684
1
Claims
1.
A compound according to formula I
R5
R6
R4
R7
A
R8 O
R9
R1
NH
R10
X
N
R11
R12
O
Q
Y
[I]
wherein A represents N, CH or CR1;
5
each R1 independently represents hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C(O)-C1-6alkyl, -C(O)-C2-6alkenyl, -C(O)-C2-6alkynyl, -C(O)-O-C1-6alkyl, -C(O)-OC2-6alkenyl, -C(O)-O-C2-6alkynyl or phenyl, wherein said phenyl, C1-6alkyl, C26alkenyl
or C2-6alkynyl is optionally substituted with one or more substituents selected
from halogen, hydroxyl, haloC1-6alkyl, nitro, C1-6alkoxy, and NR2R3;
10
X represents hydrogen, C1-6alkyl or – CRaRb-X’, wherein X’ represents a monocyclic
saturated moiety having 5-6 ring atoms one of which is N and wherein one or two
additional ring atom may be a hetero atom selected from N, O and S, which
monocyclic ring may be substituted with one or more substituent W, wherein W is
selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl or (=O);
15
Ra and Rb each individually represent hydrogen, -CH3 or halogen;
Q represents –CH2- or -NH-;
Y represents heteroaryl with 5-6 ring atoms, wherein 1, 2 or 3 ring atoms are selected
from O, N or S, or Y represents phenyl, wherein said heteroaryl or phenyl may be
substituted with one or more substituents selected from halogen, C1-6alkyl, C2-
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6alkenyl,
C2-6alkynyl or C1-6alkoxy;
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wherein each of R2 and R3 independently represents hydrogen, C1-6alkyl, C2-6alkenyl,
C2-6alkynyl, hydroxyC1-6alkyl, or haloC1-6alkyl;
each of R4-R8 and R9-R12 independently represent hydrogen, C1-6alkyl, C2-6alkenyl,
5
C2-6alkynyl, halogen, NR2R3, hydroxy, cyano, nitro, C1-6alkoxy, haloC1-6alkyl or
hydroxyC1-6alkyl;
and pharmaceutically acceptable salts thereof.
2.
The compound according to claim 1, wherein A represents CH.
3.
The compound according to claim 1or 2, wherein R1 represents C1-6alkyl.
4.
The compound according to claim 3, wherein R1 represents ethyl, cyclopropyl
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or cyclobutyl.
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5.
The compound according to any of claims 1-4, wherein each of R4-R8
independently represent hydrogen or halogen.
6.
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The compound according to claim 5, wherein R7 represents halogen and R4, R5
and R8 represent hydrogen.
7.
The compound according to any of claims 1-6, wherein each of R9-R12
independently represent hydrogen of halogen.
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8.
The compound according to claim 7, wherein R12 represents halogen and R9-
R11 represent hydrogen.
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9.
The compound according to claim 8, wherein all of R9-R12 represent hydrogen.
10.
The compound according to claim 1 according to formula I’
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R5
R6
R4
R7
H R1
C
R8 O
R9
NH
R10
X
N
R11
R12
O
Q
Y
[I']
wherein R1 represents C1-6alkyl;
X represents C1-6alkyl;
Q represents –CH2- or –NH-;
5
Y represents a heteroaryl with 5-6 ring atoms, wherein 1, 2 or 3 ring atoms are
selected from O, N or S, or alternatively Y represents phenyl, wherein said heteroaryl
or phenyl may be substituted with one or more substituents selected from halogen and
C1-6alkyl;
each of R4-R9 and R9-R12 independently represent hydrogen or halogen;
10
and pharmaceutically acceptable salts thereof.
11.
The compound according to claim 10 wherein R1 represents ethyl, cyclopropyl
or cyclobutyl;
Q represents –CH2-;
15
Y represents a heteroaryl with 5-6 ring atoms, wherein 1, 2 or 3 ring atoms are
selected from O, N or S, wherein said heteroaryl may be substituted with one or more
substituents selected from halogen and C1-6alkyl.
12.
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The compound according to any of claims 10-11, wherein R7 represents
halogen, and R5, R6 and R8 represent hydrogen.
13.
The compound according to any of claims 10-12, wherein R12 is halogen, and
R9-R11 represent hydrogen.
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14.
The compound according to any of claims 10-13, wherein Y represents
furazanyl, thiazolyl, thienyl, furanyl, imidazolyl, oxazolyl, pyrazolyl, isoxazolyl,
pyridyl or 4H[1,2,4]triazolyl.
5
15.
The compound according to claim 10, wherein Q represents –NH, and Y
represent phenyl, wherein said phenyl may be substituted with one or more
substituents selected from halogen.
10
16.
1a
The compound according to claim 1 selected from
3-Methyl-1-oxo-2-phenylamino-1,2-dihydro-isoquinoline-4-carboxylic acid
((S)-1-phenyl-propyl)-amide
1b
2-Benzyl-3-methyl-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid ((S)-1phenyl-propyl)-amide
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1c
3-Methyl-1-oxo-2-(pyridin-2-ylamino)-1,2-dihydro-isoquinoline-4-carboxylic
acid ((S)-1-phenyl-propyl)-amide
1d
2-Furan-3-ylmethyl-3-methyl-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid
((S)-1-phenyl-propyl)-amide
2a
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8-Fluoro-2-furan-3-ylmethyl-3-methyl-1-oxo-1,2-dihydro-isoquinoline-4carboxylic acid [(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-amide
2b
8-Fluoro-3-methyl-1-oxo-2-pyridin-3-ylmethyl-1,2-dihydro-isoquinoline-4carboxylic acid [(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-amide
2c
8-Fluoro-3-methyl-1-oxo-2-pyridin-4-ylmethyl-1,2-dihydro-isoquinoline-4carboxylic acid [(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-amide
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2d
2-(2,5-Difluoro-benzyl)-8-fluoro-3-methyl-1-oxo-1,2-dihydro-isoquinoline-4carboxylic acid [(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-amide
2e
2-(2,6-Difluoro-benzyl)-8-fluoro-3-methyl-1-oxo-1,2-dihydro-isoquinoline-4carboxylic acid [(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-amide
2f
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2-(3,4-Difluoro-benzyl)-8-fluoro-3-methyl-1-oxo-1,2-dihydro-isoquinoline-4carboxylic acid [(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-amide
2g
8-Fluoro-3-methyl-1-oxo-2-thiophen-3-ylmethyl-1,2-dihydro-isoquinoline-4carboxylic acid [(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-amide
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2h
8-Fluoro-3-methyl-2-(5-methyl-isoxazol-3-ylmethyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid [(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]amide
2i
5
8-Fluoro-3-methyl-1-oxo-2-thiophen-2-ylmethyl-1,2-dihydro-isoquinoline-4carboxylic acid [(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-amide
2j
8-Fluoro-2-(1H-imidazol-2-ylmethyl)-3-methyl-1-oxo-1,2-dihydro-isoquinoline4-carboxylic acid [(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-amide
2k
8-Fluoro-2-(1H-imidazol-2-ylmethyl)-3-methyl-1-oxo-1,2-dihydro-isoquinoline4-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide
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2l
8-Fluoro-2-furan-3-ylmethyl-3-methyl-1-oxo-1,2-dihydro-isoquinoline-4carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide
2m 8-Fluoro-3-methyl-2-(5-methyl-isoxazol-3-ylmethyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide
2n
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8-Fluoro-3-methyl-1-oxo-2-thiazol-2-ylmethyl-1,2-dihydro-isoquinoline-4carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide
2o
8-Fluoro-3-methyl-2-(5-methyl-4H-[1,2,4]triazol-3-ylmethyl)-1-oxo-1,2dihydro-isoquinoline-4-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)methyl]-amide
2p
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8-Fluoro-3-methyl-2-(5-methyl-2H-pyrazol-3-ylmethyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide
2q
8-Fluoro-3-methyl-2-(1-methyl-1H-pyrazol-3-ylmethyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide
2r
8-Fluoro-3-methyl-2-(4-methyl-thiazol-5-ylmethyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide
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2s
8-Fluoro-3-methyl-2-oxazol-2-ylmethyl-1-oxo-1,2-dihydro-isoquinoline-4carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide
2t
8-Fluoro-3-methyl-2-oxazol-4-ylmethyl-1-oxo-1,2-dihydro-isoquinoline-4carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide
2u
30
8-Fluoro-3-methyl-2-(5-methyl-thiazol-2-ylmethyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide
2v
8-Fluoro-3-methyl-2-(4-methyl-furazan-3-ylmethyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide
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2w
2-(4,5-Dimethyl-1H-imidazol-2-ylmethyl)-8-fluoro-3-methyl-1-oxo-1,2dihydro-isoquinoline-4-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)methyl]-amide
2x
5
2-(2,5-Dimethyl-furan-3-ylmethyl)-8-fluoro-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide
2y
8-Fluoro-3-methyl-1-oxo-2-(1,3,5-trimethyl-1H-pyrazol-4-ylmethyl)-1,2dihydro-isoquinoline-4-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)methyl]-amide
2z
10
2-(1,5-Dimethyl-1H-pyrazol-3-ylmethyl)-8-fluoro-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide
2aa 8-Fluoro-3-methyl-2-(1-methyl-1H-imidazol-4-ylmethyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide
2ac 8-Fluoro-3-methyl-2-(2-methyl-thiazol-4-ylmethyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide
15
2ad 8-Fluoro-3-methyl-2-(2-methyl-furan-3-ylmethyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide
2ae 8-Fluoro-3-methyl-2-(1-methyl-1H-pyrazol-4-ylmethyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide
2af 8-Fluoro-3-methyl-2-(3-methyl-3H-imidazol-4-ylmethyl)-1-oxo-1,2-dihydro-
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isoquinoline-4-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide
2ag 8-Fluoro-3-methyl-2-(1-methyl-1H-imidazol-2-ylmethyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide
2ah 2-(1-Ethyl-1H-imidazol-2-ylmethyl)-8-fluoro-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide
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2ai
8-Fluoro-3-methyl-2-oxazol-2-ylmethyl-1-oxo-1,2-dihydro-isoquinoline-4carboxylic acid [(S)-cyclopropyl-(4-fluoro-phenyl)-methyl]-amide
2aj
8-Fluoro-3-methyl-2-oxazol-2-ylmethyl-1-oxo-1,2-dihydro-isoquinoline-4carboxylic acid [(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-amide
2ak 8-Fluoro-2-(3H-imidazol-4-ylmethyl)-3-methyl-1-oxo-1,2-dihydro-isoquinoline30
4-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide
2al
8-Fluoro-3-methyl-2-(3-methyl-isoxazol-5-ylmethyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide
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2am 8-Fluoro-2-isoxazol-5-ylmethyl-3-methyl-1-oxo-1,2-dihydro-isoquinoline-4carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide
3a
2-(1-Ethyl-1H-imidazol-2-ylmethyl)-8-fluoro-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid [(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-
5
amide
4a
8-Fluoro-3-methyl-2-oxazol-2-ylmethyl-1-oxo-1,2-dihydro-isoquinoline-4carboxylic acid [(S)-cyclobutyl-(3,5-difluoro-phenyl)-methyl]-amide
4b
8-Fluoro-3-methyl-2-oxazol-2-ylmethyl-1-oxo-1,2-dihydro-isoquinoline-4carboxylic acid [(S)-cyclobutyl-(3,4-difluoro-phenyl)-methyl]-amide
10
4c
8-Fluoro-3-methyl-2-oxazol-2-ylmethyl-1-oxo-1,2-dihydro-isoquinoline-4carboxylic acid [(S)-cyclobutyl-(4-fluoro-phenyl)-methyl]-amide
5a
8-Fluoro-2-oxazol-2-ylmethyl-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid
[(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide
5b
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8-Fluoro-2-oxazol-2-ylmethyl-1-oxo-3-(2-oxo-pyrrolidin-1-ylmethyl)-1,2dihydro-isoquinoline-4-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)methyl]-amide
5c
3-(4-tert-Butyl-piperazin-1-ylmethyl)-8-fluoro-2-oxazol-2-ylmethyl-1-oxo-1,2dihydro-isoquinoline-4-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)methyl]-amide.
20
17. A compound according to any of claims 1-16 for use in therapy.
18. A pharmaceutical composition comprising a compound according to any of
claims 1-16 and one or more pharmaceutically acceptable carrier or excipient.
25
19. A compound according to any of claims 1-16 for use in the treatment of a
disease selected from psychosis; schizophrenia; schizophrenoform disorder;
schizoaffective disorder; delusional disorder; brief psychotic disorder; shared
psychotic disorder; psychotic disorder due to a general medical condition; substance
30
or drug induced psychotic disorder (cocaine, alcohol, amphetamine etc); schizoid
personality disorder; schizotypal personality disorder; psychosis or schizophrenia
associated with major depression, bipolar disorder, Alzheimer’s disease or
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Parkinson’s disease; major depression; general anxiety disorder; bipolar disorder
(maintenance treatment, recurrence prevention and stabilization); mania; hypomania;
cognitive impairment; ADHD; obesity; appetite reduction; Alzheimer’s disease;
Parkinson’s disease; pain; convulsions; cough; asthma; airway hyperresponsiveness;
5
microvascular hypersensitivity; bronchoconstriction; chronic obstructive pulmonary
disease; urinary incontinence; gut inflammation; and inflammatory bowel syndrome.
20. The use of a compound according to any of claims 1-16 for the manufacture of a
medicament for the treatment of a disease selected from psychosis; schizophrenia;
10
schizophrenoform disorder; schizoaffective disorder; delusional disorder; brief
psychotic disorder; shared psychotic disorder; psychotic disorder due to a general
medical condition; substance or drug induced psychotic disorder (cocaine, alcohol,
amphetamine etc); schizoid personality disorder; schizotypal personality disorder;
psychosis or schizophrenia associated with major depression, bipolar disorder,
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Alzheimer’s disease or Parkinson’s disease; major depression; general anxiety
disorder; bipolar disorder (maintenance treatment, recurrence prevention and
stabilization); mania; hypomania; cognitive impairment; ADHD; obesity; appetite
reduction; Alzheimer’s disease; Parkinson’s disease; pain; convulsions; cough;
asthma; airway hyperresponsiveness; microvascular hypersensitivity;
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bronchoconstriction; chronic obstructive pulmonary disease; urinary incontinence; gut
inflammation; and inflammatory bowel syndrome.
21. A method for the treatment of a disease selected from psychosis; schizophrenia;
schizophrenoform disorder; schizoaffective disorder; delusional disorder; brief
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psychotic disorder; shared psychotic disorder; psychotic disorder due to a general
medical condition; substance or drug induced psychotic disorder (cocaine, alcohol,
amphetamine etc); schizoid personality disorder; schizotypal personality disorder;
psychosis or schizophrenia associated with major depression, bipolar disorder,
Alzheimer’s disease or Parkinson’s disease; major depression; general anxiety
30
disorder; bipolar disorder (maintenance treatment, recurrence prevention and
stabilization); mania; hypomania; cognitive impairment; ADHD; obesity; appetite
reduction; Alzheimer’s disease; Parkinson’s disease; pain; convulsions; cough;
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asthma; airway hyperresponsiveness; microvascular hypersensitivity;
bronchoconstriction; chronic obstructive pulmonary disease; urinary incontinence; gut
inflammation; and inflammatory bowel syndrome, the method comprising the
administration of a therapeutically effective amount of a compound according to any
5
of claims 1-16 to a patient in need thereof.
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Abstract
Isoquinolone derivatives of the general formula
R5
R6
R4
R7
A
R8 O
R9
R1
NH
R10
X
N
R11
R12
O
[I]
are NK3 antagonists
Q
Y