INDAZOLES
The present invention relates to indazoles, pharmaceutical compositions comprising such
compounds and their use as medicaments. More particularly, the present invention provides 6-
phenyl-1 H-indazole derivatives which are Janus Kinase (JAK) inhibitors and useful for the
treatment of allergic and respiratory conditions, particularly chronic obstructive pulmonary
disease.
Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the US
and is characterized by airflow obstruction that is not fully reversible with bronchodilators. The
airflow limitation is usually progressive and is associated with an abnormal inflammatory
response of the lungs to noxious particles or gases, primarily cigarette smoke. Symptoms are
typically breathing-related (e.g. chronic cough, exertional dyspnea, expectoration and wheeze).
Patients experience periods of stable disease interspersed with inflammatory exacerbations
resulting in acute decline in lung function and often hospitalization.
Current treatment guidelines recommend bronchodilators as the mainstay of COPD drug
treatment. However, anti-inflammatory inhaled corticosteroids (ICS) and bronchodilator/inhaled
corticosteroid combination products, are extensively used. Whilst inhaled corticosteroids do
provide some benefits with respect to short term lung function improvements and exacerbation
frequency, they do not address the corticosteroid-refractory inflammation which is characteristic
of this disease and thought to play a key role in disease progression. There is a clear medical
need for anti-inflammatory therapies in COPD that will address the chronic inflammatory
component of the disease and ultimately provide symptomatic relief, a reduction in exacerbation
frequency and an amelioration of exacerbation severity.
The Janus kinase (JAK) family of receptor associated tyrosine kinases, JAK 1, JAK 2, JAK 3
and tyrosine kinase 2 (TYK2), are involved in signal transduction associated with a variety of
inflammatory cytokines. JAK kinases can function as either hetero or homo-dimers,
phosphorylating STAT transcription factors which regulate inflammatory gene transcription. Oral
JAK 1/JAK 3 inhibitors such as CP-690550 have shown impressive anti-inflammatory activity in
inflammatory diseases such as rheumatoid arthritis and psoriasis.
Many JAK dependent cytokines are thought to play key roles in the pathology of COPD which
involves the interplay of multiple inflammatory cells such as T lymphocytes, neutrophils,
macrophages and lung epithelium. For example the JAK 1/JAK 3 heterodimer plays a key role
in T lymphocyte survival and activation whereas JAK 2 is thought to be critical for regulation of
neutrophil activation and apoptosis. JAK 1 and JAK 2 play an important role in IL-13 mediated
inflammatory signaling in macrophages, which is thought to link acute inflammatory events to
chronic progressive disease. Importantly JAK 1, JAK 2 and TYK 2 also play an important role in
signaling mediated by IFNy, a cytokine associated with the chronic inflammation observed in
COPD, which modulates the activity of T cells, epithelium and macrophages whilst not being
modulated by corticosteroids.
Macrophage phagocytosis of bacteria is impaired in the lungs of COPD patients, potentially in
part due to high local IFNy levels. In vitro studies with isolated patient cells have shown that JAK
inhibitors increase phagocytotic rate in the presence of IFNy. Consequently, as well as exerting
a direct anti-inflammatory effect, JAK inhibitors may also increase the ability of the lung to
maintain a sterile environment.
JAK inhibitors are therefore likely to have utility in the treatment of a range of inflammatory
diseases, including lung diseases such as COPD, asthma and pulmonary vascular disease.
Compounds which have a broad inhibitory activity across the range of Janus kinases, in
particular, are likely to have a potent anti-inflammatory effect. However, such a selectivity profile
can also lead to undesirable side-effects in systemically circulating compounds, particularly
anemia and neutropenia associated with JAK 2 inhibition. For the treatment of lung diseases, it
is therefore particularly favourable to provide JAK inhibitors which can be administered by
inhalation and which inhibit Janus kinases locally in the lung without having a significant
systemic exposure.
There is thus a need to provide new JAK inhibitors that are potent, selective inhibitors of Janus
kinases with appropriate metabolic stability and pharmacokinetic properties, particularly
compounds which can be administered by inhalation and are active in lung tissue whilst having
poor systemic penetration or high systemic lability.
The invention therefore provides, as embodiment E 1 , a compound of formula (I):
(I)
or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said
compound or pharmaceutically acceptable salt, wherein:
R is halo;
R2 is C -C6 alkyl optionally substituted by one or more fluorine atoms;
X is a bond, -CO-, -S0 2- or -CH2- ;
R3 is Aryl , Het or Het2, each of which is optionally substituted by 1 substituent -Y-R4 and/or 1-4
substituents each independently selected from R5;
n is 1 or 2;
Aryl 1 is phenyl or naphthyl;
Het1 is (i) a 6-membered aromatic heterocycle containing 1-3 N atoms or (ii) a 5-membered
aromatic heterocycle containing either (a) 1-4 N atoms or (b) 1 O or S atom and 0-3 N atoms;
Het2 is (i) a 10-membered bicyclic aromatic heterocycle containing 1-4 N atoms or (ii) a 9-
membered bicyclic aromatic heterocycle containing either (a) 1-4 N atoms or (b) 1 O or S atom
and 0-3 N atoms or (iii) an 8-membered bicyclic aromatic heterocycle containing (a) 1-4 N
atoms or (b) 1 O or S atom and 1-3 N atoms or (c) 2 O or S atoms and 0-2 N atoms;
Y is a bond or -0-;
R4 is Aryl2 or Het3;
R5 is Ci-C 6 alkyl, C3-C8 cycloalkyl, halo, -CN, -OR6, -NR7R8, -SR6, -SOR9, -S0 2R9, -COR6, -
OCOR6, -COOR6, -NR6COR6, -CONR7R8, -NR6S0 2R9, -S0 2NR7R8, -NR6CONR7R8, -
NR6COOR9 or -NR6S0 2NR7R8;
R6 is H, -C6 alkyl or C3-C8 cycloalkyl, said -C6 alkyl;
R7 and R8 are each independently H, C -C6 alkyl or C3-C8 cycloalkyl or are taken together with
the nitrogen atom to which they are attached to form a 4-, 5- or 6-membered saturated
heterocyclic ring containing 1-2 nitrogen atoms or 1 nitrogen and 1 oxygen atom, said
heterocyclic ring being optionally substituted by one or more Ci-C 6 alkyl or C3-C8 cycloalkyl
groups;
R9 is Ci-C 6 alkyl or C3-C8 cycloalkyl;
Aryl2 is phenyl or naphthyl, said phenyl and naphthyl being optionally substituted with 1-5
substituents selected from -C6 alkyl, C3-C8 cycloalkyl, halo, -CN, -OR6, -NR7R8, -SR6, -SOR9,
-S0 2R9, -COR6, -OCOR6, -COOR6, -NR6COR6, -CONR7R8, -NR6S0 2R9, -S0 2NR7R8, -
NR6CONR7R8, -NR6COOR9 and -NR6S0 2NR7R8; and
Het3 is a 3 to 8-membered saturated or partially unsaturated monocyclic heterocycle, containing
1 or 2 heteroatoms selected from O and N, said heterocycle being optionally substituted by 1-5
substituents selected from Ci-C 6 alkyl, C3-C8 cycloalkyl, halo, oxo, -OR6, -NR7R8, -SR6, -SOR9,
-S0 2R9, -COR6, -OCOR6, -COOR6, -NR6COR6, -CONR7R8, -NR6S0 2R9, -S0 2NR7R8, -
NR6CONR7R8, -NR6COOR9 and -NR6S0 2NR7R8.
The invention also provides, as embodiment E2, a compound of formula (I), or a
pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said
compound or pharmaceutically acceptable salt, wherein R2, n, X and R3 are as defined in
embodiment E 1 and R is fluoro.
The invention also provides, as embodiment E3, a compound of formula (I), or a
pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said
compound or pharmaceutically acceptable salt, wherein R is as defined in either of
embodiments E 1 or E2, n, X and R3 are as defined in embodiment E 1 and R2 is -CH 2CH3 or -
The invention also provides, as embodiment E4, a compound of formula (I), or a
pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said
compound or pharmaceutically acceptable salt, wherein R is as defined in either of
embodiments E 1 or E2, R2 is as defined in either of embodiments E 1 or E3, X and R3 are as
defined in embodiment E 1 and n is 1.
The invention also provides, as embodiment E5, a compound of formula (I), or a
pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said
compound or pharmaceutically acceptable salt, wherein R is as defined in either of
embodiments E 1 or E2, R2 is as defined in either of embodiments E 1 or E3, X and R3 are as
defined in embodiment E 1 and n is 2.
The invention also provides, as embodiment E6, a compound of formula (I), or a
pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said
compound or pharmaceutically acceptable salt, wherein R is as defined in either of
embodiments E 1 or E2, R2 is as defined in either of embodiments E 1 or E3, n is defined in any
one of embodiments E 1, E4 or E5, R3 is as defined in embodiment E 1 and X is a bond.
The invention also provides, as embodiment E7, a compound of formula (I), or a
pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said
compound or pharmaceutically acceptable salt, wherein R is as defined in either of
embodiments E 1 or E2, R2 is as defined in either of embodiments E 1 or E3, n is defined in any
one of embodiments E 1, E4 or E5, R3 is as defined in embodiment E 1 and X is -CO-.
The invention also provides, as embodiment E8, a compound of formula (I), or a
pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said
compound or pharmaceutically acceptable salt, wherein R is as defined in either of
embodiments E 1 or E2, R2 is as defined in either of embodiments E 1 or E3, n is defined in any
one of embodiments E 1, E4 or E5, R3 is as defined in embodiment E 1 and X is -CH2- .
The invention also provides, as embodiment E9, a compound of formula (I), or a
pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said
compound or pharmaceutically acceptable salt, wherein R is as defined in either of
embodiments E 1 or E2, R2 is as defined in either of embodiments E 1 or E3, n is defined in any
one of embodiments E 1, E4 or E5, R3 is as defined in embodiment E 1 and X is -S0 2- .
The invention also provides, as embodiment E10, a compound of formula (I), or a
pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said
compound or pharmaceutically acceptable salt, wherein R is as defined in either of
embodiments E 1 or E2, R2 is as defined in either of embodiments E 1 or E3, n is as defined in
any one of embodiments E 1, E4 or E5, X is as defined in any one of embodiments E 1, E6, E7,
E8 or E9 and R3 is is phenyl, thiazolyl, quinolinyl, pyrimidinyl, [ 1 ,8]naphthyridinyl or pyridyl, each
of which is optionally substituted by 1 substituent -Y-R4 and 1-4 substituents each independently
selected from R5.
The invention also provides, as embodiment E 11, a compound of formula (I), or a
pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said
compound or pharmaceutically acceptable salt, wherein R is as defined in either of
embodiments E 1 or E2, R2 is as defined in either of embodiments E 1 or E3, n is as defined in
any one of embodiments E 1, E4 or E5, X is as defined in any one of embodiments E 1, E6, E7,
E8 or E9 and R3 is phenyl, thiazolyl, quinolinyl, pyrimidinyl, [ 1 ,8]naphthyridinyl or pyridyl, each of
which is optionally substituted by 1 substituent selected from piperdininyl, (fluorophenyl)oxy,
phenyloxy and morpholinyl and 1-2 substituents each independently selected from fluoro,
chloro, cyano, methoxy and hydroxy.
The invention also provides, as embodiment E12, a compound of formula (I), or a
pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said
compound or pharmaceutically acceptable salt, wherein R is as defined in either of
embodiments E 1 or E2, R2 is as defined in either of embodiments E 1 or E3, n is as defined in
any one of embodiments E 1, E4 or E5, X is as defined in any one of embodiments E 1, E6, E7,
E8 or E9 and R3 is fluorophenyl, methoxyphenyl, thiazolyl, hydroxyphenyl, phenyl, quinolinyl,
[ 1 ,8]naphthyridinyl, (piperidinyl)pyridyl, (piperidinyl)pyrimidinyl, ((fluorophenyl)oxy)pyrimidinyl,
(phenyloxy)pyridyl, (morpholinyl)pyridyl, chloropyridyl or cyanopyridyl.
The invention also provides, as embodiment E13, a compound of formula (I), or a
pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said
compound or pharmaceutically acceptable salt, wherein R is as defined in either of
embodiments E 1 or E2, R2 is as defined in either of embodiments E 1 or E3, n is defined in any
one of embodiments E 1, E4 or E5, and -X-R3 is (fluorophenyl)carbonyl, (thiazolyl)carbonyl,
benzyl, ((piperidinyl)pyrimidinyl)carbonyl, ((phenoxy)pyridyl)carbonyl,
((morpholinyl)pyridyl)sulphonyl, ((phenoxy)pyridyl)sulphonyl, (chloropyridyl)carbonyl,
(cyanopyridyl)carbonyl, (fluorophenyl)carbonyl, (thiazolyl)carbonyl, (fluorophenyl)sulphonyl,
((fluorophenoxy)pyrimidinyl)carbonyl, (quinolinyl)methyl, (hydroxyphenyl)methyl,
(cyanopyridyl)methyl, (methoxyphenyl)methyl, ((phenoxy)pyridyl)methyl,
((piperidinyl)pyridyl)methyl, ((cyanopyridyl)methyl, (fluorophenyl)methyl or
([1 ,8]naphthyridinyl)methyl.
The invention also provides, rmula:
(la)
or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said
compound or pharmaceutically acceptable salt, wherein X is as defined in any one of
embodiments E 1, E6, E7, E8 or E9 and R3 is as defined in any one of embodiments E 1 , E10,
E 11 or E12 or -X-R 3 is as defined in embodiment E13.
Particularly preferred compounds of formula (I) include:
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4,6,7-tetrahydro-imidazo
[4,5-c]pyridin-5-yl}-(4-fluoro-phenyl)-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4,6,7-tetrahydro-imidazo
[4,5-c]pyridin-5-yl}-isothiazol-3-yl-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4,6,7-tetrahydro-imidazo
[4,5-c]pyridin-5-yl}-isothiazol-3-yl-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4,6,7-tetrahydro-imidazo
[4,5-c]pyridin-5-yl}-(5-piperidin-1-yl-pyrazin-2-yl)-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4,6J-tetrahydro-imidazo
[4,5-c]pyridin-5-yl}-(6-phenoxy-pyridin-3-yl)-methanone;
5-Ethyl-2-fluoro-4-{3-[5-(6-morpholin-4-yl-pyridine-3-sulfonyl)-4,5,6J-tetrahydro-1 H-imidazo[4
c]pyridin-2-yl]-1 H-indazol-6-yl}-phenol;
5-Ethyl-2-fluoro-4-{3-[5-(6-phenoxy-pyridine-3-sulfonyl)-4,5,6,7-tetrahydro-1 H-imidazo
[4,5-c]pyridin-2-yl]-1 H-indazol-6-yl}-phenol;
(5-Chloro-pyridin-2-yl)-{2-[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-4 5 7,8-
tetrahydro-1 H-imidazo[4,5-d]azepin-6-yl}-methanone;
2-{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-4,5J 8-tetrahydro-1 H-imidazo[4,5-
d]azepine-6-carbonyl}-isonicotinonitrile;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-4,5,7,8-tetrahydro-1 H-imidazo
[4,5-d]azepin-6-yl}-(4-fluoro-phenyl)-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-4,5,7,8-tetrahydro-1 H-imidazo
[4,5-d]azepin-6-yl}-isothiazol-3-yl-methanone;
5-Ethyl-2-fluoro-4-{3-[5-(4-fluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1 H-imidazo
[4,5-c]pyridin-2-yl]-1 H-indazol-6-yl}-phenol;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4,6,7-tetrahydro-imidazo
[4,5-c]pyridin-5-yl}-[5-(2-fluoro-phenoxy)-pyrazin-2-yl]-methanone;
4-[3-(6-Benzyl-1 ,4 5 6 7 8-hexahydro-imidazo[4,5-d]azepin-2-yl)-1 H-indazol-6-yl]-5-ethyl-2-
fluoro-phenol;
(5-Chloro-pyridin-2-yl)-{2-[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4,6,7-
tetrahydro-imidazo[4,5-c]pyridin-5-yl}-methanone;
5-{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4,6,7-tetrahydro-imidazo
[4,5-c]pyridine-5-carbonyl}-pyridine-2-carbonitrile;
5-{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-4,5,7,8-tetrahydro-1 H-imidazo[4,5-
d]azepine-6-carbonyl}-pyridine-2-carbonitrile;
5-Ethyl-2-fluoro-4-[3-(5-quinolin-6-ylmethyl-4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl)-1 Hindazol-
6-yl]-phenol;
5-Ethyl-2-fluoro-4-{3-[5-(4-hydroxy-benzyl)-4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl]-1 Hindazol-
6-yl}-phenol;
5-Ethyl-2-fluoro-4-{3-[5-(3-hydroxy-benzyl)-4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl]-1 Hindazol-
6-yl}-phenol;
4-{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4,6,7-tetrahydro-imidazo[4,5-
c]pyridin-5-ylmethyl}-pyridine-2-carbonitrile;
5-Ethyl-2-fluoro-4-{3-[5-(3-methoxy-benzyl)-4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl]-1 Hindazol-
6-yl}-phenol;
5-Ethyl-2-fluoro-4-[3-(5-quinolin-3-ylmethyl-4,5,6J-tetrahydro-1 H-imidazo[4,5-c]
indazol-6-yl]-phenol;
5-Ethyl-2-fluoro-4-{3-[5-(6-phenoxy-pyridin-3-ylmethyl)-4,5,6J-tetrahydro-1 H-imidazo[4
c]pyridin-2-yl]-1 H-indazol-6-yl}-phenol;
5-Ethyl-2-fluoro-4-{3-[5-(3A5,6-tetrahydro-2H-[1
1H-imidazo[4,5-c]pyridin-2-yl]-1 H-indazol-6-yl}-phenol;
3-{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 4,6J-tetrahydro-imidazo[4,5-
c]pyridin-5-ylmethyl}-pyridine-2-carbonitrile;
5-Ethyl-2-fluoro-4-{3-[5-(4-fluoro-benzyO
indazol-6-yl}-phenol;
5-Ethyl-2-fluoro-4-[3-(5-[1 ,8]naphthyridin-2-ylmethyl-4 5,6J-tetrahydro-1 H-imidazo[
4,5-c]pyridin-2-yl)-1 H-indazol-6-yl]-phenol;
(2-{6-[5-Fluoro-4-hydroxy-2-(2,2,2-trifluoro-ethyl)-ph
imidazo[4,5-c]pyridin-5-yl)-(5-piperidin-1-yl-pyrazin-2-yl)-methanone;
(2-{6-[5-Fluoro-4-hydroxy-2-(2,2,2-trifluoro-ethyl)-ph
imidazo[4,5-c]pyridin-5-yl)-(4-fluoro-phenyl)-methanone;
4-[3-(5-Benzyl-4 5 6J-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl)-1 H-indazol-6-yl]-2-fluoro-5-
(2,2,2-trifluoro-ethyl)-phenol;
or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said
compound or salt.
Other preferred compounds of formula (I) include:
{5-[(2-Dimethylamino-ethyl)-methyl-amino]-pyrazin-2-yl}-{2-[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-
1 H-indazol-3-yl]-1 ,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl}-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4 6 7-tetrahydro-imidazo[4,5-
c]pyridin-5-yl}-[5-(2-pyrrolidin-1-yl-ethylamino)-pyrazin-2-yl]-methanone;
[5-(2-Dimethylamino-ethylamino)-pyrazin-2-yl]-{2-[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-1 Hindazol-
3-yl]-1 ,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl}-methanone;
[5-(4-Dimethylamino-piperidin-1-yl)-pyrazin-2-yl]-{2-[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-1 Hindazol-
3-yl]-1 ,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl}-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4 6 7-tetrahydro-imidazo[4,5-
c]pyridin-5-yl}-{5-[ethyl-(2-hydroxy-ethyl)-amino]-pyrazin-2-yl}-methanone;
[5-((R)-3-Dimethylamino-pyrrolidin-1-yl)-pyrazin-2-yl]-{2-[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-
1H-indazol-3-yl]-1 ,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl}-methanone;
[5-((S)-3-Dimethylamino-pyrrolidin-1-yl)-pyrazin-2-yl]-{2-[6-(2-ethyl-5-fluoro-4-hy
1H-indazol-3-yl]-1 ,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl}-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4,6J-etrahydroimidazo[4,5c]pyridin-
5-yl}-[5-(2-piperidin-1-yl-ethylamino)-pyrazin-2-yl]-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4 6 7-tetrahydro-imidazo[4,5-
c]pyridin-5-yl}-[5-(2-piperazin-1-yl-ethylamino)-pyrazin-2-yl]-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4 6 7-tetrahydro-imidazo[4,5-
]pyridin-5-yl}-(4-methyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4 6 7-tetrahydro-imidazo[4,5-
c]pyridin-5-yl}-(5-morpholin-4-yl-pyrazin-2-yl)-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4,6,7-tetrahydro-idazo[4,5c]pyridin-
5-yl}-[5-(4-methyl-piperidin-1-yl)-pyrazin-2-yl]-methanone;
(5-Cyclopentylamino-pyrazin-2-yl)-{2-[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-
1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl}-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4 6 7-tetrahydro-imidazo[4,5-
c]pyridin-5-yl}-[5-(2-morpholin-4-yl-ethylamino)-pyrazin-2-yl]-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4 6 7-tetrahydro-imidazo[4,5-
c]pyridin-5-yl}-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4 6 7-tetrahydro-imidazo[4,5-
c]pyridin-5-yl}-(5-pyrrolidin-1-yl-pyrazin-2-yl)-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4 6 7-tetrahydro-imidazo[4,5-
]pyridin-5-yl}-[5-(ethyl-methyl-amino)-pyrazin-2-yl]-methanon;
(5-Cyclohexylamino-pyrazin-2-yl)-{2-[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-
1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl}-methanone;
(5-Dimethylamino-pyrazin-2-yl)-{2-[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-,4,6,7-
tetrahydro-imidazo[4,5-c]pyridin-5-yl}-methanone;
(5-Azetidin-1-yl-pyrazin-2-yl)-{2-[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4
tetrahydro-imidazo[4,5-c]pyridin-5-yl}-methanone;
2-Fluoro-4-{3-[5-(4-fluoro-benzyl)-4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl]-1 H-indazol-6-
yl}-5-(2,2,2-trifluoro-ethyl)-phenol;
2-Fluoro-4-{3-[5-(3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-5'-ylmethyl)-4,5,6,7-tetrahydro-1 Himidazo[
4,5-c]pyridin-2-yl]-1 H-indazol-6-yl}-5-(2,2,2-trifluoro-ethyl)-phenol;
2-Fluoro-4-{3-[5-(6-phenoxy-pyridin-3-ylmethyl)-4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-
yl]-H-indazol-6-yl}-5-(2,2,2-trifluoro-ethyl)-phenol;
2-Fluoro-4-{3-[5-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl]-1 H
indazol-6-yl}-5-(2,2,2-trifluoro-ethyl)-phenol;
2-Fluoro-4-{3-[5-(4-hydroxy-benzyl)-4,5,6,7-tetrahydro-1 H-im^
indazol-6-yl}-5-(2,2,2-trifluoro-ethyl)-phenol;
2-Fluoro-4-{3-[5-(3-methoxy-benzyl)-4,5,6J-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl]-1 H
indazol-6-yl}-5-(2,2,2-trifluoro-ethyl)-phenol;
2-Fluoro-4-{3-[5-(3-hydroxy-benzyl)-4 5 6J-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl]-1 Hindazol-
6-yl}-5-(2,2,2-trifluoro-ethyl)-phenol;
2-Fluoro-4-[3-(5-quinolin-6-ylmethyl-4,5,6J-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-y
indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol;
2-Fluoro-4-[3-(5-quinolin-3-ylmethyl-4,5,6J-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-y
indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol;
2-Fluoro-4-[3-(5-[1 ,8]naphthyridin-3-ylmethyl-4,5,6J-tetrahydro-1 H-imidazo[4,5-c]pyri
1H-indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol;
((3R,5S)-3,5-Dimethyl-3,4,5,6-tetrahydro-2H-[1 ,2']b^
hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl}-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 4,6J-tetrahydro-imidazo[4,5-
c]pyridin-5-yl}-((S)-3-methyl-3,4,5,6-tetrahydro-2H -
((2S 5R)-2 5-Dimethyl-3 4 5 6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)-{2-[6-(2-ethyl-5-flu
hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl}-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 4,6J-tetrahydro-imidazo[4,5-
]pyridin-5-yl}-(3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)-methanone;
or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said
compound or salt.
Most preferred is {2-[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4,6,7-tetrahydroimidazo[
4,5-c]pyridin-5-yl}-(5-piperidin-1-yl-pyrazin-2-yl)-methanone or a pharmaceutically
acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.
The present invention also provides: a method of treating a disease for which a JAK inhibitor is
indicated, in a subject in need of such treatment, comprising administering to the subject a
therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable
salt thereof, or a pharmaceutically acceptable solvate of said compound or salt; the use of a
compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically
acceptable solvate of said compound or salt, for the manufacture of a medicament for treating a
disease or condition for which a JAK inhibitor is indicated; a compound of formula (I), or a
pharmaceutically acceptable salt or solvate thereof, for use as a medicament; a compound of
formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable
solvate of said compound or salt, for use in the treatment of a disease or condition for which a
JAK inhibitor is indicated; a pharmaceutical composition comprising a compound of formula (I),
or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said
compound or salt, and a pharmaceutically acceptable excipient; a pharmaceutical composition
for the treatment of a disease or condition for which a JAK inhibitor is indicated, comprising a
compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically
acceptable solvate of said compound or salt.
The disease or condition for which a JAK inhibitor is indicated is preferably an allergic or
respiratory condition such as allergic rhinitis, nasal congestion, rhinorrhea, perennial rhinitis,
nasal inflammation, asthma of all types, chronic obstructive pulmonary disease (COPD), chronic
or acute bronchoconstriction, chronic bronchitis, small airways obstruction, emphysema, chronic
eosinophilic pneumonia, adult respiratory distress syndrome, exacerbation of airways hyper
reactivity consequent to other drug therapy, pulmonary vasulcar disease (including pulmonary
arterial hypertension), acute lung injury, bronchiectasis, sinusitis, allergic conjunctivitis,
idiopathic pulmonary fibrosis or atopic dermatitis, particularly asthma or chronic obstructive
pulmonary disease, most particularly chronic obstructive pulmonary disease.
Other diseases and conditions of interest are inflammation (including neuroinflammation),
arthritis (including rheumatoid arthritis, spondyloarthropathies, systemic lupus erythematous
arthritis, osteoarthritis and gouty arthritis), pain, fever, pulmonary sarcoisosis, silicosis,
cardiovascular disease (including atherosclerosis, myocardial infarction, thrombosis, congestive
heart failure and cardiac reperfusion injury), cardiomyopathy, stroke, ischaemia, reperfusion
injury, brain edema, brain trauma, neurodegeneration, liver disease, inflammatory bowel
disease (including Crohn's disease and ulcerative colitis), nephritis, retinitis, retinopathy,
macular degeneration, glaucoma, diabetes (including type 1 and type 2 diabetes), diabetic
neurorpathy, viral and bacterial infection, myalgia, endotoxic shock, toxic shock syndrome,
autoimmune disease, osteoporosis, multiple sclerosis, endometriosis, menstrual cramps,
vaginitis, candidiasis, cancer, fibrosis, obesity, muscular dystrophy, polymyositis, Alzheimer's
disease, skin flushing, eczema, psoriasis, atopic dermatitis and sunburn.
Types of asthma include atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial
IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, intrinsic asthma caused
by pathophysiologic disturbances, extrinsic asthma caused by environmental factors, essential
asthma of unknown or inapparent cause, bronchitic asthma, emphysematous asthma, exerciseinduced
asthma, allergen induced asthma, cold air induced asthma, occupational asthma,
infective asthma caused by bacterial, fungal, protozoal, or viral infection, non-allergic asthma,
incipient asthma, wheezy infant syndrome and bronchiolytis.
The treatment of asthma includes palliative treatment for the symptoms and conditions of
asthma such as wheezing, coughing, shortness of breath, tightness in the chest, shallow or fast
breathing, nasal flaring (nostril size increases with breathing), retractions (neck area and
between or below the ribs moves inward with breathing), cyanosis (gray or bluish tint to skin,
beginning around the mouth), runny or stuffy nose, and headache.
The present invention also provides any of the uses, methods or compositions as defined above
wherein the compound of formula (I), or pharmaceutically acceptable salt thereof, or
pharmaceutically acceptable solvate of said compound or salt, is used in combination with
another pharmacologically active compound, particularly one of the functionally-defined classes
or specific compounds listed below. Generally, the compounds of the combination will be
administered together as a formulation in association with one or more pharmaceutically
acceptable excipients.
Suitable agents for use in combination therapy with a compound of formula (I), or
pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate of said
compound or salt, particularly in the treatment of respiratory disease, include:
a 5-lipoxygenase activating protein (FLAP) antagonist;
a leukotriene antagonist (LTRA) such as an antagonist of LTB4, LTC4, LTD4, LTE4, CysLT-i or
CysLT2, e.g. montelukast or zafirlukast;
a histamine receptor antagonist, such as a histamine type 1 receptor antagonist or a histamine
type 2 receptor antagonist, e.g. loratidine, fexofenadine, desloratidine, levocetirizine,
methapyrilene or cetirizine;
an a 1-adrenoceptor agonist or an a2-adrenoceptor agonist, e.g. phenylephrine, methoxamine,
oxymetazoline or methylnorephrine;
a muscarinic M3 receptor antagonist, e.g. tiotropium or ipratropium;
a dual muscarinic M3 receptor antagononist/p2 agonist;
a PDE inhibitor, such as a PDE3 inhibitor, a PDE4 inhibitor or a PDE5 inhibitor, e.g.
theophylline, sildenafil, vardenafil, tadalafil, ibudilast, cilomilast or roflumilast;
sodium cromoglycate or sodium nedocromil;
a cyclooxygenase (COX) inhibitor, such as a non-selective inhibitor (e.g. aspirin or ibuprofen) or
a selective inhibitor (e.g. celecoxib or valdecoxib);
a glucocorticosteroid, e.g. fluticasone, mometasone, dexamethasone, prednisolone,
budesonide, ciclesonide or beclamethasone;
an anti-inflammatory monoclonal antibody, e.g. infliximab, adalimumab, tanezumab,
ranibizumab, bevacizumab or mepolizumab;
a b2 agonist, e.g. salmeterol, albuterol, salbutamol, fenoterol or formoterol, particularly a longacting
b2 agonist;
an intigrin antagonist, e.g. natalizumab;
an adhesion molecule inhibitor, such as a VLA-4 antagonist;
a kinin B or B2 receptor antagonist;
an immunosuppressive agent, such as an inhibitor of the IgE pathway (e.g. omalizumab) or
cyclosporine;
a matrix metalloprotease (MMP) inhibitor, such as an inhibitor of MMP-9 or MMP-12;
a tachykinin NK-i , NK2 or NK3 receptor antagonist;
a protease inhibitor, such as an inhibitor of elastase, chymase or catheopsin G;
an adenosine A2a receptor agonist;
an adenosine A2b receptor antagonist;
a urokinase inhibitor;
a dopamine receptor agonist (e.g. ropinirole), particularly a dopamine D2 receptor agonist (e.g.
bromocriptine);
a modulator of the NFKB pathway, such as an IKK inhibitor;
a further modulator of a cytokine signalling pathway such as an inhibitor of JAK kinase, syk
kinase, p38 kinase, SPHK-1 kinase, Rho kinase, EGF-R or MK-2;
a mucolytic, mucokinetic or anti-tussive agent
an antibiotic;
an antiviral agent;
a vaccine;
a chemokine;
an epithelial sodium channel (ENaC) blocker or Epithelial sodium channel (ENaC) inhibitor;
a nucleotide receptor agonist, such as a P2Y2 agonist;
a thromboxane inhibitor;
niacin;
a 5-lipoxygenase (5-LO) inhibitor, e.g. Zileuton;
an adhesion factor, such as VLAM, ICAM or ELAM;
a CRTH2 receptor (DP2) antagonist;
a prostaglandin D2 receptor (DP^ antagonist;
a haematopoietic prostaglandin D2 synthase (HPGDS) inhibitor;
interferon- b;
a soluble human TNF receptor, e.g. Etanercept;
a HDAC inhibitor;
a phosphoinositotide 3-kinase gamma (R I3Kg ) inhibitor;
a phosphoinositide 3-kinase delta (R I3Kd) inhibitor;
a CXCR-1 or a CXCR-2 receptor antagonist;
an IRAK-4 inhibitor; and
a TLR-4 or TLR-9 inhibitor;
including the pharmaceutically acceptable salts of the specifically named compounds and the
pharmaceutically acceptable solvates of said specifically named compounds and salts.
Besides being useful for human treatment, compounds of formula (I) are also useful for
veterinary treatment of companion animals, exotic animals and farm animals.
When used in the present application, the following abbreviations have the meanings set out
below:
AcOH is acetic acid;
APCI (in relation to mass spectrometry) is atmospheric pressure chemical ionization;
BOP is (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate;
Calc is calculated;
CDCI 3 is deuterochloroform;
C0 2Et is ethyl carboxylate;
DCC is N,N'-dicyclohexylcarbodiimide;
DCM is dichloromethane;
DEA is diethylamine;
DIAD is diisopropyl azodicarboxylate;
DIEA is N,N-diisopropylethylamine;
DIPEA is N,N-diisopropylethylamine;
DMA is N,N-dimethylacetamide;
DMF is dimethylformamide;
DMSO-d6 is fully deuterated dimethyl sulphoxide;
EDC/EDCI is N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride;
ES (in relation to mass spectrometry) is electrospray;
Et is ethyl;
EtOAc is ethyl acetate
Ex is Example;
h is hour(s);
HATU is N,N,N',N'-tetramethyl-0-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate;
HBTU is N,N,N',N'-tetramethyl-0-(1 H-benzotriazol-1-yl)uronium hexafluorophosphate;
HCI is hydrochloric acid;
H NMR or H NMR is proton nuclear magnetic resonance;
HOAt is 1-hydroxy-7-azabenzotriazole;
HOBt is 1-hydroxybenzotriazole;
HPLC is high performance liquid chromatography;
H2S0 4 is sulphuric acid;
IPA is isopropyl alcohol;
iPr is isopropyl;
K2C0 3 is potassium carbonate;
KMn0 4 is potassium permanganate;
KOH is potassium hydroxide;
KOAc is potassium acetate;
LCMS is liquid chromatography mass spectrometry;
LRMS is low resolution mass spectrometry;
NMM is 4-methylmorpholine;
Me is methyl;
MeCN is acetonitrile;
MeOD-d4 is fully deuterated methanol;
MgS0 4 is magnesium sulphate;
2-MeTHF is 2-methyltetrahydrofuran;
min is minute(s);
MS is mass spectroscopy;
NaCI is sodium chloride;
NaH is sodium hydride;
NBS is N-bromosuccinimide;
NIS is N-iodosuccinimide;
MP is N-methylpyrrolidine;
Obs is observed;
Pd(OAc) 2 is palladium(ll)acetate;
RT is retention time;
SEM-CI is (2-chloromethoxy-ethyl)-trimethyl-silane;
SPhos is 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl;
STAB is sodium (tri-acetoxy) borohydride;
TBTU is 0-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate;
TEA is triethylamine;
TFA is trifluoroacetic acid;
THF is tetrahydrofuran;
tBME is 2-mMethoxy-2-methyl-propane;
p-TsOH is para-toluene sulfonic acid.
Unless otherwise defined herein, scientific and technical terms used in connection with the
present invention have the meanings that are commonly understood by those of ordinary skill in
the art.
The phrase "therapeutically effective" is intended to qualify the amount of compound or
pharmaceutical composition, or the combined amount of active ingredients in the case of
combination therapy. This amount or combined amount will achieve the goal of treating the
relevant condition.
The term "treatment," as used herein to describe the present invention and unless otherwise
qualified, means administration of the compound, pharmaceutical composition or combination to
effect preventative, palliative, supportive, restorative or curative treatment. The term treatment
encompasses any objective or subjective improvement in a subject with respect to a relevant
condition or disease.
The term "preventive treatment," as used herein to describe the present invention, means that
the compound, pharmaceutical composition or combination is administered to a subject to inhibit
or stop the relevant condition from occurring in a subject, particularly in a subject or member of
a population that is significantly predisposed to the relevant condition.
The term "palliative treatment," as used herein to describe the present invention, means that the
compound, pharmaceutical composition or combination is administered to a subject to remedy
signs and/or symptoms of a condition, without necessarily modifying the progression of, or
underlying etiology of, the relevant condition.
The term "supportive treatment," as used herein to describe the present invention, means that
the compound, pharmaceutical composition or combination is administered to a subject as a
part of a regimen of therapy, but that such therapy is not limited to administration of the
compound, pharmaceutical composition or combination. Unless otherwise expressly stated,
supportive treatment may embrace preventive, palliative, restorative or curative treatment,
particularly when the compounds or pharmaceutical compositions are combined with another
component of supportive therapy.
The term "restorative treatment," as used herein to describe the present invention, means that
the compound, pharmaceutical composition or combination is administered to a subject to
modify the underlying progression or etiology of a condition. Non-limiting examples include an
increase in forced expiratory volume in one second (FEV 1) for lung disorders, decreased rate
of a decline in lung function over time, inhibition of progressive nerve destruction, reduction of
biomarkers associated and correlated with diseases or disorders, a reduction in relapses,
improvement in quality of life, reduced time spent in hospital during an acute exacerbation event
and the like.
The term "curative treatment," as used herein to describe the present invention, means that
compound, pharmaceutical composition or combination is administered to a subject for the
purpose of bringing the disease or disorder into complete remission, or that the disease or
disorder is undetectable after such treatment.
The term "selective", when used to describe a functionally-defined receptor ligand or enzyme
inhibitor means selective for the defined receptor or enzyme subtype as compared with other
receptor or enzyme subtypes in the same family. For instance, a selective PDE5 inhibitor is a
compound which inhibits the PDE5 enzyme subtype more potently than any other PDE enzyme
subtype. Such selectivity is preferably at least 2 fold (as measured using conventional binding
assays), more preferably at least 10 fold, most preferably at least 100 fold.
The term "alkyl", alone or in combination, means an acyclic, saturated hydrocarbon group of the
formula C H2n+ i which may be linear or branched. Examples of such groups include methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl and hexyl.
Unless otherwise specified, an alkyl group comprises from 1 to 6 carbon atoms.
The carbon atom content of alkyl and various other hydrocarbon-containing moieties is indicated
by a prefix designating a lower and upper number of carbon atoms in the moiety, that is, the
prefix C -Cj indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive. Thus,
for example, C -C6 alkyl refers to alkyl of one to six carbon atoms, inclusive.
The term "hydroxy," as used herein, means an OH radical.
Het3 is a saturated or partially saturated (i.e. non aromatic) heterocycle and may be attached via
a ring nitrogen atom (when the heterocycle is attached to a carbon atom) or a ring carbon atom
(in all cases). Equally, when substituted, the substituent may be located on a ring nitrogen atom
(if the substituent is joined through a carbon atom) or a ring carbon atom (in all cases). Specific
examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl,
tetrahydropyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, piperazinyl, azepanyl, oxepanyl,
oxazepanyl and diazepinyl.
Het3 may be fully saturated or partially unsaturated, i.e. may have one or more degrees of
unsaturation but may not be fully aromatic.
Het1 is an aromatic heterocycle and may be attached via a ring carbon atom (in all cases) or a
ring nitrogen atom with an appropriate valency (when the heterocycle is attached to a carbon
atom). Equally, when substituted, the substituent may be located on a ring carbon atom (in all
cases) or a ring nitrogen atom with an appropriate valency (if the substituent is joined through a
carbon atom). Specific examples include thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoyl, oxazolyl,
isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl,
pyrimidinyl and pyrazinyl.
Het2 is an aromatic heterocycle and may be attached via a ring carbon atom (in all cases) or a
ring nitrogen atom with an appropriate valency (when the heterocycle is attached to a carbon
atom). Equally, when substituted, the substituent may be located on a ring carbon atom (in all
cases) or a ring nitrogen atom with an appropriate valency (if the substituent is joined through a
carbon atom). Het2 is aromatic and is therefore necessarily a fused bicycle. Specific examples
include imidazo[2,1-b][1 ,3]thiazolyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl,
indazolyl, benzotriazolyl, pyrrolo[2,3-b]pyridyl, pyrrolo[2,3-c]pyridyl, pyrrolo[3,2-c]pyridyl,
pyrrolo[3,2-b]pyridyl, imidazo[4,5-b]pyridyl, imidazo[4,5-c]pyridyl, pyrazolo[4,3-d]pyridyl,
pyrazolo[4,3-c]pyridyl, pyrazolo[3,4-c]pyridyl, pyrazolo[3,4-b]pyridyl, isoindolyl, indazolyl, purinyl,
indolizinyl, imidazo[1 ,2-a]pyridyl, imidazo[1 ,5-a]pyridyl, pyrazolo[1 ,5-a]pyridyl, pyrrolo[1 ,2-
bjpyridazinyl, imidazo[1 ,2-c]pyrimidinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl,
quinoxalinyl, phthalazinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, 1,5-
naphthyridinyl, 2,6-naphthyridinyl, 2,7-naphthyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-
djpyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[2,3-d]pyrazinyl,
pyrido[3,4-b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl, pyrazino[2,3-b]pyrazinyl and pyrimido[4,5-
djpyrimidine.
The term "cycloalkyl" means a means a monocyclic, saturated hydrocarbon group of the formula
CnH2 n-i - Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
Unless otherwise specified, a cycloalkyl group comprises from 3 to 8 carbon atoms.
The term "oxo" means a doubly bonded oxygen.
The term "alkoxy" means a radical comprising an alkyl radical that is bonded to an oxygen atom,
such as a methoxy radical. Examples of such radicals include methoxy, ethoxy, propoxy,
isopropoxy, butoxy and tert-butoxy.
The term "halo" means, fluoro, chloro, bromo or iodo.
As used herein, the terms "co-administration", "co-administered" and "in combination with",
referring to a combination of a compound of formula (I) and one or more other therapeutic
agents, includes the following:
• simultaneous administration of such a combination of a compound of formula (I) and a
further therapeutic agent to a patient in need of treatment, when such components are
formulated together into a single dosage form which releases said components at
substantially the same time to said patient,
• substantially simultaneous administration of such a combination of a compound of
formula(l) and a further therapeutic agent to a patient in need of treatment, when such
components are formulated apart from each other into separate dosage forms which are
taken at substantially the same time by said patient, whereupon said components are
released at substantially the same time to said patient,
• sequential administration of such a combination of a compound of formula (I) and a
further therapeutic agent to a patient in need of treatment, when such components are
formulated apart from each other into separate dosage forms which are taken at
consecutive times by said patient with a significant time interval between each
administration, whereupon said components are released at substantially different times
to said patient; and
• sequential administration of such a combination of a compound of formula (I) and a
further therapeutic agent to a patient in need of treatment, when such components are
formulated together into a single dosage form which releases said components in a
controlled manner.
The term 'excipient' is used herein to describe any ingredient other than a compound of formula
(I). The choice of excipient will to a large extent depend on factors such as the particular mode
of administration, the effect of the excipient on solubility and stability, and the nature of the
dosage form. The term "excipient" encompasses diluent, carrier or adjuvant.
One way of carrying out the invention is to administer a compound of formula (I) in the form of a
prodrug. Thus, certain derivatives of a compound of formula (I) which may have little or no
pharmacological activity themselves can, when administered into or onto the body, be converted
into a compound of formula (I) having the desired activity, for example by hydrolytic cleavage,
particularly hydrolytic cleavage promoted by an esterase or peptidase enzyme. Such derivatives
are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in 'Pro
drugs as Novel Delivery Systems', Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella)
and 'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (Ed. E. B. Roche, American
Pharmaceutical Association). Reference can also be made to Nature Reviews/Drug Discovery,
2008, 7, 355 and Current Opinion in Drug Discovery and Development, 2007, 10, 550.
Prodrugs in accordance with the invention can, for example, be produced by replacing
appropriate functionalities present in the compounds of formula (I) with certain moieties known
to those skilled in the art as 'pro-moieties' as described, for example, in 'Design of Prodrugs' by
H. Bundgaard (Elsevier, 1985).
Thus, a prodrug in accordance with the invention is (a) an ester or amide derivative of a
carboxylic acid in a compound of formula (I); (b) an ester, carbonate, carbamate, phosphate or
ether derivative of a hydroxyl group in a compound of formula (I); (c) an amide, imine,
carbamate or amine derivative of an amino group in a compound form formula (I); (d) a
thioester, thiocarbonate, thiocarbamate or sulphide derivatives of a thiol group in a compound of
formula (I); or (e) an oxime or imine derivative of a carbonyl group in a compound of formula (I).
Some specific examples of prodrugs in accordance with the invention include:
(i) where the compound of formula (I) contains a carboxylic acid functionality
(-COOH), an ester thereof, such as a compound wherein the hydrogen of the carboxylic acid
functionality of the compound of formula (I) is replaced by C C alkyl (e.g. ethyl) or (Ci -C8
alkyl)C(=0)OCH 2- (e.g. BuC(=0)OCH 2-);
(ii) where the compound of formula (I) contains an alcohol functionality (-OH), an ester
thereof, such as a compound wherein the hydrogen of the alcohol functionality of the compound
of formula (I) is replaced by -CO(C -C8 alkyl) (e.g. methylcarbonyl) or the alcohol is esterified
with an amino acid;
(iii) where the compound of formula (I) contains an alcohol functionality (-OH), an ether
thereof, such as a compound wherein the hydrogen of the alcohol functionality of the compound
of formula (I) is replaced by ( -C8 alkyl)C(=0)OCH 2- or -CH 2OP(=0)(OH) 2;
(iv) where the compound of formula (I) contains an alcohol functionality (-OH), a phosphate
thereof, such as a compound wherein the hydrogen of the alcohol functionality of the compound
of formula (I) is replaced by -P(=0)(OH) 2 or -P(=0)(ONa) 2 or -P(=0)(0 )2Ca2+;
(v) where the compound of formula (I) contains a primary or secondary amino functionality
(-NH 2 or -NHR where R ¹ H), an amide thereof, for example, a compound wherein, as the case
may be, one or both hydrogens of the amino functionality of the compound of formula (I) is/are
replaced by (C -C 0 )alkanoyl, -COCH 2NH2 or the amino group is derivatised with an amino
acid;
(vi) where the compound of formula (I) contains a primary or secondary amino functionality
(-NH 2 or -NHR where R ¹ H), an amine thereof, for example, a compound wherein, as the case
may be, one or both hydrogens of the amino functionality of the compound of formula (I) is/are
replaced by -CH 2OP(=0)(OH) 2.
Certain compounds of formula (I) may themselves act as prodrugs of other compounds of formula
(I). It is also possible for two compounds of formula (I) to be joined together in the form of a
prodrug. In certain circumstances, a prodrug of a compound of formula (I) may be created by
internally linking two functional groups in a compound of formula (I), for instance by forming a
lactone.
References below to compounds of formula (I) are taken to include the compounds themselves
and prodrugs thereof. The invention includes such compounds of formula (I) as well as
pharmaceutically acceptable salts of such compounds and pharmaceutically acceptable
solvates of said compounds and salts.
Pharmaceutically acceptable salts of the compounds of formula (I) include acid addition and
base salts.
Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include
the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate,
borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate,
gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride,
hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate,
mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate,
palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate,
saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, naphatlene-1 ,5-
disulfonic acid and xinofoate salts.
Suitable base salts are formed from bases which form non-toxic salts. Examples include the
aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine,
magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium
salts. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties,
Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).
Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more
of three methods:
(i) by reacting the compound of formula (I) with the desired acid or base;
(ii) by removing an acid- or base-labile protecting group from a suitable precursor of the
compound of formula (I) or by ring-opening a suitable cyclic precursor, for example, a lactone or
lactam, using the desired acid or base; or
(iii) by converting one salt of the compound of formula (I) to another by reaction with an
appropriate acid or base or by means of a suitable ion exchange column.
All three reactions are typically carried out in solution. The resulting salt may precipitate out and
be collected by filtration or may be recovered by evaporation of the solvent. The degree of
ionisation in the resulting salt may vary from completely ionised to almost non-ionised.
The compounds of formula (I), and pharmaceutically acceptable salts thereof, may exist in
unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular
complex comprising the compound of formula (I), or a pharmaceutically acceptable salt thereof,
and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The
term 'hydrate' may be employed when said solvent is water.
A currently accepted classification system for organic hydrates is one that defines isolated site,
channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K.
R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones in which the
water molecules are isolated from direct contact with each other by intervening organic
molecules. In channel hydrates, the water molecules lie in lattice channels where they are next
to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to
the metal ion.
When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry
independent of humidity. When, however, the solvent or water is weakly bound, as in channel
solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity
and drying conditions. In such cases, non-stoichiometry will be the norm.
Also included within the scope of the invention are multi-component complexes (other than salts
and solvates) wherein the drug and at least one other component are present in stoichiometric
or non-stoichiometric amounts. Complexes of this type include clathrates (drug-host inclusion
complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral
molecular constituents which are bound together through non-covalent interactions, but could
also be a complex of a neutral molecule with a salt. Co-crystals may be prepared by melt
crystallisation, by recrystallisation from solvents, or by physically grinding the components
together - see Chem Commun, 17, 1889-1896, by O. Almarsson and M. J. Zaworotko (2004).
For a general review of multi-component complexes, see J Pharm Sci, 64 (8), 1269-1288, by
Haleblian (August 1975).
The compounds of the invention may exist in a continuum of solid states ranging from fully
amorphous to fully crystalline. The term 'amorphous' refers to a state in which the material lacks
long range order at the molecular level and, depending upon temperature, may exhibit the
physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray
diffraction patterns and, while exhibiting the properties of a solid, are more formally described as
a liquid. Upon heating, a change from solid to liquid properties occurs which is characterised by
a change of state, typically second order ('glass transition'). The term 'crystalline' refers to a
solid phase in which the material has a regular ordered internal structure at the molecular level
and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated
sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is
characterised by a phase change, typically first order ('melting point').
The compounds of formula (I) may also exist in a mesomorphic state (mesophase or liquid
crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between
the true crystalline state and the true liquid state (either melt or solution). Mesomorphism arising
as the result of a change in temperature is described as 'thermotropic' and that resulting from
the addition of a second component, such as water or another solvent, is described as
'lyotropic'. Compounds that have the potential to form lyotropic mesophases are described as
'amphiphilic' and consist of molecules which possess an ionic (such as -COO Na+, -COO K+, or -
S0 3 Na+) or non-ionic (such as -N N+(CH 3)3) polar head group. For more information, see
Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4th Edition (Edward
Arnold, 1970).
Hereinafter all references to compounds of formula (I) include references to pharmaceutically
acceptable salts, solvates, multi-component complexes and liquid crystals thereof and to
solvates, multi-component complexes and liquid crystals of pharmaceutically acceptable salts
thereof.
The compounds of formula (I) may exhibit polymorphism and/or one or more kinds of isomerism
(e.g. optical, geometric or tautomeric isomerism). The compounds of formula (I) may also be
isotopically labelled. Such variation is implicit to the compounds of formula (I) defined as they
are by reference to their structural features and therefore within the scope of the invention.
Compounds of formula (I) containing one or more asymmetric carbon atoms can exist as two or
more stereoisomers. Where a compound of formula (I) contains an alkenyl or alkenylene group,
geometric cis/trans (or Z/E) isomers are possible. Where structural isomers are interconvertible
via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form
of proton tautomerism in compounds of formula (I) containing, for example, an imino, keto, or
oxime group, or so-called valence tautomerism in compounds which contain an aromatic
moiety. It follows that a single compound may exhibit more than one type of isomerism.
The pharmaceutically acceptable salts of compounds of formula (I) may also contain a
counterion which is optically active (e.g. d-lactate or l-lysine) or racemic (e.g. dl-tartrate or dlarginine).
Cis/trans isomers may be separated by conventional techniques well known to those skilled in
the art, for example, chromatography and fractional crystallisation.
Conventional techniques for the preparation/isolation of individual enantiomers include chiral
synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate
of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically
active compound, for example, an alcohol, or, in the case where the compound of formula (I)
contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid.
The resulting diastereomeric mixture may be separated by chromatography and/or fractional
crystallization and one or both of the diastereoisomers converted to the corresponding pure
enantiomer(s) by means well known to a skilled person. Chiral compounds of formula (I) (and
chiral precursors thereof) may be obtained in enantiomerically-enriched form using
chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a
hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol,
typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1%
diethylamine. Concentration of the eluate affords the enriched mixture. Chiral chromatography
using sub-and supercritical fluids may be employed. Methods for chiral chromatography useful
in some embodiments of the present invention are known in the art (see, for example, Smith,
Roger M., Loughborough University, Loughborough, UK; Chromatographic Science Series
(1998), 75 (Supercritical Fluid Chromatography with Packed Columns), pp. 223-249 and
references cited therein). In some relevant examples herein, columns were obtained from
Chiral Technologies, Inc, West Chester, Pennsylvania, USA, a subsidiary of Daicel® Chemical
Industries, Ltd., Tokyo, Japan.
When any racemate crystallises, crystals of two different types are possible. The first type is the
racemic compound (true racemate) referred to above wherein one homogeneous form of crystal
is produced containing both enantiomers in equimolar amounts. The second type is the racemic
mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each
comprising a single enantiomer. While both of the crystal forms present in a racemic mixture
have identical physical properties, they may have different physical properties compared to the
true racemate. Racemic mixtures may be separated by conventional techniques known to those
skilled in the art - see, for example, Stereochemistry of Organic Compounds by E. L. Eliel and
S. H. Wilen (Wiley, 1994).
The present invention includes all pharmaceutically acceptable isotopically-labelled compounds
of formula (I) wherein one or more atoms are replaced by atoms having the same atomic
number, but an atomic mass or mass number different from the atomic mass or mass number
which predominates in nature. Isotopically-labelled compounds of formula (I) can generally be
prepared by conventional techniques known to those skilled in the art or by processes
analogous to those described in the accompanying Examples and Preparations using an
appropriate isotopically-labelled reagent in place of the non-labelled reagent previously
employed. In particular, hydrogen atoms may be replaced by deuterium atoms since such
deuterated compounds are sometimes more resistant to metabolism.
Also included within the scope of the invention are active metabolites of compounds of formula
(I), that is, compounds formed in vivo upon administration of the drug, often by oxidatation or
dealkylation. Some examples of metabolites in accordance with the invention include
(i) where the compound of formula (I) contains a methyl group, an hydroxymethyl derivative
thereof (-CH 3 -> -CH2OH):
(ii) where the compound of formula (I) contains an alkoxy group, an hydroxy derivative
thereof (-OR -> -OH);
(iii) where the compound of formula (I) contains a tertiary amino group, a secondary amino
derivative thereof (-NRR -> -NHR or -NHR);
(iv) where the compound of formula (I) contains a secondary amino group, a primary
derivative thereof (-NHR-> -NH 2) ;
(v) where the compound of formula (I) contains a phenyl moiety, a phenol derivative thereof
(-Ph -> -PhOH); and
(vi) where the compound of formula (I) contains an amide group, a carboxylic acid derivative
thereof (-CONH 2 -> COOH).
For administration to human patients, the total daily dose of a compound of formula (I) is
typically in the range of 0.01 mg to 500mg depending, of course, on the mode of administration.
In another embodiment of the present invention, the total daily dose of a compound of formula
(I) is typically in the range of 0.1 mg to 300mg. In yet another embodiment of the present
invention, the total daily dose of a compound of formula (I) is typically in the range of 1mg to
30mg. The total daily dose may be administered in single or divided doses and may, at the
physician's discretion, fall outside of the typical range given herein. These dosages are based
on an average human subject having a weight of about 65kg to 70kg. The physician will readily
be able to determine doses for subjects whose weight falls outside this range, such as infants
and the elderly.
In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a
prefilled capsule, blister or pocket or by a system that utilises a gravimetrically fed dosing
chamber. Units in accordance with the invention are typically arranged to administer a metered
dose or "puff" containing from 1 to 5000 mg of drug. The overall daily dose will typically be in the
range g to 20mg which may be administered in a single dose or, more usually, as divided
doses throughout the day.
A compound of formula (I) can be administered per se, or in the form of a pharmaceutical
composition, which, as active constituent contains an efficacious dose of at least one compound
of the invention, in addition to customary pharmaceutically innocuous excipients and/or
additives.
Pharmaceutical compositions suitable for the delivery of compounds of the present invention
and methods for their preparation will be readily apparent to those skilled in the art. Such
compositions and methods for their preparation may be found, for example, in Remington's
Pharmaceutical Sciences , 19th Edition (Mack Publishing Company, 1995).
Compounds of formula (I) may be administered orally. Oral administration may involve
swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual
administration may be employed by which the compound enters the blood stream directly from
the mouth. Formulations suitable for oral administration include solid formulations such as
tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled),
chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays and
liquid formulations.
Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may
be employed as fillers in soft or hard capsules and typically comprise a carrier, for example,
water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one
or more emulsifying agents and/or suspending agents. Liquid formulations may also be
prepared by the reconstitution of a solid, for example, from a sachet.
Compounds of formula (I) may also be used in fast-dissolving, fast-disintegrating dosage forms
such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, by Liang
and Chen (2001).
For tablet dosage forms, depending on dose, the drug may make up from 1 weight % to 80
weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form.
In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants
include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl
cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose,
microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised
starch and sodium alginate. Generally, the disintegrant will comprise from 1 weight % to 25
weight %. In one embodiment of the present invention, the disintegrant will comprise from 5
weight % to 20 weight % of the dosage form. Binders are generally used to impart cohesive
qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin,
sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised
starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain
diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like),
mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic
calcium phosphate dihydrate. Tablets may also optionally comprise surface active agents, such
as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When
present, surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and
glidants may comprise from 0.2 weight % to 1 weight % of the tablet. Tablets also generally
contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl
fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally
comprise from 0.25 weight % to 10 weight %. In one embodiment of the present invention,
lubricants comprise from 0.5 weight % to 3 weight % of the tablet. Other possible ingredients
include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.
Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight %
binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10
weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant.
Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions
of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before
tabletting. The final formulation may comprise one or more layers and may be coated or
uncoated; it may even be encapsulated. Formulations of tablets are discussed in
Pharmaceutical Dosage Forms: Tablets, Vol. 1, by H. Lieberman and L. Lachman (Marcel
Dekker, New York, 1980).
Consumable oral films for human or veterinary use are typically pliable water-soluble or waterswellable
thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically
comprise a compound of formula (I), a film-forming polymer, a binder, a solvent, a humectant, a
plasticiser, a stabiliser or emulsifier, a viscosity-modifying agent and a solvent. Some
components of the formulation may perform more than one function. The film-forming polymer
may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is
typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %.
Other possible ingredients include anti-oxidants, colorants, flavourings and flavour enhancers,
preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils),
emollients, bulking agents, anti-foaming agents, surfactants and taste-masking agents. Films in
accordance with the invention are typically prepared by evaporative drying of thin aqueous films
coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel,
typically a combined coater dryer, or by freeze-drying or vacuuming.
Solid formulations for oral administration may be formulated to be immediate and/or modified
release. Modified release includes delayed, sustained, pulsed, controlled, targeted and
programmed release. Suitable modified release formulations for the purposes of the invention
are described in US Patent No. 6,106,864. Details of other suitable release technologies such
as high energy dispersions and osmotic and coated particles are to be found in Pharmaceutical
Technology On-line, 25(2), 1-14, by Verma et al (2001). The use of chewing gum to achieve
controlled release is described in WO-A-00/35298.
Compounds of formula (I) may also be administered directly into the blood stream, into muscle,
or into an internal organ. Such parenteral administration includes intravenous, intraarterial,
intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular
and subcutaneous administration. Suitable devices for parenteral administration include needle
(including microneedle) injectors, needle-free injectors and infusion techniques.
Compounds of the invention may also be administered topically to the skin or mucosa, that is,
dermally or transdermally.
The compounds of formula (I) can also be administered intranasally or by inhalation, typically in
the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or
as a mixed component particle, for example, mixed with phospholipids, such as
phosphatidylcholine) from a dry powder inhaler, as an aerosol spray from a pressurised
container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to
produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as
1, 1 , 1 ,2-tetrafluoroethane or 1, 1 , 1 ,2,3,3,3-heptafluoropropane, or as nasal drops. For intranasal
use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
Delivery by inhalation is the preferred route of administration for the compounds of the present
invention.
The pressurised container, pump, spray, atomizer, or nebuliser contains a solution or
suspension of the compound of formula (I) comprising, for example, ethanol, aqueous ethanol,
or a suitable alternative agent for dispersing, solubilising, or extending release of the compound,
a propellant as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an
oligolactic acid.
Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size
suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any
appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid
processing to form nanoparticles, high pressure homogenisation, or spray drying.
Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and
cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the
compound of the invention, a suitable powder base such as lactose or starch and a
performance modifier such as l-leucine, mannitol, or magnesium stearate. The lactose may be
anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients
include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a
fine mist may contain from 1mg to 20mg of the compound of the invention per actuation and the
actuation volume may vary from 1m I to 0OmI . A typical formulation may comprise a compound
of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents
which may be used instead of propylene glycol include glycerol and polyethylene glycol.
Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or
saccharin sodium, may be added to those formulations of the invention intended for intranasal
administration. Formulations for intranasal administration may be formulated to be immediate
and/or modified release using, for example, PGLA. Modified release includes delayed,
sustained, pulsed, controlled, targeted and programmed release.
Compounds of formula (I) may also be administered directly to the eye or ear, typically in the
form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline.
Compounds of formula (I) may be combined with soluble macromolecular entities, such as
cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order
to improve their solubility, dissolution rate, taste, bioavailability and/or stability when using any
of the aforementioned modes of administration. Drug-cyclodextrin complexes, for example, are
found to be generally useful for most dosage forms and administration routes. Both inclusion
and non-inclusion complexes may be used. As an alternative to direct complexation with the
drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or
solubiliser. Most commonly used for these purposes are alpha-, beta- and gammacyclodextrins,
examples of which may be found in international patent publications WO-A-
91/1 1172, WO-A-94/02518 and WO-A-98/55148.
Inasmuch as it may desirable to administer a combination of active compounds, for example, for
the purpose of treating a particular disease or condition, it is within the scope of the present
invention that two or more pharmaceutical compositions, at least one of which contains a
compound of formula (I), may conveniently be combined in the form of a kit suitable for
coadministration of the compositions. Thus, a kit of the invention comprises two or more
separate pharmaceutical compositions, at least one of which contains a compound of formula
(I), and means for separately retaining said compositions, such as a container, divided bottle, or
divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of
tablets, capsules and the like. Such a kit is particularly suitable for administering different
dosage forms, for example, oral and parenteral, for administering separate compositions at
different dosage intervals, or for titrating the separate compositions against one another. To
assist compliance, the kit typically comprises directions for administration and may be provided
with a so-called memory aid.
All the compounds of formula (I) can be made by the specific and general experimental
procedures described below in combination with the common general knowledge of one skilled
in the art (see, for example, Comprehensive Organic Chemistry, Ed. Barton and Ollis, Elsevier;
Comprehensive Organic Transformations: A Guide to Functional Group Preparations, Larock,
John Wiley and Sons). In the general methods that follow, R , R2, R3, X and n have the
meanings given in embodiment E 1 described above unless otherwise stated.
Compounds of formula (I) can be made by reacting a compound of formula:
(II)
with a compound of formula:
R -X-LG1
(III)
in which LG is a suitable leaving group such as a halogen atom. The reaction will typically be
carried out in a suitable inert solvent in the presence of a base such as diisopropylethylamine.
When X is -S0 2- , for example, a sulphonyl chloride (LG =CI) may be used. In a typical
procedure, a solution of the compound of formula (II) in DMF is treated with one equivalent of
the sulphonyl chloride and 1 equivalent of diisopropylethylamine and stirred at room
temperature. When X is -CH2-, an alkyl bromide (LG =Br) may be used. In a typical procedure,
a solution of the compound of formula (II) in DMF is treated with 1. 1 equivalents of the alkyl
bromide and 1. 1 equivalents of diisopropylethylamine and stirred at 50°C. When X is -CO-, an
acid chloride (LG =CI) may be used. In a typical procedure, a solution of the compound of
formula (II) in DMF is treated with 1. 1 equivalents of the acid chloride and 1. 1 equivalents of
diisopropylethylamine and stirred at room temperature.
Where X is a carbonyl group, the leaving group LG1 may be created in situ from the
corresponding carboxylic acid of formula
R -C0 2H
(IV)
by using a condensation reagent such as HATU. In a typical procedure, a solution of the
compound of formula (il) in DMF is treated with 1. 1 equivalents of HATU and 1. 1 equivalents of
diisopropylethylamine and stirred at room temperature for 30 minutes. An equivalent of the acid
of formula (IV) is then added. For a general review on amide bond formation, see Chem. Soc.
Rev., 2009, 38(2), 606-631
Where X is -CH2- , an aldehyde of formula:
R -CHO
(V)
may alternatively be condensed with a compound of formula (II) under reducing conditions in
order to provide the desired compound of formula (I). In a typical procedure, a solution of the
compound of formula (II) in DMF is treated with the 1.5 equivalents of the aldehyde of formula
(V), 2 equivalents of diisopropylethylamine and 1.5 equivalents of acetic acid and stirred at room
temperature for one hour. Sodium triacetoxyborohydride ( 1.5 equivalents) is then added and
stirring continued at room temperature.
Compounds of formula (II) can be assembled by successive aryl-heteroaryl and heteroarylheteroaryl
organometallic coupling reactions. One example of of a possible reaction sequence is
shown in Scheme 1 (PG = protecting group, LG = leaving group, M = metal species; where
multiple protecting groups are shown, they may be the same or different). Free NH groups will
generally need to be protected during these reactions. Suitable protecting groups, their
introduction and their removal are all part of the common general knowledge of the skilled
person - see, for instance, 'Protective Groups in Organic Chemistry' by Wuts and Greene
(Wiley-Blackwell).
Suitable reaction conditions for the various steps necessary to prepare and react together the
compounds in Scheme 1 may be found in the specific Preparations listed below. For a general
review on organometallic cross-couping chemistry, see 'Handbook of Organopalladium
Chemistry for Organic Synthesis' (Volume 1) editied by Ei-ichi Negishi (John Wiley & Sons).
Scheme 1
Compounds of formula (I) can also be prepared by treating a compound of formula:
with an acid (e.g. concentrated hydrochloric acid). PG1 is an acid-labile protecting group and
C=Y is a carbonyl group or an acid-labile, protected form of a carbonyl group (e.g. a ketal). The
reaction will usually be performed in a suitable inert solvent with heating.
Compounds of formula (X) can be made from precursors of formula:
Compounds of formula (XI) can be assembled using the aryl-heteroaryl bond forming reactions
discussed above.
The skilled person will appreciate that many compounds of formula (I) may be interconverted by
functional group manipulation.
The starting materials necessary for carrying out the methods described above are in many
cases commercially available and may otherwise be described in the literature or in the
Preparations below or may be made using analgous procedures to those described in the
liternature or in the Preparations below.
Supplementing the general methods presented above, the following experimental details
illustrate specifically how certain compounds of formula (I) may be prepared. All Examples are
compounds of formula (I). Preparations are intermediates useful in the synthesis of compounds
of formula (I).
The following HPLC methods have been used in the characterization of the Examples below:
Method A
HPLC
Analytical (QC) Preparative
conditions
Gemini-NX 3mhi C18
Gemini-NX 5mhi C18
Column 110A
2 1.2 x 100mm
Temperature Ambient Ambient
UV 225nm - ELSD -
Detection UV 225nm - ELSD - MS
MS
Injection volume 5m I- 1000 m I_
Flow rate 1.5ml_/min 18 mL/min
A: H20 + 0.1%
A: H20 + 0.1% DEA
ammonium acetate
Mobile phase
B: MeCN + 0.1%
B: MeCN + 0.1% DEA
ammonium acetate
Time
Gradient %B Time (min) %B
(min)
0 5 0-1 .0 5
0-3.0 5-95 1.0-7.0 5-98
3.0-4.0 95 7.0-9.0 98
4.0-4.1 95-5 9.0-9.10 98-5
4.1-5.0 5 9.10-10 5
Method B
Method C
HPLC
Preparative
conditions
Phenomenex Luna C18
Column 5mhn 10qA
2 1.2 x 150mm
Temperature Ambient
UV 254nm - ELSD -
Detection
MS
Injection volume IOOOmI
Flow rate 18 mL/min
A: H20 + 0.05% formic
acid
Mobile phase
B: MeCN + 0.05%
formic acid
Gradient Time (min) %B
0-2.5 5
2.5-17.5 5-95
17.5-22.5 95
22.5-22.6 95-5
22.6-23.0 5
d D
HPLC
Preparative
conditions
Zorbax SB C18 5mh
Column 100A
2 1.2 x 150mm
Temperature Ambient
UV 254nm - ELSD -
Detection
MS
Injection volume 1000m I_
Flow rate 20 mL/min
A: H20 + 0.05%
NH40Ac
Mobile phase
B: MeCN + 0.05%
NH40Ac
Gradient Time (min) %B
0-2.5 5
2.5-17.5 5-95
17.5-22.5 95
22.5-22.6 95-5
22.6-23.0
Method E
Method F
HPLC
Preparative
conditions
Xterra RP18
Column
19-250mm
Temperature Ambient
UV 254nm - ELSD -
Detection
MS
Injection volume 1000m
Flow rate 16 mL/min
A: H20 + 0.05%
NH40Ac
Mobile phase
B: MeCN + 0.05%
NH40Ac
Gradient Time (min) %B
0-2.5 5
2.5-17.5 5-95
17.5-22.5 95
22.5-22.6 95-5
22.6-25.0 5
Method G
Example 1
{2-[6-(2-Ethyl-5-fluoro-4-hvdroxy-phenyl)-1 H-indazol-3-yll-1 ,4,6,7-tetrahydro-imidazo
[4,5-clpyridin-5-yl)-(4-fluoro-phenyl)-methanone
To a solution of 5-ethyl-2-fluoro-4-[3-(4,5,6 J-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl)-1 Hindazol-
6-yl]-phenol trihydrobromide salt (Preparation 25, 50mg, dqmhio ΐ) in DMF ( 1 ml_), was
added HATU (32mg, 84mh o I) , and DIPEA (56m I_, 320mh o I) . The reaction mixture was stirred at
room temperature for 30 minutes. 4-Fluoro-benzoic acid ( 11.2mg, dqmhhoΐ) was added to the
reaction mixture and stirring was continued for 18 hours. Saturated aqueous sodium hydrogen
carbonate solution (5ml_) was added to the reaction mixture. The resulting solid was collected
by filtration, washing with further saturated aqueous sodium hydrogen carbonate solution. The
crude material was purified by HPLC Method B to afford 7.7mg of the title compound.
LCMS (Method A): RT 2.52 min (100% area), ES m/z 500.182 [M+H]+.
Example 2
{2-r6-(2-Ethyl-5-fluoro-4-hvdroxy-phenyl)-1 H-indazol-3-yll-1 ,4,6,7-tetrahvdro-imidazo
r4,5-clpyridin-5-yl)-isothiazol-3-yl-methanone
The title compound was prepared from 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1 H-imidazo[4,5-
c]pyridin-2-yl)-1 H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50mg, dqmhhoΐ) and
isothiazole-3-carboxylic acid ( 1 1mg, dqmhhoΐ) using the same method as described in Example
1. The crude material was purified by HPLC Method A to afford 7.7mg of the title compound.
LCMS (Method A) RT 2.39 min (100% area), ES m/z 469.143 [M+H]+.
Example 3
{2-[6-(2-Ethyl-5-fluoro-4-hvdroxy-phenyl)-1 H-indazol-3-yll-1 ,4,6,7-tetrahydro-imidazo
[4,5-clpyridin-5-yl)-isothiazol-3-yl-methanone
To a solution of N-(1-benzyl-4,4-diethoxy-piperidin-3-yl)-6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-1-
(tetrahydro-pyran-2-yl)-1 H-indazole-3-carboxamidine (Preparation 9, 6.06g, 9.41 mmol) in
ethanol (34mL) was added concentrated hydrochloric acid (12M, 15.8mL, 189mmol). The
reaction mixture was heated at 65°C for 18 hours. The reaction mixture was concentrated in
vacuo and recharged with fresh ethanol (34mL) and concentrated hydrochloric acid (12M,
15.8mL, 189mmol). The reaction mixture was heated at 65°C for a further 4 hours. Water
(20mL) was added to the reaction mixture at 65°C and then the reaction was allowed to cool
slowly to room temperature. The solvents were removed in vacuo and the residue was
partitioned between 2-MeTHF (200mL) and saturated sodium hydrogen carbonate aqueous
solution (100mL). The organic layer was washed with further saturated sodium hydrogen
carbonate aqueous solution (100mL). The combined aqueous layers were re-extracted with 2-
MeTHF (250mL). The combined organic layers were dried over MgS0 4 and concentrated in
vacuo to yield a brown foam. The crude material was dissolved in MeCN (150mL) and ethanol
(30mL) and heated at 50°C for 2 days. The product crystallised from this solution and was
collected by filtration and dried in vacuo to give the title compound as a crystalline white solid
(3.53g) in an 80% yield.
H NMR (400 MHz, CD3OD) d ppm 1.04 (t, 3H), 2.52 (q, 2H), 2.81 (t, 2H), 2.91 (t, 2H), 3.62 (s,
2H), 3.80 (s, 2H), 6.87 (d, 1H), 6.92 (d, 1H), 7.1 1 (d, 1H), 7.26-7.43 (m, 6H), 8.22 (d, 1H).
LCMS: m/z 468 [M+H] +, 466 [M-H]Example 4
{2-[6-(2-Ethyl-5-fluoro-4-hvdroxy-phenyl)-1 H-indazol-3-yll-1 ,4,6,7-tetrahydro-imidazo
[4,5-clpyridin-5-yl)-(5-piperidin-1-yl-pyrazin-2-yl)-methanone
To a solution of 5-piperidin-1-yl-pyrazine-2-carboxylic acid (Preparation 43, 10. 7g, 5 1.8mmol) in
DMF (200ml_) was added DIPEA (24.6ml_, 141 mmol) and HATU (21 .5g, 56.5mmol) and the
resulting mixture was stirred at room temperature for 10 minutes before being added dropwise
to a suspension of 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl)-1 Hindazol-
6-yl]-phenol dihydrochloric acid salt (Preparation 11, 19.5g, 47.1mmol) in DMF (200ml_)
over 30 minutes, using a further 75ml_ DMF to wash the vessel. The reaction mixture was then
stirred at room temperature for 18 hours. A further portion of 5-piperidin-1-yl-pyrazine-2-
carboxylic acid ( 1.07g, 5.18mmol) in DMF (40ml_) was treated with DIPEA (2.46ml_, 14.1 mmol)
and activated with HATU (2.15g, 5.65mmol) and the resulting mixture was stirred at room
temperature for 10 minutes before being added to the original reaction mixture which was then
stirred for a further 4 hours at room temperature. The reaction mixture was poured onto water
( 1.2L) and the pH was adjusted to 7 with sodium hydroxide solution. The resulting suspension
was stirred at room temperature for 30 minutes. The precipitate was collected by filtration,
washed with water (400ml_) and then dried under vacuum. The crude material was dissolved in
ethanol ( 1 13ml_) and treated with a 1M aqueous solution of sodium hydroxide. The reaction
mixture was stirred at room temperature for 18 hours. The precipitate was collected by filtration,
washed with a cold solution of 1:3 1M sodium hydroxide:ethanol (100ml_) and dried under
vacuum to give the sodium salt of the title compound, 16.14g. This material was dissolved in
water (100ml_) and treated with a 10% aqueous solution of citric acid (10ml_) to adjust the pH to
4. A few drops of 1M sodium hydroxide solution were added to bring the pH to 7. The resulting
suspension was stirred at room temperature for 1 hour and the solid was collected by filtration,
washed with water and then dried under vacuum to give the title compound as a white solid
(13.864g) in an 89% yield.
H NMR (400 MHz, DMSO-d6) d ppm 0.94 (t, 3H), 1.54-1 .60 (m, 2H), 1.60-1 .67 (m, 2H), 2.38
(q, 2H), 2.71-2.83 (m, 2H), 3.64-3.71 (m, 4H), 3.85-3.98 (m, 4H), 4.63-4.78 (m, 2H), 6.66 (d,
1H), 6.73 (d, 1H), 7.00-7.08 (m, 1H), 7.16-7.24 (m, 1H), 816-8.25 (m, 1H), 8.29 (s, 1H), 8.37 (s,
1H).
LCMS: m/z 567 [M+H] +, 565 [M-H]
Example 5
{2-r6-(2-Ethyl-5-fluoro-4-hvdroxy-phenyl)-1 H-indazol-3-yll-1 ,4,6J-tetrahvdro-imidazo
r4,5-clpyridin-5-yl)-(6-phenoxy-pyridin-3-yl)-methanone
The title compound was prepared from 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1 H-imidazo[4,5-
c]pyridin-2-yl)-1 H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50mg, dqmhhoΐ) and
6-phenoxy-nicotinic acid (17mg, 80mmol) using the method of Example 1. The crude material
was purified by HPLC Method A to afford 3.1mg of the title compound.
LCMS (Method A): RT 2.67 min (100% area), ES m/z 575.213 [M+H]+.
Example 6
5-Ethyl-2-fluoro-4-{3-[5-(6-morpholin-4-yl-pyridine-3-sulfonyl)-4,5,6,7-tetrahydro-1 H-imidazo[4,5-
clpyridin-2- n P- I H-indazol-6-yl)-phenol
To a solution of 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl)-1 Hindazol-
6-yl]-phenol trihydrobromide salt (Preparation 25, 50mg, 80mmol) in DMF (1ml_), was
added 6-morpholin-4-yl-pyridine-3-sulfonyl chloride (21 mg, dqmhhoΐ) and DIPEA (56 m I_,
320 mmol). The reaction mixture was stirred at room temperature for 18 hours. Saturated
aqueous sodium hydrogen carbonate solution (5ml_) was added and the resulting solid was
collected by filtration and washed with further saturated aqueous sodium hydrogen carbonate
solution. The crude material was purified by HPLC Method A to afford 18.7mg of the title
compound.
LCMS (Method A): RT 2.58 min (100% area), ES m/z 602.206 [M-H]Example 7
5-Ethyl-2-fluoro-4-{3-r5-(6-phenoxy-pyridine-3-sulfonyl)-4,5,6,7-tetrahvdro-1 H-imidazo
r4,5-clpyridin-2-yll-1 H-indazol-6-yl)-phenol
The title compound was prepared from 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1 H-imidazo[4,5-
c]pyridin-2-yl)-1 H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50mg, dqmhhoΐ) and
6-phenoxy-pyridine-3-sulfonyl chloride (22mg, dqmhhoΐ) using the method of Example 6. The
crude material was purified by HPLC Method A to afford 8.4mg of the title compound.
LCMS (Method A): RT 2.82 min (100% area),ES m/z 6 11.18 [M+H]+.
Example 8
(5-Chloro-pyridin-2-ylH2-r6-(2-ethyl-5-fluoro-4-hvdroxy-phenvn-1 H-indazol-3-yll-4, 5,7,8-
tetrahydro-1 H-imidazor4,5-dlazepin-6-yl)-methanone
To a solution of 5-chloro-pyridine-2-carboxylic acid (13.2mg, ddmhhoI) in DMF (1mL) was added
HATU (32mg, ddmhhoI) and the resulting reaction mixture was stirred at room temperature for 30
minutes. 5-Ethyl-2-fluoro-4-[3-(1 ,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepin-2-yl)-1 H-indazol-6-
yl]-phenol trihydrobromide salt (Preparation 32, 50mg, 80mmol) and DIPEA (56m I_, 320mmol)
were added and stirring was continued at room temperature for 18 hours. Saturated aqueous
sodium hydrogen carbonate solution (5ml_) was added to the reaction mixture. The resulting
solid was collected by filtration and washed with further saturated aqueous sodium hydrogen
carbonate solution. The crude material was purified by HPLC Method A to afford 20.5mg of the
title compound.
LCMS (Method A): RT 2.76 min (100% area), ES m/z 531 .163 [M-H]Example 9
2-{2-r6-(2-Ethyl-5-fluoro-4-hvdroxy-phenyl)-1 H-indazol-3-yll-4,5,7,8-tetrahvdro-1 H-imidazor4,5-
dlazepine-6-carbonyl)-isonicotinonitrile
The title compound was prepared from 4-cyano-pyridine-2-carboxylic acid (12.5mg, 85mh o I)
and 5-ethyl-2-fluoro-4-[3-(1 ,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepin-2-yl)-1 H-indazol-6-yl]-
phenol trihydrobromide salt (Preparation 32, 50mg, dqmhho ΐ) using the method of Example 8.
The crude material was purified by HPLC Method B to afford 6.5mg of the title compound.
LCMS (Method A): RT 2.66 min (100% area), ES m/z 522.198 [M+H]+.
Example 10
{2-r6-(2-Ethyl-5-fluoro-4-hvdroxy-phenyl)-1 H-indazol-3-yll-4,5,7,8-tetrahvdro-1 H-imidazo
[4,5-dlazepin-6-yl)-(4-fluoro-phenyl)-methanone
The title compound was prepared from 4-fluoro-benzoic acid (12.5mg, ddmhhoI) and 5-ethyl-2-
fluoro-4-[3-(1 ,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepin-2-yl)-1 H-indazol-6-yl]-phenol
trihydrobromide salt (Preparation 32, 50mg, dqmhhoΐ) using the method of Example 8. The
crude material was purified by HPLC Method B to afford 14.5mg of the title compound.
LCMS (Method A): RT 2.76 min (100% area), ES m/z 514.198 [M+H]+.
Example 11
{2-r6-(2-Ethyl-5-fluoro-4-hvdroxy-phenyl)-1 H-indazol-3-yll-4,5,7,8-tetrahvdro-1 H-imidazo
[4,5-dlazepin-6-yl)-isothiazol-3-yl-methanone
The title compound was prepared from isothiazole-3-carboxylic acid ( 11mg, ddmhhoI) and 5-
ethyl-2-fluoro-4-[3-(1 ,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepin-2-yl)-1 H-indazol-6-yl]-phenol
trihydrobromide salt (Preparation 32, 50mg, dqmhhoΐ) using the method of Example 8. The
crude material was purified by HPLC Method B to afford 10.3mg of the title compound.
LCMS (Method A): RT 2.54 min (100%area), ES m/z 503.159 [M+H]+.
Example 12
5-Ethyl-2-fluoro-4-{3-r5-(4-fluoro-benzenesulfonyl)-4,5,6,7-tetrahvdro-1 H-imidazo
r4,5-clpyridin-2-yll-1 H-indazol-6-yl)-phenol
To a solution of 5-ethyl-2-fluoro-4-[3-(4,5,6 J-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl)-1 Hindazol-
6-yl]-phenol trihydrobromide salt (Preparation 25, 50mg, dqmhhoΐ) in DMF ( 1 ml_), was
added 4-fluoro-benzenesulfonyl chloride (16mg, dqmhho ΐ) , and DIPEA (56 m I_, 320 mh o I) . The
reaction mixture was stirred at room temperature for 4 hours. Saturated aqueous sodium
hydrogen carbonate solution (5ml_) was added to the reaction mixture. The resulting solid was
collected by filtration and washed with further saturated aqueous sodium hydrogen carbonate
solution. The crude material was purified by reverse phase chromatography (Method C) to
afford 7mg of the title compound.
H NMR (400 MHz, CD3OD) d ppm 1.02 (t, 3H), 2.52 (q, 2H), 3.78-3.81 (m, 2H), 4.37-4.29 (m,
2H), 6.88-6.96 (m, 2H), 7.15 (d, 1H), 7.32-7.36 (m, 2H), 7.40 (s, 1H), 7.89-7.95 (m, 2H), 8.21
(d, 1H).
LCMS: m/z 536 [M+H]+.
Example 13
{2-[6-(2-Ethyl-5-fluoro-4-hvdroxy-phenyl)-1 H-indazol-3-yll-1 ,4,6,7-tetrahydro-imidazo
[4,5-clpyridin-5-yl)-[5-(2-fluoro-phenoxy)-pyrazin-2-yll-methanone
To a solution of 5-(2-fluoro-phenoxy)-pyrazine-2-carboxylic acid (Preparation 45, 19mg, dqmhho ΐ)
in DMF ( 1 ml_) was added HBTU (32mg, ddmhhoI) and the resulting reaction mixture was stirred
at room temperature for 30 minutes. 5-Ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1 H-imidazo[4,5-
c]pyridin-2-yl)-1 H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50mg, dqmhhoΐ) and
DIPEA (56m I_, 320 mh o I) were added and stirring was continued at room temperature for 16
hours. Saturated aqueous sodium hydrogen carbonate solution (5ml_) was added to the
reaction mixture. The resulting solid was collected by filtration and washed with further
saturated aqueous sodium hydrogen carbonate solution. The crude material was purified by
HPLC Method B to afford 8.3mg of the title compound.
LCMS (Method A): RT 2.97 min (100% area), ES m/z 594.199 [M-H]Example 14
4-r3-(6-Benzyl-1 ,4,5,6,7,8-hexahvdro-imidazor4,5-dlazepin-2-vn-1 H-indazol-6-yll-5-ethyl-2-
fluoro-phenol
To a solution of 5-ethyl-2-fluoro-4-[3-(1 ,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepin-2-yl)-1 Hindazol-
6-yl]-phenol trihydrobromide salt (Preparation 32, 50mg, dqmhhoΐ) in DMF ( 1 ml_), was
added benzyl bromide (14.4mg, 10 m I_, ddmhhoI ) , and DIPEA (56m I_, 320mh o I) . The reaction
mixture was heated at 50°C for 1d hours. The reaction mixture was then cooled to room
temperature and partitioned between EtOAc (50ml_) and water (50ml_). The organic layer was
washed with brine (50ml_), dried over sodium sulfate and concentrated in vacuo to furnish a
brown oil. The crude material was purified by reverse phase chromatography (Method C) to
afford 4mg of the title compound.
H NMR (400 MHz, CD3OD) d ppm 1.02 (t, 3H), 2.55 (q, 2H), 3.08-3.1 1 (m, 4H), 3.34-3.38 (m,
4H), 4.23 (s, 2H), 6.88-6.94 (m, 2H), 7.18 (d, 1H), 7.41-7.4 (m, 3H), 7.52-7.55 (m, 2H), 8.20 (d,
1H), 8.39 (br s, 1H).
LCMS: m/z 482 [M+H]+, 480 [M-H]Example 15
(5-Chloro-pyridin-2-ylH2-r6-(2-ethyl-5-fluoro-4-hvdroxy-phenyl)-1 H-indazol-3-yll-1 ,4,6,7-
tetrahydro-imidazo[4,5-clpyridin-5-yl)-methanone
To a solution of 5-chloro-pyridine-2-carboxylic acid (12mg, dqmhhoΐ) in DMF ( 1 ml_) was added
HBTU (32mg, ddmhhoI) and the resulting reaction mixture was stirred at room temperature for 30
minutes. 5-Ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl)-1 H-indazol-6-
yl]-phenol trihydrobromide salt (Preparation 25, 50mg, dqmhhoΐ) and DIPEA (56m I_, 320 mh o I)
were added and stirring was continued at room temperature for 18 hours. Saturated aqueous
sodium hydrogen carbonate solution (5ml_) was added to the reaction mixture. The resulting
solid was collected by filtration and washed with further saturated aqueous sodium hydrogen
carbonate solution. The crude material was purified by reverse phase chromatography (Method
C) to afford 3.3mg of the title compound.
H NMR (400 MHz, CD3OD) d ppm 1.02 (t, 3H), 2.52 (q, 2H), 2.88-2.96 (m, 2H), 3.79-3.82 (m,
2H), 4.15-4.19 (m, 2H), 6.82-6.96 (m, 2H), 7.08-7.18 (m, 1H), 7.39-7.41 (m, 1H), 7.69-7.71 (m,
1H), 7.99-8.01 (m, 1H), 8.19-8.21 (d, 1H), 8.38-8.42 (m, 1H).
LCMS: m/z 517 [M+H]+, 515 [M-H]Example 16
5-{2-r6-(2-Ethyl-5-fluoro-4-hvdroxy-phenyl)-1 H-indazol-3-yll-1 ,4,6,7-tetrahvdro-imidazo
[4,5-clpyridine-5-carbonyl)-pyridine-2-carbonitrile
To a solution of 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl)-1 Hindazol-
6-yl]-phenol trihydrobromide salt (Preparation 25, 50mg, dqmhhoΐ) in DMF ( 1 ml_), was
added 6-cyano-nicotinoyl chloride (Preparation 46, 17mg, 96mh o I) , and DIPEA (56 m I_,
320 mh o I) . The reaction mixture was stirred at room temperature for 72 hours and then
saturated aqueous sodium hydrogen carbonate solution (5ml_) was added. The resulting solid
was collected by filtration and washed with further saturated aqueous sodium hydrogen
carbonate solution. The crude material was purified by reverse phase chromatography (Method
C) to afford 6.9mg of the title compound.
H NMR (400 MHz, CD3OD) d ppm 1.02 (t, 3H), 2.52 (q, 2H), 2.85-2.98 (m, 2H), 3.75-3.79 (m,
2H), 4.15-4.19 (m, 2H), 6.82-6.96 (m, 2H), 7.08-7.18 (m, 1H), 7.38-7.40 (m, 1H), 8.00 (d, 1H),
8.15-8.20 (m, 2H), 8.22 (d, 1H).
LCMS: m/z 508 [M+H]+, 506 [M-H] .
Example 17
5-{2-r6-(2-Ethyl-5-fluoro-4-hvdroxy-phenyl)-1 H-indazol-3-yll-4.5J.8-tetrahvdro-1 H-imi
dlazepine-6-carbonyl)-pyridine-2-carbonitrile
To a solution of 5-ethyl-2-fluoro-4-[3-(1 ,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepin-2-yl)-1 Hindazol-
6-yl]-phenol trihydrobromide salt (Preparation 32, 28mg, 44mh o I) in DMF ( 1mL), was
added 6-cyano-nicotinoyl chloride (Preparation 46, 20.9mg, 141 mh o I) , and DIPEA (31 m ,
176 mh o I) . The reaction mixture was stirred at room temperature for 18 hours and then
saturated aqueous sodium hydrogen carbonate solution (5ml_) was added. The resulting solid
was collected by filtration and washed with further saturated aqueous sodium hydrogen
carbonate solution. The crude material was purified by HPLC Method A to afford 10.3mg of the
title compound.
LCMS (Method A): RT 2.69 min (100% area), ES m/z 522.198 [M-H] .
Example 18
5-Ethyl-2-fluoro-4-[3-(5-quinolin-6-ylmethyl-4,5,6,7-tetrahvdro-1 H-imidazo[4,5-clpyridin-2-yl)-1 Hindazol-
6-yll-phenol
To a solution of 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl)-1 Hindazol-
6-yl]-phenol trihydrobromide salt (Preparation 25, 50mg, 132 mh o I) in DMF (1ml_), was
added quinoline-6-carbaldehyde (31mg, 198 mhΊ q I) , DIPEA (34mg, 46m I , 264 mhΊ q I) and AcOH
( 11.8mg, 11m I_, 198 mh o I) . The reaction mixture was stirred at room temperature for 1 hour.
STAB (42mg, 198mh o I) was added and stirring was continued for 18 hours. The reaction
mixture was partitioned between EtOAc (10ml_) and saturated aqueous sodium hydrogen
carbonate solution (10ml). The organic layer was washed with further saturated aqueous
sodium hydrogen carbonate solution (2 x 10ml_), dried over magnesium sulfate and
concentrated in vacuo to furnish a brown oil. The crude material was purified by HPLC Method
A to afford 20.6mg of the title compound.
LCMS (Method A): RT 2.59 min (100% area), ES m/z 519.223 [M-H] .
Example 19
5-Ethyl-2-fluoro-4-f3-r5-(4-hvdroxy-benzvn-4.5,6,7-tetrahvdro-1 H-imidazor4,5-clpyridin-2-yll-1 Hindazol-
6-yl)-phenol
The title compound was prepared from 4-hydroxy-benzaldehyde (24.2mg, 198mh o I) and 5-
ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl)-1 H-indazol-6-yl]-phenol
trihydrobromide salt (Preparation 25, 50mg, 132mmol) using the method of Example 18. The
crude material was purified by HPLC Method A to afford 3 1.4mg of the title compound.
LCMS (Method A): RT 2.32 min (100% area), ES m/z 482.207 [M-H]Example 20
5-Ethyl-2-fluoro-4-{3-r5-(3-hvdroxy-benzyl)-4,5,6,7-tetrahvdro-1 H-imidazor4,5-clpyridin-2-yll-1 Hindazol-
6-yl)-phenol
The title compound was prepared from 3-hydroxy-benzaldehyde (24.2mg, 198mh o I) and 5-
ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl)-1 H-indazol-6-yl]-phenol
trihydrobromide salt (Preparation 25, 50mg, 132 mh o I) using the method of Example 18. The
crude material was purified by HPLC Method A to afford 39.6mg of the title compound.
LCMS (Method A): RT 2.39 min (100% area), ES m/z 484.207 [M+H] +.
Example 2 1
4-{2-r6-(2-Ethyl-5-fluoro-4-hvdroxy-phenyl)-1 H-indazol-3-yll-1 ,4,6,7-tetrahvdro-imidazor4,5-
clpyridin-5-ylmethyl)-pyridine-2-carbonitrile
The title compound was prepared from 4-formyl-pyridine-2-carbonitrile (26mg, 198 mh o I) and 5-
ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl)-1 H-indazol-6-yl]-phenol
trihydrobromide salt (Preparation 25, 50mg, 132 mh o I) using the method of Example 18. The
crude material was purified by HPLC Method B to afford 16mg of the title compound.
LCMS (Method B): RT 1.75 min (100% area), ES m/z 494.203 [M+H] +.
Example 22
5-Ethyl-2-fluoro-4-f3-r5-(3-methoxy-benzvn-4.5,6,7-tetrahvdro-1 H-imidazor4,5-clpyridin-2-yll-1 Hindazol-
6-yl)-phenol formic acid salt
To a solution of 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl)-1 Hindazol-
6-yl]-phenol trihydrobromide salt (Preparation 25, 50mg, 132 mh o I) in DMF (1mL), was
added 3-methoxy-benzaldehyde (27mg, IqdmhioI) , DIPEA (34mg, 46m , 264 mmol) and AcOH
( 11.8mg, 11m , 198mmol). The reaction mixture was stirred at room temperature for 1 hour.
STAB (42mg, 198 mh o I) was added and stirring was continued for 18 hours. Saturated aqueous
sodium hydrogen carbonate solution (5ml) was added to the reaction mixture. The resulting
solid was collected by filtration and washed with further saturated aqueous sodium hydrogen
carbonate solution. The crude material was purified by HPLC Method B to afford 30.1 mg of the
title compound.
LCMS (Method A): RT 2.64 min (100% area), ES m/z 496.223 [M-H]Example 23
5-Ethyl-2-fluoro-4-r3-(5-quinolin-3-ylmet^
indazol-6-yll-phenol
The title compound was prepared from quinoline-3-carbaldehyde (31 mg, 198 mh o I) and 5-ethyl-
2-fluoro-4-[3-(4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl)-1 H-indazol-6-yl]-phenol
trihydrobromide salt (Preparation 25, 50mg, 132 mh o I) using the method of Example 22. The
crude material was purified by HPLC Method B to afford 14.3mg of the title compound.
LCMS (Method A): RT 2.59 min (100% area), ES m/z 519.223 [M+H]+.
Example 24
5-Ethyl-2-fluoro-4-{3-[5-(6-phenoxy-pyridin-3-ylmethyl)-4,5,6,7-tetrahvdro-1 H-imidazo[4,5-
clpyridin-2- n P- I H-indazol-6-yl)-phenol
The title compound was prepared from 6-phenoxy-pyridine-3-carbaldehyde (39mg, 198 mh o I)
and 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl)-1 H-indazol-6-yl]-
phenol trihydrobromide salt (Preparation 25, 50mg, 132mh o I) using the method of Example 22.
The crude material was purified by HPLC Method A to afford 24.7mg of the title compound.
LCMS (Method B): RT 2.53 min (100% area), ES m/z 561 .234 [M+H]+.
Example 25
5-Ethyl-2-fluoro-4-{3-r5-(3,4,5,6-tetrahvdro-2H -ri ,2'lbipyridinyl-5'-ylmethyl)-4,5,6,7-tetrahvdro-
1H-imidazo[4,5-clpyridin-2-yll-1 H-indazol-6-yl)-phenol
The title compound was prepared from 3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-5'-carbaldehyde
(38mg, 198mhΊ q I) and 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl)-
1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50mg, 132 mh o I) using the method
of Example 22. The crude material was purified by HPLC Method A to afford 22.1 mg of the title
compound.
LCMS (Method B): RT 2.22 min (100% area), ES m/z 552.281 [M+H]+.
Example 26
3- 2-r6-(2-Ethyl-5-fluoro-4-hvdroxy-phenyl)-1 H-indazol-3-yll-1 ,4,6,7-tetrahvdro-imidazor4,5-
clpyridin-5-ylmethyl)-pyridine-2-carbonitrile
The title compound was prepared from 3-formyl-pyridine-2-carbonitrile (26mg, 198 mh o I) and 5-
ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl)-1 H-indazol-6-yl]-phenol
trihydrobromide salt (Preparation 25, 50mg, 132 mh o I) using the method of Example 22. The
crude material was purified by HPLC Method A to afford 14.9mg of the title compound.
LCMS (Method A): RT 1.46 min (100% area), ES m/z 494.203 [M+H] +.
Example 27
5-Ethyl-2-fluoro-4-{3-r5-(4-fluoro-benzylM.5,6,7-tetrahvdro-1 H-imidazor4,5-clDyridin-2-yll-1 Hindazol-
6-yl)-phenol
The title compound was prepared from 4-fluoro-benzaldehyde (25mg, 198mh o I) and 5-ethyl-2-
fluoro-4-[3-(4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl)-1 H-indazol-6-yl]-phenol
trihydrobromide salt (Preparation 25, 50mg, 132 mmol) using the method of Example 22. The
crude material was purified by HPLC Method A to afford 3.4mg of the title compound.
LCMS (Method A): RT 2.77 min (100% area), ES m/z 486.203 [M+H] +.
Example 28
5-Ethyl-2-fluoro-4-r3-(5 -ri ,8lnaDhthyridin-2-ylmethyl-4,5,6,7-tetrahvdro-1 H-imidazor
4,5-clpyridin-2-yl)-1 H-indazol-6-yll-phenol
The title compound was prepared from [ 1 ,8]naphthyridine-2-carbaldehyde (31 mg, 198mh o I)
and 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl)-1 H-indazol-6-yl]-
phenol trihydrobromide salt (Preparation 25, 50mg, 132mh o I) using the method of Example 22.
The crude material was purified by HPLC Method B to afford 22.5mg of the title compound.
LCMS (Method B): RT 2.28 min (100% area), ES m/z 520.218 [M+H] +.
Example 29
(2-{6-r5-Fluoro-4-hvdroxy-2-(2,2,2-trifluoro-ethyl)-phenyll-1 H-indazol-3-yl)-1 ,4,6,7-tetrahvdroimidazo[
4,5-clpyridin-5-yl)-(5-piperidin-1-yl-pyrazin-2-yl)-methanone diethylamine salt
The title compound was prepared from 5-piperidin-1-yl-pyrazine-2-carboxylic acid (Preparation
44, 35mg, 168mhΊ q I) and 2-fluoro-4-[3-(4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl)-1 Hindazol-
6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol (Preparation 39, 100mg, 168 mh o I) using the method
of Example 8. The crude material was purified by HPLC Method A to afford 29.0mg of the title
compound as the diethylamine salt.
LCMS (Method B): RT 2.66 min (100% area), ES m/z 621 .227 [M+H] +.
Example 30
(2- 6-r5-Fluoro-4-hvdroxy-2-(2,2,2-trifluoro-ethyl)-phenyll-1 H-indazol-3-yl)-1 ,4,6,7-tetrahvdroimidazo[
4,5-clpyridin-5-yl)-(4-fluoro-phenyl)-methanone diethylamine salt
The title compound was prepared from 4-fluoro-benzoic acid (24mg, 168mh o I) and 2-fluoro-4-
[3-(4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl)-1 H-indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-
phenol (Preparation 39, 100mg, 168 mh o I) using the method of Example 8. The crude material
was purified by HPLC Method A to afford 33.3mg of the title compound.
LCMS (Method B): RT 2.62 min (100% area), ES m/z 554.154 [M+H] +.
Example 3 1
4-r3-(5-Benzyl-4,5,6,7-tetrahvdro-1 H-imidazor4,5 -clDyridin-2-vn-1 H-indazol-6-yll-2-fluoro-5-
(2,2,2-trifluoro-ethyl)-phenol diethylamine salt
To a solution of 2-fluoro-4-[3-(4,5,6J-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl)-1 H-indazol-6-yl]-
5-(2,2,2-trifluoro-ethyl)-phenol (Preparation 39, 100mg, 168mhΊ q I) in DMF (1mL), was added
benzyl bromide (28.8mg, 20m I , 168mhΊ q I) , and DIPEA (120 m , 672mhΊ q I) . The reaction mixture
was heated at 80°C for 3 hours. The reaction mixture was then cooled to room temperature and
saturated aqueous sodium hydrogen carbonate solution (5ml_) was added. The resulting solid
was collected by filtration and washed with further saturated aqueous sodium hydrogen
carbonate solution. The crude material was purified by HPLC Method A to afford 10.6mg of the
title compound.
LCMS (Method A): RT 2.67 min (100% area), ES m/z 522.184 [M+H] +.
Example 32
{5-[(2-Dimethylamino-ethyl)-methyl-aminol-pyrazin-2-ylH2-[6-(2-ethyl-5-fluoro-4-hvdroxyphenyl)-
1 H-indazol-3-yll-1 ,4,6,7-tetrahydro-imidazo[4,5-clpyridin-5-yl)-methanone
To a solution of (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1 H-indazol-3-yl)-
6,7-dihydro-1 H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (80mg, 0.154mmol) in DMSO ( 1 ml_)
were added DIPEA (0.08ml_, 0.463mmol) and N,N,N-trimethylethylendiamine (31 .56mg,
0.308mmol) and the mixture stirred at room temperature for 18 hours. The crude reaction mass
was purified by prep-HPLC Method C to afford the title compound as an off white solid (25 mg,
28 %).
1H NMR (400 MHz, DMSO) d (ppm): .01 (t, 3H), 2.18(s, 6H), 2.44(m, 4H), 2.78(bs, 2H), 3.13(s,
3H), 3.70(t, 3H), 3.94(bs, 2H), 4.66-4.76(m, 2H), 6.90(d, 1H), 7.00(d, 1H), 7.09(d, 1H), 7.37(s,
1H), 8.12(s, 1H), 8.31(d, 1H), 8.38(d, 1H), 12.51(s, 1H), 13.21 (s, 1H);
LCMS: Rt = 2.59 min; m/z 584[M+H]+
Example 33
{2-r6-(2-Ethyl-5-fluoro-4-hvdroxy-Dhenvn-1 H-indazol-3-yll-1 ,4,6,7-tetrahvdro-imidazor4,5-
clpyridin-5-yl)-r5-(2-pyrrolidin-1-yl-ethylamino)-pyrazin-2-yll-methanone
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-
hydroxyphenyl)-1 H-indazol-3-yl)-6,7-dihydro-1 H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (50
mg, 96mmol) and (2-(pyrrolidin-1-yl)ethanamine, 50mg, 132 mmol) using the method of Example
32. The crude material was purified by HPLC Method E to afford (30 mg, 52%) of the title
compound.
1H NMR (400 MHz, DMSO) d (r r ) : 0.98-1 .01(t, 3H), 1.13(s, 3H), 1.22(bs, 2H), 1.68(bs, 3H),
1.90(s, 1H), 2.1 1(s, 1H), 2.60(t, 2H), 2.78(bs, 3H), 3.42(m, 2H), 3.91 (bs, 2H), 4.64-4.68(m, 2H),
6.90(d, 1H), 7.00(d, 1H), 7.08(d, 1H), 7.36(s, 1H), 7.60(bs, 1H), 7.95(s, 1H), 8.29-8.33(m, 2H),
9.80(bs, 1H), 12.52(s, 1H), 13.22(s, 1H);
LCMS: Rt = 5.71 min; m/z 596.4[M+H]+.
Example 34
[5-(2-Dimethylamino-ethylamino)-pyrazin-2-yll-{2-[6-(2-ethyl-5-fluoro-4-hvdroxy-phenyl)-1 Hindazol-
3-yll-1 ,4,6,7-tetrahvdro-imidazo[4,5-clpyridin-5-yl)-methanone
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-
hydroxyphenyl)-1 H-indazol-3-yl)-6,7-dihydro-1 H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone ( 100
mg, 193mmol) and N,N-dimethylethylendiamine, (34 mg, 386 mhhoI ) using the method of
Example 32. The crude material was purified by HPLC Method E to afford (50 mg, 46%) of the
title compound as white solid.
1H NMR (400 MHz, DMSO) 5(ppm): 1.03(t, 3H), 2.1 8(s, 6H), 2.40-2.45(m, 4H), 2.77(bs, 2H),
2.93-2.98(m, H), 3.16(s, 3H), 3.38-3.44(m, 2H), 3.78(m, 2H), 4.66(m, 2H), 6.90(d, 1H), 6.99(d,
1H), 7.09(d, 1H), 7.37(s, 1H), 7.53(bs, 1H), 7.96(s, 1H), 8.29(s, 2H):
LCMS: Rt = 2.53 min; m/z 570[M+H]+.
Example 35
r5-(4-Dimethylamino-piperidin-1-yl)-pyrazin-2-ylH2-r6-(2-ethyl-5-fluoro-4-hvdroxy-phenyl)-1 Hindazol-
3-yll-1 ,4,6,7-tetrahydro-imidazor4,5-clpyridin-5-yl)-methanone
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-
hydroxyphenyl)-1 H-indazol-3-yl)-6,7-dihydro-1 H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (80
mg, 154 mhhoI ) and 4-N,N-dimethylaminopiperidine, (40 mg, 308 mhhoI ) using the method of
Example 32. The crude material was purified by HPLC Method C to afford (60mg , 64%) of the
title compound as off-white solid.
1H NMR (400 MHz, DMSO) d (ppm): .01 (t, 3H), 1.39-1 .41 (m, 2H), 1.83-1 .86(m, 2H), 2.18(s,
6H), 2.32-2.38(m, 2H), 2.78(bs, 2H), 2.95-3.01 (t, 2H), 3.90(s, 2H), 3.92-3.94(m, 2H), 4.42-
4.45(m, 2H), 4.67-4.75(m, 2H), 6.87(d, 1H), 6.92(d, 1H), 7.03(bs, 1H), 7.37(s, 1H), 8.33-8.39(m,
3H), 12.50(bs, 1H), 13.22(bs, 1H);
LCMS: Rt = 5.46 min; m/z 610.4[M+H]+
Example 36
{2-r6-(2-Ethyl-5-fluoro-4-hvdroxy-phenylV1 Hclpyridin-
5-ylH5-rethyl-(2-hvdroxy-ethyl)-aminol-pyrazin-2-yl)-methan
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-
hydroxyphenyl)-1 H-indazol-3-yl)-6,7-dihydro-1 H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (120
mg, 231 m mol) and N-ethylaminoethanol, (41 mg, 463 mmol) using the method of Example 32.
The crude material was purified by HPLC Method D to afford (60mg, 64%) of the title compound
as off-white solid.
1H NMR (400 MHz, DMSO) d (ppm): 0.99-1 .03(t, 3H), 1.13-1 .16(t, 3H), 2.32-2.41 (m, 2H),
2.78(bs, 2H), 2.94-2.97(m„ 1H), 3.61 (bs, 5H), 3.94(m, 2H), 4.65-4.86(m, 3H), 6.90(d, 1H),
7.00(d, 1H), 7.09(bs, 1H), 7.36(s, 1H), 8.14(s, 1H), 8.31-8.38(m, 2H), 9.82(bs, 1H), 12.51 (bs,
1H), 13.20(bs, 1H);
LCMS: Rt = 2.69 min; m/z 571 .4[M+H]+.
Example 37
[5-((R)-3-Dimethylamino-pyrrolidin-1-yl)-pyrazin-2-yll-{2-[6-(2-ethyl-5-fluoro-4-hvdroxy-phenyl)-
1H-indazol-3-yll-1 ,4,6,7-tetrahydro-imidazo[4,5-clpyridin-5-yl)-methanone
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-
hydroxyphenyl)-1 H-indazol-3-yl)-6,7-dihydro-1 H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (80
mg, 154 mhhoI ) and (R)-3-dimethylaminopyrrolidine, (35 mg, 308 mmol) using the method of
Example 32. The crude material was purified by HPLC Method C to afford (35 mg, 38%) of the
title compound as white solid.
1H NMR (400 MHz, DMSO) d (ppm): 1.03(t, 3H), 1.75(m, 2H), 2.21 (s, 6H), 2.79-2.81 (m, 3H),
3.20(m, 2H), 3.41-3.47(m, 2H), 3.71(m, 1H), 3.77-3.81(m, 1H), 3.92(bs, 2H), 4.66-4.74(m, 2H),
6.90(d, 1H), 7.00(d, 1H), 7.09(d, 1H), 7.37(s, 1H), 7.98(s, 1H), 8.31(d, 1H), 8.39(m, 1H),
12.50(s, 1H), 13.21(s, 1H);
LCMS: Rt = 2.61 min; m/z 596.4[M+H]+.
Example 38
[5-((S)-3-Dimethylamino-pyrrolidin-1-yl)-pyrazin-2-yll-{2-[6-(2-ethyl-5-fluoro-4-hvdroxy-phenyl)-
1H-indazol-3-yll-l ,4,6,7-tetrahydro-imidazor4,5-clpyridin-5-yl)-methanone
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-
hydroxyphenyl)-1 H-indazol-3-yl)-6,7-dihydro-1 H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (80
mg, 154 mhhoI ) and (S)-3-dimethylaminopyrrolidine, (35 mg, 308 mhhoI ) using the method of
Example 32. The crude material was purified by HPLC Method C to afford (38 mg, 40%) of the
title compound as off-white solid.
1H NMR (400 MHz, DMSO) d (ppm): 1.03(t, 3H), 1.75-1 .83(m, 2H), 2.21 (s, 6H), 2.79-2.81 (m,
3H), 3.18-3.23(m, 2H), 3.43-3.45(m, 2H), 3.69-3.77(m, 1H), 3.79-3.81 (m, 1H), 3.90(bs, 2H),
4.66(m, 2H), 6.90(d, 1H), 7.00(d, 1H), 7.09(d, 1H), 7.37(s, 1H), 7.98(s, 1H), 8.32(m, 1H),
8.39(m, 1H), 12.51 (s, 1H), 13.22(s, 1H);
LCMS: Rt = 2.61 min; m/z 596.4[M+H]+.
Example 39
2- 6-(2-Ethyl-5-fluoro-4-hvdroxy-phenyl)-1 H-indazol-3-yll-1
5-yl)-[5-(2-piperidin-1-yl-ethylarriino)-pyrazin-2-yll-methanone
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-
hydroxyphenyl)-1 H-indazol-3-yl)-6,7-dihydro-1 H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (120
mg, 231 mhhoI ) and(2-(piperidine-1-yl)ethanamine, (59 mg, 463 mhhoI ) using the method of
Example 32. The crude material was purified by HPLC Method G to afford (38 mg, 27%) of the
title compound as off-white solid.
1H NMR (400 MHz, DMSO) d (ppm): 1.09 (t, 3H), 1.39 (Brs, 2H), 1.39-1 .50 (m, 3H), 2.32 (m,
3H), 2.43-2.54 (m, 4H), 2.77 (Brs, 2H), 3.33-3.42 (m, 2H), 3.90 (Brs, 2H), 4.68 (m, 2H), 6.90-
6.92 (d, 1H), 7.00-7.03 (d, 1H), 7.09 (m, 1H), 7.37 (s, 1H), 7.48 (s, 1H) 7.94 (s, 1H), 8.29-8.32
(s, 2H),;
LCMS: Rt = 2.64 min; m/z 610.2 [M+H]+.
Example 40
{2-r6-(2-Ethyl-5-fluoro-4-hvdroxy-phenyl)-1 H-indazol-3-yll-1 ,4,6,7-tetrahvdro-imidazor4,5-
clpyridin-5-yl)-[5-(2-piperazin-1-yl-ethylamino)-pyrazin-2-yll-methanone
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-
hydroxyphenyl)-1 H-indazol-3-yl)-6,7-dihydro-1 H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (80
mg, 154 mhhoI ) and (2-(piperazinyl-1-yl)ethanamine, (40 mg, 309 mhhoI ) using the method of
Example 32. The crude material was purified by HPLC Method D to afford (26 mg, 28%) of the
title compound as off-white solid.
1H NMR (400 MHz, DMSO) d (ppm): 0.97-1 .00 (t, 3H), 1.20 (s, 2H), 2.40-2.43 (m, 2H), 2.50 (s,
2H), 2.76 (Brs, 2H), 3.51-3.54 (d, 2H), 3.64 (Brs, 4H), 3.87-3.93 (d, 2H), 4.41-4.42 (m, 1H),
4.64-4.68 (d, 2H) 6.87-6.89 (d, 1H), 6.97-7.08 (m, 2H), 7.34 (s, 1H), 8.29 (s, 2H), 8.37 (s, 1H),
9.79 (s, 1H), 12.48 (s, 1H), 13.17 (s, 1H);
LCMS: Rt = 2.59 min; m/z 612.4 [M+H]+.
Example 4 1
{2-r6-(2-Ethyl-5-fluoro-4-hvdroxy-phenvn-1 H-indazol-3-yll-1 ,4,6,7-tetrahvdro-imidazor4,5-
lPyridin-5-yl)-(4-methyl-3,4,5,6-tetrahvdro-2H- i ,2'lbipyrazinyl-5'-yl)-methanone
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-
hydroxyphenyl)-1 H-indazol-3-yl)-6,7-dihydro-1 H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (80
mg, 154 mhhoI ) and 1-methyl-piperazine, (31 mg, 309 mhhoI ) using the method of Example 32.
The crude material was purified by HPLC Method D to afford (21 mg, 23%) of the title
compound as off-white solid.
1H NMR (400 MHz, DMSO) d (ppm): 0.90-1 .03 (m, 6H), 2.22 (s, 3H), 2.40-2.49 (m, 4H), 2.78
(Brs, 2H), 3.67 (s, 3H), 3.88 (m, 2H), 4.66 (m, 2H), 6.90-6.92 (d, 1H), 7.00-7.03 (d, 2H), 7.37(s,
1H) 8.32 (s, 3H), 9.82 (s, 1H), 12.50 (s, 1H), 13.20 (s, 1H);
LCMS: Rt = 2.63min; m/z 582.6 [M+H]+.
Example 42
{2-r6-(2-Ethyl-5-fluoro-4-hvdroxy-phenyl)-1 H-indazol-3-yll-1 ,4,6,7-tetrahvdro-imidazor4,5-
clpyridin-5-yl)-(5-morpholin-4-yl-pyrazin-2-yl)-methanone
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-
hydroxyphenyl)-1 H-indazol-3-yl)-6,7-dihydro-1 H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone ( 100
mg, 154 mhhoI ) and morpholine, (34 mg, 386 mhhoI) using the method of Example 32. The crude
material was purified by HPLC Method F to afford (42 mg, 38%) of the title compound as offwhite
solid.
1H NMR (400 MHz, DMSO) d (ppm): 0.99-1 .03(t, 3H), 2.78 (Brs, 2H), 3.65-3.72(q, 8H), 3.88 (d,
2H), 4.67-4.77(m, 2H), 6.90 (d, 1H), 2H) 7.00-7.1 1 (m, 2H), 7.37 (s, 1H), 8.26 (s, 2H), 8.42 (s,
1H), 12.50 (s, 1H), 13.20 (s, 1H);
LCMS: Rt = 3.23 min; m/z 569.4 [M+H]+.
Example 43
{2-r6-(2-Ethyl-5-fluoro-4-hvdroxy-phenyl)-1 H-indazol-3-yll-1 ,4,6,7-tetrahvdro-idazor4,5clpyridin-
5-yl)-r5-(4-methyl-piperidin-1-yl)-pyrazin-2-yll-methanone
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-
hydroxyphenyl)-1 H-indazol-3-yl)-6,7-dihydro-1 H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone ( 100
mg, 154 mhhoI ) and 4-methyl-piperidine, (38 mg, 386 mhhoI ) using the method of Example 32.
The crude material was purified by HPLC Method F to afford (34 mg, 30%) of the title compound
as off-white solid.
1H NMR (400 MHz, DMSO) d (ppm): 0.92-0.93 (d, 3H), 0.99-1 .03 (t, 3H), 1.10-1 .16 (m, 2H),
1.69-1 .75 (m, 3H), 1.85 (s, 1H), 2.78 (Brs, 2H), 2.91-2.98 (t, 2H), 3.93 (Brs, 2H), 4.42-4.45 (d,
2H), 4.66-4.75 (m, 2H) 6.90-6.92 (d, 1H), 7.00-7.03 (d, 2H), 7.37 (s, 1H), 8.31-8.39 (m, 3H),
12.51 (s, 1H), 13.21 (s, 1H);
LCMS: Rt = 3.1 1 min; m/z 581 .4 [M+H]+.
Example 44
(5-Cvclopentylamino-pyrazin-2-ylH2-r6-(2-ethyl-5-fluoro-4-hvdroxy-phenyl)-1 H-in
1,4,6,7-tetrahvdro-imidazor4,5-clpyridin-5-yl)-methanone
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-
hydroxyphenyl)-1 H-indazol-3-yl)-6,7-dihydro-1 H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone
(90mg, 173 mmol) and cylopenylamine, (30mg, 347 m mol) using the method of Example 32.
The crude material was purified by HPLC Method G to afford (28 mg, 28%) of the title
compound as off-white solid.
1H NMR (400 MHz, DMSO) d (ppm): 1.03 (t, 3H), 1.45-1 .51 (m, 2H), 1.56-1 .57 (m, 2H), 1.69
(m, 2H), 1.93-1 .95 (m, 2H), 2.53 (m, 1H), 2.78 (Brs, 2H), 3.16 (s, 1H), 3.91 (Brs, 2H), 4.14-4.19
(m 1H), 4.64 (m ,2H), 6.90-6.92 (d, 1H), 7.00-7.03 (d, 1H), 7.09 (d, 1H), 7.37 (s, 1H), 7.62 (s,
1H) 7.88(s, 1H), 8.29 (s, 2H),;
LCMS: Rt = 2.98 min; m/z 567.6 [M+H]+.
Example 45
{2-r6-(2-Ethyl-5-fluoro-4-hvdroxy-phenyl)-1 H-indazol-3-yll-1 ,4,6,7-tetrahvdro-imidazor4,5-
clpyridin-5-yl)-[5-(2-morpholin-4-yl-ethylamino)-pyrazin-2-yll-methanone
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-
hydroxyphenyl)-1 H-indazol-3-yl)-6,7-dihydro-1 H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone
(100mg, 193 mhhoI ) and 2-morpholin-4-yl-ethylamine, (30mg, 347 mhhoI ) using the method of
Example 32. The crude material was purified by HPLC Method F to afford (28 mg, 28%) of the
title compound as off-white solid.
1H NMR (400 MHz, DMSO) d (ppm): 0.99-1 .03(t, 3H), 2.49-2.57 (m, 2H), 2.77(Brs, 2H), 3.16 (s,
2H), 3.32 (s, 3H), 3.56-3.58 (m, 2H), 2H) 3.90 (m,2H) 4.69 (m,2H) 6.90-6.92 (d, 1H), 7.00-7.03
(d, 1H), 7.09 (m, 1H), 7.37 (s, 1H), 7.53 (Brs, 1H), 7.95 (s, 1H), 8.29 (s,2H);
LCMS: Rt = 5.89 min; m/z 612.4 [M+H]+.
Example 46
{2-r6-(2-Ethyl-5-fluoro-4-hvdroxy-phenyl)-1 H-indazol-3-yll-1 ,4,6,7-tetrahvdro-imidazor4,5-
clpyridin-5-yl)-(4-isopropyl-3,4,5,6-tetrahvdro-2H-[1 ,2'lbipyrazinyl-5'-yl)-methanone
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-
hydroxyphenyl)-1 H-indazol-3-yl)-6,7-dihydro-1 H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (80
mg, 154 mhhoI ) andl-isopropyl-piperazine, (40mg, 308 m h o I) using the method of Example 32.
The crude material was purified by HPLC Method D to afford (18 mg, 19%) of the title
compound as off-white solid.
1H NMR (400 MHz, DMSO) d (ppm): 0.95-1 .03(m, 9H), 2.53(m, 4H), 2.68-2.78(m, 3H), 3.65(s,
4H), 3.89-3.95(m, 2H), 4.70(m, 2H), 6.90(d, 1H), 7.00(d, 1H), 7.09(d, 1H), 7.37(s, 1H), 8.31 (m,
2H), 8.39(d, 1H), 9.82(bs, 1H), 12.51 (s, 1H), 13.20(s, 1H);
LCMS: Rt = 6.52 min; m/z 610.4[M+H]+.
Example 47
{2-r6-(2-Ethyl-5-fluoro-4-hvdroxy-phenyl^
clpyridin-5-yl)-(5-pyrrolidin-1-yl-pyrazin-2-yl)-methanone
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-
hydroxyphenyl)-1 H-indazol-3-yl)-6,7-dihydro-1 H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (80
mg, 154 mhhoI ) and pyrrolidine (22 mg, 308mh o I) using the method of Example 32. The crude
material was purified by HPLC Method D to afford (18 mg, 19%) of the title compound as offwhite
solid.
1H NMR (400 MHz, DMSO) d (ppm): 1.01 (t, 3H), 1.97(bs, 4H), 2.78(bs, 2H), 3.50(s, 4H),
3.93(bs, 2H), 4.65-4.76(m, 2H), 6.90(d, 1H), 7.00(d, 1H), 7.08(d, 1H), 7.36(s, 1H), 7.96(s, 1H),
8.31 (d, 1H), 8.39(s, 1H), 9.86(bs, 1H), 12.52(s, 1H), 13.22(s, 1H);
LCMS: Rt = 2.85min; m/z 553.4[M+H]+.
Example 48
{2-r6-(2-Ethyl-5-fluoro-4-hvdroxy-phenyl)-1 H-indazol-3-yll-1 ,4,6,7-tetrahvdro-imidazor4,5-
lPVridin-5-yl)-[5-(ethyl-methyl-amino)-pyrazin-2-yll-methanon
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-
hydroxyphenyl)-1 H-indazol-3-yl)-6,7-dihydro-1 H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (80
mg, 154 mhhoI ) and ethyl-methylamine (18 mg, 308 mmol) using the method of Example 32. The
crude material was purified by HPLC Method E to afford (38 mg, 46%) of the title compound as
off-white solid.
1H NMR (400 MHz, DMSO) d (ppm): 1.01(t, 3H), 1. 12(t, 3H), 2.78(m, 2H), 3.1 1(s, 3H), 3.65(m,
2H), 3.93(m, 2H), 4.76(m, 2H), 6.90(d, 1H), 7.00(d, 1H), 7.09(d, 1H), 7.37(s, 1H), 8.13(s, 1H),
8.31 (m, 1H), 8.39(s, 1H), 9.84(bs, 1H), 12.51 (s, 1H), 13.22(s, 1H);
LCMS: Rt = 2.85 min; m/z 541 .6[M+H]+.
Example 49
(5-Cvclohexylamino-pyrazin-2-ylH2-r6-(2-ethyl-5-fluoro-4-hvdroxy-phenyl)-1 H-indazol-3-yll-
1,4,6,7-tetrahvdro-imidazor4,5-clpyridin-5-yl)-methanone
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-
hydroxyphenyl)-1 H-indazol-3-yl)-6,7-dihydro-1 H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (126
mg, 243 mhhoI ) and cyclohexylamine (48 mg,487 mmol) using the method of Example 32. The
crude material was purified by HPLC Method D to afford (29 mg, 20%) of the title compound as
off-white solid.
1H NMR (400 MHz, DMSO) d (ppm): 0.99-1 .04(m, 3H), 1.18-1 .35(m, 6H), 1.62-1 .84(m, 6H),
1.90-1 .93(m, 1H), 2.78(m, 2H), 3.32(m, 1H), 3.76-3.91 (m, 2H), 4.66-4.72(m, 2H), 6.90(d, 1H),
7.00(d, 1H), 7.09(d, 1H), 7.37(s, 1H), 7.51(bs, 1H), 7.88(s, 1H), 8.23(s, 1H), 12.50(bs, 1H),
13.22(bs, 1H);
LCMS: Rt = 3.06 min; m/z 581 .6[M+H]+.
Example 50
(5-Dimethylamino-pyrazin-2-ylH2-[6-(2-ethyl-5-fluoro-4-hvdroxy-phenyl)-1 H-indazol-3- n P- ,4,6,7-
tetrahydro-imidazo[4,5-clpyridin-5-yl)-methanone
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-
hydroxyphenyl)-1 H-indazol-3-yl)-6,7-dihydro-1 H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone
(80mg, 154 mhhoI ) and dimethylamine HCI (25 mg, 308 mhhoI ) using the method of Example 32.
The crude material was purified by HPLC Method D to afford (17 mg, 21%) of the title
compound as off-white solid.
1H NMR (400 MHz, DMSO) d (ppm): .01 (t, 3H), 2.79(m, 2H), 3.15(s, 6H), 3.93(m, 2H),
4.70(m, 2H), 6.90(d, 1H), 7.00(d, 1H), 7.01(d, 1H), 7.09(d, 1H), 7.37(s, 1H), 8.15(s, 1H),
8.31 (m, 1H), 8.40(s, 1H), 9.84(bs, 1H), 12.51(s, 1H), 13.20(s, 1H);
LCMS: Rt = 2.81 min; m/z 527.4[M+H]+.
Example 5 1
(5-Azetidin-1-yl-Dyrazin-2-ylH2-r6-(2-ethyl-5-fluoro-4-hvdroxy-Dhenvn-1 H-indazol-3-yll-1 ,4,6,7-
tetrahvdro-imidazor4,5-clpyridin-5-yl)-methanone
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-
hydroxyphenyl)-1 H-indazol-3-yl)-6,7-dihydro-1 H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone
(80mg, 154 mhhoI ) and azetdine HCI (29 mg, 308 mhhoI ) using the method of Example 32. The
crude material was purified by HPLC Method D to afford (19 mg, 23%) of the title compound as
off-white solid.
1H NMR (400 MHz, DMSO) d (ppm): 1.03(t, 3H), 2.43-2.49(m, 2H), 2.78(bs, 2H), 3.37(m, 2H),
3.87-3.95(m, 2H), 4.13(t, 4H), 4.65-4.70(m, 2H), 6.90(d, 1H), 7.00(d, 1H), 7.09(d, 1H), 7.37(s,
1H), 7.83(s, 1H), 8.33-8.37(m, 2H), 9.84(bs, 1H), 12.52(s, 1H), 13.21(s, 1H);
LCMS: Rt = 2.78 min; m/z 539.4[M+H]+.
Example 52
2-Fluoro-4-{3-[5-(4-fluoro-benzyl)-4,5,6,7-tetrahvdro-1 H-imidazo[4,5-clpyridin-2-yll-1 H-indazol-6-
yl)-5-(2,2,2-trifluoro-ethyl)-phenol
To a solution of 2-fluoro-4-[3-(4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl)-1 H-indazol-6-yl]-
5-(2,2,2-trifluoro-ethyl)-phenol (Preparation 39, 100 mg, 0.21 mmol) and KOAc (22.75 mg, 0.23
mmol) in MeOH (1ml_), 4-fluorobenzaldehyde (57.54 mg, 0.46 mmol) was added and the
mixture stirred at room temperature for 1 hr followed by portionwise addition of sodium
triacetoxy borohydride (162.12 mg, 0.76 mmol) over 2hrs. The mixture was thereafter stirred at
room temperature for 18 hrs. The reaction mixture was concentrated and the residue partitioned
between saturated sodium bicarbonate solution & ethyl acetate. The organic phase was dried
over sodium sulphate, evaporated in vacuo, purified initially over silica and finally by Prep TLC
(Mobile Phase: 10% MeOH-DCM) to afford the title compound as a light yellow solid in 30.35 %
yield, 35 mg.
1H NMR (400 MHz, DMSO) d (ppm): 2.66(m, 2H), 2.76-2.80(m, 2H), 3.44-3.56(m, 4H), 3.71 (s,
2H), 7.07-7.10(m, 2H), 7.13-7.19(m, 2H), 7.36(s, 1H), 7.41-7.43(m, 2H), 8.29-8.36(m, 1H),
10.13(s, 1H), 12.21-12.34(m, 1H), 13.19(s, 1H);
LCMS: Rt = 3.17 min; m/z 540.4 [M+H]+
Example 53
2-Fluoro-4-{3 -r5-(3,4,5,6-tetrahvdro-2H -ri ,2'lbipyridinyl-5'-ylmethyl)-4,5,6,7-tetrahvdro-1 Himidazo[
4,5-clpyridin-2-yll-1 H-indazol-6-yl)-5-(2,2,2-trifluoro-ethyl)-phenol
The title compound was prepared from 2-fluoro-4-[3-(4,5,6,7-tetrahydro-1 H-imidazo[4,5-
c]pyridin-2-yl)-1 H-indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol (100 mg, 0.21 mmol) and 3,4,5,6-
tetrahydro-2H-[1 ,2']bipyridinyl-5'-carbaldehyde (88.2 mg, 0.46 mmol) using the method of
Example 5 1. The crude material was purified initially over silica and finally by Prep TLC (Mobile
Phase: 10% MeOH-DCM) to afford the title compound as an off white solid in 16.99 % yield, 22
mg.
1H NMR (400 MHz, DMSO) d (ppm): 1.53(m, 6H), 2.64(m, 2H), 2.73-2.77(m, 2H), 3.41-3.57(m,
10H), 6.78(d, 1H), 7.02-7. 10(m, 2H), 7.14-7.17(m, 1H), 7.36(s, 1H), 7.48(d, 1H), 8.03(s, 1H),
8.30-8.35(m, 1H), 10.15(s, 1H), 12.22-12.34(m, 1H), 13.20(s, 1H);
LCMS: Rt = 3.17 min; m/z 606.2 [M+H]+
Example 54
2-Fluoro-4-{3-[5-(6-phenoxy-pyridin-3-ylmethyl)-4,5,6,7-tetrahvdro-1 H-imidazo[4,5-clpyridin-2-
yll-H-indazol-6-ylV5-(2,2,2-trifluoro-ethylVphenol
The title compound was prepared from 2-fluoro-4-[3-(4,5,6,7-tetrahydro-1 H-imidazo[4,5-
c]pyridin-2-yl)-1 H-indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol (100 mg, 0.21 mmol) and 6-
phenoxy-pyridine-3-carbaldehyde (92.3 mg, 0.46 mmol) using the method of Example 5 1. The
crude material was purified initially over silica and finally by Prep TLC (Mobile Phase: 10%
MeOH-DCM) to afford the title compound as an off white solid in 23.6 % yield, 3 1 mg.
1H NMR (400 MHz, DMSO) d (ppm): 2.67(m, 2H), 2.77(m, 2H), 3.45-3.56(m, 4H), 3.70(s, 2H),
6.78(d, 1H), 7.00-7.22(m, 6H), 7.36(s, 1H), 7.39-7.43(t, 2H), 7.84(d, 1H), 8.1 1(s, 1H), 8.30-
8.35(m, 1H), 10.15(s, 1H), 12.24-12.36(m, 1H), 13.21(s, 1H);
LCMS: Rt = 3.20 min; m/z 615.4 [M+H]+
Example 55
2-Fluoro-4-{3-[5-(4-methoxy-benzyl)-4,5,6,7-tetrahvdro-1 H-imidazo[4,5-clpyridin-2-yll-1 H
indazol-6-yl)-5-(2,2,2-trifluoro-ethyl)-phenol
The title compound was prepared from 2-fluoro-4-[3-(4,5,6,7-tetrahydro-1 H-imidazo[4,5-
c]pyridin-2-yl)-1 H-indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol (100 mg, 0.21 mmol) and 4-
methoxybenzaldehyde (63.1 mg, 0.46 mmol) using the method of Example 5 1. The crude
material was purified initially over silica and finally by Prep TLC (Mobile Phase: 10% MeOHDCM)
to afford the title compound as an off white solid in 22.1 % yield, 26 mg.
1H NMR (400 MHz, DMSO) d (ppm): 2.65(m, 2H), 2.73-2.79(m, 2H), 3.37-3.47(m, 2H), 3.50-
3.56(m, 2H), 3.64(s, 2H), 3.75(s, 3H), 6.90-6.92(m, 2H), 7.02-7.10(m, 2H), 7.13-7.16(m, 1H),
7.27-7.29(m, 2H), 7.36(s, 1H), 8.29-8.36(m, 1H), 10.13(s, 1H), 12.20-12.35(m, 1H), 13.19(s,
1H);
LCMS: Rt = 3.15 min; m/z 552.2 [M+H]+
Example 56
2-Fluoro-4-{3-r5-(4-hvdroxy-benzyl)-4,5,6,7-tetrahvdro-1 H-imidazor4,5-clpyridin-2-yll-1 Hindazol-
6-yl)-5-(2,2,2-trifluoro-ethyl)-phenol
The title compound was prepared from 2-fluoro-4-[3-(4,5,6,7-tetrahydro-1 H-imidazo[4,5-
c]pyridin-2-yl)-1 H-indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol (100 mg, 0.21 mmol) and 4-
hydroxybenzaldehyde (56.6 mg, 0.46 mmol) using the method of Example 5 1. The crude
material was purified initially over silica and finally by Prep TLC (Mobile Phase: 10% MeOHDCM)
to afford the title compound as an off white solid in 24.4 % yield, 28 mg.
1H NMR (400 MHz, DMSO) d (ppm): 2.66(m, 2H), 2.73-2.78(m, 2H), 3.40-3.43(m, 2H), 3.47-
3.56(m, 2H), 3.59(s, 2H), 6.72-6.74(d, 2H), 7.02-7.10(m, 2H), 7.14-7.18(m, 3H), 7.36(s, 1H),
8.29-8.36(m, 1H), 9.27(s, 1H), 10.13(s, 1H), 12.20-12.32(m, 1H), 13.19(s, 1H);
LCMS: Rt = 2.86 min; m/z 538.2 [M+H]+
Example 57
2-Fluoro-4-{3-[5-(3-methoxy-benzyl)-4,5,6,7-tetrahvdro-1 H-imidazo[4,5-clpyridin-2-yll-1 Hindazol-
6-yl)-5-(2,2,2-trifluoro-ethyl)-phenol
The title compound was prepared from 2-fluoro-4-[3-(4,5,6,7-tetrahydro-1 H-imidazo[4,5-
c]pyridin-2-yl)-1 H-indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol (100 mg, 0.21 mmol) and 3-
methoxybenzaldehyde (63.1 mg, 0.46 mmol) using the method of Example 5 1. The crude
material was purified initially over silica and finally by Prep TLC (Mobile Phase: 10% MeOHDCM)
to afford the title compound as an off white solid in 2 1.2 % yield, 25 mg.
1H NMR (400 MHz, DMSO) d (ppm): 2.66(m, 2H), 2.76-2.80(m, 2H), 3.45-3.56(m, 4H), 3.69(s,
2H), 3.75(s, 3H), 6.83-6.85(d, 1H), 6.94(m, 2H), 7.02-7.1 0(m, 2H), 7.14(d, 1H), 7.24-7.28(t, 1H),
7.36(s, 1H), 8.29-8.36(m, 1H), 10.15(s, 1H), 12.23-12.35(m, 1H), 13.20(s, 1H);
LCMS: Rt = 3.14 min; m/z 552 [M+H]+
Example 58
2-Fluoro-4-{3-r5-(3-hvdroxy-benzyl)-4,5,6,7-tetrahvdro-1 H-imidazor4,5-clpyridin-2-yll-1 Hindazol-
6-yl)-5-(2,2,2-trifluoro-ethyl)-phenol
The title compound was prepared from 2-fluoro-4-[3-(4,5,6,7-tetrahydro-1 H-imidazo[4,5-
c]pyridin-2-yl)-1 H-indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol (100 mg, 0.21 mmol) and 3-
hydroxybenzaldehyde (56.6 mg, 0.46 mmol) using the method of Example 5 1. The crude
material was purified initially over silica and finally by Prep TLC (Mobile Phase: 10% MeOHDCM)
to afford the title compound as an off white solid in 26.1 % yield, 30 mg.
1H NMR (400 MHz, DMSO) d (ppm): 2.66(m, 2H), 2.76-2.81 (m, 2H), 3.43-3.53(m, 4H), 3.63(s,
2H), 6.64-6.66(d, 1H), 6.76-6.81 (m, 2H), 7.02-7.1 6(m, 4H), 7.36(s, 1H), 8.30-8.32(m, 1H),
9.28(d, 1H), 10.13(s, 1H), 12.21-12.33(m, 1H), 13.19(s, 1H);
LCMS: Rt = 2.90 min; m/z 538.2 [M+H]+
Example 59
2-Fluoro-4-r3-(5-quinolin-6-ylmethyl-4,5,6,7-tetrahvdro-1 H-imidazor4,5-clpyridin-2-yl)-1 Hindazol-
6-yll-5-(2,2,2-trifluoro-ethyl)-phenol
The title compound was prepared from 2-fluoro-4-[3-(4,5,6,7-tetrahydro-1 H-imidazo[4,5-
c]pyridin-2-yl)-1 H-indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol (100 mg, 0.21 mmol) and
quinoline-6-carbaldehyde (72.9 mg, 0.46 mmol) using the method of Example 5 1. The crude
material was purified initially over silica and finally by Prep TLC (Mobile Phase: 10% MeOHDCM)
to afford the title compound as an off white solid in 22.9 % yield, 28 mg.
1H NMR (400 MHz, DMSO) d (ppm): 2.67(m, 2H), 2.83.2.89(m, 2H), 3.49-3.55(m, 4H), 3.93(s,
2H), 7.01-7.17(m, 3H), 7.36(s, 1H), 7.51 (m, 1H), 7.80(d, 1H), 7.95(s, 1H), 7.99(d, 1H), 8.29-
8.38(m, 2H), 8.87(d, 1H), 10.13(s, 1H), 12.21-12.33(m, 1H), 13.19(s, 1H);
LCMS: Rt = 2.90 min; m/z 573.6 [M+H]+
Example 60
2-Fluoro-4-[3-(5-quinolin-3-ylmethyl-4,5,6,7-tetrahvdro-1 H-imidazo[4,5-clpyridin-2-yl)-1 Hindazol-
6-yll-5-(2,2,2-trifluoro-ethyl)-phenol
The title compound was prepared from 2-fluoro-4-[3-(4,5,6,7-tetrahydro-1 H-imidazo[4,5-
c]pyridin-2-yl)-1 H-indazol-6-yl]-5-(2 2,2-trifluoro-ethyl)-phenol (100 mg, 0.21 mmol) and
quinoline-3-carbaldehyde (72.9 mg, 0.46 mmol) using the method of Example 5 1. The crude
material was purified initially over silica and finally by Prep TLC (Mobile Phase: 10% MeOHDCM)
to afford the title compound as an off white solid in 27.8 % yield, 34 mg.
1H NMR (400 MHz, DMSO) d (ppm): 2.67-2.70(m, 2H), 2.83.2.90(m, 2H), 3.47-3.58(m, 4H),
3.95(s, 2H), 7.01-7.1 7(m, 3H), 7.36(s, 1H), 7.59(t, 1H), 7.74(t, 1H), 8.02(t, 2H), 8.29-8.38(m,
2H), 8.93(d, 1H), 10.14(s, 1H), 12.23-12.36(m, 1H), 13.20(s, 1H);
LCMS: Rt = 2.97 min; m/z 573.6 [M+H]+
Example 6 1
2-Fluoro-4-[3-(5-[1 ,8lnaphthyridin-3-ylmethyl-4,5,6,7-tetrahvdro-1 H-imidazo[4,5-clpyridin-2-yl)-
1H-indazol-6-yll-5-(2,2,2-trifluoro-ethyl)-phenol
The title compound was prepared from 2-fluoro-4-[3-(4,5,6,7-tetrahydro-1 H-imidazo[4,5-
c]pyridin-2-yl)-1 H-indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol (100 mg, 0.21 mmol) and
[ 1 ,8]naphthyridine-3-carbaldehyde (146.1 mg, 0.92 mmol) using the method of Example 5 1. The
crude material was purified initially over silica and finally by Prep TLC (Mobile Phase: 10%
MeOH-DCM) to afford the title compound as an off white solid in 9.0 % yield, 22 mg.
1H NMR (400 MHz, DMSO) d (ppm): 2.72(m, 2H), 2.89.2.92(m, 2H), 3.50-3.54(m, 2H), 3.60-
3.63(m, 2H), 4.08(s, 2H), 7.02-7.17(m, 3H), 7.36(s, 1H), 7.61-7.64(m, 1H), 7.82-7.85(m, 1H),
8.29-8.38(m, 2H), 8.44-8.47(m, 2H), 9.06(m, 1H), 10.15(s, 1H), 12.26-12.39(m, 1H), 13.21(s,
1H);
LCMS: Rt = 2.86 min; m/z 574.2 [M+H]+
Example 62
((3R.5S)-3.5-Dimethyl-3.4.5.6-tetrahvdro-2H -ri .2'lbiDyrazinyl-5'-ylH2 -r6-(2-ethyl-5-fluoro-4-
hvdroxy-phenyl)-1 H-indazol-3-yll-1 ,4,6,7-tetrahydro-imidazor4,5-clpyridin-5-yl)-methanone
To a stirring solution of (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1 Hindazol-
3-yl)-6,7-dihydro-1 H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (150mg, 0.154mmol) in
DMSO ( 1.5mL) were added DIPEA (0.143mL, 0.87mmol) and (2R,6S)-2,6-Dimethyl-piperazine-
1-carboxylic acid tert-butyl ester (124mg, 0.58mmol) and the mixture stirred at room
temperature for 18 hours. The crude reaction mass was purified by prep-HPLC Method F to
afford (3R,5S)-5'-{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4,6,7-tetrahydroimidazo[
4,5-c]pyridine-5-carbonyl}-3,5-dimethyl-2,3,5,6-tetrahydro-[1 ,2']bipyrazinyl-4-carboxylic
acid tert-butyl ester as an off white solid (80 mg, 40 %).
LCMS: Rt = 3.18 min; m/z 696.6 [M+H]+.
To a stirring solution of (3R,5S)-5'-{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-
1,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carbonyl}-3,5-dimethyl-2,3,5,6-tetrahydro-
[ 1 ,2']bipyrazinyl-4-carboxylic acid tert-butyl ester (80mg, 0.1 14mmol) in dioxane (3ml_), 10%
dioxane-HCI (2mL) was added and the mixture stirred at RT for 18 hours. The reaction mass
was evaporated in vacuo and the resulting solid triturated with ether to afford the title compound
(HCI salt) as an off white solid (62mg 91%).
1H NMR (400 MHz, DMSO) : 1.06 (t, 3H), 1.22-1 .34 (s, 6H), 2.94 (Brs, 2H), 3.01-3.07 (t, 2H),
3.32 (Brs, 2H), 3.97 (m, 2H), 4.61-4.64 (d, 2H), 4.84 (s, 2H), 6.94 (d, 1H), 7.03 (d, 1H), 7.32 (s,
1H), 7.58 (s, 1H), 8.41-8.48 (m, 3H), 9.27 (m, 1H), 9.64 (m, 1H), 9.79 (s, 1H), 14.33 (s, 1H);
LCMS: Rt = 2.65 min; m/z 596.4 [M+H]+.
Example 63
{2-r6-(2-Ethyl-5-fluoro-4-hvdroxy-Dhenvn-1 H-indazol-3-yll-1 ,4,6,7-tetrahvdro-imidazor4,5-
clpyridin-5-yl)-((S)-3-methyl-3,4,5,6-tetrahvdro-2H - i ,2'lbipyrazinyl-5'-yl)-methanone
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-
hydroxyphenyl)-1 H-indazol-3-yl)-6,7-dihydro-1 H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (200
mg, 386 mh o I) and (S)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (155mg, 773 mhhoI )
using the method from Example 6 1. After purification by HPLC Method E and deprotection
using HCI/dioxan, the title compound (58 mg, 25% yield over two steps) was obtained as offwhite
solid (HCI-salt).
1H NMR (400 MHz, DMSO) : 0.82 (t, 3H), 1.23-1 .31 (s, 3H), 2.93 (Brs, 2H), 3.07-3.18 (m, 3H),
3.97 (Brs, 2H), 4.50-4.53 (d, 2H), 4.83 (s, 2H), 6.93-6.95 (d, 1H), 7.03-7.06 (d, 1H), 7.28- 7.30
(m, 1H), 7.57 (s, 1H), 8.37 (m, 1H), 8.44 (s, 1H), 8.49 (s, 1H), 9.24 (s, 1H), 9.40 (m, 1H), 9.94
(s, 1H), 14.25 (s, 1H);
LCMS: Rt = 2.61 min; m/z 582.4 [M+H]+.
Example 64
((2S,5R)-2,5-Dimethyl-3,4,5,6-tetrahvdro-2H -ri ,2'lbipyrazinyl-5'-ylH2 -r6-(2-ethyl-5-fluoro-4-
hydroxy-phenyl)-1 H-indazol-3-yll-1 ,4,6,7-tetrahvdro-imidazo[4,5-clpyridin-5-yl)-methanone
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-
hydroxyphenyl)-1 H-indazol-3-yl)-6,7-dihydro-1 H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone ( 100
mg, 193mh o I) and (2S,5R)-2,5-Dimethyl-piperazine-1-carboxylic acid tert-butyl ester (84mg,
386 mhhoI ) using the method from Example 6 1. After purification by HPLC Method E and
deprotection using HCI/dioxan, the title compound (43 mg, 37% yield over two steps) was
obtained as off-white solid (HCI-salt).
1H NMR (400 MHz, DMSO) : 0.82 (t, 3H), 1.33-1 .34 (m, 6H), 2.95 (Brs, 3H), 3.1 1-3.14 (d, 1H),
3.37 (s, 1H), 3.51-3.62 (m, 5H), 3.83 (Brs, 2H), 4.01 (m, 1H), 4.84 (m, 3H), 6.94-6.96 (d, 1H),
7.03-7.06 (d, 1H), 7.31 (Brs, 1H), 7.58 (s, 1H), 8.36 (s, 2H), 8.49 (s, 1H), 9.33 (m, 1H), 9.53 (s,
1H), 14.33 (s, 1H);
LCMS: Rt = 2.55 min; m/z 596.2 [M+H]+.
Example 65
{2-r6-(2-Ethyl-5-fluoro-4-hvdroxy-phenyl)-1 H-indazol-3-yll-1 ,4,6,7-tetrahvdro-imidazor4,5-
lPVridin-5-yl)-(3,4,5,6-tetrahvdro-2H-[1 ,2'lbipyrazinyl-5'-yl)-methanone
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-
hydroxyphenyl)-1 H-indazol-3-yl)-6,7-dihydro-1 H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (200
mg, 386mh o I) and piperazine-1-carboxylic acid tert-butyl ester (144mg, 773 mhhoI ) using the
method from Example 6 1. After purification by HPLC Method E and deprotection using
HCI/dioxan, the title compound (64 mg, 29% yield over two steps) was obtained as off-white
solid (HCI-salt).
1H NMR (400 MHz, DMSO) : 1.00-1 .03 (t, 3H), 2.94 (Brs, 2H), 3.22 (s, 4H), 3.93-3.95 (m, 6H),
4.84 (s, 2H), 6.94-6.96 (d, 1H), 7.03-7.06 (d, 1H), 7.30-7.33 (m, 1H), 7.58 (s, 1H), 8.42 (s, 2H),
8.50 (s, 1H), 9.29 (Brs, 2H), 9.95 (s, 1H), 14.30 (s, 1H);
LCMS: Rt = 2.48 min; m/z 568.2 [M+H]+.
Preparation 1
6-Bromo-1-(tetrahvdro-pyran-2-yl)-1 H-indazole-3-carbaldehyde
To a solution of 6-bromo-1 H-indazole-3-carbaldehyde (13.97g, 6 1.9mmol) in DCM (150ml_) was
added p-TsOH (2.36g, 12.4mmol) and the mixture was cooled to 0°C. 3,4-Dihydro-2H-pyran
(8.47ml_, 92.8mmol) was added dropwise to the solution and the reaction was stirred at room
temperature overnight. The reaction mixture was diluted with DCM (200ml_) and washed with a
solution of saturated aqueous sodium hydrogen carbonate (500ml_). The aqueous layer was reextracted
with DCM (500ml_) and the combined organic layers were washed with brine (2 x 1L),
dried over MgS0 4 and concentrated in vacuo to yield a black oil. The crude material was
refluxed in cyclohexane (20ml_) and filtered while hot. The filtrate was concentrated in vacuo
and the residue was stirred in heptane for 48 hours. The resulting solid was collected by
filtration to give the title compound (13.87g) in a 73% yield.
H NMR (400 MHz, CDCI3) d ppm 1.71-1 .80 (m, 3H), 2.10-2.20 (m, 2H), 2.49-2.57 (m, 1H),
3.76-3.82 (m, 1H), 3.98-4.03 (m, 1H), 5.78 (dd, 1H), 7.46 (dd, 1H), 7.87 (d, 1H), 8.16 (d, 1H),
10.22 (s, 1H).
Preparation 2
6-Bromo-1-(tetrahvdro-pyran-2-yl)-1 H-indazole-3-carbonitrile
To a solution of 6-bromo-1-(tetrahydro-pyran-2-yl)-1 H-indazole-3-carbaldehyde (Preparation 1,
60g, 194mmol) in MeCN ( 1 .5L) was added triethylamine (68.5ml_, 485mmol) and hydroxylamine
hydrochloride (20g, 291mmol). The reaction was heated at 60°C for 3 hours. The reaction was
cooled to 0°C, further triethylamine (220ml_, 1.55mol) was added and TFAA (109ml_, 776mmol)
was added dropwise. The reaction was allowed to warm to room temperature and stirred for 2
hours. Water (2L) was added to the reaction mixture and the resulting solid was collected by
filtration. The solid was dissolved in DCM ( 1L) and the resulting solution was washed with water
(2 x 500ml_). The organic layer was dried over MgS0 4 and concentrated in vacuo to give the
title compound as a white solid (58.59g) in a 99% yield.
H NMR (400 MHz, CDCI3) d ppm 1.71-1 .80 (m, 3H), 2.08-2.18 (m, 2H), 2.43-2.50 (m, 1H),
3.73-3.79 (m, 1H), 3.92-3.96 (m, 1H), 5.77 (dd, 1H), 7.47 (dd, 1H), 7.69 (d, 1H), 7.93 (d, 1H).
Preparation 3
4-Bromo-5-ethyl-2-fluoro-phenol
To a solution of 5-ethyl-2-fluoro-phenol (WO-2007/002313, 76.36g, 545mmol) in MeCN (2.5L)
was added copper (II) bromide (361 .5g, 1.619mol). The resulting suspension was stirred at
room temperature overnight. The solvent was removed in vacuo and the residue was
suspended in EtOAc (3L) and filtered through a pad of Arbocel ®. The filtrate was washed with
water (2L) and brine (2L), dried over MgS0 4 and concentrated in vacuo to furnish the title
compound ( 19g) in 100% yield.
H NMR (400 MHz, CDCI3) d ppm 1.19 (t, 3H), 2.86 (q, 2H), 5.20 (s, 1H), 6.90 (d, 1H), 7.25 (d,
1H).
Preparation 4
[2-(4-Bromo-5-ethyl-2-fluoro-phenoxymethoxy)-ethyll-trimethyl-silane
To a solution of 4-bromo-5-ethyl-2-fluoro-phenol (Preparation 3, 80g, 365mmol) in DCM ( 1 L)
was added DIPEA (70ml_, 401mmol) and SEM-CI (71 mL, 401 mmol). The resulting solution was
stirred at room temperature for 18 hours. The reaction mixture was washed with water ( 1L),
dried over MgS0 4 and concentrated in vacuo to yield the crude product. This material was
purified by silica gel chromatography eluting with 30% DCM in heptane to give the title
compound as a pale yellow oil (109.8g, 86%).
H NMR (400 MHz, CDCI3) d ppm 0.00 (s, 9H), 0.92-0.97 (m, 2H), 1.19 (t, 3H), 2.67 (q, 2H),
3.77-3.81 (m, 2H), 5.22 (s, 2H), 7.08 (d, 1H), 7.25 (d, 1H).
Preparation 5
2-r2-Ethyl-5-fluoro-4-(2-trimethylsilanyl
,3,21dioxaborolane
To a solution of [2-(4-bromo-5-ethyl-2-fluoro-phenoxymethoxy)-ethyl]-trimethyl-silane
(Preparation 4, 105g, 300.6mmol) in dioxane ( 1 L) was added bis(pinacolato)diboron (76.4g,
300.6mmol) and KOAc (88. 5g, 902mmol). The resulting suspension was degassed with
nitrogen, Pd(dppf)CI 2 (24.54g, 30.1 mmol) was added and the reaction was heated at reflux for
18 hours. The reaction was cooled to room temperature and the solvent was removed in vacuo.
The resulting black solid was suspended in EtOAc (2L) and filtered through Arbocel ®, washing
with further EtOAc. The filtrate was washed with water ( 1.5L) and brine ( 1.5L), dried over
MgS0 4 and concentrated in vacuo to yield the title compound as a black oil (155.5g, 130%)
that was used crude in the next step.
H NMR (400 MHz, CDCI3) d ppm 0.00 (s, 9H), 0.93-0.97 (m, 2H), 1.17 (t, 3H), 1.32 (s, 12H),
2.86 (q, 2H), 3.73-3.82 (m, 2H), 5.25 (s, 2H), 7.01 (d, 1H), 7.47 (d, 1H).

Claims
1. A compound of formula(1):
or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said
compound or pharmaceutically acceptable salt, wherein:
R is halo;
R2 is Ci-C 6 alkyl optionally substituted by one or more fluorine atoms;
X is a bond, -CO-, -S0 2- or -CH2- ;
R3 is Aryl , Het1 or Het2, each of which is optionally substituted by 1 substituent -Y-R4 and/or 1-4
substituents each independently selected from R5;
n is 1 or 2;
Aryl 1 is phenyl or naphthyl;
Het1 is (i) a 6-membered aromatic heterocycle containing 1-3 N atoms or (ii) a 5-membered
aromatic heterocycle containing either (a) 1-4 N atoms or (b) 1 O or S atom and 0-3 N atoms;
Het2 is (i) a 10-membered bicyclic aromatic heterocycle containing 1-4 N atoms or (ii) a 9-
membered bicyclic aromatic heterocycle containing either (a) 1-4 N atoms or (b) 1 O or S atom
and 0-3 N atoms or (iii) an 8-membered bicyclic aromatic heterocycle containing (a) 1-4 N
atoms or (b) 1 O or S atom and 1-3 N atoms or (c) 2 O or S atoms and 0-2 N atoms;
Y is a bond or -0-;
R4 is Aryl2 or Het3;
R5 is Ce alkyi, C3-C8 cycloalkyi, halo, -CN, -OR6, -NR7R8, -SR6, -SOR9, -S0 2R9, -COR6, -
OCOR6, -COOR6, -NR6COR6, -CONR7R8, -NR6S0 2R9, -S0 2NR7R8, -NR6CONR7R8, -
NR6COOR9 or -NR6S0 2NR7R8;
R6 is H, Ci-C 6 alkyi or C3-C8 cycloalkyi, said Ci-C 6 alkyi being optionally substituted by halo or
C3-C8 cycloalkyi;
R7 and R8 are (a) each independently H, C^Ce alkyi or C3-C8 cycloalkyi, said C^Ce alkyi being
optionally substituted by -NR 0R , wherein R and R are C -C6 alkyi or taken together with the
nitrogen atom to which they are attached form a 4-, 5- or 6-membered saturated heterocyclic
ring containing 1-2 nitrogen atoms or 1 nitrogen and 1 oxygen atom, said heterocyclic ring being
optionally substituted by one or more C^Ce alkyi or C3-C8 cycloalkyi groups; or, (b) are taken
together with the nitrogen atom to which they are attached to form a 4-, 5- or 6-membered
saturated heterocyclic ring containing 1-2 nitrogen atoms or 1 nitrogen and 1 oxygen atom, said
heterocyclic ring being optionally substituted by one or more C -C6 alkyi or C3-C8 cycloalkyi
groups;
R9 is Ci-C 6 alkyi or C3-C8 cycloalkyi;
Aryl2 is phenyl or naphthyl, said phenyl and naphthyl being optionally substituted with 1-5
substituents selected from -C6 alkyi, C3-C8 cycloalkyi, halo, -CN, -OR6, -NR7R8, -SR6, -SOR9,
-S0 2R9, -COR6, -OCOR6, -COOR6, -NR6COR6, -CONR7R8, -NR6S0 2R9, -S0 2NR7R8, -
NR6CONR7R8, -NR6COOR9 and -NR6S0 2NR7R8; and
Het3 is a 3 to 8-membered saturated or partially unsaturated monocyclic heterocycle, containing
1 or 2 heteroatoms selected from O and N, said heterocycle being optionally substituted by 1-5
substituents selected from Ci-C 6 alkyi, C3-C8 cycloalkyi, halo, oxo, -OR6, -NR7R8, -SR6, -SOR9,
-S0 2R9, -COR6, -OCOR6, -COOR6, -NR6COR6, -CONR7R8, -NR6S0 2R9, -S0 2NR7R8, -
NR6CONR7R8, -NR6COOR9 and -NR6S0 2NR7R8.
2. A compound of formula (I), as claimed in claim 1, or a pharmaceutically acceptable salt
thereof, or a pharmaceutically acceptable solvate of said compound or salt, wherein R is fluoro.
3. A compound of formula (I), as claimed in claim 1 or claim 2, or a pharmaceutically
acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt,
wherein R2 is -CH 2CH3 or -CH 2CF3. .
4. A compound of formula (I), as claimed in any one of claims 1 to 3, or a pharmaceutically
acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt,
wherein n is 1.
5. A compound of formula (I), as claimed in claim any one of claims 1 to 3, or a
pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said
compound or salt, wherein n is 2.
6. A compound of formula (I), as claimed in any one of claims 1 to 5, or a pharmaceutically
acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt,
wherein X is a bond.
7. A compound of formula (I), as claimed in any one of claims 1 to 5, or a pharmaceutically
acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt,
wherein X is -CO-.
8. A compound of formula (I), as claimed in any one of claims 1 to 5, or a pharmaceutically
acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt,
wherein X is -S0 2- .
9. A compound of formula (I), as claimed in any one of claims 1 to 5, or a pharmaceutically
acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt,
wherein X is -CH 2- .
10. A compound of formula (I), as claimed in any one of claims 1 to 9, or a pharmaceutically
acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt,
wherein R3 is phenyl, thiazolyl, quinolinyl, pyrimidinyl, [ 1 ,8]naphthyridinyl or pyridyl, each of
which is optionally substituted by 1 substituent selected from piperdininyl, (fluorophenyl)oxy,
phenyloxy and morpholinyl and 1-2 substituents each independently selected from fluoro,
chloro, cyano, methoxy and hydroxy
11. A compound of formula (I), as claimed in claim 1, which is:
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4,6,7-tetrahydro-imidazo
[4,5-c]pyridin-5-yl}-(4-fluoro-phenyl)-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4,6,7-tetrahydro-imidazo
[4,5-c]pyridin-5-yl}-isothiazol-3-yl-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4,6,7-tetrahydro-imidazo
[4,5-c]pyridin-5-yl}-isothiazol-3-yl-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4,6,7-tetrahydro-imidazo
[4,5-c]pyridin-5-yl}-(5-piperidin-1-yl-pyrazin-2-yl)-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4,6,7-tetrahydro-imidazo
[4,5-c]pyridin-5-yl}-(6-phenoxy-pyridin-3-yl)-methanone;
5-Ethyl-2-fluoro-4-{3-[5-(6-morpholin-4-yl-pyridine-3-sulfonyl)-4,5,6,7-tetrahydro-1 H-imidazo[4,5-
c]pyridin-2-yl]-1 H-indazol-6-yl}-phenol;
5-Ethyl-2-fluoro-4-{3-[5-(6-phenoxy-pyridine-3-sulfonyl)-4,5,6,7-tetrahydro-1 H-imidazo
[4,5-c]pyridin-2-yl]-1 H-indazol-6-yl}-phenol;
(5-Chloro-pyridin-2-yl)-{2-[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-4, 5,7,8-
tetrahydro-1 H-imidazo[4,5-d]azepin-6-yl}-methanone;
2-{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-4,5,7,8-tetrahydro-1 H-imidazo[4,5-
d]azepine-6-carbonyl}-isonicotinonitrile;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-4,5,7,8-tetrahydro-1 H-imidazo
[4,5-d]azepin-6-yl}-(4-fluoro-phenyl)-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-4,5,7,8-tetrahydro-1 H-imidazo
[4,5-d]azepin-6-yl}-isothiazol-3-yl-methanone;
5-Ethyl-2-fluoro-4-{3-[5-(4-fluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1 H-imidazo
[4,5-c]pyridin-2-yl]-1 H-indazol-6-yl}-phenol;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4,6,7-tetrahydro-imidazo
[4,5-c]pyridin-5-yl}-[5-(2-fluoro-phenoxy)-pyrazin-2-yl]-methanone;
4-[3-(6-Benzyl-1 ,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepin-2-yl)-1 H-indazol-6-yl]-5-ethyl-2-
fluoro-phenol;
(5-Chloro-pyridin-2-yl)-{2-[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4,6,7-
tetrahydro-imidazo[4,5-c]pyridin-5-yl}-methanone;
5-{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4,6,7-tetrahydro-imidazo
[4,5-c]pyridine-5-carbonyl}-pyridine-2-carbonitrile;
5-{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-4,5J,8-tetrahydro-1
d]azepine-6-carbonyl}-pyridine-2-carbonitrile;
5-Ethyl-2-fluoro-4-[3-(5-quinolin-6-ylmethyl-4,5,6J-tetrahydro-1 H-imidazo[4,5-c]pyridin
indazol-6-yl]-phenol;
5-Ethyl-2-fluoro-4-{3-[5-(4-hydroxy-benzyl)-4 5 6J-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-^
indazol-6-yl}-phenol;
5-Ethyl-2-fluoro-4-{3-[5-(3-hydroxy-benzylH
indazol-6-yl}-phenol;
4-{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 4,6J-tetrahydro-imidazo[4,5-
c]pyridin-5-ylmethyl}-pyridine-2-carbonitrile;
5-Ethyl-2-fluoro-4-{3-[5-(3-methoxy-benzyl)-4A6J-tetrah
indazol-6-yl}-phenol;
5-Ethyl-2-fluoro-4-[3-(5-quinolin-3-ylmethyl-4,5,6J-tetrahydro-1 H-imidazo[4,5-c]pyridin
indazol-6-yl]-phenol;
5-Ethyl-2-fluoro-4-{3-[5-(6-phenoxy-pyridin-3-ylmethyl)-4,5,6J-tetrahydro-1 H-imidazo[4
c]pyridin-2-yl]-1 H-indazol-6-yl}-phenol;
5-Ethyl-2-fluoro-4-{3-[5-(3A5,6-tetrahydro-2H-[1
1H-imidazo[4,5-c]pyridin-2-yl]-1 H-indazol-6-yl}-phenol;
3-{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 4,6J-tetrahydro-imidazo[4,5-
c]pyridin-5-ylmethyl}-pyridine-2-carbonitrile;
5-Ethyl-2-fluoro-4-{3-[5-(4-fluoro-benzyl)-4,5 6J-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yO
indazol-6-yl}-phenol;
5-Ethyl-2-fluoro-4-[3-(5-[1 ,8]naphthyridin-2-ylmethyl-4 5,6J-tetrahydro-1 H-imidazo[
4,5-c]pyridin-2-yl)-1 H-indazol-6-yl]-phenol;
(2-{6-[5-Fluoro-4-hydroxy-2-(2,2,2-trifluoro-ethyl)-ph
imidazo[4,5-c]pyridin-5-yl)-(5-piperidin-1-yl-pyrazin-2-yl)-methanone;
(2-{6-[5-Fluoro-4-hydroxy-2-(2 2 2-trifluoro-ethyl)-phenyl]-1 H-indazol-3-yl}-1 4,6J-tetrah
imidazo[4,5-c]pyridin-5-yl)-(4-fluoro-phenyl)-methanone; or
4-[3-(5-Benzyl-4,5 6J-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl)-1 H-indazol-6-yl]-2-fluoro-5-
(2,2,2-trifluoro-ethyl)-phenol;
or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said
compound or salt.
12. A compound of formula (I), as claimed in claim 1, which is:
{5-[(2-Dimethylamino-ethyl)-methyl-amino]-pyrazin-2-yl}-{2-[6-(2-ethyl-5-fluoro
phenyl)-1 H-indazol-3-yl]-1 ,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl}-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4 6 7-tetrahydro-imidazo[4,5-
c]pyridin-5-yl}-[5-(2-pyrrolidin-1-yl-ethylamino)-pyrazin-2-yl]-methanone;
[5-(2-Dimethylamino-ethylamino)-pyrazin-2-yl]-{2-[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-1 H
indazol-3-yl]-1 ,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl}-methanone;
[5-(4-Dimethylamino-piperidin-1-yl)-pyrazin-2-yl]-{2-[6-(2-ethyl-5-fluoro-4-hydroxy-pheny
indazol-3-yl]-1 ,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl}-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4 6 7-tetrahydro-imidazo[4,5-
c]pyridin-5-yl}-{5-[ethyl-(2-hydroxy-ethyl)-amino]-pyrazin-2-yl}-methanone;
[5-((R)-3-Dimethylamino-pyrrolidin-1-yl)-pyrazin-2-yl]-{2-[6-(2-ethyl-5-fluoro-4-hydroxy-phen
1H-indazol-3-yl]-1 ,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl}-methanone;
[5-((S)-3-Dimethylamino-pyrrolidin-1-yl)-pyrazin-2-yl]-{2-[6-(2-ethyl-5-fluoro-4-hydroxy-pheny
1H-indazol-3-yl]-1 ,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl}-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4,6J-etrahydroimidazo[4,5c]pyridin-
5-yl}-[5-(2-piperidin-1-yl-ethylamino)-pyrazin-2-yl]-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4 6 7-tetrahydro-imidazo[4,5-
c]pyridin-5-yl}-[5-(2-piperazin-1-yl-ethylamino)-pyrazin-2-yl]-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4 6 7-tetrahydro-imidazo[4,5-
]pyridin-5-yl}-(4-methyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4 6 7-tetrahydro-imidazo[4,5-
c]pyridin-5-yl}-(5-morpholin-4-yl-pyrazin-2-yl)-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4,6,7-tetrahydro-idazo[4,5c]pyridin-
5-yl}-[5-(4-methyl-piperidin-1-yl)-pyrazin-2-yl]-methanone;
(5-Cyclopentylamino-pyrazin-2-yl)-{2-[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-
1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl}-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4 6 7-tetrahydro-imidazo[4,5-
c]pyridin-5-yl}-[5-(2-morpholin-4-yl-ethylamino)-pyrazin-2-yl]-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4 6 7-tetrahydro-imidazo[4,5-
c]pyridin-5-yl}-(4-isopropyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4 6 7-tetrahydro-imidazo[4,5-
c]pyridin-5-yl}-(5-pyrrolidin-1-yl-pyrazin-2-yl)-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4 6 7-tetrahydro-imidazo[4,5-
]pyridin-5-yl}-[5-(ethyl-methyl-amino)-pyrazin-2-yl]-methanon;
(5-Cyclohexylamino-pyrazin-2-yl)-{2-[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-
1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl}-methanone;
(5-Dimethylamino-pyrazin-2-yl)-{2-[6-(2-ethyl-5-fluoro H-indazol-3-yl]-, 4,6,7-
tetrahydro-imidazo[4,5-c]pyridin-5-yl}-methanone;
(5-Azetidin-1-yl-pyrazin-2-yl)-{2-[6-(2-ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3
tetrahydro-imidazo[4,5-c]pyridin-5-yl}-methanone;
2-Fluoro-4-{3-[5-(4-fluoro-benzyl)-4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl]-1 H-inda
yl}-5-(2,2,2-trifluoro-ethyl)-phenol;
2-Fluoro-4-{3-[5-(3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-5'-ylmethyl)-4,5,6,7-tetrahydro-1 Himidazo[
4,5-c]pyridin-2-yl]-1 H-indazol-6-yl}-5-(2,2,2-trifluoro-ethyl)-phenol;
2-Fluoro-4-{3-[5-(6-phenoxy-pyridin-3-ylmethyl)-4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-
yl]-H-indazol-6-yl}-5-(2,2,2-trifluoro-ethyl)-phenol;
2-Fluoro-4-{3-[5-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl]-1 H
indazol-6-yl}-5-(2,2,2-trifluoro-ethyl)-phenol;
2-Fluoro-4-{3-[5-(4-hydroxy-benzyl)-4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl]-1 Hindazol-
6-yl}-5-(2,2,2-trifluoro-ethyl)-phenol;
2-Fluoro-4-{3-[5-(3-methoxy-benzyl)-4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl]-1 Hindazol-
6-yl}-5-(2,2,2-trifluoro-ethyl)-phenol;
2-Fluoro-4-{3-[5-(3-hydroxy-benzyl)-4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yl]-1 Hindazol-
6-yl}-5-(2,2,2-trifluoro-ethyl)-phenol;
2-Fluoro-4-[3-(5-quinolin-6-ylmethyl-4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yO
indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol;
2-Fluoro-4-[3-(5-quinolin-3-ylmethyl-4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridin-2-yO
indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol;
2-Fluoro-4-[3-(5-[1 ,8]naphthyridin-3-ylmethyl-4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyri
1H-indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol;
((3R,5S)-3,5-Dimethyl-3,4,5,6-tetrahydro
hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl}-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4,6,7-tetrahydro-imidazo[4,5-
c]pyridin-5-yl}-((S)-3-methyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)-methanon
((2S,5R)-2,5-Dimethyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)-{2-[6-(2-ethyl-5-fluor
hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl}-methanone;
{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1 H-indazol-3-yl]-1 ,4,6,7-tetrahydro-imidazo[4,5-
]pyridin-5-yl}-(3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl-5'-yl)-methanone;
or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said
compound or salt.
13. A pharmaceutical composition comprising a compound of formula (I), as claimed in any
one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or a pharmaceutically
acceptable solvate of said compound or salt, and a pharmaceutically acceptable excipient.
14. A method of treating a disease or condition for which a JAK inhibitor is indicated, in a
subject in need of such treatment, comprising administering to the subject a therapeutically
effective amount of a compound of formula (I), as claimed in any one of claims 1 to 13, or a
pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said
compound or salt.
15. A method of treating a disease or condition selected from allergic rhinitis, nasal
congestion, rhinorrhea, perennial rhinitis, nasal inflammation, asthma of all types, chronic
obstructive pulmonary disease , chronic or acute bronchoconstriction, chronic bronchitis, small
airways obstruction, emphysema, chronic eosinophilic pneumonia, adult respiratory distress
syndrome, exacerbation of airways hyper-reactivity consequent to other drug therapy,
pulmonary vasulcar disease, pulmonary arterial hypertension, acute lung injury, bronchiectasis,
sinusitis, allergic conjunctivitis, idiopathic pulmonary fibrosis or atopic dermatitis, comprising
administering to the subject a therapeutically effective amount of a compound of formula (I), as
claimed in any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a
pharmaceutically acceptable solvate of said compound or salt.
16. A method of treating chronic obstructive pulmonary disease, comprising administering to
the subject a therapeutically effective amount of a compound of formula (I), as claimed in any
one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a pharmaceutically
acceptable solvate of said compound or salt.
17. A method of treating a disease or condition selected from inflammation,
neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthropathies, systemic lupus
erythematous arthritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoisosis, silicosis,
cardiovascular disease, atherosclerosis, myocardial infarction, thrombosis, congestive heart
failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischaemia, reperfusion injury,
brain edema, brain trauma, neurodegeneration, liver disease, inflammatory bowel disease,
Crohn's disease, ulcerative colitis, nephritis, retinitis, retinopathy, macular degeneration,
glaucoma, diabetes (type 1 and type 2), diabetic neurorpathy, viral and bacterial infection,
myalgia, endotoxic shock, toxic shock syndrome, autoimmune disease, osteoporosis, multiple
sclerosis, endometriosis, menstrual cramps, vaginitis, candidiasis, cancer, fibrosis,
obesity,muscular dystrophy, polymyositis, Alzheimer's disease, skin flushing, eczema, psoriasis,
atopic dermatitis and sunburn, comprising administering to the subject a therapeutically effective
amount of a compound of formula (I), as claimed in any one of claims 1 to 13, or a
pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said
compound or salt.
18. A method of treating psoriasis, comprising administering to the subject a therapeutically
effective amount of a compound of formula (I), as claimed in any one of claims 1 to 13, or a
pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said
compound or salt.