WO2009030270A1 - Dihydroindole derivatives useful in parkinson's disease - Google Patents

Dihydroindole derivatives useful in parkinson's disease Download PDF

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Publication number
WO2009030270A1
WO2009030270A1 PCT/EP2007/059194 EP2007059194W WO2009030270A1 WO 2009030270 A1 WO2009030270 A1 WO 2009030270A1 EP 2007059194 W EP2007059194 W EP 2007059194W WO 2009030270 A1 WO2009030270 A1 WO 2009030270A1
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Prior art keywords
alkyl
alkylamino
formula
alkoxy
aminocarbonyl
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PCT/EP2007/059194
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French (fr)
Inventor
Tewis Bouwmeester
Paulette Greenidge
Jens M. Rick
Giorgio Rovelli
Thomas J. Troxler
Kaspar Zimmermann
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Novartis Ag
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Priority to PCT/EP2007/059194 priority Critical patent/WO2009030270A1/en
Publication of WO2009030270A1 publication Critical patent/WO2009030270A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to novel heterocyclic compounds, to their preparation, to their use as medicaments and to medicaments comprising them.
  • the invention relates to a compound of the formula
  • R 1 is hydrogen; halogen; amino; N-(C 1-8 )alkylamino; N,N-di-(Ci. 8 )alkylamino, in which the two (C ⁇ sjalkyl groups are the same or different; N-(Ci -8 )alkylcarbonylamino; hydroxy; (Ci -8 )alkoxy; aminocarbonyl-(C 1-8 )alkoxy; aminocarbonyloxy; mercapto; (C 1-8 )alkyl- thio; aminosulfonyl; N,N-di-(C 1 .
  • R 2 is hydrogen; halogen; amino; N-(C 1-8 )alkylamino; N,N-di-(Ci. 8 )alkylamino, in which the two (C 1-8 )alkyl groups are the same or different; N-(C 1-8 )alkylcarbonylamino; hydroxy; (d.s)alkoxy; aminocarbonyl-(C 1-8 )alkoxy; aminocarbonyloxy; mercapto; (C 1-8 )alkylthio; aminosulfonyl; N-(Ci_ 8 )alkylaminosulfonyl; N,N-di-(C 1-8 )alkylaminosulfonyl, in which the two (C 1-8 )alkyl groups are the same or different; nitro; cyano; (C-i-aJalkyl; hydroxy-(C 1-8 )alkyl; (Ci.
  • R 1 and R 2 together form, together with the carbon atoms, to which they are attached, an optionally substituted 5-, 6- or 7-membered carbocyclic or heterocyclic ring;
  • R 3 is hydrogen; halogen; hydroxy; (C 1-8 )alkoxy; aminosulfonyl; N-(C 1-8 )alkylamino- sulfonyl; N,N-di-(C 1 . 8 )alkylaminosulfonyl, in which the two (C 1 .
  • R 4 is hydrogen; halogen; hydroxy; (Ci -8 )alkoxy; aminosulfonyl; N-(C 1-8 )alkylamino- sulfonyl; N.N-dKC ⁇ alkylaminosulfonyl, in which the two (C 1-8 )alkyl groups are the same or different; (d. 8 )alkyl; or (C 3 . 8 )cycloalkyl; either R 5 is hydrogen; or (Ci -8 )alkyl; and
  • R 6 is hydrogen; carboxy; (Ci -8 )alkoxycarbonyl; (Ci -8 )alkyl; amino-(C 1 . 8 )alkyl; N-(C 1-8 )- alkylamino-(Ci -8 )alkyl; N,N-di-(C 1 .
  • R 7 is hydrogen; (C 1 . 8 )alkyl; amino-(C 1-8 )alkyl; aminocarbonyl-(C 1-8 )alkyl; or aminocarbonyl, in free form or in salt form.
  • a corresponding compound of the formula I may exist in pure optically active form or in the form of a mixture of optical isomers, e. g. in the form of a race- mic mixture. All of such pure optical isomers and all of their mixtures, including the racemic mixtures, are part of the present invention.
  • a compound of the formula I may exist in free form or in salt form, e. g. a basic compound in acid addition salt form or an acidic compound in the form of a salt with a base. All of such free compounds and salts are part of the present invention.
  • a compound of the formula I may exist in tautomeric form. All of such tautomers are part of the present invention.
  • Halogen denotes fluorine, bromine, chlorine or iodine. Any non-cyclic carbon containing group or moiety with more than 1 carbon atom is straight- chain or branched.
  • carbon containing groups, moieties or molecules contain 1 to 8, preferably 1 to 6, more preferably 1 to 4, most preferably 1 or 2, carbon atoms.
  • the invention relates to a compound of the formula I, in free form or in salt form, in which
  • R 1 is hydrogen; halogen; amino; N-(C 1 . 8 )alkylamino; N,N-di-(C 1-8 )alkylamino, in which the two (d ⁇ alkyl groups are the same or different; N-(C 1 . 8 )alkylcarbonylamino; hydroxy; (C 1-8 )alkoxy; aminocarbonyl-(C 1 .
  • R 2 is hydrogen; halogen; amino; N,N-di-(C 1-8 )alkylamino, in which the two (C 1-8 )alkyl groups are the same or different; N-(C 1-8 )alkylcarbonylamino; hydroxy; (C 1-8 )- alkoxy; aminocarbonyl-(C 1 . 8 )alkoxy; aminocarbonyloxy; mercapto; (C 1-8 )alkylthio; aminosulfonyl; N-(Ci -8 )alkylaminosulfonyl; N.N-di ⁇ C ⁇ alkylaminosulfonyl, in which the two (C-
  • R 1 and R 2 together form, together with the carbon atoms, to which they are attached, an optionally substituted 5-, 6- or 7-membered carbocyclic or heterocyclic ring; preferably either R 1 is hydrogen; halogen; amino; N-(C 1-8 )alkylamino; N,N-di-(C 1-8 )alkylamino, in which the two (C 1-8 )alkyl groups are the same or different; N-(C 1-8 )alkylcarbonylamino; hydroxy; (C 1-8 )alkoxy; aminocarbonyl-(C 1-8 )alkoxy; aminocarbonyloxy; mercapto; (Ci -8 -8
  • R 2 is hydrogen; halogen; amino; N-(C 1-8 )alkylamino; N,N-di-(C- ⁇ - 8 )alkylamino, in which the two (C 1-8 )alkyl groups are the same or different; N-(C 1-8 )alkylcarbonylamino; hydroxy; (C 1-8 )- alkoxy; aminocarbonyl-(C 1 .
  • (Ci -8 )alkyl groups are the same or different; (C 1-8 )alkyl; MyCIrOXy-(C 1-8 )alkyl; (C 1-8 )alkoxy-(C 1-8 )- alkyl; or (C 3 . 8 )cycloalkyl; or R 1 and R 2 together form, together with the carbon atoms, to which they are attached, an optionally substituted 5-, 6- or 7-membered carbocyclic or heterocyclic ring; preferably R 1 is hydrogen; carboxy; or (C 1-8 )alkoxycarbonyl; and
  • R 2 is hydrogen; (C 1-8 )alkoxy; or N,N-di-(C 1-8 )alkylaminosulfonyl, in which the two (C 1-8 )alkyl groups are the same or different; preferably R 1 is hydrogen; carboxy; or (C 1-4 )alkoxycarbonyl; and
  • R 2 is hydrogen; (C 1-4 )alkoxy; or N,N-di-(C 1-4 )alkylaminosulfonyl, in which the two (C 1-4 )alkyl groups are the same or different; preferably R-i is hydrogen; hydroxy; aminocarbonyl; N-(C 1-8 )alkylaminocarbonyl, the alkyl group of which can be substituted by hydroxy or by aminocarbonyl; carboxy; or (C 1-8 )- alkoxycarbonyl; and
  • R 2 is hydrogen; halogen; amino; hydroxy; (C 1-8 )alkoxy; N,N-di-(C 1-8 )alkylaminosulfonyl, in which the two (C ⁇ alkyl groups are the same or different; nitro; or cyano;
  • R 3 is hydrogen; halogen; hydroxy; (C 1-8 JaIkOXy; aminosulfonyl; N-(Ci -8 )alkylaminosulfonyl; N,N-di-(C 1-8 )alkylaminosulfonyl, in which the two (C 1-8 )alkyl groups are the same or different; (C 1-8 )alkyl; or (C 3-8 )cycloalkyl; preferably hydrogen; or (Ci -8 )alkoxy; more preferably hydrogen; or (C 1-4 )alkoxy;
  • R 4 is hydrogen; halogen; hydroxy; (C 1-8 )alkoxy; aminosulfonyl; N ⁇ C ⁇ alkylaminosulfonyl; N,N-di-(C 1-8 )alkylaminosulfonyl, in which the two (C 1-8 )alkyl groups are the same or different; (C-,. 8 )alkyl; or (C 3-8 )cycloalkyl; preferably hydrogen; or (C 1-a )alkoxy; more preferably hydrogen; or (C 1-4 )alkoxy;
  • R 5 is hydrogen; or (C 1-8 )alkyl
  • R 6 is hydrogen; carboxy; (C 1-8 )alkoxycarbonyl; (d. 8 )alkyl; amino-(C-i. 8 )alkyl; N-(C 1-8 )- N,N-di-(C 1 . 8 )alkylamino-(C 1-8 )alkyl, in which the two N-(C 1-8 )alkyl groups are the same or different; carboxy-(C 1-8 )alkyl; aminocarbonyl; N,N-di-(C 1 .
  • R 5 and R 6 together form, together with the carbon atoms, to which they are attached, an optionally substituted 5- or 6-membered carbocyclic ring; preferably either R 5 is hydrogen; or (d. 8 )alkyl; and
  • R 6 is hydrogen; (Ci. 8 )alkyl; amino-(C 1-8 )alkyl; N-(C 1 . 8 )alkylamino-(Ci. 8 )alkyl; N,N-di-(Ci -8 )- alkylamino-(Ci -8 )alkyl, in which the two N-(C 1-8 )alkyl groups are the same or different; carboxy-(C 1 .
  • R 6 is hydrogen; N-[amino-(C 1-8 )alkyl]aminocarbonyl; N- ⁇ [N-(C 1-8 )alkylamino]-(C 1-8 )alkyl ⁇ - aminocarbonyl; or N- ⁇ [N, N-di-(Ci. 8 )alkylamino]-(C 1-8 )alkyl ⁇ aminocarbonyl, in which the two
  • R 6 is hydrogen; carboxy; (C 1-8 )alkoxycarbonyl; carboxy-(C 1 . 8 )alkyl; aminocarbonyl; N,N-di-
  • (C 1-8 )alkylaminocarbonyl in which the two (C 1-8 )alkyl groups are the same or different and can, independently, be substituted by N-(C 1-8 )alkylamino; morpholinocarbonyl; piperidino- carbonyl; piperazinocarbonyl, which can be substituted by (C 1-8 )alkyl; pyrrolidinocarbonyl, which can be substituted by (C 1-8 )alkoxy-(C 1-8 )alkyl; N-(C 1-8 )alkylaminocarbonyl, the alkyl group of which can be substituted by (C 1-8 )alkoxy or by hydroxy-(d.
  • the preferred embodiments (1 ) to (5) are preferred independently, collectively or in any combination or sub-combination.
  • the invention relates to one or more than one of the compounds of the formula I mentioned in the Examples hereinafter, in free form or in salt form.
  • the invention relates to a process for the preparation of a compound of the formula I, in free form or in salt form, comprising the steps of
  • the reactions can be effected according to conventional methods, for example as described in the Examples.
  • the working-up of the reaction mixtures and the purification of the compounds thus obtainable may be carried out in accordance with known procedures.
  • Salts may be prepared from free compounds in known manner, and vice-versa.
  • agents of the invention exhibit valuable pharmacological properties, when tested in vitro or in vivo, and are, therefore, useful in medicaments.
  • agents of the invention are modulators, e. g. inhibitors, of leucine-rich repeat kinase 2 (LRRK2).
  • LRRK2 leucine-rich repeat kinase 2
  • Their pharmacological properties can be evaluated, for example, in Drug Pull- Down experiments, e. g. as described in WO-2006/134056 A1 , the corresponding disclosure therein being herewith incorporated hereinto by reference.
  • Agents of the invention can, therefore, be used in the treatment or prevention of a condition, disease or disorder, in which LRRK2 plays a role.
  • agents of the invention show activity at concentrations below 20 ⁇ M.
  • the agent of the invention described in Example 3 shows an IC 50 value of 1.2 ⁇ M.
  • Agents of the invention are therefore useful, e. g., in the treatment or prevention of a condition, disease or disorder of the central nervous system, such as a neurodegenerative condition, disease or disorder, for example a Lewy bodies disease, an alpha-synucleino- pathy, Parkinson's disease, familial parkinsonism, multiple system atrophy, dementia with Lewy bodies, Parkinson's disease with dementia, Alzheimer's disease, mild cognitive impairment (MCI), a tauopathy, a poly-glutamine (polyQ) disease, Huntington's disease, a spinocerebellar ataxia disease, or amyotrophic lateral sclerosis (ALS), such as an inherited metabolic condition, disease or disorder of the nervous system, for example a sphingo- lipidose, a neuronal ceroid lipofuscinose, a glycoproteinose, a mucolipdose, a neonatal metabolic disease, or a mitochondrial disorder, such as a peripheral neuropathy, for example Char
  • Niemann-Pick type C disease g. Niemann-Pick type C disease, Pelizaeus-Merzbacher Disease, Pick's disease, primary lateral sclerosis, Refsum's disease, Sandhoff disease, Schilders disease, Steele-Richardson-Olszewski disease, Tabes dorsalis, and the like.
  • the agents of the invention are especially useful in the treatment and/or prevention of Parkinson's disease.
  • the appropriate dosage will vary depending on, e. g., the compound employed as active pharmaceutical ingredient, the host, the mode of administration, the nature and severity of the condition, disease or disorder or the effect desired.
  • a daily dosage of from about 0.1 to about 100, preferably from about 1 to about 50, mg/kg of animal body weight.
  • an indicated daily dosage is in the range of from about 0.5 to about 2000, preferably from about 2 to about 200, mg of an agent of the invention conveniently administered, for example, in divided doses up to four times a day or in sustained release form.
  • An agent of the invention may be administered by any conventional route, in particular en- terally, preferably orally, e. g. in the form of a tablet or capsule, or parenterally, e. g. in the form of an injectable solution or suspension.
  • the invention in a further aspect, relates to an agent of the invention for use as a medicament, e. g. in the treatment or prevention of a condition, disease or disorder, in which LRRK2 plays a role.
  • the invention in a further aspect, relates to the use of an agent of the invention as active pharmaceutical ingredient in a medicament, e. g. in the treatment or prevention of a condition, disease or disorder, in which LRRK2 plays a role.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an agent of the invention as active pharmaceutical ingredient in association with at least one pharmaceutically acceptable carrier or diluent.
  • Such a composition may be manufactured in conventional manner, e. g. by mixing its components.
  • Unit dosage forms contain, e. g., from about 0.1 to about 1000, preferably from about 1 to about 500, mg of an agent of the invention.
  • An agent of the invention can be administered as sole active pharmaceutical ingredient or as a combination with at least one other active pharmaceutical ingredient effective, e. g., in the treatment or prevention of a condition, disease or disorder, in which LRRK2 plays a role.
  • a pharmaceutical combination may be in the form of a unit dosage form, which unit dosage form comprises a predetermined quantity of each of the at least two active components in association with at least one pharmaceutically acceptable carrier or diluent.
  • the pharmaceutical combination may be in the form of a package comprising the at least two active components separately, e. g. a pack or dispenser-device adapted for the concomitant or separate administration of the at least two active components, in which these active components are separately arranged.
  • the invention relates to such pharmaceutical combinations.
  • the invention relates to the use of an agent of the invention for the manufacture of a medicament for the treatment or prevention of a condition, disease or disorder, in which LRRK2 plays a role.
  • the invention relates to a method for the treatment or prevention of a condition, disease or disorder, in which LRRK2 plays a role, in a subject in need of such treatment or prevention, which method comprises administering to such subject an effective amount of an agent of the invention.
  • Example 2 5-r5-Methoxv-2-oxo-1,2-dihvdro-indol-(3Z)-vlidenemethyll-2,4-dimethvl-1H- pyrrole-3-carboxylic acid (3-amino-propyl)-amide a) [3-( ⁇ 5-[5-Methoxy-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H- pyrrole-3-carbonyl ⁇ -amino)-propyl]-carbamic acid tert-butyl ester
  • Examples 4 to 50 can be prepared in a manner analogous to those described hereinbefore.
  • Example 52 3-[1 -[4-(2-Diethylamino-ethylcarbamoyl)-3,5-dimethyl-1 H-pyrrol-2-yl]- meth-(Z)-ylidene]-5-methoxy-2-oxo-2,3-dihydro-1 H-indole-4-carboxylic acid methyl ester
  • Example 53 3-[1 -[4-(2-Diethylamino-ethylcarbamoyl)-3,5-dimethyl-1 H-pyrrol-2-yl]- meth-(Z)-ylidene]-5-methoxy-2-oxo-2,3-dihydro-1H-indole-4-carboxylic acid
  • Example 54 3-[1 -[4-(2-Diethylamino-ethylcarbamoyl)-3,5-dimethyl-1 H-pyrrol-2-yl]- meth-(Z)-ylidene]-5-methoxy-2-oxo-2,3-dihydro-1 H-indole-4-carboxylic acid (2-hydroxy- ethyl)-amide
  • Examples 55 and 56 can be prepared in a manner analogous to those described hereinbefore (LC system 2).

Abstract

The invention relates to novel heterocyclic compounds of the formula (I) in which all of the variables are as defined in the specification, in free form or in salt form, to their preparation, to their use as medicaments and to medicaments comprising them.

Description

Dihvdroindole derivatives useful in Parkinson's disease
The present invention relates to novel heterocyclic compounds, to their preparation, to their use as medicaments and to medicaments comprising them.
More particularly, the invention relates to a compound of the formula
Figure imgf000002_0001
in which either R1 is hydrogen; halogen; amino; N-(C1-8)alkylamino; N,N-di-(Ci.8)alkylamino, in which the two (C^sjalkyl groups are the same or different; N-(Ci-8)alkylcarbonylamino; hydroxy; (Ci-8)alkoxy; aminocarbonyl-(C1-8)alkoxy; aminocarbonyloxy; mercapto; (C1-8)alkyl- thio; aminosulfonyl;
Figure imgf000002_0002
N,N-di-(C1.8)alkylaminosulfonyl, in which the two (C1-S )alkyl groups are the same or different; aminocarbonyl; N-(C1.8)alkylaminocarbonyl, the alkyl group of which can be substituted by hydroxy or by aminocarbonyl; carboxy; (C1-8)- alkoxycarbonyl; (C1-8)alkyl; amino-(C1-8)alkyl; N-formylamino-(C1-8)alkyl; azido-(Ci.8)alkyl; hydroxy-(C1-8)alkyl; (C-i-8)alkoxy-(C1-8)alkyl; or (C3-8 )cycloalkyl; and
R2 is hydrogen; halogen; amino; N-(C1-8)alkylamino; N,N-di-(Ci.8)alkylamino, in which the two (C1-8 )alkyl groups are the same or different; N-(C1-8)alkylcarbonylamino; hydroxy; (d.s)alkoxy; aminocarbonyl-(C1-8)alkoxy; aminocarbonyloxy; mercapto; (C1-8)alkylthio; aminosulfonyl; N-(Ci_8)alkylaminosulfonyl; N,N-di-(C1-8)alkylaminosulfonyl, in which the two (C1-8)alkyl groups are the same or different; nitro; cyano; (C-i-aJalkyl; hydroxy-(C1-8)alkyl; (Ci.8)alkoxy-(C1.8)alkyl; or (C3-8 )cycloalkyl; or R1 and R2 together form, together with the carbon atoms, to which they are attached, an optionally substituted 5-, 6- or 7-membered carbocyclic or heterocyclic ring;
R3 is hydrogen; halogen; hydroxy; (C1-8)alkoxy; aminosulfonyl; N-(C1-8)alkylamino- sulfonyl; N,N-di-(C1.8)alkylaminosulfonyl, in which the two (C1.8)alkyl groups are the same or different; (C1-8)alkyl; or (C3-8 )cycloalkyl; R4 is hydrogen; halogen; hydroxy; (Ci-8)alkoxy; aminosulfonyl; N-(C1-8)alkylamino- sulfonyl; N.N-dKC^alkylaminosulfonyl, in which the two (C1-8)alkyl groups are the same or different; (d.8)alkyl; or (C3.8)cycloalkyl; either R5 is hydrogen; or (Ci-8)alkyl; and
R6 is hydrogen; carboxy; (Ci-8)alkoxycarbonyl; (Ci-8)alkyl; amino-(C1.8)alkyl; N-(C1-8)- alkylamino-(Ci-8)alkyl; N,N-di-(C1.8)alkylamino-(C1-8)alkyl, in which the two N-(C-t.β)alkyl groups are the same or different; carboxy-(C1-8)alkyl; aminocarbonyl; N,N-di-(C1-8)alkyl- aminocarbonyl, in which the two (Ci-8)alkyl groups are the same or different and can, independently, be substituted by N-(d.8)alkylamino; morpholinocarbonyl; piperidinocarbonyl; piperazinocarbonyl, which can be substituted by (C1-8)alkyl; pyrrolidinocarbonyl, which can be substituted by (C1.8)alkoxy-(C1-8)alkyl; N-(Ci-8)alkylaminocarbonyl, the alkyl group of which can be substituted by (C1.8)alkoxy or by hydroxy-(Ci-8)alkoxy; N-[carboxy-(C1-8)alkyl]amino- carbonyl; N-[amino-(C1-8)alkyl]aminocarbonyl; N-{[N-(C1-8)alkylamino]-(C1-8)alkyl}amino- carbonyl; or N-{[N,N-di-(Ci.8)alkylamino]-(Ci-8)alkyl}aminocarbonyl, in which the two (C1-8)- alkyl groups in the N,N-di-(C1-8)alkylamino moiety are the same or different; or R5 and R6 together form, together with the carbon atoms, to which they are attached, an optionally substituted 5- or 6-membered carbocyclic ring; and
R7 is hydrogen; (C1.8)alkyl; amino-(C1-8)alkyl; aminocarbonyl-(C1-8)alkyl; or aminocarbonyl, in free form or in salt form.
E. g. on account of one or more than one asymmetrical carbon atom, which may be present in a compound of the formula I, a corresponding compound of the formula I may exist in pure optically active form or in the form of a mixture of optical isomers, e. g. in the form of a race- mic mixture. All of such pure optical isomers and all of their mixtures, including the racemic mixtures, are part of the present invention.
A compound of the formula I may exist in free form or in salt form, e. g. a basic compound in acid addition salt form or an acidic compound in the form of a salt with a base. All of such free compounds and salts are part of the present invention.
A compound of the formula I may exist in tautomeric form. All of such tautomers are part of the present invention.
Halogen denotes fluorine, bromine, chlorine or iodine. Any non-cyclic carbon containing group or moiety with more than 1 carbon atom is straight- chain or branched.
Unless defined otherwise, carbon containing groups, moieties or molecules contain 1 to 8, preferably 1 to 6, more preferably 1 to 4, most preferably 1 or 2, carbon atoms.
In preferred embodiments, the invention relates to a compound of the formula I, in free form or in salt form, in which
(1) either R1 is hydrogen; halogen; amino; N-(C1.8)alkylamino; N,N-di-(C1-8)alkylamino, in which the two (d^alkyl groups are the same or different; N-(C1.8)alkylcarbonylamino; hydroxy; (C1-8)alkoxy; aminocarbonyl-(C1.8)alkoxy; aminocarbonyloxy; mercapto; (C1-8)alkyl- thio; aminosulfonyl; N-(C1-8)alkylaminosulfonyl; N,N-di-(C1-8)alkylaminosulfonyl, in which the two (C1-8 )alkyl groups are the same or different; aminocarbonyl; N-(Ci-8 )alkylaminocarbonyl, the alkyl group of which can be substituted by hydroxy or by aminocarbonyl; carboxy; (CL8)- alkoxycarbonyl; (C1-8)alkyl; amino-(Ci-8)alkyl; N-formylamino-(C1-8)alkyl; azido-(Ci-8)alkyl; hydroxy-(C1.8)alkyl; (C1-8)alkoxy-(C1-8)alkyl; or (C3-8)cycloalkyl; and
R2 is hydrogen; halogen; amino;
Figure imgf000004_0001
N,N-di-(C1-8)alkylamino, in which the two (C1-8)alkyl groups are the same or different; N-(C1-8)alkylcarbonylamino; hydroxy; (C1-8)- alkoxy; aminocarbonyl-(C1.8)alkoxy; aminocarbonyloxy; mercapto; (C1-8)alkylthio; aminosulfonyl; N-(Ci-8)alkylaminosulfonyl; N.N-di^C^alkylaminosulfonyl, in which the two (C-|.8)alkyl groups are the same or different; nitro; cyano; (C1-8)alkyl; hydroxy-(C1-8)alkyl; (Ci-8)alkoxy-(C1-8)alkyl; or (C3-8)cycloalkyl; or R1 and R2 together form, together with the carbon atoms, to which they are attached, an optionally substituted 5-, 6- or 7-membered carbocyclic or heterocyclic ring; preferably either R1 is hydrogen; halogen; amino; N-(C1-8)alkylamino; N,N-di-(C1-8)alkylamino, in which the two (C1-8)alkyl groups are the same or different; N-(C1-8)alkylcarbonylamino; hydroxy; (C1-8)alkoxy; aminocarbonyl-(C1-8)alkoxy; aminocarbonyloxy; mercapto; (Ci-8)alkyl- thio; aminosulfonyl; N-(C1-8)alkylaminosulfonyl; N,N-di-(C1-8)alkylaminosu]fonyl, in which the two (C1-8)alkyl groups are the same or different; aminocarbonyl; carboxy; (Ci-8)alkoxycarbo- πyl; (C1-8)alkyl; amino-(Ci-8)alkyl; N-formylamino-(Ci.8)alkyl; azido-(C1-8)alkyl; hydroxy-(C1.8)al- kyl; (C1-8)alkoxy-(C1.8)alkyl; or (C3.8)cycloalkyl; and
R2 is hydrogen; halogen; amino; N-(C1-8)alkylamino; N,N-di-(C-ι-8)alkylamino, in which the two (C1-8 )alkyl groups are the same or different; N-(C1-8)alkylcarbonylamino; hydroxy; (C1-8)- alkoxy; aminocarbonyl-(C1.8)alkoxy; aminocarbonyloxy; mercapto; (C1-8)alkylthio; aminosulfonyl; N-(Ci-8 )alkylaminosulfonyl; N,N-di-(C1-8)alkylaminosulfonyl, in which the two - A -
(Ci-8)alkyl groups are the same or different; (C1-8)alkyl; MyCIrOXy-(C1-8 )alkyl; (C1-8 )alkoxy-(C1-8)- alkyl; or (C3.8)cycloalkyl; or R1 and R2 together form, together with the carbon atoms, to which they are attached, an optionally substituted 5-, 6- or 7-membered carbocyclic or heterocyclic ring; preferably R1 is hydrogen; carboxy; or (C1-8)alkoxycarbonyl; and
R2 is hydrogen; (C1-8)alkoxy; or N,N-di-(C1-8)alkylaminosulfonyl, in which the two (C1-8)alkyl groups are the same or different; preferably R1 is hydrogen; carboxy; or (C1-4)alkoxycarbonyl; and
R2 is hydrogen; (C1-4)alkoxy; or N,N-di-(C1-4)alkylaminosulfonyl, in which the two (C1-4)alkyl groups are the same or different; preferably R-i is hydrogen; hydroxy; aminocarbonyl; N-(C1-8)alkylaminocarbonyl, the alkyl group of which can be substituted by hydroxy or by aminocarbonyl; carboxy; or (C1-8)- alkoxycarbonyl; and
R2 is hydrogen; halogen; amino; hydroxy; (C1-8)alkoxy; N,N-di-(C1-8)alkylaminosulfonyl, in which the two (C^alkyl groups are the same or different; nitro; or cyano;
(2) R3 is hydrogen; halogen; hydroxy; (C1-8JaIkOXy; aminosulfonyl; N-(Ci-8)alkylaminosulfonyl; N,N-di-(C1-8)alkylaminosulfonyl, in which the two (C1-8)alkyl groups are the same or different; (C1-8)alkyl; or (C3-8)cycloalkyl; preferably hydrogen; or (Ci-8)alkoxy; more preferably hydrogen; or (C1-4)alkoxy;
(3) R4 is hydrogen; halogen; hydroxy; (C1-8)alkoxy; aminosulfonyl; N^C^alkylaminosulfonyl; N,N-di-(C1-8)alkylaminosulfonyl, in which the two (C1-8)alkyl groups are the same or different; (C-,.8)alkyl; or (C3-8)cycloalkyl; preferably hydrogen; or (C1-a)alkoxy; more preferably hydrogen; or (C1-4)alkoxy;
(4) either R5 is hydrogen; or (C1-8)alkyl; and
R6 is hydrogen; carboxy; (C1-8)alkoxycarbonyl; (d.8)alkyl; amino-(C-i.8)alkyl; N-(C1-8)-
Figure imgf000005_0001
N,N-di-(C1.8)alkylamino-(C1-8)alkyl, in which the two N-(C1-8)alkyl groups are the same or different; carboxy-(C1-8)alkyl; aminocarbonyl; N,N-di-(C1.8)alkyl- aminocarbonyl, in which the two (C1-8)alkyl groups are the same or different and can, independently, be substituted by N-(C1-8)alkylamino; morpholinocarbonyl; piperidinocarbonyl; piperazinocarbonyl, which can be substituted by (C1-8)alkyl; pyrrolidinocarbonyl, which can be substituted by (C1-8)alkoxy-(C1.8)alkyl; N-(C1.8)alkylaminocarbonyl, the alkyl group of which can be substituted by (C^alkoxy or by hydroxy-(Ci.8)alkoxy; N-[carboxy-(Ci-8)alkyl]amino- carbonyl; N-[amino-(C1-8)alkyl]aminocarbonyl; N-{[N-(C1-8)alkylamino]-(C1-8)alkyl}amino- carbonyl; or N-{[N,N-di-(Ci.8)alkylamino]-(C1-8)alkyl}aminocarbonyl, in which the two (CL8)- alkyl groups in the N,N-di-(Ci-8)alkylamino moiety are the same or different; or R5 and R6 together form, together with the carbon atoms, to which they are attached, an optionally substituted 5- or 6-membered carbocyclic ring; preferably either R5 is hydrogen; or (d.8)alkyl; and
R6 is hydrogen; (Ci.8)alkyl; amino-(C1-8)alkyl; N-(C1.8)alkylamino-(Ci.8)alkyl; N,N-di-(Ci-8)- alkylamino-(Ci-8)alkyl, in which the two N-(C1-8)alkyl groups are the same or different; carboxy-(C1.8)alkyl; N-[carboxy-(C1-8)alkyl]aminocarbonyl; N-[amino-(C1-8)alkyl]aminocarbo- nyl; N-flN^Ci-^alkylaminoKC-i-jOalkytyaminocarbonyl; or N-{[N,N-di-(C1-8)alkylamino]-(Ci-8)al- kyl}aminocarbonyl, in which the two (Ci_8)alkyl groups in the N,N-di-(C1-8)alkylamino moiety are the same or different; or R5 and R6 together form, together with the carbon atoms, to which they are attached, an optionally substituted 5- or 6-membered carbocyclic ring; preferably either R5 is (C1-8)alkyl; and
R6 is hydrogen; N-[amino-(C1-8)alkyl]aminocarbonyl; N-{[N-(C1-8)alkylamino]-(C1-8)alkyl}- aminocarbonyl; or N-{[N, N-di-(Ci.8 )alkylamino]-(C1-8)alkyl}aminocarbonyl, in which the two
(Ci-8 )alkyl groups in the N,N-di-(C1-8)alkylamino moiety are the same or different; or R5 and R6 together are -CH=CH-CH=CH- or -(CH2)4-; preferably either R5 is (Chalky!; and
R6 is hydrogen; N-[amino-(C1-6)alkyl]aminocarbonyl; or N-{[N,N-di-(C1-6)alkylamino]-(C1-6)- alkyl}aminocarbonyl, in which the two (d-6)alkyl groups in the N,N-di-(C1-6)alkylamino moiety are the same or different; or R5 and R6 together are -CH=CH-CH=CH- or -(CH2V: preferably either R5 is hydrogen; or (C1-8)alkyl; and
R6 is hydrogen; carboxy; (C1-8 )alkoxycarbonyl; carboxy-(C1.8)alkyl; aminocarbonyl; N,N-di-
(C1-8 )alkylaminocarbonyl, in which the two (C1-8)alkyl groups are the same or different and can, independently, be substituted by N-(C1-8)alkylamino; morpholinocarbonyl; piperidino- carbonyl; piperazinocarbonyl, which can be substituted by (C1-8)alkyl; pyrrolidinocarbonyl, which can be substituted by (C1-8)alkoxy-(C1-8)alkyl; N-(C1-8)alkylaminocarbonyl, the alkyl group of which can be substituted by (C1-8)alkoxy or by hydroxy-(d.8)alkoxy; N-[amino-(C1-8)- alkyl]aminocarbonyl; or N-{[N,N-di-(Ci-8)alkylamino]-(Ci-8)alkyl}aminocarbonyl) in which the two (C-ι.8)alkyl groups in the N,N-di-(Ci-8)alkylamino moiety are the same or different; or R5 and R6 together are -CH=CH-CH=CH- or -(CH2V; (5) R7 is hydrogen; (d.8)alkyl; amino-(Ci-8)alkyl; aminocarbonyl-(C1-8)alkyl; or aminocarbonyl; preferably hydrogen; or (d-8)alkyl; more preferably hydrogen; or (C-^alkyl.
The preferred embodiments (1 ) to (5) are preferred independently, collectively or in any combination or sub-combination.
In especially preferred embodiments, the invention relates to one or more than one of the compounds of the formula I mentioned in the Examples hereinafter, in free form or in salt form.
In a further aspect, the invention relates to a process for the preparation of a compound of the formula I, in free form or in salt form, comprising the steps of
reaction of a compound of the formula
Figure imgf000007_0001
in which all of the variables arc ; as defined for the formula I1 in free form or in salt form, with a compound of the formula
Figure imgf000007_0002
in which all of the variables are as defined for the formula I, in free form or in salt form,
optionally followed by reduction, oxidation or other functionalisation of the resulting compound and/or by cleavage of any protecting group(s) optionally present,
and of recovering the so obtainable compound of the formula I in free form or in salt form.
The reactions can be effected according to conventional methods, for example as described in the Examples. The working-up of the reaction mixtures and the purification of the compounds thus obtainable may be carried out in accordance with known procedures.
Salts may be prepared from free compounds in known manner, and vice-versa.
Compounds of the formula I can also be prepared by further conventional processes, which processes are further aspects of the invention, e. g. as described in the Examples.
The starting materials of the formulae Il and II! are known or may be prepared according to conventional procedures starting from known compounds, for example as described in the Examples.
Compounds of the formula I, in free form or in pharmaceutically acceptable salt form, hereinafter often referred to as "agents of the invention", exhibit valuable pharmacological properties, when tested in vitro or in vivo, and are, therefore, useful in medicaments.
E. g., agents of the invention are modulators, e. g. inhibitors, of leucine-rich repeat kinase 2 (LRRK2). Their pharmacological properties can be evaluated, for example, in Drug Pull- Down experiments, e. g. as described in WO-2006/134056 A1 , the corresponding disclosure therein being herewith incorporated hereinto by reference. Agents of the invention can, therefore, be used in the treatment or prevention of a condition, disease or disorder, in which LRRK2 plays a role.
In the above-mentioned Drug Pull-Down experiments, agents of the invention show activity at concentrations below 20 μM. Specifically, the agent of the invention described in Example 3 shows an IC50 value of 1.2 μM.
Agents of the invention are therefore useful, e. g., in the treatment or prevention of a condition, disease or disorder of the central nervous system, such as a neurodegenerative condition, disease or disorder, for example a Lewy bodies disease, an alpha-synucleino- pathy, Parkinson's disease, familial parkinsonism, multiple system atrophy, dementia with Lewy bodies, Parkinson's disease with dementia, Alzheimer's disease, mild cognitive impairment (MCI), a tauopathy, a poly-glutamine (polyQ) disease, Huntington's disease, a spinocerebellar ataxia disease, or amyotrophic lateral sclerosis (ALS), such as an inherited metabolic condition, disease or disorder of the nervous system, for example a sphingo- lipidose, a neuronal ceroid lipofuscinose, a glycoproteinose, a mucolipdose, a neonatal metabolic disease, or a mitochondrial disorder, such as a peripheral neuropathy, for example Charcot-Marie-Tooth disease, hereditary motor and sensory neuropathy (HMSN), or peroneal muscular atrophy (PMA), or such as Down's syndrome, memory impairment, dementia, an amyloid neuropathy, brain inflammation, nerve and brain trauma, vascular amyloidosis, cerebral haemorrhage with amyloidosis, Alexander disease, Alper's disease, Ataxia Telangiectasia, Canavan disease, Cockayne syndrome, Corticobasal Degeneration, Creutzfeldt-Jakob disease, Dystonia, Kennedy's disease, Krabbe disease, Machado-Joseph disease, multiple sclerosis, Niemann-Pick disease, e. g. Niemann-Pick type C disease, Pelizaeus-Merzbacher Disease, Pick's disease, primary lateral sclerosis, Refsum's disease, Sandhoff disease, Schilders disease, Steele-Richardson-Olszewski disease, Tabes dorsalis, and the like.
The agents of the invention are especially useful in the treatment and/or prevention of Parkinson's disease.
For the above-mentioned indications, the appropriate dosage will vary depending on, e. g., the compound employed as active pharmaceutical ingredient, the host, the mode of administration, the nature and severity of the condition, disease or disorder or the effect desired. However, in general, satisfactory results in animals are indicated to be obtained at a daily dosage of from about 0.1 to about 100, preferably from about 1 to about 50, mg/kg of animal body weight. In larger mammals, for example humans, an indicated daily dosage is in the range of from about 0.5 to about 2000, preferably from about 2 to about 200, mg of an agent of the invention conveniently administered, for example, in divided doses up to four times a day or in sustained release form.
An agent of the invention may be administered by any conventional route, in particular en- terally, preferably orally, e. g. in the form of a tablet or capsule, or parenterally, e. g. in the form of an injectable solution or suspension.
In accordance with the foregoing, in a further aspect, the invention relates to an agent of the invention for use as a medicament, e. g. in the treatment or prevention of a condition, disease or disorder, in which LRRK2 plays a role. In a further aspect, the invention relates to the use of an agent of the invention as active pharmaceutical ingredient in a medicament, e. g. in the treatment or prevention of a condition, disease or disorder, in which LRRK2 plays a role.
In a further aspect, the invention relates to a pharmaceutical composition comprising an agent of the invention as active pharmaceutical ingredient in association with at least one pharmaceutically acceptable carrier or diluent. Such a composition may be manufactured in conventional manner, e. g. by mixing its components. Unit dosage forms contain, e. g., from about 0.1 to about 1000, preferably from about 1 to about 500, mg of an agent of the invention.
An agent of the invention can be administered as sole active pharmaceutical ingredient or as a combination with at least one other active pharmaceutical ingredient effective, e. g., in the treatment or prevention of a condition, disease or disorder, in which LRRK2 plays a role. Such a pharmaceutical combination may be in the form of a unit dosage form, which unit dosage form comprises a predetermined quantity of each of the at least two active components in association with at least one pharmaceutically acceptable carrier or diluent. Alternatively, the pharmaceutical combination may be in the form of a package comprising the at least two active components separately, e. g. a pack or dispenser-device adapted for the concomitant or separate administration of the at least two active components, in which these active components are separately arranged. In a further aspect, the invention relates to such pharmaceutical combinations.
In a further aspect, the invention relates to the use of an agent of the invention for the manufacture of a medicament for the treatment or prevention of a condition, disease or disorder, in which LRRK2 plays a role.
In a further aspect, the invention relates to a method for the treatment or prevention of a condition, disease or disorder, in which LRRK2 plays a role, in a subject in need of such treatment or prevention, which method comprises administering to such subject an effective amount of an agent of the invention.
The following Examples illustrate the invention, but do not limit it.
Examples Abbreviations
Figure imgf000011_0001
Example 1 : 5-[5-Methoxy-2-oxo-1 ,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1 H- pyrrole-3-carboxylic acid
5-Methoxyoxindole (80 mg, 0.496 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (82 mg, 0.49 mmol) are dissolved in EtOH (4 ml) and piperidine (3 microliter, 0.03 mmol), and the mixture is heated to 600C for 40 h. After cooling, the resulting solid is collected by filtration.
HPLC-MS: [M + H]+ = 313.
1H-NMR (d6-DMSO, 400 MHz): 2.56 (2 x s, 6H), 3.79 (s, 3H), 6.76 (dd, 1H), 6.80 (d, 1 H),
7.65 (dd, 1 H), 7.73 (s, 1 H), 10.76 (s, 1H).
Example 2: 5-r5-Methoxv-2-oxo-1,2-dihvdro-indol-(3Z)-vlidenemethyll-2,4-dimethvl-1H- pyrrole-3-carboxylic acid (3-amino-propyl)-amide a) [3-({5-[5-Methoxy-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H- pyrrole-3-carbonyl}-amino)-propyl]-carbamic acid tert-butyl ester
5-[5-Methoxy-2-oxo-1 ,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3- carboxylic acid (130 mg, 0.42 mmol), N-BOC-1 ,3-diaminopropane (109 mg, 0.63 mmol), N- (3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (EDC HCI) (163 mg, 0.83 mmol) and 1-hydroxy-benzotriazole hydrate (HOBt) (114 mg, 0.84 mmol) are dissolved in DCM (15 ml) and N-methylmorpholine (NMM) (138 microliter, 1.25 mmol), and the mixture is stirred for 18 h at rt. Thereafter, the same amounts of BOC-amine, EDC HCI, HOBt and NMM are added, and the stirring is continued for another 22 h. After evaporation of the solvents, the product is purified by preparative HPLC on a C-18 reverse phase column. HPLC-MS: [M + H]+ = 469.
b) 5-[5-Methoxy-2-oxo-1 ,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1 H-pyrrole-3- carboxylic acid (3-amino-propyl)-amide
A mixture of [3-({5-[5-methoxy-2-oxo-1 ,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H- pyrrole-3-carbonyl}-amino)-propyl]-carbamic acid tert-butyl ester (2.7 g, 1.61 mmol) and DCM (20 ml) is treated with TFA (20 ml) at rt for 2 h. After evaporation of the solvent, the product is purified by preparative HPLC on a C-18 reverse phase column and lyophilized to yield a redish-yellow amorphous powder (TFA salt). HPLC-MS: [M + H]+ = 369.
1H-NMR (de-DMSO, 400 MHz): 1.80 (m, 2H), 2.24 (2 x s, 6H), 2.89 (m, 2H), 3.32 (m, 2H), 3.79 (s, 3H)1 6.75 (dd, 1H), 6.80 (dd, 1H), 7.50 (d, 1 H), 7.68 (s, 1H), 7.73 (s br, ca. 2H), 7.80 (t, 1 H), 10.75 (s, 1 H).
Example 3: 5-[5-Methoxy-2-oxo-1 ,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1 H- pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide
A mixture of 5-[5-methoxy-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1 H- pyrrole-3-carboxylic acid (210 mg, 0.67 mmol), 2-diethylamino-ethylamine (156 mg, 1.34 mmol) and BOP in DCM (12 ml) and DMF (6 ml) is stirred for 2 h at rt. After evaporation of the solvents, the product is purified by preparative HPLC on a C-18 reverse phase column and isolated (TFA salt). HPLC-MS: [M + H]+ = 411.
1H-NMR ((J6-DMSO, 400 MHz): 1.28 (t, 6H), 2.29 (2 x s, 6H), 2.38 (t, 2H), 3.23 (m, 4H), 3.59 (m, 2H), 3.79 (s, 3H), 6.72 (dd, 1 H), 6.80 (d, 1 H), 7.50 (d, 1H), 7.70 (s, 1H), 7.73 (s br, ca. 2H), 7.81 (t, 1H)1 9.50 (s br, 1 H), 10.75 (s, 1 H).
Examples 4 to 50:
The compounds of Examples 4 to 50 can be prepared in a manner analogous to those described hereinbefore.
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
LC Systems:
System 1
HPLC Agilent
Gradient water / acetonitrile, both with 0.05% TFA, from 0 to 100 in 6 min, linear gradient, flow rate 1 ml/min
Column Macherey-Nagel Nucleosil C18HD, 4x70mm, 3 micrometer
System 2
HPLC Waters Alliance 2690
Gradient water / acetonitrile, both with 0.05% TFA, from 10 to 90 in 7 min, linear gradient, flow rate 0.35 ml/min
Column XTerra, 5 cm, G 95% CH3CN, 0.35 ml, 500C, cone 30
Example 51 : 3-ri-(4-Carboxv-3,5-dimethvl-1H-pvrrol-2-vl)-meth-(Z)-vlidene1-5-methoxy- 2-oxo-2,3-dihydro-1H-indole-4-carboxylic acid methyl ester
a) δ-Methoxy-IH-indole-Φcarboxylic acid methyl ester
In an autoclave, a solution of 4-bromo-5-methoxy-1 H-indole (3 g, 13.27 mmol) and triethylamine (1.91 ml, 13.27 mmol) in MeOH (12 ml) is degassed by purging with argon. 1 ,1'- Bis(diphenylphosphino)ferrocene (193 mg, 13.2 mmol) and bis(benzonitrile)palla- dium(ll)chloride (42.4 mg, 0.11 mmol) are added, and the autoclave is pressurized with CO (25 bar). The mixture is heated at 1300C for 18 h, cooled to rt, diluted with water and twice extracted with EtOAc. The organic extracts are washed with 2M K2CO3, 2M HCI, water and brine, dried and evaporated to afford a brown oil. MPLC purification yields the desired methyl ester as an off-white powder.
b) S-Bromo-δ-methoxy-IH-indole^-carboxylic acid methyl ester
A solution of 5-methoxy-1H-indole-4-carboxylic acid methyl ester (2.75 g, 13.4 mmol) in DMF (70 ml) is cooled to 0°C and treated with a solution of Br2 in DMF (70 ml) by dropwise addition during 30 min. Stirring is continued for 5 min. Then the mixture is diluted with 200 ml of an aqueous solution of NH3 (0.5%) and sodium pyrosulfite (0.1 %) and twice extracted with EtOAc. The organic phases are washed with 2M K2CO3, water and brine, dried and evaporated to afford the desired bromo compound as a light green powder.
c) 5-Methoxy-2-oxo-2,3-dihydro-1H-indole-4-carboxylic acid methyl ester
A solution of 3-bromo-5-methoxy-1 H-indole-4-carboxylic acid methyl ester (4.3 g, 15.13 mmol) in 2-methoxyethanol (100 ml) is heated to 800C and treated with 85% phosphoric acid (8 ml) for 20 min. The mixture is quenched with 2M NH4OH and twice extracted with EtOAc. The organic phases are washed with water and brine, dried and evaporated to afford a dark solid. Purification by MPLC yields the desired indolinone as an orange powder.
d) 3-[1 -(4-Carboxy-3,5-dimethyl-1 H-pyrrol-2-yl)-meth-(Z)-ylidene]-5-methoxy-2-oxo-2,3- dihydro-1H-indole-4-carboxylic acid methyl ester
A solution of 5-methoxy-2-oxo-2,3-dihydro-1H-indole-4-carboxylic acid methyl ester (318 mg, 1.44 mmol) and 5-formyl-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid (241 mg, 1.44 mmol) in EtOH (20 ml) is treated with piperidine (0.2 ml), and the mixture is heated to reflux for 3 h. The mixture is cooled to 0°, and the precipitate formed is washed with cold EtOH and cyclohexane. Drying yields the desired product as an orange powder. HPLC-MS: [M + H]+ = 371.3; retention time = 4.01 min (LC system 2).
Example 52: 3-[1 -[4-(2-Diethylamino-ethylcarbamoyl)-3,5-dimethyl-1 H-pyrrol-2-yl]- meth-(Z)-ylidene]-5-methoxy-2-oxo-2,3-dihydro-1 H-indole-4-carboxylic acid methyl ester
A solution of 3-[1-(4-carboxy-3,5-dimethyl-1 H-pyrrol-2-yl)-meth-(Z)-ylidene]-5-methoxy-2-oxo- 2,3-dihydro-1 H-indole-4-carboxylic acid methyl ester (407 mg, 1.1 mmol) in DMF (11 ml) is treated with BOP (681 mg, 1.5 mmol) and DIEA (0.336 ml, 2 mmol), and the mixture is stirred at rt for 5 min. 2-Diethylaminoethylamine (0.172 ml, 1.2 mmol) is added, and the stirring is continued for 30 min. 2 N NaOH is added, and the mixture is extracted 4x with DCM. The organic extracts are washed with brine, dried and evaporated. The residue is triturated with cold EtOH, and the solid formed is collected by filtration and washed with cold EtOH and cyclohexanes to yield afford the desired amide as a yellow solid. HPLC-MS: [M + H]+ = 469.3; retention time = 3.59 min (LC system 2). Example 53: 3-[1 -[4-(2-Diethylamino-ethylcarbamoyl)-3,5-dimethyl-1 H-pyrrol-2-yl]- meth-(Z)-ylidene]-5-methoxy-2-oxo-2,3-dihydro-1H-indole-4-carboxylic acid
A solution of 3-[1-[4-(2-diethylamino-ethylcarbamoyl)-3,5-dimethyl-1H-pyrrol-2-yl]-meth-(Z)- ylidene]-5-methoxy-2-oxo-2,3-dihydro-1H-indole-4-carboxylic acid methyl ester (400 mg, 0.85 mmol) and KOH (96 mg, 1.71 mmol) in MeOH (4 ml) and water (1.6 ml) is irradiated in a microwave oven for 90 min at 1200C. The resulting mixture is diluted with water, acidified with concentrated HCI and extracted 3x with DCM. The aqueous phase is evaporated to dryness, the residue is re-dissolved in water, and this solution is concentrated until crystallization starts. Crystallization is allowed to finish at O0C, and the solid is collected by filtration, washed with cold water, MTBE and cyclohexanes and dried to yield the desired acid as an orange powder. HPLC-MS: [M + H]+ = 455.3; retention time = 3.08 min (LC system 2).
Example 54: 3-[1 -[4-(2-Diethylamino-ethylcarbamoyl)-3,5-dimethyl-1 H-pyrrol-2-yl]- meth-(Z)-ylidene]-5-methoxy-2-oxo-2,3-dihydro-1 H-indole-4-carboxylic acid (2-hydroxy- ethyl)-amide
A solution of 3-[1-[4-(2-diethylamino-ethylcarbamoyl)-3,5-dimethyl-1 H-pyrrol-2-yl]-meth-(Z)- ylidene]-5-methoxy-2-oxo-2,3-dihydro-1 H-indole-4-carboxylic acid (64.8 mg, 0.132 mmol) in DMF (1 ml) is treated with BOP (81 mg, 0.18 mmol) and DIEA (0.062 ml, 0.37 mmol), and the mixture is stirred at rt for 5 min. Ethanolamine (0.0087 ml, 0.145 mmol) is added, and stirring is continued for 30 min. The reaction mixture is quenched with 2N K2CO3 and extracted with MeOH/DCM 8:2 (1x) and DCM (3x). The organic extracts are washed with brine, dried and evaporated. The residue is triturated with cold EtOH, and the solid formed is collected by filtration and washed with cold EtOH and cyclohexanes to yield the desired amide as an orange solid. HPLC-MS: [M + H]+ = 498.3; retention time = 0.61 min (LC system 2).
Examples 55 and 56:
The compounds of Examples 55 and 56 can be prepared in a manner analogous to those described hereinbefore (LC system 2).
Figure imgf000021_0001

Claims

Claims
1. A compound of the formula
Figure imgf000022_0001
in which either R1 is hydrogen; halogen; amino; N-(Ci.8)alkylamino; N,N-di-(C1-8)alkylamino, in which the two (C1-8)alkyl groups are the same or different; N-(Ci.8)alkylcarbonylamino; hydroxy; (C1-8)alkoxy; aminocarbonyl-(Ci-8)alkoxy; aminocarbonyloxy; mercapto; (C^alkyl- thio; aminosulfonyl; N-(C1-8)alkylaminosulfonyl; N.N-di-^^alkylaminosulfonyl, in which the two (C-I-8 )alkyl groups are the same or different; aminocarbonyl; N-(C1-8 )alkylaminocarbonyl, the alkyl group of which can be substituted by hydroxy or by aminocarbonyl; carboxy; (C1-8)- alkoxycarbonyl; (C1-8)alkyl; amino-(C1-8)alkyl; N-formylamino-(C1-8)alkyl; azido-(C1-8)alkyl; hydroxy-(C1-8)alkyl; (C1-8)alkoxy-(C1-8)alkyl; or (C^cycloalkyl; and
R2 is hydrogen; halogen; amino; N-(Ci-8)alkylamino; N,N-di-(C1-8)alkylamino, in which the two (C1-8 )alkyl groups are the same or different; N-(C1-8)alkylcarbonylamino; hydroxy; (C1-8)alkoxy; aminocarbonyl-(C1-8)alkoxy; aminocarbonyloxy; mercapto; (C1-8)alkylthio; aminosulfonyl; N-(C1-8)alkylaminosulfonyl; N,N-di-(C1.8)alkylaminosulfonyl, in which the two (C1-8)alkyl groups are the same or different; nitro; cyano; (C1-8)alkyl; hydroxy-(C1-8)alkyl; (C1-8 )alkoxy-(C1-8)alkyl; or (C3-8)cycloalkyl; or R1 and R2 together form, together with the carbon atoms, to which they are attached, an optionally substituted 5-, 6- or 7-membered carbocyclic or heterocyclic ring;
R3 is hydrogen; halogen; hydroxy; (C1-8)alkoxy; aminosulfonyl; N-(C1-8)alkylamino- sulfonyl; N,N-di-(C1-8)alkylaminosulfonyl, in which the two (C1-8)alkyl groups are the same or different; (C1-8)alkyl; or (C3-8)cycloalkyl;
R4 is hydrogen; halogen; hydroxy; (C1-8)alkoxy; aminosulfonyl; N-(C1-8 )alkylamino- sulfonyl; N,N-di-(C1-8)alkylaminosulfonyl, in which the two (C1-8)alkyl groups are the same or different; (C1-8 )alkyl; or (C3-8)cycloalkyl; either R5 is hydrogen; or (C1-8)alkyl; and R6 is hydrogen; carboxy; (CVβJalkoxycarbonyl; (Ci-8)alkyl; amino-(C1-8)alkyl; N-(C1-8)- alkylamino-(Ci.8)alkyl; N,N-di-(C1.8)alkylamino-(C1-8)alkyl, in which the two N-(C1-8)alkyl groups are the same or different; carboxy-(C1-8)alkyl; aminocarbonyl; N,N-di-(C1-8)alkyl- aminocarbonyl, in which the two (C1-8)alkyl groups are the same or different and can, independently, be substituted by N-(C1-8)alkylamino; morpholinocarbonyl; piperidinocarbonyl; piperazinocarbonyl, which can be substituted by (C1.8)alkyl; pyrrolidinocarbonyl, which can be substituted by (C1.8)alkoxy-(Ci-8)alkyl; N-(Ci-8)alkylaminocarbonyl, the alkyl group of which can be substituted by (C1-8JaIkOXy or by hydroxy-(Ct.8)alkoxy; N-[carboxy-(C1-8)alkyl]amino- carbonyl; N-[amino-(Ci-8)alkyl]aminocarbonyl; N-{[N-(C1-8)alkylamino]-(C1-8)alkyl}amino- carbonyl; or N-{[N,N-di-(C1.8)alkylamino]-(C1-8)alkyl}aminocarbonyl, in which the two (C1-8)- alkyl groups in the N.N-dKd-sJalkylamino moiety are the same or different; or R5 and R6 together form, together with the carbon atoms, to which they are attached, an optionally substituted 5- or 6-membered carbocyclic ring; and
R7 is hydrogen; (C1-8)alkyl; amino-(C1-8)alkyl; aminocarbonyl-(C1-8)alkyl; or aminocarbonyl, in free form or in salt form.
2. A process for the preparation of a compound as defined in claim 1 of the formula I, in free form or in salt form, comprising the steps of
reaction of a compound of the formula
Figure imgf000023_0001
in which all of the variables are as defined for the formula I, in free form or in salt form, with a compound of the formula
Figure imgf000023_0002
in which all of the variables are as defined for the formula I1 in free form or in salt form, optionally followed by reduction, oxidation or other functionalisation of the resulting compound and/or by cleavage of any protecting group(s) optionally present,
and of recovering the so obtainable compound of the formula I in free form or in salt form.
3. A compound as defined in claim 1 of the formula I, in free form or in pharmaceutically acceptable salt form, for use as a medicament.
4. A compound as defined in claim 1 of the formula I, in free form or in pharmaceutically acceptable salt form, for use in the treatment or prevention of a condition, disease or disorder, in which LRRK2 plays a role.
5. A pharmaceutical composition comprising a compound as defined in claim 1 of the formula I, in free form or in pharmaceutically acceptable salt form, as active ingredient and a pharmaceutical carrier or diluent.
6. The use of a compound as defined in claim 1 of the formula I, in free form or in pharmaceutically acceptable salt form, as a medicament for the treatment or prevention of a condition, disease or disorder, in which LRRK2 plays a role.
7. The use of a compound as defined in claim 1 of the formula I, in free form or in pharmaceutically acceptable salt form, for the manufacture of a medicament for the treatment or prevention of a condition, disease or disorder, in which LRRK2 plays a role.
8. A method for the treatment or prevention of a condition, disease or disorder, in which LRRK2 plays a role, in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of a compound as defined in claim 1 of the formula I, in free form or in pharmaceutically acceptable salt form.
9. A combination comprising a therapeutically effective amount of a compound as defined in claim 1 of the formula I, in free form or in pharmaceutically acceptable salt form, and a second drug substance, for simultaneous or sequential administration.
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