DERIVATIVES OF AMINOINDANES, THEIR PREPARATION
AND THEIR APPLICATION IN THERAPEUTICS
The instant invention relates to derivatives of aminoindanes, to their preparation
and to their application in therapeutics.
Transient receptor potential cation channel, subfamily C, member 6, also known
as TRPC6, is a human gene encoding a protein of the same name. TRPC6 has been
associated with fibrotic disorders, such as focal segmental glomerulosclerosis (a) Winn et
al, Science 2005, 308, 1801-1804. b) Hsu et al., Biochim. Biophys. Acta, Molec. Basis of
Disease 2007, 1772, 928-936. c) Kriz, Trends Molec. Med. 2005, 11, 527-530. d) Winn et
al, J. Amer.Soc.Nephrol. 2005, 17, 378-387), skeletal muscle dysfunction (Millay et al.,
PNAS 2009, 106, 19023 - 19028), renal failure, atherosclerosis, heart failure (Kuwahara et
al., J. Clin. Invest. 2006, 116, 3 1 14-26), cancer (e.g. oesophageal cancer, breast cancer)
(a) Aydar et al., Cancer Cell Int. 2009, 9, 23. b) Cai et al., Int. J. Cancer. 2009, 125, 2281-
2287. c) Shi et al., Gut 2009, 58, 1443-1450), chronic obstructive pulmonary disease (Sel
et al., Clin. Exp. Allergy. 2008, 38, 1548-1 558), pain (Alessandri-Haber et al., J. Neurosci.
2009, 29, 621 7-6228), pulmonary hypertension (Yu et al., Circulation 2009, 119, 231 3-
2322), ischemic stroke, myocardial infarction (Varga-Szabo et al., J. Thromb. and
Haemost. 2009, 7, 1057-1 066), inflammation or peripheral arterial occlusive disease.
It is thus desirable to provide novel TRPC6 inhibitors for the prevention or
treatment of these pathologies.
The compounds according to the instant invention respond to the general formula
(I) :
in which
A is a 6 to 10 membered aryl radical or a 5 to 10 membered heteroaryl radical,
where the aryl and heteroaryl radical may be mono- or bicyclic, and the heteroaryl
radical may comprise one or more heteroatoms selected from the group of
nitrogen , oxygen and sulfur;
where one or more hydrogen atoms in said mono- or bicyclic aryl or
heteroaryl radicals may be replaced by substituents R 1 which are selected
independently of one another from the group of H, F, CI, Br, I, (C1-C10)-
alkyl, (C2-C 0)-alkenyl, (C2-C 0)-alkynyl, (C3-C 4)-cycloalkyl, (C4-C20)-
cycloalkylalkyl, (C4-C20)-cycloalkylalkyloxy, ( -Cio)-alkoxy, (C1-C10)-
alkylthio, (C6-C14)-aryl, (C2-C13)-heteroaryl, -CN, -OH, -NR13R14,
-C(0)R1 2, -SF5, -S(0)nR12, -C(0)OR12, -C(0)NR1 3R14, -S(0)nNR1 3R14;
where two adjacent radicals R 1 may also form a saturated or partly
unsaturated (C5-C 0)-cycloalkyl radical or a saturated or partly
unsaturated (C2-C9)-cycloheteroalkyl radicals, where the
cycloheteroalkyi radical may comprise 1, 2 or 3 nitrogen , 1 or 2
oxygen , 1 or 2 sulfur, 1 or 2 nitrogen and 1 oxygen or 1 sulfur atom ;
where said alkyl, alkenyl, alkynyl, cycloalkyi, cycloalkylalkyl,
cycloalkylalkyloxy, cycloheteroalkyi, alkoxy, and alkylthio radicals
may be substituted independently of one another one or more
times by F, OH or (Cr C 0)-alkoxy;
is a mono- or fused bicyclic radical selected from the group of
6 to 10 membered aryl radicals,
of 5 to 10 membered heteroaryl radicals,
of 3 to 10 membered cycloalkyi radicals,
of 9 to 14 membered cycloalkylaryl radicals,
of 8 to 14 membered cycloalkylheteroaryl radicals,
of 3 to 10 membered cycloheteroalkyi radicals,
of 9 to 14 membered cycloheteroalkylaryl radicals and
of 8 to 14 membered cycloheteroalkylheteroaryl radicals,
where the cycloalkyi or cycloheteroalkyi units may be saturated or partly
unsaturated, and where the heterocyclic groups may comprise one or more
heteroatoms selected from the group of nitrogen, oxygen and sulfur;
where one or more hydrogen atoms in the radicals B may be replaced by
substituents R5 which are selected independently of one another from the
group of (Cr C 0)-alkyl radicals, of (C2-C 0)-alkenyl radicals, of (C2-C 0)-
alkynyl radicals, of (CrCi 0)-alkoxy radicals, of (CrCi 0)-alkylthio radicals, of
(C3-C 4)-cycloalkyl radicals, of (C4-C20)-cycloalkylalkyl radicals, of (C4-C20)-
cycloalkylalkyloxy, of (C2-C 9)-cycloheteroalkyl radicals, of (C3-C19)-
cycloheteroalkylalkyl radicals, of (C3-Cn)-cycloalkyloxy radicals, of (C2-Cn)-
cycloheteroalkyloxy radicals, of (C6-Ci )-aryl radicals, of (CrC 9)-heteroaryl
radicals, of (C9-C 4)-cycloalkylaryl radicals, of (C5-C 3)-cycloalkylheteroaryl
radicals, (C7-C 3)-cycloheteroalkylaryl radicals, (C4-Ci 2)-
cycloheteroalkylheteroaryl radicals, where
the cycloalkyl and cycloheteroalkyl units may be saturated or
partly unsaturated,
and where one or more hydrogen atoms in said radicals R5 may
be replaced by further radicals which are selected independently
of one another from the group of R 11 radicals,
it is further possible for R5 to be one or more radicals which are selected
independently of one another from the group of H, OH, (=0), NH2, F, CI,
Br, I, CN, N0 2, -NR1 7R1 8, -NR1 6COR1 7, -NR16COOR17,
-NR16CONR1 7R1 8, -NR1 6-S(0) 2-R17, -NR1 6-S(0) 2-NR17R18,
-COOR1 6, -COR16; -CO(NR17R18), S(0) nR16, -S(0) 2NR17R18,
where R 16, R17 and R 18 independently of one another for a radical
selected from the group of H, (C2-C 9)-cycloheteroalkyl, (C3-C )-
cycloalkyl, (C6-Ci )-aryl, (d-Cio)-alkyl radicals,
all of which may be substituted independently of one another by
OH, (=0), F, CI, Br, I, CN, N0 2, -NR13R14, -NR13COR12,
-NR1 3COOR1 2, -NR1 2CONR1 3R14, -NR1 3-S(0) 2-R12,
-NR12-S(0) 2-R13R14, -COOR12, -COR12; -CO(NR1 3R14),
-S(0) nR12, -S(0) 2NR1 3R14, (C3-C14)-cycloalkyl, (C4-C20)-
cycloalkylalkyl, (C2-C 9)-cycloheteroalkyl, (C3-C 9)-
cycloheteroalkylalkyl, (C6-C )-aryl and (CrC 9)-heteroaryl,
and where R 17 and R18 can form together with the nitrogen to which
they are bonded a 4-7 membered, saturated, unsaturated or partly
unsaturated heterocycle having 1 to 13 carbon atoms which may
additionally comprise one or more heteroatoms from the list -0-,
-S(0) n- , =N- and -NR15-,
where the heterocycle formed may be substituted
independently of one another one or more times by F, OH,
(=0), NH2, NH(C C4)alkyl, N((C C4)alkyl)2, CN or (C C10)-
alkoxy, (C C10)-alkyl, (C2-C10)-alkenyl, (C2-C10)-alkynyl, (C3-
C 4)-cycloalkyl, (C4-C20)-cycloalkylalkyl, (C2-C20)-
cycloheteroalkyl, (C3-C 9)-cycloheteroalkylalkyl, each of
which may in turn carry independently of one another one or
more radicals F, OH, (=0), NH2, NH(Ci-C 4)alkyl, N((C
C4)alkyl) 2, CN or (C C10)-alkoxy;
L is a covalent bond or an alkylene bridge having 1 to 10 carbon atoms,
which may carry independently of one another one or more
substituents from the group of radicals (d-Cio)-alkyl, (C3-Ci 4)-
cycloalkyl, (C4-C20)-cycloalkylalkyl radical, -COR12, -CO(NR1 3R14),
S(0) nR12, -S(0) 2NR13R14, (=0) and F; where the alkyl, cycloalkyl
and cycloalkyl radicals may be substituted one or more times by F;
X is a group -N(R6)-, -0-, -S(0) n- , or alkylene having 1 to 5 carbon atoms, where
R6 may be hydrogen or may be (CrCi )-alkyl, (C3-C 4)-cycloalkyl,
(C4-C20)-cycloalkylalkyl radical, all of which may be substituted
independently of one another one or more times by F, or R6 may be
-COR1 2; -CO(NR1 3R14), S(0) nR12, -S(0) 2NR1 3R14;
R2 is absent or is one or more substituents which may be selected independently of
one another from the group of F, (CrCi 0)-alkyl and (CrCi 0)-alkoxy radical, where
the alkyl and alkoxy radicals may be substituted independently of one another one
or more times by F;
R3 and R4 are independently of one another a hydrogen radical or a radical which is
selected from the group of (Cr C 0)-alkyl radicals, of (C2-C 0)-alkenyl radicals, of
(C2-Cio)-alkynyl radicals, of (C3-C 4)-cycloalkyl radicals, of (C4-C20)-cycloalkylalkyl
radicals, of (C2-C 9)-cycloheteroalkyl radicals, of (C3-C 9)-cycloheteroalkylalkyl
radicals, of (C6-C 0)-aryl radicals, of (C7-C20)-arylalkyl radicals, of (CrC 9)-
heteroaryl radicals, of (C2-C 9)-heteroarylalkyl radicals, where
the radicals R3 and R4 may be substituted independently of one another
one or more times by a radical from the group of OH, NH2, (=0), F, CI,
Br, I, CN, N0 2, -NR13R14, -NR13COR12, -NR13COOR12,
-NR12CONR1 3R14, -NR13-S(0) 2-R12, -NR1 3-S(0) 2-NR13R14,
-COOR1 2, -COR12; -CO(NR13R14), S(0) nR12, -S(0) 2R13R14, or
R3 and R4 form together with the nitrogen to which they are bonded a 4-1 0 membered,
saturated, unsaturated or partly unsaturated heterocycle which may additionally
comprise one or more heteroatoms from the list -0-, -S(0) n- , =N- and -NR8-,
where
the heterocyclic radicals may be substituted independently of one another
one or more times by radicals selected from the group of R7 and R9, and
where
the heterocyclic radicals may be bridged by a bond, by a saturated or
unsaturated (d-Cio)-alkyl or (CrC 9)-heteroalkyl chain or by -NR1 5-, -0-,
-S-, and where
the alkyl and heteroalkyl chains may also form a spirocyclic ring
system with the ring system formed by R3 and R4, where the alkyl
and heteroalkyl bridges may be substituted independently of one
another one or more times by radicals selected from the group of
R7 and R9,
and where
R8 in the group NR8 may form with the ring which R3 and R4 may form a
further saturated, unsaturated or partly unsaturated heterocycle which may
be substituted independently of one another one or more times by radicals
selected from the group of R7 and R9, and may additionally comprise one
or more heteroatoms from the list -0-, -S(0) n- , -N= and -NR19-;
are a (CrCi 0)-alkyl radical or (CrCi 4)-cycloalkyl radical, where the alkyl radical
may be substituted independently of one another one or more times by R9;
is an H, a (Cr C 0)-alkyl radical or (Ci-C )-cycloalkyl radical, C0R12,
-CO(NR13R14), S(0) nR12, -S(0) 2NR13R14, where the alkyl radical may be
substituted independently of one another one or more times by R 10;
R9 is a radical selected from the group of OH, (=0), F, CI, Br, I, CN, N0 2, -NR13R14,
-NR1 3COR1 2, -NR1 3COOR1 2, -NR12CONR13R14, -NR1 3-S(0) 2-R12, -NR1 3-
S(0) 2-NR13R14, -C00R12, -C0R12, -CO(NR13R14), S(0) nR12,
-S(0) 2NR13R14, (C3-C14)-cycloalkyl, (C4-C20)-cycloalkylalkyl, (C C10)-alkoxy, (C2-
C 9)-cycloheteroalkyl, (C3-C 9)-cycloheteroalkylalkyl, (C6-C 0)-aryl radicals, of (C
C9)-heteroaryl radicals;
R10 is a radical selected from the group of F, OH, CN, (CrCi 0)-alkoxy, (C - 0)-
alkylthio, N0 2, -NR13R14, -NR13COR12, -NR13COOR12, -NR13CONR13R14,
-NR1 3-S(0) 2-R12, -NR12-S(0) 2-NR1 3R14, -COOR1 2, -COR1 2, -CO(NR1 3R14),
S(0) nR12, -S(0) 2NR13R14;
R 11 is a radical selected from the group of (d-Cio)-alkyl, (C2-C 0)-alkenyl, (C2-C 0)-
alkynyl, (CrCi 0)-alkoxy, (CrC 20)-alkylthio, (C3-C 4)-cycloalkyl, (C4-C 0)-
cycloalkylalkyl, (C2-C 3)-cycloheteroalkyl, (C4-C 9)-cycloheteroalkylalkyl, (C3-C )-
cycloalkyloxy, (C2-C 3)-cycloheteroalkyloxy,
all of which may be substituted independently of one another one or more
times by R10;
(=0), CI, Br, I and R 10;
R12, R 13 and R14 may independently of one another be H, (CrCi )-alkyl, (C2-C 0)-
alkenyl, (C2-C 0)-alkynyl, (C3-C 4)-cycloalkyl, (C4-C 0)-cycloalkylalkyl, (C2-C 3)-
cycloheteroalkyl, (C3-C 9)-cycloheteroalkylalkyl, (C6-C )-aryl, each of which may be
substituted independently of one another one or more times by F, OH, (=0), NH2,
NH(C C4)alkyl, N((C C4)alkyl) , CN or (C C10)-alkoxy;
or where R 13 and R14 may form together with the nitrogen to which they are
bonded a 4-7 membered, saturated, unsaturated or partly unsaturated heterocycle
having 1 to 13 carbon atoms, which may additionally comprise one or more
heteroatoms from the list -0-, -S(0) n- , =N- and -NR1 5-, where
the formed heterocycle may be substituted independently of one another one
or more times by F, OH, (=0), NH , NH(C C4)alkyl, N((C C4)alkyl) , CN or
(C C10)-alkoxy, (C C10)-alkyl, (C2-C10)-alkenyl, (C2-C10)-alkynyl, (C3-C14)-
cycloalkyl, (C4-C20)-cycloalkylalkyl, (C2-C20)-cycloheteroalkyl, (C3-C 9)-
cycloheteroalkylalkyl, each of which may in turn carry independently of one
another one or more radicals F, OH, (=0), NH2, NH(C C4)alkyl, N((C
C4)alkyl) 2, CN or (C C10)-alkoxy;
R 15 is a radical selected from the group of H, (CrCi 0)-alkyl, (C2-C 0)-alkenyl, (C2-C 0)-
alkynyl, (C3-C )-cycloalkyl, (C4-C20)-cycloalkylalkyl, (C2-C 3)-cycloheteroalkyl, (C3-
C 9)-cycloheteroalkylalkyl, each of which may be substituted independently of one
another one or more times by F, OH, CN or (d-Cio)-alkoxy;
R19 is an H, a (C C10)-alkyl radical or (C C14)-cycloalkyl radical, C0R12,
-CO(NR13R14), S(0) nR12, -S(0) 2NR13R14, where the alkyl radical may be
substituted independently of one another one or more times by R 10;
and in which
n is 0, 1 or 2;
p is 1 or 2 and
q is 0 or ,
and the pharmaceutically acceptable salts thereof,
and in which
i) in the case where A is phenyl, B is phenyl or benzodioxolanyl, X is -O- or -S-, L
is a bond and R3 and R4 are H, (C C10)-alkyl, (C3-C14)-cycloalkyl, (C7-C20)-
arylalkyl or R3 and R4 together are an unsubstituted pyrrolidinyl, morpholinyl,
piperidinyl or piperazinyl radical or 4-methylpiperazinyl radical, at least one R5
radical which is not a (d-Cio)-alkyl, (CrCi 0)-alkoxy, OH, CF3, F, CI, Br or I radical
must be present,
ii) in the case where A is phenyl, X is -0-, -S- or -NH- and R3 and R4 are a (C
Cio)-alkyl, (C3-C 4)-cycloalkyl or a (C4-C20)-cycloalkylalkyl radical, at least one R5
radical which is not an F, CI, Br, I, (C C4)-alkyl, (C C4)-alkoxy, CF3, OCF3, CN,
N0 2, NH2, -NH((C C10)-alkyl), -N((C C10)-alkyl)2, unsubstituted or substituted
benzoyl or an unsubstituted or substituted phenyl-(CH 2) -Y-(CH2)s- radical, with Y
being a bond or an oxygen and r and s being 0 to 4, where r+s is not greater than
4, must be present.
The compounds of the invention advantageously are of the formula (I) above,
wherein :
A is a 6 to 10 membered aryl radical or a 5 to 10 membered heteroaryl radical,
where the aryl and heteroaryl radical may be mono- or bicyclic, and the heteroaryl
radical may comprise one or more heteroatoms selected from the group of
nitrogen, oxygen and sulfur;
where one or more hydrogen atoms in said mono- or bicyclic aryl or
heteroaryl radicals may be replaced by substituents R 1 which are selected
independently of one another from the group of H, F, CI, Br, I, ( -C 0)-
alkyl, (C2-C10)-alkenyl, (C2-C10)-alkynyl, (C3-C14)-cycloalkyl, (C4-C20)-
cycloalkylalkyl, (C4-C20)-cycloalkylalkyloxy, (Cr C 0)-alkoxy, (C o)-
alkylthio, (C6-C14)-aryl, (C2-C13)-heteroaryl, -CN, -OH, -NR13R14,
-C(0)R1 2, -SF5, -S(0) nR12, -C(0)OR12, -C(0)NR1 3R14, -S(0) nNR1 3R14;
where two adjacent radicals R 1 may also form a saturated or partly
unsaturated (C5-C 0)-cycloalkyl radical or a saturated or partly
unsaturated (C2-C9)-cycloheteroalkyl radicals, where the
cycloheteroalkyi radical may comprise 1, 2 or 3 nitrogen, 1 or 2
oxygen, 1 or 2 sulfur, 1 or 2 nitrogen and 1 oxygen or 1 sulfur atom;
where said alkyl, alkenyl, alkynyl, cycloalkyi, cycloalkylalkyl,
cycloalkylalkyloxy, cycloheteroalkyi, alkoxy, and alkylthio radicals
may be substituted independently of one another one or more
times by F, OH or (d-Cio)-alkoxy;
is a mono- or fused bicyclic radical selected from the group of
6 to 10 membered aryl radicals,
of 5 to 10 membered heteroaryl radicals,
of 3 to 10 membered cycloalkyi radicals,
of 9 to 14 membered cycloalkylaryl radicals,
of 8 to 14 membered cycloalkylheteroaryl radicals,
of 3 to 10 membered cycloheteroalkyi radicals,
of 9 to 14 membered cycloheteroalkylaryl radicals and
of 8 to 14 membered cycloheteroalkylheteroaryl radicals,
where the cycloalkyi or cycloheteroalkyi units may be saturated or partly
unsaturated, and where the heterocyclic groups may comprise one or more
heteroatoms selected from the group of nitrogen, oxygen and sulfur;
where one or more hydrogen atoms in the radicals B may be replaced by
substituents R5 which are selected independently of one another from the
group of (CrCi 0)-alkyl radicals, of (C2-C 0)-alkenyl radicals, of (C2-C 0)-
alkynyl radicals, of (Cr C 0)-alkoxy radicals, of (Cr C 0)-alkylthio radicals, of
(C3-C 4)-cycloalkyl radicals, of (C4-C20)-cycloalkylalkyl radicals, of (C4-C20)-
cycloalkylalkyloxy, of (C2-C 9)-cycloheteroalkyl radicals, of (C3-C 9)-
cycloheteroalkylalkyl radicals, of (C3-Cn)-cycloalkyloxy radicals, of (C2-Cn)-
cycloheteroalkyloxy radicals, of (C6-C 0)-aryl radicals, of (CrC 9)-heteroaryl
radicals, of (C9-C 4)-cycloalkylaryl radicals, of (C5-C 3)-cycloalkylheteroaryl
radicals, (C7-C 3)-cycloheteroalkylaryl radicals, (C4-C 2)-
cycloheteroalkylheteroaryl radicals, where
the cycloalkyi and cycloheteroalkyi units may be saturated or
partly unsaturated,
and where one or more hydrogen atoms in said radicals R5 may
be replaced by further radicals which are selected independently
of one another from the group of R 11 radicals,
it is further possible for R5 to be one or more radicals which are selected
independently of one another from the group of OH, (=0), NH2, F, CI, Br, I,
CN, N0 2, -NR1 7R1 8, -NR16COR17, -NR16COOR17,
-NR1 6CONR1 7R1 8, -NR1 6-S(0) 2-R17, -NR1 6-S(0) 2-NR17R18,
-COOR1 6, -COR16; -CO(NR17R18), S(0)„R16, -S(0) 2NR17R18,
where R 16, R17 and R 18 independently of one another for a radical
selected from the group of H, (C2-C 9)-cycloheteroalkyl, (C3-Ci )-
cycloalkyl, (C6-C )-aryl, (Cr C 0)-alkyl radicals,
all of which may be substituted independently of one another by
OH, (=0), F, CI, Br, I, CN, N0 2, -NR13R14, -NR13COR12,
-NR1 3COOR1 2, -NR1 2CONR1 3R14, -NR1 3-S(0) 2-R12,
-NR12-S(0) 2-R13R14, -C00R12, -C0R12; -CO(NR1 3R14),
-S(0) nR12, -S(0) 2NR1 3R14, (C3-C14)-cycloalkyl, (C4-C20)-
cycloalkylalkyl, (C2-C 9)-cycloheteroalkyl, (C3-C 9)-
cycloheteroalkylalkyl, (C6-C 0)-aryl and ( -C9)-heteroaryl,
and where R 17 and R18 can form together with the nitrogen to which
they are bonded a 4-7 membered, saturated, unsaturated or partly
unsaturated heterocycle having 1 to 13 carbon atoms which may
additionally comprise one or more heteroatoms from the list -0-,
-S(0) n- , =N- and -NR15-,
where the heterocycle formed may be substituted
independently of one another one or more times by F, OH,
(=0), NH , NH(C C4)alkyl, N((C C4)alkyl) , CN or (C C10)-
alkoxy, (C C10)-alkyl, (C2-C10)-alkenyl, (C2-C10)-alkynyl, (C3-
C )-cycloalkyl, (C4-C20)-cycloalkylalkyl, (C2-C20)-
cycloheteroalkyl, (C3-C 9)-cycloheteroalkylalkyl, each of
which may in turn carry independently of one another one or
more radicals F, OH, (=0), NH2, NH(C C4)alkyl, N((C
C4)alkyl)2, CN or (C C10)-alkoxy;
alent bond or an alkylene bridge having 1 to 10 carbon atoms,
which may carry independently of one another one or more
substituents from the group of radicals (d-Cio)-alkyl, (C3-C )-
cycloalkyl, (C4-C20)-cycloalkylalkyl radical, -COR12, -CO(NR1 3R14),
S(0) nR12, -S(0) 2NR13R14, (=0) and F; where the alkyl, cycloalkyl
and cycloalkyl radicals may be substituted one or more times by F;
X is a group -N(R6)-, -0-, -S(0) n- , or alkylene having 1 to 5 carbon atoms, where
R6 may be hydrogen or may be (CrCi )-alkyl, (C3-C 4)-cycloalkyl,
(C4-C20)-cycloalkylalkyl radical, all of which may be substituted
independently of one another one or more times by F, or R6 may be
-COR12; -CO(NR1 3R14), S(0)„R12, -S(0) 2NR1 3R14;
R2 is absent or is one or more substituents which may be selected independently of
one another from the group of F, (Cr C 0)-alkyl and (Cr C 0)-alkoxy radical, where
the alkyl and alkoxy radicals may be substituted independently of one another one
or more times by F;
R3 and R4 form together with the nitrogen to which they are bonded a 4-1 0 membered,
saturated, heterocycle which may additionally comprise one or more heteroatoms
from the list -0-, -S(0) n- , and -NR8-, where
the heterocyclic radicals may be substituted independently of one another
one or more times by radicals selected from the group of R7 and R9, and
where
the heterocyclic radicals may be bridged by a bond, by a saturated or
unsaturated (CrCi 0)-alkyl or (CrC 9)-heteroalkyl chain or by -NR1 5-, -0-,
-S-, and where
the alkyl and heteroalkyl chains may also form a spirocyclic ring
system with the ring system formed by R3 and R4, where the alkyl
and heteroalkyl bridges may be substituted independently of one
another one or more times by radicals selected from the group of
R7 and R9,
and where
R8 in the group NR8 may form with the ring which R3 and R4 may form a
further saturated, unsaturated or partly unsaturated heterocycle which may
be substituted independently of one another one or more times by radicals
selected from the group of R7 and R9, and may additionally comprise one
or more heteroatoms from the list -0-, -S(0) n- , -N= and -NR19-;
are a (d-Cio)-alkyl radical or (CrCi 4)-cycloalkyl radical, where the alkyl radical
may be substituted independently of one another one or more times by R9;
is an H, a (Cr C 0)-alkyl radical or (Ci-C )-cycloalkyl radical, COR12,
-CO(NR13R14), S(0) nR12, -S(0) 2NR13R14, where the alkyl radical may be
substituted independently of one another one or more times by R 10;
R9 is a radical selected from the group of OH, (=0), F, CI, Br, I, CN, N0 2, -NR13R14,
-NR1 3COR1 2, -NR1 3COOR1 2, -NR12CONR13R14, -NR1 3-S(0) 2-R12, -NR1 3-
S(0) 2-NR13R14, -COOR12, -COR12, -CO(NR13R14), S(0) nR12,
-S(0) 2NR13R14, (C3-C14)-cycloalkyl, (C4-C20)-cycloalkylalkyl, (C C10)-alkoxy, (C2-
C 9)-cycloheteroalkyl, (C3-C 9)-cycloheteroalkylalkyl, (C6-C 0)-aryl radicals, of (C
C9)-heteroaryl radicals;
R10 is a radical selected from the group of F, OH, CN, (CrCi 0)-alkoxy, (C1-C10)-
alkylthio, N0 2, -NR13R14, -NR13COR12, -NR13COOR12, -NR13CONR13R14,
-NR1 3-S(0) 2-R12, -NR12-S(0) 2-NR1 3R14, -COOR1 2, -COR1 2, -CO(NR1 3R14),
S(0) nR12, -S(0) 2NR13R14;
R 11 is a radical selected from the group of (Cr C 0)-alkyl, (C2-C 0)-alkenyl, (C2-C 0)-
alkynyl, (CrCi 0)-alkoxy, (CrC 20)-alkylthio, (C3-C 4)-cycloalkyl, (C4-C 0)-
cycloalkylalkyl, (C2-C 3)-cycloheteroalkyl, (C4-C 9)-cycloheteroalkylalkyl, (C3-C )-
cycloalkyloxy, (C2-C 3)-cycloheteroalkyloxy,
all of which may be substituted independently of one another one or more
times by R10;
(=0), CI, Br, I and R 10;
R12, R 13 and R14 may independently of one another be H, (Cr C 0)-alkyl, (C2-C 0)-
alkenyl, (C2-C10)-alkynyl, (C3-C14)-cycloalkyl, (C4-C10)-cycloalkylalkyl, (C2-C13)-
cycloheteroalkyl, (C3-C 9)-cycloheteroalkylalkyl, (C6-C 0)-aryl, each of which may be
substituted independently of one another one or more times by F, OH, (=0), NH2,
NH(C C4)alkyl, N((C C4)alkyl) , CN or (C C10)-alkoxy;
or where R 13 and R14 may form together with the nitrogen to which they are
bonded a 4-7 membered, saturated, unsaturated or partly unsaturated heterocycle
having 1 to 13 carbon atoms, which may additionally comprise one or more
heteroatoms from the list -0-, -S(0) n- , =N- and -NR1 5-, where
the formed heterocycle may be substituted independently of one another one
or more times by F, OH, (=0), NH2, NH(Ci-C 4)alkyl, N((Ci-C 4)alkyl) 2 > CN or
(Ci-Cio)-alkoxy, (C C10)-alkyl, (C2-C10)-alkenyl, (C2-C10)-alkynyl, (C3-C14)-
cycloalkyl, (C4-C20)-cycloalkylalkyl, (C2-C20)-cycloheteroalkyl, (C3-C 9)-
cycloheteroalkylalkyl, each of which may in turn carry independently of one
another one or more radicals F, OH, (=0), NH2, NH(C C4)alkyl, N((C
C4)alkyl)2, CN or (C C10)-alkoxy;
R 15 is a radical selected from the group of H, (CrCi )-alkyl, (C2-C 0)-alkenyl, (C2-C 0)-
alkynyl, (C3-C 4)-cycloalkyl, (C4-C20)-cycloalkylalkyl, (C2-C 3)-cycloheteroalkyl, (C3-
C 9)-cycloheteroalkylalkyl, each of which may be substituted independently of one
another one or more times by F, OH, CN or (d-Cio)-alkoxy;
R19 is an H, a (C C10)-alkyl radical or (C C14)-cycloalkyl radical, C0R12,
-CO(NR13R14), S(0) nR12, -S(0) 2NR13R14, where the alkyl radical may be
substituted independently of one another one or more times by R 10;
and in which
n is 0, 1 or 2;
p is 1 or 2 and
q is 0 or ,
in the form of a free base or of an addition salt with an acid, as well as in the form of an
hydrate or of a solvate,
and in which :
in the case where A is phenyl, B is phenyl or benzodioxolanyl, X is -O- or -S-, L is
a bond and R3 and R4 together are an unsubstituted pyrrolidinyl, morpholinyl,
piperidinyl or piperazinyl radical or 4-methylpiperazinyl radical, at least one R5
radical which is not a (CrCi )-alkyl, (CrCi 0)-alkoxy, OH, CF3, F, CI, Br or I radical
must be present.
In one embodiment, compounds of the formula I and the pharmaceutically
acceptable salts thereof are preferred wherein:
L is a covalent bond;
X is a group -0-;
and q is 0.
The compounds of formula (I) can comprise one or more asymmetric carbon
atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These
enantiomers and diastereoisomers, as well as their mixtures, including racemic mixtures,
form part of the invention.
The compounds of formula (I) can be provided in the form of a free base or in the
form of addition salts with acids, which also form part of the invention.
These salts are advantageously prepared with pharmaceutically acceptable acids,
but salts with other acids, useful for example for the purification or for the isolation of the
compounds of formula (I), also form part of the invention.
The compounds of formula (I) can also be provided in the form of an hydrate or of
a solvate, i.e. in the form of associations or combinations with one or more water or
solvent molecules. Such hydrates and solvates also form part of the invention.
According to the present invention, the terms below have the following meanings:
- a halogen atom corresponds to a fluorine, chlorine, bromine or iodine atom;
- ( -Cio)-Alkyl radicals may in the context of the present invention be straightchain
or branched. This also applies when they carry substituents or occur as substituents
of other radicals, for example in fluoroalkyl radicals or alkoxy radicals. Examples of alkyl
radicals are methyl, ethyl, n-propyl, isopropyl (= 1-methylethyl), n-butyl, isobutyl
(= 2-methylpropyl), sec-butyl (= 1-methylpropyl), tert-butyl (= 1, 1 -dimethylethyl), n-pentyl,
isopentyl, tert-pentyl, neopentyl and hexyl. Preferred alkyl radicals are methyl, ethyl, npropyl,
isopropyl, n-butyl and tert-butyl.
- (C3-C 4)-Cycloalkyl radicals in the context of the present invention may be
saturated or partly unsaturated. This also applies when they carry substituents or occur
as substituents of other radicals. Cycloalkyl radicals having 3, 4, 5, 6, 7 or 8 carbon atoms
are preferred. Examples of cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl and cyclooctyl a fluoroalkyl group corresponds to an alkyl group,
wherein one or more hydrogen atoms have been substituted by fluorine atoms;
- (C2-C 9)-Cycloheteroalkyl radicals in the context of the present invention may
be saturated or partly unsaturated. This also applies when they carry substituents or
occur as substituents of other radicals. The cycloheteroalkyl radicals preferably have
heteroatoms selected from the group of nitrogen, oxygen and sulfur. Cycloheteroalkyl
radicals having 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms are preferred, it being possible for 1
or 2 nitrogen atoms, 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, 1 nitrogen and 1 oxygen
atom or 1 sulfur atom or 1 oxygen and 1 sulfur atom to be present as heteroatoms. The
cycloheteroalkyi radicals can be attached by any position. Examples of such heterocycles
are selected from the group of oxiranyl, thiiranyl, aziridinyl, oxetanyl, thietanyl, azetidinyl,
diazetidinyl, pyrrolidinyl, dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl,
tetrahydropyrazolyl, oxolanyl, dihydrofuranyl, dioxolanyl, thiolanyl, dihydrothiophenyl,
oxazolanyl, dihydrooxazolyl, isooxazolanyl, dihydroisooxazolyl, thiazolidinyl,
dihydrothiazolyl, isothiazolidinyl, dihydroisothiazolyl, oxathiolidinyl, - -pyranyl, 4H-pyranyl,
tetrahydropyranyl, 2/-/-thiopyranyl, 4H-thiapyranyl, tetrahydrothiopyranyl, piperidinyl, di-,
tetrahydropyridyl, piperazinyl, di-, tetrahydropyrazinyl, di-, tetra-, hexahydropyridazinyl, di-,
tetra-, hexahydropyrimidinyl, morpholinyl, thiomorpholinyl, azepanyl, thiepanyl and
oxepinyl, it also being possible for two of these heterocyclic rings to form a saturated or
partly unsaturated fused bicyclic ring system. Examples of such bicyclic ring systems are
octahydropyrrolo[1 ,2a]pyrazinyl, octahydropyrrolo[3,4b]pyrrolyl, hexahydropyrrolo[3,4-
c]pyrrolyl- and octahydropyrrolo[3,4-c]pyrrolyl. Prefered cycloheteroalkyi are azetidinyl,
pyrrolidinyl, piperidinyl, homopiperazine or 2,5-diazabicyclo[2.2.1]heptane.
- (C2-Cio)-Alkenyl radicals in the context of the present invention may likewise be
straight-chain or branched. This also applies when they carry substituents or occur as
substituents of other radicals. Examples of alkenyl radicals are ethenyl, propenyl and
butenyl.
- (C2-Cio)-Alkynyl radicals in the context of the present invention may likewise be
straight-chain or branched. This also applies when they carry substituents or occur as
substituents of other radicals. Examples of alkynyl radicals are ethynyl, propynyl and
butynyl.an alkoxy group corresponds to an -O-alkyI group, wherein the alkyl group is as
defined above;
- Examples of preferred (C6-C )-aryl radicals are phenyl and naphthyl. This also
applies when they carry substituents or occur as substituents of other radicals.
(Ci-Cg )-Heteroaryl radicals are aromatic ring compounds in which one or more ring
atoms are oxygen atoms, sulfur atoms or nitrogen atoms, e.g. 1, 2 or 3 nitrogen atoms, 1
or 2 oxygen atoms, 1 or 2 sulfur atoms or a combination of various heteroatoms. This
also applies when they carry substituents or occur as substituents of other radicals. The
heteroaryl radicals may be attached by all positions. Heteroaryl means for example
furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,
thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl,
isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl and cinnolinyl.
Preferred heteroaryl radicals are 2- or 3-thiophenyl, 2- or 3-furyl, 1-, 2- or 3- pyrrolyl,
1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 1,2,3-triazol-1 - , -4- or -5-yl, 1,2,4-triazol-
1-, -3- or -5-yl, 1- or 5-tetrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 1,2,3-
oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-oxadiazol-2-yl or -5-yl, 2-, 4- or 5-
thiazolyl, 3-, 4- or 5-isothiazolyl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,
1,2,3-thiadiazol-4- or -5-yl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 3- or 4-pyridazinyl,
pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1- , 3-, 4-, 5-, 6- or
7-indazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1- , 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 2-, 4-, 5-,
6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl,
1- , 4-, 5-, 6-, 7- or 8-phthalazinyL
Particularly preferred heteroaryl radicals are pyrazolyl, isoxasolyl, benzotriazolyl;
- (C9-C 4)-Cycloalkylaryl radicals are preferably selected from the group of fused
ring systems having a cycloalkyl ring and an aryl ring, in particular a phenyl ring.
Particularly preferred cycloalkylaryl radicals are indenyl, dihydronaphthyl,
tetrahydronaphthyl and indanyl.
- (C5-C 3)-Cycloalkylheteroaryl radicals are preferably selected from the group of
fused ring systems having a cycloalkyl ring and a heteroaryl ring.
- (C7-C 3)-Cycloheteroalkylaryl radicals are preferably fused ring systems having
a cycloheteroalkyi ring and an aryl ring, in particular a phenyl ring. Preferred
cycloheteroalkylaryl radicals are benzodihydrothiophenyl, benzothiolanyl,
benzodihydrofuranyl, benzooxolanyl, benzodioxolanyl, benzodihydropyrrolyl,
benzodihydroimidazolyl, benzodihydropyrazolyl, benzodihydrotriazolyl, benzopiperazinyl,
benzodihydrothiazolyl, benzomorpholinyl benzodihydrooxazolyl, dihydroquinolinyl,
dihydroisoquinolinyl, tetrahydroisoquinolinyl and tetrahydroquinolinyl. Particularly
preferred are cycloheteroalkylaryl radicals of formula:
- (C4-C 2)-Cycloheteroalkylheteroaryl radicals are preferably selected from the
group of fused ring systems having a cycloheteroalkyi ring and a heteroaryl ring.
- A cycloheteroalkyi corresponds to a cyclic group comprising between 3 and 19
carbon atoms and between 1 and 3 heteroatoms, preferably nitrogen atoms.
The compounds of the invention advantageously respond to the general formula
is a 6 membered aryl radical or a 6 membered heteroaryl radical, where and T" are
independently N or CR1 ;
where one or more hydrogen atoms in said aryl or heteroaryl radicals may
be replaced by substituents R 1 which are selected independently of one
another from the group of H, F, CI, Br, I, (d-Cio)-alkyl-, (Cr C 0)-alkoxy-,
-CN, -OH, -S(0) nR12, - ;
where said alkyl and alkoxy radicals may be substituted
independently of one another one or more times by F
and R 12 is H or (Cr C 0)-alkyl, optionally substituted one or more
times by F;
is a 6 membered aryl radical or a 6 membered heteroaryl radical, where T is N or
CR5;
is absent or is radical chosen from a (C6-C 0)-aryl radical and a (C3-C6)-
cycloheteroalkyl radical comprising one ore more heteroatoms chosen from O, N
and S,
where at least one hydrogen atoms in the radicals B' and/or B" is replaced
by substituents R5 which are selected independently of one another from
the group of (CrCi 0)-alkyl radicals, of (CrCi 0)-alkoxy radicals, of (C3-C 4)-
cycloalkyl radicals, of (CrC 9)-heteroaryl radicals, where
the cycloalkyl units may be saturated or partly unsaturated,
and where one or more hydrogen atoms in said radicals R5 may
be replaced by further radicals which are selected independently
of one another from the group of F, CI, Br and I,
it is further possible for R5 to be one or more radicals which are selected
independently of one another from the group of OH, F, CI, Br, I, CN, N0 2,
-COOR1 6, -CO(NR1 7R1 8),
where R 16, R17 and R 18 independently of one another for a radical
selected from the group of H and (d-Cio)-alkyl radicals, which may
be substituted independently of one another by F, CI, Br, I,
a covalent bond or a methylene bridge;
X is a group -O- or -S(0) n- ;
R3 and R4 are independently of one another a hydrogen radical, a (CrCi 0)-alkyl radical
or a (C3-C 9)-cycloheteroalkyl radical comprising at least one nitrogen atom, or
R3 and R4 form together with the nitrogen to which they are bonded a 4-7 membered,
saturated mono-or bi-cycloheteroalkyl radical which may additionally comprise one
or more -NR8- heteroatom, where
the cycloheteroalkyl radical may be substituted independently of one
another one time by a radical-(CR20R21 ) -NR22R23, in which r is 0 or 1
and R20, R21 , R22 and R23 are independently of one another H or a (C
Cio)-alkyl radical optionally substituted one or more times by F, CI, Br
and/or I,
R8 is an H or a (Cr C 0)-alkyl radical;
and in which
n is 0, 1 or 2; and
q is 0 or ,
in the form of a free base or of an addition salt with an acid, as well as in the form of an
hydrate or of a solvate.
Particularly preferred, the compounds of the invention are of formula (II) above, wherein :
A is a 6 membered aryl radical or a 6 membered heteroaryl radical, where and T" are
independently N or CR1 ;
where one or more hydrogen atoms in said aryl or heteroaryl radicals may
be replaced by substituents R 1 which are selected independently of one
another from the group of H, F, CI, Br, I, (Cr C 0)-alkyl-, (Cr C 0)-alkoxy-,
-CN, -OH, -S(0) nR12, - ;
where said alkyl and alkoxy radicals may be substituted
independently of one another one or more times by F
and R 12 is H or (d-Cio)-alkyl, optionally substituted one or more
times by F;
B' is a 6 membered aryl radical or a 6 membered heteroaryl radical, where T is N or
CR5;
B" is absent or is radical chosen from a (C6-Ci )-aryl radical and a (C3-C6)-
cycloheteroalkyl radical comprising one ore more heteroatoms chosen from O, N
and S,
where at least one hydrogen atoms in the radicals B' and/or B" is replaced
by substituents R5 which are selected independently of one another from
the group of (Cr C 0)-alkyl radicals, of (Cr C 0)-alkoxy radicals, of (C3-C 4)-
cycloalkyl radicals, of (CrC 9)-heteroaryl radicals, where
the cycloalkyl units may be saturated or partly unsaturated,
and where one or more hydrogen atoms in said radicals R5 may
be replaced by further radicals which are selected independently
of one another from the group of F, CI, Br and I,
it is further possible for R5 to be one or more radicals which are selected
independently of one another from the group of OH, F, CI, Br, I, CN, N0 2,
-COOR1 6, -CO(NR1 7R1 8),
where R 16, R17 and R 18 independently of one another for a radical
selected from the group of H and (CrCi 0)-alkyl radicals, which may
be substituted independently of one another by F, CI, Br, I,
L is a covalent bond or a methylene bridge;
X is a group -O- or -S(0) n- ;
R3 and R4 form together with the nitrogen to which they are bonded a 4-7 membered,
saturated mono-or bi-cycloheteroalkyl radical which may additionally comprise one
or more -NR8- heteroatom, where
the cycloheteroalkyi radical may be substituted independently of one
another one time by a radical-(CR20R21 ) -NR22R23, in which r is 0 or 1
and R20, R21 , R22 and R23 are independently of one another H or a (C
Cio)-alkyl radical optionally substituted one or more times by F, CI, Br
and/or I,
R8 is an H or a (d-Cio)-alkyl radical;
and in which
n is 0, 1 or 2; and
q is 0 or ,
in the form of a free base or of an addition salt with an acid, as well as in the form
of an hydrate or of a solvate as appropriate.
The compounds of the invention advantageously respond to the general formula
in which A, B B", T, T , T", R 1, R3, R4, R5, X, L and q are as defined above for
compounds of formula (II), in the form of a free base or of an addition salt with an acid, as
well as in the form of an hydrate or of a solvate.
Among the compounds of formula (I) according to the instant invention, the
following compounds may be cited, in the same order as for the compounds depicted in
the table hereafter, illustrating some examples of compounds:
(3R)-1 -{(1 R,2S)-5-chloro-1 -[(2-chloro-5-fluorobenzyl)oxy]-2,3-dihydro-1 H-inden-2-
yl}piperidin-3-amine
(3S)-1 -[(1 R,2S)-5-chloro-1 -{[2-fluoro-3-(trifluoromethyl)benzyl]oxy}-2,3-dihydro-1 Hinden-
2-yl]piperidin-3-amine
1-({(1 S,2R)-1 -[3-(trifluoromethoxy)phenoxy]-2,3-dihydro-1 H-inden-2-
yl}methyl)pyrrolidine
1-({(1 S,2R)-1 -[3-(trifluoromethoxy)phenoxy]-2,3-dihydro-1 H-inden-2-
yl}methyl)piperidine
1-[1 -(2-cyclopentylphenoxy)-2,3-dihydro-1 H-inden-2-yl]piperidin-4-amine
N-{(1 -[(6-chloropyridin-3-yl)oxy]-2,3-dihydro-1 H-inden-2-yl}-N-methylpiperidin-3-
amine
(3R)-1 -{(1 R,2R)-1 -[2-(2H-benzotriazol-2-yl)-4-methylphenoxy]-2,3-dihydro-1 H-inden-
2-yl}piperidin-3-amine
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
chlorobenzonitrile
(3R)-1 -[(1 R,2R)-4,6-dichloro-1 -(4-fluorophenoxy)-2,3-dihydro-1 H-inden-2-
yl]piperidin-3-amine
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-4,6-dichloro-2,3-dihydro-1 H-inden-1 -
yl}oxy)-3-fluorobenzonitrile
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -
yl}sulfanyl)benzonitrile
4-({(1 R,2R)-2-[(3S)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -
yl}oxy)benzonitrile
4-({(1 R,2R)-2-[(3S)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-2-
fluorobenzonitrile
4-({(1 R,2R)-2-[(3S)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
fluorobenzonitrile
4-({(1 R,2R)-2-[(3S)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
chlorobenzonitrile
4-({(1 R,2R)-2-[(3S)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-2,3-
difluorobenzonitrile
4-({(1 R,2R)-2-[(3S)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
(trifluoromethyl)benzonitrile
(3S)-1 -[(1 R,2R)-1 -(2-chloro-6-methylphenoxy)-2,3-dihydro-1 H-inden-2-yl]piperidin-3-
amine
(3S)-1 -{(1 R,2R)-1 -[2-(2H-benzotriazol-2-yl)-4-methylphenoxy]-2,3-dihydro-1 H-inden-
2-yl}piperidin-3-amine
4-({(1 R,2R)-2-[(3S)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
nitrobenzonitrile
2-({(1 R,2R)-2-[(3S)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-5-
bromobenzonitrile
2-({(1 R,2R)-2-[(3S)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-5-
chlorobenzonitrile
(3S)-1 -[(1 R,2R)-1 -(2-bromo-4,6-difluorophenoxy)-2,3-dihydro-1 H-inden-2-
yl]piperidin-3-amine
4-({(1 R,2R)-2-[(3S)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
bromobenzonitrile
1-[(1 R,2R)-1 -(2-bromophenoxy)-2,3-dihydro-1 H-inden-2-yl]-1 ,4-diazepane
1-[(1 R,2R)-1 -(2-chloro-6-methylphenoxy)-2,3-dihydro-1 H-inden-2-yl]-1 ,4-diazepane
1-[(1 R,2R)-1 -(2-bromo-4-fluorophenoxy)-2,3-dihydro-1 H-inden-2-yl]-1 ,4-diazepane
1-[(1 R,2R)-1 -(2,3,6-trifluorophenoxy)-2,3-dihydro-1 H-inden-2-yl]-1 ,4-diazepane
1-[(1 R,2R)-1 -(2,4,6-trifluorophenoxy)-2,3-dihydro-1 H-inden-2-yl]-1 ,4-diazepane
1-[(1 R,2R)-1 -(2-bromo-4,6-difluorophenoxy)-2,3-dihydro-1 H-inden-2-yl]-1 ,4-
diazepane
(3R)-1 -[(1 R,2R)-1 -(2,4-dichlorophenoxy)-2,3-dihydro-1 H-inden-2-yl]piperidin-3-
amine
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -
yl}oxy)benzonitrile
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
fluorobenzonitrile
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-2-
chlorobenzonitrile
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-2,3-
difluorobenzonitrile
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
(trifluoromethyl)benzonitrile
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
methoxybenzonitrile
(3R)-1 -[(1 R,2R)-1 -(4-chloro-2-methylphenoxy)-2,3-dihydro-1 H-inden-2-yl]piperidin-
3-amine
(3R)-1 -[(1 R,2R)-1 -(2,4-difluorophenoxy)-2,3-dihydro-1 H-inden-2-yl]piperidin-3-
amine
(3R)-1 -[(1 R,2R)-1 -(4-bromo-3-fluorophenoxy)-2,3-dihydro-1 H-inden-2-yl]piperidin-3-
amine
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
nitrobenzonitrile
(3R)-1 -[(1 R,2R)-1 -(4-fluoro-2-methylphenoxy)-2,3-dihydro-1 H-inden-2-yl]piperidin-3-
amine
2-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-5-
bromobenzonitrile
2-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-5-
chlorobenzonitrile
5-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-1 ,3-
benzoxathiol-2-one
2-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-6-
fluorobenzonitrile
(3R)-1 -{(1 R,2R)-1 -[4-bromo-2-(1 H-pyrazol-3-yl)phenoxy]-2,3-dihydro-1 H-inden-2-
yl}piperidin-3-amine
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
ethoxybenzonitrile
2-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -
yl}oxy)benzonitrile
(3R)-1 -[(1 R,2R)-1 -(4-bromophenoxy)-2,3-dihydro-1 H-inden-2-yl]piperidin-3-amine
(3R)-1 -[(1 R,2R)-1 -(4-fluorophenoxy)-2,3-dihydro-1 H-inden-2-yl]piperidin-3-amine
(3R)-1 -[(1 R,2R)-1 -(2-bromo-4-chlorophenoxy)-2,3-dihydro-1 H-inden-2-yl]piperidin-3-
amine
2-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-5-
chlorobenzamide
6-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3,4-
dihydroquinolin-2(1 H)-one
(3R)-1 -{(1 R,2R)-1 -[4-methyl-2-(1 H-pyrazol-3-yl)phenoxy]-2,3-dihydro-1 H-inden-2-
yl}piperidin-3-amine
3-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-N,Ndimethylnaphthalene-
2-carboxamide
2-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-4-
bromobenzonitrile
2-({(1 R,2R)-2-[(3S)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-6-
fluorobenzonitrile
4-({(1 R,2R)-2-[(3R)-3-aminopyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -
yl}oxy)benzonitrile
4-({(1 R,2R)-2-[(3R)-3-aminopyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
fluorobenzonitrile
4-({(1 R,2R)-2-[(3R)-3-aminopyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
chlorobenzonitrile
(3R)-1 -{(1 R,2R)-1 -[2-(2H-benzotriazol-2-yl)-4-methylphenoxy]-2,3-dihydro-1 H-inden-
2-yl}pyrrolidin-3-amine
4-({(1 R,2R)-2-[(3R)-3-aminopyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
nitrobenzonitrile
(3R)-1 -[(1 R,2R)-1 -(2-bromo-4-fluorophenoxy)-2,3-dihydro-1 H-inden-2-yl]piperidin-3-
amine
(3R)-1 -{(1 R,2R)-1 -[4-chloro-2-(1 H-pyrazol-3-yl)phenoxy]-2,3-dihydro-1 H-inden-2-
yl}piperidin-3-amine
(3R)-1 -{(1 R,2R)-1 -[4-chloro-2-(1 ,2-oxazol-5-yl)phenoxy]-2,3-dihydro-1 H-inden-2-
yl}piperidin-3-amine
(3R)-1 -[(1 R,2R)-1 -(2-bromo-4,6-difluorophenoxy)-2,3-dihydro-1 H-inden-2-
yl]piperidin-3-amine
(3R)-1 -[(1 R,2R)-1 -(4-chloro-2-fluorophenoxy)-2,3-dihydro-1 H-inden-2-yl]piperidin-3-
amine
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
bromobenzonitrile
(3R)-1 -{(1 R,2R)-1 -[4-bromo-2-(1 ,2-oxazol-5-yl)phenoxy]-2,3-dihydro-1 H-inden-2-
yl}piperidin-3-amine
4-({(1 R,2R)-2-[(3S)-3-aminopyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -
yl}oxy)benzonitrile
4-({(1 R,2R)-2-[(3S)-3-aminopyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-2-
fluorobenzonitrile
4-({(1 R,2R)-2-[(3S)-3-aminopyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
fluorobenzonitrile
4-({(1 R,2R)-2-[(3S)-3-aminopyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
chlorobenzonitrile
4-({(1 R,2R)-2-[(3S)-3-aminopyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-2,3-
difluorobenzonitrile
1-[(1 R,2R)-1 -(2-chloro-6-fluoro-3-methylphenoxy)-2,3-dihydro-1 H-inden-2-yl]-1 ,4-
diazepane
(3S)-1 -{(1 R,2R)-1 -[2-(2H-benzotriazol-2-yl)-4-methylphenoxy]-2,3-dihydro-1 H-inden2-
yl}pyrrolidin-3-amine
4-({(1 R,2R)-2-[(3S)-3-aminopyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
nitrobenzonitrile
2-({-2-[(3S)-3-aminopyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-5-
bromobenzonitrile
2-({(1 R,2R)-2-[(3S)-3-aminopyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-5-
chlorobenzonitrile
4-({(1 S,2S)-2-[(3R)-3-aminopiperidin-1 -yl]-4-methyl-2,3-dihydro-1 H-inden-1 -yljoxy)-
3-chlorobenzonitrile
4-({(1 R,2R)-2-[3-(methylamino)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -
yl}oxy)benzonitrile
3-fluoro-4-({(1 R,2R)-2-[3-(methylamino)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -
yl}oxy)benzonitrile
3-chloro-4-({(1 R,2R)-2-[3-(methylamino)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -
yl}oxy)benzonitrile
1-{(1 R,2R)-1 -[2-(2H-benzotriazol-2-yl)-4-methylphenoxy]-2,3-dihydro-1 H-inden-2-yl}-
N-methylpyrrolidin-3-amine
1-{(3R)-1 -[(1 R,2R)-1 -(4-nitrophenoxy)-2,3-dihydro-1 H-inden-2-yl]pyrrolidin-3-
yljmethanamine
1-{(3R)-1 -[(1 R,2R)-1 -(4-bromophenoxy)-2,3-dihydro-1 H-inden-2-yl]pyrrolidin-3-
yljmethanamine
1-{(3R)-1 -[(1 R,2R)-1 -(2-chloro-4-fluorophenoxy)-2,3-dihydro-1 H-inden-2-
yl]pyrrolidin-3-yl}methan amine
1-{(3R)-1 -[(1 R,2R)-1 -(2-chloro-4-nitrophenoxy)-2,3-dihydro-1 H-inden-2-yl]pyrrolidin-
3-yl}methanamine
2-({(1 R,2R)-2-[(3R)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -
yl}oxy)benzonitrile
1-{(3R)-1 -[(1 R,2R)-1 -(2-bromo-4-chlorophenoxy)-2,3-dihydro-1 H-inden-2-
yl]pyrrolidin-3-yl}methan amine
2-({(1 R,2R)-2-[(3R)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
5-chlorobenzonitrile
methyl 4-({(1 R,2R)-2-[(3R)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -
yl}oxy)-3-chlorobenzoate
4-({(1 R,2R)-2-[(3R)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
3-chlorobenzonitrile
1-{(3R)-1 -[(1 R,2R)-1 -(4-bromo-2-chlorophenoxy)-2,3-dihydro-1 H-inden-2-
yl]pyrrolidin-3-yl}methan amine
1-[(3R)-1 -{(1 R,2R)-1 -[4-bromo-2-(1 H-pyrazol-3-yl)phenoxy]-2,3-dihydro-1 H-inden-2-
yl}pyrrolidin-3-yl]methan amine
2-({(1 R,2R)-2-[(3R)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
5-bromobenzonitrile
4-({(1 R,2R)-2-[(3R)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
3-bromobenzonitrile
1-[(3R)-1 -{(1 R,2R)-1 -[4-chloro-2-(1 H-pyrazol-3-yl)phenoxy]-2,3-dihydro-1 H-inden-2-
yl}pyrrolidin-3-yl]methan amine
1-[(3R)-1 -{(1 R,2R)-1 -[4-methyl-2-(1 H-pyrazol-3-yl)phenoxy]-2,3-dihydro-1 H-inden-2-
yl}pyrrolidin-3-yl]methan amine
1-{(3R)-1 -[(1 R,2R)-1 -(2,4-dichlorophenoxy)-2,3-dihydro-1 H-inden-2-yl]pyrrolidin-3-
yljmethanamine
1-{(3R)-1 -[(1 R,2R)-1 -(4-chlorophenoxy)-2,3-dihydro-1 H-inden-2-yl]pyrrolidin-3-
yljmethanamine
4-({(1 R,2R)-2-[(3R)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
2-fluorobenzonitrile
4-({(1 R,2R)-2-[(3R)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
3-methoxybenzonitrile
4-({(1 R,2R)-2-[(3R)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
2-chlorobenzonitrile
4-({(1 R,2R)-2-[(3R)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
2,6-difluorobenzonitrile
2-({(1 R,2R)-2-[(3R)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
6-fluorobenzonitrile
4-({(1 R,2R)-2-[(3R)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
3-fluorobenzonitrile
4-({(1 R,2R)-2-[(3R)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
2,3-difluorobenzonitrile
4-({(1 R,2R)-2-[(3R)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
3-(trifluoromethyl)benzonitrile
1-{(3S)-1 -[(1 R,2R)-1 -(4-nitrophenoxy)-2,3-dihydro-1 H-inden-2-yl]pyrrolidin-3-
yljmethanamine
1-{(3S)-1 -[(1 R,2R)-1 -(2-chloro-4-nitrophenoxy)-2,3-dihydro-1 H-inden-2-yl]pyrrolidin3-
yl}methanamine
2-({(1 R,2R)-2-[(3S)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
5-chlorobenzonitrile
4-({(1 R,2R)-2-[(3S)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
3-chlorobenzonitrile
2-({(1 R,2R)-2-[(3S)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
5-bromobenzonitrile
1-{(3S)-1 -[(1 R,2R)-1 -(4-chlorophenoxy)-2,3-dihydro-1 H-inden-2-yl]pyrrolidin-3-
yljmethanamine
4-({(1 R,2R)-2-[(3S)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
2-fluorobenzonitrile
4-({(1 R,2R)-2-[(3S)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
2-chlorobenzonitrile
3-chloro-4-({(1 R,2R)-2-[4-(dimethylamino)piperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -
yl}oxy)benzonitrile
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-6-methoxy-2,3-dihydro-1 H-inden-1 -
yl}oxy)-3-chlorobenzonitrile
(2R,3R)-2-[(3R)-3-aminopiperidin-1-yl]-3-(2-chloro-4-cyanophenoxy)-2,3-dihydro-
1H-indene-5-carbonitrile
( 1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-1 -(2-chloro-4-cyanophenoxy)-2,3-dihydro-
1H-indene-5-carbonitrile
4-{[(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-6-(methylsulfonyl)-2,3-dihydro-1 H-inden-
1-yl]oxy}-3-chlorobenzonitrile
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-5-fluoro-2,3-dihydro-1 H-inden-1 -yljoxy)-
3-chlorobenzonitrile
4-({(1 R,2R)-2-[3-(2-aminopropan-2-yl)azetidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
3-chlorobenzonitrile
3-chloro-4-({(1 R,2R)-2-[(1 S,4S)-2,5-diazabicyclo[2.2.1 ]hept-2-yl]-2,3-dihydro-1 Hinden-
1 -yl}oxy)benzonitrile
methyl 4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
chlorobenzoate
3-chloro-4-({(1 R,2R)-2-[(3R)-3-(methylamino)piperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -
yl}oxy)benzonitrile
1-{(1 R,2R)-1 -[2-(2H-benzotriazol-2-yl)-4-methylphenoxy]-2,3-dihydro-1 H-inden-2-yl}-
N-methylpyrrolidin-3-amine
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-6-hydroxy-2,3-dihydro-1 H-inden-1 -
yl}oxy)-3-chlorobenzonitrile
6-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-6-methoxy-2,3-dihydro-1 H-inden-1 -
yl}oxy)-3,4-dihydroquinolin-2(1 H)-one
6-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-7-chloro-
3,4-dihydroquinolin-2(1 H)-one
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-5-bromo-2,3-dihydro-1 H-inden-1 -yljoxy)-
3-chlorobenzonitrile
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-4,6-dichloro-2,3-dihydro-1 H-inden-1 -
yl}oxy)-3-chlorobenzonitrile
6-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-5-chloro-6-methoxy-2,3-dihydro-1 Hinden-
1 -yl}oxy)-3,4-dihydroquinolin-2(1 H)-one
6-{[(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-6-(trifluoromethyl)-2,3-dihydro-1 H-inden-
1-yl]oxy}-3,4-dihydroquinolin-2(1 H)-one
4-({(5R,6R)-6-[(3R)-3-aminopiperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-5-
yl}oxy)-3-chlorobenzonitrile
4-({(6R,7S)-6-[(3R)-3-aminopiperidin-1 -yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-
yl}oxy)-3-chlorobenzonitrile
in the form of a free base or of an addition salt with an acid, as well as in the form of an
hydrate or of a solvate.
A protecting group Pg, as mentioned hereafter, corresponds to a group which
enables, on the one hand, the protection of a reactive function such as an hydroxy or an
amine during a synthesis step and, on then other hand, to recover the intact reactive
function at the end of the synthesis step. Examples of protecting groups, as well as
methods for protecting and deprotecting various functional groups, are given in
« Protective Groups in Organic Synthesis », Green et al., 2nd Edition (John Wiley & Sons,
Inc., New York).
A leaving group, as mentioned hereafter, corresponds to a group which may easily
be cleaved from a molecule by breaking a heterolytic bond, with departure of electronic
pair. This group may then easily be replaced by another functional group during a
substitution reaction, for example. Such leaving groups may consist in halogen atoms or
activated hydroxy groups, such as mesylate, tosylate, triflate or acetyl groups, etc.
Examples of leaving groups, as well as references relating to their preparation, are given
in « Advances in Organic Chemistry », J. March, 3rd Edition, Wiley Interscience, p. 3 10-
316.
General processes suitable for preparing compounds of the general formula I are
described below. The compounds of the formula I can in this connection be prepared by
different chemical processes. The groups and radicals A, B, L, X, R 1, R2, R3, R4 and R5
and index p mentioned in the following methods have the abovementioned meaning
unless they are explicitly defined otherwise.
Abbreviations:
HPLC high performance liquid chromatography
LC liquid chromatography
Rt retention time
THF tetrahydrofuran
TFA trifluoroacetic acid
DMSO dimethyl sulfoxide
DMF dimethylformamide
AcN acetonitrile
RT room temperature
min. minutes
h hour(s)
ES = ESI electrospray ionization
MS Mass Spectroscopy
HCI Hydrochloric acid
EtOAc Ethyl acetate
m multiplet
bs broad singlet
s singlet
Method A:
For example, as shown in scheme A that starting from epoxides of the formula I I
which initially, after epoxide ring opening with an amine of the formula HNR3R4, afford a
corresponding 1-amino 2-ol intermediate of the formula III, which is subsequently
subjected to a Mitsunobu reaction with an aryl or heteroaryl compounds B-OH which may
be substituted one or more times by R5. Phenols are preferably employed in this reaction.
It is also possible alternatively to employ aryl or heteroaryl thiols B-SH or aryl- or
heteroarylcarboxylic acids B-C0 2H which may be substituted one or more times by R5 in
order to obtain the corresponding -S- or -C0 2H- bridged derivatives. Mitsunobu reactions
are, as is known, carried out in the presence of a phosphine, e.g. such as
triphenylphosphine and of azodicarboxylic esters such as, for example, diisopropyl
azodicarboxylate in inert solvents such as acetonitrile, CH2CI2 or tetrahydrofuran. In the
case of 1-amino 2-ols of the formula III, this entails migration of the amine residue NR3R4
into position 2 of the basic structure (J. Org. Chem. 1991 , 56, 670-672).
Scheme A: Synthesis of compounds of the formula I via Mitsunobu inversion
in which L is a covalent bond, -C(=0)- and X is O,
or L is a covalent bond and X is S.
It is possible in this way to prepare a large number of compounds I, preferably
those in which the two substituents are in a trans configuration relative to one another. If
one of the radicals R3 and R4 of the amine substituent is to be replaced by a further
functional group such as, for example, a hydroxy group or an amino group, care must be
taken where appropriate to protect such groups during the Mitsunobu reaction. This can
take place for example by trialkyl or triarylsilyl groups in the case of OH groups or by the
BOC protective groups in the case of amino groups. After the Mitsunobu reaction, the
protective group is then removed again, for example by treatment with hydrochloric acid
or trifluoroacetic acid, to obtain the compounds of the formula I. After deprotection, these
functional groups can be further modified where appropriate, for example by alkylation
with an alkylating agent or by acylation and subsequent reduction in order to obtain
further compounds I.
The starting materials employed in scheme A, such as the epoxides of the formula
II, the amine NHR3R4, and the hydroxyaryls or hydroxyheteroaryls or the thiol derivatives
thereof are either commercially available, known from the literature or can be synthesized
easily in analogy to compounds known from the literature. A few suitable synthetic
schemes for such starting materials are reproduced by way of example in the
experimental section.
Method B:
A further method for preparing compounds of the formula I is depicted in scheme
B.
Scheme B: Synthesis of the compounds I by nucleophilic aromatic substitution
In this process, 2-bromo 1-one compounds of the formula IV are reacted with
amines of the formula R3-NH-R4 to give the corresponding amino ketones V. The keto
group is then reduced to the 1-hydroxy group, resulting in the intermediates of the formula
VI. It is possible in this connection for products VI with both the cis and the trans
configuration with regard to centers 1 and 2 to be produced. The resulting intermediates
of the formula VI are then arylated by nucleophilic aromatic substitution on aryl or
heteroaryl compounds B-Y, where B may be substituted one or more times by R5, using a
strong base such as, for example, sodium hydride or powdered NaOH in an inert solvent
such as DMSO. Y is in this connection a suitable leaving group such as, for example,
fluorine, chlorine or trifluoromesyloxy. If the radicals R3 and R4 are substituted for
example by amino or hydroxy groups, these should be protected where appropriate by
base-stable protective groups such as, for instance, alkyl- or aryl-substituted silyl groups.
It is also possible with this process to have recourse to a large extent to known or
commercially available bromo ketones IV or can easily be obtained for example by
bromination under standard conditions from the appropriate ketones.
Method C:
A further process relates to those compounds of the formula I in which the amine
group NR3R4 is linked via a carbon-containing bridge to position 2, that is q is 1 in
general formula I.
Scheme C: Synthesis of compounds of the formula I via Mannich-like products
In this case, ketones of the formula VII are reacted with formamide acetals,
preferably N,N-dimethylformamide dimethyl acetal, in order to obtain the corresponding
dimethylaminomethylene compounds of the formula VIII. The dimethylamino group can
be replaced in the next stage by other amino groups to give aminomethylene compounds
of the formula IX. This can take place for example by heating compounds of the formula
VIII in DMF in the presence of excess amine HNR3R4. Subsequent reduction, for
example by sodium borohydride in methanol, ordinarily affords mixtures of stereoisomeric
amine alcohols of the formula X which can, where appropriate after separation into the
individual components, be arylated in analogy to the illustration in scheme B to give the
compounds I of the invention.
Method D:
A further process for preparing compounds of the formula I is depicted in scheme
D. Benzoic esters I which are synthesized as in scheme A are hydrolyzed in a known
manner to give compounds of the general formula VI. This takes place for example in
solvents such as acetone/water mixtures and using suitable bases such as sodium
hydroxide. Compounds of the formula VI are then reacted with suitable alkylating agents
such as, for example, benzyl bromides in solvents such as, for example, THF in the
presence of suitable bases such as sodium hydride. The compound I obtained in this way
is available where appropriate for further manipulations.
Scheme D: Synthesis of the compounds I via alkylation
in which L is an alkylene bridge.
If the compounds I contain further functional groups such as, for example,
alcohols or amines, these can be reacted further in a known manner as in scheme E.
Suitable examples are acylations, alkylations or acylation/reduction sequences. The
procedure is described in the experimental section by means of exemplary embodiments.
Scheme E: Optional further reactions of compounds I
o
alkylation acylation — R reduction —R
l-w' " l-WH l-W l-W
W = 0 ; NH; NR for W = NH; NR
Method E:
A further process relates to those compounds of the formula I in which one or two
substituents R3 or R4 at the amine group NR3R4 equals hydrogen, that is R3 = H or R3 =
R4 = H in general formula I.
Scheme F: Synthesis of compounds of the formula I via Pd catalyzed deprotection
of allyl amines
In this process, allyl amines XI, which for example can be synthesized following
method A, are deprotected using nucleophiles, e.g. such as thiosalicylic acid or
dimethylbarbituric acid, in inert solvents such as CH2CI2 or THF. The reaction is catalyzed
by Pd. Suitable Pd sources are for example Pd(PPh3)4 or Pd(dba)2 in the presence of
stabilizing ligands such as bis(diphenylphosphino)butane. In case of bisallyl amines (R3 =
R4 = allyl) both allyl groups can be cleaved using at least 2 equivalents of a suitable
nucleophile and prolonged reaction times. Compounds of the general formula I, which are
synthesized following method F, are available for further manipulations e.g. acylation or
alkylation.
The following examples describe the synthesis of some compounds according to
the invention. These examples are not intended to be limitative and only illustrate the
present invention. The numbers of the exemplified compounds refer to those in the table
given later, which illustrate the chemical structures and the physical properties of a
number of compounds according to the invention.
LC/MS spectra were recorded according to the following methods.
Method A: Solvent: (H2O+0.05%TFA)/(AcN+0.05%TFA) 98:2 ( 1 min) to 5:95 (5min) to
5:95 (6min)
Method B: Solvent: (H2O+0,05%TFA)/(AcN+0,035%TFA) 98:2 ( 1min) to 0:100 (3min)
Method C: Solvent: (CH3COONH4 + 3%AcN)/AcN 100:0 (5 min) to 0:1 00 (5min)
Example 1: (3R)-1-{(1 ,2-c/'s)-5-chloro-1-[(2-chloro-5-fluorobenzyl)oxy]-
2,3dihydro-1 H-inden-2-yl}piperidin-3-amine compound 1)
1. 1 [(R)-1 -(cis-5-chloro-1-keto-indan-2-yl)-piperidin-3-yl]-carbamic acid tert-butyl
ester
A mixture of 1.00 eq. (20.2 mmol, 4.79 g) 2-bromo-5-chloro-indane-1 -one, 1.20
eq. (24.2 mmol, 5.00 g) (R)-3-N-Boc-aminopiperidine and 1.60 eq. (32.0 mmol, 4.47 g)
potassium carbonate in 150 ml acetone is stirred at RT for 2 h. After addition of 100 ml of
water and 100 ml of EtOAc the layers are separated and the aqueous layer is extracted
with EtOAc. The combined organic layers are dried with anhydrous MgS0 4, filtered,
concentrated under reduced pressure and the residue is used in the next step without
further purification.
1.2 [(R)-1 -(cis-5-chloro-1-hydroxy-indan-2-yl)-piperidin-3-yl]-carbamic acid tertbutyl
ester
[(R)-1 -(cis-5-chloro-1-keto-indan-2-yl)-piperidin-3-yl]-carbamic acid tert-butyl ester
is dissolved in 150 ml dry THF and 1.50 eq. (30.0 mmol, 30.0 ml of 1 M solution) of Lselectride
is added at 0 with stirring. The mixture is allowed to warm up to RT and
stirring is continued for 2 days. 150 ml water and 150 ml EtOAc are added, the layers are
separated and the aqueous layer is extracted with EtOAc. After drying, filtering and
concentrating under reduced pressure the combined organic layers, the residue is
dissolved in 100 ml THF at 0 € and 5 ml H20 2 (35 %) and NaOH ( 10 ml, 4N) are added.
After 2 h at 0 € , water (100 ml) and EtOAc ( 100 ml) are added. The aqueous layer is
extracted with EtOAc. The combined organic layers are dried over anhydrous MgS0 4,
filtered and concentrated under reduced pressure. The residue is purified via
chromatography on silica gel (EtOAc as eluent) to yield the title compound.
1.3 (3R)-1 -{(1 ,2-cis)-5-chloro-1 -[(2-chloro-5-fluorobenzyl)oxy]-2,3dihydro-1 Hinden-
2-yl}piperidin-3-amine
[(R)-1-(cis-5-chloro-1-hydroxy-indan-2-yl)-piperidin-3-yl]-carbamic acid tert-butyl
ester (0.1 mmol), 1-chloro-2-(chloromethyl)-4-fluorobenzene (0.2 mmol) and Ag20 (0.5
mmol) are stirred in 2.5 ml dry toluene for 3h at d . The cooled reaction mixture is
filtered and the filtrate is evaporated under reduced pressure. The residue is dissolved in
DMF and subjected to preparative HPLC purification.
The purified product is taken up in 1 ml TFA/CH 2CI2 (1/9) and shaken for 1 h at
RT, then evaporated ( 12 mbar, 40°C over night in a drying cabinet) to afford the desired
product: LCMS (ESI) M+ 409.2537.
Example 2 : (3R)-1-{(1 R,2R)-1-[2-(2H-benzotriazol-2-yl)-4-methylphenoxy]-2,3-
dihydro-1 H-inden-2-yl}piperidin-3-amine compound 7)
2.1 ( 1aR,6aS)-6,6a-dihydro-1 aH-indeno[1 ,2-b]oxirene
In a three-neck round bottom flask is introduce NaOCI (50.4ml, 0.31 eq., 2N). The
flask is then flushed with argon and cooled to 0°C. A solution of (R,R)-N,N'-bis(3,5-di-tertbutylsalicylidene)-
1 ,2-cyclohexanediaminomanganese(lll) chloride (2.06g, 0.01 eq.) and 4-
(3-phenylpropyl)pyridine-N-oxide (2.08g, 0.03eq.) in CH2CI2 ( 166ml) is added. The
suspension is stirred for 15 min. To the cooled solution is added simultaneously via two
addition funnels NaOCI ( 152ml, 0.93eq., 2N) and a solution of indene (37.85g, 1eq.) in
CH2CI2 ( 107ml). The mixture is then stirred at 0°C for 1h and the temperature is let
warmed up to RT over night. The suspension is diluted with water and CH2CI2 and filtered
through celite®. The aqueous layer is separated and extracted three times with CH2CI2.
The combined organic layers are washed with brine, dried over anhydrous Na2S0 4,
filtered and concentrated under reduced pressure to afford 18.64g (43%) of the desired
compound as a yellow oil, used in the next step without further purification.
2.2 tert-butyl {(3R)-1 -[(1 S,2S)-2-hydroxy-2,3-dihydro-1 H-inden-1 -yl]piperidin-3-
yljcarbamate
To a solution of (1aR,6aS)-6,6a-dihydro-1aH-indeno[1 ,2-b]oxirene (6g, 1.00eq.) in
AcN (122ml) is added tert-butyl (3R)-piperidin-3-ylcarbamate (12.27g, 1.35eq.). The
solution is brought to reflux and heated overnight. After cooling, the solvents are
evaporated under reduced pressure and the residue is purified by column
chromatography (Heptane/EtOAc, 100/0 to 70/30) to afford 12.3g (82%) of the desired
product as a solid.
2.3 (3R)-1 -{(1 R,2R)-1 -[2-(2H-benzotriazol-2-yl)-4-methylphenoxy]-2,3-dihydro-1 Hinden-
2-yl}piperidin-3-amine
Tert-butyl {(3R)-1 -[(1 S,2S)-2-hydroxy-2,3-dihydro-1 H-inden-1 -yl]piperidin-3-
yljcarbamate (3.0 mmol), 2-(2H-benzotriazol-2-yl)-4-methylphenol (3.3 mmol) and
triphenylphosphin (5.2 mmol) are dissolved in THF under Argon, then
diisopropylazodicarboxylate (4.5 mmol) is added and the mixture is stirred over night at
RT. After evaporation of the solvent, the crude product is stirred in 15% TFA in DCM at
RT over night. The solvent is evaporated under reduced pressure and the residue is
purified by preparative HPLC to afford the desired compound: H NMR (500 MHz, DMSOd6)
d 8.20 (bs, 2H), 8.05-7.90 (m, 2H), 7.65-7.40 (m, 5H), 7.35-7.15 (m, 4H), 6.25 (s, 1H),
3.90 (s, 1H), 3.40-2.95 (m, 5H), 2.85-2.55 (m, 2H), 2.38 (s, 3H), 2.00-1 .83 (m, 2H), 1.70-
1.55 (m, 1H), 1.52-1 .40 (m, 1H); LCMS (ESI) M+ 440.2551 .
Example 3 : 4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1-yl]-2,3-dihydro-1 H-inden-1 -
yl}oxy)-3-chlorobenzonitrile (compound 8)
3.1 ( 1aR,6aS)-6,6a-dihydro-1 aH-indeno[1 ,2-b]oxirene
The title compound is prepared following the method used for example 2.
3.2 tert-butyl {(3R)-1 -[(1 S,2S)-2-hydroxy-2,3-dihydro-1 H-inden-1 -yl]piperidin-3-
yljcarbamate
The title compound is prepared following the method used for example 2.
3.3 4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
chlorobenzonitrile
Tert-butyl {(3R)-1 -[(1 S,2S)-2-hydroxy-2,3-dihydro-1 H-inden-1 -yl]piperidin-3-
yljcarbamate (0.10 mmol), 3-chloro-4-hydroxybenzonitrile (0.1 2 mmol) and polymerbound
PPh3 (Argonaut, 0.25 mmol) in 2.5 ml THF are treated with di-isopropyl
azodicarboxylate (0.2 mmol). The mixture is stirred over night at RT then filtered on
celite®. The filter is washed with CH2CI2. The filtrate is evaporated under reduced
pressure. The residue is purified by column chromatography (CH2CI2/methanol, 100/0 to
90/1 0) and then dissolved in CH2CI2 and treated with HCI ( 1ml, 2N in Et20). The
precipitate is filtered and dried under reduced pressure to afford the desired compound as
an off-white solid: H NMR (400 MHz, DMSO-d6) d 8.50 (bs, 2H), 8.18 (s, 1H), 8.05-7.95
(m, 1H), 7.83-7.75 (m, 1H), 7.50-7.40 (m, 2H), 7.32-7.28 (m, 1H), 7.15-7.12 (m, 1H), 6.75
(bs, 1H), 4.18-4.12 (m, 1H), 3.45-3.40 (m, 7H), 1.94-1 .90 (m, 4H); LCMS (ES) M+ 368;
[a ] = -215.5° (CH30H); mp = 221 .3°C.
Example 4: 4-{[(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-6-(methylsulf onyl)-2,3-
dihydro-1 H-inden-1-yl]oxy}-3-chlorobenzonitrile (compound 123)
4.1 6-(methylsulfonyl)-2,3-dihydro-1 H-inden-1 -ol
To a cooled solution (0°C) of 6-(methylsulfonyl)-2,3-dihydro-1 H-inden-1 -one
(2.50g, 1eq.) in THF (48ml) and methanol (10ml) is added sodium borohydride (0.89g,
2eq.) portionwise. The suspension is stirred at RT overnight. The mixture is diluted with
water. The aqueous layer is extracted with CH2CI2. The organic layer is dried over
anhydrous Na2S0 4, filtered and concentrated under reduced pressure to afford 1.99g
(79%) of the desired product as a white solid, used in the next step without further
purification.
4.2 1H-inden-5-yl methyl sulfone
In a round bottom flask equipped with a dean starck is introduced a solution of 6-
(methylsulfonyl)-2,3-dihydro-1 H-inden-1 -ol (2g, 1eq.) in toluene (85ml). Paratoluenesulfonic
acid (0.02g, 0.01 eq.) is added and the mixture is brought to reflux. The
solution is heated for 7h. After cooling, the mixture is diluted with CH2CI2. The organic
layer is washed with saturated aqueous NaHC0 3 and water. The organic layer is dried
over anhydrous Na2S0 4, filtered and concentrated under reduced pressure. The residue
is purified by column chromatography (CH2CI2/methanol, 100/0 to 95/5) to afford 0.54g
(30%) of the desired product as a white solid.
4.3 ( 1aR,6aS)-3-(methylsulfonyl)-6,6a-dihydro-1 aH-indeno[1 ,2-b]oxirene
In a three-neck round bottom flask is introduce NaOCI (0.43ml, 0.31 eq., 2N). The
flask is then flushed with argon and cooled to 0°C. A solution of (R,R)-N,N'-bis(3,5-di-tertbutylsalicylidene)-
1 ,2-cyclohexanediaminomanganese(lll) chloride (0.02g, 0.01 eq.) and 4-
(3-phenylpropyl)pyridine-N-oxide (0.02g, 0.03eq.) in CH2CI2 ( 1ml) is added. The
suspension is stirred for 15 min. To the cooled solution is added simultaneously via two
addition funnels NaOCI ( 1 .3ml, 0.93eq., 2N) and a solution of 1H-inden-5-yl methyl
sulfone (0.55g, 1eq.) in CH2CI2 (0.7ml). The mixture is then stirred at 0°C for 1h and the
temperature is let warmed up to RT over night. The suspension is diluted with water and
CH2CI2 and filtered through celite®. The aqueous layer is separated and extracted three
times with CH2CI2. The combined organic layers are washed with brine, dried over
anhydrous Na2S0 4, filtered and concentrated under reduced pressure to afford 0.51 g
(86%) of the desired compound as a brown oil, used in the next step without further
purification.
4.4 tert-butyl {(3R)-1 -[(1 S,2S)-2-hydroxy-6-(methylsulfonyl)-2,3-dihydro-1 H-inden-
1-yl]piperidin-3-yl}carbamate
To a solution of ( 1aR,6aS)-3-(methylsulfonyl)-6,6a-dihydro-1 aH-indeno[1 ,2-
b]oxirene (0.5g, 1.00eq.) in AcN (7ml) is added tert-butyl (3R)-piperidin-3-ylcarbamate
(0.69g, 1.45eq.). The solution is brought to reflux and heated overnight. After cooling, the
solvents are evaporated under reduced pressure and the residue is purified by column
chromatography (CH2CI2/methanol, 100/0 to 95/5) to afford 0.73g (75%) of the desired
product as a greenish foam.
4.5 4-{[(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-6-(methylsulfonyl)-2,3-dihydro-1 Hinden-
1-yl]oxy}-3-chlorobenzonitrile
To a solution of 3-chloro-4-hydroxybenzonitrile (0.23g, 1.25eq.) in CH2CI2 (7ml) is
added polymer-bound PPh3 (1g, 3mmol/g, 2.50eq.) and tert-butyl {(3R)-1 -[(1S,2S)-2-
hydroxy-6-(methylsulfonyl)-2,3-dihydro-1 H-inden-1 -yl]piperidin-3-yl}carbamate (0.50g,
1eq.). The suspension is cooled to 0°C and a solution of di-tert-butyl azodicarboxylate
(0.56g, 2eq.) in CH2CI2 (3ml) added dropwise. The mixture is stirred over night at RT, then
filtered on celite®. The filter is washed twice with CH2CI2. The filtrate is evaporated under
reduced pressure and the residue is purified by column chromatography
(CH2Cl2/methanol, 100/0 to 95/5) to yield 0.66g (quantitative) of a white foam. The residue
is then dissolved in ethanol ( 1 ml) and HCI (0.6ml, 2N in Et20 ) is added. The precipitate is
filtered and dried under reduced pressure to afford 0.1 2g of the desired compound as an
off-white solid: H NMR (400 MHz, DMSO-d6) d 8.38 (bs, 2H), 8.15 (s, 1H), 8.02-8.00 (m,
1H), 8.00-7.98 (m, 1H), 7.88-7.85 (m, 1H), 7.75 (s, 1H), 7.76-7.74 (m, 1H), 6.28 (s, 1H),
3.92-3.88 (m, 1H), 3.35-3.1 0 (m, 4H), 3.1 1 (s, 3H), 2.81 -2.75 (m, 1H), 2.70-2.51 (m, 2H),
1.95-1 .80 (m, 2H), 1.65-1 .50 (m, 2H); LCMS (ES) M+ 446; [a ] = -187.1 0 (CH3OH); mp =
162 € .
Example 5: 4-({(1 R,2R)-2-[3-(2-aminopropan-2-yl)azetidin-1-yl]-2,3-dihydro-
1H-inden-1-yl}oxy)-3-chlorobenzonitrile (compound 125)
5.1 ( 1aR,6aS)-6,6a-dihydro-1 aH-indeno[1 ,2-b]oxirene
The title compound is prepared following the method used for example 2.
5.2 tert-butyl (2-{1 -[(1 S,2S)-2-hydroxy-2,3-dihydro-1 H-inden-1 -yl]azetidin-3-
yl}propan-2-yl)carbamate
To a solution of ( 1aR,6aS)-6,6a-dihydro-1 aH-indeno[1 ,2-b]oxirene (0.34g, 1.00eq.)
in AcN (7ml) is added tert-butyl [2-(azetidin-3-yl)propan-2-yl]carbamate (0.92g, 1.45eq.).
The solution is brought to reflux and heated overnight. After cooling, the solvents are
evaporated under reduced pressure and the residue is purified by column
chromatography (CH2CI2/methanol, 100/0 to 90/1 0) to afford 0.47g (53%) of the desired
product.
5.3 4-({(1 R,2R)-2-[3-(2-aminopropan-2-yl)azetidin-1 -yl]-2,3-dihydro-1 H-inden-1 -
yl}oxy)-3-chlorobenzonitrile
To a solution of 3-chloro-4-hydroxybenzonitrile (0.26g, 1.25eq.) in CH2CI2 ( 10ml) is
added polymer-bound PPh3 ( 1 . 12g, 3mmol/g, 2.50eq.) and tert-butyl (2-{1 -[(1 S,2S)-2-
hydroxy-2,3-dihydro-1 H-inden-1-yl]azetidin-3-yl}propan-2-yl)carbamate (0.47g, 1eq.). The
suspension is cooled to 0°C and a solution of di-isopropyl azodicarboxylate (0.63g, 2eq.)
in CH2CI2 (4ml) is added dropwise. The mixture is stirred over night at RT, then filtered on
celite®. The filter is washed twice with CH2CI2. The filtrate is evaporated under reduced
pressure and the residue is purified by column chromatography (cyclohexane/EtOAc,
100/0 to 70/30) to yield 0.1 Og ( 15%) of the product. The residue is then dissolved in
ethanol (2 ml) and HCI ( 1ml, 1N in Et20 ) is added. The precipitate is filtered and dried
under reduced pressure to afford 0.03g of the desired compound as a white solid: H
NMR (400 MHz, DMSO-d6) d 8.25 (bs, 2H), 8.1 0 (s, 1H), 7.94-7.90 (m, 1H), 7.76-7.74
(m, 1H), 7.46-7.43 (m, 1H), 7.43 (s, 1H), 7.32-7.28 (m, 1H), 7.22-7.1 9 (m, 1H), 6.45 (s,
1H), 4.80-4.68 (m, 1H), 4.58-4.00 (m, 5H), 1.40-1 .25 (m, 2H), 1.20 (s, 6H); LCMS (ES) M+
382; mp = 93 € .
Example 6: 3-chloro-4-({(1 R,2R)-2-[(3R)-3-(methylamino)piperidin-1 -yl]-2,3-
dihydro-1 H-inden-1-yl}oxy)benzonitrile (compound 128)
6.1 tert-butyl {(3R)-1 -[(1 R,2R)-1 -(2-chloro-4-cyanophenoxy)-2,3-dihyd
2-yl]piperidin-3-yl}carbamate
The title compound is prepared following the method used in example 3.
6.2 3-chloro-4-({(1 R,2R)-2-[(3R)-3-(methylamino)piperidin-1 -yl]-2,3-dihydro-1 Hinden-
1 -yl}oxy)benzonitrile
To a solution of tert-butyl {(3R)-1 -[(1 R,2R)-1-(2-chloro-4-cyanophenoxy)-2,3-
dihydro-1 H-inden-2-yl]piperidin-3-yl}carbamate (0.23g, 1eq.) in DMF ( 1ml) is added water
( 10m I) and sodium hydride (0.1 3g, 60% in mineral oil, 7eq.) at 0°C. After stirring for 1h at
0°C, methyl iodide (0.09g, 1.50eq.) is added and the mixture is stirred at RT overnight.
The mixture is then diluted with CH2CI2 (40ml) and water (5ml). The aqueous layer is
separated and extracted with CH2CI2. The combined organic layers are dried over
anhydrous Na2S0 4, filtered and concentrated under reduced pressure. The residue is
purified by column chromatography (CH2CI2/EtOAc, 80/20). The product is dissolved in
CH2CI2 and treated with HCI (0.1 0ml, 4N in dioxane). The precipitate is then filtered and
dried under vaccum to afford 35mg of the desired product as a beige powder: H NMR
(400 MHz, DMSO-d6) d 9.00 (bs, 1H), 8.00 (s, 1H), 7.90-7.82 (m, 1H), 7.79-7.71 (m, 1H),
7.42-7.40 (m, 1H), 7.40 (s, 1H), 7.30-7.20 (m, 2H), 6.40 (s, 1H), 4.02-3.90 (m, 1H), 3.70-
3.20 (m, 4H), 2.92-2.80 (m, 3H), 2.60 (s, 3H), 2.06-1 .60 (m, 4H); LCMS (ES) M+ 382; [a ]
= -197.7° (CH3OH).
Example 7: 6-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1-yl]-6-methoxy-2,3-dihydro-
1H-inden-1-yl}oxy)-3,4-dihydroquinolin-2(1 H)-one (compound 13 1)
7.1 6-methoxy-2,3-dihydro-1 H-inden-1-ol
To a cooled solution (0°C) of 6-methoxyindanone (4g, 1eq.) in THF (100ml) and
methanol (23ml) is added sodium borohydride ( 1 .86g, 2eq.) portionwise. The suspension
is stirred at RT overnight. The mixture is diluted with water. The aqueous layer is
extracted with CH2CI2. The organic layer is dried over anhydrous Na2S0 4, filtered and
concentrated under reduced pressure to afford 4.0g (98%) of the desired product as a
yellow oil, used in the next step without further purification
7.2 1H-inden-5-yl methyl ether
In a round bottom flaky equipped with a dean starck is introduced a solution of 6-
methoxy-2,3-dihydro-1 H-inden-1 -ol (4g, 1eq.) in toluene (121 ml). Para-toluenesulfonic
acid (0.05g, 0.01 eq.) is added and the mixture is brought to reflux. The solution is heated
for 7h. After cooling, the mixture is diluted with CH2CI2. The organic layer is washed with
saturated aqueous NaHC0 3 and water. The organic layer is dried over anhydrous
Na2S0 4, filtered and concentrated under reduced pressure. The residue is purified by
column chromatography (heptane/EtOAc, 100/0 to 50/50) to afford 2.69g (75%) of the
desired product as acolorless oil.
7.3 ( 1aR,6aS)-3-methoxy-6,6a-dihydro-1 aH-indeno[1 ,2-b]oxirene
In a three-neck round bottom flask is introduce NaOCI (2.8ml, 0.31 eq., 2N). The
flask is then flushed with argon and cooled to 0°C. A solution of (R,R)-N,N'-bis(3,5-di-tertbutylsalicylidene)-
1 ,2-cyclohexanediaminomanganese(lll) chloride (0.1 2g, 0.01 eq.) and 4-
(3-phenylpropyl)pyridine-N-oxide (0.1 2g, 0.03eq.) in CH2CI2 (9.5ml) is added. The
suspension is stirred for 15 min. To the cooled solution is added simultaneously via two
addition funnels NaOCI ( 12.5ml, 0.93eq., 2N) and a solution of 1H-inden-5-yl methyl ether
(2.69g, 1eq.) in CH2CI2 (5.8ml). The mixture is then stirred at 0°C for 1h and the
temperature is let warmed up to RT over night. The suspension is diluted with water and
CH2CI2 and filtered through celite®. The aqueous layer is separated and extracted three
times with CH2CI2. The combined organic layers are washed with brine, dried over
anhydrous Na2S0 4, filtered and concentrated under reduced pressure to afford 2.90g
(97%) of the desired compound as a brown oil, used in the next step without further
purification.
7.4 tert-butyl {(3R)-1 -[(1 S,2S)-2-hydroxy-6-methoxy-2,3-dihydro-1 H-inden-1 -
yl]piperidin-3-yl}carbamate
To a solution of ( 1aR,6aS)-3-methoxy-6,6a-dihydro-1 aH-indeno[1 ,2-b]oxirene
(0.70g, LOOeq.) in AcN ( 16ml) is added tert-butyl (3R)-piperidin-3-ylcarbamate ( 1 .25g,
1.45eq.). The solution is brought to reflux and heated overnight. After cooling, the
solvents are evaporated under reduced pressure and the residue is purified by column
chromatography (CH2CI2/methanol, 100/0 to 95/5) to afford 0.85g (85%) of the desired
product as a brown foam.
7.5 6-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1-yl]-6-methoxy-2,3-dihydro-1 H-inden-1 -
yl}oxy)-3,4-dihydroquinolin-2(1 H)-one
To a solution of 6-hydroxy-3,4-dihydroquinolin-2(1 H)-one (0.40g, 1.25eq.) in
CH2CI2 ( 1 1ml) is added polymer-bound PPh3 ( 1 .31g, 3mmol/g, 2.50eq.) and tert-butyl
{(3R)-1 -[(1 S,2S)-2-hydroxy-6-methoxy-2,3-dihydro-1 H-inden-1 -yl]piperidin-3-yl}carbamate
(0.85g, 1eq.). The suspension is cooled to 0°C and a solution of di-tert-butyl
azodicarboxylate (0.92g, 2eq.) in CH2CI2 (6.7ml) is added dropwise. The mixture is stirred
over night at RT, then filtered on celite®. The filter is washed twice with CH2CI2. The
filtrate is evaporated under reduced pressure and the residue is purified by column
chromatography (CH2CI2/methanol, 100/0 to 90/10) to yield 0.43g (43%) of an orange
foam. The residue is then dissolved in CH2CI2 (5 ml) and HCI (0.82ml, 2N in Et20 ) is
added. The precipitate is filtered and dried under reduced pressure to afford 0.25g of the
desired compound as an orange solid: H NMR (400 MHz, DMSO-d6) d 9.55 (s, 1H), 8.30
(bs, 2H), 7.21 -7.15 (m, 1H), 6.95 (s, 1H), 6.90-6.75 (m, 3H), 6.60 (s, 1H), 6.05 (s, 1H),
3.94-3.80 (m, 1H), 3.62 (s, 3H), 3.55-2.96 (m, 7H), 2.85-2.75 (m, 2H), 2.40-2.35 (m, 2H),
1.98-1 .85 (m, 1H), 1.85-1 .70 (m, 2H), 1.65-1 .50 (m, 1H); LCMS (ES) M+ 408; mp =
145.6°C.
Example 8 : 6-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1-yl]-2,3-dihydro-1 H-inden-1 -
yl}oxy)-7-chloro-3,4-dihydroquinolin-2(1 H)-one (compound 132)
8.1 tert-butyl {(3R)-1 -[(1 S,2S)-2-hydroxy-2,3-dihydro-1 H-inden-1 -yl]piperidin-3-
yljcarbamate
The title compound is prepared following the method used in example 2.
8.2 6-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-7-
chloro-3,4-dihydroquinolin-2(1 H)-one
To a solution of 6-hydroxy-7-chloro-3,4-dihydroquinolin-2(1 H)-one (0.26g, 1.25eq.)
in CH2CI2 (7ml) is added polymer-bound PPh3 (0.69g, 3mmol/g, 2.50eq.) and tert-butyl
{(3R)-1 -[(1 S,2S)-2-hydroxy-2,3-dihydro-1 H-inden-1 -yl]piperidin-3-yl}carbamate (0.35g,
1eq.). The suspension is cooled to 0°C and a solution of di-tert-butyl azodicarboxylate
(0.48g, 2eq.) in CH2CI2 (3ml) is added dropwise. The mixture is stirred over night at RT,
then filtered on celite®. The filter is washed twice with CH2CI2. The filtrate is evaporated
under reduced pressure and the residue is purified by column chromatography
(CH2CI2/methanol, 100/0 to 92/8) to yield 0.36g (67%) of the product. The residue is then
dissolved in CH2Cl2 (5 ml) and HCI (0.7ml, 2N in Et20 ) is added. The precipitate is filtered
and dried under reduced pressure to afford 0.1 8g of the desired compound as an orange
solid: H NMR (400 MHz, DMSO-d6) d 9.75 (s, 1H), 8.45 (bs, 2H), 7.42-7.38 (m, 1H), 7.35
(s, 1H), 7.32-7.1 8 (m, 3H), 7.00 (s, 1H), 6.18 (s, 1H), 4.1 0-4.00 (m, 1H), 3.60-3.20 (m,
11H), 2.09-2.78 (m, 3H), 1.72-1 .60 (m, 1H); LCMS (ES) M+ 4 12; mp = 183.7°C.
Example 9 : 4-({(5R,6R)-6-[(3R)-3-aminopiperidin-1-yl]-6,7-dihydro-5Hcyclopenta[
b]pyridin-5-yl}oxy)-3-chlorobenzonitrile (compound 137)
9.1 6,7-dihydro-5 -cyclopenta[ ]pyridine 1-oxide
To a solution of 6,7-dihydro-5H-cyclopenta [ >]pyridine (5g, 1eq.) in acetic acid (25
ml) is added H20 2 (2.51 g, 50% in water, 0.88 eq.). The solution is warmed to 70°C. After
3 hours, further H20 2 (2.51 g, 50% in water, 0.88 eq.) is added and the mixture is stirred at
70^ over night. After cooling down, the solvent is evaporated under reduced pressure
and water (20 ml) is added to the residue. Solid K2C03 is then added to have pH=9. The
aqueous layer is separated and extracted three times with CH2CI2. The combined organic
layers are dried over anhydrous Na2S0 4, filtered and evaporated under reduced pressure
to yield 5.55g (97%) of the desired compound, used in the next step without further
purification.
9.2 6,7-dihydro-5H-cyclopenta [ >]pyridin-7-yl acetate
To a solution of acetic anhydride (44g, 10.50eq.) and water (0.42g, 0.50eq.) is
added 6,7-dihydro-5H-cyclopenta [ >]pyridine 1-oxide (5.55g, 1eq.). After stirring for 1h at
RT, the mixture is heated gently to 80°C. The temperature is monitored in order not to
rise above 95 . When the exothermy is over, the Brownish red solution is heated to
100 € for 3h. After cooling to RT, water (150ml) and Et20 (300ml) are added. The
aqueous layer is separated and extracted three times with Et20 . The combined organic
layers are dried over Na2S0 4, filtered and evaporated under reduced pressure to yield
3.75g (87%) of the desired compound, used in the next step without further purification.
9.3 5H-cyclopenta[b]pyridine and 7H-cyclopenta[b]pyridine
Concentrated sulphuric acid (20.5ml, 6.63eq.) is added to 6,7-dihydro-5Hcyclopenta[£>]
pyridin-7-yl acetate (5.3g, 1eq.). The mixture is stirred at 130°C for 1h then
stirred at RT overnight. Ice is added, followed by sodium hydroxide (25ml, 35%) and
water ( 120ml). The aqueous layer is extracted 3 times with CH2CI2. The combined organic
layers are dried over anhydrous Na2S0 4, filtered and concentrated under reduced
pressure to obtain 3.2g (95%) of a 65:35 mixture of the 2 regioisomers as a black oil,
used in the next step without further purification.
9.4 ( 1aR,6aS)-6,6a-dihydro-1 aH-oxireno[4,5]cyclopenta[1 ,2-b]pyridine and
( 1aS,6aR) 2,6b-dihydro-1 aH-oxireno[3,4]cyclopenta[1 ,2-b]pyridine
In a three-neck round bottom flask is introduce NaOCI (7.1 ml, 1eq., 2N). The flask
is then flushed with argon and cooled to O'C. A solution of (R,R)-N,N'-bis(3,5-di-tertbutylsalicylidene)-
1 ,2-cyclohexanediaminomanganese(lll) chloride (0.1 7g, 0.01 eq.) and 4-
(3-phenylpropyl)pyridine-N-oxide (0.1 7g, 0.03eq.) in CH2CI2 (8ml) is added. The
suspension is stirred for 15 min. Simultaneous addition of NaOCI (10ml, 1.2eq., 2N) and a
solution of 5H-cyclopenta[b]pyridine and 7H-cyclopenta[b]pyridine (3.3g, 1eq.) in CH2CI2
(8ml) via two addition funnel follows. The mixture is then stirred at 0°C for 1h and the
temperature is let warmed up to RT over night. The suspension is diluted with water and
CH2CI2 and filtered through celite®. The aqueous layer is separated and extracted three
times with CH2CI2. The combined organic layers are washed with brine, dried over
anhydrous Na2S0 4, filtered and concentrated under reduced pressure to afford 3.70g
(quantitative) of a 65:35 mixture of the 2 desired regioisomers, used in the next step
without further purification.
9.5 tert-butyl {(3R)-1 -[(5S,6S)-6-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-5-
yl]piperidin-3-yl}carbamate and tert-butyl {(3R)-1 -[(6S,7S)-6-hydroxy-6,7-dihydro-5Hcyclopenta[
b]pyridin-7-yl]piperidin-3-yl}carbamate
To a solution of ( 1aR,6aS)-6,6a-dihydro-1 aH-oxireno[4,5]cyclopenta[1 ,2-b]pyridine
and ( 1aS,6aR)-2,6b-dihydro-1 aH-oxireno[3,4]cyclopenta[1 ,2-b]pyridine (3.70g, 1eq.) in
AcN (70ml) is added tert-butyl (3R)-piperidine-3-yl carbamate (7.98g, 1.43eq.). The
solution is brought to reflux and heated over night. After cooling, the mixture is
evaporated under reduced pressure and the resulting residue is purified by column
chromatography (CH2CI2/methanol, 100/0 to 90/10) to afford 3.08g of tert-butyl {(3R)-1-
[(5S,6S)-6-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl]piperidin-3-yl}carbamate and
1.85g of tert-butyl {(3R)-1-[(6S,7S)-6-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-7-
yl]piperidin-3-yl}carbamate.
9.6 4-({(5R,6R)-6-[(3R)-3-aminopiperidin-1 -yl]-6,7-dihydro-5Hcyclopenta[
b]pyridin-5-yl}oxy)-3-chlorobenzonitrile
To a solution of 3-chloro-4-hydroxybenzonitrile (0.48g, 1.05eq.) in THF (36ml) is
added polymer-bound PPh3 (2.36g, 3mmol/g, 3eq.) and tert-butyl {(3R)-1 -[(5S,6S)-6-
hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl]piperidin-3-yl}carbamate (1g, 1eq.). The
suspension is cooled to 0°C and a solution of di-isopropyl azodicarboxylate ( 1 .82g, 3eq.)
in THF (3ml) is added dropwise. The mixture is stirred over night at RT, then filtered on
celite®. The filter is washed twice with CH2CI2. The filtrate is evaporated under reduced
pressure and the residue is purified by column chromatography (Ch^Cb/methanol, 100/0
to 95/5) to yield 0.2g of the desired product. The residue is then dissolved in CH2CI2
( 1 .4ml) and HCI (0.5ml, 4N in Et20 ) is added. The precipitate is filtered and dried under
reduced pressure to afford 0.1 Og of the desired compound as light grey solid: H NMR
(400 MHz, DMSO-d6) d 8.60-8.55 (m, 1H), 8.32 (bs, 2H), 8.02 (s, 1H), 7.92-7.88 (m, 1H),
7.83-7.79 (m, 1H), 7.65-7.60 (m, 1H), 7.37-7.28 (m, 1H), 6.56 (s, 1H), 4.25-4.15 (m, 1H),
3.58-3.35 (m, 4H), 3.1 2-3.00 (m, 1H), 3.00-2.80 (m, 2H), 2.06-1 .60 (m, 4H); LCMS (ES)
M+ 369; [a ] = - 1 13° (CH3OH); mp = 172 C .
Example 10 : 4-({(6R,7S)-6-[(3R)-3-aminopiperidin-1-yl]-6,7-dihydro-5Hcyclopenta[
b]pyridin-7-yl}oxy)-3-chlorobenzonitrile (compound 138)
To a solution of 3-chloro-4-hydroxybenzonitrile (0.72g, 1.05eq.) in THF (53ml) is
added polymer-bound PPh3 (3.54g, 3mmol/g, 3eq.) and tert-butyl {(3R)-1 -[(6S,7S)-6-
hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl]piperidin-3-yl}carbamate ( 1 .50g, 1eq.).
The suspension is cooled to 0°C and a solution of di-isopropyl azodicarboxylate (2.73g,
3eq.) in THF (3ml) is added dropwise. The mixture is stirred over night at RT, then filtered
on celite®. The filter is washed twice with CH2CI2. The filtrate is evaporated under
reduced pressure and the residue is purified by column chromatography
(CH2Cl2/methanol, 100/0 to 95/5) to yield 0.5g of the desired product. The residue is then
dissolved in CH2CI2 (3.9ml) and HCI ( 1 .5ml, 4N in Et20 ) is added. The precipitate is
filtered and dried under reduced pressure to afford 0.1 8g of the desired product as a
white solid: H NMR (400 MHz, DMSO-d6) d 8.45-8.40 (m, 1H), 8.35 (bs, 2H), 7.99 (s,
1H), 7.90-7.80 (m, 3H), 7.42-7.38 (m, 1H), 6.45 (s, 1H), 4.25-4.15 (m, 1H), 3.58-3.35 (m,
2H), 3.35-3.20 (m, 2H) 3.1 5-2.80 (m, 3H), 2.06-1 .60 (m, 4H); LCMS (ES) M+ 369; [a ] = -
245.9° (CH3OH); mp = 180°C.
The following table illustrates the chemical structures and the physical properties
of some examples of compounds according to the present invention. In this table, in the
« salt » column, « - » represents a compound as a free base, whereas "TFA" represents a
compound in the form of a trifluoroacetic acid salt, « HCI » represents a compound in the
form of a hydrochloride, the ratio in parentheses being the acid to base ratio.

54 HCI (2) 0.68 (B)
55 TFA 2.69 (A)
56 TFA 2.48 (A)
/
57 TFA 2.48 (A)
58 TFA 2.32 (A)
59 TFA 2.30 (A)
60 TFA 2.29 (A)
6 1 TFA 2.40 (A)

The compounds of the invention underwent pharmacological studies which
demonstrated their ability to inhibit TRCP6. The method for testing the TRPC6 inhibitory
activity of the compounds of the invention is as described in the patent application
WO 2006/074802.
The IC50 of the compounds of the invention are lower than 10 mM, demonstrating
their value as therapeutically active substances. More specifically, the IC50 values of the
compounds described in table 1 are comprised between 0.001 mM and 1 mM. For
example, compounds 8 and 63 display IC50 of 1.20 x 10~8 and 8.1 1 x 10~7 mM, respectively.
The compounds according to the invention therefore display inhibition activity
towards TRPC6.
The compounds of formula (I) are inhibitors of TRCP6, and are therefore useful for
the prevention and treatment of fibrotic disorders, such as focal segmental
glomerulosclerosis, skeletal muscle dysfunction, renal failure, atherosclerosis, heart
failure, cancer (e.g. oesophageal cancer, breast cancer), chronic obstructive pulmonary
disease, pain, pulmonary hypertension, ischemic stroke, myocardial infarction,
inflammation or peripheral arterial occlusive disease.
The invention also relates to a medicament, comprising a compound of formula (I)
as defined above, or an addition salt of said compound to a pharmaceutically acceptable
salt, or an hydrate or solvate of said compound.
The invention also relates to compounds of formula (I) as drugs.
The compounds according to the invention can indeed be useful for the
preparation of drugs, specifically of medicaments inhibiting TRCP6, in particular
medicaments for the prevention and the treatment of fibrotic disorders, such as focal
segmental glomerulosclerosis, skeletal muscle dysfunction, renal failure, atherosclerosis,
heart failure, cancer (e.g. oesophageal cancer, breast cancer), chronic obstructive
pulmonary disease, pain, pulmonary hypertension, ischemic stroke, myocardial infarction,
inflammation or peripheral arterial occlusive disease.
The invention also relates to a pharmaceutical composition, comprising a
compound of formula (I) as defined above, or an addition salt of said compound to a
pharmaceutically acceptable salt, or an hydrate or solvate of said compound, as active
principle, and at least one pharmaceutically acceptable excipient.
These pharmaceutical compositions comprise an effective dose of at least one
compound according to the invention, or an addition salt thereof with a pharmaceutically
acceptable salt, or an hydrate or solvate of the latter, and at least one pharmaceutically
acceptable excipient.
Said excipients are chosen according to the pharmaceutical form and the
administration route desired, among usual excipients known of one of skill in the art.
In the pharmaceutical compositions according to the invention for the oral,
sublingual, sub-cutaneous, intramuscular, intra-venous, topical, local, intratracheal,
intranasal, transdermal or rectal administration, the active principle of formula (I) above,
its salt, solvate or hydrate, can be administered as a unitary dosage form, in blend with
usual pharmaceutical excipients, to animals and human beings for the prevention or for
the treatment of diseases mentioned above.
The appropriate unitary dosage forms comprise the oral forms, such as tablets,
hard or soft gelatin capsules, powders, granules and oral solutions or suspensions, the
sublingual, buccal, intratracheal, intraocular, intranasal forms, by inhalation, the topical,
transdermal, sub-cutaneous, intramuscular or intra-venous forms, the rectal forms and
the implants. For the topical application, the compounds of the invention may be used as
creams, gels, ointments or lotions.
As an example, a unitary dosage form for a compound according to the invention,
in the form of a tablet, can comprise the following ingredients:
Compound according to the invention 50,0 mg
Mannitol 223,75 mg
Croscarmellose sodique 6,0 mg
Maize starch 15,0 mg
Hydroxypropyl methylcellulose 2,25 mg
Magnesium stearate 3,0 mg
The present invention, according to another of its aspects, also relates to a
method for the treatment or prevention of the above pathologies, which comprises the
administration to a patient of an effective dose of a compound according to the invention,
or a salt with a pharmaceutically acceptable salt thereof, or an hydrate or a solvate
thereof.
. Compound of formula
in which
A is a 6 to 10 membered aryl radical or a 5 to 10 membered heteroaryl radical,
where the aryl and heteroaryl radical may be mono- or bicyclic, and the heteroaryl
radical may comprise one or more heteroatoms selected from the group of
nitrogen, oxygen and sulfur;
where one or more hydrogen atoms in said mono- or bicyclic aryl or
heteroaryl radicals may be replaced by substituents R 1 which are selected
independently of one another from the group of H, F, CI, Br, I, (C1-C10)-
alkyl, (C2-C 0)-alkenyl, (C2-C 0)-alkynyl, (C3-C 4)-cycloalkyl, (C4-C20)-
cycloalkylalkyl, (C4-C20)-cycloalkylalkyloxy, (d-Cio)-alkoxy, (C1-C10)-
alkylthio, (C6-C14)-aryl, (C2-C13)-heteroaryl, -CN, -OH, -NR13R14,
-C(0)R1 2, -SF5, -S(0) nR12, -C(0)OR12, -C(0)NR1 3R14, -S(0) nNR1 3R14;
where two adjacent radicals R 1 may also form a saturated or partly
unsaturated (C5-C 0)-cycloalkyl radical or a saturated or partly
unsaturated (C2-C9)-cycloheteroalkyl radicals, where the
cycloheteroalkyl radical may comprise 1, 2 or 3 nitrogen, 1 or 2
oxygen, 1 or 2 sulfur, 1 or 2 nitrogen and 1 oxygen or 1 sulfur atom;
where said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,
cycloalkylalkyloxy, cycloheteroalkyl, alkoxy, and alkylthio radicals
may be substituted independently of one another one or more
times by F, OH or (Cr C 0)-alkoxy;
B is a mono- or fused bicyclic radical selected from the group of
6 to 10 membered aryl radicals,
of 5 to 10 membered heteroaryl radicals,
of 3 to 10 membered cycloalkyl radicals,
of 9 to 14 membered cycloalkylaryl radicals,
of 8 to 14 membered cycloalkylheteroaryl radicals,
of 3 to 10 membered cycloheteroalkyi radicals,
of 9 to 14 membered cycloheteroalkylaryl radicals and
of 8 to 14 membered cycloheteroalkylheteroaryl radicals,
where the cycloalkyi or cycloheteroalkyi units may be saturated or partly
unsaturated, and where the heterocyclic groups may comprise one or more
heteroatoms selected from the group of nitrogen, oxygen and sulfur;
where one or more hydrogen atoms in the radicals B may be replaced by
substituents R5 which are selected independently of one another from the
group of (d-Cio)-alkyl radicals, of (C2-C 0)-alkenyl radicals, of (C2-C 0)-
alkynyl radicals, of (Cr C 0)-alkoxy radicals, of (Cr C 0)-alkylthio radicals, of
(C3-C 4)-cycloalkyl radicals, of (C4-C20)-cycloalkylalkyl radicals, of (C4-C20)-
cycloalkylalkyloxy, of (C2-C 9)-cycloheteroalkyl radicals, of (C3-C 9)-
cycloheteroalkylalkyl radicals, of (C3-Cn)-cycloalkyloxy radicals, of (C2-Cn)-
cycloheteroalkyloxy radicals, of (C6-C )-aryl radicals, of (CrC 9)-heteroaryl
radicals, of (C9-C 4)-cycloalkylaryl radicals, of (C5-C 3)-cycloalkylheteroaryl
radicals, (C7-C 3)-cycloheteroalkylaryl radicals, (C4-C 2)-
cycloheteroalkylheteroaryl radicals, where
the cycloalkyi and cycloheteroalkyi units may be saturated or
partly unsaturated,
and where one or more hydrogen atoms in said radicals R5 may
be replaced by further radicals which are selected independently
of one another from the group of R 11 radicals,
it is further possible for R5 to be one or more radicals which are selected
independently of one another from the group of OH, (=0), NH2, F, CI, Br, I,
CN, N0 2, -NR1 7R1 8, -NR16COR17, -NR16COOR17,
-NR1 6CONR1 7R1 8, -NR1 6-S(0) 2-R17, -NR1 6-S(0) 2-NR17R18,
-COOR1 6, -COR16; -CO(NR17R18), S(0)„R16, -S(0) 2NR17R18,
where R 16, R17 and R 18 independently of one another for a radical
selected from the group of H, (C2-C 9)-cycloheteroalkyl, (C3-C )-
cycloalkyl, (C6-C )-aryl, (Cr C 0)-alkyl radicals,
all of which may be substituted independently of one another by
OH, (=0), F, CI, Br, I, CN, N0 2, -NR13R14, -NR13COR12,
-NR1 3COOR1 2, -NR1 2CONR1 3R14, -NR1 3-S(0) 2-R12,
-NR1 2-S(0) 2-R13R14, -COOR12, -COR12; -CO(NR1 3R14),
-S(0) nR12, -S(0) 2NR1 3R14, (C3-C14)-cycloalkyl, (C4-C20)-
cycloalkylalkyl, (C2-C 9)-cycloheteroalkyl, (C3-C 9)-
cycloheteroalkylalkyl, (C6-Ci )-aryl and (CrC 9)-heteroaryl,
and where R 17 and R18 can form together with the nitrogen to which
they are bonded a 4-7 membered, saturated, unsaturated or partly
unsaturated heterocycle having 1 to 13 carbon atoms which may
additionally comprise one or more heteroatoms from the list -0-,
-S(0) n- , =N- and -NR15-,
where the heterocycle formed may be substituted
independently of one another one or more times by F, OH,
(=0), NH , NH(C C4)alkyl, N((C C4)alkyl) , CN or (CrC 10)-
alkoxy, (C C10)-alkyl, (C2-C10)-alkenyl, (C2-C10)-alkynyl, (C3-
C )-cycloalkyl, (C4-C20)-cycloalkylalkyl, (C2-C20)-
cycloheteroalkyl, (C3-C 9)-cycloheteroalkylalkyl, each of
which may in turn carry independently of one another one or
more radicals F, OH, (=0), NH2, NH(C C4)alkyl, N((C
C4)alkyl) 2, CN or (C C10)-alkoxy;
is a covalent bond or an alkylene bridge having 1 to 10 carbon atoms,
which may carry independently of one another one or more
substituents from the group of radicals (C-rC-io)-alkyl, (C3-C )-
cycloalkyl, (C4-C20)-cycloalkylalkyl radical, -COR12, -CO(NR1 3R14),
S(0) nR12, -S(0) 2NR13R14, (=0) and F; where the alkyl, cycloalkyl
and cycloalkyl radicals may be substituted one or more times by F;
is a group -N(R6)-, -0-, -S(0) n- , or alkylene having 1 to 5 carbon atoms, where
R6 may be hydrogen or may be (C-rC-io)-alkyl, (C3-C )-cycloalkyl,
(C4-C20)-cycloalkylalkyl radical, all of which may be substituted
independently of one another one or more times by F, or R6 may be
-C0R1 2; -CO(NR1 3R14), S(0) nR12, -S(0) 2NR1 3R14;
is absent or is one or more substituents which may be selected independently of
one another from the group of F, (d-C-io)-alkyl and (C-rC-io)-alkoxy radical, where
the alkyl and alkoxy radicals may be substituted independently of one another one
or more times by F;
R3 and R4 form together with the nitrogen to which they are bonded a 4-1 0 membered,
saturated, heterocycle which may additionally comprise one or more heteroatoms
from the list -0-, -S(0) n- , and -NR8-, where
the heterocyclic radicals may be substituted independently of one another
one or more times by radicals selected from the group of R7 and R9, and
where
the heterocyclic radicals may be bridged by a bond, by a saturated or
unsaturated (d-Cio)-alkyl or (CrC 9)-heteroalkyl chain or by -NR1 5-, -0-,
-S-, and where
the alkyl and heteroalkyl chains may also form a spirocyclic ring
system with the ring system formed by R3 and R4, where the alkyl
and heteroalkyl bridges may be substituted independently of one
another one or more times by radicals selected from the group of
R7 and R9,
and where
R8 in the group NR8 may form with the ring which R3 and R4 may form a
further saturated, unsaturated or partly unsaturated heterocycle which may
be substituted independently of one another one or more times by radicals
selected from the group of R7 and R9, and may additionally comprise one
or more heteroatoms from the list -0-, -S(0) n- , -N= and -NR19-;
R7 are a (CrCi 0)-alkyl radical or (CrCi 4)-cycloalkyl radical, where the alkyl radical
may be substituted independently of one another one or more times by R9;
R8 is an H, a (CrC 10)-alkyl radical or (C C14)-cycloalkyl radical, COR12,
-CO(NR13R14), S(0) nR12, -S(0) 2NR13R14, where the alkyl radical may be
substituted independently of one another one or more times by R 10;
R9 is a radical selected from the group of OH, (=0), F, CI, Br, I, CN, N0 2, -NR13R14,
-NR1 3COR1 2, -NR1 3COOR1 2, -NR12CONR13R14, -NR1 3-S(0) 2-R12, -NR1 3-
S(0) 2-NR13R14, -COOR12, -COR12, -CO(NR13R14), S(0) nR12,
-S(0) 2NR13R14, (C3-C14)-cycloalkyl, (C4-C20)-cycloalkylalkyl, (C C10)-alkoxy, (C2-
C 9)-cycloheteroalkyl, (C3-C 9)-cycloheteroalkylalkyl, (C6-C 0)-aryl radicals, of (C
C9)-heteroaryl radicals;
R10 is a radical selected from the group of F, OH, CN, (d-Cio)-alkoxy, (C1-C10)-
alkylthio, N0 2, -NR13R14, -NR13COR12, -NR13COOR12, -NR13CONR13R14,
-NR1 3-S(0) 2-R12, -NR12-S(0) 2-NR1 3R14, -COOR1 2, -COR1 2, -CO(NR1 3R14),
S(0) nR12, -S(0) 2NR13R14;
R 11 is a radical selected from the group of (CrCi )-alkyl, (C2-C 0)-alkenyl, (C2-C 0)-
alkynyl, (CrCi 0)-alkoxy, (CrC 20)-alkylthio, (C3-C 4)-cycloalkyl, (C4-C 0)-
cycloalkylalkyl, (C2-C 3)-cycloheteroalkyl, (C4-C 9)-cycloheteroalkylalkyl, (C3-C )-
cycloalkyloxy, (C2-C 3)-cycloheteroalkyloxy,
all of which may be substituted independently of one another one or more
times by R10;
(=0), CI, Br, I and R 10;
R12, R 13 and R14 may independently of one another be H, (CrCi )-alkyl, (C2-C 0)-
alkenyl, (C2-C 0)-alkynyl, (C3-C 4)-cycloalkyl, (C4-C 0)-cycloalkylalkyl, (C2-C 3)-
cycloheteroalkyl, (C3-C 9)-cycloheteroalkylalkyl, (C6-C )-aryl, each of which may be
substituted independently of one another one or more times by F, OH, (=0), NH2,
NH(C C4)alkyl, N((C C4)alkyl) , CN or (C C10)-alkoxy;
or where R 13 and R14 may form together with the nitrogen to which they are
bonded a 4-7 membered, saturated, unsaturated or partly unsaturated heterocycle
having 1 to 13 carbon atoms, which may additionally comprise one or more
heteroatoms from the list -0-, -S(0) n- , =N- and -NR1 5-, where
the formed heterocycle may be substituted independently of one another one
or more times by F, OH, (=0), NH2, NH(C C4)alkyl, N((C C4)alkyl) 2, CN or
(Ci-Cio)-alkoxy, (C C10)-alkyl, (C2-C10)-alkenyl, (C2-C10)-alkynyl, (C3-C14)-
cycloalkyl, (C4-C20)-cycloalkylalkyl, (C2-C20)-cycloheteroalkyl, (C3-C 9)-
cycloheteroalkylalkyl, each of which may in turn carry independently of one
another one or more radicals F, OH, (=0), NH2, NH(C C4)alkyl, N((C
C4)alkyl) 2, CN or (C C10)-alkoxy;
R 15 is a radical selected from the group of H, (CrCi 0)-alkyl, (C2-C 0)-alkenyl, (C2-C 0)-
alkynyl, (C3-C )-cycloalkyl, (C4-C20)-cycloalkylalkyl, (C2-C 3)-cycloheteroalkyl, (C3-
C 9)-cycloheteroalkylalkyl, each of which may be substituted independently of one
another one or more times by F, OH, CN or (d-Cio)-alkoxy;
is an H, a (Cr C 0)-alkyl radical or (Ci-C )-cycloalkyl radical, COR12,
-CO(NR13R14), S(0) nR12, -S(0) 2NR13R14, where the alkyl radical may be
substituted independently of one another one or more times by R 10;
and in which
n is 0, 1 or 2;
p is 1 or 2 and
q is 0 or ,
in the form of a free base or of an addition salt with an acid, as well as in the form of an
hydrate or of a solvate,
and in which :
in the case where A is phenyl, B is phenyl or benzodioxolanyl, X is -O- or -S-, L is
a bond and R3 and R4 together are an unsubstituted pyrrolidinyl, morpholinyl,
piperidinyl or piperazinyl radical or 4-methylpiperazinyl radical, at least one R5
radical which is not a (CrCi 0)-alkyl, (CrCi 0)-alkoxy, OH, CF3, F, CI, Br or I radical
must be present.
2. Compound according to claim 1, of formula (II) :
is a 6 membered aryl radical or a 6 membered heteroaryl radical, where and T"
are independently N or CR1 ;
where one or more hydrogen atoms in said aryl or heteroaryl radicals may
be replaced by substituents R 1 which are selected independently of one
another from the group of H, F, CI, Br, I, (CrCi 0)-alkyl-, (CrCi 0)-alkoxy-,
-CN, -OH, -S(0) nR12, - ;
where said alkyl and alkoxy radicals may be substituted
independently of one another one or more times by F
and R 12 is H or (d-Cio)-alkyl, optionally substituted one or more
times by F;
B' is a 6 membered aryl radical or a 6 membered heteroaryl radical, where T is N or
CR5;
B" is absent or is radical chosen from a (C6-Ci )-aryl radical and a (C3-C6)-
cycloheteroalkyl radical comprising one ore more heteroatoms chosen from O, N
and S,
where at least one hydrogen atoms in the radicals B' and/or B" is replaced
by substituents R5 which are selected independently of one another from
the group of (Cr C 0)-alkyl radicals, of (Cr C 0)-alkoxy radicals, of (C3-C 4)-
cycloalkyl radicals, of (CrC 9)-heteroaryl radicals, where
the cycloalkyl units may be saturated or partly unsaturated,
and where one or more hydrogen atoms in said radicals R5 may
be replaced by further radicals which are selected independently
of one another from the group of F, CI, Br and I,
it is further possible for R5 to be one or more radicals which are selected
independently of one another from the group of OH, F, CI, Br, I, CN, N0 2,
-COOR1 6, -CO(NR1 7R1 8),
where R 16, R17 and R 18 independently of one another for a radical
selected from the group of H and (CrCi 0)-alkyl radicals, which may
be substituted independently of one another by F, CI, Br, I,
L is a covalent bond or a methylene bridge;
X is a group -O- or -S(0) n- ;
R3 and R4 form together with the nitrogen to which they are bonded a 4-7 membered,
saturated mono-or bi-cycloheteroalkyl radical which may additionally comprise one
or more -NR8- heteroatom, where
the cycloheteroalkyl radical may be substituted independently of one
another one time by a radical-(CR20R21 ) -NR22R23, in which r is 0 or 1
and R20, R21 , R22 and R23 are independently of one another H or a (C
Cio)-alkyl radical optionally substituted one or more times by F, CI, Br
and/or I,
R8 is an H or a ( -C o)-alkyl radical;
and in which
n is 0, 1 or 2; and
q is 0 or ,
in the form of a free base or of an addition salt with an acid, as well as in the form
of an hydrate or of a solvate (depending on the case).
3. Compound accor
in which A, B', B", T, T , T", R 1, R3, R4, R5, X, L and q are as defined in claim 2.
in the form of a free base or of an addition salt with an acid, as well as in the form
of an hydrate or of a solvate.
4. Compound according to claim 1, chosen from the group:
(3R)-1 -{(1 R,2S)-5-chloro-1 -[(2-chloro-5-fluorobenzyl)oxy]-2,3-dihydro-1 H-inden-2-
yl}piperidin-3-amine
(3S)-1 -[(1 R,2S)-5-chloro-1 -{[2-fluoro-3-(trifluoromethyl)benzyl]oxy}-2,3-dihydro-1 Hinden-
2-yl]piperidin-3-amine
1-({(1 S,2R)-1 -[3-(trifluoromethoxy)phenoxy]-2,3-dihydro-1 H-inden-2-
yl}methyl)pyrrolidine
1-({(1 S,2R)-1 -[3-(trifluoromethoxy)phenoxy]-2,3-dihydro-1 H-inden-2-
yl}methyl)piperidine
1-[1 -(2-cyclopentylphenoxy)-2,3-dihydro-1 H-inden-2-yl]piperidin-4-amine
(3R)-1 -{(1 R,2R)-1 -[2-(2H-benzotriazol-2-yl)-4-methylphenoxy]-2,3-dihydro-1 H-inden-
2-yl}piperidin-3-amine
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
chlorobenzonitrile
(3R)-1 -[(1 R,2R)-4,6-dichloro-1 -(4-fluorophenoxy)-2,3-dihydro-1 H-inden-2-
yl]piperidin-3-amine
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-4,6-dichloro-2,3-dihydro-1 H-inden-1 -
yl}oxy)-3-fluorobenzonitrile
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -
yl}sulfanyl)benzonitrile
4-({(1 R,2R)-2-[(3S)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -
yl}oxy)benzonitrile
4-({(1 R,2R)-2-[(3S)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-2-
fluorobenzonitrile
4-({(1 R,2R)-2-[(3S)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
fluorobenzonitrile
4-({(1 R,2R)-2-[(3S)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
chlorobenzonitrile
4-({(1 R,2R)-2-[(3S)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-2,3-
difluorobenzonitrile
4-({(1 R,2R)-2-[(3S)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
(trifluoromethyl)benzonitrile
(3S)-1 -[(1 R,2R)-1 -(2-chloro-6-methylphenoxy)-2,3-dihydro-1 H-inden-2-yl]piperidin-3-
amine
(3S)-1 -{(1 R,2R)-1 -[2-(2H-benzotriazol-2-yl)-4-methylphenoxy]-2,3-dihydro-1 H-inden-
2-yl}piperidin-3-amine
4-({(1 R,2R)-2-[(3S)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
nitrobenzonitrile
2-({(1 R,2R)-2-[(3S)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-5-
bromobenzonitrile
2-({(1 R,2R)-2-[(3S)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-5-
chlorobenzonitrile
(3S)-1 -[(1 R,2R)-1 -(2-bromo-4,6-difluorophenoxy)-2,3-dihydro-1 H-inden-2-
yl]piperidin-3-amine
4-({(1 R,2R)-2-[(3S)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
bromobenzonitrile
1-[(1 R,2R)-1 -(2-bromophenoxy)-2,3-dihydro-1 H-inden-2-yl]-1 ,4-diazepane
1-[(1 R,2R)-1 -(2-chloro-6-methylphenoxy)-2,3-dihydro-1 H-inden-2-yl]-1 ,4-diazepane
1-[(1 R,2R)-1 -(2-bromo-4-fluorophenoxy)-2,3-dihydro-1 H-inden-2-yl]-1 ,4-diazepane
1-[(1 R,2R)-1 -(2,3,6-trifluorophenoxy)-2,3-dihydro-1 H-inden-2-yl]-1 ,4-diazepane
1-[(1 R,2R)-1 -(2,4,6-trifluorophenoxy)-2,3-dihydro-1 H-inden-2-yl]-1 ,4-diazepane
1-[(1 R,2R)-1 -(2-bromo-4,6-difluorophenoxy)-2,3-dihydro-1 H-inden-2-yl]-1 ,4-
diazepane
(3R)-1 -[(1 R,2R)-1 -(2,4-dichlorophenoxy)-2,3-dihydro-1 H-inden-2-yl]piperidin-3-
amine
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -
yl}oxy)benzonitrile
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
fluorobenzonitrile
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-2-
chlorobenzonitrile
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-2,3-
difluorobenzonitrile
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
(trifluoromethyl)benzonitrile
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
methoxybenzonitrile
(3R)-1 -[(1 R,2R)-1 -(4-chloro-2-methylphenoxy)-2,3-dihydro-1 H-inden-2-yl]piperidin-
3-amine
(3R)-1 -[(1 R,2R)-1 -(2,4-difluorophenoxy)-2,3-dihydro-1 H-inden-2-yl]piperidin-3-
amine
(3R)-1 -[(1 R,2R)-1 -(4-bromo-3-fluorophenoxy)-2,3-dihydro-1 H-inden-2-yl]piperidin-3-
amine
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
nitrobenzonitrile
(3R)-1 -[(1 R,2R)-1 -(4-fluoro-2-methylphenoxy)-2,3-dihydro-1 H-inden-2-yl]piperidin-3-
amine
2-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-5-
bromobenzonitrile
2-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-5-
chlorobenzonitrile
5-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-1 ,3-
benzoxathiol-2-one
2-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-6-
fluorobenzonitrile
(3R)-1 -{(1 R,2R)-1 -[4-bromo-2-(1 H-pyrazol-3-yl)phenoxy]-2,3-dihydro-1 H-inden-2-
yl}piperidin-3-amine
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
ethoxybenzonitrile
2-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -
yl}oxy)benzonitrile
(3R)-1 -[(1 R,2R)-1 -(4-bromophenoxy)-2,3-dihydro-1 H-inden-2-yl]piperidin-3-amine
(3R)-1 -[(1 R,2R)-1 -(4-fluorophenoxy)-2,3-dihydro-1 H-inden-2-yl]piperidin-3-amine
(3R)-1 -[(1 R,2R)-1 -(2-bromo-4-chlorophenoxy)-2,3-dihydro-1 H-inden-2-yl]piperidin-3-
amine
2-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-5-
chlorobenzamide
6-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3,4-
dihydroquinolin-2(1 H)-one
(3R)-1 -{(1 R,2R)-1 -[4-methyl-2-(1 H-pyrazol-3-yl)phenoxy]-2,3-dihydro-1 H-inden-2-
yl}piperidin-3-amine
3-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-N,Ndimethylnaphthalene-
2-carboxamide
2-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-4-
bromobenzonitrile
2-({(1 R,2R)-2-[(3S)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-6-
fluorobenzonitrile
4-({(1 R,2R)-2-[(3R)-3-aminopyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -
yl}oxy)benzonitrile
4-({(1 R,2R)-2-[(3R)-3-aminopyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
fluorobenzonitrile
4-({(1 R,2R)-2-[(3R)-3-aminopyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
chlorobenzonitrile
(3R)-1 -{(1 R,2R)-1 -[2-(2H-benzotriazol-2-yl)-4-methylphenoxy]-2,3-dihydro-1 H-inden-
2-yl}pyrrolidin-3-amine
4-({(1 R,2R)-2-[(3R)-3-aminopyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
nitrobenzonitrile
(3R)-1 -[(1 R,2R)-1 -(2-bromo-4-fluorophenoxy)-2,3-dihydro-1 H-inden-2-yl]piperidin-3-
amine
(3R)-1 -{(1 R,2R)-1 -[4-chloro-2-(1 H-pyrazol-3-yl)phenoxy]-2,3-dihydro-1 H-inden-2-
yl}piperidin-3-amine
(3R)-1 -{(1 R,2R)-1 -[4-chloro-2-(1 ,2-oxazol-5-yl)phenoxy]-2,3-dihydro-1 H-inden-2-
yl}piperidin-3-amine
(3R)-1 -[(1 R,2R)-1 -(2-bromo-4,6-difluorophenoxy)-2,3-dihydro-1 H-inden-2-
yl]piperidin-3-amine
(3R)-1 -[(1 R,2R)-1 -(4-chloro-2-fluorophenoxy)-2,3-dihydro-1 H-inden-2-yl]piperidin-3-
amine
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
bromobenzonitrile
(3R)-1 -{(1 R,2R)-1 -[4-bromo-2-(1 ,2-oxazol-5-yl)phenoxy]-2,3-dihydro-1 H-inden-2-
yl}piperidin-3-amine
4-({(1 R,2R)-2-[(3S)-3-aminopyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -
yl}oxy)benzonitrile
4-({(1 R,2R)-2-[(3S)-3-aminopyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-2-
fluorobenzonitrile
4-({(1 R,2R)-2-[(3S)-3-aminopyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
fluorobenzonitrile
4-({(1 R,2R)-2-[(3S)-3-aminopyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
chlorobenzonitrile
4-({(1 R,2R)-2-[(3S)-3-aminopyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-2,3-
difluorobenzonitrile
1-[(1 R,2R)-1 -(2-chloro-6-fluoro-3-methylphenoxy)-2,3-dihydro-1 H-inden-2-yl]-1 ,4-
diazepane
(3S)-1 -{(1 R,2R)-1 -[2-(2H-benzotriazol-2-yl)-4-methylphenoxy]-2,3-dihydro-1 H-inden-
2-yl}pyrrolidin-3-amine
4-({(1 R,2R)-2-[(3S)-3-aminopyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
nitrobenzonitrile
2-({-2-[(3S)-3-aminopyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-5-
bromobenzonitrile
2-({(1 R,2R)-2-[(3S)-3-aminopyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-5-
chlorobenzonitrile
4-({(1 S,2S)-2-[(3R)-3-aminopiperidin-1 -yl]-4-methyl-2,3-dihydro-1 H-inden-1 -yljoxy)-
3-chlorobenzonitrile
4-({(1 R,2R)-2-[3-(methylamino)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -
yl}oxy)benzonitrile
3-fluoro-4-({(1 R,2R)-2-[3-(methylamino)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -
yl}oxy)benzonitrile
3-chloro-4-({(1 R,2R)-2-[3-(methylamino)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -
yl}oxy)benzonitrile
1-{(1 R,2R)-1 -[2-(2H-benzotriazol-2-yl)-4-methylphenoxy]-2,3-dihydro-1 H-inden-2-yl}-
N-methylpyrrolidin-3-amine
1-{(3R)-1 -[(1 R,2R)-1 -(4-nitrophenoxy)-2,3-dihydro-1 H-inden-2-yl]pyrrolidin-3-
yljmethanamine
1-{(3R)-1 -[(1 R,2R)-1 -(4-bromophenoxy)-2,3-dihydro-1 H-inden-2-yl]pyrrolidin-3-
yljmethanamine
1-{(3R)-1 -[(1 R,2R)-1 -(2-chloro-4-fluorophenoxy)-2,3-dihydro-1 H-inden-2-
yl]pyrrolidin-3-yl}methan amine
1-{(3R)-1 -[(1 R,2R)-1 -(2-chloro-4-nitrophenoxy)-2,3-dihydro-1 H-inden-2-yl]pyrrolidin-
3-yl}methanamine
2-({(1 R,2R)-2-[(3R)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -
yl}oxy)benzonitrile
1-{(3R)-1 -[(1 R,2R)-1 -(2-bromo-4-chlorophenoxy)-2,3-dihydro-1 H-inden-2-
yl]pyrrolidin-3-yl}methan amine
2-({(1 R,2R)-2-[(3R)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
5-chlorobenzonitrile
methyl 4-({(1 R,2R)-2-[(3R)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -
yl}oxy)-3-chlorobenzoate
4-({(1 R,2R)-2-[(3R)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
3-chlorobenzonitrile
1-{(3R)-1 -[(1 R,2R)-1 -(4-bromo-2-chlorophenoxy)-2,3-dihydro-1 H-inden-2-
yl]pyrrolidin-3-yl}methan amine
1-[(3R)-1 -{(1 R,2R)-1 -[4-bromo-2-(1 H-pyrazol-3-yl)phenoxy]-2,3-dihydro-1 H-inden-2-
yl}pyrrolidin-3-yl]methan amine
2-({(1 R,2R)-2-[(3R)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
5-bromobenzonitrile
4-({(1 R,2R)-2-[(3R)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
3-bromobenzonitrile
1-[(3R)-1 -{(1 R,2R)-1 -[4-chloro-2-(1 H-pyrazol-3-yl)phenoxy]-2,3-dihydro-1 H-inden-2-
yl}pyrrolidin-3-yl]methan amine
1-[(3R)-1 -{(1 R,2R)-1 -[4-methyl-2-(1 H-pyrazol-3-yl)phenoxy]-2,3-dihydro-1 H-inden-2-
yl}pyrrolidin-3-yl]methan amine
1-{(3R)-1 -[(1 R,2R)-1 -(2,4-dichlorophenoxy)-2,3-dihydro-1 H-inden-2-yl]pyrrolidin-3-
yljmethanamine
1-{(3R)-1 -[(1 R,2R)-1 -(4-chlorophenoxy)-2,3-dihydro-1 H-inden-2-yl]pyrrolidin-3-
yljmethanamine
4-({(1 R,2R)-2-[(3R)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
2-fluorobenzonitrile
4-({(1 R,2R)-2-[(3R)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
3-methoxybenzonitrile
4-({(1 R,2R)-2-[(3R)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
2-chlorobenzonitrile
4-({(1 R,2R)-2-[(3R)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
2,6-difluorobenzonitrile
2-({(1 R,2R)-2-[(3R)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
6-fluorobenzonitrile
4-({(1 R,2R)-2-[(3R)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
3-fluorobenzonitrile
4-({(1 R,2R)-2-[(3R)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
2,3-difluorobenzonitrile
4-({(1 R,2R)-2-[(3R)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
3-(trifluoromethyl)benzonitrile
1-{(3S)-1 -[(1 R,2R)-1 -(4-nitrophenoxy)-2,3-dihydro-1 H-inden-2-yl]pyrrolidin-3-
yljmethanamine
1-{(3S)-1 -[(1 R,2R)-1 -(2-chloro-4-nitrophenoxy)-2,3-dihydro-1 H-inden-2-yl]pyrrolidin-
3-yl}methanamine
2-({(1 R,2R)-2-[(3S)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
5-chlorobenzonitrile
4-({(1 R,2R)-2-[(3S)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
3-chlorobenzonitrile
2-({(1 R,2R)-2-[(3S)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
5-bromobenzonitrile
1-{(3S)-1 -[(1 R,2R)-1 -(4-chlorophenoxy)-2,3-dihydro-1 H-inden-2-yl]pyrrolidin-3-
yljmethanamine
4-({(1 R,2R)-2-[(3S)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
2-fluorobenzonitrile
4-({(1 R,2R)-2-[(3S)-3-(aminomethyl)pyrrolidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
2-chlorobenzonitrile
3-chloro-4-({(1 R,2R)-2-[4-(dimethylamino)piperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -
yl}oxy)benzonitrile
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-6-methoxy-2,3-dihydro-1 H-inden-1 -
yl}oxy)-3-chlorobenzonitrile
(2R,3R)-2-[(3R)-3-aminopiperidin-1-yl]-3-(2-chloro-4-cyanophenoxy)-2,3-dihydro-
1H-indene-5-carbonitrile
( 1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-1 -(2-chloro-4-cyanophenoxy)-2,3-dihydro-
1H-indene-5-carbonitrile
4-{[(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-6-(methylsulfonyl)-2,3-dihydro-1 H-inden-
1-yl]oxy}-3-chlorobenzonitrile
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-5-fluoro-2,3-dihydro-1 H-inden-1 -yljoxy)-
3-chlorobenzonitrile
4-({(1 R,2R)-2-[3-(2-aminopropan-2-yl)azetidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yljoxy)-
3-chlorobenzonitrile
3-chloro-4-({(1 R,2R)-2-[(1 S,4S)-2,5-diazabicyclo[2.2.1 ]hept-2-yl]-2,3-dihydro-1 Hinden-
1 -yl}oxy)benzonitrile
methyl 4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-3-
chlorobenzoate
3-chloro-4-({(1 R,2R)-2-[(3R)-3-(methylamino)piperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -
yl}oxy)benzonitrile
1-{(1 R,2R)-1 -[2-(2H-benzotriazol-2-yl)-4-methylphenoxy]-2,3-dihydro-1 H-inden-2-yl}-
N-methylpyrrolidin-3-amine
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-6-hydroxy-2,3-dihydro-1 H-inden-1 -
yl}oxy)-3-chlorobenzonitrile
6-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-6-methoxy-2,3-dihydro-1 H-inden-1 -
yl}oxy)-3,4-dihydroquinolin-2(1 H)-one
6-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-2,3-dihydro-1 H-inden-1 -yl}oxy)-7-chloro-
3,4-dihydroquinolin-2(1 H)-one
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-5-bromo-2,3-dihydro-1 H-inden-1 -yljoxy)-
3-chlorobenzonitrile
4-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-4,6-dichloro-2,3-dihydro-1 H-inden-1 -
yl}oxy)-3-chlorobenzonitrile
6-({(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-5-chloro-6-methoxy-2,3-dihydro-1 Hinden-
1 -yl}oxy)-3,4-dihydroquinolin-2(1 H)-one
6-{[(1 R,2R)-2-[(3R)-3-aminopiperidin-1 -yl]-6-(trifluoromethyl)-2,3-dihydro-1 H-inden-
1-yl]oxy}-3,4-dihydroquinolin-2(1 H)-one
4-({(5R,6R)-6-[(3R)-3-aminopiperidin-1-yl]-67-dihydro-5H-cyclopenta[b]pyridin-5-
yl}oxy)-3-chlorobenzonitrile
4-({(6R7S)-6-[(3R)-3-aminopiperidin-1 -yl]-67-dihydro-5H-cyclopenta[b]pyridin-7-
yl}oxy)-3-chlorobenzonitrile;
in the form of a free base or of an addition salt with an acid, as well as in the form of an
hydrate or of a solvate.
5. Medicament, comprising a compound of formula (I) according to claims 1 to 4,
or an addition salt of said compound to a pharmaceutically acceptable salt, or an hydrate
or solvate of said compound.
6. Pharmaceutical composition, comprising a compound of formula (I) according to
claims 1 to 4, or an addition salt of said compound to a pharmaceutically acceptable salt,
or an hydrate or solvate of said compound, and at least one pharmaceutically acceptable
excipient.
7 . Compound of formula (I) according to claims 1 to 4 for use for the prevention
and treatment of fibrotic disorders, such as focal segmental glomerulosclerosis, skeletal
muscle dysfunction, renal failure, atherosclerosis, heart failure, cancer (e.g. oesophageal
cancer, breast cancer), chronic obstructive pulmonary disease, pain, pulmonary
hypertension, ischemic stroke, myocardial infarction, inflammation or peripheral arterial
occlusive disease.