Indole Derivatives Having Combined 5HT1A, 5HT1B and 5HT1D Receptor Antagonist Activity

专利摘要:
The compounds of formula (I), their preparation and their use as CNS agents are disclosed. <Formula I> Wherein R a is a group having formula (Ia), or <Formula I-a> Wherein P 1 is selected from phenyl, bicyclic aryl, oxygen, nitrogen and sulfur 5-7 membered heterocyclic containing 1 to 3 heteroatoms selected Ring or 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur A bicyclic heterocyclic ring comprising; R 1 is hydrogen, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, COC 1-6 alkyl, C 1-6 alkoxy, Hydroxy, hydroxyC 1-6 alkyl, hydroxyC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, C 1-6 alkanoyl, nitro, trifluoromethyl, cyano, SR 9 , SOR 9 , SO 2 R 9 , SO 2 NR 10 R 11 , CO 2 R 10 , CONR 10 R 11 , CO 2 NR 10 R 11 , CONR 10 (CH 2 ) c CO 2 R 11 , (CH 2 ) c NR 10 R 11 , (CH 2 ) c CONR 10 R 11 , (CH 2 ) c NR 10 COR 11 , (CH 2 ) c CO 2 C 1-6 alkyl, CO 2 (CH 2 ) c OR 10 , NR 10 R 11 , NR 10 CO 2 R 11 , NR 10 CONR 10 R 11 , CR 10 = NOR 11 , NR 10 COOR 11 , CNR 10 = NOR 11 , where R 9 , R 10 and R 11 are each hydrogen or C 1-6 alkyl and c is 1-4; R 2 is hydrogen, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, C 1-6 alkoxy, C 1-6 alkanoyl, aryl, acyloxy, hydroxy, nitro, Trifluoromethyl, cyano, CO2R10, CONR10R11, NR10R11Where R is10And R 11 is as defined for R 1 ; a is 1, 2 or 3); Or R a is a group of formula (ii) <Formula I-b> Wherein P 2 and P 3 are each phenyl, bicyclic aryl, oxygen, nitrogen and 5- to 7-membered having 1 to 3 heteroatoms selected from sulfur Heterocyclic ring or 1 to 1 selected from oxygen, nitrogen or sulfur Bicyclic heterocyclic groups containing three heteroatoms; A is a bond or oxygen, S (O) m where m is 0 to 2, carbonyl, CH 2 , -CH 2 -CH 2- , or NR 4 , wherein R 4 is hydrogen or C 1-6 alkyl; R 1 is as defined above or R 1 is oxygen, nitrogen or 5-7 membered containing 1 to 3 heteroatoms selected from sulfur Optionally by C 1-6 alkyl, halogen or C 1-6 alkanoyl to a heterocyclic ring Substituted; R 2 and R 3 are each hydrogen, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cyclo Alkenyl, C 1-6 alkoxy, C 1-6 alkanoyl, aryl, acyloxy, hydroxy, nitro, Trifluoromethyl, cyano, CO 2 R 10 , CONR 10 R 11 , NR 10 R 11 , wherein R 10 And R 11 is as defined for R 1 ; a and b are each 0, 1, 2 or 3); Y is -NH-, -NR 5- , wherein R 5 is C 1-6 alkyl or Y is -CH 2 -or -O-; V is oxygen or sulfur; D is nitrogen, carbon or CH group; W is (CR 16 R 17 ) t (where t is 2, 3 or 4 and R 16 and R 17 are each hydrogen or C 1-6 alkyl) W is (CR 16 R 17 ) u -J ( Wherein u is 0, 1, 2 or 3 and J is oxygen, sulfur, CR 16 = CR 17 , CR 16 = N, = CR 16 O, = CR 16 S or = CR 16 -NR 17 ); X is nitrogen or carbon; R b is C 3-7 cycloalkyl optionally substituted by hydrogen, halogen, hydroxy, C 1-6 alkyl, trifluoromethyl, C 1-6 alkoxy, C 2-6 alkenyl, C 1-4 alkyl Or aryl; R c is hydrogen or C 1-6 alkyl;
公开号:KR20010006487A
申请号:KR1019997009577
申请日:1998-04-14
公开日:2001-01-26
发明作者:레이러미 메어리 개스터；하쉐이드 칸틸랄 레이미；폴 애드리언 위먼
申请人:피터 기딩스；스미스클라인비이참피이엘시이；
IPC主号:

专利说明:

Indole derivatives having combined 5HT1A, 5HT1B and 5HT1D Receptor Antagonist Activity
The present invention relates to novel piperazine derivatives, methods for their preparation and pharmaceutical compositions comprising them.
WO 95/06637, WO 95/06044 and WO 95/04729 disclose a series of piperazine derivatives known to have 5HT _ID receptor antagonistic activity. It is claimed that these compounds can be used for the treatment of various CNS diseases such as depression. EPA 0533266/7/8 discloses a series of benzanilide derivatives known to have 5HT _ID receptor antagonistic activity.
It is currently known that structurally specific classes of compounds exhibit a combination of 5HT _IA , 5HT _IB and 5HT _ID receptor antagonist activity. Such compounds are expected to be useful for the treatment and prophylaxis of various CNS diseases because of the advantage that their action begins relatively quickly. Therefore, firstly, the present invention provides a compound of formula (I) or a salt thereof:
Wherein R ^a is a group having formula (Ia), or
Wherein P ¹ is selected from phenyl, bicyclic aryl, oxygen, nitrogen and sulfur
5-7 membered heterocyclic containing 1 to 3 heteroatoms selected
Ring or 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur
A bicyclic heterocyclic ring comprising;
R ¹ is hydrogen, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, COC _1-6 alkyl, C _1-6 alkoxy,
Hydroxy, hydroxyC _1-6 alkyl, hydroxyC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkoxy,
C _1-6 alkanoyl, nitro, trifluoromethyl, cyano, SR ⁹ , SOR ⁹ , SO ₂ R ⁹ ,
SO ₂ NR ¹⁰ R ¹¹ , CO ₂ R ¹⁰ , CONR ¹⁰ R ¹¹ , CO ₂ NR ¹⁰ R ¹¹ , CONR ¹⁰ (CH ₂ ) _c CO ₂ R ¹¹ , (CH ₂ ) _c NR ¹⁰ R ¹¹ ,
(CH ₂ ) _c CONR ¹⁰ R ¹¹ , (CH ₂ ) _c NR ¹⁰ COR ¹¹ , (CH ₂ ) _c CO ₂ C _1-6 alkyl, CO ₂ (CH ₂ ) _c OR ¹⁰ , NR ¹⁰ R ¹¹ ,
NR ¹⁰ CO ₂ R ¹¹ , NR ¹⁰ CONR ¹⁰ R ¹¹ , CR ¹⁰ = NOR ¹¹ , NR ¹⁰ COOR ¹¹ , CNR ¹⁰ = NOR ¹¹ , where
R ⁹ , R ¹⁰ and R ¹¹ are each hydrogen or C _1-6 alkyl and c is 1-4;
R ² is hydrogen, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkenyl,
C _1-6 alkoxy, C _1-6 alkanoyl, aryl, acyloxy, hydroxy, nitro,
Trifluoromethyl, cyano, CO₂R¹⁰, CONR¹⁰R¹¹, NR¹⁰R¹¹Where R is¹⁰And
R ¹¹ is as defined for R ¹ ;
a is 1, 2 or 3);
Or R ^a is a group of formula (ii)
Wherein P ² and P ³ are each phenyl, bicyclic aryl, oxygen, nitrogen and
5- to 7-membered having 1 to 3 heteroatoms selected from sulfur
Heterocyclic ring or 1 to 1 selected from oxygen, nitrogen or sulfur
Bicyclic heterocyclic groups containing three heteroatoms;
A is a bond or oxygen, S (O) _m where m is 0 to 2, carbonyl, CH ₂ ,
-CH ₂ -CH _2- , or NR ⁴ , wherein R ⁴ is hydrogen or C _1-6 alkyl;
R ¹ is as defined in formula (I) or R ¹ is oxygen, nitrogen or
5-7 membered containing 1 to 3 heteroatoms selected from sulfur
Optionally by C _1-6 alkyl, halogen or C _1-6 alkanoyl to a heterocyclic ring
Substituted;
R ² and R ³ are each hydrogen, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cyclo
Alkenyl, C _1-6 alkoxy, C _1-6 alkanoyl, aryl, acyloxy, hydroxy, nitro,
Trifluoromethyl, cyano, CO ₂ R ¹⁰ , CONR ¹⁰ R ¹¹ , NR ¹⁰ R ¹¹ , wherein R ¹⁰
And R ¹¹ is as defined for R ¹ ;
a and b are each 0, 1, 2 or 3);
Y is -NH-, -NR ^5- , wherein R ⁵ is C _1-6 alkyl or Y is -CH ₂ -or -O-;
V is oxygen or sulfur;
D is nitrogen, carbon or CH group; W is (CR ¹⁶ R ¹⁷ ) _t (where t is 2, 3 or 4 and R ¹⁶ and R ¹⁷ are each hydrogen or C _1-6 alkyl) W is (CR ¹⁶ R ¹⁷ ) _u -J ( Wherein u is 0, 1, 2 or 3 and J is oxygen, sulfur, CR ¹⁶ = CR ¹⁷ , CR ¹⁶ = N, = CR ¹⁶ O, = CR ¹⁶ S or = CR ¹⁶ -NR ¹⁷ ); X is nitrogen or carbon;
R ^b is C _3-7 cycloalkyl optionally substituted by hydrogen, halogen, hydroxy, C _1-6 alkyl, trifluoromethyl, C _1-6 alkoxy, C _2-6 alkenyl, C _1-4 alkyl Or aryl;
R ^c is hydrogen or C _1-6 alkyl;
Is a single bond when X is nitrogen or a single or double bond when X is carbon.
The C _1-6 alkyl group, alone or as part of another group, may be straight or branched chain. The term 'acyloxy' as used herein refers to an -OC (O) C _1-6 alkyl group. As used herein, the term 'aryl', unless stated otherwise, refers to a group such as phenyl. The term 'aralkyl', as used herein, unless otherwise indicated, refers to a group such as benzyl.
Preferred are bicyclic aryl groups represented by P ¹ , P ² and / or P ³ , which may be partially saturated, naphthyl.
Examples of bicyclic heterocyclic rings comprising 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur are 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 sulfur represented by P ¹ , P ² and / or P ³ are thienyl, furyl, pyrroyl, tria Zolyl, imidazolyl, oxazolyl, thiazolyl, oxdiazolyl, isothiazolyl, isoxazolyl, thiadiazoleyl, pyrimidyl, pyridazinyl and pyrazinyl and pyridyl is preferred.
The heterocyclic ring as defined above may be linked with the remaining components in the molecule via a carbon atom or, where present, an appropriate nitrogen atom. Such rings may also be saturated or partially saturated. Examples of saturated or partially saturated 5 to 7 membered heterocyclic rings are pyridine, pyrrolidine and morpholine. Examples of partially saturated bicyclic heterocyclic rings are dihydrobenzofuran, dihydrobenzothiophene, tetrahydroquinoline and tetrahydroisoquinoline.
Preferably R ¹ is a halogen atom, for example fluorine, chlorine or bromine and R ² and / or R ³ are each preferably hydrogen, halogen, for example chlorine or C _1-6 alkyl groups, eg For example, it is a methyl group. When R ¹ is a 5-7 membered heterocyclic ring, suitable optional substituents include C _1-6 alkyl, C _1-6 alkanoyl and halogen.
a and b are preferably 1 or 2, respectively.
A is preferably a bond or oxygen, most preferably a bond.
Y is preferably -NH-.
V is preferably oxygen.
D is preferably nitrogen and the W group is preferably a (CR ¹⁶ R ¹⁷ ) _t group (where R ¹⁶ and R ¹⁷ are each beneficial for hydrogen and t is 2 is appropriate).
R ^b is preferably hydrogen or a halogen atom, for example chlorine, a C _1-6 alkoxy group, for example a methoxy or C _1-6 alkyl group, for example methyl or ethyl.
X is preferably nitrogen.
R ^c is preferably a C _1-6 alkyl group, for example methyl.
Particularly preferred compounds according to the invention include;
1-[(4-bromo-3-methylphenyl) aminocarbonyl] -5-methoxy-6- (4-methylpiperazin-1-yl) -1H-indole,
1-[(4-bromo-3-methylphenyl) aminocarbonyl] -2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1H-indole,
1-[(2,3-dichlorophenyl) aminocarbonyl] -2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1H-indole,
2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H Indol,
2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1- [5- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H Indol,
1- [2,3-dichloro-4- (pyridin-4-yl) phenylaminocarbonyl] -2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl)- 1H-Indole,
2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1- (quinolin-5-ylaminocarbonyl) -1H-indole,
2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H- Indol,
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H Indol,
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) phenylaminocarbonyl] -1H-indole,
5-bromo-1- [3-chloro-4- (pyridin-4-yl) phenylaminocarbonyl] -2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H- Indol,
2,3-dihydro-5-methyl-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H- Indol,
1- [3-chloro-4- (pyridin-4-yl) phenylaminocarbonyl] -2,3-dihydro-5-methyl-6- (4-methylpiperazin-1-yl) -1H-indole ,
2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -5-vinyl-1H- Indol,
2,3-dihydro-5-ethyl-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H- Indol,
1- [3-chloro-4- (pyridin-4-yl) phenylaminocarbonyl] -2,3-dihydro-5-ethyl-6- (4-methylpiperazin-1-yl) -1H-indole ,
2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -5-trifluoromethyl -1H-indole,
1- [3-chloro-4- (pyridin-4-yl) phenylaminocarbonyl] -2,3-dihydro-6- (4-methylpiperazin-1-yl) -5-trifluoromethyl- 1H-Indole,
2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylacetyl] -1H-indole ,
2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1- [5- (pyridin-4-yl) naphth-1-ylacetyl] -1H-indole ,
2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylacetyl] -1-indole
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylacetyl] -1H-indole,
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naph-1-ylacetyl] -1H-indole ,
2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylacetyl] -5-vinyl-1H-indole,
5-Bromo-2,3-dihydro-6- (1-methylpiperidin-4-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl]- 1H-Indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [5- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H- Indol,
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [5- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H Indol,
2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1- (quinolin-6-ylaminocarbonyl) -1H-indole,
2,3-dihydro-1- [4- (t-butoxycarbonylamino) phenylaminocarbonyl] -5-chloro-6- (4-methylpiperazin-1-yl) -1H-indole,
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- (quinolin-6-ylaminocarbonyl) -1H-indole,
6-bromo-7- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1,2,3,4- Tetrahydroquinoline,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- (4-phenoxyphenylaminocarbonyl) -1H-indole,
5-chloro-2,3-dihydro-1- [4- (4-chlorophenoxy) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- (quinolin-6-ylaminocarbonyl) -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- (3-phenoxyphenylaminocarbonyl) -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyrimidin-2-yl) phenylaminocarbonyl] -1H-indole,
1- (3-benzoylphenylaminocarbonyl) -5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole,
1- (4-benzoylphenylaminocarbonyl) -5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- (2-methylquinolin-6-ylaminocarbonyl) -1H-indole,
5-chloro-2,3-dihydro-1- [4- (per-2-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (thien-2-yl) phenylaminocarbonyl] -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [5- (pyridin-2-yl) naphth-1-ylacetyl] -1H-indole,
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [5- (pyridin-4-yl) naphth-1-ylacetyl] -1H-indole ,
5-chloro-2,3-dihydro-1- [4- (1-methylpiperidin-4-yl) naphth-1-ylaminocarbonyl] -6- (4-methylpiperazin-1- 1) -1H-indole,
5-chloro-2,3-dihydro-1- [4- (2-methyloxazol-4-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole ,
5-Bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (2-methylpyridin-4-yl) phenylamino-carbonyl] -1 H- Indol,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (2-methylpyridin-4-yl) phenylaminocarbonyl] -1H-indole,
5-chloro-2,3-dihydro-1- [4- (2,6-dimethylpyridin-4-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H- Indol,
5-bromo-2,3-dihydro-1- [4- (2,6-dimethylpyridin-4-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H Indol,
2,3-dihydro-1- [4- (2,6-dimethylpyridin-4-yl) phenylaminocarbonyl] -5-methoxy-6- (4-methylpiperazin-1-yl) -1H Indol,
5-chloro-2,3-dihydro-1- [4- (2,6-dimethylpyridin-3-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H- Indol,
5-bromo-2,3-dihydro-1- [4- (2,6-dimethylpyridin-3-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H Indol,
2,3-dihydro-1- [4- (2,6-dimethylpyridin-3-yl) phenylaminocarbonyl] -5-methoxy-6- (4-methylpiperazin-1-yl) -1H Indol,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl Aminocarbonyl] -1 H-indole,
5-chloro-2,3-dihydro-1- [4- (3-methyl-1,2,4-oxadiazol-5-yl) phenylaminocarbonyl] -6- (4-methylpiperazin- 1-day) -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [3- (pyrimidin-2-yloxy) phenylaminocarbonyl] -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- {4- [N-methyl-N- (pyrimidin-2-yl) amino] phenylaminocar Carbonyl} -1H-indole,
5-bromo-2,3-dihydro-1- [4- (per-2-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (thien-3-yl) phenylaminocarbonyl] -1H-indole,
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (thiazol-2-yl) phenylaminocarbonyl] -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (thiazol-2-yl) phenylaminocarbonyl] -1H-indole,
1- [4- (5-acetylthien-2-yl) phenylaminocarbonyl] -5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole,
1- (5-bromonaft-1-ylacetyl) -5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- (8-phenylquinolin-5-ylaminocarbonyl) -1H-indole,
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- (8-phenylquinolin-5-ylaminocarbonyl) -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [2- (2-phenylethyl) quinolin-6-ylaminocarbonyl] -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [5- (1-methylpiperidin-4-yl) naphth-1-ylaminocarbox Carbonyl] -1H-indole,
5-bromo-2,3-dihydro-1- [4- (isoquinolin-4-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole,
5-chloro-2,3-dihydro-1- [4- (isoquinolin-4-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole,
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (quinolin-3-yl) phenylaminocarbonyl] -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (quinolin-3-yl) phenylaminocarbonyl] -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) Aminocarbonyl] -1 H-indole,
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl ) Aminocarbonyl] -1 H-indole,
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (quinolin-8-yl) phenylaminocarbonyl] -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (quinolin-8-yl) phenylaminocarbonyl] -1H-indole,
5-chloro-2,3-dihydro-1- [4- (imidazol-1-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) phenylaminocarbonyl] -1H-indole,
2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1-[(8-phenylquinolin-5-yl) aminocarbonyl] -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1-[(8-phenylquinolin-4-yl) aminocarbonyl] -1H-indole,
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1-[(8-phenylquinolin-4-yl) aminocarbonyl] -1H-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-yl) -3-methylphenylaminocarbonyl] -6- (4-methylpiperazin-1-yl ) -1H-indole,
5-chloro-2,3-dihydro-1- [3-methyl-4- (6-methylpyridin-2-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl)- 1H-Indole,
5-bromo-2,3-dihydro-1- [3-methyl-4- (6-methylpyridin-2-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole,
2,3-dihydro-5-methoxy-1- [3-methyl-4- (6-methylpyridin-2-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole,
5-chloro-2,3-dihydro-1- [5- (6-methylpyridin-2-yl) naphth-1-ylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole,
2,3-dihydro-5-methoxy-1- [5- (6-methylpyridin-2-yl) naphth-1-ylaminocarbonyl] -6- (4-methylpiperazin-1-yl ) -1H-indole,
5-chloro-2,3-dihydro-6- (4-ethylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H- Indol,
5-chloro-2,3-dihydro-6- (4-ethylpiperazin-1-yl) -1- [5- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H- Indol,
5-chloro-2,3-dihydro-6- (piperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H-indole hydrochloride ,
5-chloro-2,3-dihydro-6- (piperazin-1-yl) -1- [5- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H-indole hydrochloride ,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridazin-3-yl) phenylaminocarbonyl] -1H-indole,
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridazin-3-yl) phenylaminocarbonyl] -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyrazin-2-yl) phenylaminocarbonyl] -1H-indole,
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyrazin-2-yl) phenylaminocarbonyl] -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1-[(2-phenylpyridin-5-yl) aminocarbonyl] -1H-indole,
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1-[(2-phenylpyridin-5-yl) aminocarbonyl] -1H-indole,
5-chloro-2,3-dihydro-1- [4- (6-methylpyridazin-3-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole ,
5-bromo-2,3-dihydro-1- [4- (6-methylpyridazin-3-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H- Indol,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-3-yl) phenylaminocarbonyl] -1H-indole,
5-chloro-2,3-dihydro-1- [4- (5-methyloxazol-2-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole ,
2,3-dihydro-5-methoxy-1- [4- (5-methyloxazol-2-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H- Indol,
5-bromo-2,3-dihydro-1- [4- (5-methyloxazol-2-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H- Indol,
5-chloro-2,3-dihydro-1- [4- (1-methylpyrazol-4-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole ,
5-bromo-2,3-1- [4- (1-methylpyrazol-4-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole,
5-chloro-2,3-dihydro-1- [4'-cyano-3'-methylbiphenyl-4-aminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H- Indol,
5-Bromo-2,3-dihydro-1- [4'-cyano-3'-methylbiphenyl-4-aminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H Indol,
5-chloro-2,3-dihydro-1- [4- (2-methylpyridin-5-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole,
5-bromo-2,3-dihydro-1- [4- (2-methylpyridin-5-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole ,
5-chloro-2,3-dihydro-1- [5- (3-methyl-1,2,4-oxadiazol-5-yl) naphth-1-ylaminocarbonyl] -6- (4 -Methylpiperazin-1-yl) -1H-indole,
2,3-dihydro-5-methoxy-1- [5- (3-methyl-1,2,4-oxadiazol-5-yl) naphth-1-ylaminocarbonyl] -6- ( 4-methylpiperazin-1-yl) -1H-indole,
5-bromo-2,3-dihydro-1- [5- (3-methyl-1,2,4-oxadiazol-5-yl) naphth-1-ylaminocarbonyl] -6- ( 4-methylpiperazin-1-yl) -1H-indole,
5-chloro-2,3-dihydro-1- [5- (5-methyloxazol-2-yl) naphth-1-ylaminocarbonyl] -6- (4-methylpiperazin-1-yl ) -1H-indole,
2,3-dihydro-5-methoxy-1- [5- (5-methyloxazol-2-yl) naphth-1-ylaminocarbonyl] -6- (4-methylpiperazin-1- 1) -1H-indole,
5-bromo-2,3-dihydro-1- [3-methyl-4- (pyrimidin-2-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H Indol,
2,3-dihydro-5-methoxy-1- [3-methyl-4- (pyrimidin-2-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H Indol,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [3-methyl-4- (pyrimidin-2-yl) phenylaminocarbonyl] -1H- Indol,
5-bromo-2,3-dihydro-1- [3-methyl-4- (pyrimidin-5-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H Indol,
5-chloro-2,3-dihydro-1- [3-methyl-4- (pyrimidin-5-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H- Indol,
2,3-dihydro-5-methoxy-1- [3-methyl-4- (pyrimidin-5-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H Indol,
5-bromo-2,3-dihydro-1- [4- (2,6-dimethylpyridin-4-yl) -3-methylphenylaminocarbonyl] -6- (4-methylpiperazin-1-yl ) -1H-indole,
2,3-dihydro-5-methoxy-1- [4- (2,6-dimethylpyridin-4-yl) -3-methylphenylaminocarbonyl] -6- (4-methylpiperazin-1-yl ) -1H-indole,
5-chloro-2,3-dihydro-1- [5- (2,6-dimethylpyridin-4-yl) naphth-1-ylaminocarbonyl] -6- (4-methylpiperazin-1- 1) -1H-indole,
5-bromo-2,3-dihydro-1- [5- (2,6-dimethylpyridin-4-yl) naphth-1-ylaminocarbonyl] -6- (4-methylpiperazin-1 -Yl) -1H-indole,
2,3-dihydro-1- [5- (2,6-dimethylpyridin-4-yl) naphth-1-ylaminocarbonyl] -5-methoxy-6- (4-methylpiperazin-1 -Yl) -1H-indole,
Or pharmaceutically acceptable salts thereof.
Preferred salts of compounds of formula (I) are pharmaceutically acceptable salts. These include acid addition salts such as hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate and p-toluenesulfonate.
Certain compounds having formula (I) may exist in stereoisomeric forms. It is to be understood that the present invention encompasses all geometric and optical isomers of formula (I) and mixtures thereof including racemates.
The compounds of the present invention can be prepared by known methods. In another aspect, the invention
(a) a compound of formula (II), in which D is nitrogen and Y is NH in formula (I)
R ^a -NC (= V), where R ^a and V are as defined in formula (I)
Or a protective derivative thereof and a compound of formula (III)
Wherein W, X, R ^b and R ^c are as defined in formula (I)
Or a protective derivative thereof
(b) when D is nitrogen in formula (I) and Y is NH or NR ⁵ , a compound of formula (IV) with a suitable urea former
R ^a -NH ₂ or R ^a -NR ⁵ H, wherein R ^a and R ⁵ are as defined in formula (I)
Reacts with a compound of formula III
(c) when D in the formula (I) is nitrogen, the compound of formula (V)
R ^a -Y- (C = O) -L ² , wherein R ^a is as defined in formula (I), and Y is -CH ₂ -or
-O- and L ² is a suitable leaving group)
Reacted with a compound of formula (III),
(d) when D in formula (I) is carbon or CH, a compound of formula (VI)
R ^a -NH ₂ , where R ^a is as defined in formula (I)
Reacted with a compound of formula (VII),
Wherein D is carbon or CH and W, X, R ^b and R ^c are defined in Formula (I)
L ² is the appropriate leaving group)
Then randomly
· Remove any protector,
Converting a compound of formula (I) to another compound of formula (I),
Pharmaceutically acceptable salt formation
It provides a method of preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof.
The reaction of process (a) is conveniently carried out in an organic solvent, for example dichloromethane.
In process (b), the urea former can be carbonyl diimidazole, triphosgene or phosgene, inert organic solvents such as at room or elevated temperatures in the presence of a base, for example triethyleneamine or pyridine, for example The reaction can be carried out in dimethylformamide, tetrahydrofuran or dichloromethane.
In process (c), the leaving group L ² may be a halogen, for example a chlorine group and the reaction is carried out at an inert organic solvent such as tetrahydrofuran or at room or elevated temperature in the presence of a base such as triethyleneamine or pyridine or The reaction can be carried out in dichloromethane.
In process (d), the leaving group L ² may be a halogen, for example a chlorine group and the reaction is carried out at an inert organic solvent such as tetrahydrofuran or at room or elevated temperature in the presence of a base such as triethyleneamine or pyridine or It can be performed in dichloromethane.
Compounds of formula (I) may be converted to other compounds of formula (I) using standard techniques. For example, when R ^c is hydrogen, with a C _1-6 alkyl halide and 1 molar equivalent of a suitable base in an inert solvent, one molar equivalent of a C _1-6 alkyl group may be introduced by conventional alkylation.
Intermediates of formulas (II), (III), (IV), (V), (VI) and (VII) can be prepared using known methods.
Those skilled in the art will appreciate that it may be necessary to protect any reaction substituents during any of these processes. Standard protection and deprotection techniques can be used. For example, the first amine may be protected with phthalimide, benzyl, benzyloxycarbonyl or trityl derivatives. These groups can be removed by common known procedures.
Carboxylic acid groups can be protected with esters. Aldehyde or ketone groups can be protected with acetals, ketals, thioacetals or thioketals. Deprotection is achieved using standard conditions.
5HT _{1A / 1B / 1D} receptor antagonists and in particular the compounds of the present invention include CNS diseases such as emotional disorders such as depression, seasonal diseases and mood modulation; Anxiety, such as generalized anxiety, extreme fear, agoraphobia, social phobia, obsessive and post-traumatic stress diseases; Memory diseases such as dementia, forgetfulness and senile memory impairment; It can be used for the treatment of eating disorders such as anorexia nervosa and neuropathic hunger and sleep disorders (eg disturbances of periodic rhythms). Other CNS diseases include motor disorders such as Parkinson's disease, dementia caused by Parkinson's disease, nerve relaxation caused by Parkinson's disease, and chronic motor abnormalities, along with other mental disorders.
5HT _{1A / 1B / 1D} receptor antagonists and in particular the compounds of the invention are used for the treatment of visceral disorders and endocrine diseases including movement and secretion changes, such as hyperprolactin hyperemia, in the treatment of vasospasm (particularly in central vascular system) and hypertension May be used. They can also be used to treat sexual dysfunction and hypothermia.
The present invention also provides a compound of formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment of the disease.
In another aspect, the present invention provides a method for treating a disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. .
In particular, the present invention provides a compound of formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment or prevention of depression.
It will be appreciated by those skilled in the art that the compounds according to the invention may be advantageously used in combination with one or more other therapeutic agents, for example other anti-inhibitors.
The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
Pharmaceutical compositions of the invention, which may be prepared by mixing at room temperature and atmospheric pressure, are usually administered orally, parenterally or rectally, in which case tablets, capsules, oral liquid preparations, powders, granules, lozenges. , Reconstitutable flour, insertable or injectable solutions or suspensions, or suppositories. Compositions that can be administered orally are generally preferred.
Tablets and capsules for oral administration may be in unit dosage form and may include conventional excipients such as binders, fillers, tableting lubricants, disintegrating agents and acceptable wetting agents. The tablets may be coated according to methods well known in the conventional pharmaceutical arts.
Oral liquid preparations may, for example, be in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs or in the form of dry products for reconstitution with water or other suitable vehicle prior to use. The liquid preparations may include customary adducts such as suspending agents, emulsifiers, non-aqueous vehicles (which may include edible oils), preservatives and, if desired, conventional flavoring or coloring agents.
For parenteral administration, liquid unit dosage forms can be prepared using the compounds of the present invention or their pharmaceutically acceptable salts and sterile vehicles. The compound may be suspended or dissolved in the vehicle, depending on the vehicle and concentration used. In solution preparation, the compounds may be dissolved in sterile injectables and filtrates before filling and sealing in appropriate vials or ampoules. Advantageously, auxiliaries such as local anesthetics, preservatives and buffers are dissolved in the vehicle. In order to increase the stability, the composition can be filled into vials and then frozen, followed by removal of water under vacuum. Parenteral suspensions are prepared in substantially the same manner except that the compounds are suspended instead of dissolved in the vehicle and sterilization cannot be achieved by filtration. The compound can be sterilized by exposure to ethylene oxide prior to suspension in a sterile vehicle. Advantageously, the composition comprises a surfactant or wetting agent so that the compound is easily and uniformly distributed.
The composition may comprise 0.1 to 99% by weight, preferably 10 to 60% by weight of active agent, depending on the method of administration.
The dosage of a compound that can be used to treat the disease will generally vary depending on the severity of the disease, the weight of the patient and other similar factors. However, as a general method, a suitable unit dose may be 0.05 to 1000 mg, more suitably 1.0 to 200 mg and the unit dose may be administered one or more times per day, for example twice or three times a day. The therapy can last for weeks or months.
The following examples show the preparation of the compounds of the invention.
Article item 1
4-bromo-3-methylphenyl isocyanate
Three drops of DMF after oxalyl chloride (11.94 g, 0.094 mole) were added to a stirred suspension of 4-bromo-3-methylbenzoic acid (10.0 g, 0.047 mole) in dichloromethane (300 ml). After the mixture was stirred at room temperature for 60 hours, the solution was concentrated in vacuo to give acid chloride as a red oil. This material was redissolved in dichloromethane (300 ml) and cooled to 0 ° C. Tetrabutylammonium aodide (0.150 g) is added followed by a solution of sodium azide (4.36 g, 0.066 mole) in water (75 ml) and the mixture is vigorously stirred at 0 ° C. for 3 h and then with water (200 ml) Diluted and the dichloromethane layer was separated, dried (Na ₂ SO ₄ ) and concentrated in vacuo (but not until complete drying) to obtain acyl azide as a pale orange solid. This material was dissolved in toluene (300 ml), heated for 1 h with stirring under reflux, cooled and concentrated in vacuo to afford the title compound as a reddish brown oil (9.42 g, 95%).
Article item 2
4- (pyridin-4-yl) naphth-1-ylamine
A stirred suspension of 1,2-dimethoxyethane (400 ml) comprising sodium carbonate (14 g) and 4-bromonaft-1-ylamine (10 g, 45 mmol) in water (100 ml) was flushed under argon for 0.3 h. flush). Tetrakis (triphenylphosphine) palladium (O) (2,75 g, 2.4 mmol) was added followed by the addition of 4-pyridylboronic acid (5.7 g, 46 mmol) and the mixture was heated at reflux for 5 hours. The mixture was concentrated in vacuo to form a brown slurry and partitioned between dichloromethane and water. The aqueous solution was further extracted with dichloromethane and the combined organics were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a brown solid (13.2 g). Purification of the solid by flash chromatography eluting with ethyl acetate gave the title compound as a yellow crystalline solid (7.8 g, 78%).
Article item 3
5- (pyridin-4-yl) -1-naphthoic acid
The title compound was prepared from 5-bromo-1-naphthoic acid (EP 547442 A1) and 4-pyridylboronic acid using a procedure similar to that described in Item 2.
Article item 4
5- (pyridin-4-yl) naphth-1-yl isocyanate
The title compound was prepared from 5- (pyridin-4-yl) -1-naphthoic acid (D3) using a procedure similar to that described in Item 1.
Article item 5
4- (pyridin-4-yl) aniline
The title compound was prepared as a white solid from 4-bromoaniline and 4-pyridinylboronic acid using a procedure similar to that described in Item 2 (17%).
Article item 6
3-chloro-4- (pyridin-4-yl) aniline
3-chloro-4-broroacetanilide was reacted with 4-pyridinylboronic acid using a procedure similar to that described in Item 2 to obtain 3-chloro-4- (pyridin-4-yl) acetanilide. The title compound was obtained as a pale yellow solid by hydrolysis of this material by heating under reflux for 6 hours in a mixture of 2M NaOH solution and ethanol (5.5 g, 73%).
List item 7
2,3-dichloro-4- (pyridin-4-yl) aniline
The title compound was prepared by base hydrolysis from 4-bromo-2,3-dichloroacetanilide and 4-pyridinylboronic acid using a procedure similar to that described in Item 6.
Article item 8
1-acetyl-2,3-dihydro-6-nitro-1H-indole
A stirred solution of 2,3-dihydro-6-nitro-1H-indole (100 g, 0.61 mol) in dichloromethane (1000 ml) was added dropwise to acetic anhydride (62 ml, 0.66 mol) for 20 minutes at room temperature. The reaction mixture was stirred for an additional 2 hours and then washed with 10% 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 (125 g, 100%).
Article item 9
1-acetyl-6-amino-2,3-dihydro-1H-indole
A stirred suspension of 1-acetyl-2,3-dihydro-6-nitro-1H-indole (D8, 125 g, 0.61 mol) in THF (5500 ml) was added to 10% Pd-C (20 g) at 50 psi for 20 hours. Hydrogenated. Filtration through a kieselguhr plug removed the catalyst and the filtrate was concentrated in vacuo to afford the title compound as a beige solid (102 g, 95%).
Article item 10
1-acetyl-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole
1-acetyl-6-amino-2,3-dihydro-1H-indole (D9, 37.8 g, 0.22 moles), mechlorethamine hydrochloride (46 g, 0.24 moles) in 1-butanol (1800 ml) and potassium anhydride The carbonate (80 g, 0.58 mole) was heated under reflux for 8 hours after which additional mechlorethamine hydrochloride (25 g, 0.13 mole) and potassium carbonate (41 g, 0.30 mole) were added and reflux continued for 3 hours. The reaction mixture was cooled down and washed with water (1000 ml). The aqueous wash was extracted with ethyl acetate and the extract was mixed with 1-butanol solution and concentrated in vacuo. The brown oily residue (60 g) was chromatographed on silica gel eluting with 0-8% MeOH / DCM to give an orange oil, which was triturated with ether to give the title compound as a beige solid (12.2 g, 22%).
Article item 11
2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole
The title compound was prepared as a beige solid from 1-acetyl-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole (D10) using a procedure similar to that described in Item 13. (92%).
Article item 12
1-acetyl-5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole
1-acetyl-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole (D10, 1,1 g, 0.0040 mol in dichloromethane (100 ml) in the presence of argon ) Was stirred dropwise for 15 minutes with a solution of N-chlorosuccinimide (0.73 g, 0.0054 mol) in DCM (10 ml), and then stored at -5 ° C for an additional 0.5 hours, and left at room temperature for 1 hour. I got it. The reaction mixture was extracted with 2M HCl acid (60 ml) and the acid extract was basified by addition of solid K ₂ CO 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 (1.45 g, 100%).
Article item 13
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole
Stirring of 1-acetyl-5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole (D12, 1.4 g, 0.0048 mol) in 2M HCl acid (120 ml) The solution was heated for 5 hours under reflux in the presence of argon. The reaction mixture was left to cool, basified by addition of solid K ₂ CO 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 (0.93 g, 78%).
List item 14
1-acetyl-5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole
1-acetyl-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole (D10) in a mixture of dichloromethane (100 ml) and methanol (50 ml) at -5 ° C in the presence of argon. , 2.0 g, 0.0077 mole) of the stirred mixture was treated in portions with benzyltrimethylammonium tribromide (3.14 g, 0.0081 mole) for 20 minutes. The mixture was left to stand for 1 h, allowed to come to room temperature and concentrated in vacuo, and the residue was dissolved in dichloromethane (150 ml), washed with water (2 × 100 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo. The compound was obtained as a beige solid (2.52 g, 97%).
List item 15
5-Bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole
1-acetyl-2,3-dihydro-5-bromo-6- (4-methylpiperazin-1-yl) -1H-indole (D14, 0,60 g, 1.8 mmol) in 2M hydrobromic acid (50 ml) ) Solution was stirred at room temperature for 5 days, then basified by addition of solid K ₂ CO ₃ and extracted with DCM. The extract was dried (Na ₂ SO ₄ ) and concentrated in vacuo to afford the title compound as a brown solid (0.31 g, 58%).
List item 16
1-acetyl-2,3-dihydro-5-methyl-6- (4-methylpiperazin-1-yl) -1H-indole
The title compound was purified using 1-acetyl-2,3-dihydro-5-bromo-6- (4-methylpiperazin-1-yl) -1H-indole (D14) using a procedure similar to that described in Item 18, and Prepared as a beige solid from tetramethyltin (63%).
List item 17
2,3-dihydro-5-methyl-6- (4-methylpiperazin-1-yl) -1H-indole
The title compound was beige from 1-acetyl-2,3-dihydro-5-methyl-6- (4-methylpiperazin-1-yl) -1H-indole (D16) using a procedure similar to that described in Item 13. Prepared as a color solid (89%).
List item 18
1-acetyl-2,3-dihydro-6- (4-methylpiperazin-1-yl) -5-vinyl-1H-indole
1-acetyl-2,3-dihydro-5-bromo-6- (4-methylpiperazin-1-yl) -5-vinyl-1H-indole (D14, 600 mg, 1.8 mmol) in dry DMF (15 ml) ) The stirred solution was treated with vinyltributyltin (0.78ml, 2.7mmole) and degassed by bubbling argon for 20 minutes, followed by triethylamine (0.50ml, 3.6mmole) and tetrakis (triphenylphosphine) palladium (O ) (200 mg) was added and the mixture was heated at 100 ° C. for 7 hours in the presence of argon. The reaction mixture was left to cool, diluted with EtOAc (150 ml) and extracted with 0.5 M HCl acid (2 × 100 ml). The acid extract was basified with addition of solid K ₂ CO ₃ and extracted with DCM (2 × 100 ml) and the extract was dried (Na ₂ SO ₄ ) and concentrated in vacuo to afford the title compound as a beige solid (480 mg). , 95%).
List item 19
2,3-dihydro-6- (4-methylpiperazin-1-yl) -5-vinyl-1H-indole
A stirred solution of 1-acetyl-2,3-dihydro-6- (4-methylpiperazin-1-yl) -5-vinyl-1H-indole (D18, 250 mg, 9.0 mmol) in ethanol (25 ml) was prepared. Treated with% NaOH solution (45 ml) and degassed by bubbling argon for 15 minutes followed by heating under reflux for 7 hours. The mixture was left to cool, concentrated in vacuo to about 40 ml volume and 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, 80%).
Article item 20
1-acetyl-2,3-dihydro-5-ethyl-6- (4-methylpiperazin-1-yl) -1H-indole
A stirred solution of 1-acetyl-2,3-dihydro-6- (4-methylpiperazin-1-yl) -5-vinyl-1H-indole (D18, 400 mg, 1.4 mmol) in ethanol (100 ml) Hydrogenated to 10% Pd-C (100 mg) for 24 h at atmospheric pressure. The catalyst was removed by filtration through a Keithley razer and the filtrate was concentrated in vacuo to yield the title compound as a beige solid (380 mg, 94%).
List item 21
2,3-dihydro-5-ethyl-6- (4-methylpiperazin-1-yl) -1H-indole
The title compound was beige from 1-acetyl-2,3-dihydro-5-ethyl-6- (4-methylpiperazin-1-yl) -1H-indole (D20) using a procedure similar to that described in Item 13. A colored solid was prepared (94%).
List item 22
1-acetyl-2,3-dihydro-6- (4-methylpiperazin-1-yl) -5-trifluoromethyl-1H-indole
1-acetyl-5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole (D14, 500 mg, 1.5 in dry DMF (16 ml) and toluene (10 ml) mmole), potassium trifluoroacetate (410mg, 2.7mmole) and a copper iodide (I) (572mg, 3.0mmole) stirred solution using argon and stark heads to trap toluene / water Heated at 130 ° C. for 0.5 h. Replace the Dean and Stark heads with a condenser and heat the mixture at 155 ° C. for 34 hours, then add additional potassium trifluoroacetate (410 mg) and copper iodide (570 mg) for 3 hours at 155 ° C. Heating continued. The reaction mixture was left to cool, treated with dilute ammonium solution (200 ml) and DCM (150 ml), shaken well and filtered through a plug of a Kiesligger. The organic layer was separated, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by chromatography on basic ammonia, eluting with ethyl acetate to give the title compound as a beige solid (63%).
List item 23
2,3-dihydro-6- (4-methylpiperazin-1-yl) -5-trifluoromethyl-1H-indole
1-acetyl-2,3-dihydro-6- (4-methylpiperazin-1-yl) -5-trifluoromethyl-1H-indole (D22, in 2M HCl acid (25 ml) and ethanol (25 ml) 260 mg, 1.1 mmol) solution was stored at room temperature for 7 days and concentrated in vacuo until the volume became about 25 ml. The aqueous residue was basified with solid K ₂ CO ₃ , extracted with DCM and the extract was dried (Na ₂ SO ₄ ) and concentrated in vacuo to afford the title compound as a beige solid (300 mg, 91%).
Article item 24
4- (pyridin-4-yl) naphth-1-ylacetic acid
4-Bromonaph-1-ylacetic acid (1 g, 3.78 mmol, J. Org. Chem., 1951, 16, 1588) in 1,2-dimethoxyethane (50 ml) was pyridine-4-ylboronic acid. (465 mg, 3.78 mmol), sodium hydrogen carbonate (952 mg, 11.3 mmol) and water (10 ml). The argon stream was bubbled through the mixture for 15 minutes, after which tetrakis (triphenylphosphine) palladium (O) (200 mg, 0.17 mmole) was added and the mixture was heated at reflux for 18 hours. The mixture was then concentrated in vacuo until a gum and 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 afford the title compound which crystallized from ether with a needle at mp210-215 ° C.
List item 25
5- (pyridin-4-yl) naphth-1-ylacetic acid
The title compound was prepared from 5-bromonaft-1-ylacetic acid (Bull. Soc. Chim. Fr., 1968, 7, 2957) and pyridin-4-ylboronic acid using a procedure similar to that described in Item 24. Prepared.
List item 26
Quinolin-6-yl Isocyanate
The title compound was prepared from 6-quinolinecarboxylic acid using a procedure similar to Description 1.
List item 27
3- (4-methylpiperazin-1-yl) -1-nitrobenzene
K ₂ CO ₃ (52.5 g, 0.385 mol) and mechlorethamine hydrochloride (31.4 g, 0.16 mol) were added to a solution of 3-nitroaniline (15.0 g, 0.11 mol) in 2-butanol (500 ml). The mixture was refluxed with stirring for 18 hours in the presence of argon, followed by the addition of additional mechlorethamine hydrochloride (17.5 g, 0.09 mol) and K ₂ CO ₃ (25.0 g, 0.18 mol) and heating under reflux for 24 hours. Continued for a while. The 2-butanol was removed in vacuo and the residue was partitioned between H ₂ O (300 ml) and CH ₂ Cl ₂ (300 ml). The CH ₂ Cl ₂ was separated and the aqueous solution was re-extracted with CH ₂ Cl ₂ (3 × 200 ml). The organics were mixed, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give 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 orange oil (16.72 g, 70%).
List item 28
3- (4-methylpiperazin-1-yl) aniline
3- (4-Methylpiperazin-1-yl) -1-nitrobenzene (D27, 8.10 g, 0.037 mol) was dissolved in EtOH (250 ml) and 18 h at 10% Pd / C (2 g) at room temperature and atmospheric pressure. While hydrogenated. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to afford the title compound as a pale yellow oil (6.64 g, 95%).
List item 29
7- (4-methylpiperazin-1-yl) quinoline
Cover 3- (4-methylpiperazin-1-yl) aniline (D28, 6.6 g, 0.035 moles) with glycerol (8 ml, 0.1 moles) and carefully add concentrated sulfuric acid (5.2 ml, 0.097 moles) for 10 minutes while stirring I dropped it. The air condenser was adjusted and iodine (100 mg) was added and the reaction heated with stirring at 100 ° C. for 3 hours and then with stirring at 150 ° C. for 4 hours. The reaction was cooled and poured into water (250 ml). The aqueous solution was basified to pH ₁₀ with K ₂ CO ₃ and extracted with CH ₂ Cl ₂ (3 × 300 ml). The organics were combined, dried (Na ₂ SO ₄ ) and concentrated in vacuo to afford a dark brown oil which was purified by column chromatography on basic ammonia, eluting with 2% MeOH / CH ₂ Cl ₂ . The title compound was an orange solid (4.05 g, 52%).
List item 30
7- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydroquinoline
Dissolve 7- (4-methylpiperazin-1-yl) quinoline (D29, 3.71 g, 0.016 mol) in EtOH (100 ml) and AcOH (5 ml) and 5% Pt / C (1.0 g) at 50 psi and room temperature Hydrogenated for 84 hours. The catalyst was removed by filtration, the solvent was removed in vacuo and the filtrate was partitioned between 10% Na ₂ CO ₃ (aq) and CH ₂ Cl ₂ . The CH ₂ Cl ₂ was separated, dried (Na ₂ SO ₄ ) and concentrated in vacuo to afford the title compound as a pale orange / brown solid (3.60 g, 95%).
List item 31
7- (4-methylpiperazin-1-yl) -1-trifluoroacetyl-1,2,3,4-tetrahydroquinoline
Trifluoroacetic anhydride (0.67 ml, 4.8 mmole) was added 7- (4-methylpiperazin-1-yl) -1,2,3,4- in CH ₂ Cl ₂ (30 ml) cooled on ice in the presence of argon. Add dropwise to tetrahydroquinoline (D30, 1.0 g, 4.3 mmol). After 30 minutes at 0 ° C. the mixture was warmed to room temperature for 30 minutes and then washed with dilute Na ₂ HCO ₃ (aq). The CH ₂ Cl ₂ was separated, dried (Na ₂ SO ₄ ) and concentrated in vacuo to afford the title compound as a viscous yellow oil (1.42 g, 100%).
List item 32
6-bromo-7- (4-methylpiperazin-1-yl) -1-trifluoroacetyl-1,2,3,4-tetrahydroquinoline
The title compound was prepared from 7- (4-methylpiperazin-1-yl) -1-trifluoroacetyl-1,2,3,4-tetrahydroquinoline (D31) using a procedure similar to that described in Item 14. It was.
List item 33
6-bromo-7- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydroquinoline
K ₂ CO ₃ (solid) (0.50 g, 3.6 mmol) was added to 6-bromo-7- (4-methylpiperazin-1-yl) -1-trifluoroacetyl-1,2, in MeOH (30 ml). To a stirred solution of 3,4-tetrahydroquinoline (D32, 0.74 g, 1.8 mmole) was added. After 18 hours at room temperature the MeOH was removed in vacuo and the residue was partitioned between CH ₂ Cl ₂ and 10% Na ₂ CO ₃ (aq). The CH ₂ Cl ₂ was separated, dried (Na ₂ SO ₄ ) and concentrated in vacuo to afford the title compound as an orange / brown solid (0.55 g, 98%).
List item 34
1-butyryl-2,3-dihydro-6-nitro-1H-indole
2,3-dihydro-6-nitro-1H-indole (16.4 g, 100 mmol) in CH ₂ Cl ₂ (200 ml) was mixed with butyryl chloride (10.6 g, 100 mmol) and Et _{3 with} continuous stirring at room temperature for 2 hours. Treated with N (10.1 g, 100 mmol). The reaction was then washed with 5N HCl and saturated with aqueous K ₂ CO ₃ solution. The reaction was then dried (Na ₂ SO ₄ ) and concentrated in vacuo until a gum crystallized in needle form from petrol to obtain as the title compound (23.4 g, 100%).
List item 35
6-amino-2,3-dihydro-1-butyryl-1-H-indole
1-butyryl-2,3-dihydro-6-nitro-1H-indole (D34, 19.8 g, 84.4 mmole) was heated to 10% palladium on char (2 g) in MeOH (200 ml) at 50 psi under hydrogen atmosphere. Stirred at a rate rising to 60 ° C. and stopped hydrogen absorption. The reaction was then filtered through celite and the celite was washed with hot MeOH to leave no reaction product. The filtrate was evaporated in vacuo (13.3 g, 77%) to obtain the title compound in needle form.
List item 36
1-butylyl-2,3-dihydro-6-iodo-1H-indole
6-amino-1-butylyl-2,3-dihydro-1H-indole (D35, 3.0 g, 0.015 mol) in a mixture of concentrated H ₂ SO ₄ (3 ml) and water (35 ml) at 0 ° C 10 ml) was treated dropwise (the end of the addition funnel touching the liquid surface) with a solution of sodium nitrite (1.1 g, 0.016 mol), during which the temperature was kept below 5 ° C. The mixture was then stirred for an additional 20 minutes at <3 ° C. before dropwise addition to a solution of potassium iodide (2.66 g, 0.016 mol) in water (10 ml) at 0 ° C. Some boiling was observed and a dark orange suspension formed. The mixture was stirred for an additional 1.5 hours while left to come to room temperature. On evaporation the product was extracted with EtOAc (3 ×) to afford the title compound as an orange solid, the organics were washed (Na ₂ S ₂ O ₃ solution) and dried (Na ₂ SO ₄ ) (3.3 g, 70%).
List item 37
1-butylyl-2,3-dihydro-6- (pyridin-4-yl) -1H-indole
Dimethoxyethane (120 ml) with Na ₂ CO ₃ (3.85 g, 36.4 mmole) and 1-butyryl-2,3-dihydro-6-iodo-1H-indole (D36, 3.28) in water (30 ml) g, 10.4 mmol) was flushed with argon for 1 hour. 4-pyridylboronic acid (1.3 g, 10.8 mmol) and tetrakis (triphenylphosphine) palladium (O) (600 mg, 0.52 mmol) were added to the mixture and the mixture was heated at reflux for 1 hour. The mixture was left to cool, evaporated in vacuo and the residue partitioned between water and CH ₂ Cl ₂ . The aqueous solution was further extracted with CH ₂ Cl ₂ (2 ×), and the organics were mixed and dried (Na ₂ SO ₄ ) to give a dark brown oil upon evaporation, which was subjected to flash chromatography (5% MeOH / CH ₂ Cl _2). Purification by eluent) afforded the title compound as a brown solid (1.5 g, 54%).
List item 38
1-butyryl-2,3-dihydro-6- (1-methylpiperidin-4-yl) -1H-indole
Iodomethane (1.6 g, 11.3 mmol) was converted to 1-butyryl-2,3-dihydro-6- (pyridin-4-yl) -1 H-indole (D37, 1.5 g, 5.63 mmol) in acetone (50 ml). The solution was added and the mixture was stored overnight. Filtration gave an orange solid (1.2 g) dissolved in ethanol (25 ml) and water (25 ml) and the solution was cooled to 0 ° C. Sodium borohydride (166 mg, 4.4 mmole) was added to the solution in portions over 5 minutes and the mixture was stirred for an additional 10 minutes. 2M NaOH solution (16ml) and water (40ml) were added to the mixture and the product was extracted with CH ₂ Cl ₂ (2 ×), dried (Na ₂ SO ₄ ) and vacuum evaporated to give a brown oil (1.0 g). . The oil was then dissolved in ethanol (50 ml) and hydrogenated with 10% Pd-C (100 mg) at 50 psi and 50 ° C. for 72 hours. Filtration and evaporation of the filtrate in vacuo gave the title compound as a white solid (710 mg, 44%).
List item 39
5-Bromo-2,3-dihydro-6- (1-methylpiperidin-4-yl) -1H-indole
N-bromosuccinimide (454 mg, 2.55 mmol) was dissolved in 1-butyryl-2,3-dihydro-6- (1-methylpiperidin-4-yl) -1H-indole in acetic acid (20 ml). D38, 2.32 mmol) was added and the mixture was stirred overnight at room temperature. The mixture was diluted with water and basified with solid K ₂ CO ₃ . The organics were extracted with CH ₂ Cl ₂ , dried (Na ₂ SO ₄ ) and evaporated in vacuo to yield an off-white solid (890 mg). A portion of solid (790 mg, 2.16 mmol) in ethanol (20 ml) and 2 M NaOH solution (30 ml) was heated at 80 ° C. for 72 h in the presence of argon. The product was extracted with CH ₂ Cl ₂ and the organics were dried (Na ₂ SO ₄ ) and evaporated in vacuo to give the title compound as an orange solid (647 mg, 100%).
NH not found.
List item 40
4- (t-butoxycarbonylamino) aniline
Di-tert-butyl dicarbonate (4.25 ml, 18.5 mmol) was added to a stirred solution of phenylenediamine (2.0 g, 18.5 mmol) in CH ₂ Cl ₂ (50 ml) at 0 ° C. and the mixture was stirred at this time 16 Warmed to RT. Evaporation in vacuo gave the title compound with a purity of 80% (3.79 g, 98%), allowing the di-Boc compound to form a residue.
List item 41
4- (pyrimidin-2-yl) benzoic acid
The title compound obtained as a light buff colored powder was prepared from 4-carboxyphenylboronic acid and 2-bromopyrimidine (35%) in a similar manner as described in Item 2.
List item 42
4- (pyrimidin-2-yl) phenyl isocyanate
The title compound obtained as a pale yellow powder was prepared from 4- (pyrimidin-2-yl) benzoic acid (D41) in a similar manner as described in Item 1 (83%).
(Not observed as insoluble in ¹ H NMR-CDCl ₃ ).
List item 43
5-chloro-2,3-dihydro-1- (4-iodophenylaminocarbonyl) -6- (4-methylpiperazin-1-yl) -1H-indole
The title compound obtained as an off-white powder was subjected to 5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole (D13) and 4- in a similar manner to Example 4. Prepared from iodoaniline (54%).
List item 44
N- [4- (pyridin-4-yl) naphth-1-yl] acetamide
A solution of acetyl chloride (0.5 ml, 7.0 mmol) in CH ₂ Cl ₂ (10 ml) was washed with 4- (pyridin-4-yl) naphth- in CH ₂ Cl ₂ and triethylamine (1.0 ml, 7.1 mmol) at 0 ° C. To the 1-ylamine (D2, 1.5 g, 6.8 mmole) solution was added dropwise and the mixture was stirred, at which point it was left to stand for 1 hour to room temperature. The solution was washed with aqueous 10% Na ₂ CO ₃ and the organics were dried (Na ₂ SO ₄ ) and evaporated in vacuo to afford the title compound as a yellow solid (1.9 g, 100%).
List item 45
N- [4- (1-methyl-1,2,5,6-tetrahydropyridin-4-yl) naphth-1-yl] acetamide
Iodomethane (1.92 g, 13.6 mmol) was added to a solution of N- [4- (pyridin-4-yl) naphth-1-yl] acetamide (D44, 1.8 g, 6.8 mmol) in acetone (50 ml) The mixture was stored overnight. Filtration gave a yellow solid (1.2 g) dissolved in ethanol (25 ml) and water (25 ml), cooled to 0 ° C., treated with sodium borohydride (166 mg, 4.4 mmol) for 5 minutes and stirred for 1 hour. did. Aqueous 10% NaOH (16 ml) and water (40 ml) were added to the mixture and the product was extracted with CH ₂ Cl ₂ , dried (Na ₂ SO ₄ ) and evaporated in vacuo to afford the title compound as a brown solid ( 880 mg, 44%).
List item 46
4- (1-methylpiperidin-4-yl) naphth-1-ylamine
A solution of N- [4- (1-methyl-1,2,5,6-tetrahydropyridin-4-yl) naphth-1-yl] acetamide (D45, 800 mg, 2.9 mmol) in ethanol (50 ml) Hydrogenated with 10% Pd-C for 192 hours at 50 psi and 50 ° C. Filtration through celite and evaporation of the filtrate gave a white solid (683 mg) upon evaporation. The solid was dissolved in ethanol (10 ml) and aqueous 2M NaOH (16 ml) and heated for 72 hours while refluxing in the presence of argon. The mixture was extracted with CH ₂ Cl ₂ , the organics were dried (Na ₂ SO ₄ ) and evaporated in vacuo to afford the title compound as an orange oil (520 mg, 76%).
List item 47
4- (4-aminophenyl) -2-methyloxazole
A mixture of 2-methyl-4- (4-nitrophenyl) oxazole (1.70 g, 8.2 mmol, J. Het. Chem. 1981, 18,885) in THF (70 ml) and 10% palladium (0.20 g) on carbon Was stirred for 42 h in the presence of hydrogen under atmospheric pressure. 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 Cl ₂ . The title compound was obtained as a yellow powder (0.92 g).
List item 48
4- (2-Methyl-pyridin-4-yl) benzoic acid
The title compound was prepared as a white solid from 4-bromo-2-methylpyridine (J. Org. Chem. 1985, 50, 4410) and 4-carboxyphenylboronic acid using a procedure similar to that described in Item 2. (84%).
List item 49
4- (2-methyl-pyridin-4-yl) aniline
To obtain the amine as a beige solid, the title compound formed an isocyanate followed by basic hydrolysis with NaOH to give 4- (2-methyl-pyridin-4-yl) benzoic acid ( D48) (31%).
List item 50
N- (tert-butylooxycarbonyl) -4-iodoaniline
4-iodoaniline (3 g, 0.014 mole) in dry dichloromethane (20 ml) in an amount capable of catalyzing di-tert-butyl dicarbonide (2.99 g, 0.014 mole) followed by 4-dimethylaminopyridine Added to solution. The reaction was stirred overnight at room temperature, washed with water (2 x 20ml) and dried (MgSO ₄ ). Filtration and evaporation gave an off-white solid (1.90 g, 43%).
List item 51
N- (tert-butyloxycarbonyl) -4- (thiazol-2-yl) aniline
N- (tert-butyloxycarbonyl) -4-iodoaniline (D50, 319 mg, 1 mmol), bis (pinacolato) diboron (279 mg, 1.1 mole), DCM (1: 1) in dry DMF (6 ml) ) (24 mg, 0.029 mmol) and 1,1′-bis (diphenylphosphino) perrocene dichloropalladium (II) complex and potassium acetate (294 mg, 3 mmole) were heated at 80 ° C. for 2 hours. 2-bromothiazole (328 mg, 2 mmole), 2M sodium carbonate (2.5 ml) and DCM (1: 1) (24 mg, 0.029 mmol) and 1,1′-bis (diphenylphosphino) perrocene dichloropalladium after cooling (II) The complex was added and the reaction heated at 80 ° C. for 18 hours. After cooling the solution was diluted with water (20 ml). Extract with ethyl acetate (2 × 20 ml), then dry (MgSO ₄ ), filter under reduced pressure and evaporate to give an oil. This was chromatographed on silica gel eluting with 10% ethyl acetate in hexanes to give the title compound as an oil (137 mg, 50%).
List item 52
4- (thiazol-2-yl) aniline
N- (tert-butyloxycarbonyl) -4- (thiazol-2-yl) aniline (D51, 122mg, 0.44mmole) solution in dichloromethane (2ml) and trifluoroacetic acid (0.1ml) After stirring for hours water (20 ml) was added. The aqueous phase was extracted with dichloromethane (2 × 10 ml) and the extract was washed with 10% aqueous sodium hydrogen carbonate (2 × 20 ml) and then dried (MgSO ₄ ) under reduced pressure to obtain a light yellow oil. Evaporated and solidified while leaving still (70 mg, 90%).
List item 53
4- (isoquinolin-2-yl) benzoic acid
The title compound obtained as an off-white solid was prepared from 4-carboxyphenylboronic acid and 4-bromoisoquinoline (58%) using a procedure similar to that described in Item 2.
List item 54
4- (isoquinolin-4-yl) phenyl isocyanate
The title compound was prepared from 4- (isoquinolin-4-yl) benzoic acid (D53) using a procedure similar to that described in Item 1. The isocyanate was used as a toluene solution without concentrating as a pure compound.
List item 55
4- (quinolin-3-yl) benzoic acid
The title compound obtained as an off-white solid (72%) was prepared from 4-carboxyphenylboronic acid and 3-bromoquinoline using a similar procedure as described in Item 2.
List item 56
4- (quinolin-3-yl) phenyl isocyanate
The title compound was prepared from 4- (quinolin-3-yl) benzoic acid (D55) using a procedure similar to that described in Item 51. The isocyanate was used as a toluene solution without concentrating to pure compound.
List item 57
4- (quinolin-8-yl) benzoic acid
The title compound obtained as an off-white solid was prepared from 4-carboxyphenylboronic acid and 8-bromoquinoline (65%) using a procedure similar to that described in Item 2.
List item 58
4- (quinolin-8-yl) phenyl isocyanate
The title compound was prepared from 4- (quinolin-8-yl) benzoic acid (D57) using a procedure similar to that described in Item 51. The isocyanate was used as a toluene solution without concentrating to pure compound.
List item 59
3-bromo-2,6-dimethylpyridine (D59a) and 4-bromo-2,6-dimethylpyridine (D59b)
A stirred solution of phosphorus oxybromide (25 g, 0.085 mol) in 1,2-dichloroethane (250 ml) at room temperature in the presence of argon was treated with 2,6-lutidine-N-oxide (10 g, 0.081 mol) and then refluxed. Under heating for 6 hours. The mixture was left to cool and then poured slowly into well stirred ice / water (400 ml) and basified by addition of solid K ₂ CO ₃ . The aqueous mixture was extracted with dichloromethane and the extract was dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 1: 1 ether / 60-80 petrol to separate into four components. The second component was 3-bromo-2,6-dimethylpyridine, a yellow oil (2.5 g, 21%);
The third component was 4-bromo-2,6-dimethylpyridine as a pale yellow oil (1.5 g, 12%).
List item 60
4- (2,6-Dimethyl-pyridin-4-yl) benzoic acid
The title compound was prepared as a white solid (76%) from 4-bromo-2,6-dimethylpyridine (D59b) and 4-carboxyphenylboronic acid using a procedure similar to that described in Item 2.
Acid protons not found.
List item 61
4- (2,6-Dimethyl-pyridin-3-yl) benzoic acid
The title compound was prepared as a beige solid from 3-bromo-2,6-dimethylpyridine (D59a) and 4-carboxyphenylboronic acid using a procedure similar to that described in Item 2 (76%).
Acid protons not found.
List item 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 (D60) using a procedure similar to that described in Item 1. The isocyanate was used as a toluene solution without concentrating the pure compound.
List item 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 procedure similar to that described in Item 1. The isocyanate was used as a toluene solution without concentrating the pure compound.
List item 64
8-bromo-5-nitroquinoline
8-bromoquinoline (1.5 g, 7.2 mmole) was added dropwise to well stirred concentrated H ₂ SO ₄ (5 ml), concentrated HNO ₃ (10 ml) and fuming HNO ₃ (2 ml) solutions and cooled on ice. The mixture was heated at 65 ° C. for 30 h and then poured into H ₂ O (350 ml) with cooling and stirring. The precipitate formed was filtered off, washed with H ₂ O and dried in vacuo to afford the title compound as a pale milky solid (1.10 g, 60%).
List item 65
5-nitro-8-phenylquinoline
The title compound was prepared as an orange / brown solid (99%) from 8-bromo-5-nitroquinoline (D64) and phenylboronic acid using a procedure similar to that described in Item 2.
List item 66
5-amino-8-phenylquinoline
The title compound was prepared as an orange / brown solid (97%) from 5-nitro-8-phenylquinoline (D65) using a similar procedure as described in Item 20.
List item 67
6-acetamido-2-methylquinoline
The title compound was prepared as a green solid using 6-amino-2-methylquinoline and acetic anhydride (95%) using a procedure similar to that described in Item 8.
Description68
6-amino-2- (2-phenylethenyl) quinoline
The 6-acetamido-2-methylquinoline (D67, 600 mg, 3.0 mmol) suspension in acetic anhydride (6 ml) was treated with benzaldehyde (954 mg, 9.0 mmol) and the mixture was heated at 120 ° C. for 40 hours before cooling Acetic anhydride was removed in vacuo. The residue was dissolved in 2M NaOH (30 ml) and EtOH (10 ml) and heated under reflux with stirring. After 18 h EtOH was removed in vacuo and the residue was extracted with EtOAc (3 × 100 ml). The organics were combined, dried (Na ₂ SO ₄ ) and concentrated in vacuo to afford a cloudy brown oil which was purified by chromatography on basic alumina eluting with EtOAc. The title compound was obtained as a brown solid (210 mg, 28%) and partly cloudy with benzyl alcohol.
List item 69
6-amino-2- (2-phenylethyl) quinoline
The title compound was prepared from a 6-amino-2- (2-phenylethenyl) quinoline (D68) as a yellow oil partially clouded with benzene alcohol using a procedure similar to that described in Item 20 (41%).
List item 70
2- (3-nitrophenoxy) pyrimidine
A stirred mixture of 3-nitrophenol (2.08 g, 15 mmol), 2-bromopyrimidine (2.38 g, 15 mmol) and anhydrous potassium carbonate (2.76 g, 20 mmol) in dry DMF was heated at 80 ° C. for 4 hours. The cold mixture was concentrated to dryness in vacuo and the residue was partitioned between CH ₂ Cl ₂ (75 ml) and water (50 ml). 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 Cl ₂ . The title compound was isolated as pale yellow powder (1.94 g, 60%).
List item 71
3- (pyrimidin-2-yloxy) aniline
Concentrated HCl (0.7 ml) was added to a stirred solution of 2- (3-nitrophenoxy) pyrimidine (D70, 0.65 g, 3 mmoles) and tin (II) chloride (2.28 g, 12 mmoles) in methanol (30 ml). The mixture was heated at reflux for 2 h, cooled and concentrated in vacuo to dryness. The residue was treated with CH ₂ Cl ₂ (50 ml) and water (25 ml) and 2N NaOH solution was added to adjust pH to 12. The mixture was filtered, the organic phase was separated, washed with water, dried (Na ₂ SO ₄ ) and concentrated in vacuo to dryness to afford the title compound as a yellow powder (0.50 g, 89%).
List item 72
N-methyl-4-nitro-N- (pyrimidin-2-yl) aniline
Potassium tert-butoxide (1.79 g, 16 mmol) was added to a stirred solution of N-methyl-4-nitroaniline (2.20 g, 14.5 mmol) in dry DMF (25 ml). After stirring for 1 hour at room temperature, 2-bromopyrimidine (2.30 g, 14.5 mmole) was added and the mixture was warmed at 80 ° C. for 6 hours and then stored at room temperature overnight. After concentrated to dryness in vacuo, the residue was partitioned between CH ₂ Cl ₂ (100 ml) and water (30 ml). The organic phase was washed with water, dried (Na ₂ SO ₄ ) and concentrated to dryness. The residue was triturated in diethyl ether to give the title compound as a pale yellow-orange powder (1.24 g, 37%).
List item 73
4- [N-methyl-N- (pyrimidin-2-yl) amino] aniline
N-methyl-4-nitro-N- (pyrimidin-2-yl) aniline (D72, 1.30 g, 5.6 mmole) solution in methanol (70 ml) and ethyl acetate (70 ml) was dissolved in 10% palladium on carbon (0.25 g). And oscillated for 48 hours under 1 atmosphere in the presence of hydrogen. The filtered mixture was concentrated to dryness and the residue was triturated in diethyl ether to give the title compound as a pale orange-brown powder (0.78 g, 68%).
List item 74
5- (pyridin-4-yl) naphth-1-ylamine
The title compound was prepared using 5-bromo-1-naphthylamine (JP 08151353 A2) and 4-pyridylboronic acid using a procedure similar to that described in Item 2.
List item 75
N- [5- (pyridin-4-yl) naphth-1-yl] acetamide
The title compound was prepared from 5- (pyridin-4-yl) naphth-1-ylamine (D74) in a similar manner as described in Item 44. MH ⁺ 263.
List item 76
N- [5- (1-methyl-1,2,5,6-tetrahydropyridin-4-yl) naphth-1-yl] acetamide
The title compound was prepared from N- [5- (pyridin-4-yl) naphth-1-yl] acetamide (D75) in a similar manner as described in Item 45. MH ⁺ 281.
List item 77
5- (1-methylpiperidin-4-yl) naphth-1-ylamine
The title compound was obtained from N- [5- (1-methyl-1,2,5,6-tetrahydropyridin-4-yl) naphth-1-yl] acetamide (D76) in a similar manner as described in Item 46. Prepared.
List item 78
N-2- (4-nitrophenyl) ethyl-trifluoroacetamide
A solution of trifluoroacetic anhydride (10.6 ml) in dichloromethane (100 ml) was added dropwise to a stirred solution of 2,6-lutidine (17.4 ml) and 4-nitrophenethylamine hydrochloride (15.2 g, 75 mmol) at 0 ° C. did. The mixture was stirred overnight at 25 ° C. in the presence of argon and then washed with dilute citric acid (× 2), brine and dried (Na ₂ SO ₄ ). The title compound was obtained as a pale yellow solid from the material of the organic phase (19.04 g).
List item 79
7-nitro-1,2,3,4-tetrahydro-2-trifluoroacetylisoquinoline
N-2- (4-nitrophenyl) ethyl-trifluoroacetamide (D78, 2.26 g, 9.15 mmol) in acetic acid (10 ml) and concentrated H ₂ SO ₄ (15 ml) is described in GEStokker, Tet. Lett., 1996, 37, 5453] was stirred for 20 hours at 25 ℃. Finishing gave the title compound as a white solid (2.17 g).
List item 80
7-nitro-1,2,3,4-tetrahydroisoquinoline
7-nitro-1,2,3,4-tetrahydro-2-trifluoroacetylisoquinoline (D79, 17.2 g; 63 mmole) using a solution of potassium carbonate (46.6 g) in 10% aqueous methanol (660 ml) Hydrolysis at room temperature. Finishing with dichloromethane gave the title compound (11 g).
List item 81
2-methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline
7-nitro-1,2,3,4-tetrahydroisoquinoline (D80, 2.08 g; 11.7 mmoles) is described by GM Carrera and DS Garvey, J. Het. Chem., 1992, 29, 847] were treated with 88% formic acid (3.45 ml) and 37% aqueous formaldehyde (5.88 ml) at 80 ° C. for 2 hours. An orange gum (2.3 g) was obtained by basifying first with 10% sodium hydroxide and then extracting with ethyl acetate. Chromatography on silica gel in 0-3% methanol / ethyl acetate gave the title compound as an orange solid (1.7 g). MH ⁺ 193.
List item 82
7-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline
2-Methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline (D81, 0.25 g; 1.3 mmoles) in methanol (40 ml) was hydrogenated overnight at 10% palladium on carbon (100 mg) under atmospheric pressure. . The catalyst was removed by filtration through a Keisligger pad and evaporated in vacuo to yield the title compound as a white solid (213 mg). MH ⁺ 163.
List item 83
8-bromoquinoline-2,4-dicarboxylic acid
7-Broisatin (10 g, 0.044 moles, Proc. Royal Soc., 1958, 148, 481) for 1 minute followed by pyruvic acid (5.35 ml, 0.077 moles) for 1 minute H ₂ O (64 ml). To a stirred solution of KOH (21.3 g, 0.38 mol) in water. The remaining solution was stirred at room temperature for 1 hour, then heated to reflux for 1.5 hours, cooled to room temperature, diluted with H ₂ O (100 ml) and filtered. The filtrate was acidified with concentrated hydrochloric acid until pH1 and filtered, the solid was washed with H ₂ O and dried under vacuum. The title compound was a brown solid (10.1 g, 77%).
Acid protons not found.
List item 84
8-bromoquinoline-4-carboxylic acid
A solution of 8-bromoquinoline-2,4-dicarboxylic acid (D83, 10 g, 34 mmole) in nitrobenzene (40 ml) was heated under reflux for 2 hours, then left to cool to room temperature and diluted with hexane (60 ml). The title compound was then filtered off as a brown solid (8.5 g, 100%).
Acid protons not found
List item 85
8-phenylquinoline-4-carboxylic acid
The title compound was prepared as a brown solid (63%) from 8-bromoquinoline-4-carboxylic acid (D84) and phenylboronic acid using a procedure similar to that described in Item 2.
Acid protons not found.
List Item 86
8-phenylquinolin-4-yl isocyanate
The title compound was prepared from 8-phenylquinoline-4-carboxylic acid (D85) using a procedure similar to that described in Item 1. Isocyanate was used as toluene solution without concentrating to pure compound.
List item 87
4-Amino-2-methylphenylboronic acid
A stirred solution of 4-bromo-3-methylaniline (20 g, 0.107 mol) and triethylamine (33 ml, 0.237 mol) in dichloromethane (250 ml) at 0 ° C. under argon was added bis (chlorodimethylsilyl in dichloromethane (100 ml). The solution was added dropwise over 15 minutes with a ethane (25.3 g, 0.12 mol) solution. The mixture was allowed to warm to rt and stirred for 20 h, then filtered and concentrated in vacuo. The residue was extracted with 60-80 petrol (400 ml) and the filtrate was concentrated in vacuo to leave the star base as an orange oil (35 g, 100%). It was dissolved in dry THF (400 ml) and cooled to -65 ° C. under argon and then dropwise treated with 2.5 M n-butyllithium (52 ml, 0.13 mol) in hexane over 15 minutes. The mixture was stirred at −65 ° C. for 1 hour, then treated dropwise with triisopropylborate (30 ml, 0.13 mol) over 10 minutes and stirred at −65 ° C. for an additional 1.5 hours, followed by saturated aqueous NH ₄ Cl solution (100 ml). And left to stand at room temperature. The mixture was diluted with water (200 ml), acidified with concentrated hydrochloric acid (50 ml) and stirred for 20 minutes, then concentrated in vacuo to a volume of about 400 ml. 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, the extract was dried (Na ₂ SO ₄ ) and concentrated in vacuo to precipitate a solid when the volume reached about 150 ml. The mixture was cooled to 8 ° C. and the solid was filtered off and dried to give the title compound as a white solid (9.2 g, 51%).
Acid protons not found.
List item 88
4- (2,6-dimethyl-pyridin-4-yl) -3-methylaniline
The title compound was prepared using a procedure similar to that described in Item 2, 4-chloro-2,6-dimethylpyridine (Chem. Abs. 1952, 46, 4541) and 4-amino-2-methylphenylboronic acid (D87 ) As a beige solid (4%).
Listed Items 89
3-methyl-4- (6-methyl-pyridin-2-yl) aniline
The title compound was prepared as a beige solid from 2-bromo-6-methylpyridine and 4-amino-2-methylphenylboronic acid (D87) using a procedure similar to that described in Item 2 (100%).
List item 90
5-carboxy-naphth-1-ylboronic acid
A stirred solution of 5-bromo-1-naphthoic acid (Bull. Soc. Chim. Fr., 1968, 7, 2957), 22.3 g, 0.089 mol) in dry THF (1000 ml) at -60 ° C. under argon was added with hexane. The dropwise treatment was performed with 1.6 M n-butyllithium (125 ml, 0.20 mol) in 15 minutes. Beige precipitate formed in the initial brown solution upon the addition of the first equivalent and dissolved again when the second equivalent was added. The resulting solution was stirred at −60 ° C. for 40 minutes, then triisopropylborate (51 ml, 0.22 mol) was added and the mixture was stirred at −60 ° C. for an additional 1 hour and then gradually heated to −10 ° C. NH ₄ Cl saturated aqueous solution was added (300 ml) followed by water (400 ml) followed by 5M hydrochloric acid (200 ml). The resulting mixture was concentrated in vacuo to a volume of about 1000 ml, then basified by addition of 40% NaOH solution and washed with ethyl acetate. The aqueous solution was added to excess 5M hydrochloric acid and the precipitated solid was filtered off, washed with water and dried to give a white solid (9.67 g) which contained about 50% of the title compound with 1-naphthoic acid.
List item 91
5- (6-Methyl-pyridin-2-yl) -1-naphthoic acid
The title compound was prepared as a beige solid from 2-bromo-6-methylpyridine and 5-carboxy-naphth-1-ylboronic acid (D90) using a procedure similar to that described in Item 2 (46%).
Acid protons not found.
List item 92
5- (6-methyl-pyridin-2-yl) naphth-1-yl isocyanate
The title compound was prepared from 5- (6-methyl-pyridin-2-yl) -1-naphthoic acid (D 91) using a procedure similar to that described in Item 1. The isocyanate was used in the next step as a toluene solution without isolation.
List item 93
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1-trifluoroacetyl-1H-indole
The title compound was converted from 5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole (D13) to a beige solid using a procedure similar to that described in Item 31. Prepared (96%).
List item 94
5-chloro-2,3-dihydro-6- (piperazin-1-yl) -1-trifluoroacetyl-1H-indole
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) trifluoroacetyl-1H-indole (D93, 7.0 g, in argonol 1,2-dichloroethane (200 ml) Diisopropylethylamine (3.50 ml, 20 mmol) was added followed by 1-chloroethyl chloroformate (4.35 ml, 40 mmol). After 1 h the mixture was washed with dilute NaHCO ₃ aqueous solution, dried (Na ₂ SO ₄ ) and concentrated in vacuo to yield a brown solid (8.86 g, 100%). The suspension in MeOH (200 ml) was stirred at reflux for 3 hours, then cooled and MeOH was removed in vacuo. The residue was partitioned between dilute NaHCO ₃ aqueous solution and CH ₂ Cl ₂ . CH ₂ Cl ₂ was separated and the aqueous solution was reextracted with CH ₂ Cl ₂ ( ₂ × 50 ml). The organic layer was mixed, dried (Na ₂ SO ₄ ) and concentrated in vacuo to yield the title compound as a brown solid (4.79 g, 72%).
NH not found.
List item 95
6- (4-acetylpiperazin-1-yl) -5-chloro-2,3-dihydro-1-trifluoroacetyl-1H-indole
5-chloro-2,3-dihydro-6- (piperazin-1-yl) -1-trifluoroacetyl-1H-indole (D94, 1.0 g, in ice-cold CH ₂ Cl ₂ (50 ml) 3.0 mmol) The stirred solution was treated with acetic anhydride (0.34 g, 3.3 mmol) and then warmed to room temperature. After 6 h the mixture was washed with dilute NaHCO ₃ (aq), dried (Na ₂ SO ₄ ) and concentrated in vacuo to yield the title compound as a brown solid (1.10 g, 97%).
List item 96
6- (4-acetylpiperazin-1-yl) -5-chloro-2,3-dihydro-1H-indole
The title compound was prepared in the same manner as described in Item 33 using 6- (4-acetylpiperazin-1-yl) -5-chloro-2,3-dihydro-1-trifluoroacetyl-1H-indole (D95). ) As a brown bubble (81%).
NH not found.
List item 97
5-chloro-2,3-dihydro-6- (4-ethylpiperazin-1-yl) -1H-indole
Agitated a 6- (4-acetylpiperazin-1-yl) -5-chloro-2,3-dihydro-1H-indole (D96, 0.65 g, 2.3 mmole) stirred solution in THF (30 ml) at room temperature under argon to THF. Treated with 1M borane-THF complex in (9.3ml, 9.3mmole) and heated under reflux for 5 hours. The mixture was cooled to 0 ° C. and then dropwise treated with concentrated hydrochloric acid (6 ml) in methanol (25 ml). After 30 minutes, the solution was heated to reflux for 2 hours and then concentrated in vacuo. The residue was treated with ethyl acetate (50 ml) and 2M hydrochloric acid (40 ml) and shaken well, the aqueous layer was separated, basified with K ₂ CO ₃ and extracted with dichloromethane. The extract was dried (Na ₂ SO ₄ ), concentrated in vacuo and the residue purified by chromatography on silica gel, eluting with 2-10% methanol / dichloromethane to afford the title compound as a beige solid (0.31). g, 50%).
Article item 98
6- [4- (tert-butyloxycarbonyl) piperazin-1-yl] -5-chloro-2,3-dihydro-1-trifluoroacetyl-1H-indole
The title compound was prepared using a procedure similar to that described in Item 95, using 5-chloro-2,3-dihydro-6- (piperazin-1-yl) -1-trifluoroacetyl-1H-indole (D94) and di Prepared as brown foam from -tert-butyl dicarbonate (100%).
List item 99
6- [4- (tert-butyloxycarbonyl) piperazin-1-yl] -5-chloro-2,3-dihydro-1H-indole
The title compound was purified using 6- [4- (tert-butyloxycarbonyl) piperazin-1-yl] -5-chloro-2,3-dihydro-1-trifluoro using a procedure similar to that described in Item 33. Prepared as a brown solid from acetyl-1H-indole (D98) (84%).
Article item 100
6- [4- (tert-butyloxycarbonyl) piperazin-1-yl] -5-chloro-2,3-dihydro-1- [4- (pyridin-4-yl) naphth-1-yl Aminocarbonyl] -1H-indole
The title compound was subjected to 4- (pyridin-4-yl) naphth-1-ylamine (D2) and 6- [4- (tert-butyloxycarbonyl) piperazine-1 using a procedure similar to Example 4. Prepared as a yellow / brown solid from -yl] -5-chloro-2,3-dihydro-1H-indole (D99) (67%).
List item 101
6- [4- (tert-butyloxycarbonyl) piperazin-1-yl] -5-chloro-2,3-dihydro-1- [5- (pyridin-4-yl) naphth-1-yl Aminocarbonyl] -1H-indole
The title compound was subjected to a procedure similar to Example 4 using 5- (pyridin-4-yl) naphth-1-ylamine (D74) and 6- [4- (tert-butyloxycarbonyl) piperazine-1 Prepared as a yellow / brown solid from -yl] -5-chloro-2,3-dihydro-1H-indole (D99) (74%).
List item 102
4- (pyridazin-3-yl) benzoic acid
The title compound was prepared as a brown solid (87%) from 3-chloropyridazine and 4-carboxyphenylboronic acid using a procedure similar to that described in Item 24. MS: m / z = 199 (M-H).
List item 103
4- (pyridazin-2-yl) benzoic acid
The title compound was prepared as a white solid from 2-chloropyrazine and 4-carboxyboronic acid using a procedure similar to that described in Item 24 (88%). MS: m / z = 156 (M-CO ₂ ).
List item 104
6-phenylnicotinic acid
The title compound was prepared as an off-white solid (54%) from 6-chloronicotinic acid and phenylboronic acid using a procedure similar to that described in Item 24. MS: m / z = 200 (MH ⁺ ).
List item 105
4- (6-Methyl-pyridazin-3-yl) benzoic acid
The title compound was prepared as a yellow solid from 3-chloro-6-methylpyridazine and 4-carboxyphenylboronic acid using a similar procedure as described in Item 24 (52%). MS: m / z = 213 (M-H).
List item 106
4- (4-cyano-3-methylphenyl) benzoic acid
The title compound was prepared as a white solid from 4-bromo-2-methylbenzonitrile and 4-carboxyphenylboronic acid using a procedure similar to that described in Item 24 (75%). MS: m / z = 236 (M-H).
Article item 107
4- (5-methyl-oxazol-2-yl) aniline
5-Methyl-2- (4-nitrophenyl) oxazole in THF (75 ml) (Chim. Ther. 1973, 8 (4), 437] (3.0 g, 15 mmole) and 10% palladium (0.25 on carbon) g) was stirred for 24 h under a hydrogen atmosphere. The mixture was filtered and concentrated in vacuo for drying to afford the title compound as a pale pale yellow powder (2.29 g, 89%).
List item 108
5-nitro-naphth-1-ylcarboxamide
5-nitro-naphth-1-ylcarboxylic acid (Chem. Pharm. Bull 1984, 32 (10), 3968) (3.50 g, 16 mmol) stirred solution in CH ₂ Cl ₂ (200 ml) was converted to oxalyl chloride. (2.1 ml, 24 mmol) and DMF (2 drops). The mixture was stirred at rt for 5 h. The solution was concentrated in vacuo for drying and the residue was dissolved in dry THF (200 ml). Ammonia was bubbled slowly through the solution for 0.5 h. The mixture was concentrated in vacuo for drying and the residue was softened in water and the solids were filtered off and dried in vacuo to afford the title compound as a light brown powder (3.34 g, 95%).
Article item 109
N- [1- (dimethylamino) ethylidene] -5-nitronaphth-1-ylcarboxamide
The stirring mixture of 5-nitro-naphth-1-ylcarboxamide (D108, 1.50 g, 7 mmol) and N, N-dimethylacetamide dimethylacetal (3 ml) was heated at 110 ° C. for 2 hours. The cold mixture was diluted with water (20 ml) and the precipitated solid was filtered off, washed with water and dried in vacuo to afford the title compound as a light brown powder (1.60 g, 80%).
Article item 110
3-methyl-5- (5-nitro-naphth-1-yl) -1,2,4-oxadiazole
N- [1- (dimethylamino) ethylidene] -5-nitronaphth-1-ylcarboxamide (D109, 1.55 g, 5.4 mmoles) was converted to hydroxylamine hydrochloride (0.47 g, 6.75 mmoles) and 5 M NaOH. Solution (1.35 ml, 6.75 mmol) was added to the stirred solution. The mixture was warmed to 80 ° C. for 4 h, then cooled and diluted with water (50 ml). The precipitated solid was filtered off, washed with water and dried in vacuo to leave the title compound as a pale pale yellow powder (1.11 g, 80%).
List item 111
5- (3-methyl-1,2,4-oxadiazol-5-yl) naphth-1-ylamine
The title compound was prepared as a pale yellow powder from 3-methyl-5- (5-nitro-naphth-1-yl) -1,2,4-oxadiazole (D110) using a procedure similar to that described in item 71. (54%).
List item 112
5-nitro-N-propazylnaph-1-ylcarboxamide
A stirring solution of 5-nitronaphth-1-ylcarboxylic acid (Chem. Pharm. Bull 1984, 32 (10), 3968) (1.10 g, 5 mmol) in CH ₂ Cl ₂ (50 ml) was added to oxalyl chloride ( 0.5 ml, 6 mmoles) and DMF (1 drop). After 3 hours at room temperature the mixture was concentrated in vacuo and dried. The residue was dissolved in CH ₂ Cl ₂ (30 ml), treated with triethylamine (1.4nl, 10 mmol) and then a solution of propazylamine (0.28 g, 5 mmol) in CH ₂ Cl ₂ (10 ml) was added dropwise. After stirring for 18 hours at room temperature, the mixture was washed with water, dried (Na ₂ SO ₄ ) and concentrated in vacuo to dryness. The residue was triturated with diethyl ether (0.79 g, 61%) to afford the title compound as a pale yellow powder.
List item 113
5-methyl-2- (5-nitronaphth-1-yl) oxazole
5-nitro-N-propazylnaph-1-ylcarboxamide (D112, 0.75g, 3mmole) and acetonitrile (0.04g, 0.12mmole) stirring mixture in glacial acetic acid (10ml) was heated to reflux for 4 hours. It was. The cooled mixture was concentrated in vacuo to dryness and the residue was dissolved in CH ₂ Cl ₂ , washed with aqueous K ₂ CO ₃ aqueous solution, dried (Na ₂ SO ₄ ) and concentrated in vacuo to dryness. The residue was flash chromatographed on silica gel eluting with CH ₂ Cl ₂ to afford the title compound as a yellow powder (0.50 g, 66%).
List item 114
5- (5-methyloxazol-2-yl) naphth-1-ylamine
The title compound was prepared as a yellow / green gum from 5-methyl-2- (5-nitronaphth-1-yl) oxazole (D113) using a procedure similar to that described in Item 28 (95%).
List item 115
3-methyl-4- (pyrimidin-2-yl) aniline
The title compound was prepared as a yellow solid from 2-bromopyrimidine and 4-amino-2-methylphenyl boronic acid (D87) using a procedure similar to that described in Item 2 (46%).
List item 116
3-methyl-4- (pyrimidin-5-yl) aniline
The title compound was prepared as a pale yellow solid from 5-bromopyrimidine and 4-amino-2-methylphenylboronic acid (D87) using a procedure similar to that described in Item 2 (91%).
Article item 117
2,6-dimethyl-4-iodopyridine
4-chloro-2,6-dimethylpyridine (Chem. Abs. 1952, 46, 4541) (2.6 g, 18 mmol) stirring solution in 2-butanone (250 ml) was added sodium aodide (17.6 g, 120 mmol). ) And 4-toluenesulfonic acid (3.4 g, 18 mmol) and the mixture was heated under reflux for 72 h under argon. The reaction mixture was cooled and then concentrated in vacuo and the residue was treated with water (200 ml) and extracted with ethyl acetate. The extract was washed with aqueous sodium thiosulfate solution, 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 using acetone (3.44 g, 69% ).
Article item 118
5- (2,6-dimethyl-pyridin-4-yl) -1-naphthoic acid
The title compound was prepared as a white solid from 2,6-dimethyl-4-iodopyridine (D117) and 5-carboxynaph-1-ylboronic acid (D90) using a procedure similar to that described in Item 2 (70%). ).
Acid protons not found.
Article item 119
5- (2,6-dimethyl-pyridin-4-yl) naphth-1-yl isocyanate
The title compound was prepared from 5- (2,6-dimethyl-pyridin-4-yl) -1-naphthoic acid (D118) using a procedure similar to that described in Item 1. The isocyanate was used in the next step as a toluene solution without isolation.
Article item 120
4- (2,6-dimethylpyridin-3-yl) -3-methylaniline
The title compound was prepared as a pale yellow oil from 3-bromo-2,6-dimethylpyridine (D59a) and 4-amino-2-methylphenylboronic acid (D87) using a procedure similar to that described in Item 2 (6.5%). ).
List item 121
3-methyl-4- (thiazol-2-yl) aniline
The title compound was prepared as a light yellow / brown oil from 2-bromothiazole and 4-amino-2-methylphenylboronic acid (D87) using a procedure similar to that described in Item 2 (65%).
List Item 122
5- (pyrimidin-5-yl) -1-naphthoic acid
The title compound was prepared as a beige oil from 5-bromopyrimidine and 5-carboxynaft-1-ylboronic acid (D90) using a procedure similar to that described in Item 2 (78%).
Article item 123
5- (pyrimidin-5-yl) naphth-1-yl isocyanate
The title compound was prepared from 5- (pyrimidin-5-yl) -1-naphthoic acid (D122) using a procedure similar to that described in Item 1. The isocyanate was used in the next step as a toluene solution without isolation.
Article item 124
5-acetylnaphth-1-ylamine
1-acetyl-5-nitronaphthalene (Aust. J. Chem. 1995, 48 (12), 1969), 10% Pd-C (0.20 g) and cyclohexene (10 ml) stirred solution in methanol (75 ml) Was heated under reflux for 6 h. 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 concentrated to dryness. The residue was triturated with ether / hexanes to give the title compound as a yellow / brown powder (0.52 g, 80%).
List item 125
5- (pyrimidin-2-yloxy) naphth-1-ylamine
The title compound was prepared as a light pale yellow powder from 5-hydroxynaphth-1-ylamine and 2-bromopyrimidine (58%) using a procedure similar to that described in Item 70.
Article item 126
5-cyanonaph-1-ylamine
Iron powder (0.21 g, 3.7 mmole) and ammonium chloride (0.02 g, 0.4 mmole) were added to 5-nitronaphth-1-ylcarbonitrile (D128, 0.15 g, 0.76 mmol) in ethanol (10 ml) and water (5 ml). After addition to the stirred solution, the mixture was heated at reflux for 0.5 h. The mixture was cooled slightly, filtered and concentrated in vacuo. The residue was partitioned between ethyl acetate (25 ml) and water (15 ml). The organic layer was separated, dried (Na ₂ SO ₄ ) and concentrated in vacuo to afford the title compound as a yellow / green powder (0.11 g, 85%).
Article item 127
5-nitronaphth-1-ylcarbonitrile
A trimethylsilylphosphate 2.5M solution (Synthesis, 1982, 591) in CH ₂ Cl ₂ (5 ml) was added a stirring solution of 5-nitronaphth-1-ylcarboxamide (D108, 0.20 g, 0.93 mmol) The mixture was heated to reflux for 2 hours. The cooled mixture was treated with water (10 ml) and stirred for 10 minutes, after which the organic phase was separated, washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to dryness. The residue was flash chromatographed on silica gel eluting with CH ₂ Cl ₂ to afford the title compound as a colorless powder (0.12 g, 66%).
Article item 128
5-nitronaph-1-ylamidoxim
Hydroxylamine hydrochloride (1.23 g, 1.78 mmol) was added to a solution of sodium hydroxide (0.71 g, 17.8 mmol) in methanol (100 ml). The mixture was treated with 5-nitronaphth-1-ylcarbonitrile (D127, 1.60 g, 8.1 mmole) and heated to reflux for 48 hours. The cooled mixture was evaporated to concentration to 10 ml and treated with water (50 ml). The precipitate was collected, washed with water and dried in vacuo to afford the title compound as a pale yellow powder (1.65 g, 88%).
Listed Items 129
5-methyl-3- (5-nitronaphth-1-yl) -1,2,4-oxadiazole
Acetyl chloride (0.78 ml, 11 mmol) was added dropwise to a stirring solution of 5-nitronaphth-1-ylamidosim (D128, 1.28 g, 5.5 mmol) in pyridine (10 ml). The mixture was stirred at rt for 0.5 h and then heated to reflux for 24 h. The cooled mixture was treated with water (100 ml) and extracted with ethyl acetate (3 × 25 ml). The combined organic extracts were washed with dilute HCl, water, dried (Na ₂ SO ₄ ) and concentrated to dryness. The residue was flash chromatographed on silica gel eluting with CH ₂ Cl ₂ to afford the title compound in pale yellow color (0.86 g, 61%).
List item 130
5- (5-methyl-1,2,4-oxadiazol-3-yl) naphth-1-ylamine
The title compound was prepared as a brown gum following the procedure described in entry item 126. This was converted to its hydrochloride salt to get gray flour.

Example 1
1-[(4-bromo-3-methylphenyl) aminocarbonyl] -5-methoxy-6- (4-methylpiperazin-1-yl) indole
Potassium t-butoxide (59 mg, 0.50 mmole) of 5-methoxy-6- (4-methylpiperazin-1-yl) indole (130 mg, 0.50 mmole, WO 95/06637) in dry THF (10 ml) under argon Was added to intermediate 2) and the mixture was stirred for 15 minutes. To this was added a solution of 4-bromo-3-methylphenyl isocyanate (D1, 127 mg, 0.60 mmol) in dry THF (10 ml). The residual mixture was stirred at rt under argon for 16 h and then concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 0-6% MeOH / CH ₂ Cl ₂ to afford the title compound as a pale yellow solid (108 mg, 45%).
Example 2
1-[(4-bromo-3-methylphenyl) aminocarbonyl] -2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) indole
2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1H-indole (0.10 g, 0.40 mmol, Intermediate 3 of WO 95/06627) in dichloromethane (10 ml) Was added to 4-bromo-3-methylphenyl isocyanate (D1, 0.11 g, 0.50 mmol) in dichloromethane (10 ml). The mixture was stirred at rt for 17 h and then concentrated in vacuo to give a dark yellow oil. The oil was stirred with diethyl ether and then the solid was filtered off and dried to afford the title compound as a yellow solid (0.17 g, 92%).
Example 3
1-[(2,3-dichlorophenyl) aminocarbonyl] -2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1H-indole
The title compound was prepared using 2,3-dichlorophenyl isocyanate and 2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1H-indole ( From intermediate 3) of WO 95/06627.
Example 4
2,3-hydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H- Indole
Ar and CH ₂ Cl ₂ (10ml) of the binary tree Force 4- (pyridin-4-yl) naphth-1-yl amine in (84mg, 0.28mmole) was added to _{CH 2 Cl 2 (10ml) (} D2, 196mg , 0.89 mmole) and NEt ₃ (90 mg, 0.89 mmole) dropwise over 30 minutes. After the addition was completed, the mixture was stirred at room temperature for 15 minutes and then 2,3-dihydro-5-methoxy-6- (4-methylpyrazin-1-yl) -1H-indole in CH ₂ Cl ₂ (10 ml). (Intermediate 3 of WO 95/06627, 200 mg, 0.81 mmole) was added. After 6 hours, the mixture was washed with 10% Na ₂ CO ₃ (aq), dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a cloudy green oil which was eluted with 2-5% MeOH / CH ₂ Cl ₂ with silica gel. Purify by chromatography on. The title compound was obtained as a beige solid (292 mg, 73%).
Example 5
2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1- [5- (4-pyridine) naphth-1-ylaminocarbonyl] -1H-indole
The title compound was purified using a procedure similar to Example 2 using 5- (pyridin-4-yl) naphth-1-yl isocyanate (D4) and 2,3-dihydro-5-methoxy-6- (4- Methylpiperazin-1-yl) -1H-indole (Intermediate 3 of WO 95/06627).
Example 6
1- [2,3-dichloro-4- (pyridin-4-yl) phenylaminocarbonyl] -2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl)- 1H-indole
The title compound was prepared in a similar manner to Example 4 using 2,3-dichloro-4- (pyridin-4-yl) aniline (D7) and 2,3-dihydro-5-methoxy-6- (4- Prepared as an orange / brown solid from methylpiperazin-1-yl) -1H-indole (Intermediate 3 of WO 95/06627) (54%).
Example 7
2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1- (quinolin-5-ylaminocarbonyl) -1H-indole
The title compound was purified using 5-aminoquinoline and 2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1H-indole (WO 95) using a procedure similar to Example 4. / 06627 intermediate 3).
Example 8
2,3-dihydro- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H-indole
The title compound was prepared in a similar manner to Example 4 using 4- (pyridin-4-yl) naphth-1-ylamine (D2) and 2,3-dihydro-6- (4-methylpiperazin-1 Prepared as a beige solid from -yl) -1H-indole (D11) (50%).
Example 9
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H- Indole
The title compound was prepared in a similar manner to Example 4 using 4- (pyridin-4-yl) naphth-1-ylamine (D2) and 5-chloro-2,3-dihydro-6- (4-methyl Prepared from piperazin-1-yl) -1H-indole (D13) (38%). This was converted to its hydrochloride salt as a yellow solid using acetone.
Example 10
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H Indol
The title compound was purified using 2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1 using a procedure similar to that described in Item 14. Prepared as a beige solid from -ylaminocarbonyl] -1H-indole (E8) and benzyltrimethylammonium tribromide (86%). This material was converted to its hydrochloride salt as a yellow solid using acetone.
Example 11
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) phenylaminocarbonyl] -1H-indole
The title compound was purified using 4- (pyridin-4-yl) aniline (D5) and 5-bromo-2,3-dihydro-6- (4-methylpiperazin-1- using a similar procedure as in Example 4. Prepared as a white solid from I) -1H-indole (D15) (24%).
Example 12
5-bromo-1- [3-chloro-4- (pyridin-4-yl) phenylaminocarbonyl] -2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H- Indole
The title compound was purified using 3-chloro-4- (pyridin-4-yl) aniline (D6) and 5-bromo-2,3-dihydro-6- (4-methylpipepe using a similar procedure to Example 4. Prepared as a white solid from razin-1-yl) -1H-indole (D15) (13%).
Example 13
2,3-dihydro-5-methyl-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H- Indole
The title compound was prepared using a procedure similar to Example 4 using 4- (pyridin-4-yl) naphth-1-ylamine (D2) and 2,3-dihydro-5-methyl-6- (4-methyl Prepared from piperazin-1-yl) -1H-indole (D17) (52%). This material was converted to its hydrochloride salt as a yellow solid using acetone.
Example 14
1- [3-chloro-4- (pyridin-4-yl) phenylaminocarbonyl] -2,3-dihydro-5-methyl-6- (4-methylpiperazin-1-yl) -1H-indole
The title compound was purified using 3-chloro-4- (pyridin-4-yl) aniline (D6) and 2,3-dihydro-5-methyl-6- (4-methylpiperazin using a similar procedure as in Example 4. Prepared as a white solid from -1-yl) -1H-indole (D17) (67%).
Example 15
2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -5-vinyl-1H- Indole
The title compound was prepared in a similar manner to Example 4 using 4- (pyridin-4-yl) naphth-1-ylamine (D2) and 2,3-dihydro-6- (4-methylpiperazin-1 Prepared from -yl) -5-vinyl-1H-indole (D19) (50%). This material was converted to its hydrochloride salt as a yellow solid using acetone.
Example 16
2,3-dihydro-5-ethyl-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H- Indole
The title compound was prepared in a similar manner to Example 4 using 4- (pyridin-4-yl) naphth-1-ylamine (D2) and 2,3-dihydro-5-ethyl-6- (4-methyl Prepared as a beige solid from piperazin-1-yl) -1H-indole (D21) (43%). This material was converted to its hydrochloride salt as a yellow solid using acetone.
Example 17
1- [3-chloro-4- (pyridin-4-yl) phenylaminocarbonyl] -2,3-dihydro-5-ethyl-6- (4-methylpiperazin-1-yl) -1H-indole
The title compound was purified using 3-chloro-4- (pyridin-4-yl) aniline (D6) and 2,3-dihydro-5-ethyl-6- (4-methylpiperazin using a similar procedure to Example 4. Prepared as a white solid from -1-yl) -1H-indole (D21) (33%).
Example 18
2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -5-trifluoromethyl -1H-indole
The title compound was prepared in a similar manner to Example 4 using 4- (pyridin-4-yl) naphth-1-ylamine (D2) and 2,3-dihydro-6- (4-methylpiperazin-1 Prepared as a beige solid from -yl) -5-trifluoromethyl-1H-indole (D23) (42%). This material was converted to its hydrochloride salt as a yellow solid using acetone.
Example 19
1- [3-chloro-4- (pyridin-4-yl) phenylaminocarbonyl] -2,3-dihydro-6- (4-methylpiperazin-1-yl) -5-trifluoromethyl- 1H-indole
The title compound was purified using 3-chloro-4- (pyridin-4-yl) aniline (D6) and 2,3-dihydro-6- (4-methylpiperazin-1-yl using a similar procedure as in Example 4. Prepared as a beige solid from) -5-trifluoromethyl-1H-indole (D23) (17%).
Example 20
2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylacetyl] -1H-indole
Oxalyl chloride (206 mg, 1.6 mmol) followed by one drop of DMF (4- (pyridin-4-yl) naphth-1-ylacetic acid (D24, 213 mg, 0.81 mmol) stirred suspension in CH ₂ Cl ₂ (30 ml) Added to. After 2 hours, the solvent and excess oxalylchloride were removed in vacuo to give the acid chloride as a pale yellow solid. This CH ₂ Cl ₂ (15ml) 2,3- dihydro-5-methoxy-dissolved in the presence of argon at 0 ℃ over 10 minutes, CH ₂ Cl ₂ (15ml) to the 6- (4-methylpiperazin-l- 1-day) -1H-indole (intermediate 3 of WO 95/06627, 200 mg, 0.81 mmole) and NEt ₃ (164 mg, 1.6 mmole) were added in portions. After 30 minutes at 0 ° C., the mixture was stirred at room temperature for 5 hours, then washed with 10% Na ₂ CO ₃ (aq), dried (Na ₂ SO ₄ ) and concentrated in vacuo. The turbid green / brown oil was purified by chromatography on silica eluting with 2-5% MeCH / CH ₂ Cl ₂ to afford the title compound as a yellow solid (340 mg, 85%).
Example 21
2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1- [5- (pyridin-4-yl) naphth-1-ylacetyl] -1H-indole
The title compound was prepared in a similar manner to Example 20 using 5- (pyridin-4-yl) naphth-1-ylacetic acid (D25) and 2,3-dihydro-5-methoxy-6- (4- Prepared from methylpiperazin-1-yl) -1H-indole (Intermediate 3 of WO 95/06627).
Example 22
2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylacetyl] -1H-indole
The title compound was purified using 4- (pyridin-4-yl) naphth-1-ylacetic acid (D24) and 2,3-dihydro-6- (4-methylpiperazin-1 using a procedure similar to Example 20. Prepared as a beige solid formed from ethyl acetate from -yl) -1H-indole (D11) (72%).
Example 23
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylacetyl] -1H-indole
The title compound was prepared using a procedure similar to Example 20 using 4- (pyridin-4-yl) naphth-1-ylacetic acid (D24) and 5-chloro-2,3-dihydro-6- (4-methyl Prepared as a yellow oil from piperazin-1-yl) -1H-indole (D13) (50%). This material was converted to its hydrochloride salt as a beige solid formed from ethyl acetate.
Example 24
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naph-1-ylacetyl] -1H-indole
The title compound was purified using 2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1 using a procedure similar to that described in Item 14. Prepared from -ylacetyl] -1H-indole (E22) and benzyltrimethylammonium tribromide (62%). This material was converted from ethyl acetate to its hydrochloride salt as a beige solid.
Example 25
2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylacetyl] -5-vinyl-1H-indole
The title compound was subjected to 4- (pyridin-4-yl) naphth-1-ylacetic acid (D24) and 2,3-dihydro-6- (4-methylpiperazin-1 using a procedure similar to Example 20. Prepared from -yl) -5-vinyl-1H-indole (D19) (45%). This material was converted from acetone / ethyl acetate to its hydrochloride salt as a white solid.
Example 26
5-bromo-2,3-dihydro-6- (1-methylpiperazin-4-yl) -1- [4- (pyridin-4-yl) naph-1-ylacetyl] -1H-indole
The title compound was prepared using a procedure similar to that of Example 4, using 4- (pyridin-4-yl) naphth-1-ylamine (D2) and 5-bromo-2,3-dihydro-6- (1- Prepared from methylpiperidin-4-yl) -1H-indole (D39) (11%).
Example 27
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [5- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H- Indole
The title compound was purified using a procedure similar to Example 2 5- (pyridin-4-yl) naphth-1-yl isocyanate (D4) and 5-chloro-2,3-dihydro-6- (4-methyl Prepared from piperazin-1-yl) -1H-indole (D13).
Example 28
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [5- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H Indol
The title compound was prepared using a procedure similar to Example 2, using 5- (pyridin-4-yl) naphth-1-yl isocyanate (D4) and 5-bromo-2,3-dihydro-6- (4- Prepared from methylpiperazin-1-yl) -1H-indole (D15).
Example 29
2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1- (quinolin-6-ylaminocarbonyl) -1H-indole
The title compound was subjected to quinolin-6-yl isocyanate (D26) and 2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1H using a procedure similar to Example 2. Prepared from indole (Intermediate 3 of WO 95/06627).
Example 30
1- [4- (t-butoxycarbonylamino) phenylaminocarbonyl] -5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole
The title compound was purified using 4- (t-butoxycarbonylamino) aniline (D40) and 5-chloro-2,3-dihydro-6- (4-methylpiperazin-1 using a similar procedure as in Example 4. Prepared from -yl) -1H-indole (D13) (29%).
Example 31
5-Bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- (quinolin-6-ylaminocarbonyl) -1H-indole
The title compound was subjected to quinolin-6-yl isocyanate (D26) and 5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H using a procedure similar to Example 2. Prepared from indole (D15).
Example 32
6-bromo-2,3-dihydro-7- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1 , 2,3,4-tetrahydroquinoline
The title compound was prepared in a similar manner to Example 4 using 4- (pyridin-4-yl) naphth-1-ylamine (D2) and 6-bromo-7- (4-methylpiperazin-1-yl ), 1,2,3,4-tetrahydroquinoline (D33).
Example 33
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- (4-phenoxyphenylaminocarbonyl) -1H-indole
The title compound was prepared using a procedure similar to that of Example 2, using 5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole (D13) and 4-phenoxyphenyl Prepared from isocyanates.
Example 34
5-chloro-1- [4- (4-chlorophenoxy) phenylaminocarbonyl] -2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole
The title compound was prepared using a procedure similar to that of Example 4, using 5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole (D13) and 4- (4- From chlorophenoxy) aniline.
Example 35
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- (quinolin-6-ylaminocarbonyl) -1H-indole
The title compound was prepared using a procedure similar to that of Example 2, using quinolin-6-yl isocyanate (D26) and 5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H- Prepared from indole (D13).
Example 36
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- (3-phenoxyphenylaminocarbonyl) -1H-indole
The title compound was prepared using a procedure similar to that of Example 4, using 5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole (D13) and 3-phenoxyaniline Prepared from.
Example 37
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyrimidin-2-yl) phenylaminocarbonyl] -1H-indole
The title compound was prepared using a procedure similar to that of Example 2, using 5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole (D13) and 4- (pyrimidine). Prepared as a pale milky powder from -2-yl) phenyl isocyanate (D42) (69%).
Example 38
1- (3-benzoylphenylaminocarbonyl) -5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole
The title compound was prepared using a procedure similar to Example 4 using 3-aminobenzophenone and 5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole (D13). Prepared from.
Example 39
1- (4-benzoylphenylaminocarbonyl) -5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole
The title compound was prepared in the same manner as in Example 4 using 4-aminobenzophenone and 5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole (D13) Prepared from.
Example 40
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- (2-methylquinolin-6-ylaminocarbonyl) -1H-indole
The title compound was purified using 6-amino-2-methylquinoline and 5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole using a procedure similar to that of Example 4. Prepared from (D13).
Example 41
5-chloro-2,3-dihydro-1- [4- (per-2-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole
The title compound obtained as a light pale yellow powder was obtained from 5-chloro-2,3-dihydro-1- (4-iodophenylaminocarbonyl) -6- (4-methylpiperazin-1-yl) -1H- Prepared from indole (D43) and 2-furylboronic acid (64%).
2 × CH ₂ signal not found by DMSO signal.
Example 42
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (thien-2-yl) phenylaminocarbonyl] -1H-indole
The title compound obtained as a pale milky powder was subjected to 5-chloro-2,3-dihydro-1- (4-iodophenylaminocarbonyl) -6- (4-methylpiperazin in a similar manner as described in Item 2. Prepared from -1-yl) -1H-indole (D43) and 2-thienylboronic acid (56%).
Example 43
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [5- (pyridin-4-yl) naphth-1-ylacetyl] -1H-indole
The title compound was prepared in a similar manner to Example 20 using 5- (pyridin-4-yl) naphth-1-ylacetic acid (D25) and 5-chloro-2,3-dihydro-6- (4-methyl Prepare from piperazin-1-yl) -1H-indole (D13).
Example 44
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [5- (pyridin-4-yl) naphth-1-ylacetyl] -1H-indole
The title compound was prepared using a procedure similar to Example 20, using 5- (pyridin-4-yl) naphth-1-ylacetic acid (D25) and 5-bromo-2,3-dihydro-6- (4- Prepared from methylpiperazin-1-yl) -1H-indole (D15).
Example 45
5-chloro-2,3-dihydro-1- [4- (1-methylpiperidin-4-yl) naphth-1-ylaminocarbonyl] -6- (4-methylpiperazin-1- 1) -1H-indole
The title compound was prepared in a similar manner to Example 4 using 4- (1-methylpiperidin-4-yl) naphth-1-ylamine (D46) and 5-chloro-2,3-dihydro-6 Prepared from-(4-methylpiperazin-1-yl) -1H-indole (D13).
Example 46
5-chloro-2,3-dihydro-1- [4- (2-methylloxazol-4-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H- Indole
The title compound was prepared using a procedure similar to that of Example 4, using 4- (4-aminophenyl) -2-methyloxazole (D47) and 5-chloro-2,3-dihydro-6- (4-methylpiperazin Prepared as a pale yellow powder from -1-yl) -1H-indole (D13) (67%).
2 × CH ₂ signal not found by H ₂ O signal.
Example 47
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (2-methylpyridin-4-yl) phenylaminocarbonyl] -1H-indole
The title compound was prepared using a procedure similar to that of Example 4, using 4- (2-methylpyridin-4-yl) aniline (D49) and 5-bromo-2,3-dihydro-6- (4-methylpiperazin Prepared as a white solid from -1-yl) -1H-indole (D15) (48%).
Example 48
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (2-methylpyridin-4-yl) phenylaminocarbonyl] -1H-indole
The title compound was prepared using a procedure similar to that of Example 4, using 4- (2-methylpyridin-4-yl) aniline (D49) and 5-chloro-2,3-dihydro-6- (4-methylpiperazin- Prepared as a beige solid from 1-yl) -1H-indole (D13) (79%).
Example 49
5-chloro-2,3-dihydro-1- [4- (2,6-dimethylpyridin-4-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H- Indole
The title compound was prepared in a similar manner to Example 2 using 4- (2,6-dimethylpyridin-4-yl) phenyl isocyanate (D62) and 5-chloro-2,3-dihydro-6- (4-methyl Prepared as a white solid (55%) from piperazin-1-yl) -1H-indole (D13).
Example 50
5-bromo-2,3-dihydro-1- [4- (2,6-dimethylpyridin-4-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H Indol
The title compound was prepared in a similar manner to Example 2 using 4- (2,6-dimethylpyridin-4-yl) phenyl isocyanate (D62) and 5-bromo-2,3-dihydro-6- (4- Prepared as a white solid (36%) from methylpiperazin-1-yl) -1H-indole (D15).
Example 51
2,3-dihydro-1- [4- (2,6-dimethylpyridin-4-yl) phenylaminocarbonyl] -5-methoxy-6- (4-methylpiperazin-1-yl) -1H Indol
The title compound was prepared in a similar manner to Example 2 using 4- (2,6-dimethylpyridin-4-yl) phenyl isocyanate (D62) and 2,3-dihydro-5-methoxy-6- (4- Prepared as a beige solid from methylpiperazin-1-yl) indole (Intermediate 3 of WO 95/06627) (28%).
Example 52
5-chloro-2,3-dihydro-1- [4- (2,6-dimethylpyridin-3-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H- Indole
The title compound was prepared in a similar manner to Example 2 using 4- (2,6-dimethylpyridin-3-yl) phenyl isocyanate (D63) and 5-chloro-2,3-dihydro-6- (4-methyl Prepared as a white solid from piperazin-1-yl) -1H-indole (D13) (21%).
Example 53
5-bromo-2,3-dihydro-1- [4- (2,6-dimethylpyridin-3-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H Indol
The title compound was prepared in a similar manner to Example 2 using 4- (2,6-dimethylpyridin-3-yl) phenyl isocyanate (D63) and 5-bromo-2,3-dihydro-6- (4- Prepared as a white solid (44%) from methylpiperazin-1-yl) -1H-indole (D15).
Example 54
2,3-dihydro-1- [4- (2,6-dimethylpyridin-3-yl) phenylaminocarbonyl] -5-methoxy-6- (4-methylpiperazin-1-yl) -1H Indol
The title compound was prepared in a similar manner to Example 2 using 4- (2,6-dimethylpyridin-3-yl) phenyl isocyanate (D63) and 2,3-dihydro-5-methoxy-6- (4- Prepared as a beige solid from methylpiperazin-1-yl) -1H-indole (Intermediate 3 of WO 95/06627) (17%).
Example 55
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl Aminocarbonyl] -1H-indole
The title compound was prepared in a similar manner to Example 4 using 4- (5-methyl-1,2,4-oxadiazol-3-yl) aniline (Ger. Offen DE 2046928) and 5-chloro-2, Prepared from 3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole (D13). The product was isolated as a pale milky powder (44%).
Example 56
5-chloro-2,3-dihydro-1- [4- (3-methyl-1,2,4-oxadiazol-5-yl) phenylaminocarbonyl] -6- (4-methylpiperazin- 1-day) -1H-indole
The title compound was prepared in a similar manner to Example 4 with 4- (3-methyl-1,2,4-oxadiazol-5-yl) aniline (J. Het. Chem. 1980, 17 (6), 1273 -5]) and 5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole (D13) as a white powder (0.13 g, 48%).
NH protons not found.
Example 57
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [3- (pyrimidin-2-yloxy) phenylaminocarbonyl] -1H-indole
The title compound was prepared in a similar manner to Example 4 using 3- (pyrimidin-2-yloxy) aniline (D71) and 5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl ) -1H-indole (D13). The product was isolated as a light pale yellow powder (32%).
Example 58
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- {4- [N-methyl-N- (pyrimidin-2-yl) amino] phenylaminocar Carbonyl} -1H-indole
The title compound was prepared in a similar manner to Example 4 using 4- [N-methyl-N- (pyrimidin-2-yl) amino] aniline (D73) and 5-chloro-2,3-dihydro-6- (4 -Methylpiperazin-1-yl) -1H-indole (D13). The product was isolated as a pale milky powder (54%).
Example 59
5-bromo-2,3-dihydro-1- [4- (per-2-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole
The title compound is referred to as 4- (per-2-yl) aniline (Synthesis 1976, 1, 40) and 5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl ) -1H-indole (D15). The title compound was isolated as milky flour (38%).
Example 60
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (thien-3-yl) phenylaminocarbonyl] -1H-indole
The title compound obtained as a milky powder was prepared by 5-chloro-2,3-dihydro-1- (4-iodophenylaminocarbonyl) -6- (4-methylpiperazin- Prepared from 1-day) -1H-indole (D43) (31%).
Example 61
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (thiazol-2-yl) phenylaminocarbonyl] -1H-indole
The title compound was purified using 4- (thiazol-2-yl) aniline (D52) and 5-bromo-2,3-dihydro-6- (4-methylpiperazin-1 using a similar procedure as in Example 4. Prepared from -yl) -1H-indole (D15) (19%).
Example 62
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (thiazol-2-yl) phenylaminocarbonyl] -1H-indole
The title compound was purified by 5-chloro-2,3-dihydro-1- (4-iodophenylaminocarbonyl) -6- (4-methylpiperazin-1-yl) -1H using a procedure similar to D51. Prepared from indole (D43) and 2-bromothiazole (8%).
Example 63
1- [4- (5-acetylthien-2-yl) phenylaminocarbonyl] -5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole
The title compound obtained as a pale yellow solid was subjected to 5-chloro-2,3-dihydro-1- (4-iodophenylaminocarbonyl) -6- (4-methylpiperazin-1 in a similar manner as described in Item 2. Prepared from -yl) -1H-indole (D43) and 5-acetylthien-2-ylboronic acid (42%).
Urea NH not found.
Example 64
1- (5-bromonaft-1-ylacetyl) -5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole
The title compound was purified using 5-bromonaft-1-ylacetic acid (Bull. Soc. Chim. Fr. 1968, 7, 2957) and 5-chloro-2,3- using a similar method as in Example 20. Prepared with light yellow foam from dihydro-6- (4-methylpiperazin-1-yl) -1H-indole (D13) (62%).
Example 65
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- (8-phenylquinolin-5-ylaminocarbonyl) -1H-indole
The title compound was purified using 5-amino-8-phenylquinoline (D66) and 5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl)-using a procedure similar to that of Example 4. Prepared as a milky solid from 1H-indole (D13) (40%).
Example 66
5-Bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- (8-phenylquinolin-5-ylaminocarbonyl) -1H-indole
The title compound was purified using 5-amino-8-phenylquinolin (D66) and 5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) using procedures similar to those of Example 4. Prepared as a milky solid from -1H-indole (D15) (25%).
Example 67
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [2- (2-phenylethyl) quinolin-6-ylaminocarbonyl] -1H-indole
The title compound was purified using 6-amino-2- (2-phenylethyl) quinoline (D69) and 5-chloro-2,3-dihydro-6- (4-methylpiperazin- Prepared as a white solid from 1-yl) -1H-indole (D13) (77%).
Example 68
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [5- (1-methylpiperidin-4-yl) naphth-1-ylaminocarbox Carbonyl] -1H-indole
The title compound was prepared using a procedure similar to Example 4 using 5- (1-methylpiperidin-4-yl) naphth-1-ylamine (D77) and 5-chloro-2,3-dihydro-6 Prepared as a white solid from-(4-methylpiperazin-1-yl) -1H-indole (D13) (15%).
Example 69
5-bromo-2,3-dihydro-1- [4- (isoquinolin-4-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole
The title compound was prepared using a procedure similar to that of Example 2. 4- (isoquinolin-4-yl) phenyl isocyanate (D54) and 5-bromo-2,3-dihydro-6- (4-methylpiperazin- Prepared as a white solid from 1-yl) -1H-indole (D15) (24%).
Example 70
5-chloro-2,3-dihydro-1- [4- (isoquinolin-4-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole
The title compound was prepared using a procedure similar to that of Example 2. 4- (isoquinolin-4-yl) phenyl isocyanate (D54) and 5-chloro-2,3-dihydro-6- (4-methylpiperazin-1 Prepared as a white solid from -yl) -1H-indole (D13) (25%).
Example 71
5-Bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (quinolin-3-yl) phenylaminocarbonyl] -1H-indole
The title compound was prepared in a similar manner to Example 2 using 4- (quinolin-3-yl) phenyl isocyanate (D56) and 5-bromo-2,3-dihydro-6- (4-methylpiperazin-1 Prepared as an off-white solid from -yl) -1H-indole (D15) (6%).
Example 72
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (quinolin-3-yl) phenylaminocarbonyl] -1H-indole
The title compound was prepared in a similar manner to Example 2 using 4- (quinolin-3-yl) phenyl isocyanate (D56) and 5-chloro-2,3-dihydro-6- (4-methylpiperazin-1- Prepared as a light beige solid from I) -1H-indole (D13) (10%).
Example 73
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) Aminocarbonyl] -1H-indole
The title compound was purified using 7-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline (D78) and 5-chloro-2,3-dihydro-6- using a procedure similar to that of Example 4. Prepared as an off-white solid from (4-methylpiperazin-1-yl) -1H-indole (D13) (23%).
Example 74
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl Aminocarbonyl] -1 H-indole
The title compound was purified using 7-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline (D78) and 5-bromo-2,3-dihydro-6 using a procedure similar to Example 4. Prepared as an off-white solid from-(4-methylpiperazin-1-yl) -1H-indole (D13) (41%).
Example 75
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (quinolin-8-yl) phenylaminocarbonyl] -1H-indole
The title compound was prepared in a similar manner to Example 2 using 4- (quinolin-8-yl) phenyl isocyanate (D58) and 5-bromo-2,3-dihydro-6- (4-methylpiperazin-1 Prepared as a white solid from -yl) -1H-indole (D15) (52%).
Example 76
5-chloro-6- (4-methylpiperazin-1-yl) -1- [4- (quinolin-8-yl) phenylaminocarbonyl] -1H-indole
The title compound was prepared in a similar manner to Example 2 using 4- (quinolin-8-yl) phenyl isocyanate (D58) and 5-chloro-2,3-dihydro-6- (4-methylpiperazin-1- Prepared as a white solid from I) -1H-indole (D13) (71%).
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 a similar manner to Example 4 with 4- (imidazol-1-yl) aniline (J. Med. Chem. 1988. 31 (11), 2136) and 5-chloro-2,3- Prepared from dihydro-6- (4-methylpiperazin-1-yl) -1H-indole (D13). The product was isolated as a pale milky powder (42%).
Example 78
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) phenylaminocarbonyl] -1H-indole
The title compound was prepared using a procedure similar to that described in Item 2, using 5-chloro-2,3-dihydro-1- [4-iodophenylaminocarbonyl] -6- (4-methylpiperazin-1-yl). -1H-indole (D43) and 4-pyridylboronic acid (Med. Chem. 1997, 40 (22), 3542). The product was isolated as a pale yellow solid (46%).
4H not detected by DMSO signal.
Example 79
2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1-[(8-phenylquinolin-5-yl) aminocarbonyl] -1H-indole
The title compound was prepared using a procedure similar to that of Example 4, using 5-amino-8-phenylquinolin (D66) and 2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) Prepared as a yellow / brown oil from -1H-indole (Intermediate 3 of WO 95/06627) (20%). This was converted to HCl salt as a yellow solid using acetone.
Example 80
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1-[(8-phenylquinolin-4-yl) aminocarbonyl] -1H-indole
The title compound was purified using 8-phenylquinolin-4-yl isocyanate (D86) and 5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) using a procedure similar to that of Example 2. Prepared as a yellow solid from -1H-indole (D13) (75%).
Example 81
5-Bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1-[(8-phenylquinolin-4-yl) aminocarbonyl] -1H-indole
The title compound was subjected to 8-phenylquinolin-4-yl isocyanate (D86) and 5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl using a similar procedure as in Example 2. Prepared as a yellow solid from) -1H-indole (D15) (75%).
Example 82
2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1-[(8-phenylquinolin-4-yl) aminocarbonyl] -1H-indole
The title compound was subjected to 8-phenylquinolin-4-yl isocyanate (D86) and 2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl using a similar procedure as in Example 2. Prepared as a beige oil from) -1H-indole (Intermediate 3 of WO 95/06627) (73%).
Example 83
5-chloro-1- [4- (2,6-dimethylpyridin-4-yl) -3-methylphenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole
The title compound was converted to 4- (2,6-dimethylpyridin-4-yl) -3-methylaniline (D88) and 5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl Prepared as a pale yellow solid from) -1H-indole (D13) (41%).
Example 84
5-chloro-2,3-dihydro-1- [3-methyl-4- (6-methylpyridin-2-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl)- 1H-indole
The title compound was prepared using a procedure similar to Example 4 using 3-methyl-4- (6-methylpyridin-2-yl) aniline (D89) and 5-chloro-2,3-dihydro-6- (4- Prepared as a pale yellow gum from methylpiperazin-1-yl) -1H-indole (D13) (86%). This was converted to its hydrochloride salt as a pale yellow solid using acetone.
Example 85
5-bromo-2,3-dihydro-1- [3-methyl-4- (6-methylpyridin-2-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole
The title compound was prepared using a procedure similar to Example 4 using 3-methyl-4- (6-methylpyridin-2-yl) aniline (D89) and 5-bromo-2,3-dihydro-6- (4 Prepared as a yellow bubble from -methylpiperazin-1-yl) -1H-indole (D15) (67%). This was converted to its hydrochloride salt as a beige solid using acetone.
Example 86
2,3-dihydro-5-methoxy-1- [3-methyl-4- (6-methylpyridin-2-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole
The title compound was prepared using a procedure similar to Example 4 using 3-methyl-4- (6-methylpyridin-2-yl) aniline (D89) and 2,3-dihydro-5-methoxy-6- (4 Prepared as pale yellow bubbles from -methylpiperazin-1-yl) -1H-indole (Intermediate 3 of WO 95/06627) (84%). This was converted to its hydrochloride salt as a pale yellow solid using acetone.
Example 87
5-chloro-2,3-dihydro-1- [5- (6-methylpyridin-2-yl) naphth-1-ylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole
The title compound was purified using a procedure similar to Example 4 using 5- (6-methylpyridin-2-yl) naphth-1-yl isocyanate (D92) and 5-chloro-2,3-dihydro-6- ( Prepared as a pale yellow solid from 4-methylpiperazin-1-yl) -1H-indole (D13) (59%). This was converted to its hydrochloride salt as a pale yellow solid using acetone.
Example 88
2,3-dihydro-5-methoxy-1- [5- (6-methylpyridin-2-yl) naphth-1-ylaminocarbonyl] -6- (4-methylpiperazin-1-yl ) -1H-indole
The title compound was purified using a procedure similar to Example 4 using 5- (6-methylpyridin-2-yl) naphth-1-yl isocyanate (D92) and 2,3-dihydro-5-methoxy-6- Prepared as a pale yellow gas from (4-methylpiperazin-1-yl) -1H-indole (Intermediate 3 of WO 95/06627) (55%). This was converted to its hydrochloride salt as a pale yellow solid using acetone.
Example 89
5-chloro-2,3-dihydro-6- (4-ethylpiperazin-1-yl) -1-[(4-pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H- Indole
The title compound was prepared in a similar manner to Example 4 using 4- (pyridin-4-yl) naphth-1-ylamine (D2) and 5-chloro-2,3-dihydro-6- (4-ethyl Prepared as a beige solid from piperazin-1-yl) -1H-indole (D97) (60%). HCl salt was isolated as a yellow solid using acetone.
Example 90
5-chloro-2,3-dihydro-6- (4-ethylpiperazin-1-yl) -1- [5- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H- Indole
The title compound was prepared in a similar manner to Example 4 using 5- (pyridin-4-yl) naphth-1-ylamine (D74) and 5-chloro-2,3-dihydro-6- (4-ethyl Prepared as a beige solid from piperazin-1-yl) -1H-indole (D97) (68%). HCl salt was isolated as a yellow solid using acetone.
Example 91
5-chloro-2,3-dihydro-6- (piperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H-indole hydrochloride
6- [4- (tert-butyloxycarbonyl) piperazin-1-yl] -5-chloro-2,3-dihydro-1- [4- (pyridin-4-yl) in methanol (30 ml) A FT-1-ylaminocarbonyl] -1 H-indole (D100, 345 mg, 0.59 mmole) stirred solution was treated with 1 M HCl in ether (3 ml). After 18 h additional HCl in ether (2.5 ml) was added at room temperature. After 24 hours, the mixture was concentrated in vacuo and the residue was triturated with acetone to solidify to give the title compound as a yellow solid (260 mg, 84%).
Example 92
5-chloro-2,3-dihydro-6- (piperazin-1-yl) -1- [5- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H-indole hydrochloride
The title compound was purified using 6- [4- (tert-butyloxycarbonyl) piperazin-1-yl] -5-chloro-2,3-dihydro-1- [5- using a similar procedure as in Example 91. Prepared as a beige solid from (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H-indole (D100) (60%).
Example 93
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridazin-3-yl) phenylaminocarbonyl] -1H-indole
5-Chloro-2,3-dihydro-6- (4-methylpiperazin-) after forming its isocyanate from 4- (pyridazin-3-yl) benzoic acid (D102) using a procedure similar to that described in item 1 1-yl) -1H-indole (D13) was added to afford the title compound urea as a pale yellow solid (7%).
Example 94
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridazin-3-yl) phenylaminocarbonyl] -1H-indole
5-Bromo-2,3-dihydro-6- (4-methylpiperazin after formation of its isocyanate from 4- (pyridazin-3-yl) benzoic acid (D102) using a procedure similar to that described in Item 1 -1-yl) -1H-indole (D15) was added to give the title compound as a gray solid urea (3%).
Example 95
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyrazin-2-yl) phenylaminocarbonyl] -1H-indole
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1) after the formation of its isocyanate from 4- (pyrazin-2-yl) benzoic acid (D103) using a procedure similar to that described in item 1 -Yl) -1H-indole (D13) was added to afford the title compound as a light yellow solid urea (30%).
Example 96
5-Bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyrazin-2-yl) phenylaminocarbonyl] -1H-indole
5-Bromo-2,3-dihydro-6- (4-methylpiperazin- after forming its isocyanate from 4- (pyrazin-2-yl) benzoic acid (D103) using a procedure similar to that described in item 1 1-yl) -1H-indole (D15) was added to afford the title compound as a yellow solid urea (49%).
Example 97
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1-[(2-phenylpyridin-5-yl) aminocarbonyl] -1H-indole
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H- after forming its isocyanate from 6-phenylnicotinic acid (D104) using a procedure similar to that described in item 1 Indole (D15) was added to afford the title compound as a white solid urea (48%).
Example 98
5-Bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1-[(2-phenylpyridin-5-yl) aminocarbonyl] -1H-indole
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H after forming its isocyanate from 6-phenylnicotinic acid (D104) using a procedure similar to that described in item 1 -Indole (D15) was added to afford the title compound as an off-white solid urea (46%).
Example 99
5-chloro-2,3-dihydro-1- [4- (6-methylpyridazin-3-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole
5-Chloro-2,3-dihydro-6- (4-methyl) after forming its isocyanate from 4- (6-methylpyridazin-3-yl) benzoic acid (D102) using a procedure similar to that described in Item 1 Piperazin-1-yl) -1H-indole (D13) was added to afford the title compound as a pale yellow solid urea (23%).
Example 100
5-bromo-2,3-dihydro-1- [4- (6-methylpyridazin-3-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H- Indole
5-bromo-2,3-dihydro-6- (4- after forming its isocyanate from 4- (6-methylpyridazin-3-yl) benzoic acid (D102) using a procedure similar to that described in item 1 Methylpiperazin-1-yl) -1H-indole (D15) was added to afford the title compound as a pale yellow solid urea (28%).
Example 101
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-3-yl) phenylaminocarbonyl] -1H-indole
The title compound obtained as a pale milky powder was prepared by 5-chloro-2,3-dihydro-1- (4-iodophenylaminocarbonyl) -6- (4-methylpiperazin in a similar manner as described in Item 2. -1-yl) -1H-indole (D43) and 3-pyridylboronic acid (Chem. Pharm. Bull, 1983, 31 (12), 4573) (19%).
2 × CH ₂ signal not found by DMSO signal.
Example 102
5-chloro-2,3-dihydro-1- [4- (5-methyloxazol-2-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole
The title compound obtained as a pale milky powder was obtained using a method similar to that of Example 4, using 5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole (D13). ) And 4- (5-methyloxazol-2-yl) aniline (D107) (63%).
Example 103
2,3-dihydro-5-methoxy-1- [4- (5-methyloxazol-2-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H- Indole
The title compound obtained as a pale milky powder was treated with 2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1H-indole ( Intermediate 3) and 4- (5-methyloxazol-2-yl) aniline (D107) of WO 95/06627 (44%).
Example 104
5-bromo-2,3-dihydro-1- [4- (5-methyloxazol-2-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H- Indole
The title compound obtained as a pale milky powder was purified using 5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole ( D15) and 4- (5-methyloxazol-2-yl) aniline (D107) (23%).
Example 105
5-chloro-2,3-dihydro-1- [4- (1-methylpyrazol-4-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole
5-Bromo-2,3-dihydro-6- after forming its isocyanate from 4- (1-methylpyrazol-4-yl) benzoic acid (WO 97/43262) using a procedure similar to that described in Item 1 (4-methylpiperazin-1-yl) -1H-indole (D13) was added to afford the title compound as a pale yellow solid urea (18%).
Example 106
5-bromo-2,3-dihydro-1- [4- (1-methylpyrazol-4-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H- Indole
5-Bromo-2,3-dihydro-6- after forming its isocyanate from 4- (1-methylpyrazol-4-yl) benzoic acid (WO 97/43262) using a procedure similar to that described in Item 1 (4-Methylpiperazin-1-yl) -1H-indole (D15) was added to afford the title compound as a pale yellow solid urea (30%).
Example 107
5-chloro-1- [4'-cyano-3'-methylbiphenyl-4-aminocarbonyl] -2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H- Indole
5-Chloro-2,3-dihydro-6- (4-methylpipe) after forming a isocyanate thereof from 4- (4-cyano-3-methylphenyl) benzoic acid (D106) using a procedure similar to that described in Item 1 Razin-1-yl) -1H-indole (D13) was added to afford the title compound as a gray solid urea (39%).
Example 108
5-bromo-1- [4'-cyano-3'-methylbiphenyl-4-aminocarbonyl] -2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H Indol
5-Bromo-2,3-dihydro-6- (4-methyl) after forming its isocyanate from 4- (4-cyano-3-methylphenyl) benzoic acid (D106) using a procedure similar to that described in Item 1 Piperazin-1-yl) -1H-indole (D15) was added to afford the title compound as a pale yellow solid urea (28%).
Example 109
5-chloro-2,3-dihydro-1- [4- (2-methylpyridin-5-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole
A procedure similar to that described in Item 1 was used to form its isocyanate from 4- (2-methylpyridin-5-yl) benzoic acid (WO 97/43262), followed by 5-chloro-2,3-dihydro-6- (4 -Methylpiperazin-1-yl) -1H-indole (D13) was added to afford the title compound as a pale yellow solid urea (2%).
Example 110
5-bromo-2,3-dihydro-1- [4- (2-methylpyridin-5-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole
A procedure similar to that described in Item 1 was used to form its isocyanate from 4- (2-methylpyridin-5-yl) benzoic acid (WO 97/43262), followed by 5-bromo-2,3-dihydro-6- ( 4-methylpiperazin-1-yl) -1H-indole (D15) was added to afford the title compound as a pale yellow solid urea (10%).
Example 111
5-chloro-2,3-dihydro-1- [5- (3-methyl-1,2,4-oxadiazol-5-yl) naphth-1-ylaminocarbonyl] -6- (4 Methylpiperazin-1-yl) -1H-indole
The title compound was prepared in a similar manner to Example 4 using 5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole (D13) and 5- (3- Prepared from methyl-1,2,4-oxadiazol-5-yl) naphth-1-ylamine (D111). The title compound was converted to the hydrochloride salt as a light pale yellow powder (59%).
Example 112
2,3-dihydro-5-methoxy-1- [5- (3-methyl-1,2,4-oxadiazol-5-yl) naphth-1-ylaminocarbonyl] -6- ( 4-methylpiperazin-1-yl) -1H-indole
The title compound was prepared in a similar manner to Example 4 using 2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1H-indole (Intermediate 3 of WO 95/06627). ) And 5- (3-methyl-1,2,4-oxadiazol-5-yl) naphth-1-ylamine (D111). The title compound was converted to the hydrochloride salt as a colorless powder (68%).
Example 113
5-bromo-2,3-dihydro-1- [5- (3-methyl-1,2,4-oxadiazol-5-yl) naphth-1-ylaminocarbonyl] -6- ( 4-methylpiperazin-1-yl) -1H-indole
The title compound was purified using 5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole (D15) and 5- (3 using a similar method as in Example 4. Prepared from -methyl-1,2,4-oxadiazol-5-yl) naphth-1-ylamine (D111). The title compound was converted to the hydrochloride salt as a light pale yellow powder (36%).
2 × CH ₂ not found by H ₂ 0 signal.
Example 114
5-chloro-2,3-dihydro-1- [5- (5-methyloxazol-2-yl) naphth-1-ylaminocarbonyl] -6- (4-methylpiperazin-1-yl ) -1H-indole
The title compound was purified in a similar manner to Example 4 using 5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole (D13) and 5- (5-methyloxa Zol-2-yl) naphth-1-ylamine (D114), which was converted to the hydrochloride salt as a pale yellow powder (41%).
CH ₃ signal not detected by DMSO signal.
Example 115
2,3-dihydro-5-methoxy-1- [5- (5-methyloxazol-2-yl) naphth-1-ylaminocarbonyl] -6- (4-methylpiperazin-1- 1) -1H-indole
The title compound obtained as a hydrochloride salt as a pale yellow powder was prepared in the same manner as in Example 4 using 2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1H-indole (Intermediate 3 of WO 95/06627) and 5- (5-methyloxazol-2-yl) naphth-1-ylamine (D114) (56%).
Example 116
5-bromo-2,3-dihydro-1- [3-methyl-4- (pyrimidin-2-yl) naphth-1-ylaminocarbonyl] -6- (4-methylpiperazin-1 -Work) -1H-indole
The title compound was purified using 3-methyl-4- (pyrimidin-2-yl) aniline (D115) and 5-bromo-2,3-dihydro-6- (4-methyl using a similar method as in Example 4. Prepared as beige bubbles from piperazin-1-yl) -1H-indole (D15) (34%). This bubble was converted to its hydrochloride salt as a yellow solid using acetone.
Example 117
2,3-dihydro-5-methoxy-1- [3-methyl-4- (pyrimidin-2-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H Indol
The title compound was purified using 3-methyl-4- (pyrimidin-2-yl) aniline (D115) and 2,3-dihydro-5-methoxy-6- (4-methyl using a similar method as in Example 4. Prepared as beige foam from piperazin-1-yl) -1H-indole (Intermediate 3 of WO 95/06627) (32%). This bubble was converted to its hydrochloride salt as a tan powder using acetone.
Example 118
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [3-methyl-4- (pyrimidin-2-yl) phenylaminocarbonyl] -1H- Indole
The title compound was purified using 3-methyl-4- (pyrimidin-2-yl) aniline (D115) and 5-chloro-2,3-dihydro-6- (4-methylpipepe using a similar method as in Example 4. Prepared as beige bubbles from razin-1-yl) -1H-indole (D13) (47%). This bubble was converted to its hydrochloride salt as a yellow solid using acetone.
Example 119
5-bromo-2,3-dihydro-1- [3-methyl-4- (pyrimidin-5-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H Indol
The title compound was purified using 3-methyl-4- (pyrimidin-5-yl) aniline (D116) and 5-bromo-2,3-dihydro-6- (4-methyl using a similar method as in Example 4. Prepared from foam (82%) from piperazin-1-yl) -1H-indole (D15). This bubble was converted to its hydrochloride salt as an off-white solid using acetone.
Example 120
5-chloro-2,3-dihydro-1- [3-methyl-4- (pyrimidin-5-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H- Indole
The title compound was purified using 3-methyl-4- (pyrimidin-5-yl) aniline (D116) and 5-chloro-2,3-dihydro-6- (4-methylpipepe using a similar method as in Example 4. Prepared as bubbles from razin-1-yl) -1H-indole (D15) (84%). This bubble was converted to its hydrochloride salt as an off-white solid using acetone.
Example 121
2,3-dihydro-5-methoxy-1- [3-methyl-4- (pyrimidin-5-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H Indol
The title compound was purified using 3-methyl-4- (pyrimidin-5-yl) aniline (D116) and 2,3-dihydro-5-methoxy-6- (4-methyl using a similar method as in Example 4. Prepared from foam (97%) from piperazin-1-yl) -1H-indole (Intermediate 3 of WO 95/06627). This bubble was converted to its hydrochloride salt as an off-white solid using acetone.
Example 122
5-bromo-2,3-dihydro-1- [4- (2,6-dimethylpyridin-4-yl) -3-methylphenylaminocarbonyl] -6- (4-methylpiperazin-1-yl ) -1H-indole
The title compound was prepared using a procedure similar to that of Example 4, using 4- (2,6-dimethylpyridin-4-yl) -3-methylaniline (D88) and 5-bromo-2,3-dihydro-6- Prepared as a pale yellow bubble from (4-methylpiperazin-1-yl) -1H-indole (D15) (89%). This was converted to its hydrochloride salt as a pale yellow solid using acetone.
Example 123
2,3-dihydro-5-methoxy-1- [4- (2,6-dimethylpyridin-4-yl) -3-methylphenylaminocarbonyl] -6- (4-methylpiperazin-1-yl ) -1H-indole
The title compound was prepared using a procedure similar to that of Example 4, using 4- (2,6-dimethylpyridin-4-yl) -3-methylaniline (D88) and 2,3-dihydro-5-methoxy-6- Prepared as a pale yellow bubble from (4-methylpiperazin-1-yl) -1H-indole (Intermediate 3 of WO 95/06627) (95%). This was converted to its hydrochloride salt as a yellow solid using acetone.
Example 124
5-chloro-2,3-dihydro-1- [5- (2,6-dimethylpyridin-4-yl) naphth-1-ylaminocarbonyl] -6- (4-methylpiperazin-1- 1) -1H-indole
The title compound was purified using a procedure similar to Example 4 using 5- (2,6-dimethylpyridin-4-yl) naphth-1-yl isocyanate (D119) and 5-chloro-2,3-dihydro-6 Prepared as a white bubble from-(4-methylpiperazin-1-yl) -1H-indole (D13) (83%). This was converted to its hydrochloride salt as a white solid using acetone.
Example 125
5-bromo-2,3-dihydro-1- [5- (2,6-dimethylpyridin-4-yl) naphth-1-ylaminocarbonyl] -6- (4-methylpiperazin-1 -Day) -indolin
The title compound was prepared using a procedure similar to that of Example 4. 5- (2,6-dimethylpyridin-4-yl) -1-naphthyl isocyanate (D119) and 5-bromo-6- (4-methylpiperazin Prepared as white bubbles from -1-yl) -1H-indole (D15) (64%). This was converted to its hydrochloride salt as a white solid using acetone.
Example 126
1- [5- (2,6-dimethyl-4-pyridyl) -1-naphthylaminocarbonyl] -5-methoxy-6- (4-methylpiperazin-1-yl) -1H-indole
The title compound was purified using a procedure similar to Example 4 using 5- (2,6-dimethylpyridin-4-yl) naphth-1-yl isocyanate (D119) and 2,3-dihydro-5-methoxy- Prepared as a colorless oil from 6- (4-methylpiperazin-1-yl) -1H-indole (Intermediate 3 of WO 95/06627) (88%). This was converted to its hydrochloride salt as a pale yellow solid using acetone.
Example 127
2,3-dihydro-1- [4- (2,6-dimethylpyridin-3-yl) -3-methylphenylaminocarbonyl] -5-methoxy-6- (4-methylpiperazin-1-yl ) -1H-indole
The title compound was prepared using a procedure similar to that of Example 4, using 4- (2,6-dimethylpyridin-3-yl) -3-methylaniline (D120) and 2,3-dihydro-5-methoxy-6- Prepared as a pale yellow oil from (4-methylpiperazin-1-yl) -1H-indole (Intermediate 3 of WO 95/06627) (44%). This was converted to its hydrochloride salt as an orange solid using acetone.
Example 128
5-bromo-2,3-dihydro-1- [3-methyl-4- (thiazol-2-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H Indol
The title compound was prepared using a procedure similar to Example 4 using 3-methyl-4- (thiazol-2-yl) aniline (D121) and 5-bromo-2,3-dihydro-6- (4-methyl Prepared from foam (64%) from piperazin-1-yl) -1H-indole (D15). This was converted to its hydrochloride salt as a yellow solid using acetone.
Example 129
5-chloro-2,3-dihydro-1- [3-methyl-4- (thiazol-2-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H- Indole
The title compound was prepared using a procedure similar to Example 4 using 3-methyl-4- (thiazol-2-yl) aniline (D121) and 5-chloro-2,3-dihydro-6- (4-methylpipepe Prepared as beige bubbles from razin-1-yl) -1H-indole (D13) (70%). This was converted to its hydrochloride salt as a yellow solid using acetone.
Example 130
2,3-dihydro-5-methoxy-1- [3-methyl-4- (thiazol-2-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H Indol
The title compound was prepared using a procedure similar to Example 4 using 3-methyl-4- (thiazol-2-yl) aniline (D121) and 2,3-dihydro-5-methoxy-6- (4-methyl Prepared as a light yellow oil from piperazin-1-yl) -1H-indole (Intermediate 3 of WO 95/06627) (68%). This was converted to its hydrochloride salt as a yellow solid using acetone.
Example 131
1- (5-acetylnaphth-1-ylaminocarbonyl) -5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole
The title compound was purified using 5-acetylnaphth-1-ylamine (D124) and 5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) using procedures similar to those of Example 4. ) -1H-indole (D13). This was converted to its hydrochloride salt as a pale yellow powder (60%).
Example 132
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [5- (pyrimidin-2-yloxy) naphth-1-ylaminocarbonyl]- 1H-indole
The title compound was prepared in a similar manner to Example 4 using 5- (pyrimidin-2-yloxy) naphth-1-ylamine (D125) and 5-chloro-2,3-dihydro-6- (4 Prepared from -methylpiperazin-1-yl) -1H-indole (D13). This was converted to its hydrochloride salt as a pale milky powder (61%).
Example 133
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [5- (pyrimidin-5-yl) naphth-1-ylaminocarbonyl] -1H Indol
The title compound was purified using a procedure similar to Example 2 using 5- (pyrimidin-5-yl) naphth-1-yl isocyanate (D123) and 5-chloro-2,3-dihydro-6- (4- Prepared as white foam from methylpiperazin-1-yl) -1H-indole (D13) (43%). This was converted to its hydrochloride salt as a white solid using acetone.
Example 134
2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1- [5- (pyrimidin-5-yl) naphth-1-ylaminocarbonyl]- 1H-indole
The title compound was purified using a procedure similar to Example 2 using 5- (pyrimidin-5-yl) naphth-1-yl isocyanate (D123) and 2,3-dihydro-5-methoxy-6- (4 Prepared as white foam from -methylpiperazin-1-yl) -1H-indole (Intermediate 3 of WO 95/06627) (50%). This was converted to its hydrochloride salt as a white solid using acetone.
Example 135
5-chloro-1- (5-cyanonaph-1-ylaminocarbonyl) -2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole
The title compound was purified using 5-cyanonaph-1-ylamine (D126) and 5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl using a procedure similar to that of Example 4. ) -1H-indole (D13). This was converted to its hydrochloride salt as a milky powder (81%).
Example 136
5-chloro-2,3-dihydro-1- [5- (5-methyl-1,2,4-oxadiazol-3-yl) naphth-1-ylaminocarbonyl] -6- (4 Methylpiperazin-1-yl) -1H-indole
The title compound was prepared using a procedure similar to that of Example 4. 5- (5-methyl-1,2,4-oxadiazol-3-yl) naphth-1-ylamine (D130) and 5-chloro-2 Prepared from, 3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole (D13). This was converted to its hydrochloride salt as a pale yellow powder (84%).
2H signal not found due to H ₂ O signal.
Pharmacological data
5-HT _1A , 5-HT _1B and 5-HT _1D Receptor Binding
HEK 293 cells expressing 5-HT _1A receptor (4 × 10 ⁷ / ml) were homogenized in Tris buffer and stored in 1 ml aliquots. CHO cells expressing 5-HT _1B receptor (4 × 10 ⁷ cells / ml) were homogenized in Tris buffer and stored in 1.5 ml aliquots. CHO cells expressing 5-HT _1D receptor (0.563 × 10 ⁸ / ml) were homogenized in Tris buffer and stored in 1 ml aliquots.
0.4 ml of cell suspension was added to [ ³ H] -5HT (4 nM) for 5-HT _{1B / 1D} receptor and [ ³ H] -8-OH DPAT for 5-HT _1A receptor in Tris Mg HCl buffer (pH7.7). (1 nM) and the experimental drug were incubated together at 37 ° C. for 45 minutes. Each experimental drug was tested at 10 concentrations (0.01 mM to final concentration 0.3 nM), while limiting non-specific binding using 0.01 mM 5-HT. Total assay volume is 0.5 ml. Incubation was stopped by rapid filtration using Packard Filtermate (pre-soaked filter in 0.3% polyethyleneimine) and radioactivity was measured by Topcount scintillation counting. pKi values were measured from IC ₅₀ shown by an iterative least square curve fitting program.
Examples 5, 9, 10, 15, 21, 24, 25, 27, 28, 43, 44, 45, 47, 48, 49, 50, 52, 53, 67, 68, 69, 70, 71, 72, 76, 78, 80, 81, 82, 83, 89, 97, 98 and 110 had pKi values greater than 8.0 at the 5-HT _1A , 5-HT _1B and 5-HT _1D receptors.

权利要求:
Claims (12)
[1" claim-type="Currently amended] Compounds of formula (I) or salts thereof.
<Formula I>

Wherein R ^a is a group having formula (Ia), or
<Formula I-a>

Wherein P ¹ is selected from phenyl, bicyclic aryl, oxygen, nitrogen and sulfur
5-7 membered heterocyclic containing 1 to 3 heteroatoms selected
Ring or 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur
A bicyclic heterocyclic ring comprising;
R ¹ is hydrogen, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, COC _1-6 alkyl, C _1-6 alkoxy,
Hydroxy, hydroxyC _1-6 alkyl, hydroxyC _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkoxy,
Acyl, nitro, trifluoromethyl, cyano, SR ⁹ , SOR ⁹ , SO ₂ R ⁹ ,
SO ₂ NR ¹⁰ R ¹¹ , CO ₂ R ¹⁰ , CONR ¹⁰ R ¹¹ , CO ₂ NR ¹⁰ R ¹¹ , CONR ¹⁰ (CH ₂ ) _c CO ₂ R ¹¹ , (CH ₂ ) _c NR ¹⁰ R ¹¹ ,
(CH ₂ ) _c CONR ¹⁰ R ¹¹ , (CH ₂ ) _c NR ¹⁰ COR ¹¹ , (CH ₂ ) _c CO ₂ C _1-6 alkyl, CO ₂ (CH ₂ ) _c OR ¹⁰ , NR ¹⁰ R ¹¹ ,
NR ¹⁰ CO ₂ R ¹¹ , NR ¹⁰ CONR ¹⁰ R ¹¹ , CR ¹⁰ = NOR ¹¹ , NR ¹⁰ COOR ¹¹ , CNR ¹⁰ = NOR ¹¹ , where
R ¹⁰ and R ¹¹ are each hydrogen or C _1-6 alkyl and c is 1-4;
R ² is hydrogen, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkenyl,
C _1-6 alkoxy, C _1-6 alkanoyl, aryl, acyloxy, hydroxy, nitro,
Trifluoromethyl, cyano, CO₂R¹⁰, CONR¹⁰R¹¹, NR¹⁰R¹¹Where R is¹⁰And
R ¹¹ is as defined for R ¹ ;
a is 1, 2 or 3);
Or R ^a is a group of formula (ii)
<Formula I-b>

Wherein P ² and P ³ are each phenyl, bicyclic aryl, oxygen, nitrogen and
5- to 7-membered having 1 to 3 heteroatoms selected from sulfur
Heterocyclic ring or 1 to 1 selected from oxygen, nitrogen or sulfur
Bicyclic heterocyclic groups containing three heteroatoms;
A is a bond or oxygen, S (O) _m where m is 0 to 2, carbonyl, CH ₂ ,
-CH ₂ -CH _2- , or NR ⁴ , wherein R ⁴ is hydrogen or C _1-6 alkyl;
R ¹ is as defined in formula (I) or R ¹ is oxygen, nitrogen or
Optionally substituted comprising 1 to 3 heteroatoms selected from sulfur
5 to 7-membered heterocyclic ring;
R ² and R ³ are each hydrogen, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cyclo
Alkenyl, C _1-6 alkoxy, C _1-6 alkanoyl, aryl, acyloxy, hydroxy, nitro,
Trifluoromethyl, cyano, CO ₂ R ¹⁰ , CONR ¹⁰ R ¹¹ , NR ¹⁰ R ¹¹ , wherein R ¹⁰
And R ¹¹ is as defined for R ¹ ;
a and b are 1, 2 or 3, respectively;
Y is -NH-, -NR ^5- , wherein R ⁵ is C _1-6 alkyl or Y is -CH ₂ -or -O-;
V is oxygen or sulfur;
D is nitrogen, carbon or CH group; W is (CR ¹⁶ R ¹⁷ ) _t (where t is 2, 3 or 4 and R ¹⁶ and R ¹⁷ are each hydrogen or C _1-6 alkyl) W is (CR ¹⁶ R ¹⁷ ) _u -J ( Wherein u is 0, 1, 2 or 3 and J is oxygen, sulfur, CR ¹⁶ = CR ¹⁷ , CR ¹⁶ = N, = CR ¹⁶ O, = CR ¹⁶ S or = CR ¹⁶ -NR ¹⁷ ); X is nitrogen or carbon;
R ^b is C _3-7 cycloalkyl optionally substituted by hydrogen, halogen, hydroxy, C _1-6 alkyl, trifluoromethyl, C _1-6 alkoxy, C _2-6 alkenyl, C _1-4 alkyl Or aryl;
R ^c is hydrogen or C _1-6 alkyl;
Is a single bond when X is nitrogen or a single or double bond when X is carbon.
[2" claim-type="Currently amended] The compound of claim 1, wherein R ¹ is a halogen atom.
[3" claim-type="Currently amended] The compound of claim 1 or 2, wherein R ² and / or R ³ are each hydrogen, halogen or a C _1-6 alkyl group.
[4" claim-type="Currently amended] The compound of any one of claims 1-3, wherein P ¹ and P ² are phenyl, naphthyl or quinolinyl.
[5" claim-type="Currently amended] The compound of any one of claims 1-4 wherein Y is -NH-.
[6" claim-type="Currently amended] 6. The compound of claim 1, wherein D is nitrogen and W is of the formula
Compounds having a group of-(CH ₂ ) _2- .
[7" claim-type="Currently amended] The compound of any one of claims _1-6 , wherein R ^b is a C _1-6 alkyl group.
[8" claim-type="Currently amended] 8. A compound according to any one of claims 1 to 7, wherein X is nitrogen.
[9" claim-type="Currently amended] The method of claim 1,
1-[(4-bromo-3-methylphenyl) aminocarbonyl] -5-methoxy-6- (4-methylpiperazin-1-yl) -1H-indole,
1-[(4-bromo-3-methylphenyl) aminocarbonyl] -2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1H-indole,
1-[(2,3-dichlorophenyl) aminocarbonyl] -2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1H-indole,
2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H Indol,
2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1- [5- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H Indol,
1- [2,3-dichloro-4- (pyridin-4-yl) phenylaminocarbonyl] -2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl)- 1H-Indole,
2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1- (quinolin-5-ylaminocarbonyl) -1H-indole,
2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H- Indol,
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H Indol,
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) phenylaminocarbonyl] -1H-indole,
5-bromo-1- [3-chloro-4- (pyridin-4-yl) phenylaminocarbonyl] -2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H- Indol,
2,3-dihydro-5-methyl-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H- Indol,
1- [3-chloro-4- (pyridin-4-yl) phenylaminocarbonyl] -2,3-dihydro-5-methyl-6- (4-methylpiperazin-1-yl) -1H-indole ,
2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -5-vinyl-1H- Indol,
2,3-dihydro-5-ethyl-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H- Indol,
1- [3-chloro-4- (pyridin-4-yl) phenylaminocarbonyl] -2,3-dihydro-5-ethyl-6- (4-methylpiperazin-1-yl) -1H-indole ,
2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -5-trifluoromethyl -1H-indole,
1- [3-chloro-4- (pyridin-4-yl) phenylaminocarbonyl] -2,3-dihydro-6- (4-methylpiperazin-1-yl) -5-trifluoromethyl- 1H-Indole,
2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylacetyl] -1H-indole ,
2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1- [5- (pyridin-4-yl) naphth-1-ylacetyl] -1H-indole ,
2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylacetyl] -1-indole
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylacetyl] -1H-indole,
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naph-1-ylacetyl] -1H-indole ,
2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylacetyl] -5-vinyl-1H-indole,
5-Bromo-2,3-dihydro-6- (1-methylpiperidin-4-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl]- 1H-Indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [5- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H- Indol,
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [5- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H Indol,
2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1- (quinolin-6-ylaminocarbonyl) -1H-indole,
2,3-dihydro-1- [4- (t-butoxycarbonylamino) phenylaminocarbonyl] -5-chloro-6- (4-methylpiperazin-1-yl) -1H-indole,
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- (quinolin-6-ylaminocarbonyl) -1H-indole,
6-bromo-7- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1,2,3,4- Tetrahydroquinoline,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- (4-phenoxyphenylaminocarbonyl) -1H-indole,
5-chloro-2,3-dihydro-1- [4- (4-chlorophenoxy) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- (quinolin-6-ylaminocarbonyl) -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- (3-phenoxyphenylaminocarbonyl) -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyrimidin-2-yl) phenylaminocarbonyl] -1H-indole,
1- (3-benzoylphenylaminocarbonyl) -5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole,
1- (4-benzoylphenylaminocarbonyl) -5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- (2-methylquinolin-6-ylaminocarbonyl) -1H-indole,
5-chloro-2,3-dihydro-1- [4- (per-2-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (thien-2-yl) phenylaminocarbonyl] -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [5- (pyridin-2-yl) naphth-1-ylacetyl] -1H-indole,
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [5- (pyridin-4-yl) naphth-1-ylacetyl] -1H-indole ,
5-chloro-2,3-dihydro-1- [4- (1-methylpiperidin-4-yl) naphth-1-ylaminocarbonyl] -6- (4-methylpiperazin-1- 1) -1H-indole,
5-chloro-2,3-dihydro-1- [4- (2-methyloxazol-4-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole ,
5-Bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (2-methylpyridin-4-yl) phenylamino-carbonyl] -1 H- Indol,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (2-methylpyridin-4-yl) phenylaminocarbonyl] -1H-indole,
5-chloro-2,3-dihydro-1- [4- (2,6-dimethylpyridin-4-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H- Indol,
5-bromo-2,3-dihydro-1- [4- (2,6-dimethylpyridin-4-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H Indol,
2,3-dihydro-1- [4- (2,6-dimethylpyridin-4-yl) phenylaminocarbonyl] -5-methoxy-6- (4-methylpiperazin-1-yl) -1H Indol,
5-chloro-2,3-dihydro-1- [4- (2,6-dimethylpyridin-3-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H- Indol,
5-bromo-2,3-dihydro-1- [4- (2,6-dimethylpyridin-3-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H Indol,
2,3-dihydro-1- [4- (2,6-dimethylpyridin-3-yl) phenylaminocarbonyl] -5-methoxy-6- (4-methylpiperazin-1-yl) -1H Indol,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl Aminocarbonyl] -1 H-indole,
5-chloro-2,3-dihydro-1- [4- (3-methyl-1,2,4-oxadiazol-5-yl) phenylaminocarbonyl] -6- (4-methylpiperazin- 1-day) -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [3- (pyrimidin-2-yloxy) phenylaminocarbonyl] -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- {4- [N-methyl-N- (pyrimidin-2-yl) amino] phenylaminocar Carbonyl} -1H-indole,
5-bromo-2,3-dihydro-1- [4- (per-2-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (thien-3-yl) phenylaminocarbonyl] -1H-indole,
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (thiazol-2-yl) phenylaminocarbonyl] -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (thiazol-2-yl) phenylaminocarbonyl] -1H-indole,
1- [4- (5-acetylthien-2-yl) phenylaminocarbonyl] -5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole,
1- (5-bromonaft-1-ylacetyl) -5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- (8-phenylquinolin-5-ylaminocarbonyl) -1H-indole,
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- (8-phenylquinolin-5-ylaminocarbonyl) -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [2- (2-phenylethyl) quinolin-6-ylaminocarbonyl] -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [5- (1-methylpiperidin-4-yl) naphth-1-ylaminocarbox Carbonyl] -1H-indole,
5-bromo-2,3-dihydro-1- [4- (isoquinolin-4-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole,
5-chloro-2,3-dihydro-1- [4- (isoquinolin-4-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole,
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (quinolin-3-yl) phenylaminocarbonyl] -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (quinolin-3-yl) phenylaminocarbonyl] -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) Aminocarbonyl] -1 H-indole,
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl ) Aminocarbonyl] -1 H-indole,
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (quinolin-8-yl) phenylaminocarbonyl] -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (quinolin-8-yl) phenylaminocarbonyl] -1H-indole,
5-chloro-2,3-dihydro-1- [4- (imidazol-1-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-4-yl) phenylaminocarbonyl] -1H-indole,
2,3-dihydro-5-methoxy-6- (4-methylpiperazin-1-yl) -1-[(8-phenylquinolin-5-yl) aminocarbonyl] -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1-[(8-phenylquinolin-4-yl) aminocarbonyl] -1H-indole,
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1-[(8-phenylquinolin-4-yl) aminocarbonyl] -1H-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-yl) -3-methylphenylaminocarbonyl] -6- (4-methylpiperazin-1-yl ) -1H-indole,
5-chloro-2,3-dihydro-1- [3-methyl-4- (6-methylpyridin-2-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl)- 1H-Indole,
5-bromo-2,3-dihydro-1- [3-methyl-4- (6-methylpyridin-2-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole,
2,3-dihydro-5-methoxy-1- [3-methyl-4- (6-methylpyridin-2-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole,
5-chloro-2,3-dihydro-1- [5- (6-methylpyridin-2-yl) naphth-1-ylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole,
2,3-dihydro-5-methoxy-1- [5- (6-methylpyridin-2-yl) naphth-1-ylaminocarbonyl] -6- (4-methylpiperazin-1-yl ) -1H-indole,
5-chloro-2,3-dihydro-6- (4-ethylpiperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H- Indol,
5-chloro-2,3-dihydro-6- (4-ethylpiperazin-1-yl) -1- [5- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H- Indol,
5-chloro-2,3-dihydro-6- (piperazin-1-yl) -1- [4- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H-indole hydrochloride ,
5-chloro-2,3-dihydro-6- (piperazin-1-yl) -1- [5- (pyridin-4-yl) naphth-1-ylaminocarbonyl] -1H-indole hydrochloride ,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridazin-3-yl) phenylaminocarbonyl] -1H-indole,
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridazin-3-yl) phenylaminocarbonyl] -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyrazin-2-yl) phenylaminocarbonyl] -1H-indole,
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyrazin-2-yl) phenylaminocarbonyl] -1H-indole,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1-[(2-phenylpyridin-5-yl) aminocarbonyl] -1H-indole,
5-bromo-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1-[(2-phenylpyridin-5-yl) aminocarbonyl] -1H-indole,
5-chloro-2,3-dihydro-1- [4- (6-methylpyridazin-3-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole ,
5-bromo-2,3-dihydro-1- [4- (6-methylpyridazin-3-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H- Indol,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [4- (pyridin-3-yl) phenylaminocarbonyl] -1H-indole,
5-chloro-2,3-dihydro-1- [4- (5-methyloxazol-2-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole ,
2,3-dihydro-5-methoxy-1- [4- (5-methyloxazol-2-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H- Indol,
5-bromo-2,3-dihydro-1- [4- (5-methyloxazol-2-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H- Indol,
5-chloro-2,3-dihydro-1- [4- (1-methylpyrazol-4-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole ,
5-bromo-2,3-1- [4- (1-methylpyrazol-4-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole,
5-chloro-2,3-dihydro-1- [4'-cyano-3'-methylbiphenyl-4-aminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H- Indol,
5-Bromo-2,3-dihydro-1- [4'-cyano-3'-methylbiphenyl-4-aminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H Indol,
5-chloro-2,3-dihydro-1- [4- (2-methylpyridin-5-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole,
5-bromo-2,3-dihydro-1- [4- (2-methylpyridin-5-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H-indole ,
5-chloro-2,3-dihydro-1- [5- (3-methyl-1,2,4-oxadiazol-5-yl) naphth-1-ylaminocarbonyl] -6- (4 -Methylpiperazin-1-yl) -1H-indole,
2,3-dihydro-5-methoxy-1- [5- (3-methyl-1,2,4-oxadiazol-5-yl) naphth-1-ylaminocarbonyl] -6- ( 4-methylpiperazin-1-yl) -1H-indole,
5-bromo-2,3-dihydro-1- [5- (3-methyl-1,2,4-oxadiazol-5-yl) naphth-1-ylaminocarbonyl] -6- ( 4-methylpiperazin-1-yl) -1H-indole,
5-chloro-2,3-dihydro-1- [5- (5-methyloxazol-2-yl) naphth-1-ylaminocarbonyl] -6- (4-methylpiperazin-1-yl ) -1H-indole,
2,3-dihydro-5-methoxy-1- [5- (5-methyloxazol-2-yl) naphth-1-ylaminocarbonyl] -6- (4-methylpiperazin-1- 1) -1H-indole,
5-bromo-2,3-dihydro-1- [3-methyl-4- (pyrimidin-2-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H Indol,
2,3-dihydro-5-methoxy-1- [3-methyl-4- (pyrimidin-2-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H Indol,
5-chloro-2,3-dihydro-6- (4-methylpiperazin-1-yl) -1- [3-methyl-4- (pyrimidin-2-yl) phenylaminocarbonyl] -1H- Indol,
5-bromo-2,3-dihydro-1- [3-methyl-4- (pyrimidin-5-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H Indol,
5-chloro-2,3-dihydro-1- [3-methyl-4- (pyrimidin-5-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H- Indol,
2,3-dihydro-5-methoxy-1- [3-methyl-4- (pyrimidin-5-yl) phenylaminocarbonyl] -6- (4-methylpiperazin-1-yl) -1H Indol,
5-bromo-2,3-dihydro-1- [4- (2,6-dimethylpyridin-4-yl) -3-methylphenylaminocarbonyl] -6- (4-methylpiperazin-1-yl ) -1H-indole,
2,3-dihydro-5-methoxy-1- [4- (2,6-dimethylpyridin-4-yl) -3-methylphenylaminocarbonyl] -6- (4-methylpiperazin-1-yl ) -1H-indole,
5-chloro-2,3-dihydro-1- [5- (2,6-dimethylpyridin-4-yl) naphth-1-ylaminocarbonyl] -6- (4-methylpiperazin-1- 1) -1H-indole,
5-bromo-2,3-dihydro-1- [5- (2,6-dimethylpyridin-4-yl) naphth-1-ylaminocarbonyl] -6- (4-methylpiperazin-1 -Yl) -1H-indole,
2,3-dihydro-1- [5- (2,6-dimethylpyridin-4-yl) naphth-1-ylaminocarbonyl] -5-methoxy-6- (4-methylpiperazin-1 -Yl) -1H-indole compound or a pharmaceutically acceptable salt thereof.
[10" claim-type="Currently amended] (a) a compound of formula (II), in which D is nitrogen and Y is NH in formula (I)
<Formula II>
R ^a -NC (= V), where R ^a and V are as defined in formula (I)
Or a protective derivative thereof and a compound of formula (III)
<Formula III>

Wherein W, X, R ^b and R ^c are as defined in formula (I)
Or a protective derivative thereof
(b) when D is nitrogen in formula (I) and Y is NH or NR ⁵ , a compound of formula (IV) with a suitable urea former
<Formula IV>
R ^a -NH ₂ or R ^a -NR ⁵ H, wherein R ^a and R ⁵ are as defined in formula (I)
Reacts with a compound of formula III
(c) when D in the formula (I) is nitrogen, the compound of formula (V)
<Formula V>
R ^a -Y- (C = O) -L ² , wherein R ^a is as defined in formula (I), and Y is -CH ₂ -or
-O- and L ² is a suitable leaving group)
Reacted with a compound of formula (III),
(d) when D in formula (I) is carbon or CH, a compound of formula (VI)
<Formula VI>
R ^a -NH ₂ , where R ^a is as defined in formula (I)
Reacted with a compound of formula (VII),
<Formula VII>

Wherein D is carbon or CH and W, X, R ^b and R ^c are defined in Formula (I)
L ² is the appropriate leaving group)
Then randomly
· Remove any protector,
Converting a compound of formula (I) to another compound of formula (I),
Pharmaceutically acceptable salt formation
A process for preparing a compound of formula (I) according to claim 1 and a pharmaceutically acceptable salt thereof.
[11" claim-type="Currently amended] 10. A compound according to any one of claims 1 to 9 for use in therapy.
[12" claim-type="Currently amended] A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier.

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IL132409D0|2001-03-19|

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CA2288662A1|1998-11-12|

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JP2001524116A|2001-11-27|

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AR013076A1|2000-12-13|

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PL336317A1|2000-06-19|

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HU0001123A3|2002-04-29|

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AU7431098A|1998-11-27|

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NZ500252A|2001-07-27|

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HU0001123A2|2001-04-28|

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CO4950608A1|2000-09-01|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1997-04-18|Priority to GB9707829.9

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1997-04-18|Priority to GBGB9707829.9A

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1998-01-29|Priority to GBGB9801882.3A

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1998-01-29|Priority to GB9801882.3

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1998-04-14|Application filed by 피터 기딩스, 스미스클라인비이참피이엘시이

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2001-01-26|Publication of KR20010006487A

优先权:

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申请号 | 申请日 | 专利标题

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GB9707829.9|1997-04-18|

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GBGB9707829.9A|GB9707829D0|1997-04-18|1997-04-18|Novel compounds|

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GBGB9801882.3A|GB9801882D0|1998-01-29|1998-01-29|Novel compounds|

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GB9801882.3|1998-01-29|