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CLAIMS
1.
A compound of formula (1) or a pharmaceutically acceptable salt thereof or if possible
tautomers thereof:
R3
A
Y
R2
N
(1)
O
R4
R1
wherein:

Y is CH or N; and

R1 is methyl, ethyl, isopropyl, tert. butyl, or cyclopropyl; and

R2 is methyl, ethyl, propyl, 2-propenyl, or 2-propynyl; and

R3 is hydrogen, chloro, fluoro, bromo, iodo, hydroxy, methoxy, methyl, or
trifluoromethyl; and

R4 is hydrogen, chloro, fluoro, bromo, iodo, hydroxy, methoxy, methyl, or
trifluoromethyl; and

A is a bi- or tricyclic carbon- or heterocyclic ring system of which one, two, or three
cycles can be aryl or heteroaryl and each of which is optionally substituted once or
more;
o
wherein a bicyclic or tricyclic system as described above contains 7 to 13 ring
atoms;
o
wherein a bicyclic or tricyclic system as described above contains 7 to 13 ring
atoms one or more of which are selected from the group of O, N, S or C=O;
o
wherein the optional substituent or substituents are independently selected
from the group consisting of phenyl, hydroxyl, trifluoromethyl, methyl, ethyl,
branched or unbranched C3-C4-alkyl, 2-thiophen, 3-thiophen, hydroxymethyl,
hydroxyethyl, methylcarbonyloxymethyl, ethylcarbonyloxyethyl,
carboxymethyl, carboxyethyl, methoxycarbonyl, ethoxycarbonyl, branched or
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unbranched C3-C4-alkyloxycarbonyl, methoxy, ethoxy, branched or
unbranched C3-C4-alkyloxy, branched or unbranched C3-C5-alkyloxycarbonylmethyl, branched or unbranched C3-C5-alkyloxycarbonylethyl, methylcarbonyl, ethylcarbonyl, branched or unbranched C3-C4-alkylcarbonyl, phenylcarbonyl, chloro, fluoro, bromo, iodo, cyano, nitro, furanyl, pyrrolyl, thiazolyl,
benzothiazolyl, pyridinyl, amino, sulfanyl, sulfonyl, oxycarbonyl, sulfinyl,
aminosulfonyl, sulfonylamino, carbonyl, carbonyloxy, carbonyl amino,
carboxyl, acyl, acylamino, or carbamoyl;
o
wherein the optional substituents or substituents as defined above can be
again optionally substituted by one or several substituents of the group
consisting of methyl, ethyl, branched or unbranched C3-C4 alkyl, fluoro,
chloro, bromo, iodo, trifluoromethyl, hydroxy, methoxy, amino, alkylamino,
dialkylamino, cyano, carboxyl, methylcarboxyl, ethylcarboxyl, branched or
unbranched C3-C5alkylcarboxyl, acetyl, 2-hydroxyethyl and 3-hydroxypropyl.
2.
A compound of formula (3) or a pharmaceutically acceptable salt thereof:
A1
Y
N
O
(3)
wherein:

Y is CH or N; and

A1 is being independently selected from the group consisting of
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X2
X1
X4
X3
X5
X2
X6
X8
X7
X 5'
X 2' X 4
X3
,
X1
X4
X3
X5 X6
X 5'
X2' X4
X6 '
,
X7 '
X7
X3
X8
X1' X10
X5 X6
X 6'
X7 '
X2
,
X1' X10
X1
X4
X3
X 7'
X7
X2 X4
X5 ' X '
6
C
, or
X11' X8'
C
X1 X3
X8
X13 X12
wherein

X1, X2 is each independently N, O , S, or C; and

X1’, X2’ is each independently C, N, or O; and

X3, X4 is each independently C or N; and

X5, X6, X7, X8, X12, X13 is each independently C, N, O, or C=O; and

X5’, X6’, X7’, X11' is each independently C, N, O, S, C=O; and

X10 is C=O, C, or N; and

wherein the bonds within the cycles are single, double or aromatic; and
,
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
wherein the cyclic groups can be optionally substituted as follows:
R5
X2
X4
X1
X5
X3
R9
R5
R5
R6
X2
X6
X7
X8
R7
X4
X3
X1
,
X6 '
X2 ' X4
R6
X7 '
X3
,
X1 '
R8
R9
R8
X5
X5 '
X1 '
R5
R6
X6 '
R9
X7 '
X5 '
X2 '
R8
X10
X4
X3
,
R5
X1
R9
R6
X 2 ' X4
X6 '
X3
X7 '
,
X1 '
R8
X2 '
R7
X8
X6
X4
X7
X3
,
,
R8
X4
X3
X5
X5 ' X '
6
X7 '
R7
X11' X8'
R11
R8
R9
X6 '
X2 '
X7 '
R8
X 2 X4
, or
R6
X5 '
X4
X3
,
X6 '
X7 '
X1' X10
R6
R5
R6
X10
R5
R6
C
X1 X3
X13
X6
X7
R7
C
X8
R11
X12
R12
wherein R5, R6, R7, R8, R9, R11,or R12 is each independently selected from
the group consisting of phenyl, hydroxyl, trifluoromethyl, methyl, ethyl,
branched or unbranched C3-C4-alkyl, 2-thiophen, 3-thiophen, hydroxymethyl,
hydroxyethyl, methylcarbonyloxymethyl, ethylcarbonyloxyethyl,
carboxymethyl, carboxyethyl, methoxy, ethoxy, branched or unbranched C3C4-alkyloxy, branched or unbranched C3-C4-alkyloxycarbonylmethyl,
branched or unbranched C3-C4-alkyloxycarbonylethyl, methylcarbonyl,
ethylcarbonyl, branched or unbranched C3-C4-alkylcarbonyl, phenylcarbonyl,
chloro, fluoro, bromo, iodo, cyano, nitro, furanyl, thienyl, pyrrolyl, thiazolyl,
benzothiazolyl, pyridinyl, amino, sulfanyl, sulfonyl, amino, oxycarbonyl,
hydroxyl, sulfinyl, aminosulfonyl, sulfonylamino, carbonyl, carbonyloxy,
carbonyl amino, carboxyl, acyl, acylamino, and carbamoyl; or from
ethoxycarbonyl, N-(2-hydroxyethyl)-aminocarbonyl, N-(3-hydroxypropyl)aminocarbonyl, N-methylaminocarbonyl and N,N-dimethylaminocarbonyl; and

R7
X8
X1' X10
R8
R9
R8

X7
X10
X5 '
X1' X10
R9
X2
X6
R6
X5
R5
X5 '
X3
R9
R9
R5
X2 ' X4
R5
R6
wherein neighbored residues of R5, R6, R7, R8, R9, R11, or R12 can form
together an alicycle, heterocycle or an aromatic or heteroaromatic cycle
which can itself be optionally substituted by methyl, ethyl, branched or
unbranched C3-C4-alkyl; wherein said aromatic cycle can then form together
R8
,
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with the other bicycle e.g. perimidinyl, e.g. 2-perimidinyl or said heteroaromtic
cycle can e.g. be phenanthrolinyl, naphtothienyle such as naphtho[2,3b]thienyl or naphthooxazole such as naphtho[1,2-d]oxazole.
3.
A compound or pharmaceutically acceptable salt thereof selected from the group
consisting of 1-{2-[4-(4-Isopropyl-phenyl)-6-prop-2-ynyloxy-quinazolin-2-yl]-1,6-dimethyl-1Hbenzoimidazol-5-yl}-butan-1-one; 4-(4-Isopropyl-phenyl)-2-(4-methyl-1H-benzoimidazol-2-yl)6-prop2-ynyloxy-quinazoline; 2-[4-(4-Isopropyl-phenyl)-6-prop-2-ynyloxy-quinazolin-2-yl]-3Hbenzoimidazole-5-carbonitrile; 2-(1-Isobutyl-1H-benzoimidazol-2-yl)-4-(4-isopropyl-phenyl)-6prop-2-ynyloxy-quinazoline; 2-(5-Fluoro-1-methyl-1H-benzoimidazol-2-yl)-4-(4-isopropylphenyl)-6-prop-2-ynyloxy-quinazoline; 4-(4-Isopropyl-phenyl)-2-(5-methoxy-1-methyl-1Hbenzoimidazol-2-yl)-6-prop-2-ynyloxy-quinazoline; 2-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4(4-isopropyl-phenyl)-6-prop-2-ynyloxy-quinazoline; 4-(4-Isopropyl-phenyl)-2-(1-methyl-1Hbenzoimidazol-2-yl)-6-prop-2-ynyloxy-quinazoline; 4-(4-Isopropyl-phenyl)-2-(1-methyl-1Himidazo[4,5-b]pyridin-2-yl)-6-prop-2-ynyloxy-quinazoline; 2-(1H-Imidazo[4,5-b]pyridin-2-yl)-4(4-isopropyl-phenyl)-6-prop-2-ynyloxy-quinazoline; 4-(4-Isopropyl-phenyl)-6-prop-2-ynyloxy2-(9H-purin-8-yl)-quinazoline; 4-(4-Isopropyl-phenyl)-2-(1-phenyl-1H-benzoimidazol-2-yl)-6prop-2-ynyloxy-quinazoline; 1-{1-Butyl-2-[4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-quinazolin2-yl]-6-methyl-1H-benzoimidazol-5-yl}-butan-1-one; 4-(4-Isopropyl-phenyl)-6-prop-2-ynyloxy2-(6-trifluoromethyl-1H-benzoimidazol-2-yl)-quinazoline; 4-(4-Isopropyl-phenyl)-2-(6methoxy-1H-benzoimidazol-2-yl)-6-prop-2-ynyloxy-quinazoline; 2-(6-Chloro-1Hbenzoimidazol-2-yl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-quinazoline; 2-[4-(4-Isopropylphenyl)-6-prop-2-ynyloxy-quinazolin-2-yl]-3H-benzoimidazole-5-carboxylic acid ethyl ester;
{2-[4-(4-Isopropyl-phenyl)-6-prop-2-ynyloxy-quinazolin-2-yl]-3H-benzoimidazol-5-yl}-phenylmethanone; 2-(6-Bromo-1H-benzoimidazol-2-yl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxyquinazoline; 2-(6-Fluoro-1H-benzoimidazol-2-yl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxyquinazoline; 2-(6-Chloro-5-fluoro-1H-benzoimidazol-2-yl)-4-(4-isopropyl-phenyl)-6-prop-2ynyloxy-quinazoline; 4-(4-Isopropyl-phenyl)-2-(1-methyl-5-trifluoromethyl-1H-benzoimidazol2-yl)-6-prop-2-ynyloxy-quinazoline; 2-[4-(4-Isopropyl-phenyl)-6-prop-2-ynyloxy-quinazolin-2yl]-1-methyl-1H-benzoimidazole-5-carboxylic acid ethyl ester; 1-{2-[4-(4-Isopropyl-phenyl)-6prop-2-ynyloxy-quinazolin-2-yl]-1-methyl-1H-benzoimidazol-5-yl}-ethanone; 2-(5,6-Difluoro1H-benzoimidazol-2-yl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-quinazoline; 1-{2-[4-(4Isopropyl-phenyl)-6-prop-2-ynyloxy-quinazolin-2-yl]-3H-benzoimidazol-4-yl}-ethanone; 2-[4(4-Isopropyl-phenyl)-6-prop-2-ynyloxy-quinazolin-2-yl]-1H-perimidine; 4'-(4-Isopropyl-phenyl)-
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6'-prop-2-ynyloxy-3H-[2,2']biquinazolinyl-4-one; 4-(4-Isopropyl-phenyl)-6-prop-2-ynyloxy-2-(5trifluoromethyl-benzothiazol-2-yl)-quinazoline; 2-Benzothiazol-2-yl-4-(4-isopropyl-phenyl)-6prop-2-ynyloxy-quinazoline; 2-(6-Chloro-benzooxazol-2-yl)-4-(4-isopropyl-phenyl)-6-prop-2ynyloxy-quinazoline; 2-[4-(4-Isopropyl-phenyl)-6-prop-2-ynyloxy-quinazolin-2-yl]-naphtho[1,2d]oxazole; 1-{2-[1-(4-Isopropyl-phenyl)-7-prop-2-ynyloxy-isoquinolin-3-yl]-1,6-dimethyl-1Hbenzoimidazol-5-yl}-butan-1-one; 1-(4-Isopropyl-phenyl)-7-prop-2-ynyloxy-3-(5trifluoromethyl-1H-benzoimidazol-2-yl)-isoquinoline; 1-(4-Isopropyl-phenyl)-3-(1-methyl-5trifluoromethyl-1H-benzoimidazol-2-yl)-7-prop-2-ynyloxy-isoquinoline, 5-ethoxycarbonyl-3methyl-3H-benzoimidazole-2-yl, 5-carboxyl-3-methyl-3H-benzoimidazole-2-yl,.5-[N-(2hydroxyethyl)aminocarbonyl]-3-methyl-3H-benzoimidazol-2-yl, 5-(N,N-dimethyl-carbamoyl)3-methyl-3H-benzimidazol-2-yl and 5-(N-methyl-carbamoyl)-3-methyl-3H-benzimidazol-2-yl.
4. A compound selected from the group consisting of 1-{2-[4-(4-Isopropyl-phenyl)-6-prop-2ynyloxy-quinazolin-2-yl]-1,6-dimethyl-1H-benzoimidazol-5-yl}-butan-1-one; 4-(4-Isopropylphenyl)-2-(4-methyl-1H-benzoimidazol-2-yl)-6-prop2-ynyloxy-quinazoline; 2-[4-(4-Isopropylphenyl)-6-prop-2-ynyloxy-quinazolin-2-yl]-3H-benzoimidazole-5-carbonitrile; 2-(1-Isobutyl-1Hbenzoimidazol-2-yl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-quinazoline; 2-(5-Fluoro-1methyl-1H-benzoimidazol-2-yl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-quinazoline; 4-(4Isopropyl-phenyl)-2-(5-methoxy-1-methyl-1H-benzoimidazol-2-yl)-6-prop-2-ynyloxyquinazoline; 2-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-(4-isopropyl-phenyl)-6-prop-2ynyloxy-quinazoline; 4-(4-Isopropyl-phenyl)-2-(1-methyl-1H-benzoimidazol-2-yl)-6-prop-2ynyloxy-quinazoline; 4-(4-Isopropyl-phenyl)-2-(1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-6prop-2-ynyloxy-quinazoline; 2-(1H-Imidazo[4,5-b]pyridin-2-yl)-4-(4-isopropyl-phenyl)-6-prop2-ynyloxy-quinazoline; 4-(4-Isopropyl-phenyl)-6-prop-2-ynyloxy-2-(9H-purin-8-yl)-quinazoline;
4-(4-Isopropyl-phenyl)-2-(1-phenyl-1H-benzoimidazol-2-yl)-6-prop-2-ynyloxy-quinazoline; 1{1-Butyl-2-[4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-quinazolin-2-yl]-6-methyl-1H-benzoimidazol-5-yl}-butan-1-one; 4-(4-Isopropyl-phenyl)-6-prop-2-ynyloxy-2-(6-trifluoromethyl-1H-benzoimidazol-2-yl)-quinazoline; 4-(4-Isopropyl-phenyl)-2-(6-methoxy-1H-benzoimidazol-2-yl)-6prop-2-ynyloxy-quinazoline; 2-(6-Chloro-1H-benzoimidazol-2-yl)-4-(4-isopropyl-phenyl)-6prop-2-ynyloxy-quinazoline; 2-[4-(4-Isopropyl-phenyl)-6-prop-2-ynyloxy-quinazolin-2-yl]-3Hbenzoimidazole-5-carboxylic acid ethyl ester; {2-[4-(4-Isopropyl-phenyl)-6-prop-2-ynyloxyquinazolin-2-yl]-3H-benzoimidazol-5-yl}-phenyl-methanone; 2-(6-Bromo-1H-benzoimidazol-2yl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-quinazoline; 2-(6-Fluoro-1H-benzoimidazol-2-yl)4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-quinazoline; 2-(6-Chloro-5-fluoro-1H-benzoimidazol-
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2-yl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-quinazoline; 4-(4-Isopropyl-phenyl)-2-(1methyl-5-trifluoromethyl-1H-benzoimidazol-2-yl)-6-prop-2-ynyloxy-quinazoline; 2-[4-(4-Isopropyl-phenyl)-6-prop-2-ynyloxy-quinazolin-2-yl]-1-methyl-1H-benzoimidazole-5-carboxylic
acid ethyl ester; 1-{2-[4-(4-Isopropyl-phenyl)-6-prop-2-ynyloxy-quinazolin-2-yl]-1-methyl-1Hbenzoimidazol-5-yl}-ethanone; 2-(5,6-Difluoro-1H-benzoimidazol-2-yl)-4-(4-isopropyl-phenyl)6-prop-2-ynyloxy-quinazoline; 1-{2-[4-(4-Isopropyl-phenyl)-6-prop-2-ynyloxy-quinazolin-2-yl]3H-benzoimidazol-4-yl}-ethanone; 2-[4-(4-Isopropyl-phenyl)-6-prop-2-ynyloxy-quinazolin-2yl]-1H-perimidine; 4'-(4-Isopropyl-phenyl)-6'-prop-2-ynyloxy-3H-[2,2']biquinazolinyl-4-one; 4(4-Isopropyl-phenyl)-6-prop-2-ynyloxy-2-(5-trifluoromethyl-benzothiazol-2-yl)-quinazoline; 2Benzothiazol-2-yl-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-quinazoline; 2-(6-Chloro-benzooxazol-2-yl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-quinazoline;
or a pharmaceutically acceptable salt thereof.
5. A compound selected from the group consisting of 2-[4-(4-Isopropyl-phenyl)-6-prop-2ynyloxy-quinazolin-2-yl]-3-methyl-3H-benzoimidazole-5-carboxylic acid ethyl ester, 2-[4-(4Isopropyl-phenyl)-6-prop-2-ynyloxy-quinazolin-2-yl]-3-methyl-3H-benzoimidazole-5-carboxylic
acid, 2-[4-(4-Isopropyl-phenyl)-6-prop-2-ynyloxy-quinazolin-2-yl]-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethyl)-amide, 2-[4-(4-Isopropyl-phenyl)-6-prop-2-ynyloxyquinazolin-2-yl]-3-methyl-3H-benzoimidazole-5-carboxylic acid dimethylamide and 2-[4-(4Isopropyl-phenyl)-6-prop-2-ynyloxy-quinazolin-2-yl]-3-methyl-3H-benzoimidazole-5-carboxylic
acid methylamide;
or a pharmaceutically acceptable salt thereof.
6.
A pharmaceutical composition for preventing or treating bone conditions comprising a
compound of claim 1, claim 2, claim 3, claim 4 or claim 5 in association with a
pharmaceutically acceptable excipient, diluent or carrier.
7.
A compound of claim 1, claim 2, claim 3, claim 4 or claim 5 for promoting the release
of parathyroid hormone.
8.
A process for preparation of a compound of claim 2 in free or salt form, comprising the
step of:
reacting a compound of formula (10)
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OH
R3
Y
R2
O
N
O
R4
R1
(10)
with a compound selected from the group consisting of
R5
R13
X5
X2
H
H X
1
X7
X8
R9
X2
X6
H
,
H X
1
R7
X4 '
X3 '
R13
X5 '
X6 '
R6
X5
,
H
X2 '
H
H
R6
X6 '
R9
,
X5 '
X2 '
R8
H
R9
R6
X6 '
,
X5 '
X1' X10
X1' X10
R9
X6 '
,
R8
X1' X10
R8
R7 ,
R8
R5
R6
X7 '
H
H
X7
R13
X2 '
X7 '
H
X1' X10
R13
R6
X6
X8
R5
R5
X7 '
H
H
X5
R8
R9
X5 '
X2 '
R7 ,
X8
X1' X10
R5
R13
R9
X6
X7
H
X7 '
R5
R6
X2 '
R8
R9
R8
R5
R5
R13
R6
R9
X5 '
X2 '
H
H
R6
X6 '
,
X7 '
R8
X1' X10
R13
R13
R13
X2
H
H
X1
R9
R5
X4
X3
X5
R13
X5 ' X '
6
X7 '
R6
R5
R6
R7
X11' X8'
R11
R8
X2
, or
H
X4
C
H
X 1 X3
R9
X13
R8
X6
X7
R7
C
X8
R11
X12
R12

wherein the residues R1 to R12, Y are as defined in claim 2; and

wherein the H forms part of an amino, thiol, hydroxy, or basic CHn group, the reaction
being carried out in the presence of a coupling reagent; and

9.
wherein R13 is an electron lone pair or H, in case R9 is not H, R14 must be H.
A combination comprising a therapeutically effective amount of a compound of claim 1,
claim 2, claim 3, claim 4 or claim 5 and a second drug substance selected from the group
consisting of: calcium, a calcitonin or an analogue or derivative thereof, a steroid hormone, a
partial estrogen agonist or estrogen-gestagen combination, a SERM (Selective Estrogen
Receptor Modulator), a RANKL antibody, a cathepsin K inhibitor, vitamin D or an analogue
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thereof or PTH, a PTH fragment or a PTH derivative for simultaneous, separate or
sequential treatment.
10.
A method for preventing or treating bone conditions which are associated with
increased calcium depletion or resorption or in which stimulation of bone formation and
calcium fixation in the bone is desirable in which an effective amount of a compound of
compound of claim 1, claim 2, claim 3, claim 4 or claim 5 is administered to a patient in need
of such treatment.
11.
Use of a compound of claim 1, claim 2, claim 3, claim 4 or claim 5 in the manufacture
of a medicament for preventing or treating bone conditions which are associated with
increased calcium depletion or resorption or in which stimulation of bone formation and
calcium fixation in the bone is desirable.