpiperazin. 1 -yl)-1I Hindole, l-( 4 -Benzoylphenylaminocarbony)5choro2,3-dihydro-6(4-methylpiperazin. I -yl)-1I Hindole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin- I-yl)- 1 -(2-methylquinolin-6ylaminocarbonyl)-1 H-indole, 5-Chloro-2,3-dihydro- Il-[ 4 -(fur- 2 -yl)phenylaminocarbonyl]-6-(4-metiylpiperazin. I-yl)- 1 H-indole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin- 1 -yl)-1I 4 -(thien- 2 -yl)phenylaminocarbonyl]- 1H-indole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin- 1l-yl)-1I -15-(pyridin-2-yl)naphth-1 -ylacetyl]- 1 H-indole, -6- WO 98/50358 PTE9/26 PCT/EP98/02262 5-Bromo-2,3-dihydro-6-(4-methylpiperain-. l-yl)-l 1-II-(pyridin-4-yl)naphth- I -ylacetyli- 1 H-indole, 5-Chloro-2,3-dihydro- 1 -nlethylpiperidin-4-yl)naphth- 1 -ylaminocarbonyl].6-(4 methylpiperazin- 1 -yl)-1I H-indole, 5-Chloro-2 ,3-dihydro-I 4 2 -methyloxazol-4-yI)phenylaminocarbonyl]y6(4methylpiperazin- Il-yl)-1I H-indole, -Bromo- 2 ,3-dihydro-6-(4-methylpiperazin-.1 -yl)-1 -I 4 -(2-methylpyridin-4.
yl)phenylamino-carbonyl]- 1H-indole, 2 ,3-dihydro-6-(4-.methylpiperazin.1 -yl)-1 -[4-(2-methylpyridin-4.
yl)phenylaminocarbonyl]j. 1H-indole, -Chloro-2,3 -dihydro- I- 4 2 6 -dimethylpyridin-4-y)phenylaminocarbonyl]y6(4methylpiperazin- 1 1 H-indole, 5-Bromo-2,3-dihydro-I 4 2 6 -dimethylpyridin-4-yl)phenylaminocarbonyl]-6(4methylpiperazin- 1 -yI)-1I H-indole, 2,3-Dihydro-1 4 2 6 -dimethylpyridin..4-yl)phenylaminocarbony].5methoxy-6 (4-methylpiperazin- Il-yl)-1I H-indole, 5-Chloro-2,3-dihydro- l-[ 4 2 6 -dimethylpyridin-3.yl)phenylaminocarbonyl]..6-(4methylpiperazin- I -yl)-1I H-indole, 5-Bromo-2,3-dihydro- l-[ 4 2 6 -dimethylpyridin.3yl)phenylaminocarbonyl].6-(4methylpiperazin- 1-yI)-1 H-indole, 2,3-Dihydro- l-[ 4 2 6 -Dimethylpyridin..3-yl)phenyaminocarbny].s-methoxy-6 (4-methylpiperazin- l-yl)-1 H-judo le, -Chloro-2,3-dihydro-6-(4.methylpiperazn-.I -yl)-l1 -[4-(5-methyl- 1 ,2,4-oxadiazol- 3 -yl)phenylaminocarbonyl]- 1H-indole, 5-ChlorO-2,3 -dihydro- 1 -[4-(3-methyl- 1 ,2,4-oxadiazol-5yl)phenylaminocarbonyl]-6-(4-methylpiperazin- I yl)- IHindole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin-1 -yl)-1 -[3-(pyrimidin-2yloxy)phenylaminocarbonyl]- 1H-indole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin. 1l-yl)-l 4 -[N-methyl-N-(pyrimidin- 2 -yl)aminolphenylaminocarbonyl} -1I H-indole, 5-Bromo-2,3-dihydro- l-[ 4 -(fur- 2 -yl)phenylaminocarbonyI]-6-(4-methylpiperazin- I -yl)-1 H-indole, -7- WO 98/50358 PTE9/26 PCT/EP98/02262 5-Chloro-2,3-dihydro-6-(4-methylpiperazin-1 -yl)-lI -[4-(thien-3yl)phenylaminocarbonyl]-l1H-indole, 5-Bromo-2,3-dihydro-6-(4-methylpiperain-I l-yl)-lI 4 -(thiazol-2-yl)phenylamino.
carbonyl]-1 H-indole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin.1
I-[
4 -(thiazol-2-yl)phenylarninocarbonyl]- 1H-indole, I -1 4 -(-Acetylthien-2-yl)phenylaminocarbonyl] -5-chloro-2,3-dihydro-6-(4.
methylpiperazin- Il-yl)-lI H-indole, 1 -Bromonaphth- I -ylacetyl)-5-chloro-2,3 -dihydro-6-(4.methylpiperain- 1 -yl)- 1 H-indole, -Chloro-2,3 -dihydro-6-(4-methylpiperazin. I-yl)-lI -(8-phenylquinolin-s ylaminocarbonyl)- I H-indole, 5-Bromo-2,3-dihydro-6-(4-methylpiperazin. 1 -yl)-1I ylaminocarbonyl)- 1H-indole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin.1 1 -[2-(2-phenylethy1)quinolin-6ylaminocarbonyl]- 1 H-indole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin. Il-yl)-l1 -methylpiperidin-4-yl)naphth 1ylaminocarbonyl]- IH-indole, 5-Bromo-2,3-dihydro- 1 4 -(isoquinolin-4-yl)phenylaminocarbonyl].6-(4methylpiperazin- Il-yl)-l1 H-indole, 5-Chloro-2,3-dihydro- I 4 -(isoquinolin-4-yl)phenylaminocarbony]6(4.
methylpiperazin- I -yl)-1I H-indole, 5-Bromo-2,3-dihydro-6-(4-methylpiperain.1 -yl)-l -[4-(quinolin-3yl)phenylaminocarbonyl]- 1H-indole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin-1 -yl)-1 -[4-(quinolin-3yl)phenylaminocarbonyl)]- 1H-indole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazi-1 -yl)-l1-[(2-methyl- 1,2,3,4tetrahydroisoquinoin-7-yl)aminocarbonyJ.. H-indole, 5-Bromo-2,3-dihydro-6-(4-methypiperzin-1-yl) I-[(2-methyl- 1,2,3,4tetrahydroisoquinolin-7-y1)amninocarbonyl]pH..jndole, 5-Bromo-2,3-dihydro-6-(4-methylpiperain.1 1-[4-(quinolin-8yl)phenylaxninocarbonyl]-l1H-indole, t. WO 98/50358 WO 9850358PCT/EP98/02262 5-Chloro-.2,3-dihydro-6-(4-methylpiperazin. Il-yl)-lI -[4-(quinolin-8yl)phenylaminocarbonyl]- 1H-indole, 5-Chloro-2,3-Dihydro- 1 -[4-(imidazol- 1 -yl)phenylaminocarbonyl]-6-(4methylpiperazin- l-yl)- 1H-indole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin-I I -[4-(pyridin-4yl)phenylaminocarbonyl]- 1H-indole, 2,3 -Dihydro-5-methoxy-6-(4-methylpiperaziw. 1-yI)-1 yl)aminocarbonyl]- 1H-indole 5-Chloro-2,3-dihydro-6-(4-methylpiperazin. I-yl)-lI -[(8-phenylquinolin-4yl)aminocarbonyl]- 1 1-indole, 5-Bromo-2,3-dihydro-6-(4-methylpiperazin-l-yl)-lI -[(8-phenylquinolin-4yl)aminocarbonyl]- 1H-indole, 2 3 -Dihydro-5-methoxy-6-(4-methylpiperazin- I-yl)-lI -[(8-phenylquinolin-4yl)aminocarbonyl]- IH-indole, 5-Chloro-2,3-dihydro- 1 -[4-(2,6-dimethyl-pyridin-4-yl)-3 -methylphenylaminocarbonyl]-6- (4-methylpiperazin- Il-yl)-lI H-indole, 5-Chloro-2,3-dihydro-l1-[ 3 -methyl-4-(6-methylpyridin-2-yl)phenylaminocarbonyl]y6-(4.
methylpiperazin- Il-yl)-lI H-indole, 5-Bromo-2,3-dihydro-l1-[ 3 -methyl-4-(6-methylpyridin-2-yl)phenyainocarbonyl]y6{4.
methylpiperazin-1I -yl)-1IH-indole, 2,3-Dihydro-5 -methoxy-. 1 J[ 3 -methyl-4-(6-methylpyridin-2.yl)phenylaminocarbonyl] 6- (4-methylpiperazin- Il-yl)-lI H-indole, 5-Chloro-2,3-dihydro-l1-[5-(6-methylpyridin-2-yl)naphth- 1-ylamninocarbonyl]-6-(4methylpiperazin- 1-yl)-1 H-indole, 2,3 -Dihydro-5 -methoxy- 1 -(6-methylpyridin-2-yl)naphth- 1 -ylamninocarbonyl] methylpiperazin- Il-yl)-lI H-indole, -Chloro-2,3-dihydro-6-(4-ethylpiperazin- 1-yl)-1I [4-(pyridin-4-yl)naphth- 1 ylaminocarbonyl]- 1H-indole, -Chloro-2,3 -dihydro-6-(4-ethylpiperazin. 1 -yl)-1I [5 -(pyridin-4-yl)naphth- 1 ylaminocarbonyl]- IH-in dole, 5-Chloro-2,3-dihydro-6-(piperazin- 1 -yl)-1I -14-(pyridin-4-yl)naphth- 1 -ylaminocarbonyl]- 1 H-indole hydrochloride, WO 98/50358 WO 9850358PCT/EP98/02262 5-Chloro-2,3-dihydro-6-(piperazin- I-yl)-l 1-15-(pyridin-4-yl)naphth- 1 -ylaminocarbonyl]- 1 H-indole hydrochloride, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin- I -yl)-1I -[4-(pyridazin-3yl)phenylaniinocarbonyl]- 1 1-indole, 5-Bromo-2,3-dihydro-6-(4-methylpiperain. I -yl)-1I -[4-(pyridazin-3 yl)phenylaminocarbonyl]- 1H-indole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin 1 -yl)-1I -[4-(pyrazin-2yl)phenylaminocarbonyl]- 1H-indole, 5-Bromo-2,3-dihydro-6-(4-methylpiperazin. Il-yl)-lI -[4-(pyrazin-2yl)phenylaminocarbonyl]- 1H-indole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin-1 1 yl)aminocarbonyl]- 1 1-indole, 5-Bromo-2,3 -dihydro-6-(4-methylpiperazin..I -yl)-1 yl)aminocarbonyl]- 1H-indole, 5 -Chloro-2,3-dihydro- 1 4 6 -methylpyridazin-3-y1)phenylainiocarbonyl]y6.(4.
methylpiperazin- Il-yl)-lI H-indole, -Bromo-2,3 -dihydro- 1 4 6 -methylpyridazin-3 -y)phenyainocarbonyl}.6-(4.
methylpiperazin- l-yl)-l H-indole, -Chloro-2,3 -dihydro-6-(4-methylpiperazin-1.yl)- 1 [4-(pyridin-3 yl)phenylaminocarbonyl]-1H-indole, 5-Chloro-2,3-dihydro- 1 4 -methyloxazol-2-yl)phenylaxninocarbonyl].6-(4methylpiperazin- l-yl)-l H-indole, 2,3-Dihydro-5-methoxy-l1-[ 4 -(5-methyloxazo-2-y)phenylainocarbonyl].6-(4methylpiperazin- 1-yl)-1 H-indole, 5-Bromo-2,3-dihydro-l1-[ 4 -(5-methyloxazol-2-yl)phenylaminocarbonyly6-(4methylpiperazin- l-yl)-l H-indole, -Chloro-2,3-dihydro- 1 -methylpyrazol-4-y1)phenylaminocarbonyl]..6-(4methylpiperazin- l-yl)-1 H-indole, 5-Bromo-2,3 -1 l-methylpyrazol-4-yl)phenylaminocarbonyl]y6-(4-methylpiperazinyl)-1H-indole, 5-Chloro-2,3-dihydro- 1 -[4'-cyano-3 '-methylbiphenyl-4-aminocarbonyly6-(4methylpiperazin- l-yl)-l H-indole, WO 98/50358 WO 9850358PCT/EP98/02262 5-Bromo-2,3-dihydro-l1-[ 4 -cyano-3'-methylbiphenyl-4-aminocarbonyl].6(4.
methylpiperazin- Il-yl)-lI H-indole, 5-Chloro-2,3-dihydro-lI-[ 4 -(2-methylpyridin-5-y)phenylaxinocar,onyl]-6-.(4.
methylpiperazin- Il-yl)-lI H-indole, 5-Bromo-2,3 -dihydro- I 4 2 -methylpyridin-5 -yl)phenylaminocarbony]6-.(4methylpiperazin- I1-yI)-lI H-indole, -Chloro-2,3 -dihydro- 1 -methyl- 1 ,2,4-oxadi azol-5 -yl)naphth- 1 -ylaminocarbonyl]-6- (4-methylpiperazin- 1-yI)-1 H-indole, 2,3-Dihydro-5-methoxy-l1-[5-(3-methyl- 1,2,4-oxadiazol-5-yl)naphth- 1-ylaminocarbonyl]- 6-(4-methylpiperazin- 1 -yl)-1I H-indole.
5-Bromo-2,3-dihdyro- 1 -[5-(3-methyl- 1 ,2,4-oxadiazol-5-yl)naphth- 1 -ylaminocarbonyl] -6- (4-methylpiperazin- Il-yI)- I1H-indole, -Chloro-2,3 -dihydro- I [5-(5-methyloxazol-2-yl)naphth- 1 -ylaminocarbonyl] methylpiperazin- Il-yl)- 1il-indole, 2,3-Dihyclro-5-methoxy- 1 -methyloxazol-2-yl)naphth- 1 -ylaminocarbonyl] methylpiperazin- Il-yl)-l1 H-indole, 5-Bromo-2,3-dihydro-l1-[ 3 -methyl-4-(pyrimidin-2-y)phenylaminocarbonyly6-(4.
methylpiperazin- 1l-yl)-l1 H-indole, 2,3-Dihydro-5-methoxy-l1-[ 3 -methyl-4-(pyrimidin-2-yl)phenylaminocarbonyl]y6(4methylpiperazin- Il-yl)-1I H-indole, S-Chloro-2,3-dihydro-6-(4-methylpiperazin. Il-yl)-l1 -methyl-4-(pyrimidin-2yl)phenylaminocarbonyl]- IH-indole, 5-Bromo-2,3 -dihydro- 1 -[I 3 -methy-4-(pyrimidin-5 -y1)phenylaminocarbony]..6-(4methylpiperazin- Il-yl)-lI H-indole, 5-Chloro-2,3 -dihydro- 1 -methyl-4-(pyrimidin-5 -yl)phenylaminocarbonyl] methylpiperazin- 1 -yl)-1I H-indole, 2,3-Dihydro-5-methoxy-l1-[ 3 -methy1-4-(pyrimidin-5-y)phenyaminocarbony].6(4.
methylpiperazin- 1 -yl)-1I H-indole, 5-Bromo-2,3-dihydro-l1-[ 4 2 6 -dimethylpyridin-4-y)-3-methylphenylaminocabonyl]-6- (4-methylpiperazin- 1-yl)-1 H-indole, 2,3-Dihydro-5 -methoxy- I 4 2 6 -dimethylpyridin-4-y)-3-methylphenylaminocarbonyl]..
6-(4-methylpiperazin- 1-yl)-1 H-indole, -11- S WO 98/50358 PCT/EP98/02262 5-Chloro-2,3-dihydro- 2 ,6-dimethylpyridin-4-yl)naphth-1 -ylaminocarbonyl]-6-(4methylpiperazin- 1H-indole, 5-Bromo-2,3-dihydro- 2 ,6-dimethylpyridin-4-yl)naphth--ylaminocarbonyl]-6-(4methylpiperazin-1 -yl)-1 H-indole, 2,3-Dihydro-1 2 6 -dimethylpyridin-4-yl)naphth-1 -ylaminocarbonyl]-5-methoxy-6-(4methylpiperazin-1 -yl)-1H-indole or pharmaceutically acceptable salts thereof.
Preferred salts of the compounds of formula are pharmaceutically acceptable salts. These include acid addition salts such as hydrochlorides, hydrobromides, phosphates, acetates, fumarates, maleates, tartrates, citrates, oxalates, methanesulphonates and p-toluenesulphonates.
Certain compounds of formula are capable of existing in stereoisomeric forms.
It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula and the mixtures thereof including racemates.
Compounds of the invention can be prepared using procedures known in the art.
In a further aspect the present invention provides a process for the preparation of a compound of formula or a pharmaceutically acceptable salt thereof which comprises: where D is nitrogen and Y is NH coupling a compound of formula (II): Ra
(II)
in which R a and V are as defined in formula or a protected derivative thereof with a compound of formula (III):
RC
HN
W Rb \w^
(III)
in which W, X, Rb and RC are as defined in formula or a protected derivative thereof; or where D is nitrogen and Y is NH or NR 5 reacting a compound of formula (IV)
R
a -NH2 or R a
-NR
5 H (IV) -12- WO 98/50358 PCT/EP98/02262 in which R a and R 5 are as defined in formula with a compound of formula (III) together with an appropriate urea forming agent; where D is nitrogen, reacting a compound of formula (V) Ra
L
2
(V)
in which R a is as defined in formula Y is -CH 2 or and L 2 is an appropriate leaving group, with a compound of formula
(III);
d) where D is carbon or CH, reacting a compound of formula (VI)
R
a -NH2
(VI)
in which R a is as defined in formula with a compound of formula (VII) Rc
N
L2 D
X
W b
(VII)
in which D is carbon or CH, W, X, Rb and Rc are as defined in formula and L 2 is an appropriate leaving group and optionally thereafter: removing any protecting groups, converting a compound of formula into another compound of formula forming a pharmaceutically acceptable salt.
The reaction in process is conveniently effected in an organic solvent such as dichloromethane.
In process the urea forming agent can be carbonyl diimidazole, triphosgene or phosgene, and carried out in an inert organic solvent such as dimethylformamide, tetrahydrofuran or dichloromethane at ambient or elevated temperature in the presence of a base such as triethylamine or pyridine.
In process the leaving group L 2 may be a halogen e.g. chloro group and the reaction may be carried out in an inert organic solvent such as tetrahydrofuran or dichloromethane at ambient or elevated temperature in the presence of a base such as triethylamine or pyridine.
13- WO 98/50358 PCT/EP98/02262 In process the leaving group L 2 may be a halogen e.g. chloro group and the reaction may be carried out in an inert organic solvent such as tetrahydrofuran or dichloromethane at ambient or elevated temperature in the presence of a base such as triethylamine or pyridine.
Compounds of formula can be converted into further compounds of formula using standard techniques. For example, in the case wherein Rc is hydrogen, it is possible to introduce a C 1 -6alkyl group by conventional alkylation using 1 molar equivalent of a C 1 -6alkyl halide and 1 molar equivalent of a suitable base in an inert solvent.
Intermediate compounds of formula (III), and (VII) can be prepared using standard procedures known in the art.
It will be appreciated to those skilled in the art that it may be necessary to protect certain reactive substituents during some of the above procedures. Standard protection and deprotection techniques can be used. For example, primary amines can be protected as phthalimide, benzyl, benzyloxycarbonyl or trityl derivatives. These groups can be removed by conventional procedures well known in the art.
Carboxylic acid groups can be protected as esters. Aldehyde or ketone groups can be protected as acetals, ketals, thioacetals or thioketals. Deprotection is achieved using standard conditions.
5HT1A/1B/1D receptor antagonists, and in particular the compounds of the present invention, are expected to be of use in the treatment of CNS disorders such as mood disorders, including depression, seasonal affective disorder and dysthymia; anxiety disorders, including generalised anxiety, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and post-traumatic stress disorder; memory disorders, including dementia, amnestic disorders and age-associated memory impairment; disorders of eating behaviours, including anorexia nervosa and bulimia nervosa and sleep disorders (including disturbances of Circadian rhythm). Other CNS disorders include motor disorders such as Parkinson's disease, dementia in Parkinson's disease, neurolepticinduced Parkinsonism and tardive dyskinesias, as well as other psychiatric disorders.
5HTIA/1B/1D receptor antagonists, and in particular compounds of the present invention, may also be of use in the treatment of endocrine disorders such as hyperprolactinaemia, in the treatment of vasospasm (particularly in the cerebral vasculature) and hypertension, as well as disorders in the gastrointestinal tract where -14- WO 98/50358 PCT/EP98/02262 changes in motility and secretion are involved. They may also be of use in the treatment of sexual dysfunction and hypothermia.
The present invention also provides a compound of general formula or a physiologically acceptable salt or solvate thereof for use in the treatment of the aforementioned disorders.
In a further aspect the invention provides a method of treating the aforementioned disorders which comprises administering an effective amount to a patient in need of such treatment of a compound of general formula or a pharmaceutically acceptable salt or solvate thereof.
In particular the invention provides a compound of general formula or a physiologically acceptable salt or solvate thereof for use in the treatment or prophylaxis of depression.
It will be appreciated by those skilled in the art that the compounds according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, different antidepressant agents.
The present invention also provides a pharmaceutical composition, which comprises a compound of formula or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.
Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying WO 98/50358 PCT/EP98/02262 agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colorants.
For parenteral administration, fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The composition may contain from 0.1% to 99% by weight, preferably from 10 to by weight, of the active material, depending on the method of administration.
The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks or months.
The following Examples illustrate the preparation of compounds of the invention.
Description 1 4-Bromo-3-methylphenyl isocyanate To a stirred suspension of 4 -bromo-3-methylbenzoic acid (10.0g, 0.047 mole) in dichloromethane (300ml) was added oxalyl chloride (11.94g, 0.094 mole) followed by 3 drops of DMF. The mixture was stirred at room temperature for 60h, then the solution was concentrated in vacuo to afford the acid chloride as a red oil. This material was redissolved in dichloromethane (300ml) and cooled to 0°C. Tetrabutylammonium iodide (0.150g) was added, followed by a solution of sodium azide (4.36g, 0.066 mole) in water -16- WO 98/50358 PCT/EP98/02262 and the mixture was stirred vigorously at 0°C for 3h, then diluted with water (200ml) and the dichloromethane layer separated, dried (Na 2
SO
4 and concentrated in vacuo (but not to complete dryness) to afford the acyl azide as a pale orange solid. This material was dissolved in toluene (300ml) and heated under reflux for Ih with stirring, then cooled and concentrated in vacuo to afford the title compound as a red brown oil (9.42g, 'H NMR (250MHz, CDCl 3 8 (ppm): 7.54 1H), 7.06 1H), 6.88 (dd, 1H), 2.46 (s, 3H).
Description 2 4-(Pyridin-4-yl)naphth-l-ylamine A stirred suspension of 4-bromonaphth-1-ylamine (10g, 45 mmole) in 1,2dimethoxyethane (400 ml) and water (100 ml) containing sodium carbonate (14g) was flushed with argon for 0.3h. Tetrakis(triphenylphosphine)palladium (2.75g, 2.4 mmole) was added followed by 4-pyridylboronic acid (5.7g, 46 mmole) and the mixture heated at reflux for 5h. The mixture was concentrated in vacuo to a brown slurry and partitioned between dichloromethane and water. The aqueous was further extracted with dichloromethane and the combined organics dried (Na 2
SO
4 and concentrated in vacuo to a brown solid (13.2g). Purification of the solid by flash chromatography eluting with ethyl acetate afforded the title compound as a yellow crystalline solid (7.8g, 78%).
1 H NMR (250 MHz, CDC13) 8 (ppm): 8.68 2H), 7.90 2H), 7.30 5H), 6.84 (d, 1H), 4.32 2H) Description 3 5-(Pyridin-4-yl)-l-naphthoic acid The title compound was prepared from 5-bromo-l-naphthoic acid (EP 547442 Al) and 4pyridylboronic acid using a similar procedure to Description 2.
1 H NMR (250 MHz, d6DMSO) 8 (ppm): 8.75 1H), 8.56 (dd, 2H), 7.98 1H), 7.78 1H), 7.56 1H), 7.45-7.34 4H) Description 4 5-(Pyridin-4-yl)naphth-l-yi isocyanate -17- WO 98/50358 PTE9/26 PCT/EP98/02262 The title compound was prepared from 5-(pyridin-4-yl)-1-napthoic acid (D3) using a similar procedure to Description 1.
IH NMR (250 MiHz, CDCI 3 8 (ppm): 8.74 2H), 8.21 111), 7.61-7.69 (in, 2H1), 7.49-7.33 (in, Description 4-(Pyridin-4-yl)aniline The title compound was prepared from 4-bromoaniline and 4-pyridinylboronic acid using a similar -procedure to Description 2 as a white solid 1 H NMR (250 MHz, d 6 DMSO) 8 (ppm): 8.68-8.63 (in, 2H1), 7.78-7.68 (in, 4H), 6.84 (d, 2H), 5.94 (br s, 2H).
Description 6 3-Chloro-4-(pyridin-4-yI)aniline 3-Chloro-4-bromoacetanilide was reacted with 4-pyridinylboronic acid using a similar procedure to Description 2 to afford 3 -chloro-4-(pyridin-4-yl)acetanilide. This material was hydrolysed by heating under reflux in a mixture of 2M NaOH solution and ethanol for 6h to afford the title compound as a pale yellow solid (5.5g, 111 NMR (250 MiHz, CDCl 3 8 (ppmn): 8.65-8.58 (in, 2H1), 7.38-7.33 (in, 211), 7.13 (d, 1 6.80 I1H), 6.64 (dd, 11H), 3.90 (br s, 2H).
Description 7 2 3 -Dicbloro-4-(pyridin-4-yl)aniline The title compound was prepared from 4 -bromo-2,3-dichloroacetanilide and 4pyridinylboronic acid, followed by basic hydrolysis, using a similar procedure to the preparation of Description 6.
111 NMR (250 MHz, CDCl 3 8 (ppm): 8.64 2H), 7.32 2H), 7.05 lH), 6.85 (d, 11H), 4.40 (br s, 211).
Description 8 1 -Acetyl-2,3-dihydro-6-nitro-1il-indole A stirred solution of 2,3-dihydro-6-nitro-IH-indole (100g, 0.61 mole) in dichloromethane (1000 ml) at room temperature was treated dropwise over 20 min with acetic anhydride 18- WO 98/50358 PCT/EP98/02262 (62 ml, 0.66 mole). The reaction mixture was stirred for a further 2h, then washed with Na 2
CO
3 solution (300 ml) dried (Na 2
SO
4 and concentrated in vacuo to afford the title compound as a yellow solid (125g, 100%).
Description 9 1-Acetyl-6-amino-2,3-dihydro-lH-indole A stirred suspension of 1-acetyl-2,3-dihydro-6-nitro-1H-indole (D8, 125g, 0.61 mole) in THF (5500 ml) was hydrogenated over 10% Pd-C (20g) at 50 psi for 20h. The catalyst was removed by filtration through a plug ofkieselguhr and the filtrate concentrated in vacuo to afford the title compound as a beige solid (102g, 1 H NMR (250 MHz, CDC13) 6 (ppm): 7.64 1H), 6.92 1H), 6.34 (dd, 1H), 4.01 (t, 2H), 3.82 (br s, 2H), 3.06 2H), 2.19 3H).
Description 1-Acetyl-2,3-dihydro-6-(4-methylpiperazin- -yl)-1H-indole A stirred mixture of l-acetyl-6-amino-2,3-dihydro-1H-indole (D9, 3 7.8g, 0.22 mole), mechlorethamine hydrochloride (46g, 0.24 mole) and anhydrous potassium carbonate 0.58 mole) in 1-butanol (1800 ml) was heated at reflux for 8h, then additional mechlorethamine hydrochloride (25g, 0.13 mole) and potassium carbonate (41g, 0.30 mole) were added and reflux continued for 3h. The reaction mixture was allowed to cool and then washed with water (1000 ml). The aqueous wash was extracted with ethyl acetate, and the extract combined with the 1-butanol solution and concentrated in vacuo.
The brown oily residue (60g) was chromatographed on silica gel eluting with 0-8% MeOH/DCM to give an orange oil, which was trituated with ether to afford the title compound as a beige solid (12.2g, 22%).
1 H NMR (250 MHz, CDC13) 5 (ppm): 7.98 1H), 7.04 1H), 6.59 (dd, 1H), 4.04 (t, 2H), 3.23-3.18 4H), 3.10 2H), 2.60-2.53 4H), 2.34 3H), 2.21 3H).
Description 11 2 3 -Dihydro-6-(4-methylpiperazin-l-yl)-lH-indole The title compound was prepared from 1-acetyl-2,3-dihydro-6-(4-methylpiperazin- -yl)- 1H-indole (D10) using a similar procedure to Description 13 as a beige solid -19- WO 98/50358 WO 9850358PCTIEP98/02262 IH NMR (250 MHz, CDCI 3 8 (ppm): 6.98 (dd, 1H), 6.34-6.27 (in, 2H), 3.53 2H), 3.32 (br s, 1H), 3.17-3.11 (in, 4H), 2.94 2H), 2.61-2.52 (in, 4H), 2.34 3H).
Description 12 l-AcetyI-5-chloro-2,3dihydro6(4methylpiperaziD.1ylI)1Hjndole A stirred solution of 1 -acetyl-2,3-dihydro-6-(4-methylpiperazin- 1 -yl)-1I H-indole (Dl 1.1g, 0.0040 mole) in dichioromethane (100 ml) at -5*C under argon was treated dropwise over 15 min with a solution of N-chlorosuccinimide (0.73g, 0.0054 mole) in DCM (10 ml), then kept at -5'C for a further 0.5h and allowed to warm to room temperature over lh. The reaction mixture was extracted with 2M HCl acid (60 ml) and the acid extract basified by addition of solid K 2 C0 3 and extracted with DCM. The.
organic extract was dried (Na 2
SO
4 and concentrated in vacuo to afford the title compound as a beige solid (1.45g, 100%).
1 H NMR (250 MHz, CDCl 3 8 (ppm): 8.05 1H), 7.15 1H), 4.06 2H), 3.20-3.05 (in, 4H), 3.12 2H), 2.70-2.55 (in, 4H), 2.37 3H), 2.22 3H).
Description 13 -Chloro- 2 ,3-dihydro-6-(4-methylpiperazin-1 -yI)-1H-indole A stirred solution of 1 -acetyl-5-chloro-2,3-dihydro-6-(4-methylpiperazin-1 -yl)-1 H-indole (D 12, 1.4g, 0. 0048 mole) in 2M HCl acid (120 ml) was heated at reflux under argon for The reaction mixture was allowed to cool, basified by addition of solid K 2 C0 3 and extracted with DCM. The extract was dried (Na 2
SO
4 and concentrated in vacuo to afford the title compound as a beige solid (0.93g, 78%).
IH NMR (250 MHz, CDCl 3 8 (ppm): 7.07 1H), 6.40 1H), 3.76 (br s, lH), 3.56 (t, 2H), 3.01 (br s, 4H), 2.96 2H), 2.60 (br s, 4H), 2.35 3H).
Description 14 l-Acety-5-bromo2,3-dihydro6(4-methylpiperazin.1 -yI)-1H-indole A stirred mixture of I -acetyl- 2 ,3-dihydro-6-(4-nethylpiperazin- I -yl)-lI H-indole (Dl 2.0g, 0.0077 mole) and anhydrous potassium carbonate (2.12g, 0.0 15 mole) in a mixture of dichloromethane (100 ml) and methanol (5 0 ml) at -5 0 C under argon was treated portionwise over 20 min with benzyltrimnethylammonium tribromide (3.14g, 0.008 1 mole). The mixture was allowed to warm to room temperature over ib, then concentrated 20 WO 98/50358 PCTIEP98/02262 in vacuc and the residue dissolved in dichloromethane (150 ml), washed with water (2x 100 ml), dried (Na 2
SO
4 and concentrated in vacuo to afford the title compound as a beige solid 2 .52g, 97%).
IH NMR (250 MHz, CDCl 3 8 (ppm): 8.06 111), 7.34 1H), 4.06 2H), 3.13 (t, 2H), 3.07 (hr s, 4H), 2.06 (hr s, 4H), 2.35 3H), 2.21 3H).
Description 5-Bromo-2,3-dihydro-6-(4-methylpiperazin-1y).1H-in dole A solution of 1 -acetyl- 2 3 -dihydro-5-bromo-6-(4.methylpiperazin-l-yl)-1 H-indole (Dl 4, 0.60g, 1.8 mmole) in 2M hydrobromic acid (50 ml) was stirred at room temperature for days, then basified by addition of solid K 2 C0 3 and extracted with DCM. The extract was dried (Na 2
SO
4 and concentrated in vacuc to afford the title compound as a brown solid (0.31lg, 58%).
IH NMR (250 MHz, CDC1 3 5 (ppm): 7.24 lH), 6.42 lH), 3.80 (hr s, lH), 3.56 (t, 2H), 3.01-2.92 (in, 6H), 2.59 (hr s, 4H), 2.35 3H).
Description 16 1 -Acetyl- 2 3 -dihydro-5metlyI6.(4methylpiperazin1yl)1 il-indole The title compound was prepared from 1 -acetyl-2,3-dihydro-5-bromo-6-(4methylpiperazin- I y1)- 1 H-ndole (D 14) and tetramnethyltin using a similar procedure to Description 18 as a beige solid IH NMR (250 MHz, CDCl 3 8 (ppm): 8.0 1H), 6.98 1H), 4.02 2H), 3.11 (t, 2H), 2.97-2.92 (in, 4H), 2.56 (hr s, 4H), 2.35 3H), 2.25 3H), 2.20 3H).
Description 17 2 3 -Dihydro-5-methyl-6-(4-methylpiperazin...pyi).1H-indole The title compound was prepared from 1-acetyl-2,3-dihydro-5-methyl-6.(4.
.methylpiperazin-l-yl)-lH-indole (DI16) using a similar procedure to Description 13 as a beige solid IH NMR (250 MHz, CDCl 3 8 (ppm): 6.94 IH), 6.44 lH), 3.52 2H), 2.95 (t, 2H), 2.92-2.86 (in, 4H), 2.55 (hr s, 4H), 2.35 3H), 2.19 3H).
Description 18 21 WO 98/50358 PCT1EP98/02262 1 -AcetyI-2,3-dihydro-6-(4-methylpiperazin-.. yI)-5-vinyl-1 il-in dole A stirred suspension of I-ctl23dhdo5bom--4mtypprzn1 -yl)-1 Hindole (D 14, 600 mg, 1. 8 mmole) in dry DMF (15 ml) was treated with vinyltributyltin (0.78 ml, 2.7 mmole) and de-gassed by bubbling argon through for 20 min, then triethylamine (0.50 ml, 3.6 mmole) and tetrakis(triphenylphosphine)palladium(0) (200 mg) were added and the mixture was heated at 1 00 0 C under argon for 7 h. The reaction mixture was allowed to cool, diluted with EtOAc (150 ml), then extracted with 0.5M HCI acid (2 x 100 ml). The acid extract was basifled by addition of solid K 2 C0 3 then extracted with DCM (2 x 100 ml) and the extract dried (Na 2
SO
4 and concentrated in vacuc to afford the title compound as a beige solid (480 mg, 1 H NMvR (250 MHz, CDCI 3 5 (ppm):7.99 IH), 7.31 1H), 7.00 (dd, 1H), 5.58 (dd, IH), 5.14 (dd, 1H), 4.05 2H), 3.14 2H), 3.02-2.94 (in, 4H), 2.57 (br s, 4H), 2.35 (s, 3H), 2.22 3H).
Description 19 2 3 -Dihydro-6-(4-methylpiperazin-1..yi).5-vinyl11H.indole A stirred solution of 1 -acetyl-2,3-dihydro-6-(4-methylpiperazin- I -yl)-5-vinyl- 1 H-indole (D 18, 250 mg, 9.0 minole) in ethanol (25 ml) was treated with 10% NaOH solution ml), de-gassed by bubbling argon through for 15 min, then heated under reflux for 7 h.
The mixture was allowed to cool, concentrated in vacuo to approx. 40 ml volume and then extracted with DCM. The extract was dried (Na 2
SO
4 and concentrated in vacuo to afford the title compound as a brown solid (170 mg, IH NMR (250 MHz, CDCI 3 8 (ppm): 7.30 1H), 6.98 (dd, IR), 6.38 1H), 5.49 (dd, 1H), 5.01 (dd, IH), 3.81 (br s, 111), 3.56 2H), 2.99 2H), 2.96-2.90 (in, 4H), 2.56 (br s, 4H), 2.35 3H).
Description l-Acetyl-2,3-dihydro-5-ethyI-6-(4..methylpiperazin...pyI)1 H-indole A stirred solution of 1 -acetyl-2,3-dihydro-6-(4-methylpiperazin-1 -yl)-5-vinyl- 1H-indole (D 18, 400 mg, 1.4 mmole) in ethanol (100 ml) was hydrogenated over 10% Pd-C (100 mng) at atmospheric pressure and temperature for 24 h. The catalyst was removed by filtration through kieselguhr and the filtrate concentrated in vacuc to afford the title compound as a beige solid (380 mg, 94%).
22 WO 98/50358 PTE9/26 PCT/EP98/02262 IH NMR (250 MHz, CDCl 3 8 (ppm): 8.05 1H), 7.03 1H), 4.03 2H), 3.13 (t, 2H), 2.96-2.90 (in, 4H), 2.65 2H), 2.57 (br s, 4H), 2.35 3H), 2.20 3H), 1.21 (t, 3H).
5 Description 21 2 3 -Dihydro-5-ethy-6-(4-methylpiperazin-.1 -yl)-1H-indole The title compound was prepared from 1-acetyl-2,3-dihydro-5-ethyl-6-(4methylpiperazin- 1-yl)-1 H-indole (D20) using a similar procedure to Description 13 as a beige solid IH NMR (250 MHz, CDCl 3 8 (ppm): 6.99 1H), 6.49 1H), 3.6 (br s, 111), 3.53 (t, 2H), 2.97 2H), 2.90-2.83 (in, 4H), 2.59 2H), 2.54 (br s, 4H), 2.35 3H), 1. 19 (t, 3H).
Description 22 1l-Acetyl- 2 3 dihydro6(4methypiperzin1yl)-5trifluoromethy-1 Hn dole A stirred mixture of 1 -acetyl-5-bromo-2,3-dihydro.6(4-methylpiperazin. 1 -yl)-1I H-indole (D14, 500 mg, 1.5 mniole), potassium trifluoroacetate (410 mg, 2.7 mmole) and copper iodide (572 mg, 3.0 nimole) in dry DMF (16 ml) and toluene (10 ml) was heated at 1 30'C for 0.5 h under argon using a Dean and Stark head to trap toluene/water. The Dean and Stark head was replaced with a condenser and the mixture heated at 155'C for 34 h, then further potassium trifluoroacetate (410 mg) and copper iodide (570 mng) were added and heating continued at 155 0 C for 3h. The reaction mixture was allowed to cool, then treated with dilute ammonia solution (200 ml) and DCM (150 ml), shaken well and then filtered through a plug of kieselguhr. The organic layer was separated, dried (Na 2
SO
4 and concentrated in vacuo. The residue was purified by chromatography on basic alumina eluting with ethyl acetate to afford the title compound as a beige solid IH NMR (250 MHz, CDCI 3 8 (ppm): 8.28 1H), 7.40 1H), 4.10 2H), 3.18 (t, 2H), 2.98-2.92 (in, 4H), 2.56 (br s, 4H), 2.35 3H), 2.24 3H).
Description 23 2 3 -Dihydro- 6 4 -methylpiperazin-I .yl).5-.trifluoromethyl1 H-.in dole 23 WO 98/50358 PCTIEP98/02262 A solution of 1 -acetyl-2,3-dihydro-6-(4-methylpiperazin- 1-yl)-5-trifluoromethyl- 1Hindole (D22, 260 mg, 1.1 mmole) in 2M HCI acid (25 ml) and ethanol (25 ml) was kept at room temperature for 7 days, then concentrated in vacuo to approx. 25 ml volume. The aqueous residue was basified with solid K 2 C0 3 then extracted with DCM and the extract dried (Na 2
SO
4 and concentrated in vacuo to afford the title compound as a beige solid (300 mg, 91%).
1 H NMR (250 MHz, CDC1 3 8 (ppm): 7.30 1H), 6.57 1H), 4.01 (br s, 1H), 3.63 (t, 2H), 3.01 2H), 2.92-2.85 4H), 2.54 (br s, 4H), 2.34 3H).
Description 24 4-(Pyridin-4-yl)naphth-l-ylacetic acid 4-Bromonaphth-l-ylacetic acid (Ig, 3.78 mmole, J. Org. Chem., 1951, 16, 1588) in 1,2dimethoxyethane (50 ml) was treated with pyridin-4-ylboronic acid (465 mg, 3.78 mmole), sodium hydrogen carbonate (952 mg, 11.3 mmole) and water (10 ml). A stream of argon was bubbled through the mixture for 15 min, then tetrakis (triphenylphosphine) palladium (200 mg, 0.17 mmole) was added and the mixture heated under reflux for 18h. The mixture was then concentrated in vacuo to a gum, which was partitioned between 2M sodium hydroxide solution and dichloromethane. The aqueous layer was separated, adjusted to pH 7 by addition of aqueous potassium carbonate solution and extracted with dichloromethane. The dichloromethane extract was dried (Na 2
SO
4 and concentrated in vacuo to give the title compound, which crystallised from ether as needles mp 210-215 0 C (465 mg, 46%).
1H NMR (250 MHz, CDCl 3 8 (ppm): 8.55 2H), 8.0 1H), 7.7 1H), 7.5-7.3 (m, 7.2 1H), 6.1 (br s, 1H), 4.0 2H).
Description 5-(Pyridin-4-yl)napth-l-ylacetic acid The title compound was prepared from 5-bromonaphth-1-ylacetic acid (Bull. Soc. Chim.
Fr., 1968, 7, 2957) and pyridin-4-ylboronic acid using a similar procedure to Description 24.
1H NMR (250 MHz, CDC13) 5 (ppm): 8.72 2H), 8.13 1H), 7.76 1H), 7.60 (t, 1H), 7.40-7.50 3H), 7.44 2H), 4.12 2H).
-24i WO 98/50358 WO 9850358PCT/EP98/02262 Description 26 Quinolin-6-yl isocyanate The title compound was prepared from 6-quinolinecarboxylic acid using a similar procedure to Description 1.
1'HNMR (250 MHz, CDC1 3 8 (ppm): 8.89 (dd, 1H), 8.13 8.06 (in, 2H), 7.52 1H), 7.48 7.41 (in, 2H).
Description 27 3-(4-Methylpiperazin-1 -yI)-1 -nitrobenzene To a solution of 3-nitroaniline (1 5.0g, 0. 11 mole) in 2-butanol (500m1) was added K 2 C0 3 (52.5g, 0.385 mole) and mechioretharnine hydrochloride (31.4g, 0. 16 mole). The mixture was refluxed under argon with stirring for 1 8h, then more mechlorethamine hydrochloride (I17.5g, 0.09 mole) and K 2 C0 3 2 5.0g, 0. 18 mole) were added and heating under reflux was continued for 24h. The 2-butanol was removed in vacuo and the residue partitioned between H 2 0 (300 ml) and CH 2
CI
2 (300m1). The CH 2 Cl 2 was separated and the aqueous re-extracted with CH 2
CI
2 (3 x 200m1). The organics were combined, dried (Na 2
SO
4 and concentrated in vacuc to afford an orange oil, which was purified by column chromatography on silica gel eluting with 0-4% MeOH/CH 2 Cl 2 The title compound was an orange oil (16.72g, 'H NMR (250 MHz, CDC1 3 8 (ppm): 7.72 1H), 7.65 (dd, 1H), 7.37 1H), 7.19 (dd, 1H), 3.31 4H), 2.59 4H), 2.37 3H).
Description 28 3 -(4-Methylpiperazin-1-yl)aniline 3 4 -Methylpiperazin-1-yl)-1-nitrobenzene (D27, 8.10g, 0.037 mole) was dissolved in EtOH (250m1) and hydrogenated over 10% Pd/C (2g) at room temperature and pressure for 1 8h. The catalyst was filtered off and the filtrate concentrated in vacuc to afford the title compound as a pale yellow oil (6.64g, H NMR (250 Mffz, CDCl 3 8 (ppm): 7.04 lH), 6.37 (dd, IH), 6.26 1H), 6.21 (dd, 1H), 3.60 (br s, 2H), 3.18 4H), 2.56 4H1), 2.34 3H).
Description 29 7-(4-Methylpiperazin-1 -yl)quinoline 25 WO 98/50358 PCT/EP98/02262 3 4 -Methylpiperazin-1-yl)aniline (D28, 6.6g, 0.035mole) was covered with glycerol (8ml, 0.1 mole) and cone. H 2
SO
4 acid (5.2ml, 0.097 mole) was carefully added dropwise, with stirring, over 10 min. An air condenser was fitted, iodine (100mg) added and the reaction heated with stirring at 100 0 C for 3h, then at 150 0 C for 4h. The reaction was cooled and poured into water (250ml). The aqueous was basified to pH10 with KCO 3 and extracted into CH 2 C12 (3 x 300ml). The organics were combined, dried (Na 2
SO
4 and concentrated in vacuo to give a dark brown oil, which was purifed by column chromatography on basic alumina eluting with 2% MeOH/CH 2
CI
2 The title compound was a yellow solid (4.05g, 52%).
'H NMR (250 MHz, CDCl 3 8 (ppm): 8.78 1H), 8.0 (dd, 1H), 7.67 1H), 7.37 (d, 1H), 7.33 (dd, 1H), 7.19 (dd, 1H), 3.40 4H), 2.63 4H), 2.38 3H).
Description 7-(4-Methylpiperazin-1-yl)-l, 2 3 ,4-tetrahydroquinoline 7 4 -Methylpiperazin-1-yl)quinoline (D29, 3.71g, 0.016 mole) was dissolved in EtOH (100ml) and AcOH (5ml) and hydrogenated at 50psi and room temperature over 5% Pt/C for 84h. The catalyst was filtered off, the solvents removed in vacuo and the residue partitioned between 10% Na 2
CO
3 (aq) and CH 2
CI
2 The CH 2 C1 2 was separated, dried (Na 2
SO
4 and concentrated in vacuo to afford the title compound as a pale orange/brown solid (3.60g, 'H NMR (250 MHz, CDC13) 5 (ppm): 6.84 1H), 6.27 (dd, 1H), 6.05 1H), 3.5 (br s, 1H), 3.27 2H), 3.12 4H), 2.68 2H), 2.55 4H), 2.33 3H), 1.91 (quintet, 2H).
Description 31 7-(4-Methylpiperazin-l-yl)-l-trifluoroacetyl-1,2,3,4-tetrahydroquinoline To a stirred solution of 7-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydroquinoline 4.3 mmole) in CH 2 Cl 2 (30ml), cooled in ice, under argon, was added trifluoroacetic anhydride (0.67ml, 4.8 mmole) dropwise. After 30 min at 0°C the mixture was warmed to room temperature over 30 min, then washed with dilute NaHCO 3 The CH 2 C1 2 was separated, dried (Na 2
SO
4 and concentrated in vacuo to afford the title compound as a viscous yellow oil (1.42g, 100%).
'H NMR (250 MHz, CDC1 3 8 (ppm): 7.26 1H), 7.06 1H), 6.78 (dd, 1H), 3.81 (t, 2H), 3.25 4H), 2.72 (br s, 6H), 2.45 3H), 2.05 (quintet, 2H).
-26- "I WO 98/50358 PCT/EP98/02262 Description 32 6 -Bromo-7-(4-methylpiperazin-1y)..-trifluoroacetyl-1 2 3 4 -tetrahydroquinoline The title compound was prepared from 7-(4-methylpiperazin- 1 1 -trifluoroacetyll, 2 ,3,4-tetrahydroquinoline (D3 1) using a similar procedure to Description 14.
1H NMR (250 MHz, CDCl 3 8 (ppm): 7.39 1H), 7.26 1H), 3.82 2H1), 3.29 (br s, 4H), 2.99 (br s, 4H), 2.82 (br s, 2H), 2.62 3H), 2.05 (quintet, 2H).
Description 33 6 -Bromo- 7 4 -methypiperazin1yl)-1,2,3,4-tetrahydroquinoline To a stirred solution of 6-bromo-7-(4-methylpiperazin- 1 1 -trifluoroacetyl- 1,2,3,4tetrahydroquinoline (D32, 0.74g, 1.8 mmole) in MeOH (30m1) was added K 2 C0 3
(S)
(0.50g, 3.6 mmole). After 1 8h at room temperature the MeOH was removed in vacuc and the residue partitioned between CH 2 Cl 2 and 10% Na 2
CO
3 The CH 2 C1 2 was separated, dried (Na 2
SO
4 and concentrated in vacuo to afford the title compound as a yellow/brown solid (0.55g, 98%).
I NMR (250 MIHz, CDCl 3 8 (ppm): 7.10 lH), 6.19 111), 3.85 (br s, 1H1), 3.26 (in, 2H),,2.99 (br s, 411), 2.67 2H), 2.59 (br s, 2.35 3H), 1.89 (quintet, 2H).
Description 34 l-Butyryl-2,3-dihydro-6-nitro-1 H-in dole 2,3-Dihydro-6-nitro-lH-indole (16.4g, 100 mmole) in CH 2 Cl 2 (200m1) was treated with butyryl chloride (I10.6g, 100 mmole) and Et 3 N (10. 1ig, 100 mmole) with continuous stirring at room temperature for 2h. The reaction was then washed successively with HC1 and saturated aqueous K 2 C0 3 solution. The reaction was then dried (Na 2
SO
4 and concentrated in vacuc to a gum which crystallised from petrol as needles to give the title compound (23.4g, 100%).
IH NMR (250 MHz, CDC1 3 8 (PPM): 9.0 111), 7.85 (dd, 111), 7.25 111), 4.15 (t, 2H), 3.3 2H1), 2.4 211), 1.8 211), 1.0 3H).
Description 6-Amino-2,3-dihydro-l-butyryl-1 -H-indole -27- WO 98/50358 PCT/EP98/02262 1-Butyryl-2,3-Dihydro-6-nitro-1H-indole (D34, 19.8g, 84.4 mmole) was stirred with palladium on charcoal (2g) in MeOH (200ml) under an atmosphere of hydrogen at at such a rate that the temperature rose to 60 0 C and the uptake of hydrogen ceased. The reaction was then filtered through celite and the celite washed with hot MeOH to ensure that no product was retained. The filtrate was evaporated in vacuo to give the title compound (13.3g, 77%) as needles.
'H NMR (250 MHz, CDC1 3 8 (ppm): 7.5 1H), 6.85 1H), 6.2 (dd, 1H), 4.9 2H), 2H), 2.9 2H), 2.4 2H), 1.6 2H), 0.95 3H).
Description 36 1-Butyryl-2,3-dihydro-6-iodo-lH-indole A stirred solution of 6-amino-l-butyryl-2,3-dihydro-1H-indole (D35, 3.0g, 0.015mole) in a mixture of cone. H 2 S0 4 (3ml) and water (35ml) at 0 0 C was treated dropwise (tip of the addition funnel touching the liquid surface) with a solution of sodium nitrite (1.1g, 0.016mole) in water (10ml) whilst maintaining the temperature below 5 0 C. This mixture was then stirred for a further 20 min at <30C before adding it dropwise to a solution of potassium iodide (2.66g, 0.016mole) in water (10ml) at 0 0 C. Slight effervescence was seen and a dark orange suspension formed. The mixture was stirred for a further while allowing to warm to room temperature. The product was extracted with EtOAc the organics washed (Na 2
S
2 0 3 solution) and dried (Na 2
SO
4 to give, on evaporation, the title compound as an orange solid (3.3g, 1 H NMR (250 MHz,CDCI 3 6(ppm): 8.64 1H), 7.32 (dd, 1H), 6.90 1H), 4.04 (t, 2H), 3.13 2H), 2.39 2H), 1.75 2H), 1.02 3H).
Description 37 1-Butyryl-2,3-dihydro-6-(pyridin-4-yl)-lH-indole A suspension of 1-butyryl-2,3-dihydro-6-iodo-l H-indole (D36, 3.28g, 10.4mmole) in dimethoxyethane (120ml) and water (30ml) containing Na 2
CO
3 (3.85g, 36.4mmole) was flushed with argon for lh. To the mixture was added 4-pyridylboronic acid (1.3g, 10.8mmole) and tetrakis(triphenylphosphine)palladium(0) 6 00mg, 0.52mmole) and the mixture heated at reflux for lh. The mixture was allowed to cool, evaporated in vacuo and the residue partitioned between water and CH 2 C1 2 The aqueous was extracted further with CH 2 C1 2 the organics combined and dried (Na 2
SO
4 to give on evaporation a -28- S WO 98/50358 PCT/EP98/02262 dark brown oil, which was purified by flash chromatography (eluant 5% MeOH/CH2Cl 2 to give the title compound as a brown solid (1.5g, 54%).
1 H NMR (250 MHz,CDC1 3 8(ppm): 8.61 3H), 7.53 2H), 7.29 2H), 4.13 (t, 2H), 3.25 2H), 2.44 2H), 1.79 2H), 1.04 3H).
Description 38 1-Butyryl-2,3-dihydro-6-(1-methylpiperidin-4-yl)-H-indole To a solution of 1-butyryl- 2 ,3-dihydro-6-(pyridin-4-yl)- 1H-indole (D37, 5.63mmole) in acetone (50ml) was added iodomethane (1.6g, 11.3mmole) and the mixture left to stand overnight. Filtration gave an orange solid (1.2g) which was dissolved in ethanol (25ml) and water (25ml) and the solution cooled to 0OC. To the solution was added sodium borohydride (166mg, 4.4mmole) portionwise over 5 min. and the mixture stirred for a further 10 min. To the mixture was added 2M NaOH solution (16ml) and water (40ml) and the product extracted with CH 2 Cl 2 dried (Na 2
SO
4 and evaporated in vacuo to a brown oil The oil was then dissolved in ethanol and hydrogenated over 10% Pd-C (100mg) at 50 psi and 50 0 C for 72h. Filtration and evaporation of the filtrate in vacuo gave the title compound as a white solid (710mg, 44%).
1H NMR (250 MHz,CDCl 3 5(ppm): 8.19 1H), 7.11 1H), 6.88 1H), 4.04 (t, 2H), 3.15 2H), 2.96 (br d, 2H), 2.48 1H), 2.39 2H), 2.31 3H), 2.03 2H), 1.82 6H), 1.02 3H).
Description 39 5-Bromo-2,3-dihydro-6-(l-methylpiperidin-4-yl)-H-indole To a stirred solution of 1-butyryl-2,3-dihydro-6-(1-methylpiperidin-4-yl)-lH-indole (D38, 2.32mmole) in acetic acid (20ml) was added N-bromosuccinimide(454mg, 2.55mmole) and the mixture stirred at room temperature overnight. The mixture was diluted with water and basified with solid K 2 C0 3 Extraction with CH 2
C
2 drying (Na 2
SO
4 of the organics and evaporation in vacuo gave an off-white solid (890mg). A portion of the solid (790mg, 2.16mmole) in ethanol (20ml) and 2M NaOH solution (30ml) was heated at 0 C under argon for 72h. The product was extracted with CH 2 C1 2 the organics dried (Na 2
SO
4 and evaporated in vacuo to give the title compound as an orange solid (647mg, 100%).
-29- WO 98/50358 PTE9/26 PCT/EP98/02262 I H NMR (250 MIflz,CDCI 3 8(ppm): 7.24 111), 6.57 1H), 3.55 211), 2.99 (in, 4H), 2.88 (in, 111), 2.33 3H), 2.10 (in, 2H), 1.75 (mn, 4H). NHl not observed Description 4 -(t-Butoxycarbonylamino)aniline To a stirred solution of phenylenediaxnine (2.0g, l8.5minole) in CH 2 Cl 2 (50mi) at OOC was added di-tert-butyl dicarbonate (4.25m1, 1 8.5mmole) and the mixture stirred whilst warming to room temperature for 1 6h. Evaporation in vacuo gave the title compound in purity, with the di-Boc compound making up the remainder (3.79g, 98%).
11H NMR (of title compound) (250 MHz,CDCI 3 5(ppm): 7.13 2H), 6.63 211), 6.27 (hr s, 111), 3.50 (hr s, 211), 1.50 9H).
Description 41 4-(Pyrimidin-2-yI)benzoic acid The title compound was prepared from 4-carboxyphenylboronic acid and 2broinopyrimidine in a similar manner to Description 2, obtained as a pale buff powder IH NMR (250 MHz, d'DMSO) 8 (ppm): 12.95 1H), 8.87 2H), 8.41 2H), 8.00 211), 7.41 I1H).
Description 42 4-(Pyrirnidin-2-yI)phenyl isocyanate The title compound was prepared ftrm 4-(pyrimidin-2-yl)benzoic acid (D41) in a similar manner to Description 1, obtained as a pale yellow powder NMR not recorded due to insolubility in CDC1 3 Description 43 -Chloro- 2 3 -dihydro1l-(4-iodophenylaminocarbonyl).6-(4-methypiperazin-1-.yI)-.
1 H-indole The title compound was prepared from 5-chloro-2,3-dihydro-6-(4-methylpiperazin- I yl).
111-indole (D 13) and 4-iodoaniline in a similar mannmer to Example 4, obtained as an offwhite powder WO 98/50358 WO 9850358PCT/EP98/02262 1 H NMR (250 MHz, CDC1 3 8 (ppm): 7.79 1H), 7.60 21-1), 7.23 2H), 7.15 (s, 11H), 6.3 7 11H), 4.07 2H), 3.18 211), 3. 10 (br s, 4H), 2.61 (br s, 411), 2.36 311).
Description 44 5 N-14-(Pyridin-4-yI)naphth-1 -ylj acetamide To a solution of 4 -(pyridin-4-yl)naphth-1I y1amnine (D2, 1.5g, 6.8mmole) in CH 2 Cl2 and triethylamine (1.Oml, 7.lmmole) at OOC was added dropwise a solution of acetyl chloride (0.5m1, 7.Omxnole) in CH 2 Cl 2 (l0mi) and the mixture stirred whilst allowing to warm to room temperature for Ilh. The solution was washed with aqueous 10% Na 2
CO
3 the organics dried (Na 2
SO
4 and evaporated in vacuo to give the title compound as a yellow solid 9g, 100%).
111 NMR (250 MHz,CDCI1 3 5(ppm): 8.73 211), 7.99-7.40 (in, 811), 2.37 3H). NE not observed.
Description -Methyl-1,2,5,6tetrahydropyridin-4.y1)naphth-1pylacetamide To a solution of N-[4-(pyridin-4-yl)naphth- 1-yl]acetarnide (D44, 1. 8g, 6. 8mmole) in acetone (50ml) was added iodomethane (1.92g, l3.6mmole) and the mixture left to stand overnight. Filtration gave a yellow solid (1 .2g) which was dissolved in ethanol (25m1) and water (25m1), cooled to 0O'C and treated portionwise with sodium borohydride (166mg, 4.4mmole) over 5mmn and then stirred for lh. To the mixture was added aqueous NaOH (I16m1) and water (40ml), the product extracted with CH 2 Cl 2 dried (Na 2
SO
4 and evaporated in vacuc to give the title compound as a brown solid (880mg, 44%).
1 H NMR (250 MHz,CDC1 3 8(ppm): 8.06 (dd, 1H), 7.86 (dd, 111), 7.73 111), 7.53 (in, 2H), 7.30 IH), 5.74 (in, lH), 3.18 (br d, 2H), 2.75 2H), 2,56 (mn, 2H), 2,47 311), 2.32 3H1). NH not observed.
Description 46 4 -(l-Methylpiperidin-4-yl)naphth-1-ylamine A solution of 1-methyl-i 2 ,5,6-tetrahydropyridin-4-yl)naphth-1 -yl]acetamide (D345, 800mg, 2.9mmole) in ethanol (50m1) was hydrogenated over 10% Pd-C at 50psi and 0 C for 192h. Filtration through celite and evaporation of the filtrate gave, on -31 WO 98/50358 PCT/EP98/0262 evaporation, a white solid (683mg). The solid was dissolved in ethanol (10ml) and aqueous 2M NaOH (16ml) and heated at reflux under argon for 72h. The mixture was extracted with CH 2 Cl 2 the organics dried (Na 2
SO
4 and evaporated in vacuo to give the title compound as an orange oil (520mg, 76%).
1 H NMR (250 MHz,CDC1 3 8(ppm): 8.06 (dd, 1H), 7.87 (dd, 1H), 7.53-7.40 2H), 7.22 1H), 6.78 1H), 4.06 (br s, 2H), 3.19 1H), 3.04 (br d, 2H), 2.36 3H), 2.20 2H), 1.92 4H).
Description 47 4 4 -Aminophenyl)-2-methyloxazole A mixture of 2 -methyl-4-(4-nitrophenyl)oxazole (1.70g, 8.2 mmole, J. Het. Chem. 1981, 18, 885) and 10% palladium on carbon (0.20g) in THF (70ml) was stirred under hydrogen at atmospheric pressure for 42h. The mixture was filtered and concentrated to dryness in vacuo. The residue was purified by chromatography on silica gel eluting with 2% MeOH in CH 2
CI
2 The title compound was obtained as a yellow powder (0.92g).
'H NMR (250 MHz, CDCI 3 8 (ppm): 7.66 1H), 7.52 2H), 6.70 2H), 3.73 (s, 2H), 2.49 3H).
Description 48 4 -(2-Methyl-pyridin-4-yI)benzoic acid The title compound was prepared from 4-bromo-2-methylpyridine Org. Chem. 1985, 4410) and 4 -carboxyphenylboronic acid using a similar procedure to Description 2 as a white solid 'H NMR (250 MHz, dDMSO) 8 (ppm): 8.52 1H), 8.03 2H), 7.80 2H), 7.61 (s, 1H), 7.52 (dd, 1H), 2.55 3H). COOH not observed.
Description 49 4-(2-Methyl-pyridin-4-yl)aniline The title compound was prepared from 4 2 -methyl-pyridin-4-yl)benzoic acid (D48) using a similar procedure to Description 1 to form the isocyanate, then by base hydrolysis using NaOH, to afford the amine as a beige solid 'H NMR (250 MHz, CDC1 3 8 (ppm): 8.46 1H), 7.52 7.45 2H), 7.31 1H), 7.29 7.24 1H), 6.80 6.73 2H), 3.87 2H), 2.59 3H).
-32- WO 98/50358 WO 9850358PCT/EP98/02262 Description N-(tert-Butyloxycarbonyl)4iodoaniline To a solution of 4-iodoaniline (3g, 0.0 14 mole) in dry dichioromethane 2 Oml) was added di-tert-butyl dicarbonate 2 .99g, 0.014 mole) followed by a catalytic amount of 4dimethylaminopyridine. The reaction was stirred overnight at ambient temperature then washed with water (2x20ml) and dried (MgSO 4 Filtration and evaporation gave an offwhite solid (Il.
9 0g, 43%).
1 HNMR (250M~z, CDCl 3 8 (ppm): 7.57 2H), 7.14 2H), 6.43 (br, 1H), 1.5 1 (s, 9H).
Description 51 N-(tert-Butyloxycarbonyl).4-(thiazol.2-y1)aniline A mixture of N-(tert-butyloxycarbonyl).4-iodoailine (D50, 3 19mg, 1 nmnole), bis (pinacolato)diboron (279mg, 1. 1 inmole), 1, l'-bis(diphenylphosphino)ferrocene dichloropalladium (11) complex with DCM (24mg, 0.029 mmole) and potassium acetate (294mg, 3 mmole) in dry DMvF (6m1) was heated at 80*C for 2h. After cooling 2bromothiazole (328mg, 2 mmole), 2M sodium carbonate (2.5m1) and 1,1 '-bis (diphenylphosphino)ferrocene dichloropalladium. (II) complex with DCM 1) (24mg, 0.029 mmole) was added and the reaction heated at 80'C for 1 8h. After cooling the solution was diluted with water (20m1). Extraction using ethyl acetate (2x20m1) followed by drying (Mg9SO 4 filtration and evaporation under reduced pressure gave an oil. This was chromatographed on silica gel eluting with 10% ethyl acetate in hexane to afford the title compound as an oil (137mg, 1 HNMR (250MHz, CDC1 3 8 (ppm): 7.91 2H), 7.82 1H), 7.48 2H), 7.27 (d, 1H), 6.62 (br, 1H), 1.54 9H).
Description 52 4 -(Thiazol-2-yI)aniline A solution of N-(tert-butyloxycarbonyl)-4(tliazo12.yl)aniline (D5 1, 122mg, 0.44 mmole) in dichloromethane, (2m1) and trifluoroacetic acid 1lml) was stirred at ambient temperature for 18h and then water (20m1) was added. The aqueous phase was extracted with dichloromethane (2x 1 Omi) and the extract washed with 10% aqueous sodium 33 WO 98/50358 PCT/EP98/02262 hydrogen carbonate (2x20ml), then dried (MgSO 4 and evaporated under reduced pressure to give a light yellow oil, which solidified on standing (70mg, 'H NMR (250MHz, CDC13) 8 (ppm): 7.76 3H), 7.20 1H), 6.72 2H), 3.90 (br s, 2H).
Description 53 4-(Isoquinolin-2-yl)benzoic acid The title compound was prepared from 4-carboxyphenylboronic acid and 4bromoisoquinoline using a similar procedure to Description 2, obtained as an off-white solid 'H NMR (250MHz, d'DMSO) 8 (ppm): 13.15 (br s, 1H), 9.39 1H), 8.49 1H), 8.25 1H), 8.13 2H), 7.90 7.67 Description 54 4-(Isoquinolin-4-yl)phenyl isocyanate The title compound was prepared from 4 -(isoquinolin-4-yl)benzoic acid (D53) using a similar procedure to Description 1. The isocyanate was used as its toluene solution without concentration to the neat compound.
Description 4-(Quinolin-3-yl)benzoic acid The title compound was prepared from 4 -carboxyphenylboronic acid and 3bromoquinoline using a similar procedure to Description 2, obtained as a white solid 'H NMR (250MHz, d 6 DMSO) 8 (ppm): 13.09 (br s, 1H), 9.32 1H), 8.76 (d, 1H), 8.07 5H), 7,83 2H), 7.67 1H).
Description 56 4-(Quinolin-3-yl)phenyl isocyanate The title compound was prepared from 4 -(quinolin-3-yl)benzoic acid (D55) using a similar procedure to Description 51. The isocyanate was used as its toluene solution without concentration to the neat compound.
-34- WO 98/50358 PCT/EP98/02262 Description 57 4-(Quinolin-8-yl)benzoic acid The title compound was prepared from 4 -carboxyphenylboronic acid and 8bromoquinoline using a similar procedure to Description 2, obtained as a white solid 'H NMR (250MHz, d 6 DMSO) 6 (ppm): 12.98 (br s, 1H), 8.92 1H), 8.46 (d, 1H), 8.06 3H), 7.80 4H), 7.60 1H).
Description 58 4-(Quinolin-8-yl)phenyl isocyanate The title compound was prepared from 4 -(quinolin-8-yl)benzoic acid (D57) using a similar procedure to Description 51. The isocyanate was used as its toluene solution without concentration to the neat compound.
Description 59 3-Bromo-2,6-dimethylpyridine (D59a) and 4 -Bromo-2,6-dimethylpyridine (D59b) A stirred solution of phosphorus oxybromide (25g, 0.085 mole) in 1,2dichloroethane (250ml) at room temperature under argon was treated with 2,6lutidine-N-oxide (10g, 0.081mole), then heated at reflux for 6h. The mixture was allowed to cool, then poured slowly into well stirred ice/water (400ml) and basified by addition of solid K 2
CO
3 The aqueous mixture was extracted with dichloromethane and the extract dried (Na 2
SO
4 and concentrated under vacuum.
The residue was chromatographed on silica gel eluting with 1:1 ether/60-80 petrol to separate four components. The second component was 3-bromo-2,6dimethylpyridine (2.5g, 21%) as a yellow oil; 1H NMR (250MHz, CDC13) 8 (ppm): 7.66 1H), 6.86 1H), 2.63 3H), 2.48 3H) and the third component was 4 -bromo-2,6-dimethylpyridine (1.5g, 12%) as a pale yellow oil 'H NMR (250MHz, CDC1 3 6 (ppm): 7.16 2H), 2.50 6H).
Description WO 98/50358 PCT/EP98/02262 4 -(2,6-Dimethyl-pyridin-4-yl)benzoic acid The title compound was prepared from 4 -bromo-2,6-dimethylpyridine (D59b) and 4-carboxyphenylboronic acid using a similar procedure to Description 2 as a white solid 'H NMR (250MHz, d6DMSO) 6 (ppm): 8.05 2H), 7.86 2H), 7.42 2H), 2.50 6H). Acid proton not observed.
Description 61 4-(2,6-Dimethyl-pyridin-3-yl)benzoic acid The title compound was prepared from 3-bromo-2,6-dimethylpyridine (D59a) and 4-carboxyphenylboronic acid using a similar procedure to Description 2 as a beige solid 'H NMR (250MHz, d 6 DMSO) 8 (ppm): 8.00 2H), 7.52 1H), 7.42 2H), 7.18 1H), 2.47 3H), 2.40 3H). Acid proton not observed.
Description 62 4-(2,6-Dimethyl-pyridin-4-yl)phenyl isocyanate The title compound was prepared from 4 2 6 -dimethyl-pyridin-4-yl)benzoic acid using a similar procedure to Description 1. The isocyanate was used as its toluene solution without concentration to the neat compound.
Description 63 4-(2,6-Dimethyl-pyridin-3-yl)phenyl isocyanate The title compound was prepared from 4 -(2,6-dimethyl-pyridin-3-yl)benzoic acid (D61) using a similar procedure to Description 1. The isocyanate was used as its toluene solution without concentration to the neat compound.
Description 64 8-Bromoquinoline (1.5g, 7.2 mmole) was added dropwise to a well stirred solution of cone. H 2 S0 4 (5ml), cone. HNO 3 (10ml) and fuming HNO 3 (2ml), cooled in ice. The mixture was heated at 65°C for 30h, then cooled and poured into H20 (350ml) with stirring. The precipitate that formed was filtered, washed -36- WO 98/50358 PCT/EP98/02262 with H 2 0 and dried under vacuum to give the title compound as a pale cream solid (I.lIOg, 1 HNMR (250NMz, CDCl 3 5 (PPM): 9.17 (dd, 1H), 9.07 (dd, lH), 8.26 111), 8.20 111), 7.74 (dd, 111).
Description 5-Nitro-8-phenylquinoline The title compound was prepared from 8-bromo-5-nitroquinoline (D64) and phenylboronic acid using a similar procedure to Description 2, as an orange/brown solid 1 H NMR (250NMz,
CDCI
3 6 (PPM): 9.11 9.05 (in, 2H), 8.44 lH), 7.82 (d, lH), 7.70 7.63 (in, 3H), 7.59 7.46 (in, 3H).
Description 66 5-Amino-8-phenylquinoline The title compound was prepared from 5-nitro-8-phenylquinoline (D65) using a similar procedure to Description 20, as an orange/brown solid 1H NMR (250MHz, CDCl 3 8 (PPM): 8.93 (dd, 1H), 8.21 (dd, 1H1), 7.76 (dd, 1H), 7.66 1H), 7.59 7.32 (in, 511), 6.89 1H), 4.23 2H).
Description 67 6 -Acetamido-2-methylquinoline The title compound was prepared from 6 -amino-2-methylquinoline and acetic anhydride using a similar procedure to Description 8, as a green solid H NMvIR (250M~z, CDCl 3 6 (ppm): 8.30 1H), 8.01 1H), 7.95 1H), 7.49 (in, 211), 7.27 1H), 2.72 311), 2.25 3H).
Description 68 6 -Amino-2-(2-phenylethenyl)quinoline A suspension of 6 -acetamnido-2-methylquinoline (D67, 600mg, 3.0 inmole) in acetic anhydride (6m1) was treated with benzaldehyde (954mg, 9.0 mmole) and the mixture heated at 1 20'C for 40h, then cooled and the acetic anhydride removed in vacuo. The residue was dissolved in 2M NaOH (30in1) and EtOH -37- WO 98/50358 PCT/EP98/02262 and heated under reflux with stirring. After 18h the EtOH was removed in.
vacuo and the residue extracted with EtOAc (3x100ml). The organics were combined, dried (Na 2
SO
4 and concentrated in vacuo giving a crude brown oil, which was purified by chromatography on basic alumina eluting with EtOAc.
The title compound was obtained as a brown solid (210mg, partially contaminated with benzyl alcohol.
IH NMR (250MHz, CDCl 3 8 (ppm): 7.91 7.87 2H), 7.60 7.56 2H), 7.54 1H), 7.42 7.28 5H), 7.15 (dd, 1H), 6.89 1H), 3.96 2H).
Description 69 6-Amino-2-(2-phenylethyl)quinoline The title compound was prepared from 6 -amino-2-(2-phenylethenyl)quinoline (D68) using a similar procedure to Description 20, as a yellow oil partially contaminated with benzyl alcohol.
1H NMR (250MHz, CDC13) 8 (ppm): 7.87 1H), 7.80 1H), 7.38 7.08 (m, 7H), 6.89 1H), 3.90 2H), 3.25 3.07 4H).
Description 2-(3-Nitrophenoxy)pyrimidine A stirred mixture of 3-nitrophenol (2.08g, 15 mmole), 2-bomopyrimidine (2.38g, mmole) and anhydrous potassium carbonate (2.76g, 20 mmole) in dry DMF was heated at 80 0 C for 4h. The cooled mixture was concentrated to dryness in vacuo and the residue partitioned between CH 2 C12 (75ml) and water The organic phase was separated, washed with water, dried (Na 2
SO
4 and concentrated to dryness in vacuo. The residue was purified by chromatography on silica gel eluting with CH 2 C1 2 The title compound was isolated as a pale yellow powder (1.94g, 1H NMR (250MHz, CDC13) 8 (ppm): 8.60 2H), 8.14 2H), 7.58 2H), 7.12 1H).
Description 71 3-(Pyrimidin-2-yloxy)aniline -38- WO 98/50358 PCT/EP98/02262 To a stirred mixture of 2 3 -nitrophenoxy)pyrimidine (D70, 0.65g, 3 mmole) and tin (II) chloride (2.28g, 12 mmole) in methanol (30ml) was added cone. HCI (0.7ml). The mixture was heated at reflux for 2h, cooled and concentrated in vacuo to near dryness. The residue was treated with CH 2
CI
2 (50ml) and water (25ml) and 2N NaOH solution was added to adjust the pH to 12. The mixture was filtered and the organic phase separated, washed with water, dried (Na 2
SO
4 and concentrated to dryness in vacuo to afford the title compound as a yellow powder (0.50g, 89%).
'H NMR (250MHz, CDC13) 8 (ppm): 8.55 2H), 7.19 1H), 7.02 1H), 6.59 6.51 3H), 3.76 2H).
Description 72 N-Methyl-4-nitro-N-(pyrimidin-2-yl)aniline To a stirred solution of N-methyl-4-nitroaniline (2.20g, 14.5 mmole) in dry DMF (25ml) was added potassium tert-butoxide (1.79g, 16 mmole). After stirring for lh at room temperature 2-bromopyrimidine (2.30g, 14.5 mmole) was added and the mixture warmed to 80 0 C for 6h and then stood overnight at room temperature.
After concentrating to dryness in vacuo, the residue was partitioned between
CH
2
CI
2 (100ml) and water (30ml). The organic phase was washed with water, dried (Na 2
SO
4 and concentrated to dryness. Trituration of the residue in diethyl ether afforded the title compound as a pale yellow-orange powder (1.24g, 37%).
'H NMR (250MHz, CDCl 3 5 (ppm): 8.43 2H), 8.25 2H), 7.56 2H), 6.77 1H), 3.67 3H).
Description 73 4-[N-Methyl-N-(pyrimidin-2-yl)amino]aniline A solution of N-methyl-4-nitro-N-(pyrimidin-2-yl)aniline (D72, 1.30g, 5.6 mmole) in methanol (70ml) and ethyl acetate (70ml) was treated with palladium on carbon (0.25g), and shaken under hydrogen at 1 atmosphere for 48h.
The filtered mixture was concentrated to dryness and the residue triturated in diethyl ether to afford the title compound as a pale orange-brown powder (0.78g, 68%).
-39- WO 98/50358 PCT/EP98/02262 I H NMR (25ONMz, CDC1 3 8 (ppm): 8.30 211), 7.07 2H), 6.68 2H), 6.48 1H), 3.66 (br s, 2H), 3.45 3H).
Description 74 5-(Pyridin-4-yI)naphth-1-ylamine The title compound was prepared from 5-bromo-1-naphthylamine (YP 08151353A2) and 4-pyridylboronic acid using a similar procedure to Description 2.
IH NMR (25OMHz,CDC] 3 5(ppm): 8.75-8.67 (in, 2H), 7.93 1H), 7.70-7.35 (in, 4H), 7.28-7.20 (in, 2H), 6.85-6.80 (in, 1H), 4.25 2H).
Description N-15-(Pyridin-4-yI)naplith-1 -yljacetamide The title compound was prepared from 5-(pyridin-4-yl)naphth-1I-ylamine (D74) in a similar manner to Description 44. NM 263.
Description 76 N-15-(1-Methyl-1 2 ,5, 6 -tetrahydropyridin-4-yl)naphth-1-ylJ acetamide The title compound was prepared from N-[5-(pyridin-4-yl)naphtfr.1.yl]acetiide in a similar manner to Description 45. MH+ 28 1.
Description 77 5-(1 -Methylpiperidin-4-y)naphthl1ylamine The title compound was prepared from N-[5-(l-methyl-1,2,5,6-tetrahydropyridin-4yl).
naphth- I-yl] acetamide (D76) in a similar manner to Description 46.
IH NMR (25OMiHz,CDCl 3 8(ppm):7.72 (in, 1H), 7.57 1H), 7.42 (in, 2H), 7.32 (t, 1H), 6.78 1H), 4.16 (br s, 2H), 3.28 (in, 1H), 3.05 (br d, 2H), 2.37 3H), 2.20 (in, 2H), 1.93 (mn, 4H).
Description 78
N-
2 4 -NitrophenyI)ethyI-trifluoroacetamide A solution of tiifluoroacetic anhydride (10.6m1) in dichioromethane (lO0mI) was added dropwise to a stirred solution of 2,6-lutidine (I17.4m1) and 4nitrophenethylamine hydrochloride (15.2g, 75 minole) at 0 0 C. The mixture was I WO 98/50358 WO 9850358PCT/EP98/02262 stirred at 25'C overnight under argon and then washed with dilute citric acid (x2), brine and dried (Na 2
SO
4 The material in the organic phase gave the title compound as a pale yellow solid (I19.04g).
Description 79 7 -Nitro-l, 2 3 4 -tetrahydro-2-trifluoroacetyisoquinoline
N-
2 -(4-Nitrophenyl)ethyl-trifluoroacetamide (D78, 2.26g, 9.15 mmole) and paraformaldehyde (0.45g, 14.4 mmole) in acetic acid (l0mi) and conc. H 2 S0 4 (1 5m1) were stirred at 25'C for 20h according to the procedure of G.E. Stokkcr, Tet. Lett., 1996, 37, 5453. Work-up afforded the title compound as a white solid (2.17g).
I H NMR (250MHz, CDCI 3 8 (ppm): 8. 10 (in, 7.38 I1H), 4.92-4.85 (2 x s, 2H), 3.92 (in, 2H), 3. 10 (in, 2H). MiH+ 274.
Description 7-Nitro-1 2 ,3,4-tetrahydroisoquinoline 7-Nitro- 1, 2 3 4 -tetrahydro-2-trifluoroacetylisoquinoline (D79, 1 7.2g; 63 mmole) was hydrolysed at room temperature using a solution of potassium carbonate (46.6g) in 10% aqueous methanol (660m1). Work-up with dichioromethane gave the title compound (1 I g).
Description 81 2-Methyl-7-nitro-1 2 3 4 -tetrahydroisoquinoline 7 -Nitro- 1,2,3,4-tetrahydroisoquinoline (D80, 2.08g; 11.7 mmole) was treated with 88% formic acid (3.45m1) and 37% aqueous formaldehyde (5.88m1) at 80'C for .2h according to the procedure of G.M. Carrera. and D.S. Garvey, J. Het. Chem., 1992, 29, 847. Basification with 10% sodium hydroxide followed by extraction with ethyl acetate afforded an orange gum Chromatography on silica gel in 0-3% methanol/ethyl acetate gave the title compound as an orange solid (1 .7g).
MH+ 193.
Description 82 7-Amino-2-methyl-1 2 3 4 -tetrahydroisoquinoline -41- WO 98/50358 PCT/EP98/02262 2 -Methyl- 7 -nitro-l,2,3,4-tetrahydroisoquinoline (D81, 0.25g; 1.3 mmole) in methanol (40ml) was hydrogenated over 10% palladium on carbon (100mg) at atmospheric pressure overnight. The catalyst was removed by filtration through a pad of kieselguhr and evaporation in vacuo gave the title compound as a white solid (213mg). MH 163.
Description 83 8 -Bromoquinoline-2,4-dicarboxylic acid To a stirred solution of KOH 2 1.3g, 0.38 mole) in H 2 0 (64ml) was added 7-bromoisatin (10g, 0.044 mole, Proc. Royal Soc., 1958, 148, 481) over 1 min, followed by pyruvic acid (5.35ml, 0.077 mole) over 1 min. The resultant solution was stirred at room temperature for lh, then heated under reflux for 1.5h, then cooled to room temperature, diluted with
H
2 0 (100ml) and filtered. The filtrate was acidified to pH1 with cone. HCI acid, filtered, and the solid washed with H 2 0 and dried under vacuum. The title compound was a brown solid (10.1g, 77%).
1 H NMR (250 MHz, d 6 DMSO) 5(ppm) 8.92 (dd, 1H), 8.64 1H), 8.44 (dd, 1H), 7.86 1H). Acid protons not observed.
Description 84 8-Bromoquinoline-4-carboxylic acid A solution of 8-bromoquinoline-2,4-dicarboxylic acid (D83, 10g, 34 mmole) in nitrobenzene (40ml) was heated under reflux for 2h, then allowed to cool to room temperature, diluted with hexane (60ml) and the title compound filtered off as a brown solid (8.5g, 100%).
1 H NMR (250 MHz, d 6 DMSO) 5(ppm) 8.95 1H), 8.50 (dd, 1H), 8.04 (dd, 1H), 7.82 1H), 7.44 1H). Acid proton not observed.
Description 8 -Phenylquinoline-4-carboxylic acid The title compound was prepared from 8-bromoquinoline-4-carboxylic acid (D 84) and phenylboronic acid using a similar procedure to Description 2, as a brown solid 1 H NMR (250 MHz, CDC1 3 6 (ppm) 9.12 1H), 8.89 (dd, 1H), 8.05 1H), 7.84- 7.73 7.68-7.64 2H), 7.54-7.40 3H). Acid proton not discernible.
-42- WO 98/50358 PCT/EP98/02262 Description 86 8-Phenylquinolin-4-yl isocyanate The title compound was prepared from 8-phenylquinoline-4-carboxylic acid (D 85) using a similar procedure to Description 1. The isocyanate was used as its toluene soloution without concentration to the neat compound.
Description 87 4 -Amino-2-methylphenylboronic acid A stirred solution of4-bromo-3-methylaniline (20g, 0.107 mole) and triethylamine (33ml, 0.237 mole) in dichloromethane (250ml) at 0°C under argon was treated dropwise over min with a solution of bis(chlorodimethylsilyl)ethane (25.3g, 0.12 mole) in dichloromethane (100ml). The mixture was warmed to room temperature and stirred for then filtered and concentrated in vacuo. The residue was extracted with 60-80 petrol (400ml) and the filtrate concentrated in vacuo to leave the stabase as an orange oil 100%). This was dissolved in dry THF (400ml), coled to -65 0 C under argon and treated dropwise over 15 min with 2.5M n-butyllithium in hexane (52ml, 0.13mole). The mixture was stirred at -65 0 C for lh, then treated dropwise over 10 min with triisopropylborate (30ml, 0.13 mole), stirred at -65 0 C for a further 1.5h, then treated with saturated aqueous NH 4 CI solution (100ml) and allowed to warm to room temperature.
The mixture was diluted with water (200ml), acidified with cone. HCI acid (50ml), stirred for 20 min, then concentrated under vacuum to approx. 400ml volume. The aqueous residue was washed with ethyl acetate and then basified by addition of solid K 2
CO
3 The basic mixture was extracted with ethyl acetate and the extract dried (Na 2
SO
4 and concentrated under vacuum to approx. 150ml volume, when a solid began to precipitate out. The mixture was cooled to 8 0 C and the solid filtered off and dried to afford the title compound as a white solid (9.2g, 51%).
IH NMR (250MHz, d6DMSO) 8 (ppm): 7.69 1H), 6.40-6.32 2H), 5.34 (br s, 2H), 2.52 3H). Acid protons not observed.
Description 88 4 2 ,6-Dimethyl-pyridin-4-yl)-3-methylaniline -43- WO 98/50358 PCT/EP98/02262 The title compound was prepared from 4-chloro-2,6-dimethylpyridine (Chem. Abs. 1952, 46; 4541) and 4 -amino-2-methylphenylboronic acid (D87) using a similar procedure to Description 2 as beige solid 'H NMR (250MHz, CDCl 3 8 (ppm): 7.01 1H), 6.90 2H), 6.62-6.54 2H), 3.70 (br s, 2H), 2.55 6H), 2.22 3H).
Description 89 3-Methyl-4-(6-methyl-pyridin-2-yl)aniline The title compound was prepared from 2-bromo-6-methylpyridine and 4-amino-2methylphenylboronic acid (D87) using a similar procedure to Description 2 as beige solid (100%).
'H NMR (250MHz, CDC13) 8 (ppm): 7.62-7.55 1H), 7.22 1H), 7.15 1H), 7.05 1H), 6.62-6.55 2H), 3.68 (br s, 2H), 2.59 3H), 2.31 3H).
Description acid A stirred solution of 5-bromo-l-naphthoic acid (Bull. Soc. Chim. Fr., 1968, 7, 2957, 22.3g, 0.089 mole) in dry THF (1000ml) at -60 0 C under argon was treated dropwise over min with 1.6M n-butyllithium in hexane (125ml, 0.20 mole). The initial brown solution gave a beige precipitate as the first equivalent was added, which redissolved on addition of the second equivalent. The resulting solution was stirred at -60 0 C for 40 min, then triisopropylborate (51ml, 0.22 mole) was added, and the mixture stirred at -60 0 C for a further lh, before warming gradually to -10 0 C. Saturated aqueous NH 4 C1 solution was added (300ml), followed by water (400ml) and then 5M HCI acid (200ml). The resulting mixture was concentrated in vacuo to approx. 1000ml volume, then basified by addition of 40% NaOH solution and washed with ethyl acetate. The aqueous was added to excess HC1 acid and the solid which precipitated out was filtered off, washed with water and dried to afford a white solid 9 .67g), which contained approx. 50% of the title compound together with 1-naphthoic acid.
Description 91 5-(6-Methyl-pyridin-2-yl)-l-naphthoic acid -44- WO 98/50358 WO 9850358PCT/EP98/02262 The title compound was prepared from 2-bromo-6-methylpyridine and 1-ylboronic acid (D90) using a similar procedure to Description 2 as beige solid 1H NMIR (250MHz, d'DMSO) 5 (ppm): 8.90 1H), 8.13 IH), 8.06 (dd, 1H), 7.84 (t, 1H), 7.67 1H), 7.62-7.46 (in, 2H), 7.41 1H), 7.32 1H), 2.55 3H). Acid proton not observed.
Description 92 5-(6-Methyl-pyridin-2-yI)naphth-1 -yI isocyan ate The title compound was prepared from 5-(6-methyl-pyridin-2-yi)-1I-naphthoic acid (D91) using a similar procedure to Description 1. The isocyanate was not isolated, but used in the next step as its toluene solution.
Description 93 5-Chloro-2,3-dihydro-6-(4-methylpiperazin-1 -yl)-1-trifluoroacetyl-lH-indole The title compound was prepared from 5-chloro-2,3-dihydro-6-(4-methylpiperazin Il-yl)- 1 H-indole (Dl 13) using a similar procedure to Description 3 1, as a beige solid IH NMR (250 MHz, CDCI3) 5 (ppm) 8.02 1H), 7.25 1 4.29 2H), 3.19 (t, 2H), 3. 10 (br s, 4H), 2.64 (br s, 4H), 2.3 9 3H).
Description 94 5-Chloro-2,3-dihydro-6-(piperazin-1 -yI)-l -trifluoroacetyl-lil-indole To a stirred soloution of 5-chloro-2,3-dihydro-6-(4-methylpiperazin- 1-yl)trifluoroacetyl- IH-indole (D93, 7.0g, 20 mmole) in 1,2-dichloroethane (200m1) under argon, was added diisopropylethylamine (3.50ml, 20 minole) followed by I1-chioroethyl chloroformate (4.3 Smi, 40mmole). After 1h the mixture was washed with dilute NaHCO 3 then dried (Na 2
SO
4 and concentrated in vacuo -giving a brown solid (8.86g, 100%). A suspension in MeOH (200m1) was stirred under reflux for 3h, then allowed to cool and the MeGH removed in vacuc. The residue was partitioned between dilute NaHCO 3 (aq) and CH 2 Cl 2 The CH 2 C1 2 was seperated and the aqueous reextracted with CH 2 Cl 2 (2 x 50mi). The organics were combined, dried (Na 2
SO
4 and concentrated in vacuc giving the title compound as a brown solid (4.79g, 72%).
1 H NMR (250 MHz, CDCl 3 8 (ppm): 8.00 1H), 7.25 1H), 4.30 2H), 3.20 (t, 2H), 3.10-3.08 (br m, 8 NH not disernible.
WO 98/50358 PCTIEP98/02262 Description 6-(4-Acetylpiperazin-1-yI)-5-chloro-2,3-dihydro..1-trifluoroacetyl- lH-indole A stirred soloution of 5-chloro-2,3-dihydro-6-(piperazin- Il-yl)-lI -trifluoroacetyl- 1 H-indole (D 94, 1.0g, 3.0 mmole) in CH 2 Cl 2 (50m1) cooled in ice, was treated with acetic anhydride (0.34g, 3.3 minole) then allowed to warm to room temperature. After 6h the mixture was washed with dilute NaHCO 3 dried (Na 2
SO
4 and concentrated in vacuo to afford the title compound as a brown solid 1Og, 97%).
11H NMR (250 MHz, CDCl 3 8 (ppm) :7.98 I1H), 7.26 I1H), 4.31 211), 3.79 (br s, 2H), 3.64 (br s, 2H), 3.21 211), 3.05-3.00 (in, 4H), 2.15 3H).
Description 96 6-(4-Acetylpiperazin-1 -yI)-5-chloro-2,3-dihydro-1 H-indole The title compound was prepared from 6-(4-acetylpiperazin- 1 -yl)-5-chloro-2,3-dihydro- I1trifluoroacetyl-1IH-indole (D 95) using a similar procedure to Description 33, as a brown foam (8
I
1 H NMIR (25 0 MHz, CDCl 3 6 (ppm) 7.09 1 6.33 1lH), 3.79-3.75 (in, 2H), 3.63-3.54 3.01-2.91 (in, 611), 2.13 3H). NH not discernible.
Description 97 5-Chloro-2,3-dihydro-6-(4-ethylpiperazin1 -in dole A stirred solution of 6-(4-acetylpiperazin-1I-yl)-5-chloro-2,3-dihydro- 1H-indole (1396, 0.65g, 2.3 inmole) in THlE (30m1) at room temperature under argon was treated with IM borane-THF complex in THE (9.3m1, 9.3 inmole), then heated at reflux for 5h. The mixture was cooled to 0 0 C then treated dropwise with conc HC1 acid (6m1) in methanol (25m1). After 30 min, the solution was heated to reflux for 2h, then concentrated in vacuo. The residue was treated with ethyl acetate (50m1) and 2M HCI acid shaken well and the aqueous layer separated, basified with K 2 C0 3 and extracted with dichioromethane. The extract was dried (Na 2
SO
4 concentrated in vacuo and the residue purified by chromatography on silica gel eluting with 2-10% methanot/dichloroemethane to afford the title compound as a beige solid 31 g, 5 1H1 NN4P (250MI-z, CDCl 3 6 (ppm): 7.07 1H), 6.41 111), 3.73 (br s, 111), 3.56 (t, 2H1), 3.03 (br s, 4H), 2.97 2H1), 2.63 (br s, 4H), 2.49 2H), 1. 13 311).
-46 WO 98/50358 PCT/EP98/02262 Description 98 6 4 -(terl-Butyloxycarbonyl)piperazin-1 -ylJ-5-chloro- 2 ,3-dihydro-l-trifluoroacetyl- 1 H-indole The title compound was prepared from 5-chloro-2,3-dihydro-6-(piperazin- I yl)j..
trifluoroacetyl-1IH-indole (D94) and di-tert-butyl dicarbonate using a similar procedure to Description 95, as a brown foam (100%).
1 H NMR (250MHz, CDCl 3 (ppm): 7.99 1H), 7.26 1H), 4.30 2H), 3.60 (t, 4H), 3.20 21), 2.98 4H), 1.49 9H).
Description 99 6- I 4 -(tert-Butyloxycarbonyl)piperazin-1 -yll-5-chloro-2,3-dihydro-1 H-indole The title compound was prepared from 6 4 -(tert-butyloxycarbonyl)piperazin- 1 chloro-2,3-dihydro-l-trifluoroacetyl-lH-indole (D98) using a similar procedure-to Description 33, as a brown solid 1 H NMR (250MHz, CDCl 3 8 (ppm): 7.08 1H), 6.35 1H), 3.60 3.53 61), 3.01 2.89 6H), 1.48 9H), Ni not discernible.
Description 100 6 4 -(tert-Butyloxycarbonyl)piperazinl -ylj-5-chloro-2,3-dihydro-l -[4-(pyridin-4yl)naphth-1 -ylaminocarbonylJ-1 H-indole The title compound was prepared from 4 -(pyridin-4-yl)naphth-1-ylamine (D2) and 6-[4- (tert-butyloxycarbonyl)piperazin I -yll-5-chloro-2,3-dihydroindole (D99) using a similar procedure to Example 4, as a yellow/brown solid 11 NMR (250MHz, CDCI 3 (ppm): 8.74 21), 7.99 1H), 7.91 7.86 31), 7.67 7.41 511), 7.21 1H), 6.81 1H), 4.31 2H), 3.56 4H), 3.30 211), 2.96 41), 1.46 91).
Description 101 6
-I
4 -(tert-Butyloxycarbonyl)piperazin-1-yl -5-chloro-2,3-dihydro-l1 5-(pyridin-4yl)naphth-1 -ylaminocarbonyll-1H-indole -47- WO 98/50358 WO 9850358PCT/EP98/02262 The title compound was prepared from 5-(pyridin-4-yl)naphth-1-ylamine (D74) and 6-[4- (tert-butyloxycarbonyl)piperazin.1 -yl]-5-chloro-2,3-dihydro- 1H-indole (D99) using a similar procedure to Example 4, as a yellow/brown solid 1H NMIR (250M!Hz, CDCI 3 8 (ppm): 8.75 2H), 8.02 1H), 7.85 11H), 7.78 7.42 (in, 7H), 7.21 1H), 6.74 1H), 4.30 2H), 3.56 4H), 3.30 2H), 2.95 4H), 1.45 911).
Description 102 4 -(Pyridazin-3-yI)benzoic acid The title compound was prepared from 3-chioropyridazine and 4 -carboxyphenylboronic acid using a similar procedure to Description 24 as a brown solid MS: m/z =199 Description 103 4-(Pyrazin-2-yI)benzoic acid The title compound was prepared from 2-chloropyrazine and 4 -carboxyphenylboronic acid using a similar procedure to Description 24 as a white solid MS: in/z 156 (M-C0 2 Description 104 6-Phenylnicotinic acid The title compound was prepared from 6-chloronicotinic acid and phenylboronic acid using a similar procedure to Description 24 as an off white solid MS: m/z 200 Description 105 4 -(6-Methyl-pyridazin-3-yl)benzoic acid The title compound was prepared from 3-chloro-6-methylpyridazine and 4carboxyphenylboronic acid using a similar procedure to Description 24 as a yellow solid MS: m/z 213 Description 106 4 -(4-Cyano-3-methylphenyl)benzoic acid -48 WO 98/50358 PCT/EP98/02262 The title compound was prepared from 4-bromo-2-methylbenzonitrile and 4carboxyphenylboronic acid using a similar procedure to Description 24 as a white solid MS: m/z 236 Description 107 4 -(5-Methyl-oxazol-2-yl)aniline A mixture of 5-methyl- 2 -(4-nitrophenyl)oxazole (Chim. Ther. 1973, 437) and 10% palladium on carbon (0.25g) in THF (75ml) was stirred under an atmosphere of hydrogen for 24h. The mixture was filtered and concentrated in vacuo to dryness to afford the title compound as a pale buff powder (2.29g, 89%).
'H NMR (250 MHz, d 6 DMSO) 8 (ppm): 7.70 2H), 7.15 1H), 6.73 2H), 5.74 (s, 2H), 2.42 3H).
Description 108 A stirred suspension of 5-nitro-naphth-l-ylcarboxylic acid (Chem. Pharm. Bull 1984, 32(10), 3968) (3.50g, 16mmole) in CH 2
CI
2 (200ml) was treated with oxalyl chloride (2.1 ml, 24 mmole) and DMF (2 drops). The mixture was stirred at room temperature for The solution was concentrated to dryness in vacuo, and the residue dissolved in dry THF (200ml). Ammonia was slowly bubbled through the solution for 0.5h. The mixture was concentrated to dryness in vacuo and the residue triturated in water, and the solid filtered off and dried in vacuo to afford the title compound as a pale brown powder (3.34g, 'H NMR (250 MHz, d 6 DMSO) 6(ppm): 8.47 1H), 8.23-8.13 2H), 8.05 1H) 7.71-7.59 4H).
Description 109 N-[1-(Dimethylamino)ethylidene]-5-nitronaphth-1-ylcarboxamide A stirred mixture of 5-nitro-naphth-l-ylcarboxamide (D108, 1.50g, 7 mmole) and N,Ndimethylacetamide dimethylacetal (3ml) was heated to 110 0 C for 2 h. The cooled mixture was diluted with water (20ml) and the precipitated solid filtered off, washed with water and dried in vacuo to afford the title compound as a pale brown powder (1.60g, -49- WO 98/50358 WO 9850358PCT/EP98/02262 I H NMR (250 MHz, CDCl 3 8 (PPM): 9.31 1H), 8.53 1H), 8.22 (dd, 1H) 8.15 (dd, 111), 7.72-7.56 (in, 2H), 3.19 6H), 2.45 3H).
Description 110 3-Methyl-5-(5-nitro-naphth-1 -yl)-1 ,2,4-oxadiazole To a stirred solution of hydroxylamine hydrochloride (0.47g, 6.75 mmole) and 5M NaGH solution (1.35 ml, 6.75 mmole) in 70% aqueous acetic acid (10 ml) was added N-[1- -(dimethylainino)ethylidene]-5-nitronaphth-1lylcarboxamide (Dl09, 1.55g, 5.4 minole).
The mixture was warmed to 80'C for 4h, then cooled and diluted with water (50mi). The precipitated solid was filitered off, washed with water and dried in vacuc to leave the title compound as a pale buff powder 11 g, 1H NMR (250 MHz, CDCl 3 8 (PPM): 9.52 111), 8.71 1H), 8.44 (dd, 1H) 8.25 (dd, 111), 7.87-7.73 (in, 2H1), 2.59 3H).
Description 111 5-(3-Methyl-1 ,2,4-oxadiazol-5-yl)naphth-1 -ylamine The title compound was prepared from 3-methyl-5-(5-nitronaphth- l-yl)-1 ,2,4-oxadiazole (DlI 10) using a similar procedure to Description 71 as a pale yellow powder 1H NMR (250 MHz CDCI 3 6 (ppm): 8.52 1H), 8.30 (dd, 1H1), 8.09 111), 7.58-7.44 (in, 2H), 6.88 (dd, 111), 4.23 2H) 2.56 311).
Description 112 -Nitro-N-propargylnaphtb-1 -ylcarboxamide A stirred suspension of 5-nitronaphth-1-ylcarboxylic acid (Chem. Pharm Bull. 1984, 32(10), 3986) (1.10g, 5 mmole) in CH 2
CI
2 (50ml) was treated with oxalyl chloride ml, 6 nimole) and DMF (1 drop). After 3h at room temperature the mixture was concentrated to dryness in vacuc. The residue was dissolved in CH 2
CI
2 (30m1), treated with triethylamine (1 .4n1, 10 mmole) followed with dropwise addition of a solution of propargylamine (0.28g, 5 nmmole) in CH 2 Cl 2 (l0mi). After stirring at room temperature for 18h the mixture was washed with water, dried (Na 2
SO
4 and concentrated to dryness in vacuc. The residue was triturated in diethyl ether to afford the title compound as a pale yellow powder (0.79g, 61%).
50 WO 98/50358 WO 9850358PCT/EP98/02262 I H NMR (250 MHz, CDCl 3 8 (ppm): 8.62 2H), 8.24 1H), 7.73-7.59 (in, 6.30 lH) 4.34 (dd, 2H), 2.33 1H).
Description 113 5-Methyl-2-(5-nitronaphth-1 -yI)oxazole A stirred mixture of 5-nitro-N-propargylnaphth-1-ylcarboxamide (DI 12, 0.75g, 3 inmole) and mercuric acetate (0.04g, 0.12 mmole) in glacial acetic acid (10 ml) was heated to reflux for 4h. The cooled mixture was concentrated to dryness in vacuo, and the residue dissolved in CH 2 Cl 2 washed with aq. K 2 C0 3 solution, dried (Na 2
SO
4 and concentrated to dryness in vacuo. The residue was subjected to flash chromatography on silica gel eluting with CH 2 Cl 2 to afford the title compound as a yellow powder (0.50g, 66%).
H NMR (250 MHz, CDC1 3 8 (PPM): 9.75 111), 8.54 IH), 8.26 lH), 8.19 (d, lH), 7.79-7.64 (in, 2H), 7.01 111), 2.47 3H).
Description 114 5-(5-Methyloxazol-2-yl)naphth-1-ylamine The title compound was prepared from S-methyl-2-(5-nitronaphth-l-yl)oxazole (DI 13) using a similar procedure to Description 28, obtained as a yellow/green gum 1H NMR (250 MHz, d'DMSO) 5 (ppm): 8.64 1H), 8.11 (dd, 1H), 7.94 lH), 7.53- 7.39 (mn, 2H), 6.97 1H), 6.48 1H), 4.18 2H), 2.45 3H).
Description 115 3 -Methyl-4-(pyrimidin-2-yl)aniline The title compound was prepared from 2-bromopyrimidine and 4-amino-2-inethylphenyl boronic acid (D87) using a similar procedure to Descripton 2 as yellow solid 1H NMR (250 MHz,-CDC1 3 6 (ppm): 8.76 2H), 7.75 1H), 7.11 1H), 6.62 (d, 1H), 6.59 1H), 3.78 (br, 2H), 2.55 3H).
Description 116 3-Methyl-4-(pyrimidin-5-yI)aniline The title compound was prepared from 5-bromnopyriinidine and 4-ainino-2inethylphenylboronic acid (D87) using a similar procedure to Description 2 as a straw coloured solid -51 WO 98/50358 PCT/EP98/02262 'H NMR (250 MHz, CDC13) 8 (ppm): 9.14 1H), 8.70 2H), 7.67 1H), 7.01 (d, 1H), 6.65 1H), 6.62 1H), 3.60 (br, 2H), 2.23 3H).
Description 117 2,6-Dimethyl-4-iodopyridine A sirred solution of 4 -chloro-2,6-dimethylpyridine (Chem. Abs. 1952, 46, 4541) (2.6g, 18 mmole) in 2-butanone (250ml) was treated with sodium iodide (17.6g, 120 mmole) and 4toluenesulphonic acid (3.4g, 18 mmole) and the mixture heated at reflux under argon for 72h. The reaction mixture was cooled, then concentrated in vacuo and the residue was treated with water (200ml) and extracted with ethyl acetate. The extract was washed with aqueous sodium thiosulphate solution, then dried (Na 2
SO
4 and concentrated in vacuo to afford the title compound as a white solid, which was converted to its hydrochloride salt as a white solid from acetone (3.44g, 69%).
'H NMR (free base) (250 MHz, CDC13) 8 (ppm): 7.37 2H), 2.46 6H). MH 234.
Description 118 5-(2,6-Dimethyl-pyridin-4-yl)-l-naphthoic acid The title compound was prepared from 2,6-dimethyl-4-iodopyridine (D 117) and carboxynaphth-l-ylboronic acid (D90) using a similar procedure to Description 2 as a white solid 'H NMR (250 MHz, d 6 DMSO) 6 (ppm): 8.75 1H), 7.99 (dd, 1H), 7.80 1H), 7.60- 7.52 1H), 7.50-7.32 2H), 7.00 2H), 2.36 6H). Acid proton not observed.
Description 119 5-(2,6-Dimethyl-pyridin-4-yl)naphth-l-yl isocyanate The title compound was prepared from 5-( 2 6 -dimethyl-pyridin-4-yl)-1-naphthoic acid (D 18) using a similar procedure to Description 1. The isocyanate was not isolated, but used as its toluene solution in the next step.
Description 120 4 2 6 -Dimethylpyridin-3yl)-3-methylaniline -52- WO 98/50358 PCT/EP98/02262 The title compound was prepared from 3 -bromo-2,6-dimethylpyridine (D59a) and 4amino-2-methylphenylboronic acid (D87) using a similar procedure to Description 2 as a pale yellow oil IH NMvR (250 MHz, CDC1 3 8 (ppm): 7.32-7.25 (in, 1H), 7.00 lH), 6.87 6.65- 6.52 (in, 2H), 3.67 (br s, 2H), 2.56 3H), 2.28 3H), 1.98 3H).
Description 121 3-Methyl-4-(thiazol-2-yI)aniline The title compound was prepared from 2-bromothiazole and 4-amino-2methylphenylboronic acid (D87) using a similar procedure to Description 2 as a yellow/brown oil 1H NMR (400 MHz, CDCl 3 8 (ppm): 7.83 1H), 7.57 1H), 7.28 (mn, 1H), 6.57 (in, 2H), 3.80 (br, 2H), 2.53 3H).
Description 122 acid The title compound was prepared from 5-bromopyrimidine and ylboronic acid (D90) using a similar procedure to Description 2 as a beige solid 1H NNM (250 MLHz, d 6 DMSO) 8 (ppm): 13.30 (br, 1H), 9.35 1H), 9.00 2H), 8.96 1H), 8.19 1H), 7.93 1H), 7.78 (in, 1H),7.65 (in, 2H).
Description 123 5-(Pyrimnidin-5-yl)naphth-1-yI isocyanate The title compound was prepared from 5-(.pyrimnidin-5-yl)-1I-naphthoic acid (D 122) using a similar procedure to Deesription 1. The isocyanate was not isolated, but used as its toluene solution in the next step.
Description 124 5-Acetylnaphth-1 -ylamine A stirred solution of I1-acetyl-5-nitronaphthalene (Aust. J. Chemn. 1995, 48(12), 1969) (0.75g, 3.5 inmole), 10% Pd-C (0.20g) and cyclohexene (10 ml) in methanol (75 ml) was heated under reflux for 6h. The cooled mixture was filtered and concentrated in vacuo.
The residue was dissolved in CH 2 Cl 2 (50 ml), washed with water, dried (Na 2
SO
4 and -53- WO 98/50358 PCT/EP98/02262 concentrated to dryness. Trituration of the residue with ether/hexane afforded the title compound as a yellow/brown powder (0,52g, 'H NMR (250 MHz, CDC1 3 8 (ppm): 8.03 2H), 7.83 (dd, 1H), 7.49-7.36 2H), 6.83 1H), 4.17 2H), 2.73 3H).
Description 125 5-(Pyrimidin-2-yloxy)naphth-1-ylamine The title compound was prepared from 5-hydroxynaphth-l-ylamine and 2bromopyrimidine using a similar procedure to Description 70, as a pale buff coloured powder 'H NMR (250 MHz, CDC1 3 5 (ppm): 8.52 2H), 7.73 1H), 7.48 1H), 7.40-7.21 3H), 7.01 1H), 6.78 1H), 4.13 2H).
Description 126 To a stirred suspension of 5-nitronaphth-1-ylcarbonitrile (D128, 0.15g, 0.76 mmole) in ethanol (10ml) and water (5ml) was added iron powder (0.21g, 3.7 mmole) and ammonium chloride (0.02g, 0.4 mmole), then the mixture was heated under reflux for The mixture was cooled slightly, filtered and concentrated in vacuo. The residue was partitioned between ethyl acetate (25ml) and water (15ml). The organic layer was separated, dried (Na 2
SO
4 and concentrated to dryness to afford the title compound as a yellow/green powder (0.1 g, 'H NMR (250 MHz, CDC13) 5 (ppm): 8.06 1H), 7.88 1H), 7.68 1H), 7.49 (m, 2H), 6.88 1H), 4.27 2H).
Description 127 To stirred solution of 5-nitronaphth-l-ylcarboxamide (D108, 0.20g, 0.93mmole) in
CH
2 C1 2 (10ml) was added 2.5M solution of trimethylsilylphosphate in CH 2 C1 2 (Synthesis, 1982, 591) and the mixture heated to reflux for 2h. The cooled mixture was treated with water (10ml) and after stirring for 10 min the organic phase was separated, washed with brine, dried (Na 2
SO
4 and concentrated to dryness in vacuo. The residue -54- WO 98/50358 PCT/EP98/02262 was subjected to flash chromatography on silica gel eluting with CH 2 C12 to afford the title compound as a colourless powder (0.12g, 66%).
'H NMR (250 MHz, CDCl 3 8 (ppm): 8.82 1H), 8.57 1H), 8.35 1H), 8.06 (d, 1H), 7.83 2H) Description 128 To a solution of sodium hydroxide (0.71g, 17.8mmole) in methanol (100ml) was added hydroxylamine hydrochloride (1.23g, 1.78mmole). The mixture was treated with nitronaphth-1 -ylcarbonitrile (D127, 1.60g, 8. mmole) and heated to reflux for 48h. The cooled mixture was concentrated by evaporation to 10ml and then treated with water The precipitate was collected, washed with water and dried in vacuo to afford the title compound as a pale yellow powder (1.65g, 88%).
'H NMR (250 MHz, d 6 DMSO) 8 (ppm): 9.74 1H), 8.66 1H), 8.30 2H), 7.86- 7.72 3H), 6.14 2H).
Description 129 5-Methyl-3-(5-nitronaphth-l-yl)-1,2,4-oxadiazole To a stirred solution of 5-nitronaphth-l-ylamidoxime (D128, 1.28g, 5.5mmole) in pyridine (10ml) was added dropwise acetyl chloride (0.78ml, 1 Immole). The mixture was stirred at room temperature for 0.5h, then heated to reflux for 24h. The cooled mixture was treated with water (100ml) and extracted with ethyl acetate (3x25ml). The combined organic extracts were washed with dilute HC1, water, dried (Na 2
SO
4 and concentrated to dryness. The residue was subjected to flash chromatography on silica gel eluting with CH 2 C1 2 to afford the title compound as a pale yellow powder (0.86g, 61%).
1 H NMR (250 MHz, CDCl 3 5 (ppm): 9.27 1H), 8.63 1H), 8.36, (dd, 1H), 8.24 (dd, 1H), 7.81 1H), 7.69 1H), 2.75 3H).
Description 130 5 -(5-Methyl-l,2,4-oxadiazol-3-yl)naphth-l-ylamine The title compound was prepared according to the procedure outlined in Description 126, as brown gum. This was converted to its hydrochloride salt to afford a grey powder.
WO 98/50358 PTE9/26 PCT/EP98/02262 H NMR (HCl salt) (250 MIHz, CD 3 OD) 8 (ppm): 8.72 111), 8.08 (dd, 1H), 7.91 111), 7.60 (dd, 11-1), 7.44 2H), 4.63 211), 2.46, 3H1).
Example 1 4 -Bromo- 3 -methylphenyl)aminocarbony1I.5methoxy6-.(4methypiperazin-lyI)indole To a solution of 5-methoxy-6-(4-methylpiperazin-1 -yl)indole (130mg, 0.50 mmole, intemediate 2 in W095/06637) in anhydrous THIF (l0mi) under argon, was added potassium t-butoxide (59mg, 0.50 nimole) and the mixture stirred for 15 min. To this was added a solution of 4-bromo-3-methylphenyl isocyanate (DI, 127mg, 0.60 mmole) in anhydrous THIF (IlOmi). The resulting mixture was stirred under argon at room temperature for 16h, then concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 0-6% MeOW-ICH 2
CI
2 to afford the title compound as a pale yellow solid (1 08mg, H NMR (250MHz, CDC1 3 8 (ppm):7.67 1H1), 7.34 1H1), 7.30 111), 7.21 (d, 11-1), 7.15 7.05 (dd, 1H), 6.86 11-1), 6.42 111), 3.76 311), 3.03 (br s, 4H), 2.59 (br s, 411), 2.25 6H).
Example 2 4 -Bromo-3-methylphenyl)aminocarbonyl2,3dihydro5methoxy-6( 4 methylpiperazin-1-yI)-1II-indole 2 3 -Dihydro-5-methoxy-6-(4-methylpipezin- 1 1 H-indole 1 Og, 0.40 mmole, intermediate 3 in WO 95/06627) in dichloromethane (l0ml) was added to a solution of 4bromo-3-methylphenyl isocyanate (Dl1, 0.11 ig, 0.50 mimole) in dichloromethane (IlOmI).
The mixture was stirred at room temperature for 1 7h, then concentrated in vacuc to afford a dark yellow oil. This oil was stirred with diethyl ether producing the title compound as a yellow solid, which was filtered off and dried 1 7g, 92%).
1H NMiR (250MHz, CDCl 3 6 (ppm): 7.59 111), 7.36 1H), 7.29 1H), 7.03 (dd, 111), 6.65 11-1), 6.25 1H), 3.98 211), 3.76 3H), 3.13 211), 3.05 (br s, 411), 2.54 (br s, 4H), 2.30 311), 2.28 3H).
Example 3 -56- WO 98/50358 PCT/EP98/02262 1 -I( 2 3 -Dichlorophenyl)aminocarbonyl..2,3-dihydro5methoxy6.( 4 methylpiperazin-1-yl)-1il-indole The title compound was prepared from 2,3-dichiorophenyl isocyanate and 2,3-dihydro-5methoxy-6-(4-methylpiperzin- l-yl)-l H-indole (intermediate 3 in W095/06627) following 5 a similar procedure to Example 2.
H NMIR (250MHz, CDCl 3 8 (ppm):8.27 (dd, 1H), 7.68 1H1), 7.23-7.13 (in, 2H), 7.15 (dd, 1H), 6.75 1H), 4.15 2H1), 3.85 3H), 3.22 2H), 3.13 (br s, 4H), 2.63 (br s, 4H), 2.36 3H).
Example 4 2 3 -Dihydro-5-methoxy-6..(4-methylpiperazin.1 -yI)-1 4-(Pyridin-yl)naphth-l1 ylaminocarbonylJ -1 H-in dole To a stirred solution of triphosgene (84 mg, 0.28 minole) in CH 2 Cl 2 (10 ml) under argon, was added to a solution of 4 -(pyridin-4-y)naphth-1-ylamine (D2, 196 mg, 0.89 mmole) and NEt 3 (90 mg, 0.89 nmmole) in CH 2 Cl 2 (10 ml) dropwise over 30 min. After the addition was complete, the mixture was stirred at room temperature for 15 min, then a solution of 2 3 -dihydro-5-methoxy-6-(4-methylpiperazin-l-yl)-1 H-indole (intermediate 3 in W095/06627, 200 mg, 0.81 mmole) in CH 2 Cl 2 (10 ml) was added. After 6h the mixture was washed with 10% Na 2
CO
3 dried (Na 2
SO
4 and concentrated in vacuo giving a crude green oil, which was purified by chromatography on silica eluting with 2- MeOH-/CH 2 C1 2 The title compound was obtained as a beige solid (292 mg, 73%).
1 H NMIR (250 MHz, CDC1 3 8 (ppm): 8.73 (dd, 2H), 7.99 (dd, 1H), 7.91 7.88 (dd, IH), 7.75 1H), 7.60-7.49 (in, 2H), 7.46 1H), 7.42 (dd, 2H), 6.81 1H1), 6.7 1H), 4.27 2H), 3.85 3H), 3.28 2H), 3.11 (br s, 4H), 2.60 (br s, 4H), 2.34 (s, 3H).
Example 2 ,3-Dihydro.-5-methoxy-6-(4-methylpiperazin.1yi)1- 15-(4-pyridyl)naphth-1 ylaminocarbonylJ-1 H-in dole The title compound was prepared from 5-(pyridin-4-yl)naphth-1-yI isocyanate (D34) and 2 3 -dihydro-5-methoxy-6-(4-methylpiperazin-1 lH-indole (intermediate 3 in W095/06627) using a similar procedure to Example 2.
57 WO 98/50358 WO 9850358PCT/EP98/02262 IH NMR (250 MHz, CDCl 3 8 (ppm): 8.72 2H), 8.02 1H), 7.74 IH), 7.72 (d, 111)1 7.66 1H), 7.55 1H), 7.41-7.46 (in, 2H), 7.40 2H), 6.85 1H), 6.75 1H), 4.21 2H4), 3.84 3H), 3.24 2H), 3.07 (brs, 4H), 2.56 (br s, 4H), 2.31 3H).
Example 6 l-[ 2 3 -Dichloro- 4 -(pyridin-4-yl)phenylaminocarbonyIJ2,3dihydro..5.methoxy 6 4 methylpiperazin-1 -yI)-l H-indole The title compound was prepared from 2 ,3-dichloro-4-(pyridin-4-yl)aniline (D7) and 2,3dihydro-5-methoxy-6-(4-methylpiperazin-l-yl)- 1H-indole (intermediate 3 in WO 95/06627) using a similar procedure to Example 4 as an orange/brown solid IIH NMR (250 MHz, CDCl 3 8 (ppm): 8.67 2H), 8.41 IH), 7.70 1H), 7.36 (d, 2H), 7.27 1H), 7.26 1H), 6.76 11H), 4.18 2H), 3.85 3H), 3.24 2H), 3.18 (br s, 4H), 2.71 (br s, 4H), 2.41 3H).
Example 7 2 3 -Dihydro-5-methoxy-6-(4-methypperazin-1-yI)1I(quinolin-5-ylamjflocarboly)- 1H-indole The title compound was prepared from 5-aminoquinoline and 2,3-dihydro-5-methoxy-6- 4 -methylpiperazin-1-yl)-1H-indole (intermediate 3 in W095/06627) using a similar procedure to Example 4.
IH NMvR (250 MHz, CDCl 3 8 (ppm): 8.92 (dd, 1H), 8.27 (dd, 11H), 7.99 (t 111), 7.69- 7.71 (in, 3H), 7.41 (dd, 1H), 6.75 1H), 6.70 1H), 4.20 2H), 3.85 3H), 3.25 (t, 2H), 3.09 (br s, 4H), 2.59 (br s, 4H), 2.32 3H).
Example 8 2,3-Dihydro-(4-methylpiperazin-1 -yl)-1 -14-(pyridin-4-yl)naphth-1ylaminocarbonyll-1H-indole The title compound was prepared from 4 -(pyridin-4-yl)naphth-1-ylamine (D2) and 2,3dihydro-6-(4-inethylpiperazin- 1-yl)- IH-indole (D 11) using a similar procedure to Example 4 as a beige solid IHNMR (250 MLHz, GDC1 3 8 (ppm): 8.75-8.70 (in, 211), 7.99 11H), 7.92-7.86 (in, 2H), 7.75 1H), 7.62-7.40 (in, 5H), 7.09 1H1), 6.90 11-1), 6.56 (dd, 11-1), 4.26 (t, 2H), 3.28-3.17 (in, 6H), 2.55-2.50 (in, 411), 2.32 311).
58 WO 98/50358 WO 9850358PCTIEP98/02262 Example 9 5-Chloro-2,3-dihydro-6-(4-methylpiperazin-1-.yi)- -1 4 -(pyridin-4-y)naphth-lylaminocarbonyllI1H-indole The title compound was prepared from 4 -(Jpyridin-4-yl)naphth-1-ylamine (D2) and chloro-2,3-dihydro-6-(4-methylpiperazin- I-yl)- I H-indole (D 13) using a similar procedure to Example 4 This was converted to its hydrochloride salt as a yellow solid from acetone.
I H NMR (free base) (250 MHz, CDCl 3 8 (ppm): 8.73-8.67 (in, 2H), 8.00 (dd, 1H1), 7.91-7.82 (in, 3H), 7.62-7.37 (in, 5H), 7.18 111), 6.92 1H1), 4.26 2H), 3.24 (t, 2H), 3.06 (br s, 4H), 2.56 (br s, 4H1), 2.32 3H).
Example 5-rm-,-iyr--4mtypprzn1y)l[-prdn4y~ahhl ylaminocarbonylj-1 H-indole The title compound was prepared from 2 3 -dihydro-6-(4-methylpiperazin-1 1-[4- (pyridin-4-yl)naphth- 1 -ylaminocarbony1]- 1 Hindole (E8) and benzyltrimethylanimonium tribromide using a similar procedure Description 14 as a beige solid This material was converted to its hydrochloride salt as a yellow solid from acetone.
IH NMR (250 MHz, CDCl 3 8 (ppm): 8.76-8.70 (in, 2H), 8.00 lH), 7.9 1-7.82 (in, 3H), 7.62-7.34 (in, 614), 6.93 111), 4.26 2H1), 3.24 211), 3.05 (br s, 411), 2.56 (br s, 4H), 2.32 311).
Example 11 5-Bromo-2,3-dihydro-6-(4-methylpiperazin.1 -yl)-1 -[4-(pyridin-4yl)phenylaminocarbonylj-lH-indole The title compound was prepared from 4-(pyridin-4-yl)aniline (D5) and 5-bromo-2,3dihydro-6-(4-methylpiperazin- I yl)..l H-ndole (D 15) using a similar procedure to Example 4 as a white solid 11H NMR (250 MHz, CDCl 3 8 (ppm): 8.52-8.45 (in, 211), 8.00 111), 7.71 111), 7.60-7.45 (in, 411), 7.37 (dd, 211), 7.18 111), 4.05 211), 3.03 211), 2.92 (br s, 411), 2.45 (br s, 4H), 2.20 311).
-59- WO 98/50358 PCTIEP98/02262 Example 12 5-Bromo-l-[3clr--prdn4y hnlaioabnl-,-iyr--4 methylpiperazin-1 -yl)-1 H-in dole The title compound was prepared from 3 -chloro-4-(pyridin-4-yl)aniline (D6) and bromo-2,3-dihydro-6-(4-methylpiperazin-l-yl)-l H-indole (Dl 5) using a similar procedure to Example 4 as a white solid 1 H NMR (250 IvIHz, CDC1 3 d 6 DMSO) 8 (ppm): 8.75 2H), 8.40 1H), 7.92 (s, 7.88 1H), 7.75 (dd, 111), 7.52 111), 7.42 2H), 7.33 11H), 4.27 211), 3.25 2H), 2.97 (br s, 4H), 2.60 (br s, 4H), 2.35 3H).
Example 13 2 ,3-Dihydro-5-methyl-6-(4-methylpiperazin.1 -yl)-1 -[4-(pyridin-4-yl)naphth-1 ylaminocarbonylJ-1 -indole The title compound was prepared from 4 -(pyridin-4-yl)naphth-1-ylamine (D2) and 2,3dihydro-5-methyl-6-(4-methylpiperazin-l-yl)-lil-indole (Dl 7) using a similar procedure to Example 4 This material was converted to its hydrochloride salt as a yellow solid from acetone.
III NMiR (free base) (250 MHz, CDCl 3 8 (ppm): 8.73-8.70 (in, 2H), 7.98 111), 7.93- 7.85 (in, 211), 7.73 111), 7.60-7.48 (in, 5H1), 7.02 11H), 6.95 IH), 4.23 2H), 3.22 2H), 2.95-2.90 (in, 4H), 2.54 (br s, 4H), 2.31 3H), 2.26 3H).
Example 14 l-I 3 -Chloro- 4 -(pyridin-4-yl)phenyaminocarbonyl-2,3-dihydro-5-methyI&6(4methylpiperazin-1 -yl)-1H-indole The title compound was prepared from 3-chloro-4-(pyridin-4-yl)aniline (D6) and 2,3- -methyl-6-(4-methylpiperazin. 1 1 H-indole (D 17) using a similar procedure to Example 4 as a white solid IIH NMR (250 MHz, d 6 DMSO) 6 (ppm): 8.92 1H), 8.80 2H), 8.08 IH), 7.87- 7.83 (in, 2H1), 7.63 2H), 7.56 IH), 7.14 IR), 4.27 2H), 3.24 2H), 2.94 (br s, 4H), 2.65 (br s, 4H1), 2.38 3H1), 2.32 3H).
Example WO 98/50358 WO 9850358PCT/EP98/02262 2,3-Dihydro-6-(4-methylpiperazin-1 -yl)-1 -14-(pyridin-4-yl)naphth-1 ylaminocarbonyl]-5-vinyl-1 H-indole The title compound was prepared from 4 -(Ipyridin-4-yl)naphth-1I-ylamnine (D32) and 2,3 dihydro-6-(4-methylpiperazin- 1 -yl)-5-vinyl- 1 H-indolc (D 19) using a similar procedure to Example 4 This material was converted to its hydrochloride salt as a yellow solid from ethyl acetate.
IH NMR (free base) (250 MIHz, CDCl 3 8 (ppm): 8.77-8.70 (in, 2H), 8.00 1H), 7.96- 7.86 (mn, 2H), 7.76 1H), 7.65-7.40 (mn, 5H), 7.37 11H), 7.0 (dd, 1H), 6.92 1H), 5.60 (dd, 1H), 5.15 (dd, 111), 4.28 211), 3.29 2H), 3.05-2.95 (in, 4H), 2.55 (br s, 411), 2.33 311).
Example 16 2,-iyr--ty--4mtypprai- l--4(yii--lnptylaminocarbonylJ-1 il-in dole The title compound was prepared from 4-(pyridin-4-yl)naphth- I ylainine (D2) and 2,3 dihydro-5-ethyl-6-(4-inethylpiperazin-1 lH-indole (D2 1) using a similar procedure to Example 4 as a beige solid This material was converted to its hydrochloride salt as a yellow solid from acetone.
1 H NMR (free base) (250 MHz, CDC1 3 8 (ppm): 8.74-8.70 (in, 211), 8.03-7.87 (in, 3H), 7.77 1H), 7.60-7.38 (in, 5H), 7.09 1H), 6.92 1H), 4.26 2H), 3.26 2H1), 2.98- 2.92 (mn, 4H), 2.66 2H), 2.61 (br s, 4H), 2.36 3H1), 1.23 3H1).
Example 17 1-1- oo-prdn4y~hnlmnoabnl-,-iyr--ty--4 methylpiperazin-1-yl)- lH-indole The title compound was prepared from 3-chloro-4-(pyridin-4-yl)aniline (136) and 2,3dihydro-5.-ethyI-6-(4-methylpiperazin.1-yl)..lH-indole (D21) using a similar procedure to Example 4 as a white solid lH NMR (250 MFz, CDC1 3 6 (ppm): 8.72-8.62 (in, 2H), 7.73-7.65 (mn, 2H),.7.50-7.20 (in, 4H), 7.07 1H), 6.60 1H), 4.09 2H1), 3.18 2H1), 2.97-2.90 (in, 4H), 2.66 (q, 2H), 2.57 (br s, 4H), 2.35 3H), 1.22 3H).
Example 18 -61- WO 98/50358 PCT/EP98/02262 2 3 -Dihydro- 6 4 -methylpiperazin-.1-.yi)1.[4(pyridin.4..y)naphth-l lH-indole The title compound was prepared from 4 -(pyridin-4-yl)naphth- I-ylamine (D32) and 2,3dihydro-6-(4-methylpiperazin-1 -yl)-5-trifluoromethyl-l1H-indole (D323) using a similar procedure to Example 4 as a beige solid This material was converted to its hydrochloride salt as a yellow solid from acetone.
I H NMR (free base) (250 Mffz, CDCl 3 8 (ppm): 8.77-8.71 (in, 211), 8.07 1H1), 8.01- 7.85 (in, 3H), 7.63-7.39 (mn, 6H), 6.94 111), 4.33 2H), 3.32 2H), 3.05-2.96 (in, 411), 2.64 (br s, 4H1), 2.38 3H).
Example 19 l-[ 3 -Chloro- 4 -(pyridin-4-yl)phenylaminocarbonyll2,3.dihydro.6(4methylpiperazin-1 -yI)-S-trifluoromethyl-1H-indole The title compound was prepared from 3 -chloro-4-(pyridin-4-yl)aniline and 2,3dihydro-6-(4-inethylpiperazin- 1-yl)-5-trifluoroinethyl- 1 1-indole (D23) using a similar procedure to Example 4 as a beige solid III NMR (250 MIz, CDC1 3 5 (ppm): 8.69-8.65 (in, 211), 8.05 11H), 7.67 111), 7.46 (dd, 1H1), 7.44-7.37 (in, 3H), 7.31 111), 6.59 111), 4.16 2H), 3.27 211), 3.00-2.94 (in, 4H), 2.55 (br s, 411), 2.34 311).
Example 2 3 -Dihydro--methoxy-6-(4-methylpiperazin..1.yl)I..[4(pyridin4yl)aphthylacetyl]-1 H-indole To a stirred suspension of 4 -(pyridin-4-yl)naphth-1-ylacetic acid (D324, 213 mng, 0.81 minole) in CH 2 Cl 2 (30 ml) was added oxalyl chloride (206 mg, 1.6 minole) followed by DMF (1 drop). After 2h the solvents and excess oxalyl chloride were removed in vacuo to afford the acid chloride as a pale yellow solid. This was dissolved in CH 2 Cl 2 (15 ml) and added portionwise over 10 min to a stirred solution of 2,3-dihydro-5-methoxy-6-(4methylpiperazin-1-yl)-1H-indole (intermediate 3 in WO 95/06627, 200 mg, 0.81 mmole) and NEt 3 (164 mg, 1.6 iniole) in CH 2
CI
2 (15 ml) at OTC under argon. After 30 min at 0 0 C the mixture was stirred at room temperature for 5h, then washed with 10% Na 2
CO
3 dried (Na 2
SO
4 and concentrated in vacuo. The crude green/brown oil was purified 62 WO 98/50358 WO 9850358PCT/EP98/02262 by chromatography on silica eluting with 2-5% MeCH/CH 2
CI
2 to afford the title compound as a yellow solid (340 mg, IH NMR (250 MHz, CDC1 3 8 (ppm): 8.72 2H), 8.02 1H), 8.02 1H), 7.87 (d, 1H), 7.37-7.60 (in, 6H), 6.74 1H), 4.26 2H), 4.25 2H), 3.85 3H), 3.22 2H), 3.08 (br s, 4H), 2.57 (br s, 4H), 2.32 3H).
Example 21 2,-iyr--ehx--4mtypprai- ylacetylJ-1 H-indole The title compound was prepared from 5-(pyridin-4-yl)naphth-1-ylacetic acid (D25) and 2 3 -dihyro-5-methoxy-6-(4-methylpiperazin.1 1H-indole (intermediate 3 in WO 95/06627) using a similar procedure to Example IH NMR (250 MHz, CDCl 3 8 (ppm): 8.72, 2H), 8.03 1H), 8.02 1H), 7.78 (dd, 1H), 7.59 1H), 7.45-7.39 (in, 5H), 6.74 1H), 4.25 2H), 4.22 2H), 3.84 3H), 3.20 2H), 3.07 (br s, 4H), 2.57 (br s, 4H), 2.31 3H) Example 22 2 ,3-Dihydro-6-(4-methylpiperazin-1 -yl)-1 -I4-(pyridin-4-yI)naphth-1 -ylacetylJ-1 Hindole The title compound was prepared from 4-(pyridin-4-yl)naphth-1-ylacetic acid (D24) and 2 3 -dihydro-6-(4-methylpiperazin- I yl)4 IH-ndole (D 11) using a similar procedure to Example 20 as a beige solid from ethyl acetate IH NMIR (250 MHz, CDCI 3 6 (ppm): 8.75-8.70 (in, 2H), 8.04-7.94 (in, 2H), 7.88 (d, 1H), 7.62-7.33 (in, 6H), 7.09 IH), 6.61 (dd, IH), 4.26 2H), 4.25 2H), 3.25-3.13 (mn, 6H), 2.55-2.47 (in, 4H), 2.30 3H).
Example 23 5-hoo23dhdo6(4mtypprzn1y l-4(yii--lnptylacetyll-1 H-indole The title compound was prepared from 4 -(pyridin-4-yl)naphthl.1.ylacetic acid (D24) and 5-chloro-2,3-dihydro-6-(4-inethylpiperazin-1 1H-indole (D 13) using a similar procedure to Example 20 as a yellow oil This material was converted to its hydrochloride salt as a beige solid from ethyl acetate.
63 WO 98/50358 PTE9/26 PCT/EP98/02262 111 NMR (free base) (250 MHz, CDC1 3 5 (ppm): 8.75-8.70 (in, 2H), 8.08 111), 8.00 1H), 7.88 111), 7.65-7.35 (in, 611), 7.19 11-1), 4.27 4H), 3.20 211), 3.06 (br s, 411), 2.57 (br s, 4H1), 2.33 3H).
Example 24 5-Bromo-2,3-dihydro-6-(4-methylpiperazin-1 -yl)-1 -14-(pyridin-4-yl)naphth-1 ylacetylj-l H-in dole -The title compound was prepared from 2 3 -dihydro-6-(4-methylpiperazin-1yl).1..[4.
(pyridin-4-yl)naphth- 1 -ylacetyl]- 1 11-indole (E22) and benzyltrimethylamn-onium tribromide using a similar procedure to Description 14 This material was converted to its hydrochloride salt as a white solid from ethyl acetate.
111 NMR (free base) (250 Mi1z, CDCI 3 8 (ppm): 8.75-8.70 (in, 2H), 8.08 111), 8.00 111), 7.89 1H1), 7.63-7.35 (in, 7H), 4.27 411), 3.20 2H1), 3.04 (br s, 4H), 2.56 (br s, 4H), 2.32 3H).
Example 2,3-Dihydro-6-(4-methylpiperazin.1 -yl)-1 4 -(pyridin-4-yl)naphth-1-ylacetyll-5.
vinyl-iHi-indole The title compound was prepared from 4-(pyridin-4-yl)naphth- I -ylacetic acid (D24) and 2 3 -dihydro-6-(4-methylpiperazin-l.yl)5vinyl..1-indole (D19) using a similar procedure to Example 20 This material was converted to its hydrochloride salt as a white solid from acetone/ethyl acetate.
11H NMR (free base) (250 MHz, CDCl 3 8 (ppm): 8.75-8.68 (in, 211), 8.05-7.96 (mn, 2H), 7.88 1H), 7.65-7.30 (in, 711), 7.00 (dd, 11H), 5.60 (dd, 111), 5.15 (dd, 1H), 4.28 211), 4.26 211), 3.22 2H1), 2.98-2.91 (in, 4H), 2.52 (br s, 411), 2.31 311).
Example 26 5-Bromo-2,3-dihydro-6.(1-methylpiperidin-4-yl)-l1-(pyridin-4yl)naphth-lylaminocarbonyll-1 H-in dole The title compound was prepared from 4 -(pyridin-4-yl)naphth-1-ylamine (D2) and bromo-2,3-dihydro-6-(1 -methylpiperidin-4-yl)- 1 H-indole (D39) using a similar procedure to Example 4 64- WO 98/50358 PTE9/26 PCT/EP98/02262 IH NfvIR (250 MHz, d 6 DMSO) 5(ppm): 8.95 1H), 8.78 (dd, 211), 8.19 (dd, 1H), 7.93 (in; 1H), 7.85 (dd, 7.54-7.69 (in, 6H), 7.46 1H), 4.37 2H), 3.27 2H), 2.95 (hr d, 2H), 2.82 (in, IB), 2.27 3H), 2.10 (in, 2H), 1.65 (in, 4H).
Example 27 5-Chloro-2,3-dihydro-6-(4-methylpiperain.1 -yl)-1 -15-(pyridin-4-yl)naphthl ylaminocarbonylj-1H-indole The title compound was prepared from 5-(pyridin-4-yl)naphth- Il-yl isocyanate (D4) and 2 ,3-dihydro-6-(4-inethylpiperazin-1 -yl)-1 H-indole (D313) using a similar procedure to Example 2.
1 H NMvR (250 Mhfz, CDCl 3 8 (ppm): 8.73 2H1), 8.02 1H), 7.83 1H), 7.74 (d, 1H), 7.70 11H), 7.59 1H), 7.47 7.40 (mn, 4H), 7.17 1H), 6.86 1H), 4.27 (t, 2H), 3.25 2H), 3.11 (hr s, 4H), 2.66 (br s, 4H), 2.38 3H1).
Example 28 5-Bromo-2,3-dihydro-6-(4-methylpiperain1.y).1 5-(pyridin-4-yl)naphth-1 ylaminocarbonylj-1 H-indole The title compound was prepared from 5-(pyridin-4-yl)naphth- I yl isocyanate (D34) and 5-bromo-2,3-dihydro-6-(4-methylpiperazin- I-yl)-lI H-indole (D 15) using a similar procedure to Example 2.
H NMR (250 MHz, CDC1 3 8 (ppm): 8.73 2H), 8.02 1H1), 7.84 1H), 7.75 (d, 1H), 7.72 1H), 7.59 1H1), 7.50 7.44 (mn, 2H), 7.41 2H), 7.37 111), 6.78 (s, 1H1), 4.27 2H), 3.26 2H), 2.97 (hr s, 4H), 2.56 (hr s, 4H), 2.32 3H1).
Example 29 2 3 -Dihydro-5-methoxy-6-(4-methylpiperain-1 -yl)-l-(quinolin-6-ylaminocarbonyl)lil-indole- The title compound was prepared from quinolin-6-yl isocyanate (1326) and 2,3-dihydro-5methoxy-6-(4-methylpiperazinl1-yl)IH-indole (intermediate 3 in WO 95/06627) using a similar procedure to Example 2.
1'HNMR (250 M]Fz, CDCl 3 8 (ppm): 8.78 (dd, 111), 8.19 1H), 8.13 (dd, 111), 8.03 (d, 111), 7.73 1H), 7.58 (dd, 1H1), 7.37 (dd, 1H), 6.83 1H), 6.74 11H), 4.13 2H), 3.84 3H), 3.20 211), 3.16 (hr s, 4H), 2.66 (hr s, 4H), 2.37 3H).
65 WO 98/50358 WO 9850358PCT/EP98/02262 Example 1 -I 4 -(t-Butoxycarbonylamino)phenylaminocarbonyIJ-5-choro2,3dihydro6( 4 methylpiperazin-1-yl)-1 H-in dole The title compound was prepared from 4 -(t-butoxycarbonylamnino)aniline (1340) and chloro-2,3-dihydro-6-(4-methylpiperazin- l-yl)- 11H-indole (DI 3) using a similar procedure to Example 4 IH NM~R (250MHz, d 6 DMSO) 8(ppm): 9.25 11H), 8.45 11H), 7.78 111), 7.40 (in, 4H1), 7.22 11-1), 4.12 2H), 3.11 2H), 2.89 (mn, 4H1), 2.50 (in, 411), 2.25 3H), 1.48 9H).
Example 31 5-rm-,-iyr--4mtypprzn--i--qioi--lmncroy) 1 H-in dole The title compound was prepared from quinolin-6-yl isocyanate (D26) and 5-bromo-2,3dihydro-6-(4-methylpiperazin--yl)- IH-indole (Di15) using a similar procedure to Example 2.
1 H NMR (250 MHz, CDC1 3 8 (ppm): 8.82 (dd, 11-1), 8.17 111), 8.13 (dd, 1H), 8.05 (d, 111), 7.85 1H1), 7.57 (dd, 111), 7.39 111), 7.36 11H), 6.62 11-1), 4.16 2H1), 3.22 211), 3.12 4H), 2.63 (br s, 411), 2.37 311).
Example 32 ylaminocarbonyl]-1 ,2,3,4-tetrahydroquinoline The title compound was prepared from 4-(pyridin-4-yl)naphth- I-ylamine (D32) and 6bromo-7-(4-methylpiperazin-1I-yl)-1 ,2,3,4-tetrahydroquinoline (D33) using a similar procedure to Example 4.
1 H NMR (250 MHz, CDCl 3 8 (ppm): 8.72 211), 8.07 111), 7.86 (dd, 111), 7.67 (dd, 1H),7.51 111), 7.47 7.40 (in, 611), 7.26 111), 3.89 211), 3.03 411), 2.81 211), 2.56 411), 2.31 311), 2.03 (quintet, 211).
Example 33 -66 WO 98/50358 PCTIEP98/02262 5-Chloro-2,3-dihydro-6-(4-methylpiperazin1..y)1.(4phenoxyphenylaminocarbonyl)- lH-indole The title compound was prepared from 5-chloro- 2 ,3 -dihydro-6-(4-methylpiperazin. I-yl)- I1H-indole (D 13) and 4-phenoxyphenyl isocyanate using a similar procedure to Example 2.
H NMR (250 MHz, CDCI 3 8 (ppm): 7.81 1H), 7.38 7.28 (in, 4H1), 7.13 1H1), 7.10 -'6.96 (in, 5H), 6.43 1H), 4.04 2H), 3.15 2H), 3.08 (br s, 4H), 2.58 (br s, 4H), 2.33 3H).
Example 34 5-Chloro-1 4 4 -chlorophenoxy)phenylaminocarbonylp-2,3.dihydro.6-(4.
methylpiperazin-1 lH-indole The title compound was prepared from 5-chloro- 2 ,3-dihydro-6-(4-methylpiperazin- I-yl)- IH-indole (D 13) and 4 4 -chlorophenoxy)aniline using a similar procedure to Example 4.
'H NNM (250 MHz, CDCl 3 6 (ppm): 7.81 11H), 7.38 2H), 7.26 2H), 7.14 (s, 11H), 6.98 2H), 6.91 2H), 6.41 1H), 4.08 2H), 3.18 2H), 3.09 (br s, 4H), 2.61 (br s, 4H), 2.35 3H).
Example 5-Chloro-2,3-dihydro-6-(4-methylpiperazin.1 -yl)-l-(quinolin-6-ylaminocarbonyl)lil-indole The title compound was prepared from quinolin-6-yl isocyanate (D26) and 5-chloro-2,3dihydro-6-(4-methylpiperazin-1-yl)-1H..indole (DI13) using a similar procedure to Example 2.
H NMiR (250 MHz, CDC1 3 8 (ppm): 8.79 (dd, 1H), 8.18 1H), 8.13 (dd, 1H), 8.03 (d, 111), 7.85 11H), 7.59 (dd, 7.38 (dd, IH), 7.15 1H), 6.90 1H), 4.15 2H), 3.19 2H), 3.15 (br s, 4H), 2.67 (br s, 4H), 2.39 3H1).
Example 36 5-Chloro-2,3-dihydro-6-(4-methylpiperazin.1y).1-(3phenoxyphenylaminocarbonyl)-lH-indole The title compound was prepared from 5-chloro-2,3-dihydro-6-(4-methylpiperazin- Il-yl)- I1H-indole (D13) and 3-phenoxyaniline using a similar procedure to Example 4.
-67 WO 98/50358 PCT/EP98/02262 'H NM~~R (250 MiHz, CDCl 3 6 (ppm): 7.77 1H), 7.36 6.96 (in, 9H), 6.71 (ddd, 1H), 6.46 1H), 4.03 2H), 3.13 2H), 3.08 (br s, 4H), 2.60 (br s, 4H), 2.35 3H).
Example 37 5 -Chloro-2,3-dihydro-6-(4-methylpiperazin-1-yl)-1 4 -(pyrimidin-2-yI)phenylaminocarbonylJ-1il-indole The title compound was prepared from 5-chloro-2,3-dihydro-6-(4-methylpiperazin.1y).
1H-indole (D13) and 4 -(pyrimidin-2-yl)phenyl isocyanate (D42) using a similar procedure to Example 2, giving a pale cream powder 1'H NIVIR (250 MHz, CDCl 3 8 (ppm): 8.78 2H), 8.40 2H), 7.83 1H), 7.60 (d, 2H), 7.15 (in, 2H), 6.56 1H), 4.12 2H), 3.18 2H), 3.11 (hr s, 4H), 2.60 (br s, 4H), 2.35 3H).
Example 38 l-( 3 -Benzoylphenylaminocarbonyl)5-chloro-2,3-dihydro.6(4-methylpiperazin..1 yl)-1H-indole The title compound was prepared from 3-aminobenzophenone and 5-chloro-2,3-dihydro- 6-(4-methylpiperazin-lI-yl)- 1H-indole (D 13) using a similar procedure to Example 4.
1H NMR (250 MHz, CDCl 3 8 (ppm): 7.88 (in, 1H), 7.78 7.74 (in, 4H), 7.57 1H), 7.49 -7.40 (in, 4H),'7.11I I1H), 6.95 I1H), 4. 10 2H), 3.16 -3.04 (mn, 2.63 (hr s, 4H), 2.37 3H).
Example 39 1-( 4 -Benzoylphenyaminocarbony)5chloro2,3dihydro6(4-methylpiperazin-lyI)-1H-indole The title compound was prepared from 4-aminobenzophenone and 5-chloro-2,3-dihydro- 6-(4-methylpiperazin-1I-yl)-1IH-indole (D 13) using a similar procedure to Example 4.
'H NMR (250 MIHz, CDC1 3 6 (ppm): 7.81 7.74 (mn, 5H), 7.58 (in, 1H), 7.56 2H), 7.47 2H), 7.13 1H), 6.85 1H), 4.10 2H), 3.15 2H), 3.09 (hr s. 4H), 2.59 (hr s, 4H), 2.35 3H).
Example 68 WO 98/50358 WO 9850358PCT/EP98/02262 5-Chloro-2,3-dihydro-6-(4-methylpiperain.1 -yI)-1-(2-methylquinolin..& ylaminocarbonyl)-1ifl-indole The title compound was prepared from 6-amino-2-methylquinoline and 5-chloro-2,3dihydro-6-(4-methylpiperazin-lI-yl).IlH-indole (D 13) using a similar procedure to Example 4.
H NMR (250 MHz, CDCI 3 8 (ppm): 8.05 1H), 7.95 11H), 7.93 1H), 7.83 (s, I1H), 7.54 (dd, IlH), 7.22 1lH), 7.12 IlH), 6.75 IlH), 4.07 2H), 3.16 3.09 (in, 6H), 2.70 3H), 2.61 (br s, 4H), 2.35 3H).
Example 41 yI)-M -in dole The title compound was prepared from 5-chloro-2,3-dihydro-1-(4iodophenylaminocarbonyl)-6-(4-methylpiperazin-l-yl)- lH-indole (D43) and 2fuirylboronic acid in a similar manner to Description 2, obtained as a pale buff powder H NMVR (250 MI-lz, d 6 DMSO) 8 (ppm): 8.68 1H), 7.82 1H), 7.73 1H), 7.76 (s,411), 7.25 1H), 6.86 1H), 6.61 (dd, 1H), 4.18 2H), 3.15 2H), 2.95 (br s, 4H), 2.26 3H). 2 x CH 2 signals obscurred by DMSO signal.
Example 42 yI)phenylaminocarbonylJ- lH-indole The title compound was prepared from 5-chloro-2,3-dihydro-1-(4iodophenylaminocarbonyl)-6-(4-methylpiperain. Il-yl)-lI H-indole (D43) and 2thienylboronic acid in a similar manner to Description 2, obtained as a cream powder I'H NMR (250 MHz, CDC1 3 8 (ppm): 7.82 1H1), 7.58 2H), 7.42 2H), 7.24 (d, 2H), 7.14 I1H), 7.08 (mn, I1H), 6.45 IlH), 4.09 2H), 3.18 2H), 3.10 (br s, 4H1), 2.60 (br s, 4H), 2.35 3H).
Example 43 69 WO 98/50358 WO 9850358PCT/EP98/02262 5-Choro2,3dihyro--(4methlpierain--yl)I-[-(Pridi-4-l~nphtylacetylj-1H-indoline The title compound was prepared from 5-(pyridin-4-yl)naphth-1I-ylacetic acid (D25) and -chloro-2,3 -dihydro-6-(4-methylpiperazin- I1-yl)-l1 H-indole (Dl 13) using a similar procedure to Example H NMR (250 MIHz, CDCl 3 8 (ppm): 8.73 (dd, 2H), 8.07 1H), 8.01 1H), 7.79 (dd, 1H), 7.61 (dd, 1H), 7.45 7.41 (in, 5H), 7.19 1H1), 4.27 2H), 4.26 2H), 3.19 (t, 2H), .3.05 (br s, 4H), 2.56 (br s, 4H), 2.32 3H).
Example 44 5-Bromfo-2,3-dihydro-6-(4-methylpiperazin-1-yl)-.. 5-(pyridin-4-yl)naphth-1 ylacetylj-1 -in dole The title compound was prepared from 5-(pyridin-4-yl)naphth-1I-ylacetic acid (D25) and -bromo-2,3 -dihydro-6-(4-methylpiperazin- 1 -yl)-1I H-indole (D 15) using a similar procedure to Example 1H NMR (250 MHz, CDC1 3 8 (ppm): 8.73 2H), 8.08 1H), 8.00 1H), 7.78 (dd, 1H), 7.60 (dd, 1H), 7.44 7.41 (in, 5H), 7.37 1H), 4.26 2H), 4.25 2H), 3.18 (t, 2H), 3.03 (br s, 4H), 2.56 (br s, 4H), 2.32 3H).
Example 5-Chloro-2,3-dihydro-l-14-(1 -methylpiperidin-4-yl)naphth-1-ylaminocarbonylj methylpiperazin-1 -yl)-1H-indole The title compound was prepared from 4-(1-methylpiperidin-4-yl)naphth-1-ylamine (D346) and 5-chloro-2,3-dihydro-6-(4-methylpiperazin- 1-yl)- 1H-indole (D 13) using a similar procedure to Example 4.
'H NMR (dihydrochioride salt) (250 MHz, d 6 DMSO) 8 (ppm): 11.06 (br s, 11H), 10.94 (br s, 1H), 8.82 LH), 8.27 (dd, 111), 8.11 (dd, 1H), 7.78 1H), 7.63 (in, 2H), 7.54 IH), 7.42 1H), 7.33 111), 4.30 partially obscurred, 2H), 3.74 (in, 1H), 3.24 2H), 3.60 2.96 (in, 12H), 2.84 3H), 2.83 3H), 2.18 (in, 4H).
Example 46 5-Chloro-2,3-dihydro--[4-(2-methyloxazol.4-yl)phenylaminocarbonyI1.6-(4methylpiperazin-1-yl)-lH-indole 70 WO 98/50358 PCT/EP98/02262 The title compound was prepared from 4 4 -aminophenyl)-2-nethyloxazole (D47) and chloro-2, 3 -dihydro-6-(4-methylpiperazin- I -yl)-1 H-indole (D 13) using a similar procedure to Example 4 as a pale yellow powder H NvR (250 MHz, d DMSO) 6 (Jpm): 8.61 11), 8.30 1H), 7.74 1H), 7.57 (dd, 4H), 7.21 1H), 4.13 2H), 3.08 6H), 2.75 3H), 2.38 3H). 2 x CH 2 signals obscurred by H 2 0 signal.
Example 47 S-Bromo-2,3-dihydro-6-(4-methylpiperazin-1 -yl)-1 4-(2-methylpyridin-4yl)phenylaminocarbonyl-1H-indole The title compound was prepared from 4 -(2-methylpyridin-4-yl)aniline (D49) and bromo-2,3-dihydro-6-(4-methylpiperazin- 1 1 H-indole (D 15) using a similar procedure to Example 4 as a white solid H NMR (250 MHz, CDCl 3 8 (ppm): 8.52 1H), 7.83 1H), 7.64 7.52 4H), 7.38-7.33 2H), 7.29 1H), 6.54 1H), 4.11 2H), 3.19 2H), 3.09 (br s, 4H), 2.62 (br s, 4H s, 3H), 2.35 3H).
Example 48 5-Chloro-2,3-dihydro-6-(4-methylpiperazin1 [4-(2-metbylpyridin-4yl)phenylaminocarbonyl]-il-indole The title compound was prepared from 4 -(2-methylpyridin-4-yl)aniline (D49) and 2 ,3-dihydro-6-(4-methylpiperazin 1-yl)-1H-indole (Dl3) using a similar procedure to Example 4 as a beige solid 'H NMR (250MHz,
CDCI
3 6 (ppm): 8.52(d, 1H), 7.82 1H), 7.62-7.50 (m, 4H), 7.34 1H), 7.28 (dd, 1H), 7.14 1H), 6.52 1H), 4.11 2H), 3.18 (t, 2H), 3.13-3.04 4H), 2.61 3H), 2.60 (br s, 4H), 2.34 3H).
Example 49 5Chloro-2-dihydro-l [4-(2,6-dimethylpyridin-4-yl)phenylamino 6-(4-methylpiperazin-1-y)-lH-indole The title compound was prepared from 4 2 6 -dimethypyridin4-yl)phenyI isocyanate (D62) and 5-chloro-2,3-dihydro-6-(4-methylpiperazin 1-yl)- 1-indole (D13) using a similar procedure to Example 2 as a white solid -71- WO 98/50358 PCT/EP98/02262 'H NMR (250MHz, CDC1 3 5 (ppm): 7.82 11), 7.60 7.50 4H), 7.16 7.11 3H), 6.63 1H), 4.07 211), 3.15 2H), 3.09 (br s, 4H), 2.61 (br s, 4H), 2.57 6H), 2.35 3H).
Example 5-Bromo-2,3-dihydro1 4 2 6 -dimethylpyridin4-yl)phenylaminocarbonyJ 6 4 -methylpiperazin-1-yl)-lH-indole The title compound was prepared from 4 2 ,6-dimethylpyridin-4-yl)phenyl isocyanate (D62) and 5-bromo-2,3-dihydro-6-(4-methylpiperazin l-yl)-1H-indole (D 15) using a similar procedure to Example 2 as a white solid 'H NMR (250MHz, CDC1 3 8 (ppm): 7.83 11), 7.61 7.51 4H), 7.34 (s, 1H), 7.16 2H), 6.54 1H), 4.11 2H), 3.19 21), 3.09 (br s, 4H), 2.62 (br s, 4H), 2.58 6H), 2.35 3H).
Example 51 2,3-Dihydro-1
-I
4 2 6 methoxy-6-(4-methylpiperazin-1..yl)-lH-indole The title compound was prepared from 4 2 ,6-dimethylpyridin-4-yl)pheny isocyanate (D62) and 2 3 -dihydro-5-methoxy-6-(4-methylpiperazin- I-yl)-1 Hindole (intermediate 3 in WO 95/06627) using a similar procedure to Example 2 as a beige solid 'H NMR (250MHz, CDC1 3 8 (ppm): 7.70 1H), 7.61 7.50 4H), 7.16 (s, 2H), 6.74 1H), 6.51 1H), 4.11 2H), 3.84 3H), 3.20 21), 3.13 (br s, 4H), 2.62 (br s, 4H), 2.58 6H), 2.35 31).
Example 52 5-Chloro-2, 3 -dihydro-1 I4-(2,6-dimethylpyridin-3-yl)phenylaminocarbonyll- 6 4 -methylpiperazin-1 -yl)-1H-in dole The title compound was prepared from 4 2 ,6-dimethylpyridin-3-yl)phenyl isocyanate (D63) and 5-chloro- 2 3 -dihydro-6-(4-methylpiperazin- 1-indole (D13) using a similar procedure to Example 2 as a white solid -72- WO 98/50358 PCT/EP98/02262 'H NMR (250MHz, CDC 3 8 (ppm): 7.83 1H), 7.48 2H), 7.40 11), 7.28 2H), 7.16 11), 7.04 11), 6.49 1H), 4.11 2H), 3.20 2H), 3.10 (br s, 4H), 2.60 (br s, 4H), 2.57 31), 2.49 3H), 2.35 3H).
Example 53 2 3 -dihydro-l [4-(2,6-dimethylpyridin-3-yl)phenylaminocarbonyl- 6-(4-methylpiperazin-1-y)-l H-indole The title compound was prepared from 4 -(2,6-dimethylpyridin-3-yl)phenyl isocyanate (D63) and 5-bromo-2,3-dihydro-6-(4-methylpiperazin l-yl)-1H-indole (D15) using a similar procedure to Example 2 as a white solid 'H NMR (250MHz, CDC1 3 8 (ppm): 7.84 1H), 7.50 211), 7.41 1H), 7.35 11-1), 7.29 2H), 7.06 1H), 6.48 11), 4.12 21), 3.21 2H), 3.09 (br s, 4H), 2.60 (br s, 411), 2.57 311), 2.49 311), 2.35 3H).
Example 54 2 3 -dihydro-l-I4-(2,6-dimethylpyridin-3-yl)phenylaminocarbony]-5methoxy-6-(4-methylpiperazin-1.yl)-lH-indole The title compound was prepared from 4-(2,6-dimethylpyridin-3-yl)phenyl isocyanate (D63) and 2 3 -dihydro-5-methoxy-6-(4-methylpiperazin 1-yl)-1Hindole (intermediate 3 in WO 95/06627) using a similar procedure to Example 2 as a beige solid IH NMR (250MHz, GDCI 3 8 (ppm): 7.72 11), 7.48 21), 7.39 111), 7.25 21), 7.03 11), 6.73 111), 6.54 111), 4.09 21), 3.83 31), 3.18 (t, 2H), 3.12 (br s, 411), 2.60 (br s, 41), 2.56 311), 2.48 31), 2.34 31).
Example 5-Chloro-2,3-dihydro-6-(4-methylpiperazin1..yl)-l-1 4-(5-methyl-1,2,4oxadiazol-3-yl)phenylaminocarbonyll .H-indole The title compound was prepared in an analogous manner to Example 4 from 4- (5-methyl-1,2,4-oxadiazol-3-yl)aniline (Ger. Offen DE 2046928) and 2,3-dihydro-6-(4-methylpiperazin-l-yl)- 1-indole(D13). The product was isolated as a pale cream powder -73- WO 98/50358 WO 9850358PCT/EP98/02262 H1 NMiR (25OMI~z, CDCl 3 5 (ppm): 8.04 2H), 7.81 1H), 7.58(d, 2H), 7.15 IlH), 6.53 I 4. 10 2H), 3.19 2H), 3. 10 (br s, 411), 2.65 3H), 2.60 (br s, 2.35 3H).
Example 56 5-Chloro-2,3-dihydro-l-4-(3-methy-1 ,2,4-oxadiazol-5yl)phenylaminocarbonyl-6-(4-methylpiperain-1y).H-indole The title compound was prepared in an analogous manner to Example 4 from 4- 3 -methyl- 1,2,4-oxadiazol-5-yl)apnjline Het. Chem. 1980, 17 1273-5) and 5-chloro-2,3-dihydro-6-(4-methylpiperain-l-yl)-l H-indole (Dl The product was isolated as a cream powder 13g, 48%).
HI NMR (250MHz, d 6 DMSO) 8 (ppm): 8.81 1H), 7.84 2H), 7.71 2H), 7.63 1H), 4.02 2H1), 2.96 2H), 2.76 (br s, 4H), 2.34 (hr s, 4H), 2.07 (s, 3H), 1.93 3H). NH proton not observed.
Example 57 2 ,3-dihydro-6-(4-methylpiperazin.1-yl)..[3.(pyrimidin.2 yloxy)phenylaminocarbonyl..1H.indole The title compound was prepared in analogous manner to Example 4 -from 3- (pyrimidin-2-yloxy)aniline (D7 1) and 5-chloro-2,3-dihydro-6-(4-methylpiperain.
l-yl)-1H-indole (D13). The product was isolated as a pale buff powder 1H NMR (250MHz, d 6 DMSO) 8 (ppm): 8.55 (in, 3H), 7.63 1H1), 7.35 (mn, 2H), 7.26 7.10 (in, 3H), 6.75 11H), 4.02 2H1), 2.99 2H), 2.78 (br s, 4H1), 2.39 (hr s, 4H), 2. 10 3H1).
Example 58 (pyrimidin- 2 -yl)aminolphenylaminocarbonyl...H..jfdole The title compound was prepared in analogous manner to Example 4 from 4-[Ninethyl-N-(pyrimidin-2.yl)amino]aniline (1373) and 5-chloro-2,3-dihydro-6-(4methylpiperazin-1-yl)-1H-indole (D13). The product was isolated as a pale cream powder 74- WO 98/50358 WO 9850358PCT/EP98/02262 iH NMR (250Mliz, CDC1 3 5 (ppm): 8.34 2H1), 7.80 1H), 7.46 2H1), 7.29 2H), 7.15 1H), 6.56 111), 6.42 1H), 4.08 2H), 3.50 3H), 3.18 (t, 2H), 3.09 (br s, 4H), 2.60 (br s, 4H), 2.35 3H).
Example 59 2 3 -dihydro-1-4-(fur-2-yl)phenylamincarbonyJs-j.{4 methylpiperazin-1 -yi)-1H-indole The title compound was prepared in an analogous manner to Example 4 from 4- (fur-2-yl)aniline (Synthesis 1976, 1, 40) and 5-bromo-2,3-dihydro-6-(4methylpiperazin-1I-yl)-1IH-indole (Di15). The title compound was isolated as a cream powder 1 H NMR (250MHz, d 6 DMSO) 8 (ppm): 8.60 1H), 7.71 1H), 7.60 1H), 7.54 411), 7.32 1H), 6.74 1H), 6.74 1H), 4.08 2H1), 3.2 (br s, 4H), 3.04 2H1), 2.97 (br s, 4H), 2.68 3H).
Example 5-Chloro-2,3-dihydro-6-(4-methylpiperazin-1 14-(thien-3yl)phenylaminocarbonyl]-1H-indole The title compound was prepared from 5-chloro-2,3-dihydro-1-(4iodophenylaminocarbonyl)-6-(4-methylpiperazin. 1 I H-indole (D43) and 3thienylboronic acid in a similar manner to Description 2, obtained as a cream powder (3 I'H NirvR (250MHz, CDCl 3 8 (ppm): 7.83 1H), 7.57 211), 7.45 2H), 7.38 (in, 3H1), 7.15 I1H), 6.42 I 4. 10 2H), 3.18 2H), 3. 10 (br s, 4H1), 2.60 (br s, 4H), 2.35 3H).
Example 61 5-Bromo-2,3-dihydro-6-(4methylpiperzin1y1}.q14(thiazol-2 yl)phenylaminocarbonyl]-1H-indole The title compound was prepared from 4-(thiazol-2-yl)aniline (D52) and 2,3-dihydro-6-(4-methylpiperazin- I-yl)-lI H-indole (D 15) using a similar procedure to Example 4 75 WO 98/50358 WO 9850358PCT/EP98/02262 'H NMR (250MHz,
CDCI
3 5 (ppm): 7.92 2H), 7.84 2H), 7.52 2H), 7.32 2H4), 6.57 1H), 4.11 2H), 3.15 2H), 3.13 (br s, 4H), 2.69 (br s, 411), 2.42 3H).
Example 62 5-Chloro-2,3-dihydro-6-(4-methylpiperazin-.1-yI)-l-[4-(thiazol-2yl)phenylaminocarbonyll-lH-indole The title compound was prepared from 5-chloro-2,3-dihydro-1-(4iodophenylaminocarbonyl)-6-(4-methylpiperain. I-yI)-lI H-indole (1343) and 2bromothiazole using a similar procedure to D5 1 1 H NNMR (250NMz, CDCl 3 8 (ppm): 7.93 2H), 7.83 2H), 7.58 2H), 7.28 11H), 7.14 1H), 6.57 1H), 4.10 2H), 3.17 2H), 3.11 (br s, 4H), 2.61 (br s, 4H1), 2.35 3H).
Example 63 l-[ 4 5 -Acetylthien-2-yl)phenylaminocarbonyJ5chloro-2,3-dihydro- 6 4 methylpiperazin-1-y)-lH..jndole The title compound was prepared from 5-chloro-2,3-dihydro- 1-(4iodophenylaminocarbony1)-6-(4-methylpiperazin. I-yl)- I H-indole (D343) and acetylthien-2-ylboronic acid in a similar manner to Description 2, obtained a straw coloured solid H NMR (250MHz, d 6 DMSO) 8 (ppm): 8.77 1H), 7.91 1H), 7.83 IH), 7.70 (in, 3H), 7.55 1H), 7.22 111), 4.16 211), 3.18 2H), 2.92 (br s, 4H), 2.51 (in, 7H1), 2.23 3H). Urea NH not observed.
Example 64 1-(5-Bromonaphtb..1.yacety).5.chloro2,3dihydro.6-(4..methylpiperazinlyl)-1H-indole The title compound was prepared from 5-bromonaphth-1-ylacetic acid (Bull. Soc.
Chim. Fr. 1968, 7, 2957) and 5-chloro- 2 ,3-dihydro..6(4..methylpiperazinl1y)- I1H-indole (D 13) using a similar procedure to Example 20 as a light yellow foamn 76 WO 98/50358 WO 9850358PCT/EP98/02262 H NMR (250MHz,
CDCI
3 5 (ppm): 8.26 1H), 7.98 1H), 7.95 1H), 7.83 1H), 7.65 1H), 7.45 1H), 7.37 7.15 1H), 4.22 2H), 4.19 (t, 2H), 3.15 2H), 2.95 (br s, 4H), 2.48 (br s, 2.17 3H).
Example 5-Chloro-2,3-dihydro-6-(4..methylpiperain.1 -yl)-1-(8-phenylquinolin-5 ylaminocarbonyl)-1 H-indole The title compound was prepared from 5-amnino-8-phenylquinoline (D66) and chloro-2,3-dihydro-6-(4-methylpiperain. I-yl)-1 H-indole (DI 3) using a similar procedure to Example 4, as a cream coloured solid IIH NMR (250MHz, CDCl 3 8 (ppm): 8.95 (dd, 1H) 8.29 (dd, 11H) 7.83 1H-), 7.72 7.65 (in, 3H), 7.53 7.38 (in, 5H), 7.18 1H), 6.67 lH), 4.22 2H), 3.24 2H), 3.06 (br s, 4H), 2.56 (br s, 4H), 2.32 3H).
Example 66 2 3 -dihydro-6..(4-methylpiperazin..1.yI)1{8.phenylquilolins5 ylaminocarbonyl)-1 H-indole The title compound was prepared from 5-amnino-8-phenylquinoline (D366) and bromo-2,3 -dihydro-6-(4-methylpiperazin- 1H-indole (D 15) using a similar procedure to Example 4, as a cream coloured solid 1H NMiR (250MHz, CDCl 3 5 (ppm): 8.96 (dd, 11H), 8.31 (dd, 1H), 7.84 lE), 7.74 7.66 (in, 4H), 7.52 7.41 (mn, 4H), 7.38 111), 6.65 1H), 4.25 2H), 3.27 2H), 3.05 (br s, 4H), 2.57 (br s, 4H), 2.32 311).
Example 67 phenylethyl)quinolin-6-ylaminocarbonyl.. lH-indole The title compound was prepared from 6 -amnino-2-(2-phenylethyl)quinoline (D69) and 5 -chloro-2,3 -dihydro-6-(4-methylpiperazin- Il-yl)-lI H-indole (Dl 13) using a similar procedure to Example 4, as a white solid IH NMR (250MHz, CDC1 3 5 (ppm): 8.09 111), 8.01 111), 7.99 111), 7.85 111), 7.56 (dd, 1H), 7.31 7.15 (mn, 711), 6.62 1H), 4.12 2H), 3.30 3.11 (in, 1011), 2.61 (br s, 411), 2.35 3H)., 77 WO 98/50358 PCTIEP98/02262 Example 68 5-Chloro-2,3-dihydro-6-(4-methypiperzi-1 -yl)-1 -15-(1 -methylpiperidin4yl)naphth-1-ylaminocarbonyl..1il-indole The title compound was prepared from 5 -(1l-methylpiperidin-4-yl)naphth-.I .ylamine (D77) and 5-chloro- 2 3 -dihydro-6-(4-methylpiperain-l-yl)-lil-indole (1313) using a similar procedure to Example 4as a white solid I 1 H NMiR (25OMIFz,CDCI 3 8(ppm):7.99 1H), 7.79 (in, 3H), 7.50 (in, 3H), 7.16 (s, I 6.70 I1H), 4.24 2H), 3.3 2 (in, I1H), 3.24 2H), 3.04 (br s, 4H), 2.5 6 (br s, 6H), 2.38 3H), 2.32 3H), 2.21 (mn, 2H), 1.97 (in, 411).
Example 69 5-Bromo-2,3-dihydro-1 -[4-(isoq uinoliD-4-yl)phenylamin ocarbonylj-6-(4methylpiperazin-1-yl)- lH-indole The title compound was prepared from 4 -(isoquinolin-4-yl)phenyl isocyanate (D54) and 5-bromo-2,3 -dihydro-6-(4-methylpiperazin-1 1H-indole (Dl using a similar procedure to Example 2, as a white solid H NMR (250MHz, CDCl 3 8 (PPM): 9.25 1H), 8.47 1H), 8.05 1H), 8.01 11H), 7.86 111), 7.68 (in, 2H), 7.59 2H), 7.50 2H), 7.36 1H), 6.57 I 4.16 211), 3.26 2H), 3. 10 (hr s, 4H), 2.61 (br s, 4H), 2.36 3H).
Example 5-Chloro-2,3-dihydro-1
-I
4 -(isoquinolin-4-y)phenylaminocarbonyl-6-(4methylpiperazin-1-yl)..1H-indole The title compound was prepared from 4 -(isoquinolin-4-yl)phenyl isocyanate (D54) and 5-chloro-2,3-dihydro-6-(4-methylpiperazin-.1 -yl)-1 H-indole (D 13) using a similar procedure to Example 2, as a white solid 1H NMR (250MIHz, CDC1 3 8 (PPM): 9.25 1H), 8.47 111), 8.02 IH), 7.94 1H), 7.85 111), 7.67 (mn, 2H), 7.61 2H1), 7.49 2H), 7.16 1H), 6.60 1H1), 4.16 2H1), 3.25 2H), 3.18 (hr s, 4H1), 2.61 (hr s, 4H), 2.35 3H).
Example 71 78 WO 98/50358 WO 9850358PCT/EP98/02262 5-Bromo-2,3-dihydro-6-(4-methylpiperain.1y)..1..4.qujfloijl3yl)phenylaminocarbonylJ-lH-indole The title compound was prepared from 4 -(quinolin-3-yl)phenyl isocyanate (D56) and 5-bromo-2,3-dihydro-6-(4-methylpiperazin. -yl)-l H-indole (Dl 5) using a similar procedure to Example 2, as an off white solid H NMR (250MHz, CDCl 3 5 (PPM): 9.17 1H1), 8.27 111), 8.13 1H), 7.85.(in, 2H), 7.62 (in, 6H), 7.34 111), 6.57 1H), 4.14 2H), 3.20 2H), 3.17 (br s, 4H), 2.62 (hr s, 4H), 2.37 3H).
Example 72 5-Chloro-2,3-dihydro-6-(4-methylpiperazin-1y)..1 4-(quinolin-3yl)phenylaminocarbonylj -1H-indole The title compound was prepared from 4-(quinolin-3-yl)phenyl isocyanate (1356) and 5-chloro-2,3-dihydro-6-(4-methylpiperazin-l-yl)-l H-indole (Dl 3) using a similar procedure to Example 2, as a light beige solid IH NMvR (250M~z, CDC1 3 8 (PPM): 9.17 1H), 8.27 1H), 8.13 1H), 7.87 111), 7.84 111), 7.73 (in, 3H), 7.60 (in, 3H1), 7.16 1H1), 6.54 111), 4.14 2H), 3.21 2H), 3.12 (hr s, 4H), 2.62 (br s, 4H1), 2.36 3H1).
Example 73 -Chloro-2,3-dihydro-6-(4-methylpiperain1yI.l(2-.methyll ,2,3,4tetrahydroisoquinolin-7-y)aminocarbonylJ..1 il-in dole The title compound was prepared from 7-amnino-2-methyl- 1,2,3,4tetrahydroisoquinoline (D78) and 5-chloro-2,3-dihydro-6-(4-inethylpiperazin 1yl)-1IH-indole (D 13) using a similar procedure to Example 4 as a off-white solid 1 H NMR (250MIHz,CDC1 3 5(ppm): 7.80 1H), 7.10 (in, 4H), 6.36 1H), 4.04 2H), 3.55 2H), 3.15 211), 3.09 (hr s, 4H), 2.87 (mn, 2H1), 2.66 (in, 2H), 2.59 (hr s, 4H), 2.44 3H), 2,34 3H).
Example 74 5-Bromo-2,3-dihydro-6-(4-methylpiperazin-1 -yl).-1-[(2-methyl-1 ,2,3,4tetrahydroisoquinolin-7-yI)aminocarbony1J.1H-indole 79 WO 98/50358 WO 9850358PCT/EP98/02262 The title compound was prepared from 7-amino-2-methyl-1,2,3,4tetrahydroisoquinoline (D378) and 5-bromo-2,3-dihydro-6-(4-methylpiperain-.1yl)- 1 11-indole (Dl 15) using a similar procedure to Example 4 as an off-white solid 11H NMR (25OMHz,CDC1 3 8(ppm): 7.80 111), 7.32 I1H), 7.09 (in, 3H), 6.35 1H), 4.05 2H1), 3.55 2H), 3.16 2H), 3.07 (hr s, 4H), 2.87 (in, 2H), 2.67 (in, 2H), 2.59 (hr s, 4H1), 2.44 311), 2.34 3H).
Example 5-rm-,-iyr--4mtypieai--l--4(unln8 yl)phenylaminocarbonyll-1H..indole The title compound was prepared from 4 -(quinolin-8-yl)phenyl isocyanate (D58) and 5 -bromo- 2 ,3 -dihydro-6-(4-methylpiperain- I-yl)-1I H-indole (D 15) using a similar procedure to Example 2, as a white solid 'H NMR (250MHz, CDC1 3 8 (ppm): 8.94 (mn, 1H), 8.20 (in, 7.84 lH), 7.82 1H), 7.62 (mn, 6H1), 7.41 (in, 111), 7.36 IH), 6.53 11-1), 4.12 211), 3.19 211), 3. 10 (hr s, 4H), 2.61 (hr s, 411), 2.3 5 311).
Example 76 5-Chloro-6-(4-methylpiperazin-1yl)-1..4(quinolin.8yI)phenylaminocarbonyl]-1H-indole The title compound was prepared from 4 -(quinolin-8-yl)phenyl isocyanate (D58) and 5 -chloro- 2 3 -dihydro-6-(4-methylpiperazin- I-yl)-lI H-indole (D 13) using a similar procedure to Example 2, as a white solid (7 1 1 H NMvR (250MHz, CDC1 3 8 (ppm): 8.93 (in, 111), 8.20 11-1), 7.80 (in, 211), 7.57 (in, 611), 7.41 (in, 111), 7.15 111), 6.53 11H), 4.12 211), 3.19 211), 3.12 (hr s, 411), 2.62 (hr s, 411), 2.37 311).
Example 77 5-Chloro-2,3-dihydro-1-[4-(imidazol..1.yl)phenylaminocarbonyl-6-( 4 methylpiperazin-1-yl)-1H-indole The title compound was prepared in an analogous manner to Example 4 from 4- (imidazol-1-yl)aniline Med. Chem. 1988, 31(11), 2136) and 5-chloro-2,3- WO 98/50358 WO 9850358PCTIEP98/02262 dihydro-6-(4-methylpiperazin-. -yl)-l H-indole (Dl The product was isolated as a pale cream powder 1H NMR (250M-Hz, d 6DMSO) 8 (ppm): 8.70 1H), 8.20 1H), 7.81 III), 7.72 (in, 311), 7.57 211), 7.25 1H), 7.12 111), 4.21 2H1), 3.15 2H), 2.94 (in, 4H1), 2.52 (br s, 4H), 2.25 3H1).
Example 78 -Chloro-2,3-dihydro-6-(4-methylpiperazin-1l..yI)...4..(Pyridin-4 yI)phenylaminocarbonylj-l H-indole The title compound was prepared in an analogous manner to Description 2 from 5-chloro-2,3-dihydro-l1-[ 4 -iodophenylaminocarbonyl]-6-(4-metiylpiperazin-l-yl)- I1H-indole (D43) and 4-pyridylboronic acid Med Chem. 1997, 40(22), 3 542).
The product was isolated as a pale yellow solid 1NMR (250MHz, d 6DMSO) 8 (ppm): 8.51 1H), 8.36 2H), 7.57 7.42 (in, 711), 7.00 1H1), 3.92 211), 2.94 2H1), 2.71 (in, 411), 2.02 3H1).
4H obscured by DMSO signal.
Example 79 2 3 -Dihydro-5-methoxy-6-(4-methylpiperazin.1 yI)aminocarbonylJ-IH-indole The title compound was prepared from 5-amino-8-phenylquinoline (D66) and 2,3dihydro-5-methoxy-6-(4-methylpiperazin-l-yl)-l 1-indole (intermediate 3 in WO 95/06627) using a similar procedure to Example 4, as a yellow/brown oil This was converted to the HCI salt as a yellow solid from acetone.
111 NMR (free base) (250MHz, CDCI 3 8 (ppm): 8.95 (dd, 1H1), 8.35 (dd, 111), 7.77 7.65 (in, 411), 7.52 7.37 (in, 511), 6.79 111), 6.76 1H1), 4.25 211), 3.85 311), 3.27 211), 3.14 (br s, 411), 2.66 (br s, 411), 2.37 3H1).
Example 5-Chloro-2,3-dihydro-6-(4-methylpiperazin-1y)1...[(8-phenyqunojji...
yI)aminocarbonyll-1 H-indole -81 WO 98/50358 WO 9850358PCT/EP98/02262 The title compound was prepared from 8-phenylquinolin-4-yl isocyanate (D386) and chloro-2,3-dihydro-6-(4-methylpiperazin-1 -yI)-1 H-indole (D1 3) using a similar procedure to Example 2, as ayellow solid 111 NMIR (250M1{z, CDCI 3 8 (ppm): 8.86 111), 8.15 111), 7.85 111), 7.77 7.38 (in, 911), 7.19 1H), 4.27 2H), 3.25 211), 3.12 (br s, 411), 2.63 (br s, 4H), 2.37 311).
Example 81 5-Bromo-2,3-dihydro-6-(4-methylpiperazin.1 -yI)-1-[(8-phenylquinolin-4yl)aminocarbonylj-1H-indole The title compound was prepared from 8-phenylquinolin-4-yl isocyanate (1386) and bromo-2,3-dihydro-6-(4-methylpiperazinl yl)..IH-indole (D 15) using a similar procedure to Example 2, as a yellow solid 111 NMvR (250MHz, CDCI 3 8 (ppm): 8.87 111), 8.16 111), 7.85 111), 7.78 7.39 (in, 9H), 7.28 lH), 4.29 211), 3.27 2H1), 3.11 (br s, 411), 2.63 (br s, 4H), 2.37 3H).
Example 82 2 3 -Dihydro-5-methoxy-6-(4-methylpiperazin.1 -yl)-1 (8-phenylquinolin-4yl)aminocarbonylJ-1H-indole The title compound was prepared from 8-phenylquinolin-4-yl isocyanate (1386) and 2,3dihydro-5-methoxy-6-(4-methylpiperazin- I-yl)- I11-indole (intermediate 3 in WO 95/06627) using a similar procedure to Example 2, as a beige solid 1II NMIR (250M1{z, CDCl 3 8 (ppm): 8.86 1H), 8.19 IH), 7.79 7.38 (in, 911), .7.33 111), 6.78 111), 4.28 211), 3.86 311), 3.27 2H), 3.14 (br s, 411), 2.63 (br s, 4H), 2.36 314).
Example 83 -Chloro-l-[ 4 2 ,6-dimethylpyridin4-yl).3methylphenylaminocarbonyl-6-(4methylpiperazin-1-yl)-ll-indole The title compound was prepared from 4 2 ,6-dimethylpyridin-4-yl)-3methylaniline (1388) and 5-chloro-2,3-dihydro-6-(4-methylpiperazin-l-yl)-1Hindole (D 13) using a similar procedure to Example 4 as a pale yellow solid (41 82 WO 98/50358 PCT/EP98/02262 'H NMR (250MHz, CDC1 3 8 (ppm): 7.82 1H), 7.36 1H), 7.31 (dd, 1H), 7.20-7.10 2H), 6.90 2H), 6.46 1H), 4.10 2H), 3.18 2H), 3.10 (br s, 4H), 2.60 (br s, 4H), 2.56 6H), 2.35 3H), 2.27 3H).
Example 84 5-Chloro-2,3-dihydro--[3-methyl-4-(6-methylpyridin-2-yl)phenylaminocarbonyl]-6- (4-methylpiperazin-1-yl)-1H-indole The title compound was prepared from 3 -methyl-4-(6-methylpyridin-2-yl)aniline (D89) and 5-chloro- 2 ,3-dihydro-6-(4-methylpiperazin- I1-yl)-1H-indole (D13) using a similar procedure to Example 4 as a pale yellow gum This was converted to its hydrochloride salt as a pale yellow solid from acetone.
'H NMR (free base) (250MHz, CDC1 3 8 (ppm): 7.83 1H), 7.62 1H), 7.40-7.28 (m, 3H), 7.20-7.14 2H), 7.09 1H), 6.42 1H), 4.10 2H), 3.18 2H1), 3.10 (br s, 4H), 2.61 (br s, 7H), 2.36 3H), 2.35 3H).
Example 5-Bromo-2,3-dihydro-1-I 3 -methyl- 4 6 -methylpyridin-2-yl)phenylaminocarbonyl-6- (4-methylpiperazin-1-yl)-l H-indole The title compound was prepared from 3 -methyl-4-(6-methylpyridin-2-yl)-3methylaniline (D89) and 5-bromo-2,3-dihydro-6-(4-methylpiperazin -1-yl)-1Hindole (D15) using a similar procedure to Example 4 as a yellow foam This was converted to its hydrochloride salt as a beige solid from acetone.
IH NMR (free base) (250MHz, CDC1 3 8 (ppm): 7.83 1H), 7.62 1H), 7.40-7.28 (m, 4H), 7.16 1H), 7.09 1H), 6.42 1H), 4.10 2H), 3.19 2H), 3.09 (br s, 4H), 2.61 (br s, 7H11), 2.36 3H), 2.35 3H).
Example 86 2,3-Dihydro-5-methoxy-l1-[ 3 -methyl- 4 6 -methylpyridin-2-yl)phenylaminocarbonyl]- 6-(4-methylpiperazin-1-yl)-1 H-indole The title compound was prepared from 3 -methyl-4-(6-methylpyridin-2-yl)aniline (D89) and 2,3-dihydro-5-methoxy-6-(4-methylpiperaz in-1-yl)-1H-indole (intermediate 3 in WO 95/06627) using a similar procedure to Example 4 as a pale 83 WO 98150358 PTE9126 PCT/EP98/02262 yellow foam This was converted to its hydrochloride salt as a yellow solid from acetone.
'H NMR (free base) (250NMz, CDCl 3 8 (ppm): 7.71 11-1), 7.61 11H), 7.38-7,28 (in, 3H), 7.16 1H1), 7.08 1H1), 6.72 11H), 6.42 1H), 4.07 2H), 3.83 3H), 3.18 2H), 3.12 (br s, 4H1), 2.60 (br s, 7H), 2.36 3H4), 2.34 3H).
Example 87 5-Chloro-2,3-dihydro-l- [5-(6-methylpyridin-2-yI)naphth-1 -ylaminocarbonylj-6-(4methylpiperazin-1 -yl)-1 H-in dole The title compound was prepared from 5-(6-methylpyridin-2-yl)naphth-1I..y isocyanate (D392) and 5-chloro-2,3-dihydro-6-(4-methylpiperazin-. -yl)-1 H-indole (1313) using a similar procedure to Example 4 as a pale yellow solid This was converted to its hydrochloride salt as a pale yellow solid from acetone.
H NMR (free base) (250MHz, CDCl 3 8 (ppm): 7.97 7.87(d, 111), 7.85 1H), 7.76-7.68 (in, 2H), 7.62-7.55 (mn, 2H), 7.50-7.40 (in, 1H), 7.33 11H), 7.23 1H), 7.16 1H), 6.80 1H1), 4.24 2H), 3.23 2H), 3.09 (br s, 4H), 2.67 3H), 2.61 (br s, 4H), 2.35 3H).
Example 88 2,3-Dihydro-5-methoxy-1 -1 5 6 -methylpyridin-2-yl)naphth-1-ylaminocarbony-6-(4methylpiperazin-I -yl)-1 H-in dole The title compound was prepared from 5-(6-methylpyridin-2-yl)naphth-1-yI isocyanate (D92) and 2 3 -dihydro-5-methoxy-6-(4-methylpiperazin-1 1Hindole (intermediate 3 in WO 95/06627) using a similar procedure to Example 4 as a pale yellow foam This was converted to its hydrochloride salt as a pale yellow solid from acetone.
'H NNvII (free base) (250MHz, CDCl 3 8 (ppm): 7.99 (dd, 1H), 7.85 1H), 7.82-7.68 (in, 3H), 7.62-7.55 (mn, 2H1), 7.50-7.41 (mn, 1H1), 7.34 1H1), 7.21 1H), 6.76 211), 4.24 2H), 3.85 3H), 3.26 2H1), 3.15 (br s, 4H), 2.67 (br s, 7H), 2.38 3H).
Example 89 5-hoo23dhdo6(4ehlieai- l-l1-yii--lnptylaminocarbonyl]-1 H-in dole 84 WO 98/50358 PCT/EP98/02262 The title compound was prepared from 4 -(pyridin-4-yl)naphth--ylamine (D32) and chloro-2,3-dihydro-6-(4-ethylpiperazin-l-yl)- 1H-indole (D97) using a similar procedure to Example 4, as a beige solid The HCI salt was isolated as a yellow solid from acetone.
1 H NMR (free base) (250MHz, CDC1 3 8 (ppm): 8.74 2H), 8.00 1H), 7.91 1H), 7.91 7.86 (in, 2H), 7.61 7.42 (in, 5H), 7.19 1H), 6.81 IH), 4.30 2H), 3.28 (t, 2H), 3.11 (br s, 4H), 2.62 (br s, 4H), 2.48 2H), 1. 11 3H4).
Example 5-Chloro-2,3-dihydro-6-(4-ethypiperzin1 -yl)-l-I 5 -(pyridin-4-yl)naphth-I ylaminocarbonylJ- lH-indole The title compound was prepared from 5-(pyridin-4-yl)naphth-l-ylamine (D74) and chloro-2,3-dihydro-6-(4-ethylpiperazin yl)llIlHindole (D97) using a similar procedure to Example 4, as a beige solid The HCl salt was isolated as a yellow solid from acetone.
IH NMR (free base) (250M~z, CDCl 3 6 (ppm): 8.74 2H), 8.02 111), 7.84 III), 7.77 1lH), 7.71 I1H), 7.60 I1H), 7.49 IlH), 7.45 7.41 (in, 3H), 7.19 I1H), 6.73 IH), 4.28 2H), 3.27 2H), 3.09 (br s, 4H), 2.60 (br s, 4H), 2.46 2H), 1.09 3H).
Example 91 5-Chloro-2,3-dihydro-6-(piperazin-.1..yl)-l-14-(pyridin.4.yl)naphth.1 ylaminocarbonyII-1H-indole hydrochloride A stirred solution of 6 4 -(tert-butyloxycarbonyl)piperazin-1 -yl]-5-chloro-2,3-dihydro- 1- 4 -(pyridin-4-yl)naphth-l-ylaminocarbonyl]y1H..jfdole (DIQO, 3 45mg, 0.59 mmole) in methanol (30m1) was treated with IM HC1 in ether (3m1). After 18h at room temperature additional HC1 in ether (2.5m1) was added. After 24h the mixture was concentrated in vacuc and the residue solidified by trituration with acetone to afford the title compound as a yellow solid (260mg, 84%).
111 NMR (250MI-z, d 6 DMSO) 8 (ppm): 9.32 2H), 9.09 111), 9.04 2H1), 8.23 8.19 (mn, 3H), 7.88 (dd, 11H), 7.77 7.59 (in, 5H), 7.30 1H), 4.37 3.24 3.18 6H), 3.10 (br s, 4H).
85 WO 98/50358 WO 9850358PCT/EP98/02262 Example 92 5-hoo23dhdo6-pprzn1y)l15(yii- lnptylaminocarbonylJ-1il-indole hydrochloride The title compound was prepared from 6 4 -(tert-butyloxycarbonyl)piperazin-1 chloro-2,3-dihydro-l1-[5-(pyridin-4-yl)naphth- 1-ylaxninocarbonyl]- 1 1-indole (D3100) using a similar procedure to Example 91 as a beige solid 1 H NMvR (250MHz, d 6 DMSO) 8 (ppm): 9.41 211), 9.17 9.13 (in, 311), 8.37 -8.28 (in, 3H), 7.84 7.64 (in, 6H), 7.40 11H), 4.45 2H), 3.35 3.26 (in, 6H), 3.19 (br s, 411).
Example 93 5-Chloro-2,3-dihydro-6-(4-methylpiperazin..1.yl)l14.(pyridain.3 yl)phenylaminocarbonylj-1il-indole The title compound was prepared from 4-(pyridizin-3-yl)benzoic acid (D 102) using a similar procedure to Description 1 to form the isocyanate followed by addition of chloro-2,3-dihydro-6-(4-methylpiperazin..I 1H-indole (D 13) to afford the urea as a pale yellow solid 11 NMR (25OMHz,CDC1 3 8(ppm): 9.12 I1H), 8.06 2H), 7.82 (in, 211), 7.61 (d, 2H), 7.51 (in, 1H), 7.14 111), 6.63 IH), 4.12 2H1), 3.19 211), 3.11 (br s, 4H), 2.61 (br s, 4H), 2.36 311).
Example 94 5-rm-,-iyr--4mtyppeai--l--4(yiai.3 yl)phenylaminocarbonylj- lH-indole The title compound was prepared from 4 -(pyridazin-3-yl)benzoic acid (D102) using a similar procedure to Description 1 to form the isocyanate followed by addition of bromo-2,3-dihydro6(4iethylpiperazin yl)1 IHidole (DI15) to afford the urea as a grey solid 111 NMR (250MHz,CDC1 3 8(ppm): 9.12 (dd, 111), 8.08 2H), 7.83 (in, 2H1), 7.62 (d, 2H1), 7.52 (in, 111), 7.34 111), 6.60 1H), 4.13 2H), 3.20 2H), 3. 10 (br s, 411), 2.61 (br s, 411), 2.36 3H).
Example 86 WO 98/50358 WO 9850358PCT/EP98/02262 5-Chloro-2,3-dihydro-6.(4-methylpiperazin.1 -yl)-1-[4-(pyrazin-2yl)phenylaminocarbonyll-1H-indole The title compound was prepared from 4-(pyrazin-2-yl)benzoic acid (D 103) using a similar procedure to Description 1 to form the isocyanate followed by addition of chloro- 2 3 -dihydro-6-(4-methylpiperazinl yl) IH..indole (D 13) to afford the urea as a pale yellow solid IH NMvR (25OMHz,CDC1 3 8(ppm): 9.01 111), 8.61 1H), 8.47 1H), 8.02 2H), 7.83 111), 7.61 2H), 7.16 1H), 6.55 1H), 4.13 2H), 3.20 2H), 3.11 (br s, 4H), 2.61 (br s, 4H), 2.36 311).
Example 96 5-Bromo-2,3-dihydro-6-(4methypiperazin-1.yl)1I[4.(pyrazin-2 yl)phenylaminocarbonylJ-1 H-indole The title compound was prepared from 4-(pyrazin-2-yl)benzoic acid (D 103) using a similar procedure to Description 1 to form the isocyanate followed by addition of bromo- 2 ,3-dihydro-6-(4-methylpiperazin- 1 1 H-indole (D 15) to afford the urea as a pale yellow solid 1 H NMR (250MHz,CDC1 3 8(PPm): 9.00 1H), 8.60 IH), 8.48 lH), 8.01 2H1), 7.83 IlH), 7.61 2H), 7.34 I 6.5 7 1lH), 4.13 2H), 3.20 2H), 3. 10 (br s, 4H), 2.62 (br s, 4H1), 2.36 3H).
Example 97 2 3 -dihydro-6-(4-methypiperazin-1..y)1.[(2phenylpyridinS5 yl)aminocarbonyl-1 -indole The title compound was prepared from 6-phenylnicotinic acid (D104) using a similar procedure to Description 1 to form the isocyanate followed by addition of 5-chloro-2,3dihydro-6-(4-methylpiperazin- l)11H.indole (D 13) to afford the urea as a white solid IH NMR (25OMHz,d 6 DMSO) 8.87 (dd, 2H), 8.12 (in, 3H1), 7.96 1H), 7.83 (s, IH), 7.47 (in, 3H), 7.28 111), 4.22 2H), 3.17 2H), 2.95 (br s, 4H), 2.54 (br s, obscured by DMSO peak, 4H), 2.26 3H).
Example 98 87 WO 98/50358 PCT/EP98/02262 -Bromo-2,3-dihydro-6-(4-methylpiperazin-1 -yl)-1-I(2-phenylpyridin.5 yl)aminocarbonylJ- lH-indole The title compound was prepared from 6-phenylnicotinic acid (D 104) using a similar procedure to Description 1 to form the isocyanate followed by addition of 5-bromo-2,3dihydro-6-(4methylpiperain-1yl).1H-indole (DI 5) to afford the urea as an off white solid IH NMR (25OMHz,d 6 DMSO) 8(jppm): 8.86 (dd, 2H), 8.12 (in, 3H), 8.09 1H), 7.83 (s, 1H), 7.47 (in, 4H), 4.22 2H), 3.18 2H1), 2.94 (br s, 4H), 2.53 (br s, obscured by DMSO peak, 4H1), 2.26 3H1).
Example 99 5-Chloro-2,3-dihydro- 4 6 -methylpyridazin-3-yl)phenylaminocarbonyl..6(4methylpiperazin-1-yl)-1 H-indole The title compound was prepared from 4 6 -methylpyridazin-3-yl)benzoic acid (D 105) using a similar procedure to Description 1 to form the isocyanate followed by addition of 5-chloro-2,3-dihydro-6-(4-methylpiperazin-1 -yl)-1 H-indole (Dl 3) to afford the urea as a buff solid 1H NMR (25OMHz,CDC1 3 5(ppm): 8.03 2H), 7.83 IR), 7.71 1H), 7.58 (d, 2H), 7.35 11H), 7.14 1H), 6.59 111), 4.11 2H1), 3.18 2H), 3.11 (br s, 4H), 2.74 3H), 2.60 (br s, 4H1), 2.36 3H1).
Example 100 5-Bromo-2,3-dihydro.- 1 4 6 -methylpyridazin-3-yI)phenylaminocarbonylj&6(4- methylpiperazin-1-yI)-1 H-indole The title compound was prepared from 4 6 -methylpyridazin-3 -yl)benzoic acid (Di105) using a similar procedure to Description 1 to form the isocyanate followed by addition of 5-bromo-2,3-dihydro-6-(4-methylpiperazin-1 -yl)-1 H-indole (Dl 5) to afford the urea as a buff solid IH NMR (2501v11z,CDCl 3 5(ppm): 8.05 2H), 7.84 11H), 7.72 1H), 7.60 (d, 2H1), 7.3 5 (in, 2H), 6.5 7 I1H), 4.13 2H1), 3.20 2H), 3.10 (br s, 4H), 2.75 3H), 2.62 (br s, 411), 2.36 3H).
Example 101 88 WO 98/50358 PCT/EP98/02262 5-Chloro-2,3-dihydro-6-(4-methylpiperazin-1.y)..q4a(Pyridin-3 yl)phenylaminocarbonylJ-1 H-indole The title compound was prepared from 5-chloro.-2,3 -dihydro- 1-(4iodophenylaminocarbonyl)-6-(4-methylpiperazin. Il-yl)-lI H-indole (D43) and 3 pyridylboronic acid (Chem. Pharm. Bull, 1983, 31(12), 4573) in a similar manmer to Description 2, obtained as a pale cream powder 1H NMR (250 MHz, d 6DMSO) 8 (ppm): 8.81 1H), 8.61 1H), 8.45 7.96 (d, 111), 7.7 1H), 7.62 (in, 4H1), 7.38 (in, 1H), 7.14 1H), 4.08 2H),.3.04 2H), 2.83 (br s, 4H), 2.15 3H). 2xCH 2 signals obscured by DMSO signal.
Example 102 5-Chloro-2,3-dihydro-1-14-(5-methyloxazol-2-yl)pbenylaminocarbonyl1-.6-(4methylpiperazin-1 -yl)-lHi-indole The title compound was prepared from 5-chloro-2,3-dihydro-6-(4-methylpiperazin -yl)- 1H-indole (1313) and 4 -(5-methyloxazol-2-yl)aniline (D107) using a similar procedure to Example 4, obtained as a pale cream powder 1H NMR (250 MiHz, d'DMSO) 8 (ppm): 8.78 iH), 7.72 (in, 5H), 7.20.(s, 111), 6.90 (s, 1H), 4.14 2H1), 3.08 2H), 2.96 (br s, 4H), 2.72 (br s, 4H), 2.38 3H1), 2.33 3H).
Example 103 2,3-Dihydro-5-methoxy-1 -1 4 5 -methyloxazol-2-yl)phenylaminocarbonyl.6(4methylpiperazin-1-yl)-1H-indole The title compound was prepared from 2 3 -dihydro-5-methoxy-6-(4-methylpiperazin 1yl)-lIH-indole (Intermediate 3 in WO 95/06627) and 4 -(5-methyloxazol-2-yl)aniline (D 107) using a similar procedure to Example 4, obtained as a pale cream powder H NMR (250 MHz, d6DMSO) 8 (ppm): 8.80 1H), 7.97 2H), 7.86 2H), 7.77 (s, 1H), 7.08 11H), 7.00 11H), 4.27 2H), 3.89 3H), 3.25 2H), 3.07 (br s, 4H), 2.61 (br s, 4H), 2.52 3H), 2.37 3H1).
Example 104 2 3 -dihydro-1-[4-(5-methyoxazol2yI)phenylaminocarbonyll- 6 (4methylpiperazin-1 -yI)-1H1-indole -89- WO 98/50358 PCT/EP98/02262 The title compound was prepared from 5-bromo-2,3-dihydro-6-(4-methylpiperazin- 1l-yI)- 1H--indole (D15) and 4-(5-methyloxazol-2-yl)aniline (D107) using a similar procedure to Example 4, obtained as a pale cream powder 1H NMR (250MHz, CDCL 3 8 (ppm): 7.94 2H1), 7.82 114), 7.52 2H), 7.33 (s, 1 6.81 1 6.5 8 I 4.11 2H), 3.15 (in, 6H), 2.69 (br s, 4H), 2.42 3H), 2.39 3H).
Example 105 5-Chloro-2,3-dihydro-l-[4-(1 -methylpyrazol-4-yl)pheuiylaminocarbonyl1-6-(4methylpiperazin-1-yl)-1H-indole The title compound was prepared from 4-(1 -methylpyrazol-4-yl)benzoic acid (WO 97/43262) using a similar procedure to Description 1 to form the isocyanate followed by addition of 5-chloro-2,3-dihydro-6-(4-methylpiperazin- l-yl)-1 H-indole (D1 3) to afford the urea as an off white solid IH NIVR (25OMHz,CDC1 3 8(ppm): 7.82 1H), 7.72 114), 7.55 1H), 7.41 4H), 7.13 1H), 6.44 1H1), 4.07 2H), 3.93 3H), 3.16 2H), 3.10 (br s, 4H), 2.60 (br s, 4H1), 2.35 3H1).
Example 106 5-Bromo-2,3-dihydro-1-14-(1-methylpyrazol-4-yl)phenylaminocarbonyl-6-(4methylpiperazin-1-yl)-1 H-in dole The title compound was prepared from 4-(1-methylpyrazol-4-yl)benzoic acid (WO 97/43 262) using a similar procedure to Description 1 to form the isocyanate followed by addition of 5-bromo-2,3-dihydro-6-(4-methylpiperazin- Il-yl)-lI H-indole (D 15) to afford the urea as a buff solid IHNMR (25OMHz,CDC1 3 8(ppm): 7.83 1H), 7.71 IH), 7.54 1H), 7.40 4H), 7.31 1H), 6.46 1H1), 4.05 2H), 3.93 3H), 3.15 2H), 3.08 (br s, 4H), 2.60 (br s, 4H), 2.35 3H).
Example 107 5-Chloro-1 -[4'-cyano-3'-methylbiphenyl-4-aminocarbonyl-2,3-dihydro-6-(4methylpiperazin-1-yl)- lH-indole WO 98/50358 WO 9850358PCT/EP98,'02262 The title compound was prepared from 4 4 -cyano-3-methylphenyl)benzoic acid (D 106) using a similar procedure to Description 1 to form the isocyanate followed by addition of 2 ,3-dihydro-6-(4-methylpiperazin-.1 -yl)-1 H-indole (Dl 3) to afford the urea as a pale yellow solid lH NMR (25OMHz,CDC1 3 85Qpm): 7.82 1H), 7.64 1H), 7.44-7.55 (in, 6H), 7.15 I1H), 6.52 IlH), 4.11 211), 3.19 2H), 3. 10 (hr s, 4H), 2.60 (br s, 7H), 2.3 5 (s, 311.
Example 108 5-Bromo- 4 -cyano- 3 '-methylbipheny-4aminocarbonyIJ-2,3dihydro-6(4.
methylpiperazin-1 -yl)-1H-indole The title compound was prepared from 4 4 -cyano-3-methylphenyl)benzoic acid (D 106) using a similar procedure to Description 1 to form the isocyanate followed by addition of -bromo-2,3 -dihydro-6-(4-methylpiperazinl 1H-indole (Dl 15) to afford the urea as a buff solid (2 IH NMR (25OMHz,CDC1 3 8(ppin): 7.83 1H), 7.64 1H), 7.42-7.55 (in, 6H), 7.33 1lH), 6.54 1 4. 10 2H), 3.18 2H1), 3.08 (hr s, 4H), 2.60 (br s, 7H), 2.35 (s, 311).
Example 109 -Chloro- 2 3 -dihydro-l-[4-(2methypyridin5yl)phenylaminocarbonylp6-(4methylpiperazin-1-yl)-1H-indole The title compound was prepared from 4 2 -methylpyridin-5-yl)benzoic acid (WO 97/43262) using a similar procedure to Description I to form the isocyanate followed by addition of 5-chloro-2,3-dihydro-6-(4-methylpiperain-l-yl)- 1H-indole (D1 3) to afford the urea. as a buff solid 1 H NMiR (25OMHz,CDC1 3 5(ppm): 8.68 11H), 7.82 1H), 7.74 (dd, 7.53 (s, 4H), 7.21 11H), 7.14 111), 6.50 1H), 4.11 2H1), 3.18 2H), 3.11 (br s, 4H), 2.59 (br s, 7H), 2.36 3H).
Example 110 -Bromo- 2 3 -dihydro-l-[4-(2-methylpyridin-5.yl)phenylamibocarbonylI..6-(4methylpiperazin-1-yl)-lH-indole -91- WO 98/50358 WO 9850358PCT/EP98/02262 The title compound was prepared from 4 -(2-methylpyridin-5-yl)benzoic acid (WO 97/43 262) using a similar. procedure to Description 1 to form the isocyanate followed by addition of 5-bromo-2,3-dihydro-6-(4-methylpiperazin- l-yl)-l 1-indole (D1 5) to afford the urea as a buff solid Iii NMR (250MHz,d 6 DMSO) 8(ppm): 8.79 1H), 8.73 1H), 7.99 (dd, 1H), 7.84 (s, I 7.71 411), 7.43 11H), 7.3 6 I 4.21 2H1), 3.17 2H4), 2.96 (br s, 4H1), 2.54 (br s, obscured by DMSO peak, 711), 2.31 311).
Example 111 5-Chloro-2,3-dihydro-1 -15-(3-methyl-1 ,2,4-oxadiazol-5-yl)naphth-1 ylaminocarbonylj-6-(4-methylpiperazin-1 -yl)-l il-in dole The title compound was prepared from 5-chloro-2,3-dihydro-6-(4-methylpiperazin..1 -yl)- I11-indole (DI13) and 5-( 3 -methyl-1,2,4-oxadiazol-5-yl)naphth-1 -ylarnine (Dill1) using a similar procedure to Example 4. The title compound was converted to the hydrochloride salt as a pale buff powder 11H NMR (HCl salt) (250MHz, d 6DMSO) 8 (ppmn): 10.82 1H), 9.03 1H), 8.92 (d, I1H), 8.42 (in, 2H), 7.78 7.65 (mn, 411), 7.31 1 4.34 211), 3.48 2.94 (in, IlOH), 2.80 311), 2.54 311).
Example 112 2,3-;Dihydro-5-methoxy-1 -15-(3-methyl-1 ,2,4-oxadiazol-5-yl)naphtlylaminocarbonylJ-6-(4-methylpiperazin-I -yl)-l il-in dole The title compound was prepared from 2 3 -dihydro-5-methoxy-6-(4-methylpiperazin1yl)-IH-indole (intermediate 3 in WO 95/06627) and 5-(3-methyl-1,2,4-oxadiazol-5yI)naphth-1-ylamine (DI 11) in a similar procedure to Example 4. The title compound was converted to the hydrochloride salt as colourless powder 1H NMR (HCl salt) (250MHz, d6DMSO) 8 (ppm): 10.87 11-1), 8,92 111), 8,87 (d, 111), 8.41 8.33 (mn, 2H1), 7.78 7.65 (in, 3H), 7.60 1H), 6.94 11H), 4.30 211), 3.77 311), 3.40 (in, 4H1), 3.20 (in, 411), 2.89 2H), 2.75 3H), 2.53 311).
Example 113 5-Bromo-2,3-dihydro-l-[5-(3-methyl-1 ,2,4-oxadiazol-5-yl)naphth-1 ylaminocarbonyll-6-(4-methylpiperazin-1-yl)-IHvindole 92 WO 98/50358 PCT/EP98/02262 The title compound was prepared from 5-bromo- 2 3 -dihydro-6-(4-methylpiperazin. I-yl)indole (D3i5) and 5-( 3 -methyl-l,2,4-oxadiazol-5-yl)naphth-14ylamine (DIll1) in a similar procedure to Example 4. The title compound was converted to the hydrochloride salt as a pale buff powder (3 1H NMvlR (HCl salt) (250MHz, d 6DMSO) 8 (ppm): 10.75 9.07 1H), 8.92 (d, 111), 8.39 (dd, 2H), 7.80 7.65 (in, 4H), 7.46 1H), 4.34 2H), 3.36 2.93 (in, 6H), 2.81 3H), 2.61 311). 2xCH 2 signals obscurred by H 2 0 signal.
Example 114 5-Chloro-2,3-dihydro-1 -15-(5-methyloxazol-2-yl)naphth-1 -ylaminocarbonylj-6-(4methylpiperazin-1 -yI)-1il-indole The title compound was prepared from 5-chloro-2,3-dihydro-6-(4-methylpiperazin- 1 -yl)lH--indole (1313) and 5-(5-methyloxazol-2-yl)naphth-1-ylamine (DI 14) in a similar procedure to Example 4, converted to the hydrochloride salt as a pale yellow power 1NMR (HCL salt) (250Mliz, d 6DMSO) 8 (ppm): 10.94 1H1), 9.16 1H), 8.96 (s, 111), 8.18 (dd, 211), 7.75 111), 7.70 7.59 (in, 3H), 7.30 11-1), 7.16 111), 4.34 2H1), 3.47 211), 3.37 2.95 (mn, 8H), 2.78 311). CH 3 signal obscurred by DMSO signal.
Example 115 2 3 -Dihydro-5-methoxy--5-(5-methyoxazo..2yl)naphth-1.ylaminocarbonyI methylpiperazin-1 -yl)-1 H-indole The title compound was prepared from 2 3 -dihydro-5-methoxy-6-(4-inethylpiperazin-l yl)-1IH-indole (intermediate 3 in WO 95/06627) and 5-(5-methyloxazol-2-yl)naphth-
I-
ylamnine (D 114) in a similar procedure to Example 4, obtained as the hydrochloride salt as a pale yellow powder 1H NMIR (HCl salt) (250M~z, d 6DMSO) 5 (ppm): 10.95 11-1), 9.14 111), 8.79 (s, 111), 8.17 (dd, 211), 7.69 7.58 (in, 411), 7.17 1H1), 6.94 111), 4.29 2H), 3.77 (s, 311), 3.38 (in, 411), 3.16 (in, 411), 2.95 211), 2.77 3H), 2.51 311).
Example 116 93 WO 98/50358 PCT/EP98/02262 5-Bromo-2,3-dihydro-1 [3-methyl-4-(pyrimidin-2-yl)phenylaminocarbonyl]-6-(4methylpiperazin-1-yl)-1H-indole The title compound was prepared from 3-methyl-4-(pyrimidin-2-yl)aniline (D 115) and bromo-2,3-dihydro-6-(4-methylpiperazin- l-yl)-1H-indole (D15) using a similar procedure to Example 4 as a beige foam This foam was converted to its hydrochloride salt as a yellow solid from acetone.
H NMR (HCI salt) (250MHz, d 6 DMSO) 8 (ppm): 10.50 (br s, 1H), 8.90 2H), 8.75 (s, 1H), 7.84 2H11), 7.60 2H11), 7.43 2H), 4.20 2H), 3.54 1H), 3.33 1H), 3.10 6H11), 2.85 3H11), 2.54 3H).
Example 117 2,3-dihydro-5-methoxy-1-[3-methyl-4-(pyrimidin-2-yl)phenylaminocarbonyl]-6-(4methylpiperazin-1-yl)-l H-indole The title compound was prepared from 3-methyl-4-(pyrimidin-2-yl)aniline (D115) and 2,3-dihydro-5-methoxy-6-(4-methylpiperazin- l-yl)-1H-indole (intermediate 3 in WO 95/06627) using a similar procedure to Example 4 as a beige foam This foam was converted to its hydrochloride salt as a yellow-brown solid from acetone.
IH NMR (HCI salt) (250MHz, d DMSO) 6 (ppm): 10.45 (br s, 1H), 8.90 2H), 8.59 (s, 1H), 7.83 1H), 7.67 1H), 7.60 2H11), 7.40 1H), 6.92 1H), 4.15 2H), 3.77 3H), 3.45 4H11), 3.17 4H), 2.96 2H), 2.82 3H), 2.54 3H).
Example 118 5-Chloro-2,3-dihydro-6-(4-methylpiperazin-1-yl)-1-[3-methyl-4-(pyrimidin-2yl)phenylaminocarbonyl]-1H-indole The title compound wa prepared from 3-methyl-4-(pyrimidin-2-yl)aniline (DI 15) and chloro-2,3-dihydro-6-(4-methylpiperazin-1-yl)- 1H-indole (D13) using a similar procedure to Example 4 as a beige foam This foam was converted to its hydrochloride salt as a yellow solid from acetone.
H NMR (HCl salt) (250MHz, d DMSO) 8 (ppm): 10.50 (br s, 1H), 8.90 2H), 8.71 (s, 1H), 7.84 1H), 7.82 1H), 7.60 2H11), 7.41 1H), 7.29 1H), 4.20 2H11), 3.53 2H), 3.37 (d 2H11), 3.14 6H), 2.86 3H11), 2.54 3H).
Example 119 -94- WO 98/50358 PCT/EP98/02262 5-Bromo-2,3-dihydro-1 -[3-methyl-4-(pyrimidin -5-yl)phenylaminocarbonyll methylpiperazin-1-yl)-l H-indole The title compound was prepared from 3-methyl-4-(pyrimidin-5-yl)aniline (D116) and bromo-2,3-dihydro-6-(4-methylpiperazin-1-yl)- 1H-indole (D15) using a similar procedure to Example 4 as a foam This foam was converted to its hydrochloride salt as an off white solid from acetone.
IH NMR (HC salt) (250MHz, d 6 DMSO) 5 (ppm): 10.65 (br s, 1H), 9.18 1H), 8.86 (s, 2H), 8.73 1H), 7.82 1H), 7.62 1H), 7.55 (dd, 1H), 7.45 1H), 7.25 1H), 4.19 2H), 3.54-2.98 10H), 2.85 3H), 2.28 3H).
Example 120 5-Chloro-2,3-dihydro-1-[ 3 -methyl-4-(pyrimidin-5-yl)phenylaminocarbonylj-6-(4methylpiperazin-1-yl)-1H-indole The title compound was prepared from 3-methyl-4-(pyrimidin-5-yl)aniline (D116) and chloro-2,3-dihydro-6-(4-methylpiperazin- l-yl)-1H-indole (D13) using a similar procedure to Example 4 as foam This foam was converted to its hydrochloride salt as an off white solid from acetone.
'H NMR (HCI salt) (250MHz, d 6 DMSO) 8 (ppm): 10.67 (br s, 1H), 9.18 1H), 8.86 (s, 2H), 8.73 1H), 7.82 1H), 7.58 1H), 7.55 (dd, 1H), 7.27 2H), 4.19 2H), 3.53-3.00 10H), 2.84 3H), 2.28 3H).
Example 121 2,3-Dihydro-5-metoxy-1-[3-methyl-4-(pyrimidin-5-yl)phenylaminocarbonyl]-6-(4methylpiperazin-1-yl)-1H-indole The title compound was prepared from 3 -methyl-4-(pyrimidin-5-yl)aniline (D116) and 2 3 -dihydro-5-methoxy-6-(4-methylpiperazin-1-yl)-1H-indole (intermediate 3 in WO 95/06627) using a similar procedure to Example 4 as a foam This foam was converted to its hydrochloride salt as an off white solid from acetone.
IH NMR (HCl salt) (250MHz, d6DMSO) S (ppm): 10.74 (br s, 1H), 9.18 1H), 8.88 (s, 2H), 8.59 1H), 7.60 3H), 7.22 1H), 6.92 1H), 4.15 2H), 3.77 3H), 3.45 4H), 3.10 4H), 2.98 2H), 2.81 3H), 2.28 3H).
Example 122 WO 98/50358 WO 9850358PCT/EP98/02262 5-Bromo-2,3-dihydro-1-[4-(2,6-dimethylpyridin-4-yl)-3methylphenylaminocarbonylj-6-(4-methylpiperazin-l -yl)-1II-indole The title compound was prepared from 4-(2,6-dimethylpyridin-4-yl)-3methylaniline (D88) and 5-bromo-2,3-dihydro-6-(4-methylpiperazin- l-yl)-l Hindole (D 15) using a similar procedure to Example 4 as a pale yellow foam This was converted to its hydrochloride salt as a pale yellow solid from acetone.
H NMR (free base) (250MHz, CDCl 3 8 (ppm): 7.83 1H), 7.38-7.27 (in, 3H), 7.14 (d, 1H), 6.90 2H), 6.47 IH), 4.11 2H1), 3.19 2H), 3.08 (br m, 4H), 2.60 (br in, 4H), 2.56 6H), 2.35 3H), 2.27 3H).
Example 123 2,3-Dihydro-5-methoxy-1 -14-(2,6-dimethylpyridin-4-yl)-3methylphenylaminocarbonyll-6-(4-methylpiperazin-1-yI)-1 H-indole The title compound was prepared from 4-(2,6-dimethylpyridin-4-yl)-3methylaniline (D88) and 2,3-dihydro-5-methoxy-6-(4-methylpiperazin- l-yl)-l Hindole (intermediate 3 in WO 95/06627) using a similar procedure to Example 4 as a pale yellow foam This was converted to its hydrochloride salt as a yellow solid from acetone.
H NMR (free base) (250MHz, CDC1 3 8 (ppm): 7.70 1H), 7.37 1H), 7.30 (dd, 11H), 7.14 6.90 2H), 6.73 1H), 6.42 1H1), 4.09 2H), 3.84 3H1), 3.20 (t, 2H), 3.12 (br, s, 4H1), 2.61 (br s, 4H1), 2.56 6H), 2.34 3H), 2.27 3H).
Example 124 5-Chloro-2,3-dihydro-l-15-(2,6-dimethylpyridin-4-yI)naphth-1-ylaminocarbonyl-6.
(4-methylpiperazin-1 -yl)-1H-indole The title compound was prepared from 5-(2,6-diinethylpyridin-4-yl)naphth- I-yl isocyanate (DI 9) and 5-chloro-2,3-dihydro-6-(4-inethylpiperazin- 1-yl)-1 Hindole (D13) using a similar procedure to Example 4 as a white foam This was converted to its hydrochloride salt as a white solid from acetone.
1 HNMR (free base) (250NMz, CDCl 3 8 (ppm): 7.98 1H), 7.83 111), 7.77-7.69 (in, 2H), 7.60-7.38 (in, 3H), 7.17 1H1), 7.07 2H1), 6.75 1H), 4.25 2H), 3.24 2H1), 3.06 (br in, 4H), 2.62 6H), 2.56 (br m, 4H), 2.32 311).
96 WO 98/50358 WO 9850358PCT/EP98/02262 Example 125 5-Bromo-2,3-dihydro-1 -t5-(2,6-dimethylpyridin-4-yl)naphth-1-ylaminocarbonylj-6- (4-methylpiperazin-1 -yl)indoline The title compound was prepared from 5-(2,6-dimethyl-4-pyridyl)-1-naphthyI isocyanate (D 19) and 5-bromo-6-(4-methylpiperazin-lI-yl)indoline (D 15) using a similar procedure to Example 4 as a white foam This was converted to its hydrochloride salt as a white solid from acetone.
'H NMR (free base) (250M!Hfz, CDCI 3 8 (ppm): 7.98 (di, 111), 7.84 111), 7.78-7.68 (in, 2H1), 7.60-7.38 (in, 3H), 7.36 1H), 7.08 2H), 6.75 1H), 4.25 2H), 3.25 2H), 3.05 (br m, 4H1), 2.62 6H1), 2.57 (br m, 4H), 2.32 3H).
Example 126 1-15-(2,6DimethyI-4-pyridyl)-l-naphthylaminocarbonyl-5-metoxy-6-(4methylpiperazin-1-yl)-1H-indole The title compound was prepared from 5-(2,6-dimethylpyridin-4-yl)naphth-1-yl isocyanate (Dl 19) and 2,3 -dihydro-5-methoxy-6-(4-methylpiperazin- Il-yl)-lI Hindole (intermediate 3 in WO 95/06627) using a similar procedure to Example 4 as a colourless oil This was converted to its hydrochloride salt as a pale yellow solid from acetone.
1 H NMR (free base) (250 Mz, CDCl 3 8 (ppm): 7.99 (di, 111), 7.78 (di, 1H), 7.74 111), 7.68 (di, 111), 7.60-7.36 (in, 3H), 7.08 2H1), 6.76 111), 6.72 111), 4.24 2H), 3.85 311), 3.27 211), 3.09 (br s, 411), 2.62 611), 2.57 (binm, 4H), 2.32 3H).
Example 127 2,3-Dihydro-1-[4-(2,6-dimethylpyridin-3-yl)-3-methylphenylaminocarbonyl-5methoxy-6-(4-methylpiperazin-1-yl)-lH-indole The title compound was prepared ftrm 4-(2,6-dimethylpyridin-3-yl)-3methylaniline (D 120) and 2,3-dihydro-5-methoxy-6-(4-methylpiperazin- 1-yl)- 11indole (intermediate 3 in WO 95/06627) using a similar procedure to Example 4 as a pale yellow oil This was converted to its hydrochloride salt as an orange solid from acetone.
97 WO 98/50358 WO 9850358PCT/EP98/02262 I H NMR (free base) (250MHz, CDCl 3 8 (ppm): 7.72 1H), 7.38 1W), 7.32-7.25 (in, 2H), 7.07-7.00 (in, 2H), 6.74 1H), 6.43 11H), 4.09 211), 3.84 3H), 3.20 2H), 3.15 (br s 4H), 2.65 (br s, 4H1), 2.58 3H), 2.37 3H), 2.28 3H), 2.06 3H).
Example 128 5-Bromo-2,3-dihydro-1 -13-methyl-4-(thiazol-2-yl)phenylaminocarbonyll-6-(4methylpiperazin-1 -yI)-1H1-indole The title compound was prepared from 3 -methyl-4-(thiazol-2-yl)aniline (D 121) and 5-bromo-2,3-dihydro-6-(4-methylpiperazin- l-yl)-l H-indole (D1 5) using a similar procedure to Example 4 as a foam This was converted to its hydrochloride salt as a yellow solid from acetone.
IIH NMR (HCl salt) (400MHz, d 6 DMSO) 8 (ppm): 10.74 (br, 1H), 8.75 LW), 7.95 (in, 111), 7.83 1H), 7.79 (in, 111), 7.71 1H), 7.61 7.59 1H), 7.45 lH), 4.20 2H), 3.45 2H), 3.35 211), 3.25-3.05 (in, 6H), 2.84 (d, 3H), 2.56 3H).
Example 129 5-Chloro-2,3-dihydro-l-[3-methyl-4-(thiazol-2-yl)phenylaminocarbonyj-6-(4methylpiperazin-1 -yl)-1H-indole The title compound was prepared from 3-inethyl-4-(thiazol-2-yl)aniline (D121) and 5-chloro-2,3-dihydro-6-(4-inethylpiperazin- 1-yl)- 1H-indole (D 13) using a similar procedure to Example 4 as a beige foam This was converted to its hydrochloride salt as a yellow solid from acetone.
I'H NMiR (HCI salt) (400M&z, d 6 DMSO) 8 (ppm): 10.77 (br, 1H), 8.79 114), 7.93 111), 7.82 111), 7.79 114), 7.71 1H), 7.61 7.59 1H), 7.29 111), 4.20 211), 3.50 2H), 3.34 2H), 3.23-3.04 (in, 6H), 2.83 (d, 3W1), 2.56 3H).
Example 130 2,3-Dihydro-5-methoxy-1-13-methyl-4-(thiazol-2-yl)phenylaminocarbonyl]-6-(4methylpiperazin-1-yl)-lH-indole The title compound was prepared from 3-methyl-4-(thiazol-2-yl)aniline (D121) and 2,3-dihydro-5-inethoxy-6-(4-methylpiperazin-1 1H-indole (intermediate 3 98 WO 98/50358 WO 9850358PCT/EP98/02262 in WO 95/06627) using a similar procedure to Example 4 as a pale yellow oil This was converted to its hydrochloride salt as a yellow solid from acetone.
I'H NMR (HCI salt) (400MHz, d 6 DMSO) 8 (ppm): 10.56 (br, 11H), 8.64 11H), 7.94 111), 7.77 1H), 7.69 1H), 7.65 7.60 1H), 7.58 1H), 6.92 11-1), 4.15 2H), 3.77 311), 3.45 (hr t, 4H), 3.14 (in, 4H), 2.96 211), 2.81 311), 2.55 3H).
Example 131 1 -(5-Acetylnaphth-1 -ylaminocarbonyl)-5-chloro-2,3-dihydro-6-(4-methylpiperazin- 1-yl)-1H-indole The title compound was prepared from 5-acetylnaphth- 1-ylamine (D 124) and chloro-2,3 -dihydro-6-(4-methylpiperazin- 1 1 11-indole (D 13) using a similar procedure to Example 4. This was converted to its hydrochloride salt as a buff coloured powder 1H NMR (HCl salt) (250NMz, d 6 DMSO) 8 (ppm): 10.74 IH), 8.94 1H1), 8.46 (d, 111), 8.25 111), 8.12 111), 7.74 111), 7.60 (in, 311), 7.30 111), 4.32 (hr s, 2H), 3.45-2.90 (mn, 1011), 2.75 611).
Example 132 5-Chloro-2,3-dihydro-6-(4-methylpiperazin-1-y)-l-[5-(pyrimidin-2-yloxy)naphth-1ylaminocarbonyl]-1 -in dole The title compound was prepared from 5-(pyrimidin-2-yloxy)naphth- I-ylamine (D 125) and 5-chloro-2,3-dihydro-6-(4-methylpiperazin- 1-yl)- 1 1-indole (D 13) using a similar procedure to Example 4. This was converted to its hydrochloride salt as a pale cream powder (6 I H NMR (HCl salt) (250NMz, d 6 DMSO) 6 (ppm): 10.64 1H), 8.93 111), 8.64 (d, 211), 7.95 11H), 7.76 111), 7.69-7.39 (in, 511), 7.31 (in, 2H), 4.33 (br, 211), 3.45 (in, 211), 3.33-3.10 (in, 611), 2.93 211), 2.81 311).
Example 133 5-Chloro-2,3-dihydro-6-(4-methylpiperazin-1-y)-I-15-(pyrimidin-5-yl)naphth-1ylaminocarbonyll-1 i-indole 99 WO 98/50358 WO 9850358PCT/EP98fJ2262 The title compound was prepared from 5-(pyrimidin-5-yl)naphth-l-yl isocyanate (D123) and 5-chloro-2,3-dihydro-6-(4-methylpiperazin- l-yl)-1 H-indole (Dl 3) using a similar procedure to Example 2 as a white foam This was converted to its hydrochloride salt as a white solid from acetone.
IH NMR (HCl salt) (400M\Hz, d 6 DMSO) 8 (ppm): 10.48 (br, 1H), 9.33 111), 8.98 (s, lH), 8.95 1H1), 8.20 111), 7.76 1H), 7.57-7.67 (in, 6H), 7.31 1H), 4.39 211), 3.43 (2H1, obscured by water peak), 3.32 2H), 3.12-3.24 (in, 4H), 2.94 2H), 2.80 (d, 3H1).
Example 134 2,3-Dihydro-5-methoxy-6-(4-methylpiperazin-1 -yl)-l1[5-(pyrimidin-5-yl)naphth-1 ylaminocarbonyl]-1H1-indole The title compound was prepared from 5-(pyrimidin-5-yl)naphth-1-yl isocyanate (D1 23) and 2,3-dihydro-5-methoxy-6-(4-methylpiperazin-1I-yl)-IH-indole (intermediate 3 in WO 95/06627) using a similar procedure to Example 2 as a white foam This was converted to its hydrochloride salt as a white solid from acetone.
H NMR (HC1 salt) (400MHz, d 6 DMSO) 8 (ppm): 10.38 (br, 111), 9.32 1H), 8.98 (s, 2H1), 8.78 IH), 8.18 IH), 7.64 1H), 7.58 (in, 5H), 6.94 111), 4.30 2H), 3.77 3H1), 3.42 (411, obscured by water peak), 3.12-3.23 (in, 411), 2.89 211), 2.78 3H).
Example 135 5-Chloro-1-(5-cyanonaphth-1-ylaminocarbonyl)-2,3-dihydro-6-(4-methylpiperazin- 1-yl)-1H1-indole The title compound was prepared from 5-cyanonaphth-1I-ylamnine (D 126) and chloro-2,3 -dihydro-6-(4-mcthylpiperazin- 1 1 H-indole (D 13) using a similar procedure to Example 4. This was converted to its hydrochloride salt as a cream powder (8 1'HNMR (free base) (250MHz, CDC1 3 8 (ppm): 8.17 111), 8.11 1H), 7.91 1H1), 7.80 (in, 211), 7.70 1H), 7.56 111), 7.18 1H), 6.71 1H), 4.25 2H), 3.26 (t, 2H1), 3.07 (br s, 411), 2.59 (br s, 411), 2.34 311).
Example 136 -100- WO 98/50358 PCT/EP98/02262 5-Chloro-2,3-dihydro-l-[5-(5-methyl-1,2,4-oxadiazol-3-yl)naphth-1ylaminocarbonyl]-6-(4-methylpiperazin-l-yl)-lH-indole The title compound was prepared from 5-(5-methyl-1,2,4-oxadiazol-3-yl)naphth-1ylamine (D130) and 5-chloro-2,3-dihydro-6-(4-methylpiperazin- -yl)-1H-indole (D13) using a similar procedure to Example 4. This was converted to its hydrochloride salt as a buff coloured powder 'H NMR (HC1 salt) (250MHz, d 6 DMSO) 5 (ppm): 10.67 1H), 8.98 1H), 8.65 (d, 1H), 8.28 1H), 8.19 1H), 7.75-7.61 4H), 7.31 1H), 4.31 2H), 3.33-3.13 6H), 2.97 2H), 2.80 3H), 2.75 3H). 2H signal obscurred by H 2 0 signal.
Pharmacological Data 5-HT1A, 5-HT1B and 5-HT1D Receptor Binding HEK 293 cells expressing 5-HT1A receptors (4 x 10 7 /ml) were homogenised in Tris buffer and stored in lml aliquots. CHO cells expressing 5-HT1B receptors (4 x 107 cells/ml) were homogenised in Tris buffer and stored in 1.5 ml aliquots. CHO cells expressing 5-HT1D receptors (0.563 x 10 8 /ml) were homogenised in Tris buffer and stored in 1 ml aliquots.
0.4 ml of a cell suspension was incubated with 3 H]-5-HT (4nM) for 5-HTiB/1D receptors and 3 H]-8-OH DPAT (InM) for 5-HT1A receptors in Tris Mg HCI buffer (pH 7.7) and test drug, at 37 0 C for 45 minutes. Each test drug was tested at 10 concentrations (0.01 mM to 0.3 nM final concentration), with non-specific binding defined using 0.01 mM 5-HT. The total assay volume was 0.5 ml. Incubation was stopped by rapid filtration using a Packard Filtermate (filters pre-soaked in 0.3% polyethylenimine) and radioactivity measured by Topcount scintillation counting. pKi values were calculated from the IC 5 0 generated by an iterative least squares curve fitting programme.
Examples 5, 9, 10, 15, 21, 24, 25, 27, 28, 43, 44, 45, 47, 48, 49, 50, 52, 53, 67, 68, 69, 71, 72, 76, 78, 80, 81, 82, 83, 89, 97, 98 and 110 had pKi values >8.0 at 5-HT1A, HT1B and 5-HT1D receptors 101 l':\OI'CR\Kbli\7 431l)-y i pc.doc-15/lfl 1 Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.
o• go o* O11A-
Claims (8)
1. A compound of formula or a salt thereof: r N R C R a Y C D in which Ra is a group of formula (i) R 1 (R 2 )a(i in which P 1 I is phenyl, bicyclic aryl, a 5 to 7 membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, or a bicyclic heterocyclic ring containing I to 3 heteroatoms selected from oxygen, nitrogen and sulphur; RI is hydrogen, halogen, CI- 6 alkyl, C 3 6 cycloalkyl, COCI 1 6 alkyl, CI- 6 alkoxy, hydroxy, hydroxyC 1 6 alkyl, hydroxyC I 6 alkoxy, C 1 I 6 alkoxyC I 6 alkoxy, acyl, nitro, trifluoromethyl, cyano, SR 9 SOR 9 S0 2 R 9 S0 2 NRlORI 1 C0 2 Rl 0 C0NR 1 0 RI 1 C0 2 NR 1 OR' 1 CONR 1 0 (CH2)cCO 2 RI 1, (CH 2 )cNR 1 0 OR 1 1, (CH2)cCONRI ORI 1, (CH2)cNRl 0 CORI 1, (CH2)cCO2C1.6alkyl, C0 2 (CH 2 )CORIO, NRIORI 1 NRlOC0 2 RI 1 NR 1 0 CONRI 0 R 1 1, CRIO=NOR 1 1, NRIOC00RI I CNRIO=N0R 1 1 where R 1 0 and RI 1 are independently hydrogen or CI- 6 alkyl and c is 1 to 4 R 2 is hydrogen, halogen, C 1 6 alkyl, C 3 -6.cycloalkyl, C 3 6 cycloalkenyl, CI- 6 alkoxy, CI- 6 alkanoyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, C0 2 Rl 0 CONRIORI 1, NRP 0 RI I where RIO and RI I are as defined for RI; a is 1, 2 or 3; or Ra' is a group of formula (ii) 102 WO 98/50358 PCT/EP98/02262 Ri -P A P (ii) wherein P2 and P3 are independently phenyl, bicyclic aryl, a 5- to 7- membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, or a bicyclic heterocyclic group containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur; A is a bond or oxygen, S (O)m where m is 0 to 2, carbonyl, CH 2 -CH 2 CH2_, or NR 4 where R 4 is hydrogen or C 1 l_6alkyl; R 1 is as defined above for formula or R 1 is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur;; R 2 and R 3 are independently hydrogen, halogen, C 1 -6alkyl, C 3 6 cycloalkyl, C 3 6 cycloalkenyl, C 1 -6alkoxy, C 1 -6alkanoyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO 2 R 10 CONR 10 R 1 1 NR 1 0 R 1 1 where R 10 and R 1 1 are as defined for R 1 and a and b are independently 1, 2 or 3; Y is -NR 5 where R 5 is C 1 -6alkyl, or Y is -CH 2 or V is oxygen or sulphur; D is nitrogen, carbon or a CH group; W is (CR 16 R 1 7 t where t is 2, 3 or 4 and R 16 and R 17 are independently hydrogen or Cl_ 6 alkyl or W is (CR 16 R 1 7 )u-J where u is 0, 1, 2 or 3 and J is oxygen, sulphur, CR 16 =CR 17 CR 16 N, =CR 1 6 0, =CR 16 S or =CR 16 NR 17 X is nitrogen or carbon; Rb is hydrogen, halogen, hydroxy, C1- 6 alkyl, trifluoromethyl, C 1 -6alkoxy, C 2 6 alkenyl, C 3 7 cycloalkyl optionally substituted by Cl-4alkyl, or aryl; RC is hydrogen or C 1 -6alkyl; and is a single bond when X is nitrogen or a single or double bond when X is carbon.
2. A compound according to claim 1 in which R 1 is a halogen atom. -103- A compound according to claim I or 2 in which R 2 ado 3 acec hydrogen, halogen or a C 1 6 alkyl group.
4. A compound according to any of the preceding claims in which P 1 I and p 2 are phenyl, naphthyl or quinolinyl. A compound according to any one of the preceding claims in which Y is -NH-.
6. A compound according to any one of the preceding claims in which D is nitrogen and W is a group of formula -(CH 2 2
7. A compound according to any one of the preceding claims in which R b is a C 1 6 alkoxy group.
8. A compound according to any one of the preceding claims in which X is nitrogen.
9. A compound according to claim I which is: I -[(4-bromo-3-methylphenyl)aminocarboflyl-5-methoxy-6-(4-mfethylpiperazil- I -yl)-l H- indole, 1 -[(4-bromo-3-methylpheny)aminocarbonyl-2,3-dhydro-5-methoxy-6-(4- 9: methylpiperazin- I-yl)-I H-indole, I [(2,3-dichlorophenyl)aminocarbonyl]-2 ,3-dihydro- 5-methoxy-6-(4-methylpiperazi n-I- yl)-lIH-indole, -D ihydro- 5-methoxy-6-(4-methylpiperazin- I-yI)-I [4-(pyri din-4-yl)naphth- I1- ylaminocarbonyl]- 1H-indole, 2,3 -Dihydro-5-methoxy-6-(4-methylpiperazin- l-yl)-l -f5-(pyridin-4-yl)naphth-lI- ylaminocairbonyl]-1H-indole, -D ichloro-4-(pyri din -4-yl)phenylaminocarbonyl] -2,3 -dihydro- 5-methoxy- 6-(4- methylpiperazin- Il-yl)-lI H-indole, 2,3-Dihydro-5-methoxy-6-(4-methylpiperazin- 1 -yl)-lI -(quinolin-5-ylamninocarbonyl)- I H- 2,3'-Dihydro-6-(4-methylpiperazin- 1-yl)-l -[4-(pyndin-4-yl)naphth-1I-ylaminocarbonyl]- I 1--indole, 104 WO 98/50358 PCTIEP98/02262 5-Chloro-2,3-dihydro-6-(4-methylpiperazifI l-yl)-lI -[4-(pynidin-4-yl)naphth- 1- ylaminocarbonyl]- 1H-indole, 5-Bromo-2,3-dihydro-6-(4-melthylpiperazifl 4 -yl)-l -[4-(pyridin-4-yl)naphth- 1- ylaminocarbonyl]-1H-ildole 5-Bromo-2,3-dihydro-6-(4-mfethylpiperazifl l-yl)-l -[4-(pyridin-4- yl)phenylamninocarbonyl] IH-indole, 1 lr--(yii--l~hnlriocroyl23-iyr--4 methylpiperazin- l-yl)-l H-indole, 2,3-Dihydro-5-methyl-6-(4-methylpiperazifl- Il-yl)-l1 -[4-(pyridin-4-yl)naphth- 1 ylaminocarbonyl]- 1 1-indole, 1 -[3-Clr--prdn4y peyaioabnl-,3dhdo5mty--4 methylpiperazin- I1-yl)-l1 H-indole, 2,3-Dihydro-6-(4-methylpiperazin-I -yl)-lI -[4-(pyridin-4-yl)naphth- 1 vinyl-I1 H-indole, 2,3-Dihydro-5 -ethyl-6-(4-methylpiperazin- 1-yl)-l1 -[4-(pyridin-4-yl)naphth- I1- ylaminocarbonyll- lH-indole, 1 [-hoo4(yii--y~hnlmncroy]2,-iyr--ty--4 methylpiperazin- l-yl)-lil-indole, 2,3-Dihydro-6-(4-methylpiperazin-1 -yl)-l -[4-(pyridin-4-yl)naphth- 1 trifluoromethyl- 1H-indole, 1 [-hoo4(yrdn4y~hnlanncroy 1,-iyr--4-ehliei- IH-indole, 2,3-Dihydro-5-methoxy-6-(4-methylpiperazil-I 1-yl)-l -[4-(pyridin-4-yl)naphth- 1- ylacetyl]-l1H-indole, 2,3-Dihydro-5-methoxy-6-(4-methylpiperazifl- 1-yI)-l -[5-(pyridin-4-yl)-naphth- 1- ylacetyl]- 1H-indole, 2,3-Dihydro-6-(4-methylpiperazin- l-yl)-l -[4-(pyridin-4-yl)naphth- 1-ylacety1]-1H-indole 5-Chloro-2,3-dihydro-6-(4-methylpiperazif- l-yl)-l -[4-(pyridin-4-yl)naphth- 1-ylacetyl]- 1 H-indole, 5-Bromo-2,3-dihydro-6-(4-mlethylpiperazifl4 -yl)-l -[4-(pyridin-4-yl)naphth- 1 -ylacetyl]- 1 H-indole, 2,3 -Dihydro-6-(4-methylpiperazifl- -yl)-l -[4-(pyridin-4-yl)naphth- 1 -ylacetyl] -5 -vinyl- I H-indole, 105 WO 98/50358 PCT/EP98/02262 5-Bromo-2,3-dihydro-6-( I -methylpiperidin-4-yl)-l1-[4-(pyridin-4-yl)naphth- I -ylamnino- carbonyl]- IH-indole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin- l-yl)-l -[5-(pyridin-4-yl)naphth- 1- ylaminocarbonyl]- 1 1-indole, 5-Bromo-2,3-dihydro-6-(4-methylpiperazin- l-yl)-l -[5-(pyridin-4-yl)naphth- 1- ylaxninocarbonyl]- 1H-indole, 2,3-Dihydro-5 -methoxy-6-(4-methylpiperazin- 1-yl)-l -(quinolin-6-ylaminocarbonyl)-l1H- -indole, 2,3-Dihydro-l1-[4-(t-butoxycarbonylamino)phenylaminocarbolyll-5-chloro-6-(4- methylpiperazin- Il-yl)-1I H-indole, 5-Bromo-2,3 -dihydro-6-(4-methylpiperazin- 1l-yl)-lI -(quinolin-6-ylaminocarbonyl)- 1 H- indole, 6-Bromo-7-(4-methylpiperazin- Il-yl)- I [4-(pyridin-4-yl)naphth- 1 -ylaminocarbonyl] 1 ,2,3,4-tetrahydroquinoline, 5 -Chloro-2,3-dihydro-6-(4-methylpiperazin- Il-yl)-lI -(4-phenoxyphenylaminocarbonyl)- IH-indole -Chloro-2,3-dihydro- 1 -[4-(4-chlorophenoxy)phenylaniinocarbonyl]-6-(4- methylpiperazin- 1-yl)-1H-indole, -Chloro-2,3-dihydro-6-(4-methylpiperazin- Il-yl)-lI -(quinolin-6-ylaminocarbonyl)- 1 H- indole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin- l-yl)-l -(3-phenoxyphenylaminocarbonyl)- I H-indole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin-1 -yl)-l -[4-(pyrimidin-2-y1)phenylamino- carbonyl]- IH-indole, 1 -(3-Benzoylphenylaminocarbonyl)-5-chloro-2,3-dihydro-6-(4-methylpiperazin- l-yl)-I H- indole, 1 -(4-Benzoylphenylaminocarbonyl)-5-chloro-2,3-dihydro-6-(4-methylpiperazin- 1-yl)-1H- indole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin- I-yl)-l -(2-methylquinolin-6- ylaminocarbonyl)- 1H-indole, 5-Chloro-2,3 -dihydro- 1 -[4-(fur-2-yl)phenylaminocarbonyl]-6-(4-methylpiperazin- Il-yI)- 1 H-indole, 106 WO 98/50358 WO 9850358PCT/EP98/02262 5-Chloro-2,3-dihydro-6-(4-methylpiperazil-1 1-yl)-l -[4-(thien-2-yl)phenylaminocarbonyl]- 1 H-iftdole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazil-I l-yl)-l -[5-(pyridin-2-yl)naphth- I -ylacetyl]- 1 H-indole, 5-Bromo-2,3-dihydro-6-(4-methylpiperazil-I -yl)-l -[5-(pyridin-4-yl)naphth- 1 -ylacetyl]- 1H-indole, 5-Chloro-2,3-dihydro-lI-[4-(l1-methylpiperidin-4-yl)naphth-1I-ylaminocarbonyl]-6-(4- methylpiperazin- l-yl)- 1H-indole, 5-Chloro-2,3-dihydro-l1-[4-(2-methyloxazol-4-y)phenylaminocarbofll-6-(4- methylpiperazin- 1-yl)-l H-indole, 5-Bromo-2,3-dihydro-6-(4-methylpiperazil-I l-yl)-lI -[4-(2-methylpyridin-4- yl)phenylamino-carbonyl]-1I-indole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin-I I -[4-(2-methylpyridin-4- yl)phenylamninocarbonyl]- 1H-indole, 5-Chloro-2,3-dihydro-l1-[4-(2,6-dimethylpyridin-4-yl)phenylaminocarbonyl]-6-(4- methylpiperazin- l-yl)-l H-indole, 5-Bromo-2,3-dihydro- I -[4-(2,6-dimethylpyridin-4-yl)phenylaminocarbonyll-6-(4- methylpiperazin- l-yl)-l H-indole, 2,3-Dihydro- 1 -[4-(2,6-dimethylpyridin-4-yl)phenylaminocarbonyl]-5 -methoxy-6- (4-methylpiperazin- l-yl)-l H-indole, 5-Chloro-2,3-dihydro- I -[4-(2,6-dimethylpyridin-3-yl)phenylaminocarbonyl]-6-(4- methylpiperazin- l-yl)-l H-indole, 5-Bromo-2,3-dihydro-l1-[4-(2,6-dimethylpyridin-3-yI)phenylaminocarbonyl]-6-(4- methylpiperazin- 1 IH-indole, 2,3-Dihydro- I -[4-(2,6-Dimethylpyridin-3-yl)phenylaminocarbonyl]-5-methoxy-6-: (4-methylpiperazin- Il-yl)-l I -indole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin- l-yl)-l -[4-(5-methyl- 1,2,4-oxadiazol- 3-yl)phenylamninocarbonyl]-iI-indole, -Chloro-2,3 -dihydro- 1 -methyl- 1 ,2,4-oxadiazol-5- yl)phenylaminocarbonyl] -6-(4-methylpiperazin- Il-yl)-l1 H-indole, -Chloro-2,3 -dihydro-6-(4-methylpiperazin- Il-yl)-l1 -[3-(pyrimidin-2- yloxy)phenylamninocarbonyl]- 1H-indole,
107- WO 98/50358 WO 9850358PCT/EP98/02262 5-Chloro-2,3-dihydro-6-(4-methylpiperazin- 1-yl)-1{4-[N-methyl-N-(pyrimidin. 2-yl)amino]phenylaminocarbonyl}- 1H-indole, 5-Bromo-2,3-dihydro- 1 4 -(fur-2-yl)phenylaminocarbonyl]-6-(4-methylpiperazin- 1-yl)-l H-indole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin- l-yl)-l -[4-(thien-3- yl)phenylaminocarbonyl]- 1H-indole, 5-Bromo-2,3-dihydro-6-(4-methylpiperazin- l-yl)-l 4 -(thiazol-2-yl)phenylamino- carbonyl]- 1H-indole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin- l-yl)-l 4 -(thiazol-2-yl)phenylamino- carbonyl]- 1H-indole, I -[4-(5-Acetylthien-2-yl)phenylaminocarbonyl]-5-chloro-2,3-dihydro.6-(4- methylpiperaz in- 1-yl)-1H-indole, 1 -(5-Bromonaphth- 1 -ylacety1)-5-chloro-2,3-dihydro-6-(4-methylpiperazin- l-yl)- 1 H-indole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin- l-yl)-l ylaminocarbonyl)- 1H-indole, -Bromo-2,3-dihydro-6-(4-methylpiperazin- Il-yl)-l ylaminocarbonyl)- 1H-indole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin- l-yl)-l -[2-(2-phenylethyl)quinolin-6- ylarninocarbonyl]- IH-indole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin- Il-yl)-l -methylpiperidin-4-yl)naphth- 1- ylaminocarbonyl]- 1H-indole, 5-Bromo-2,3-dihydro- 1 4 -(isoquinolin-4-yl)phenylaminocarbonyl]-6-(4. methylpiperazin- Il-yl)-lI H-indole, 5-Chloro-2,3-dihyclro- 1 -[4-(isoquinolin-4-yl)phenylaniinocarbonyl]-6-(4- methylpiperazin- Il-yI)- 1H-indole, 5-Bromo-2,3-dihydro-6-(4-methylpiperazin- l-yl)-1 -[4-(quinolin-3- yl)phenylaminocarbonyl]-l1H-indole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin- l-yl)-I -[4-(quinolin-3- yl)phenylaminocarbonyl)]- 1H-indole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin-1 1-[(2-methyl- 1,2,3,4- tetrahydroisoquinolin-7-yl)aminocarbonyl]-l1H-indole, -108- WO 98/50358 WO 9850358PCT/EP9R/02262 5-Bromo-2,3-dihydro-6-(4-methylpiperazin- 1-yl)-lI -[(2-methyl- 1,2,3,4- tetrahydroisoquinoin-7-y1)aminocarbonyl]. 1H-indole, 5-Bromo-2,3-dihydro-6-(4-methylpiperazin 1 1 44-(quinolin-8- yl)phenylaminocarbonyl]- 1H-indole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin- Il-yl)-lI -[4-(quinolin-8- yl)phenylamninocarbonyl]- 1H-indole, 5-Chloro-2,3-Dihydro- 1 -[4-(imidazol- 1 -yl)phenylaminocarbonyl]-6-(4- methylpiperazin- l -yl)-lI H-indole, -Chloro-2,3-dihydro-6-(4-methylpiperazin- Il-yl)- I 44-(pyridin-4- yl)phenylaminocarbonyl]- 1H-indole, 2,3-Dihydro-5 -methoxy-6-(4-methylpiperazin- 1 -yl)-1I [(8-phenylquinolin-5 yl)aminocarbonyl]- 1H-indole 5-Chloro-2,3 -dihydro-6-(4-methylpiperazin- 1 1-[(8-phenylquinolin-4- yl)aminocarbonyl]- 1H-indole, 5-Bromo-2,3-dihydro-6-(4-methylpiperazin-I -yl)-1 -[(8-phenylquinolin-4- yl)aminocarbonyl]l H-indole, 2 3 -Dihydro-5-methoxy-6-(4-methylpiperazin-1 -yl)-1 -[(8-phenylquinolin-4- yl)aminocarbonyl]- 1H-indole, 5-Chloro-2,3-dihydro- 1 4 2 6 -dimethyl-pyridin-4-y1)-3-methylphenylaminocarbonyl].6. (4-methylpiperazin- Il-yl)-lI H-indole, 5-Chloro-2,3 -dihydro-l 1 tyl4(-etyprdi--lphnlmnoabn methylpiperazin- l-yl)-l H-indole, 5-Bromo-2,3-dihydro-l1-[ 3 -methyl-4-(6methylpyrdin2-y)phenyarinocarbonyly6-(4- methylpiperazin- 1 -yl)-1H-indole, 2,3-Dihydro-5-methoxy-l1-[ 3 -methyl-4-(6-methylpyridin-2-y1)phenylaminocarbonyl] -6- (4-methylpiperazin- Il-yl)-lI H-indole, 5-Chloro-2,3 -dihydro- 1 [5-(6-methylpyridin-2-yl)naphth- 1 -ylaminocarbonyl]-6-(4- methylpiperazin- l-yl)-1 H-indole, 2,3-Dihydro-5 -methoxy- 1 -[5-(6-methylpyridin-2-yl)naphth. 1 -ylaminocarbonyl] methylpiperazin- l-yl)- 1H-indole, -Chloro-2,3-dihydro-6-(4-ethylpiperazin- Il-yl)-lI 4 -(pyridin-4-yl)naphth- 1 ylaminocarbonyll- 1H-indole, 109 WO 98/50358 WO 9850358PCT/EP98/02262 -Chloro-2,3-dihydro-6-(4-ethylpiperazin- 1 -yl)-1 -[5-(pyridin-4-yl)naphth- I1- ylaminocarbonyl]-l1H-indole, 5-Chloro-2,3-dihydro-6-(piperazin- Il-yl)- 1 -fI4-(pyridin-4-y1)naphth- 1 -ylamninocarbonyl]- 1 H-indole hydrochloride, 5-Chloro-2,3-dihydro-6-(piperazin- I1-yl)-l1 -[5-(pyridin-4-yl)naphth- 1 -ylaminocarbonyl]- 1 H-indole hydrochloride, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin- 1-yl)-l -[4-(pyridazin-3- yl)phenylamninocarbonyl]- 1H-indole, 5-Bromo-2,3-dihydro-6-(4-methylpiperazin- Il-yl)-1 -[4-(pyridazin-3 yl)phenylaninocarbonyl]- 1 H-indole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin- 1 -yl)-1 -[4-(pyrazin-2- yl)phenylamninocarbonyl]-l1H-indole, 5-Bromo-2,3-dihydro-6-(4-methylpiperazin. Il-yl)-l -[4-(pyrazin-2- yl)phenylamninocarbonyl]- 1H-indole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin. 1 -yl)-1 yl)aminocarbonyl]- 1H-indole, -Bromo-2,3-dihydro-6-(4-methylpiperazin- Il-yl)-l -[(2-phenylpyridin-5 yl)aminocarbonyl]- 1H-indole, 5-Chloro-2,3-dihydro-l1-[4-(6-methylpyridazin-3-yl)phenylaninocarbonyl]y6-(4. methylpiperazin- Il-yl)-l1 H-indole, -Bromo--2,3-dihydro- 1 -[4-(6-methylpyridazin-3-yl)phenylamninocarbony1] -6(4. methylpiperazin- 1l-yl)-lI H-indole, -Chloro-2,3-dihydro-6-(4-methylpiperazin-1-yl).I-[4-(pyridin-3- yl)phenylaminocarbonyl]- 1H-indole, 5-Chloro-2,3-dihydro-1 -[4-(5-methyloxazol-2-yl)phenylaminocarbonyl]6(4- methylpiperazin- Il-yl)-lI H-indole, 2,3-Dihydro-5 -methoxy- 1 4 -(5-methyloxazol-2-yl)phenylaininocarbonyl].6-(4. methylpiperazin- Il-yl)-l1 H-indole, -Bromo-2,3-dihydro- 1 4 -methyloxazol-2-yl)phenylaminocarbonyl 6-(4- methylpiperazin- 1l-yl)-lI H-indole, 5-Chloro-2,3-dihydro-l1-[4-( 1-methylpyrazol-4-yl)phenylam-inocarbonyl] methylpiperazin- Il-yl)-lI H-indole, -110- WO 98/50358 WO 9850358PCT/EP98/02262 5-Bromo-2,3- 14-4-( l-methylpyrazol- 4 -yl)phenylaminocarbony-6(4-methylpiperazin- 1- yl)- 1 1-indole, 5-Chloro-2,3-dihydro- 1 4 '-cyano-3'-methylbiphenyl-4-aminocarbonyl-6-(4- methylpiperazin- Il-yl)-l1 H-indole, 5-Bromo-2,3-dihydro- I -[4'-cyano-3'-methylbiphenyl-4-aminocarbonyl]y6(4- methylpiperazin- l-yl)-l H-indole, 5-Chloro-2,3-dihydro-l1-[ 4 2 -methylpyridin-5-y1)phenylaminocarbonyl]y6(4- methylpiperazin- l-yl)-l H-indole, 5-Bromo-2,3-dihydro- 1 4 -(2-methylpyridin-5-y1)phenylaminocarbonyl-6-(4- methylpiperazin-I -yl)-l H-indole, 5-Chloro-2,3-dihydro-l1-[5-(3-methyl- 1,2,4-oxadiazol-5-yl)naphth- 1 -ylaminocarbonyl]-6- (4-methylpiperazin- l-yl)-1 H-indole, 2,3-Dihydro-5-methoxy-l1-15-(3-methyl- 1,2,4-oxadiazol-5-yl)naphth- I -ylaminocarbonyl]- 6-(4-methylpiperazin- Il-yl)-lI H-indole. 5 -Bromo-2,3-dihdyro- 1 -[5-(3-methyl- 1 ,2,4-oxadiazol-5 -yl)naphth- 1 -ylaminocarbonyl]-6- (4-methylpiperazin- l-yl)-l H-indole, 5-Chloro-2,3-dihydro- 1 -methyloxazol-2-yl)naphth- I -ylaminocarbonyl] methylpiperazin- Il-yl)-lI H-indole, 2,3 -Dihydro-5 -methoxy- 1 -methyloxazol-2-yl)naphth- 1 -ylaminocarbonyl methylpiperazin- Il-yl)-lI H-indole, 5-Bromo-2,3-dihydro-l1-[3-methy1-4-(pyrimidin-2-y)phenylamninocarbony]y6-(4 methylpiperazin- Il-yl)-l I-indole, 2,3-Dihydro-5-methoxy-l1-[3-methyl-4-(pyrimidin-2-yl)phenylaminocarbonyl]p6(4. methylpiperazin- l-yl)-l H-indole, 5-Chloro-2,3-dihydro-6-(4-methylpiperazin- 1-yl)-1 -13-methyl-4-(pyrimidin-2- yl)phenylaniinocarbonyl]-l1H-indole, 5-Bromo-2,3-dihydro- I 3 -methyl-4-(pyrimidin-5-y1)phenylaminocarbonyl]-6(4. methylpiperazin- 1l-yl)-lI H-indole, -Chloro-2,3-dihydro- 1 3 -methyl-4-(pyrimidin-5 -y1)phenylaminocarbonyl]..6-(4- methylpiperazin- Il-yl)-lI H-indole, 2,3-Dihydro-5-methoxy- 1 3 -methy1-4-(pyrimidin-5-y)phenyainocarbonyl]y6.(4- methylpiperazin- I -yI)-lI H-indole, ill WO 98/50358 PCT/EP98/02262 5-Bromo-2,3-dihydro- l-[ 4 2 ,6-dimethylpyridin-4-y1)-3-methylphenylaminocarbony]'6 (4-methylpiperazin- I-yl)-l H-indole, 2,3-Dihydro-5-methoxy-l-[ 4 2 6 -dimethylpyridin-4-y1)-3-methylphenylainocarbony]. 6-(4-methylpiperazin- I-yl)-1H-indole, 5-Chloro-2,3-dihydro- 1 -II-( 2 ,6-dimethylpyridin-4-yl)naphth- I -ylaminocarbonyl]-6-(4. methylpiperazin- l-yl)-l H-indole, 5-Bromo-2,3-dihydro- 1 5 -(2,6-dimethylpyridin-4-yl)naphth- 1 -ylaminocarbonyl]-6-(4- methylpiperazin-l-yl)-l H-indole, 2,3-Dihydro- 1-[5-(2,6-dimethylpyridin-4-yl)naphth-1 -ylaminocarbonyl]-5-methoxy-6-(4- methylpiperazin- l-yl)-l H-indole or a pharmaceutically acceptable salt thereof. A process for the preparation of a compound of formula according to claim 1 or a pharmaceutically acceptable salt thereof which comprises: where D is nitrogen and Y is NH, coupling a compound of formula (II): Ra (II) in which Ra and V are as defined in formula or a protected derivative thereof with a compound of formula (III). RC N x HN Rb W R in which W, X, Rb and RC are as defined in formula or a protected derivative thereof; or where D is nitrogen and Y is NH or NR 5 reacting a compound of formula (IV) Ra -NH 2 or Ra -NR 5 H (IV) in which Ra and R5 are as defined in formula with a compound of formula (III) together with an appropriate urea forming agent; where D is nitrogen, reacting a compound of formula (V) -112- PAOPER\Kbl\74-31o-9 spc doc-23/02/01 Ra-Y-(C=O)-L 2 (V) in which Ra is as defined in formula Y is -CH 2 or and L 2 is an appropriate leaving group, with a compound of formula (III) where D is carbon or CH, reacting a compound of formula (VI) Ra-NH 2 (VI) in which Ra is as defined in formula with a compound of formula (VII) Rc SN 0 x' L2 D Rb (VII) in which D is carbon or CH, W, X, Rb and Rc are as defined in formula and L 2 is an appropriate leaving group *and optionally thereafter: removing any protecting groups, S. converting a compound of formula into another compound of formula S 20 forming a pharmaceutically acceptable salt. 11. A compound according to any one of claims 1 to 9 for use in therapy. 12. A pharmaceutical composition which comprises a compound according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier. 13. A method of treating CNS disorders comprising administering an effective 25 amount of a compound of any one of claims 1 to 9 or a pharmaceutical composition of claim 12 to a patient in need of such treatment. 14. A method of claim 13 wherein the CNS disorder is selected from mood disorders, including depression, seasonal affective disorder and dysthymia; anxiety disorders, including generalised anxiety, panic disorder, agoraphobia, social phobia, SRA, obsessive compulsive disorder and post-traumatic stress disorder; memory disorders, including dementia, amnestic disorders and age-associated memory impairment; disorders -113- P:\OPER\Kbn74310-9 spc doc-23/02/01 of eating behaviours, including anorexia nervosa and bulimia nervosa; sleep disorders (including disturbances of Cicardian rhythm) and motor disorders such as Parkinson's disease, dementia in Parkinson's disease, neuroleptic-induced Parkinsonism and tardive dyskinesias, as well as other psychiatric disorders. 15. A method of treating endocrine disorders comprising administering an effective amount of a compound of any one of claims 1 to 9 or a pharmaceutical composition of claim 12 to a patient in need of such treatment. 16. A method of claim 15 wherein the endocrine disorder is selected from hyperprolactinaemia, vasospasm and hypertension. 17. A method of treating disorders of the gastrointestinal tract where changes in motility and secretion are involved comprising administering an effective amount of a compound of any one of claims 1 to 9 or a pharmaceutical composition of claim 12 to a patient in need of such treatment. 18. A method of treating sexual dysfunction or hypothermia comprising administering an effective amount of a compound of any one of claims 1 to 9 or a pharmaceutical composition of claim 12 to a patient in need of such treatment. 19. A method for the treatment or prophylaxis of depression and/or anxiety comprising administering an effective amount of a compound of any one of claims 1 to 9 or a pharmaceutical composition of claim 12 to a patient in need of suchtreatment. 20 20. Use of a compound of any one of claims 1 to 9 in the manufacture of a medicament for the treatment of CNS disorders. 21. Use of claim 20 wherein the CNS disorder is selected from mood disorders, including depression, seasonal affective disorder and dysthymia; anxiety disorders, including generalised anxiety disorder, panic disorder, agoraphobia, social phobia, 25 obsessive compulsive disorder and post-traumatic stress disorder; memory disorders, including dementia, amnestic disorders and age-associated memory impairment; disorders of eating disorders, including anorexia nervosa and bulimia nervosa; sleep disorders (including disturbances of Cicardian rhythm) and motor disorders such as Parkinson's disease, dementia in Parkinson's disease, neuroleptic-induced Parkinsonism and tardive dyskinesias, as well as other psychiatric disorders. S22. Use of a compound of any one of claims 1 to 9 in the manufacture of a medicament for the treatment of endocrine disorders. -114- P:\OPER\Kb\7431(1-9X sp.doc-23/A2/01 23. Use according to claim 22 wherein the endocrine disorder is selected from hyperprolactinaemia, vasospasm and hypertension. 24. Use of a compound of any one of claims 1 to 9 in the manufacture of a medicament for the treatment of disorders of the gastrointestinal tract where changes in motility and secretion are involved. Use of a compound of any one of claims 1 to 9 in the manufacture of a medicament for the treatment of sexual dysfunction or hypothermia. 26. Use of a compound of any one of claims 1 to 9 in the manufacture of a medicament for the treatment or prophylaxis of depression and/or anxiety. 27. A compound of formula according to claim 1, substantially as hereinbefore described with reference to the Examples. 28. A process for the preparation of a compound of formula according to claim 9, substantially as hereinbefore described with reference to the Examples. DATED this 23rd day of February, 2001 SmithKline Beecham plc By DAVIES COLLISON CAVE Patent Attorneys for the Applicants *0 go -115-
Applications Claiming Priority (5)
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| GBGB9707829.9A GB9707829D0 (en) | 1997-04-18 | 1997-04-18 | Novel compounds |
| GB9801882 | 1998-01-29 | ||
| GBGB9801882.3A GB9801882D0 (en) | 1998-01-29 | 1998-01-29 | Novel compounds |
| PCT/EP1998/002262 WO1998050358A1 (en) | 1997-04-18 | 1998-04-14 | Indole derivatives having combined 5ht1a, 5ht1b and 5ht1d receptor antagonist activity |
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| AU7431098A AU7431098A (en) | 1998-11-27 |
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| EP (1) | EP0975593A1 (en) |
| JP (1) | JP2001524116A (en) |
| KR (1) | KR20010006487A (en) |
| CN (1) | CN1260781A (en) |
| AR (1) | AR013076A1 (en) |
| AU (1) | AU732863B2 (en) |
| BR (1) | BR9809092A (en) |
| CA (1) | CA2288662A1 (en) |
| CO (1) | CO4950608A1 (en) |
| HU (1) | HUP0001123A3 (en) |
| IL (1) | IL132409A0 (en) |
| NO (1) | NO995065D0 (en) |
| NZ (1) | NZ500252A (en) |
| PL (1) | PL336317A1 (en) |
| TR (1) | TR199902590T2 (en) |
| TW (1) | TW509687B (en) |
| WO (1) | WO1998050358A1 (en) |
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| GB9725931D0 (en) * | 1997-12-05 | 1998-02-04 | Smithkline Beecham Plc | Novel compounds |
| WO2000006550A1 (en) * | 1998-07-31 | 2000-02-10 | Nippon Soda Co., Ltd. | Phenylazole compounds, process for producing the same and drugs for hyperlipemia |
| GB9827882D0 (en) * | 1998-12-17 | 1999-02-10 | Smithkline Beecham Plc | Novel compounds |
| UA62015C2 (en) | 1998-12-28 | 2003-12-15 | Pfizer Prod Inc | Benzoizoxazol derivatives, a pharmaceutical composition (variants) based thereon (variants) and a method for treatment (variants) |
| GB9912417D0 (en) | 1999-05-28 | 1999-07-28 | Pfizer Ltd | Compounds useful in therapy |
| GB9912413D0 (en) | 1999-05-28 | 1999-07-28 | Pfizer Ltd | Compounds useful in therapy |
| WO2001005758A2 (en) * | 1999-07-15 | 2001-01-25 | Nps Allelix Corp. | Indoles and indazoles for the treatment of migraine |
| TR200200795T2 (en) * | 1999-09-25 | 2002-07-22 | Smithkline Beecham P. L. C. | Piperazine derivatives as 5-HT1B antagonists |
| JP2003513075A (en) * | 1999-11-05 | 2003-04-08 | スミスクライン ビーチャム パブリック リミテッド カンパニー | Isoquinoline and quinazoline derivatives having complex 5HT1A, 5HT1B and 5HT1D receptor activity |
| GB9926303D0 (en) * | 1999-11-05 | 2000-01-12 | Smithkline Beecham Plc | Novel compounds |
| DE10051981A1 (en) | 2000-10-20 | 2002-05-02 | Bayer Ag | Substituted phenyluracile |
| GB0106419D0 (en) | 2001-03-15 | 2001-05-02 | Smithkline Beecham Plc | Novel compounds |
| GB0106586D0 (en) * | 2001-03-16 | 2001-05-09 | Smithkline Beecham Plc | Novel compounds |
| BR0210929A (en) * | 2001-06-07 | 2004-06-08 | Hoffmann La Roche | 5-ht6 receptor affinity indole derivatives |
| AU2003245773A1 (en) | 2002-02-15 | 2003-09-04 | Glaxo Group Limited | Vanilloid receptor modulators |
| PT1506179E (en) | 2002-05-13 | 2006-06-30 | Hoffmann La Roche | BENZOXAZINE DERIVATIVES AS 5-HT6 MODULATORS AND THEIR UTILIZATIONS |
| ATE371653T1 (en) | 2003-12-09 | 2007-09-15 | Hoffmann La Roche | BENZOXAZINE DERIVATIVES AND USES THEREOF |
| AU2008335709A1 (en) * | 2007-12-13 | 2009-06-18 | Amgen Inc. | Gamma secretase modulators |
| CA2794153C (en) | 2010-03-25 | 2018-01-02 | Glaxosmithkline Llc | Substituted indoline derivatives as perk inhibitors |
| GB201106817D0 (en) | 2011-04-21 | 2011-06-01 | Astex Therapeutics Ltd | New compound |
| CN102924330A (en) * | 2012-09-03 | 2013-02-13 | 华东理工大学 | Method for large-scale preparation of 5-amino-1-naphthyl nitrile |
| GB201218850D0 (en) | 2012-10-19 | 2012-12-05 | Astex Therapeutics Ltd | Bicyclic heterocycle compounds and their uses in therapy |
| GB201218864D0 (en) | 2012-10-19 | 2012-12-05 | Astex Therapeutics Ltd | Bicyclic heterocycle compounds and their uses in therapy |
| GB201218862D0 (en) | 2012-10-19 | 2012-12-05 | Astex Therapeutics Ltd | Bicyclic heterocycle compounds and their uses in therapy |
| US9980973B2 (en) | 2012-10-19 | 2018-05-29 | Astex Therapeutics Limited | Bicyclic heterocycle compounds and their uses in therapy |
| CN103467374A (en) * | 2013-08-30 | 2013-12-25 | 江苏弘和药物研发有限公司 | Synthesis method of 8-bromine-4-carboxyl quinoline |
| BR122022015241B1 (en) | 2013-12-20 | 2023-09-26 | Astex Therapeutics Limited | INTERMEDIATE BICYCLIC HETEROCYCLIC COMPOUNDS FOR THE PREPARATION OF A COMPOUND OF FORMULA (I) |
| JP6693107B2 (en) * | 2015-12-04 | 2020-05-13 | 東ソー株式会社 | Method for purifying lutidine compound |
| CN115197099A (en) * | 2022-05-30 | 2022-10-18 | 安徽昊帆生物有限公司 | Preparation method of N-Boc-1,4-phenylenediamine |
| WO2025259929A1 (en) * | 2024-06-13 | 2025-12-18 | Third Harmonic Bio, Inc. | COMPOUNDS AND COMPOSITIONS AS c-Kit KINASE INHIBITORS |
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| PT533268E (en) * | 1991-09-18 | 2002-02-28 | Glaxo Group Ltd | BENZANILIDA DERIVATIVES AS 5-HT1D ANTAGONISTS |
| GB9119920D0 (en) * | 1991-09-18 | 1991-10-30 | Glaxo Group Ltd | Chemical compounds |
| GB9119932D0 (en) * | 1991-09-18 | 1991-10-30 | Glaxo Group Ltd | Chemical compounds |
| WO1995004729A1 (en) * | 1993-08-06 | 1995-02-16 | Smithkline Beecham Plc | Amide derivatives as 5ht1d receptor antagonists |
| US5905080A (en) * | 1993-08-20 | 1999-05-18 | Smithkline Beecham, P.L.C. | Amide and urea derivatives as 5HT1D receptor antagonists |
| JP3328936B2 (en) * | 1993-09-03 | 2002-09-30 | スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー | Indole and indoline derivatives for 5HT1D receptor antagonists |
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1998
- 1998-04-14 EP EP98921462A patent/EP0975593A1/en not_active Withdrawn
- 1998-04-14 BR BR9809092-5A patent/BR9809092A/en not_active IP Right Cessation
- 1998-04-14 KR KR1019997009577A patent/KR20010006487A/en not_active Withdrawn
- 1998-04-14 NZ NZ500252A patent/NZ500252A/en unknown
- 1998-04-14 CN CN98806185A patent/CN1260781A/en active Pending
- 1998-04-14 IL IL13240998A patent/IL132409A0/en unknown
- 1998-04-14 AU AU74310/98A patent/AU732863B2/en not_active Ceased
- 1998-04-14 HU HU0001123A patent/HUP0001123A3/en unknown
- 1998-04-14 PL PL98336317A patent/PL336317A1/en unknown
- 1998-04-14 WO PCT/EP1998/002262 patent/WO1998050358A1/en not_active Ceased
- 1998-04-14 TR TR1999/02590T patent/TR199902590T2/en unknown
- 1998-04-14 JP JP54766098A patent/JP2001524116A/en active Pending
- 1998-04-14 CA CA002288662A patent/CA2288662A1/en not_active Abandoned
- 1998-04-16 AR ARP980101760A patent/AR013076A1/en not_active Application Discontinuation
- 1998-04-17 CO CO98021149A patent/CO4950608A1/en unknown
- 1998-04-17 TW TW087105843A patent/TW509687B/en active
-
1999
- 1999-10-15 NO NO995065A patent/NO995065D0/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| NO995065L (en) | 1999-10-15 |
| HUP0001123A2 (en) | 2001-04-28 |
| NZ500252A (en) | 2001-07-27 |
| CO4950608A1 (en) | 2000-09-01 |
| TR199902590T2 (en) | 2000-06-21 |
| EP0975593A1 (en) | 2000-02-02 |
| NO995065D0 (en) | 1999-10-15 |
| PL336317A1 (en) | 2000-06-19 |
| CA2288662A1 (en) | 1998-11-12 |
| CN1260781A (en) | 2000-07-19 |
| JP2001524116A (en) | 2001-11-27 |
| AR013076A1 (en) | 2000-12-13 |
| HUP0001123A3 (en) | 2002-04-29 |
| BR9809092A (en) | 2002-01-22 |
| WO1998050358A1 (en) | 1998-11-12 |
| IL132409A0 (en) | 2001-03-19 |
| TW509687B (en) | 2002-11-11 |
| AU7431098A (en) | 1998-11-27 |
| KR20010006487A (en) | 2001-01-26 |
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Legal Events
| Date | Code | Title | Description |
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| FGA | Letters patent sealed or granted (standard patent) | ||
| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |