ANDROGEN RECEPTOR MODULATING CARBOXAMIDES
Technical field
The present invention relates to therapeutically active compounds and
pharmaceutically acceptable salts and esters thereof useful in the treatment of nuclear
receptor, especially steroid receptor, and in particular androgen receptor (AR)
dependent conditions and diseases, and to pharmaceutical compositions containing
such compounds. In particular, the invention discloses non-steroidal carboxamide
and structured compounds having utility as tissue-selective androgen receptor
modulators (SARM). The compounds of the invention, which possess AR antagonist
activity, are useful for treating patients requiring androgen receptor antagonist
therapy. In particular, AR antagonists of the invention are useful in the treatment or
prevention of cancer, particularly AR dependent cancer such as prostate cancer, and
other diseases where AR antagonism is desired.
Background of the invention
In recent years, there has been growing interest in the development of
nonsteroidal modulators for steroid receptors for therapeutical use. It has been shown
that nonsteroidal ligands can achieve better receptor selectivity and better
physicochemical, pharmacokinetic and pharmacological properties. For androgen
receptor (AR), nonsteroidal antagonists (antiandrogens) are now used clinically to
counteract the undesirable actions of excessive androgens.
Androgens, functioning through the AR, are essential for the initiation and
progression of prostate cancer. Thus, treatment of advanced prostate cancer involves
androgen-ablation therapies, such as surgical castration or hormonal manipulation
using gonadotropin-releasing hormone (GnRH) agonists, anti-androgens or both.
Although such therapies initially lead to disease regression, eventually all patients
progress to a castration resistant late stage that is refractory to current therapies.
Castration-resistant prostate cancer (CRPC) is associated with increased levels of
AR. First generation anti-androgens such as bicalutamide display agonistic properties
in cells engineered to express higher AR levels. In vitro and in vivo, increased AR
expression has been shown to confer resistance of prostate cancer cell lines to anti-
androgen therapy. To overcome resistance problems, second generation anti-
androgens that retain antagonism in cells expressing excess AR may have utility in
the treatment of CRPC.
Non-steroidal androgen receptor antagonists have been described earlier e.g.
in patent publications EP 100172, EP 1790640, US 6,087,509, US 6,673,799, US
7271188, WO 03/057669, WO 2004/ 099188, WO 2006/133567, WO 2008/124000,
WO 2009/028543 and WO 2009/055053.
Related carboxamide structured compounds have been described in WO
2008/062878.
Summary of the invention
It has been found that compounds of formula (I) or (II) are potent androgen
receptor (AR) modulators, in particular AR antagonists. Compounds of formula (I) or
(II) show remarkably high affinity and strong antagonistic activity in androgen
receptor. Also in cells which overexpress AR ("AR overexpressing cells") the
compounds of the invention possess from high to full AR antagonism while
exhibiting only minimal agonism. The compounds of the invention also effectively
inhibited proliferation of prostatic cancer cell line. Moreover, the compounds of the
invention have low potential for drug-drug interactions, high selectivity to androgen
receptor, favourable safety profile and sufficient water solubility.
The compounds of the invention are therefore particularly useful as
medicaments in the treatment of prostate cancer and other AR dependent conditions
and diseases where AR antagonism is desired.
The present invention provides novel carboxamide structured compounds of
formula (I) or (II)
wherein ring A is any one of the following groups or tautomers thereof

wherein
Rx is halogen or CF3;
Rz is hydrogen or halogen;
R1 is hydroxy C3-7 alkyl, imidazolyl or -Ra-OC(O)-Rb;
Ra is C1-7 alkyl;
Rb is C1-7 alkyl, hydroxy C1-7 alkyl or carboxy C1-7 alkyl;
R2 is C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1-7 alkyl,
methylpyrazolyl or pyrimidinyl;
R3 is halogen or pyridinyl;
R4 is pyridinyl;
R5 is C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1-7 alkyl, cyano,
hydroxy C1-7 alkyl, oxo C1-7 alkyl, halogen or methylpyrazolyl;
R6 is C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1-7 alkyl,
hydroxy, hydroxy C1-7 alkyl, cyano C1-7 alkyl or C1-7 alkoxycarbamoyl C1-7 alkyl;
R7 is hydroxy C4 alkyl;
R8 is halogen, C2-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1-7
alkyl, cyano, carboxy, oxo C1-7 alkyl, halo C1-7 alkyl, hydroxy C1-7 alkyl, tetrahydro-
2H-thiopyran or -C(O)-NHR20;
R9 is hydrogen, hydroxy, halogen, nitro, amino, cyano, oxo, C1-7 alkyl, C2-7
alkenyl, C3-7 cycloalkyl, C1-7 alkoxy, halo C1-7 alkyl, hydroxy C1-7 alkyl, cyano C1-7
alkyl, amino C1-7 alkyl, oxo C1-7 alkyl, C1-7 alkoxy C1-7 alkyl, C1-7 alkylamino,
hydroxy C1-7 alkylamino, C1-7 alkoxy C1-7 alkylamino, C1-7 alkylamino C1-7 alkyl,
hydroxy C1-7 alkylamino C1-7 alkyl, hydroxyimino C1-7 alkyl, C1-7 alkoxycarbamoyl
C1-7 alkyl, -C(O)Rn, -OC(O)R17 , -NH-C(O)R18 -NH-SO2-R19 or an optionally
substituted 5-12 membered carbocyclic or heterocyclic ring, each group linked to
B-ring via a bond or via a C1-7 alkylene linker;
R10 is hydrogen, halogen, C1-7 alkyl, C2.7 alkenyl, C3-7 cycloalkyl, C3-7
cycloalkyl C1-7 alkyl, oxo, hydroxy C1-7 alkyl, oxo C1-7 alkyl or an optionally
substituted 5 or 6 membered carbocyclic or heterocyclic ring;
Rn is hydrogen, hydroxy, C1-7 alkyl, hydroxy C1-7 alkyl, C2-7 alkenyl, C3-7
cycloalkyl, halo C1-7 alkyl, C1-7 alkoxy, NR12R13, or an optionally substituted 5-12
membered carbocyclic or heterocyclic ring;
R12 is hydrogen, C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1-7
alkyl, C1-7 alkoxy, hydroxy C1-7 alkyl, amino C1-7 alkyl or C1-7 alkyl amino C1-7 alkyl;
R13 is hydrogen or C1-7 alkyl;
R14 and R15 are, independently, hydrogen or C1-7 alkyl;
R14' and R15' are, independently, hydrogen or C1-7 alkyl, or R14' and R15'
together form a bond;
R17 is C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1-7 alkyl, C1-7
alkoxy, amino C1-7 alkyl, C1-7 alkylamino or C1-7 alkylamino C1-7 alkyl;
R18 is C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1-7 alkyl, amino
C1-7 alkyl, C1-7 alkylamino or C1-7 alkylamino C1-7 alkyl;
R19 is C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl or C3-7 cycloalkyl C1-7 alkyl;
R20 is hydrogen, C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1-7
alkyl or C1-7 alkoxy;
R21 is cyano C1-7 alkyl or, in case Rx is CF3, R21 can also be hydroxy C1-7
alkyl;
R22 is hydroxy C1-7 alkyl;
R23 is C1-7 alkyl or hydroxy C1-7 alkyl;
R24 is hydroxy, halogen or C1-7 alkoxy;
ring B is any one of the following groups or tautomers thereof

and pharmaceutically acceptable salts thereof;
with the proviso that the compound of formula (II) is not any of the following
compounds:
(5)-3-acetyl-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-
propan-2-yl)-1H-pyrazole-5 -carboxamide;
(S)-N-( 1 -(3 -(3 -chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
1 -(pyridin-4-yl)-1H-pyrazole-3-carboxamide;
(S)-N-( 1 -(3 -(3 -chloro-4-cyano-5 -fluorophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
1 -(2-fluoroethyl)-2-methyl-1H-imidazole-4-carboxamide;
(S)-N-( 1 -(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
3-(lH-imidazol-4-yl)-l,2,4-oxadiazole-5-carboxamide;
(S)-5-acetyl-N-(l-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-
yl)propan-2-yl)isoxazole-3-carboxamide;
N-((S)-1 -(3 -(3 -chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
5-( 1 -hydroxyethyl)isoxazole-3-carboxamide;
(S)-5-acetyl-N-(2-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-
yl)propyl)isoxazole-3-carboxamide;
(S)-N-(2-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propyl)-2-
methyl-1H-imidazole-4-carboxamide;
N-((S)-1 -(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
3-(l -hydroxyethyl)-1H-pyrazole-5-carboxamide;
(R)-N-(1-(3 -(3 -chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
2-methyl-1H-imidazole-4-carboxamide;
(S)-N-{1 - [3 -(3 -Chloro-4-cyano-5 -fluorophenyl)-1H-pyrazol-1 -yl]propan-2-
yl}-2-methyl-1H-imidazole-4-carboxamide;
(S)-N-{1 -[3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl]propan-2-
yl}-1-methyl-1H-imidazole-4-carboxamide;
(S)-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-
3H-imidazo[4,5-b]pyridine-5-carboxamide;
(S)-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-
2-(pyridin-3-yl)thiazole-4-carboxamide;
(S)-N-(1 -(3 -(3 -chloro-4-cyano-5 -fluorophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
1-(pyridin-3-yl)-1H-pyrazole-3-carboxamide;
(S)-N-(1 -(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
2-methyl-1 -(3 -oxobutyl)-1H-imidazole-4-carboxamide;
(S)-N-(l-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-
1 -(3 -hydroxy-3 -methylbutyl)-2 -methyl-1H-imidazole-4-carboxamide;
(S)-N-( 1 -(3 -(3 -chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)imidazo[ 1,2-a]pyridine-2-carboxamide;
(S)-N-( 1 -(3 -(3-chloro-4-cyano-5 -fluorophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
1-(pyridin-3-yl)-1H-imidazole-4-carboxamide;
(S)-N-( 1 -(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
2-(2-hydroxypropan-2-yl)oxazole-4-carboxamide;
(S)-N-( 1 -(3 -(3 -chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)imidazo[1,2-a]pyrimidine-2-carboxamide;
(S)-N-( 1 -(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
3-fluoroimidazo[1,2-a]pyridine-2-carboxamide;
(S)-N-( 1 -(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
4,5,6,7-tetrahydro-2H-indazole-3 -carboxamide;
(S)-N-(1 -(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
6,7-dihydro-5H-pyrazolo[5,1-b][l,3]oxazine-2-carboxamide;
(S)-N-(1 -(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
2,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxamide;
(S)-N-( 1 -(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
1 -(6-methylpyridin-2-yl)-1H-imidazole-4-carboxamide;
(S)-N-( 1 -(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
6,7-dihydro-4H-pyrano[3,4-d]isoxazole-3-carboxamide;
(S)-N-( 1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-
5-(2-hydroxypropan-2-yl)isoxazole-3-carboxamide.
It is to be understood that each B-ring (1') to (45') above are substituted by
R9 and R10 as shown in formula (II).
In a subclass of compounds of formula (I) or (II) as defined above are
compounds of formula (I') or (IF) and pharmaceutically acceptable salts thereof,
wherein Rx, Rz, R9; R10, A and B are as defined above.
In a subclass of preferred compounds of formula (I) or (I') as defined above
are compounds and pharmaceutically acceptable salts thereof wherein Rx is halogen,
R14 is C1-7 alkyl, and ring A is any of groups (1), (2), (3), (5), (6), (7) or (8). A further
subclass of preferred compounds formula (I) or (F) as defined above are compounds
and pharmaceutically acceptable salts thereof wherein Rx is chloro, R14 is methyl, and
ring A is any of groups (1), (2), (5), (6) or (7), R1 is hydroxy C3-7 alkyl, imidazolyl or
carboxy C1-7 alkyl carbonyloxy C1-7 alkyl, R2 is C1-7 alkyl, C2-7 alkenyl or methyl-
pyrazolyl, R5 is C1-7 alkyl, C3-7 cycloalkyl, hydroxy C1-7 alkyl or methylpyrazolyl, R6
is C1-7 alkyl, cyano C1-7 alkyl or hydroxy C1-7 alkyl and R8 is C1-7 alkyl, halogen, oxo
C1-7 alkyl or hydroxy C1-7 alkyl.
In a subclass of preferred compounds of formula (II) or (II') as defined above
are compounds and pharmaceutically acceptable salts thereof wherein R14 is C1-7
alkyl, R14', R15 and R15' is hydrogen, ring B is any of groups (1'), (2'), (3'), (4'), (8'),
(16'), (17'),(21'), (23'), (24'), (25'), (26'), (29'), (39'), (40'), (42') or (43'), R9 is
hydrogen, halogen, cyano, oxo, C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, halo C1-7
alkyl, cyano C1-7 alkyl, hydroxy C1-7 alkyl, oxo C1-7 alkyl, -NH-SO2-R19 or an
optionally substituted 5-12 membered heterocyclic ring, each R9 group linked to B-
ring via a bond or via a C1-7 alkylene linker, R10 is hydrogen, C1-7 alkyl or C3-7
cycloalkyl, and R19 is C1-7 alkyl. Particularly preferred 5-12 membered heterocyclic
ring in R9 is pyrazole, pyridine, isoxazole or imidazole ring, which is attached to B-
ring via a bond or via C1-7 alkylene linker. Particularly preferred substituents in the
5-12 membered heterocyclic ring in R9 are 1 to 3 substituents selected from C1-7
alkyl, C3-7 cycloalkyl, halogen or hydroxy C1-7 alkyl groups.
Still another class of preferred compounds are compounds of formula (II) or
(II') as defined above and pharmaceutically acceptable salts thereof wherein Rz is
hydrogen or fluoro, R14 is methyl, R14', R15 and R15' is hydrogen, ring B is any of
groups (1'), (2'), (4'), (17'),(21') or (25'), R9 is hydrogen, halogen, cyano, oxo, C1-7
alkyl, C2-7 alkenyl, C3-7 cycloalkyl, halo C1-7 alkyl, hydroxy C1-3 alkyl, cyano C1-7
alkyl, pyrazolyl, N-methyl pyrazolyl, pyridinyl, isoxazolyl, imidazolyl or imidazolyl
methyl, and R10 is hydrogen, C1-7 alkyl or C3-7 cycloalkyl.
The present invention provides further a method for the treatment or
prevention of androgen receptor (AR) dependent conditions, comprising
administering to a subject in need thereof a therapeutically effective amount of a
compound of formula (I) or (II) or pharmaceutically acceptable salts thereof. For
example, the AR dependent condition to be treated is cancer, particularly AR
dependent cancer such as prostate cancer, benign prostatic hyperplasia, androgenic
alopecia and acne. According to one embodiment of the invention, the AR dependent
condition to be treated is castration-resistant prostate cancer (CRPC).
The present invention also provides a pharmaceutical composition comprising
a compound of formula (I) or (II) or pharmaceutically acceptable salts thereof
together with a pharmaceutically acceptable carrier.
Detailed description of the invention
The compounds of the invention can be prepared by a variety of synthetic
routes analogously to the methods known in the literature using suitable starting
materials. For example, compounds of formula (I) or (II) can be prepared according
to the reaction Scheme 1, wherein Rz, R14, R14', R15, R15', B, R9, and R10 are as
defined above and X is a halogen. Preparation of compounds of formula (II) is shown
in Schemes 1 and 2, but compounds of formula (I) can be prepared in analogous
manner following the methods of Schemes 1 and 2. Optically active enantiomers or
diastereomers of compounds of formula (I) or (II) can be prepared e.g. by using
suitable optically active starting materials. Similarly, racemic compounds of formula
(I) or (II) can be prepared by using racemic starting materials. Some compounds
included in the formula (I) or (II) can be obtained by converting the functional groups
of the other compounds of formula (I) or (II) obtained in accordance with Scheme 1,
by well known reaction steps such as oxidation, reduction, hydrolysis, acylation,
alkylation, amidation, amination and others.

SCHEME 1
Alternatively, compounds of formula (I) or (II) can be prepared according to
the Scheme 2. Rz, R14, R14', R15, R15', B, R9, and R10 are as defined above and X is a
halogen.
The starting compound [11] of Scheme 2 can be suitably prepared from 3-chloro-5-
fluoroaniline according to Scheme 3, wherein X is a halogen.

Other starting materials of the above Schemes are commercially available or
can be prepared according to known methods.
Pharmaceutically acceptable salts, e.g. acid addition salts with both organic
and inorganic acids are well known in the field of pharmaceuticals. Non-limiting
examples of these salts include chlorides, bromides, sulfates, nitrates, phosphates,
sulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates and
ascorbates. Pharmaceutically acceptable esters, when applicable, may be prepared by
known methods using pharmaceutically acceptable acids that are conventional in the
field of pharmaceuticals and that retain the pharmacological properties of the free
form. Non-limiting examples of these esters include esters of aliphatic or aromatic
alcohols, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl
esters. Phosphate esters and carbonate esters, are also within the scope of the
invention.
The definition of formula (I) or (II) above are inclusive of all the possible
isotopes and stereoisomers of the compounds, including geometric isomers, e.g. Z
and E isomers (cis and trans isomers), and optical isomers, e.g. diastereomers and
enantiomers, and all prodrug esters, e.g. phosphate esters and carbonate esters.
Furthermore, the invention includes in its scope both the individual isomers and any
mixtures thereof, e.g. racemic mixtures.
In one embodiment, the term "isomer" is meant to encompass optical isomers
of the compounds of the invention. It will be appreciated by those skilled in the art
that the compounds of the present invention contain at least one chiral center.
Accordingly, the compounds of the invention may exist in optically active or racemic
forms. It is to be understood that the present invention encompasses any racemic or
optically active form, or mixtures thereof. In one embodiment, the compounds of the
invention are the pure (R)-isomers. In another embodiment, the compounds of the
invention are the pure (S)-isomers. In another embodiment, the compounds of the
invention are a mixture of the (R) and the (S) isomers. In another embodiment, the
compounds of the invention are a racemic mixture comprising an equal amount of the
(R) and the (S) isomers. The compounds of the invention may contain two chiral
centers. In such case, according to one embodiment of the invention, the compounds
of the invention are pure diasteromers. According to other embodiment of the
invention, the compounds of the invention are a mixture of several diasteromers. The
individual isomers may be obtained using the corresponding isomeric forms of the
starting material or they may be separated after the preparation of the end compound
according to conventional separation methods. For the separation of optical isomers,
e.g. enantiomers or diastereomers, from the mixture thereof the conventional
resolution methods, e.g. fractional crystallisation, may be used.
The terms employed herein have the following meanings:
The term "halo" or "halogen", as employed herein as such or as part of
another group, refers to chlorine, bromine, fluorine or iodine.
The terms "C1-7 alkyl", "C2-7 alkyl" and "C4 alkyl", as employed herein as
such or as part of another group, refers to a saturated straight or branched carbon
chain having 1 to 7 carbon atoms, 2 to 7 carbon atoms and 4 carbon atoms,
respectively. Representative examples of C1-7 alkyl include, but are not limited to,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,
isopentyl, neopentyl, n-hexyl, and the like.
The term "C2-7 alkenyl", as employed herein as such or as part of another
group, refers to a straight or branched chain radical having 2 to 7 carbon atoms,
which chain contains at least one double bond. Representative examples of C2-7
alkenyl include, but are not limited to, ethenyl, propenyl, butenyl, and the like.
The term "C1-7 alkylene linker" means a saturated straight or branched C1-7
alkyl chain which connects two groups together. Representative examples of C1-7
alkylene linker are methylene (-CH2-) and ethylene (-CH2-CH2-) chains.
The term "C3-7 cycloalkyl", as employed herein as such or as part of another
group, refers to a saturated cyclic hydrocarbon group containing 3 to 7 carbons.
Representative examples of C3-7 cycloalkyl include, but are not limited to,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
The term "C3-7 cycloalkyl C1-7 alkyl", as employed herein refers to a C3-7
cycloalkyl group, as defined herein, appended to the parent molecular moiety through
a C1-7 alkyl group, as defined herein.
The term "hydroxy", as employed herein as such or as part of another group,
refers to an -OH group.
The term "cyano", as employed herein as such or as part of another group,
refers to a -CN group.
The term "hydroxy C1-7 alkyl", as employed herein as such or as part of
another group, refers to at least one hydroxy group, as defined herein, appended to
the parent molecular moiety through a C1-7 alkyl group, as defined herein.
Representative examples of hydroxy C1-7 alkyl include, but are not limited to,
hydroxymethyl, 2,2-dihydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 1-hydroxy-
propyl, 1-methyl-1-hydroxyethyl, 1-methyl-1-hydroxypropyl, and the like.
The term "halo C1-7 alkyl", as employed herein as such or as part of another
group, refers to at least one halogen, as defined herein, appended to the parent
molecular moiety through a C1-7 alkyl group, as defined herein. Representative
examples of halo C1-7 alkyl include, but are not limited to, fluoromethyl, difluoro-
methyl, trifluoromethyl, 2-chloroethyl, 3-bromopropyl, and the like.
The term "cyano C1-7 alkyl", as employed herein as such or as part of another
group, refers to at least one cyano group, appended to the parent molecular moiety
through a C1-7 alkyl group, as defined herein. Representative examples include, but
are not limited to, cyanomethyl, 3-cyanopropyl, and the like.
The term "C1-7 alkoxy C1-7 alkyl", refers to C1-7 alkoxy group as defined
herein, appended to the parent molecular moiety through a C1-7 alkyl group, as
defined herein.
The term "oxo" as employed herein as such or as part of another group, refers
to group (=O) attached as a substituent.
The term "carboxyl", as employed herein as such or as part of another group,
refers to a -COOH group.
The term "carbamoyl", as employed herein as such or as part of another
group, refers to a -(C=O)-NH2 group.
The term "carbamoyl C1-7 alkyl", as employed herein as such or as part of
another group, refers to carbamoyl group appended to the parent molecular moiety
through a C1-7 alkyl group.
The term "carboxy C1-7 alkyl" employed herein, refers to -COOH group
appended to the parent molecular moiety through a C1-7 alkyl group, as defined
herein.
The term "C1-7 alkoxycarbamoyl C1-7 alkyl" as employed herein, refers to
-C1-7 alkyl-(C=O)-NH-O- C1-7 alkyl group wherein C1-7 alkyl is as defined herein.
The term "amino", as employed herein as such or as part of another group, refers to a
-NH2 group.
The term "oxo C1-7 alkyl", as employed herein by itself or as part of another
group, refers a C1-7 alkyl group as defined herein containing a carbonyl radical
anywhere in an alkyl chain. Examples thereof include acetyl, propanoyl, iso-
propanoyl, butanoyl, sec-butanoyl, tert-butanoyl and pentanoyl.
The term "amino C1-7 alkyl", as employed herein, refers to at least one amino
group, as defined herein, appended to the parent molecular moiety through a
C1-7 alkyl group, as defined herein. Representative examples of amino C1-7 alkyl
include, but are not limited to, aminomethyl, 2-aminoethyl, 1-aminoethyl, 2,2-di-
aminoethyl, 3-aminopropyl, 2-aminopropyl, 4-aminobutyl, 1-methyl-1-aminoethyl,
and the like.
The term "C1-7 alkylamino", as employed herein as such or as part of another
group, refers to one or two C1-7 alkyl group(s), as defined herein, appended to the
parent molecular moiety through an amino group, as defined herein. Representative
examples of C1-7 alkylamino include, but are not limited to methylamino, ethylamino,
propylamino, dimethylamino, diethylamino, N-ethyl-N-methylamino, and the like.
The term "C1-7 alkylamino C1-7 alkyl", as employed herein, refers to C1-7
alkylamino group, as defined herein, appended to the parent molecular moiety
through a C1-7 alkyl group, as defined herein. Representative examples of C1-7 alkyl-
amino C1-7 alkyl include, but are not limited to, N,N-dimethylaminomethyl, N,N-di-
ethylaminomethyl, N-methylaminoethyl, N-methylaminopropyl, N-ethyl-N-methyl-
aminomethyl, and the like.
The term "hydroxy C1-7 alkylamino", as employed herein, refers to at least one
hydroxy group appended to the parent molecular moiety through a C1-7 alkylamino
group, as defined herein. Representative examples of C1-7 alkylamino C1-7 alkyl
include, but are not limited to, N-hydroxymethylamino, N-ethyl-N-hydroxymethyl-
amino, and the like.
The term "C1-7 alkoxy C1-7 alkylamino", as employed herein refers to at least
one C1-7 alkoxy group appended to the parent molecular moiety through a C1-7 alkyl-
amino group, as defined herein. Representative examples include, but are not limited
to, N-ethoxymethylamino, N-ethyl-N-metoxymethylamino and the like.
The term "hydroxy C1-7 alkylamino C1-7 alkyl", as employed herein, refers to
hydroxy C1-7 alkylamino group, as defined herein, appended to the parent molecular
moiety through a C1-7 alkyl group, as defined herein. Representative examples of C1-7
alkylamino C1-7 alkyl include, but are not limited to, N-hydroxymethylaminoethyl, N-
ethyl-N-hydroxymethylaminomethyl, and the like.
The term "C1-7 alkoxy C1-7 alkyl", as employed herein, refers to at least one
C1-7 alkoxy group, as defined herein, appended to the parent molecular moiety
through a C1-7 alkyl group, as defined herein. Representative examples of C1-7 alkoxy
C1-7 alkyl include, but are not limited to methoxymethyl, ethoxymethyl, 2-methoxy-
ethyl, 2-ethoxyethyl, 3,3-dimethoxypropyl, 2,4-dimethoxybutyl and the like.
The term "imino C1-7 alkyl", as employed herein, refers to at least one imino
group (=NH) appended to the parent molecular moiety through a C1-7 alkyl group, as
defined herein.
The term "hydroxyimino C1-7 alkyl", as employed herein, refers to =N-OH
group appended to the parent molecular moiety through a C1-7 alkyl group, as defined
herein.
The term "5- or 6-membered heterocyclic ring" as employed herein, refers to
a saturated, partially saturated or aromatic ring with 5 or 6 ring atoms, of which 1-3
atoms are heteroatoms selected from a group consisting of N, O and S.
Representative examples of 5- or 6-membered heterocyclic ring include, but are not
limited to, pyrazolyl, pyridinyl,isoxazolyl, imidazolyl, furanyl, piperazinyl,
piperidinyl, rings and the like.
The term "5- or 6-membered carbocyclic ring" as employed herein, refers to a
saturated, partially saturated or aromatic ring with 5 or 6 ring atoms consisting of
carbon atoms only. Representative examples of 5- or 6-membered carbocyclic ring
include, but are not limited to, phenyl and cyclohexyl rings and the like.
The term "5-12 membered heterocyclic ring" as employed herein, refers to a
monocyclic or bicyclic saturated, partially saturated or aromatic ring with 5 to 12 ring
atoms, of which 1-4 atoms are heteroatoms selected from a group consisting of N, O
and S. Representative examples of 5 - 12 membered heterocyclic ring include, but are
not limited to, pyrazolyl, pyridinyl,isoxazolyl, imidazolyl, furanyl, piperazinyl,
piperidinyl, morpholinyl, pyrazinyl, indazolyl, pyrazolo[1,5-a]pyrimidinyl, isoxazolyl
and thiazolyl rings and the like.
The term "5-12 membered carbocyclic ring" as employed herein, refers to a
monocyclic or bicyclic saturated, partially saturated or aromatic ring with 5 to 12 ring
atoms consisting of carbon atoms only. Representative examples of 5-12 membered
carbocyclic rings include, but are not limited to, phenyl and naphtyl rings and the
like.
The term "optionally substituted" as used herein in connection with various
residues refers to halogen, C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, hydroxy, amino,
halo C1-7 alkyl, hydroxy C1-7 alkyl, C1-7 alkoxy, oxo C1-7 alkyl, C1-7 alkylamino,
amino C1-7 alkyl, methylsulfonyl, nitro, cyano or thiol substituents. Preferred
substituents are halogen, C1-7 alkyl, C3-7 cycloalkyl, hydroxy C1-7 alkyl, oxo C1-7
alkyl substituents. The "optionally substituted" groups may contain 1 to 3, preferably
1 or 2, most preferably 1 of the above mentioned substituents.
Examples of preferred compounds of formula (I) or (II) include
(S)-N-(1-(3-(3-Chloro-4-cyano-2,5-difluorophenyl)-1H-pyrazol-1-yl)propan-
2-yl)-2-methyl-1H-imidazole-5-carboxamide;
(S)-N-(1-(3-(3-Chloro-4-cyano-2,5-difluorophenyl)-1H-pyrazol-1-yl)-propan-
2-yl)-2-(2-hydroxypropan-2-yl)oxazole-5-carboxamide;
(S)-N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-6-cyanoimidazo[1,2-a]pyridine-2-carboxamide;
(S)-N-(1-(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-7-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-2-carboxamide;
(S)-N-(1-(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-3-isopropyl-1,2,4-oxadiazole-5-carboxamide;
(S)-N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-5,7-dimethylimidazo[1,2-c]pyrimidine-2-carboxamide;
(S)-5-((1H-Imidazol-1-yl)methyl)-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-
1 H-pyrazol-1-yl)propan-2-yl)isoxazole-3 -carboxamide;
(S)-N-(l-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-5-oxo-5,6-dihydroimidazo[l,2-c]pyrimidine-2-carboxamide;
(S)-N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-1,6-dihydropyrrolo[2,3-c]pyrazole-5-carboxamide;
(S)-N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)imidazo[2,1-b]thiazole-6-carboxamide;
(S)-N-(1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-6-nitroimidazo[ 1,2-a]pyridine-2-carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)-propan-2-
yl)-1 -isopropyl-2-methyl-1H-imidazole-4-carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-5-(2-hydroxypropan-2-yl)-1H-pyrazole-3-carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)-propan-2-
yl)-1 -(2,2-difluoroethyl)-2-methyl-1H-imidazole-4-carboxamide;
N-((S)-1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2-
yl)-1 -((R)-2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxamide;
(S)-N-( 1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-1'-methyl-1'H-1,4'-bipyrazole-3 -carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5 -fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-1H,2'H-3,3'-bipyrazole-5-carboxamide;
N-((S)-1 -(3-(3 -Chloro-4-cyano-5 -fluorophenyl)-1H-pyrazol-1-yl)-propan-2-
yl)-1 -((S)-2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5 -fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-3,3'-bipyridine-6-carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)-propan-2-
yl)-6-(3,3 -dimethylureido)imidazo [ 1,2-a]pyridine-2-carboxamide;
(S)-N-(1 -(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)-propan-2-
yl)-6-(methylsulfonamido)imidazo [ 1,2-a]pyridine-2-carboxamide;
N-((S)-1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-5-(1-hydroxy-2-methylpropyl)isoxazole-3-carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-5-(l,5-dimethyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole-3-carboxamide;
(S)-N-( 1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-5-(isoxazol-3-yl)-l,2,4-oxadiazole-3-carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)-propan-2-
yl)-3-(l H-imidazol-4-yl)-1H-pyrazole-5-carboxamide;
(S)-N-( 1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-2-(chloropropan-2-yl)oxazole-4-carboxamide;
(S)-N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2-
yl)-2-(2-propen-2-yl)oxazole-4-carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-N5-cyclopropylisoxazole-3,5-dicarboxamide;
(S)-2-Bromo-N-( 1 -(3 -(3 -chloro-4-cyano-5 -fluorophenyl)-1H-pyrazol-1 -yl)-
propan-2-yl)-1H-imidazole-4-carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-1 -(2-methylprop-1 -enyl)-1H-pyrazole-3 -carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-1 -cyclopropyl-1H-pyrazole-3 -carboxamide;
N-((S)-1 -(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-2-( 1 -hydroxyethyl)-1H-imidazole-4-carboxamide ;
(S)-2-acetyl-N-(1 -(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)-
propan-2-yl)-1H-imidazole-4- carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-2-(2-hydroxypropan-2-yl)-1H-imidazole-4-carboxamide ;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)-propan-2-
yl)-2-cyclopropyl-1 -methyl-1H-imidazole-4-carboxamide;
(S)-N4-( 1 -(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-1H-imidazole-2,4-dicarboxamide:
4-( 1 -(3 -((S)-1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl-
carbamoyl)-1H-pyrazol-5-yl)ethoxy)-4-oxobutanoic acid;
(S)-5-Chloro-N-( 1 -(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)-propan-2-
yl)pyrazine-2-carboxamide;
N-((S)-1 -(3-(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-1 -((S)-
2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxamide;
(S)-1 -Butyl-N-( 1 -(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
2-methyl-1H-imidazole-4-carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-5 -(2-
hydroxypropan-2-yl)-1H-pyrazole-3 -carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-1'-
methyl-1'H-1,4'-bipyrazole-3-carboxamide;
N-((S)-1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-1 -((R)-
2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxamide;
(S)-2-Bromo-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-
yl)-1H-imidazole-4-carboxamide;
N-((S)-1 -(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-5-(1 -
hydroxy-2-methylpropyl)isoxazole-3-carboxamide;
(S)-N-(1 -(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-1 -(2-
cyanoethyl)-2-methyl-1H-imidazole-4-carboxamide;
N-((S)-1 -(3 -(3-Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-1 -(1 -
cyanoethyl)-2-methyl-1H-imidazole-4-carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-1 -(2-
methylprop-1 -enyl)-1H-pyrazole-3 -carboxamide;
(S)-N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(lH-
imidazol-4-yl)-1H-pyrazole-5-carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-1 -cyclo-
propyl-1H-pyrazole-3-carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-1 -(6-
(dimethylamino)pyridin-3 -yl)-1H-pyrazole-3 -carboxamide;
(S)-N-(1-(3-(3-Chloro-4-cyanophenyl)-l H-pyrazol-1-yl)propan-2-yl)-4,5,6,7-
tetrahydropyrazolo [1,5 -a]pyridine-2-carboxamide);
N-((S)-1 -(3-(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-2-( 1 -
hydroxyethyl)-1H-imidazole-4-carboxamide;
(S)-N-(1-(3-(3-Chloro-4-cyanophenyl)-l H-pyrazol-1-yl)propan-2-yl)-2-iso-
propyl-1H-imidazole-4-carboxamide;
(S)-2-Butyl-N-( 1 -(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
1 -methyl-1H-imidazole-4-carboxamide;
(S)-N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(2-
hydroxypropan-2-yl)-1 -methyl-1H-imidazole-4-carboxamide;
(S)-N-( 1 -(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-1 -
methyl-2-( 1 -methyl-1H-pyrazol-4-yl)-1H-imidazole-4- carboxamide;
(S)-N-( 1 -(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-2-
cyclopropyl-1 -methyl-1H-imidazole-4-carboxamide;
(S)-N4-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-
imidazole-2,4-dicarboxamide;
(S)-N-(1 -(3-(4-Cyano-3-(trifluoromethyl)phenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-2-(2-hydroxypropan-2-yl)oxazole-4-carboxamide
and pharmaceutically acceptable salts thereof.
Compounds of the invention may be administered to a patient in
therapeutically effective amounts which range usually from about 0.1 to about 5000
mg, preferably from about 1 to about 2000 mg, per day depending on the age, weight,
ethnic group, condition of the patient, condition to be treated, administration route
and the androgen (AR) modulator used. The compounds of the invention can be
formulated into dosage forms using the principles known in the art. It can be given to
a patient as such or in combination with suitable pharmaceutical excipients in the
form of tablets, granules, capsules, suppositories, emulsions, suspensions or
solutions. Choosing suitable ingredients for the composition is a routine for those of
ordinary skill in the art. It is evident that suitable carriers, solvents, gel forming
ingredients, dispersion forming ingredients, antioxidants, colours, sweeteners,
wetting compounds and other ingredients normally used in this field of technology
may be also used. The compositions containing the active compound can be given
enterally or parenterally, the oral route being the preferred way. The contents of the
active compound in the composition is from about 0.5 to 100 %, preferably from
about 1 to about 85 %, per weight of the total composition.
The present invention will be explained in more detail by the following
examples. The examples are meant only for illustrating purposes and do not limit the
scope of the invention defined in claims.
EXPERIMENTS
Experiment 1.
AR binding affinity (Ki) of the test compound was measured.
AR antagonism of the test compound was measured as IC50 value (nM) to
human AR in hAR/HEK293 cells.
AR agonism of the test compound in AR overexpressing hAR/HEK293 cells
was measured as % of testosterone-induced AR activity at 10 µM concentration.
The IC50 value of the test compound for inhibition of mibolerone-induced
VCaP cell proliferation was measured.
Bicalutamide was used as a reference compound in the measurements.
Methods
Androgen Receptor Binding Assay
Androgen receptor (AR) binding affinities of test compounds were studied in
cytosolic lysates obtained from ventral prostates of castrated rats by competition
binding assay (Schilling K. and Liao S., The Prostate, 1984; 5(6):581-588). Cytosol
preparations and 1 nM [3H]mibolerone were incubated with increasing
concentrations of test compounds. To determine non-specific binding, parallel
incubations were carried out using excess of unlabelled testosterone. After
incubation, bound and free steroids were separated by treatment with dextran-coated
charcoal suspension. Bound radioactivity was determined by counting of supernatant
fraction in scintillation fluid. Radioactivity was measured using a Microbeta counter.
All data points were done as quadrublicates. Dissociation constant of
[3H]mibolerone for rat androgen receptor was determined by saturation binding assay
obtained from ventral prostates of castrated rats essentially as described (Isomaa V. et
al., Endocrinology, 1982; 111(3):833-843).
Analysis of data
For analysis of saturation binding affinity, one site binding equation
(hyperbola) was used

where
Bmax = the maximum specific binding
Kd = the equilibrium dissociation constant
X = radioligand concentration
Equilibrium dissociation constant (Ki) was calculated using the equation of
Cheng and Prusoff:

where
[radioligand] = the concentration of free radioligand
Kd = the dissociation constant of the radioligand for the receptor
IC50 = IC50 value measured in a competition radioligand binding assay
AR antagonism
Antagonism of test compounds for AR was measured by reporter gene assay
in human embryonic kidney (HEK293) cells stably transfected with an expression
vector encoding full-length human AR and androgen responsive luciferase reporter
gene construct (hAR/HEK293 cells). To determine antagonism for hAR, the cells
were treated simultaneously with increasing concentrations of the test compound and
submaximal concentration of testosterone (usually 0.45 nM). The final DMSO
concentration was 1%. All test compounds were studied in triplicates. The cells were
incubated for 24 before measurement of luciferase activity using Luciferase Assay
System (Promega Corporation).
Agonism of test compounds in AR overexpressing cells was measured by
reporter gene assay in HEK293 cells stably transfected with an expression vector
encoding full-length human AR and androgen responsive luciferase reporter gene
construct. A clone expressing high levels of androgen receptor (5 times more than
AR levels in AR-HEK293 cells) was selected to study agonism in AR overexpressing
cells. To determine agonism, the cells were treated with increasing concentrations of
the test compound. The final DMSO concentration was 1%. The test compounds
were studied in triplicates and luciferase activity was determined as described above.
Cell proliferation assays
The ability of test compounds to inhibit prostate cancer cell growth was
studied by measuring inhibition of cell proliferation using androgen-sensitive VCaP
prostate cancer cell line. Cells were seeded at a density of 50 000 cells/well in a 96-
well plate in the appropriate culture medium (phenol red-free RPMI-1640
supplemented with 10 % charcoal stripped FBS and 4 mM Glutamax + 100IU
penicillin, 100 IU streptomycin). The cells were allowed to attach for 2-3 days and
were subsequently treated with the test compounds in the presence of mibolerone (a
concentration capable of inducing submaximal increase in cell proliferation, usually
0.1 nM) for 4-5 days. Cell proliferation was measured using WST-1 Cell
Proliferation Assay (Roche).
EXAMPLES:
The end products of the following Examples were prepared as a mixture of
diastereomers unless otherwise indicated.
Example 1.
(S)-N-(1-(3-(3-Chloro-4-cyano-2,5-difluorophenyl)-1H-pyrazol-1-yl)propan-
2-yl)-2-methyl-1H-imidazole-5-carboxamide
a) 4-Bromo-2-chloro-3,6-difluoroaniline
2-Chloro-3,6-difluoroaniline (18.34 mmol, 3 g) was dissolved in ACN and
cooled to 0 °C with an ice bath. A solution of N-bromosuccinimide (18.34 mmol,
3.26 g) dissolved in ACN was added using a dropping funnel maintaining the internal
temperature of the reaction mixture below 5 °C. After addition the mixture was
stirred for 15 min letting the temperature slowly rise to ambient temperature. The
reaction mixture was diluted with 10 % aq. NaHSO3, stirred for 10 min and evapo-
rated to 1/3 of the original volume. The residue was diluted with water and extracted
twice with excess of ethyl acetate. The organics were dried, filtered and evaporated.
The product was purified with flash chromatography. 4.087 g of the title compound
was obtained. 'H-NMR (400 MHz, DMSO-d6): d 5.97 (s, 2H), 7.42-7.52 (m, 1H).
b)2-Chloro-3,6-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-
aniline
4-Bromo-2-chloro-3,6-difluoroaniline (12.37 mmol, 3 g) and 1-(tetrahydro-
2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (12.37 mmol, 3.44 g) were
dissolved in DME. Bis(triphenylphosphine)palladium(II) chloride (0.619 mmol,
0.434 g) and sodium carbonate, 2 M solution (12.37 mmol, 1.311 g) were added. The
reaction mixture was refluxed at 80 °C for 4 h and the stirring was continued at 50 °C
overnight. The solvent was evaporated and the residue was extracted three times with
EtOAc. The combined organics were washed with water and brine. The organics
were dried, filtered and evaporated. The crude product was purified by flash
chromatography. 1.935 g of the title compound was obtained. 1H-NMR (400 MHz,
MeOH-d4): d 1.49-1.79 (m, 2H), 1.80-1.88 (m, 1H), 1.93-2.19 (m, 2H), 2.33-2.47 (m,
1H), 3.47-3.77 (m, 1H), 3.96-4.07 (m, 1H), 5.09-5.43 (m, 1H), 6.30-6.39 (m, 1H),
7.04-7.13 (m, 1H), 7.50-7.63 (m, 1H).
c) 5-(3-Chloro-2,5-difluoro-4-iodophenyl)-1 -(tetrahydro-2H-pyran-2-yl)-1H-
pyrazole
Copper(I) iodide (7.43 mmol, 1.415 g) and tert-butyl nitrite (10.40 mmol,
1.073 g) were stirred in ACN. The mixture was warmed to 75 °C. 2-Chloro-3,6-di-
fluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)aniline (6.17 mmol, 1.935 g)
dissolved in ACN was added dropwise during 20 min. The resulting mixture was
stirred for 6 h at 75 °C. The mixture was cooled to RT and a solution of aqueous
sodium thiosulfate was added. The mixture was extracted three times with ethyl
acetate. The combined organics were washed with brine, dried, filtered and
evaporated. The crude product was purified by flash chromatography. 0.716 g of the
title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): d 1.48-1.74 (m, 3H),
1.81-2.02 (m, 2H), 2.30-2.44 (m, 1H), 3.47-3.58 (m, 1H), 3.86-3.96 (m, 1H), 5.28
(dd, 1H), 6.60-6.65 (m, 1H), 7.46-7.52 (m, 1H), 7.69-7.72 (m, 1H).
d)2-Chloro-3,6-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-
benzonitrile
5-(3-Chloro-2,5-difluoro-4-iodophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-
pyrazole (1.686 mmol, 0.716 g) and copper(I) cyanide (1.686 mmol, 0.151 g) were
suspended in NMP. The resulting mixture was stirred at 170 °C for 7 h. The reaction
was quenched by pouring the mixture onto 12 % ammonia solution and stirred for 20
min. The formed precipitate was filtered and washed with water. 0.276 g of the title
product was obtained. Identification after the next step due to low solubility of the
product.
e) 2-Chloro-3,6-difluoro-4-(1H-pyrazol-5-yl)benzonitrile
2-Chloro-3,6-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-
benzonitrile (0.853 mmol, 0.276 g) was stirred in ethanol. 10 % HCl/EtOH solution
(5 ml) was slowly added. The resulting mixture was stirred at RT overnight. The
reaction mixture was neutralized with NaHCO3 and extracted twice with EtOAc. The
combined organics were washed with water, dried, filtered and evaporated. 0.219 g
of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): d 6.86 (bs,
1H), 7.88-8.10 (m, 2H), 13.57 (bs, 1H).
f) (S)-4-(1-(2-Aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3,6-difluorobenzo-
nitrile
2-Chloro-3,6-difluoro-4-(1H-pyrazol-5-yl)benzonitrile (0.835 mmol, 0.2 g)
was dissolved in THF under nitrogen atmosphere. (S)-tert-butyl (1-hydroxypropan-2-
yl)carbamate (0.835 mmol, 0.146 g) and triphenylphosphine (1.252 mmol, 0.328 g)
were dissolved in THF and added to the previous mixture. The resulting mixture was
cooled to 0 °C. Di-tert-butyl azodicarboxylate (1.252 mmol, 0.288 g) was added in
small portions and stirred under cold conditions for 10 min. The flask was warmed to
RT and stirred overnight. The solvent was evaporated. The residue was dissolved in
ethanol and 10 % HCl(g)/EtOH solution (15 ml) was slowly added. The resulting
mixture was stirred overnight. The mixture was diluted with water and extracted
twice with DCM. The combined organics were washed with water. The aqueous
phases were combined and the pH was adjusted to 12 with 2 M NaOH. The aqueous
phase was extracted three times with DCM. The combined organics were dried,
filtered and evaporated. 0.167 g of the title compound was obtained. 1H-NMR (400
MHz, CDCl3): d 1.17 (d, 3H), 1.31 (bs, 2H), 3.53 (bs, 1H), 3.88-4.04 (m, 1H), 4.09 -
4.26 (m, 1H), 6.82 (dd, 1H), 7.55 (d, 1H), 7.88 (dd, 1H).
g)(S)-N-(1-(3-(3-Chloro-4-cyano-2,5-difluorophenyl)-1H-pyrazol-1-yl)-
propan-2-yl)-2-methyl-1H-imidazole-5-carboxamide
2-Methyl-1H-imidazole-4-carboxylic acid (0.202 mmol, 0.026 g) was
dissolved in DMF (5 ml) under nitrogen atmosphere. EDCI (0.202 mmol, 0.039 g),
DIPEA (0.270 mmol, 0.035 g) and HBTU (0.034 mmol, 0.013 g) were added and the
resulting mixture was stirred for 20 min at RT. (S)-4-(1-(2-aminopropyl)-1H-pyrazol-
3-yl)-2-chloro-3,6-difluorobenzonitrile (0.135 mmol, 0.04 g) dissolved in DMF (2
ml) was added and the resulting mixture was stirred at RT for 3 days. The mixture
was diluted with water and EtOAc, washed with 2M Na2CO3, water and brine. The
combined organics were dried, filtered and evaporated. The crude product was
purified by flash chromatography. 0.0324g of the title compound was obtained. 1H-
NMR (400 MHz, MeOH-d4) d ppm 1.23 (d, 3H), 2.38 (s, 3H), 4.28-4.47 (m, 2H),
4.48-4.58 (m, 1H), 6.77-6.82 (m, 1H), 7.46 (s, 1H), 7.77 (d, 1H), 7.83-7.96 (m, 1H).
Example 2.
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-2,5-difluorophenyl)-1H-pyrazol-1 -yl)-propan-
2-yl)-2-(2-hydroxypropan-2-yl)oxazole-5-carboxamide
a) Ethyl 2-chlorooxazole-4-carboxylate
Ethyl 2-aminooxazole-4-carboxylate (20 g, 128 mmol) was added to a
solution of cupric chloride (32.8 g, 192 mmol) and t-butylnitrite (23 ml, 192 mmol)
in ACN (500 ml) at 80 °C and the resulting mixture was refluxed for 4 h. The
reaction mixture was concentrated and treated with concentrated HC1 and extracted
with EtOAc. The product was purified with flash chromatography. Yield 10.5 g. 1H-
NMR (400MHz; CDCl3): d 1.36 (t, 3H), 4.39 (q, 2H), 8.47 (s, 1H).
b) Ethyl 2-(1-ethoxyvinyl)oxazole-4-carboxylate
Ethyl 2-(1-ethoxyvinyl)oxazole-4-carboxylate was prepared using the
procedure described in Example 33(a), starting from ethyl 2-chlorooxazole-4-
carboxylate (10.5 g, 59.8 mmol) and tributyl(l-ethoxyvinyl)stannane (24 ml, 65.8
mmol), The product was purified with flash-chromatography. Yield 10.3 g. 1H-NMR
(400MHz; CDCl3): d ppm 1.23-1.46 (m, 6H), 3.94-3.99 (m, 2H), 4.36-4.42 (m, 2H),
4.8 (d, 1H), 5.33 (s, 1H), 8.19 (s, 1H).
c) Ethyl 2-acetyloxazole-4-carboxylate
Ethyl 2-acetyloxazole-4-carboxylate was prepared using the procedure
described in Example 33(b), starting from ethyl 2-(1-ethoxyvinyl)oxazole-4-carboxy-
late (10.3 g, 48.8 mmol). Yield 7.0 g. 1H-NMR (400MHz; CDCl3): d 1.46 (t, 3H),
2.73 (s, 3H), 4.41 (q, 2H), 8.34 (s, 1H).
d) Ethyl 2-(2-hydroxypropan-2-yl)oxazole-4-carboxylate
Into a flask containing a solution of ethyl 2-acetyloxazole-4-carboxylate (2.0
g, 10.9 mmol) in THF (50 ml), 3M solution of MeMgl in ether (5.0 ml, 13.11 mmol)
was added at 0 °C. The resulting mixture was stirred at RT for 5 h. The mixture was
quenched with aqueous NH4Cl solution and extracted with EtOAc. The organic layer
was concentrated and purified with flash chromatography. Yield 1.0 g. 1H-NMR (400
MHz; CDCl3): d 1.59 (s, 3H), 1.66 (s, 6H), 2.70 (s, 1H), 4.39 (q, 2H), 8.17 (s, 1H).
e) 2-(2-Hydroxypropan-2-yl)oxazole-4-carboxylic acid
2-(2-Hydroxypropan-2-yl)oxazole-4-carboxylic acid was prepared using the
procedure described in Example 32(d) starting from ethyl 2-(2-hydroxypropan-2-yl)-
oxazole-4-carboxylate (1.0 g, 5.02 mmol). Yield 500 mg. 1H-NMR (400 MHz;
DMSO-d6): d 1.50 (s, 6H), 5.67 (s,lH), 8.67(s, 1H), 12.98 (s, 1H).
f)(S)-N-(1-(3-(3-Chloro-4-cyano-2,5-difluorophenyl)-1H-pyrazol-1-yl)-
propan-2-yl)-2-(2-hydroxypropan-2-yl)oxazole-5-carboxamide
2-(2-Hydroxypropan-2-yl)oxazole-4-carboxylic acid (0.514 mmol, 0.088 g)
was dissolved in DMF (10 ml) under nitrogen atmosphere. EDCI (0.514 mmol, 0.098
g), DIPEA (0.856 mmol, 0.111 g) and HOBt (0.214 mmol, 0.029 g) were added and
the resulting mixture was stirred for 20 min at RT. (S)-4-(1-(2-amino-propyl)-1H-
pyrazol-3-yl)-2-chloro-3,6-difluorobenzonitrile (0.428 mmol, 0.127 g) dissolved in
DMF (5 ml) was added and the resulting mixture was stirred at RT for 3 days. The
mixture was diluted with water and EtOAc, washed with 2 M Na2CO3, water and
brine. The combined organics were dried, filtered and evaporated. The crude product
was purified by flash chromatography. 0.059 g of the title compound was obtained.
1H-NMR (400 MHz, MeOH-d4): d 1.26 (d, 3H), 1.61 (s, 6H), 4.34-4.46 (m, 2H),
4.54-4.63 (m, 1H), 6.78-6.82 (m, 1H), 7.76 (d, 1H), 7.87-7.93 (m, 1H), 8.24 (s, 1H).
Example 3.
(S)-N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-6-cyanoimidazo[ 1,2-a]pyridine-2-carboxamide
a)4-Bromo-3-chloro-5-fluoroaniline
3-Chloro-5-fluoroaniline (2061 mmol, 300 g) was dissolved in ACN (3000
ml) and the solution cooled to 0°C. NBS (2061 mmol, 367 g) was added to the
reaction mixture in small portions keeping the temperature below 10 °C. Reaction
mixture was stirred at 10 ± 5 °C for 3.5 h. 10 % Aqueous NaHSO3 was added and the
reaction mixture was concentrated under vacuum to remove organic solvents. Water
and DCM was added, stirred for 15 min and the phases were separated. The water
phase was extracted with DCM. The combined organics were washed with water.
The organic phase was evaporated. 2-Propanol was added to the residue and distilled
until the steam temperature was 80 °C. Water was added and the temperature was
kept at 40 ± 10 °C. The mixture was cooled to 5 °C and stirred for 4 h. The precipi-
tate was removed by filtration, washed with water and dried under vacuum. 440.7 g
of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): d 5.87 (s, 2H),
6.42-6.49 (m, 1H), 6.62-6.66 (m, 1H).
b)4-Amino-2-chloro-6-fluorobenzonitrile
4-Bromo-3-Chloro-5-fluoroaniline (980 mmol, 220 g), copper(I)cyanide (980
mmol, 88 g) and NMP (1000 ml) were added into the reaction flask, heated up to 160
°C and stirred for 3 h to complete the reaction. The reaction mixture was cooled to
RT. Water and 25 % ammonia solution was added keeping the mixture at RT. The
mixture was stirred overnight and the formed precipitate was separated by filtration
and flushed with water. The filtered precipitate was dried under vacuum to give
117.7 g of the title compound. 1H-NMR (400 MHz, DMSO-d6): d 6.41-6.47 (m, 1H),
6.58-6.62 (m, 1H), 6.86 (bs, 2H).
c)2-Chloro-6-fluoro-4-iodobenzonitrile
4-Amino-2-chloro-6-fluorobenzonitrile (293 mmol, 50 g) was dissolved in
ACN (1550 ml) and water (460 ml). Sulphuric acid (879 mmol, 46.9 ml) was added
carefully. The reaction mixture was cooled to 0 °C. Sodium nitrite (322 mmol, 22.25
g) dissolved in water (150 ml) was slowly added keeping the reaction temperature
below 10 °C. Thereafter potassium iodide (586 mmol, 97 g) dissolved in 150 ml of
water was added slowly while keeping the reaction temperature below 10 °C. The
reaction mixture was allowed to warm up to RT and stirred overnight at RT. The
phases were separated and the organic phase was evaporated. Ethyl acetate was
added into the evaporation residue and washed three times with 10 % aqueous
NaHSO3. The organic phase was evaporated and the residue was dissolved in DCM.
5 g of active carbon was added and stirred for 2 h. The mixture was filtered through a
layer of Celite and washed with DCM. The DCM-phase was evaporated and heptanes
were added into the residue. The mixture was heated to 60 °C and stirred for 2 h. The
oil and heptanes layers were separated by decantation. The heptanes phase was
evaporated and 39.6 g of the title compound was obtained. 1H-NMR (400 MHz,
DMSO-d6): d 8.06-8.10 (m, 1H), 8.10-8.11 (m, 1H).
d) 2-Chloro-6-fluoro-4-( 1 -(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzo-
nitrile
2-Chloro-6-fluoro-4-iodobenzonitrile (291 mmol, 82 g), THF (800 ml) and 1-
(tetra-hydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (350 mmol, 97
g) were added into a flask and stirred. Bis(triphenylphosphine)palladium(II) chloride
(14.57 mmol, 10.22 g), sodium carbonate (699 mmol, 74.1 g) and water (350 ml)
were added. The resulting mixture was heated to 60 °C and stirred for 2 h. The
solvents were evaporated. Water was added and the mixture was left to stir overnight.
EtOAc and water were added and the insoluble precipitates were removed by
filtration. The organic phase was separated from the filtrate and the water phase was
extracted with more EtOAc. The combined organics were evaporated and the residue
was combined with previously filtrated solid. The collected solids were suspended in
EtOH and water. The mixture was heated to boiling point, allowed to cool to RT and
stirred for an hour at ambient temperature. The mixture was cooled to 0 °C and
stirred for another hour. The precipitate was washed with a small amount of cold 1:1
water/EtOH. The filtered solids were dried under vacuum. 91.2 g of the title
compound was obtained. 1H-NMR (400 MHz, DMSO-d6): d 1.50-1.70 (m, 3H), 1.79-
1.89 (m, 1H), 1.92-2.03 (m, 1H), 2.30-2.44 (m, 1H), 3.56-3.67 (m, 1H), 3.93-4.02
(m, 1H), 5.36 (dd, 1H), 6.78 (d, 1H), 7.66 (d, 1H), 7.73 (dd, 1H), 7.80-7.83 (m, 1H).
e) 2-Chloro-6-fluoro-4-(lH-pyrazol-5-yl)benzonitrile hydrochloride
2-Chloro-6-fluoro-4-( 1 -(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzo-
nitrile (298 mmol, 91 g) and 10 % HCl/EtOH (339 ml) were mixed in a flask under
nitrogen atmosphere. The resulting mixture was refluxed for 5 h during which 113 ml
of 10 % HCl/EtOH was added. The mixture was cooled to RT and stirred overnight.
Next morning 40 ml of 10 % HCl/EtOH was added and the mixture was refluxed for
3.5 h, cooled to 0 °C and stirred for an hour. The precipitate was removed by
filtration and dried under vacuum. Half of the solvents in filtrate were evaporated and
the remaining mixture was stirred at 0 °C for 3 h. The precipitates were again
removed by filtration and dried under vacuum. The collected solids were combined
to afford 51.8 g of the title compound. 1H-NMR (400 MHz, DMSO-d6): d 7.06 (d,
1H), 7.88 (d, 1H), 7.95 (dd, 1H), 8.03-8.07 (m, 1H).
f) 2-Chloro-6-fluoro-4-(1H-pyrazol-5-yl)benzonitrile
2-Chloro-6-fluoro-4-(1H-pyrazol-5-yl)benzonitrile hydrochloride (201 mmol,
51.8 g) was dissolved in THF (510 ml). Sodium hydroxide 50 % (401 mmol, 32.1 g)
was added and the resulting mixture was stirred at RT for 3 h. Almost all the solvents
were evaporated and water was added to the residue. The mixture was stirred
overnight at RT. The precipitate was removed by filtration the solid was flushed
twice with water. The solid was dried under vacuum. 35.8 g of the title compound
was obtained. 1H-NMR (400 MHz, DMSO-d6): d 7.05 (d, 1H), 7.88-7.97 (m, 2H),
8.02-8.07 (m, 1H), 13.37 (bs, 1H).
g) (S)-4-( 1 -(2-Aminopropyl)-1H-pyrazol-3 -yl)-2-chloro-6-fluorobenzonitrile
(S)-tert-Butyl (1-hydroxypropan-2-yl)carbamate (259 mmol, 45.4 g) and tri-
phenylphosphine (259 mmol, 68.0 g) were mixed in dry EtOAc (380 ml) under
nitrogen atmosphere. 2-Chloro-6-fluoro-4-(1H-pyrazol-3-yl)benzonitrile (130 mmol,
35.9 g) was added and the resulting mixture was stirred for 10 min. DIAD (259
mmol, 52.4 g) was added slowly while keeping the temperature between 15-25 °C
with an ice bath. After the addition the mixture was allowed to warm to RT and
stirred for 4 h. Water and concentrated HCl (1296 mmol, 106 ml) was added to the
mixture and stirred for 6 days during which more HCl (107 ml in total) was added.
Water and DCM was added and the mixture was stirred for a while before separating
the phases. The organic phase was extracted twice with water. The water phases were
combined and washed twice with DCM. DCM was added to the water phase and the
pH of the water phase was adjusted to 12.5 with 50 % NaOH. The phases were
separated and the water phase was extracted once more with DCM. The DCM phases
were combined and washed once with water. The separated DCM phase was
evaporated and dried under vacuum. 24.0 g of the title compound was obtained. 1H-
NMR (400 MHz, DMSO-d6): d 0.96 (d, 3H), 1.18 (bs, 2H), 3.19-3.29 (m, 1H), 3.97-
4.08 (m, 2H), 7.03 (d, 1H), 7.85-7.92 (m, 2H), 7.98-8.02 (m, 1H).
h) (S)-N-( 1 -(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-6-cyanoimidazo[ 1,2-a]pyridine-2-carboxamide
6-Cyanoimidazo[1,2-a]pyridine-2-carboxylic acid (0.770 mmol, 0.144 g),
HOBt (0.770 mmol, 0.104 g) and DIPEA (1.539 mmol, 0.199 g) were dissolved in
DCM (5 ml) and DMF (1 ml). EDCI (0.770 mmol, 0.148 g) was added and the
resulting mixture was stirred for 10 min at RT. (S)-4-(1-(2-aminopropyl)-1H-pyrazol-
3-yl)-2-chloro-6-fluorobenzonitrile (0.592 mmol, 0.22 g) dissolved in small amount
of DCM was added and the reaction mixture was stirred overnight at RT. The
mixture was diluted with DCM, washed with 1M Na2CO3 and water. The organic
phase was dried, filtered and evaporated. The crude product was purified by tritu-
ration from ACN. 0.054 g of the title compound was obtained. 1H-NMR (400 MHz,
DMSO-d6): d 1.15 (d, 3H), 4.31-4.45 (m, 2H), 4.46-4.57 (m, 1H), 7.00 (d, 1H), 7.61-
7.66 (m, 1H), 7.72-7.77 (m, 1H), 7.86-7.92 (m, 2H), 7.93-7.96 (m, 1H), 8.35-8.37
(m, 1H), 8.69 (d, 1H), 9.34-9.37 (m, 1H).
Example 4.
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-7-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-2-carboxamide
a) Ethyl 7-oxo-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrimidine-2-carboxylate
Ethyl 2-amino-1H-imidazole-4-carboxylate (6.45 mmol, 1 g) and triethyl-
amine (10.04 mmol, 1.016 g) were suspended in dry ACN (30 ml) and cooled to 0
°C. Acryloyl chloride (9.67 mmol, 0.875 g) dissolved in dry ACN (4 ml) was added
dropwise. The resulting mixture was slowly warmed to RT and subsequently heated
to 50 °C for 16 h. The solvent was evaporated and the residue purified by flash
chromatography. 0.358 g of the title compound was obtained. 1H-NMR (400 MHz,
CDCl3): d 1.37 (t, 3H), 2.92 (t, 2H), 4.18 (t, 2H), 4.37 (q, 2H), 7.40 (s, 1H), 8.78 (bs,
1H).
b) 7-Oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-2-carboxylic acid
Ethyl 7-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-2-carboxylate (1.711
mmol, 0.358 g) was dissolved in ethanol (5 ml) and cooled to 0 °C. 1N solution of
NaOH (5 ml) was slowly added. The resulting mixture was heated to 60 °C for 1.5 h.
Ethanol was evaporated, the residue diluted with tert-butyl methyl ether and acidified
with 2 N HCl solution under cold conditions. The mixture was stirred for overnight.
DCM and water was added and the precipitate was filtered. Phases in the filtrate were
separated and the water phase was evaporated. The residue from water and precipi-
tate were combined. 0.592 g of the title compound was obtained. 1H-NMR (400
MHz, DMSO-d6): d 2.73 (t, 2H), 4.12 (t, 2H), 7.58 (s, 1H), 11.09 (bs, 1H).
c) (S)-N-( 1 -(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-7-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-2-carboxamide
7-Oxo-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrimidine-2-carboxylic acid (1.513
mmol, 0.274 g) was dissolved in DMF (5 ml) under nitrogen atmosphere. EDCI
(1.891 mmol, 0.362 g), DIPEA (3.78 mmol, 0.489 g) and HOBt (1.891 mmol, 0.255
g) were added and the resulting mixture was stirred for 20 min at RT. (S)-4-(1-(2-
Aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (1.260 mmol, 0.351 g)
dissolved in DMF (5 ml) was added and the resulting mixture was stirred at RT for 2
days. The mixture was diluted with water and EtOAc, washed with 2M Na2CO3,
water and brine. The combined organics were dried, filtered and evaporated. The
crude product was purified by preparative HPLC. 0.0089 g of the title compound was
obtained. 1H-NMR (400 MHz, CDCl3): d 1.28 (d, 3H), 2.89 (t, 2H), 4.16 (t, 2H),
4.33-4.39 (m, 2H), 4.54-4.65 (m, 1H), 6.59 (d, 1H), 7.36 (s, 1H), 7.53 (d, 1H), 7.57
(dd, 1H), 7.72-7.75 (m, 1H), 7.83 (d, 1H).
Example 5.
(S)-N-( 1 -(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-3-isopropyl-l,2,4-oxadiazole-5-carboxamide
a) Ethyl 3-isopropyl-l,2,4-oxadiazole-5-carboxylate
(E)-N'-hydroxyisobutyrimidamide (27.6 mmol, 2.82 g) was dissolved in
pyridine (10 ml) and cooled to 0 °C. Ethyl oxalyl chloride (35.9 mmol, 4.90 g) was
added dropwise to the previous mixture and stirred for 10 min at 0 °C, warmed to RT
and later heated to 70 °C for 1.5 h. The mixture was poured to ice-cold water. The
residue was extracted twice with t-butyl methyl ether and water. The organic phase
was dried, filtered and evaporated. The crude product was purified by flash
chromatography. 1.919 g of the title compound was obtained. 1H-NMR (400 MHz,
CDCl3): d 1.39 (d, 6H), 1.47 (t, 3H), 3.14-3.28 (m, 1H), 4.54 (q, 2H).
b) 3-Isopropyl-l,2,4-oxadiazole-5-carboxylic acid
Ethyl 3-isopropyl-l,2,4-oxadiazole-5-carboxylate (10.42 mmol, 1.919 g) was
dissolved in EtOH (20 ml). Sodium hydroxide pellets (12.50 mmol, 0.500 g) were
dissolved in cold water (10 ml) and solution slowly added. The resulting solution was
heated at 60 °C for 1.5 h. EtOH was removed under vacuum. The residue was diluted
with tert-butyl methyl ether. The mixture was acidified under cold conditions by
adding 2 N HCl solution. The mixture was stirred overnight and washed with DCM.
Water phase was evaporated precipitating the product. 1.673 g of the title compound
was obtained. 1H-NMR (400 MHz, D2O): d 1.33 (d, 6H), 3.10 - 3.25 (m, 1H).
c) (S)-N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-3-isopropyl-l,2,4-oxadiazole-5-carboxamide
3-Isopropyl-l,2,4-oxadiazole-5-carboxylic acid (1.281 mmol, 0.2 g) was
dissolved in DMF (5 ml) under nitrogen atmosphere. EDCI (1.601 mmol, 0.307 g),
DIPEA (3.20 mmol, 0.414 g) and HOBt (1.601 mmol, 0.216 g) were added and the
resulting mixture was stirred for 20 min at RT. (S)-4-(1-(2-Aminopropyl)-1H-pyra-
zol-3-yl)-2-chloro-6-fluorobenzonitrile (1.067 mmol, 0.298 g) dissolved in DMF (5
ml) was added and the resulting mixture was stirred at RT for 2 days. The mixture
was diluted with water and EtOAc, washed with 2 M Na2CO3, water and brine. The
combined organics were dried, filtered and evaporated. The crude product was
purified by preparative HPLC. 0.0056 g of the title compound was obtained. 'H-
NMR (400 MHz, CDCl3): d 1.25 (d, 3H), 1.38 (d, 6H), 3.11-3.26 (m, 1H), 4.26-4.35
(m, 1H), 4.41-4.50 (m, 1H), 4.55-4.67 (m, 1H), 6.65-6.69 (m, 1H), 7.54-7.57 (m,
1H), 7.64-7.69 (m, 1H), 7.74-7.77 (m, 1H), 8.39 (d, 1H).
Example 6.
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5 -fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-5,7-dimethylimidazo[1,2-c]pyrimidine-2-carboxamide
a) Ethyl 5,7-dimethylimidazo[1,2-c]pyrimidine-2-carboxylate
4-Amino-2,6-dimethylpyrimidine (16.24 mmol, 2 g) was mixed with ethanol
(30 ml) and stirred well. Ethyl bromopyruvate (20.30 mmol, 3.96 g) was added in
small portions. The resulting mixture was refluxed for 5.5 h and stirred at RT
overnight. The solvent was evaporated, DCM was added and washed with Na2HCO3.
The organic phase was dried, filtered and evaporated. The crude product was purified
by flash chromatography and trituration from EtOAc/heptane, respectively. 0.287 g
of the title product was obtained. 1H-NMR (400 MHz, DMSO-d6): d 1.33 (t, 3H),
2.42 (d, 3H), 2.80 (s, 3H), 4.33 (q, 2H), 7.32 (s, 1H), 8.50 (d, 1H).
b) 5,7-Dimethylimidazo[1,2-c]pyrimidine-2-carboxylic acid
Ethyl 5,7-dimethylimidazo[1,2-c]pyrimidine-2-carboxylate (1.268 mmol,
0.278 g) was dissolved in ethanol (10 ml) and cooled to 0 °C. 2 M NaOH solution
was added to the reaction mixture. The resulting mixture was stirred at 0 °C for 30
min and for an hour at RT. The solvent was evaporated and water added to the
residue. The water phase was made acidic with 1 M HCl and extracted three times
with EtOAc. The combined organics were dried, filtered and evaporated. 0.292 g of
the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): d 2.46 (s, 3H),
2.83 (s, 3H), 7.39 (s, 1H), 8.57 (s, 1H).
c) (S)-N-( 1 -(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-5,7-dimethylimidazo[ 1,2-c]pyrimidine-2-carboxamide
The title compound was prepared using the procedure described in Example
3(h) starting from 5,7-dimethyl-imidazo[1,2-c]pyrimidine-2-carboxylic acid (0.753
mmol, 0.144 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluoro-
benzonitrile (0.538 mmol, 0.2 g). DMF (6 ml) was used as a solvent and HBTU
(0.054 mmol, 0.020 g) was used instead of HOBt. The crude product was purified by
trituration from ACN. 0.045 g of the title compound was obtained. 1H-NMR (400
MHz, CDCl3): d 1.26 (d, 3H), 2.53-2.56 (m, 3H), 2.82 (s, 3H), 4.30 (dd, 1H), 4.48
(dd, 1H), 4.60-4.72 (m, 1H), 6.63 (d, 1H), 7.23-7.26 (m, 1H), 7.52 (d, 1H), 7.75-7.83
(m, 2H), 8.00-8.06 (m, 1H), 8.27 (d, 1H).
Example 7.
(S)-5-((1H-Imidazol-1-yl)methyl)-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-
1 H-pyrazol-1 -yl)propan-2-yl)isoxazole-3-carboxamide
a) 5-(Bromomethyl)isoxazole-3-carboxylic acid
Ethyl 5-(bromomethyl)isoxazole-3-carboxylate (4.27 mmol, 1 g) and lithium
hydroxide (10.68 mmol, 0.256 g) were dissolved in THF (6.5 ml) and water (6.5 ml).
The resulting mixture was stirred for 30 min at RT. The pH was adjusted to 4 with 1
M HCl and diluted with water. The mixture was extracted three times with EtOAc.
The combined organics were dried, filtered and evaporated. 0.543 g of the title
compound was obtained. 1H-NMR (400 MHz, DMSO-d6): d 4.88 (s, 2H), 6.92 (s,
1H), 14.09 (bs, 1H).
b) (S)-5-(Bromomethyl)-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyra-
zol-1 -yl)propan-2-yl)isoxazole-3 -carboxamide
5-(Bromomethyl)isoxazole-3-carboxylic acid (0.718 mmol, 0.148 g) was
dissolved in DCM (5 ml) and THF (1 ml). 1,3-Dicyclohexylcarbodiimide (0.718
mmol, 0.148 g) was added and the resulting mixture was stirred at RT. The
precipitate formed was filtered and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-
chloro-6-fluorobenzonitrile (0.359 mmol, 0.1 g), triethylamine (0.359 mmol, 0.036 g)
and dry DCM (5 ml) was added to the filtrate. The filtrate was stirred at RT under
nitrogen atmosphere for two days during which more 1,3-dicyclohexylcarbo-diimide
(0.148 g), triethylamine (0.050 ml) and 5-(bromomethyl)isoxazole-3-carboxylic acid
(0.1 g) were added. The reaction mixture was diluted with DCM and washed with
NaHCO3. The organic phase was dried, filtered and evaporated. The crude product
was purified with flash chromatography. 0.064 g of the title compound was obtained.
1H-NMR (400 MHz, CDCl3): d 1.25 (d, 3H), 4.00-4.09 (m, 2H), 4.23-4.31 (m, 1H),
4.41-4.48 (m, 1H), 4.53-4.63 (m, 1H), 6.60-6.66 (m, 1H), 6.74-6.78 (m, 1H), 7.48-
7.53 (m, 1H), 7.64 (d, 1H), 7.79-7.88 (m, 2H).
c) (S)-5-((1 H-Imidazol-1 -yl)methyl)-N-( 1 -(3-(3-chloro-4-cyano-5-fluoro-
phenyl)-1H-pyrazol-1 -yl)propan-2-yl)isoxazole-3 -carboxamide
(S)-5-(Bromomethyl)-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-
l-yl)propan-2-yl)isoxazole-3-carboxamide (0.137 mmol, 0.064 g) was suspended in
DMF (5 ml). Imidazole (2.74 mmol, 0.187 g) was added and the resulting mixture
was stirred at RT for 2.5 h. The reaction mixture was heated to 60 °C for 1.5 h. The
mixture was diluted with EtOAc and washed four times with water. The organic
phase was dried, filtered and evaporated. The crude product was purified by
preparative HPLC. 0.017 g of the title compound was obtained. 1H-NMR (400 MHz,
DMSO-d6): d 1.15 (d, 3H), 4.31 (d, 2H), 4.37-4.50 (m, 1H), 5.50 (s, 2H), 6.63 (s,
1H), 6.94 (s, 1H), 6.99 (d, 1H), 7.22-7.24 (m, 1H), 7.76 (s, 1H), 7.83 (d, 1H), 7.84-
7.88 (m, 1H), 7.96 (s, 1H), 8.81 (d, 1H).
Example 8: (S)-N-( 1 -(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -
yl)propan-2-yl)-5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-2-carboxamide
a) ethyl 5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-2-carboxylate
Ethyl bromopyruvate (18.00 mmol, 3.51 g) was dissolved in ethanol (50 ml).
Cytosine (18.00 mmol, 2 g) was added and the resulting mixture was refluxed for 5.5
h. The mixture was evaporated and DCM was added. The precipitate was filtered and
washed with water. The filtrate was washed with NaHCO3, water and evaporated.
The evaporation residue and the previously filtered precipitate were purified by flash
chromatography and trituration from water, respectively. 0.526 g of the title
compound was obtained. 1H-NMR (400 MHz, DMSO-d6): d 1.31 (t, 3H), 4.29 (q,
2H), 6.60 (d, 1H), 7.30-7.38 (m, 1H), 8.22 (s, 1H), 11.77 (bs, 1H).
b) 5-Oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-2-carboxylic acid
Ethyl 5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-2-carboxylate (2.510
mmol, 0.52 g) was suspended in ethanol (20 ml). Cesium carbonate (5.02 mmol,
1.635 g) dissoved in water (4 ml) was added and the resulting mixture was stirred at
RT for 3.5 h after which the mixture was refluxed for 8 h. The ethanol was evapo-
rated, and the residue was diluted with water. The pH was adjusted to 4 with 1 M
HCl and the solvent was evaporated. The residue was purified by trituration from
DMF. 0.137 g of the title compound was obtained. 1H-NMR (400 MHz, CDCl3): d
7.17-7.31 (m, 2H), 7.86-7.99 (m, 1H).
c) (S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5 -fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-2-carboxamide
5-Oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-2-carboxylic acid (0.323 mmol,
0.058 g), HBTU (0.027 mmol, 10.21 mg), DIPEA (0.323 mmol, 0.042 g) and EDCI
(0.323 mmol, 0.062 g) were suspended in DMF (2 ml) and the resulting mixture was
stirred at RT for 10 min. (S)-4-(1-(2-Aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-
fluorobenzonitrile (0.269 mmol, 0.1 g) dissolved in DMF (2 ml) was added and the
resulting mixture was stirred for 17 h at RT. At this point more starting materials
were added so that the amount of every starting material was raised by half of the
original amount. The amount of (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-
6-fluorobenzonitrile was not changed. The reaction was continued for another 22 h
after which the temperature was raised to 80 °C for 4.5 h. The reaction mixture was
diluted with EtOAc and washed with 1M Na2CO3, brine and water. The organic
phase was dried, filtered and evaporated. The crude product was purified by
preparative HPLC. 0.006 g of the title compound was obtained. 1H-NMR (400 MHz,
MeOH-d4): d 1.25 (d, 3H), 4.30-4.37 (m, 1H), 4.42-4.49 (m, 1H), 4.54-4.65 (m, 1H),
6.61 (dd, 1H), 6.70 (d, 1H), 7.18 (d, 1H), 7.63 (d, 1H), 7.75-7.82 (m, 2H), 8.26 (s,
1H).
Example 9.
(S)-N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-l,6-dihydropyrrolo[2,3-c]pyrazole-5-carboxamide
a) Ethyl l,6-dihydropyrrolo[2,3-c]pyrazole-5-carboxylate
3-Aminopyrazole (1.203 mmol, 0.1 g), ethyl bromopyruvate (1.504 mmol,
0.293 g) and methanol were added into a flask and refluxed for 1.5 h. The solvent
was evaporated and the residue was dissolved in DCM and washed with Na2HCO3.
The organic phase was dried, filtered and evaporated. 0.238 g of the title compound
was obtained. 1H-NMR (400 MHz, DMSO-d6): d 1.30 (t, 3H), 4.26 (q, 2H), 6.76 (d,
1H), 7.68 (s, 1H).
b) 1,6-Dihydropyrrolo[2,3-c]pyrazole-5-carboxylic acid
Ethyl l,6-dihydropyrrolo[2,3-c]pyrazole-5-carboxylate (1.328 mmol, 0.238 g)
was dissolved in ethanol (10 ml). Cesium carbonate (2.66 mmol, 0.866 g) dissolved
in water (2 ml) was added and the resulting mixture was stirred at RT for a day after
which more cesium carbonate (2.66 mmol, 0.866 g) dissolved in water (2 ml) was
added. The temperature was raised to 80 °C for 7 h. Ethanol was evaporated and the
residue was diluted with water. pH was adjusted to 4 with 2 M HCl and extracted
three times with EtOAc and washed with water. The combined organics were dried,
filtered and evaporated. 0.041 g of the title compound was obtained. LC-MS [M+1]:
152.
c) (S)-N-( 1 -(3-(3 -Chloro-4-cyano-5 -fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-1,6-dihydropyrrolo[2,3-c]pyrazole-5-carboxamide
The title compound was prepared using the procedure described in Example
3(h), starting from l,6-dihydropyrrolo[2,3-c]pyrazole-5-carboxylic acid (0.280 mmol,
0.042 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzo-
nitrile (0.215 mmol, 0.080 g). The crude product was purified by preparative HPLC.
0.0164 g of the title compound was obtained. 1H-NMR (400 MHz, MeOH-d4): d 1.29
(d, 3H), 4.27-4.34 (m, 1H), 4.36-4.43 (m, 1H), 4.50-4.60 (m, 1H), 6.75-6.79 (m, 2H),
7.58 (s, 1H), 7.60-7.65 (m, 1H), 7.69 (d, 1H), 7.79-7.82 (m, 1H).
Example 10.
(S)-N-( 1 -(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)imidazo[2,1 -b]thiazole-6-carboxamide
The title compound was prepared using the procedure described in Example
3(h) starting from imidazo[2,l-b]thiazole-6-carboxylic acid (1.041 mmol, 0.175 g)
and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (1.041
mmol, 0.290 g). DMF (10 ml) was used as the solvent and the reaction time was 2
days. The work up was done by diluting the reaction mixture with water and ethyl
acetate and washing it with 2M Na2CO3, water and brine. The combined organics
were dried, filtered and eveaporated. The crude product was purified by flash
chromatography. 0.186 g of the title compound was obtained. 1H-NMR (400 MHz,
MeOH-d4): d 1.24 (d, 3H), 4.32-4.39 (m, 1H), 4.40-4.47 (m, 1H), 4.53-4.61 (m, 1H),
6.79 (d, 1H), 7.20 (d, 1H), 7.73 (d, 1H), 7.76 (d, 1H), 7.77-7.81 (m, 1H), 7.89-7.91
(m, 1H), 8.10 (s, 1H).
Example 11.
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-6-nitroimidazo[ 1,2-a]pyridine-2-carboxamide
The title compound was prepared using the procedure described in Example
3(h) starting from 6-nitroimidazo[1,2-a]pyridine-2-carboxylic acid (0.551 mmol,
0.114 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzo-
nitrile (0.459 mmol, 0.128 g). DMF (4 ml) was used as the solvent and HBTU (0.046
mmol, 0.017 g) was used instead of HOBt. The crude product was purified by
preparative HPLC. 0.0405 g of the title compound was obtained. 1H-NMR (400
MHz, MeOH-d4): d 1.37 (d, 3H), 4.30-4.37 (m, 1H), 4.38-4.46 (m, 1H), 4.59-4.72
(m, 1H), 6.72 (d, 1H), 7.54 (d, 1H), 7.68 (d, 1H), 7.72 (s, 1H), 7.78 (d, 1H), 8.15-
8.21 (m, 1H), 8.38 (s, 1H), 10.40-10.44 (m, 1H).
Example 12: (S)-N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-
yl)propan-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide
The title compound was prepared using the procedure described in Example
3(h) starting from 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid (2.58
mmol, 428 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluoro-
benzonitrile (1.717 mmol, 479 mg). DMF (10 ml) was used as the solvent. The
reaction mixture was diluted with water and extracted three times with DCM. The
combined organics were washed twice with water. The organic phase was
evaporated. The crude product was purified by flash chromatography. 515 mg of the
title compound was obtained. 1H-NMR (400 MHz, DMSO-d4): d 1.07 (d, 3H), 1.78-
1.94 (m, 4H), 2.76 (t, 2H), 3.95 (t, 2H), 4.24-4.31 (m, 1H), 4.33-4.46 (m, 2H), 7.01
(d, 1H), 7.43 (s, 1H), 7.84 (d, 1H), 7.90-7.95 (m, 1H), 8.00 (s, 1H), 8.08 (d, 1H).
Example 13.
(S)-N-( 1 -(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)-propan-2-
yl)-1 -isopropyl-2-methyl-1H-imidazole-4-carboxamide
a) Ethyl l-isopropyl-2-methyl-1H-imidazole-4-carboxylate
Ethyl 2-methyl-1H-imidazole-4-carboxylate (0.649 mmol, 100 mg) and KOH
(0.973 mmol, 54.6 mg) were dissolved in DMF (2 ml) under nitrogen atmosphere. 2-
Iodopropane(isopropyliodide), stabilized over copper (+98 %, 0.973 mmol, 165 mg)
was added and the resulting mixture was stirred at RT overnight. NH4Cl solution was
added and the mixture was extracted three times with EtOAc. The combined organics
were washed with water, dried, filtered and evaporated. The crude product was
purified by flash chromatography. 83 mg of the title compound was obtained. 1H-
NMR (400 MHz, DMSO-d6): d 1.25 (t, 3H), 1.36 (d, 6H), 2.32 (s, 3H), 4.18 (q, 2H),
4.31-4.43 (m,lH), 7.87 (s, 1H).
b) l-Isopropyl-2-methyl-1H-imidazole-4-carboxylic acid
Ethyl l-isopropyl-2-methyl-1H-imidazole-4-carboxylate (0.423 mmol, 83 mg)
was dissolved in methanol (0.5 ml) and THF (4 ml). NaOH 2 M (2.115 mmol, 1.057
ml) was added and the resulting mixture was stirred at RT overnight. The pH of the
reaction mixture was adjusted to about 5 with 1 M HCl and the mixture was
evaporated. Ethanol was added and the salt was removed by filtration. The salt was
flushed few times with ethanol. 51 mg of the title compound was obtained. 1H-NMR
(400 MHz, DMSO-d6): d 1.38 (d, 6H), 2.39 (s, 3H), 4.35-4.49 (m, 1H), 7.97 (s, 1H).
c) (S)-N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-1 -isopropyl-2-methyl-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in Example
3(h) using l-isopropyl-2-methyl-1H-imidazole-4-carboxylic acid (0.303 mmol, 51
mg), (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.253
mmol, 70.4 mg) and only a catalytic amount of HOBt (0.025 mmol, 3.41 mg). DMF
(2 ml) was used as the solvent in the reaction. The work up was done by adding water
to the reaction mixture and extracting it three times with DCM. The combined
organics were washed twice with water. The organic phase was evaporated and the
residue was purified by flash chromatography. 86 mg of the title compound was
obtained. 1H-NMR (400 MHz, DMSO-d6): d 1.06 (d, 3H), 1.34 (d, 6H), 2.35 (s, 3H),
4.23-4.47 (m, 4H), 7.02 (d, 1H), 7.62 (s, 1H), 7.86 (d, 1H), 7.90-7.96 (m, 1H), 8.00
(s, 1H), 8.04 (d, 1H).
Example 14.
(S)-N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-5-(2-hydroxypropan-2-yl)-1H-pyrazole-3-carboxamide
a) Ethyl 5-(2-hydroxypropan-2-yl)-1H-pyrazole-3-carboxylate
Zinc trifluoromethanesulfonate (2.378 mmol, 0.864 g), 2-methyl-3-butyn-2-ol
(11.89 mmol, 1 g) and triethylamine (17.83 mmol, 1.804 g) were added into a flask
under nitrogen atmosphere. Ethyl diazoacetate (14.27 mmol, 1.628 g) was added
slowly and the temperature was carefully raised to 100 °C and stirred for 8 h. Water
was added and the mixture was extracted twice with DCM. The combined DCM
phases were dried, filtered and evaporated. The crude product was purified by flash
chromatography. 0.658 g of the title compound was obtained. 1H-NMR (400 MHz,
DMSO-d6): d 1.28 (t, 3H), 1.45 (s, 6H), 4.24 (q, 2H), 5.34 (s, 1H), 6.52 (s, 1H), 13.22
(bs, 1H).
b) 5-(2-Hydroxypropan-2-yl)-1H-pyrazole-3-carboxylic acid
Ethyl 5-(2-hydroxypropan-2-yl)-1H-pyrazole-3-carboxylate (1.609 mmol,
0.319 g) was dissolved in ethanol (1 ml) and THF (4 ml). 2 M NaOH (8.05 mmol,
4.02 ml) was added and the resulting mixture was stirred overnight at RT. The
reaction mixture was carefully neutralized with HCl and evaporated. The residue was
dissolved in a small amount of ethanol and the salts were removed by filtration. The
filtrate was evaporated. 0.227 g of the title compound was obtained. 1H-NMR (400
MHz, DMSO-d6): d 1.39 (s, 6H), 4.72 (bs, 1H), 6.24 (s, 1H), 12.20 (bs, 1H).
c) (S)-N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-5-(2-hydroxypropan-2-yl)-1H-pyrazole-3-carboxamide
The title compound was prepared using the procedure described in Example
3(h) using 5-(2-hydroxypropan-2-yl)-1H-pyrazole-3-carboxylic acid (0.646 mmol,
110 mg) and (S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzo-
nitrile (0.539 mmol, 150 mg) and only a catalytic amount of HOBt (0.054 mmol,
7.28 mg). DMF was used as the solvent. Water was added to the reaction mixture and
the mixture was extracted it three times with DCM. The combined organics were
washed twice with water. The organic phase was evaporated and the residue was
purified by flash chromatography and preparative HPLC, respectively. 45.4 mg of the
title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): d 1.13 (d, 3H), 1.43
(s, 6H), 4.17-4.55 (m, 3H), 5.27 (bs, 1H), 6.37 (bs, 1H), 6.99 (d, 1H), 7.82 (d, 1H),
7.86 (d, 1H), 7.97 (s, 1H), 8.08 (bs, 1H), 12.94 (bs, 1H).
Example 15.
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)-propan-2-
yl)-1 -(2,2-difluoroethyl)-2-methyl-1H-imidazole-4-carboxamide
a) Ethyl l-(2,2-difluoroethyl)-2-methyl-1H-imidazole-4-carboxylate
Ethyl 2-methyl-1H-imidazole-4-carboxylate (1.622 mmol, 250 mg) and KOH
(2.432 mmol, 136 mg) were suspended in DMF (2 ml). 1,1-Difluoro-2-iodoethane
(4.86 mmol, 934 mg) was added and the resulting mixture was stirred overnight at
RT. During the stirring additional 0.3 ml of l,l-difluoro-2-iodoethane was added to
complete the reaction. Aqueous NH4Cl solution was added and the mixture was
extracted three times with EtOAc. The combined organics were washed with water,
dried, filtered and evaporated. The crude product was purified by flash chromato-
graphy. 0.3 g of the title compound was obtained. Two isomers were obtained in the
reaction and separated in later steps. Isomer 1: 1H-NMR (400 MHz, DMSO-d6): d
1.28 (t, 3H), 2.33 (s, 3H), 4.25 (q, 2H), 4.45-4.58 (m, 2H), 6.23-6.53 (m, 1H), 7.80
(s, 1H). Isomer 2: 1H-NMR (400 MHz, DMSO-d6): d 1.25 (t, 3H), 2.39 (s, 3H), 4.19
(q, 2H), 4.70-4.83 (m, 2H), 6.18-6.49 (m, 1H), 7.59 (s, 1H).
b) l-(2,2-Difluoroethyl)-2-methyl-1H-imidazole-4-carboxylic acid
Ethyl l-(2,2-difluoroethyl)-2-methyl-1H-imidazole-4-carboxylate (1.375
mmol, 300 mg) was dissolved in methanol (0.5 ml) and THF (4 ml). NaOH 2 M
(4.12 mmol, 2.062 ml) was added and the resulting mixture was stirred for 2.5 h at
RT. The pH of the mixture was adjusted to about 6 with 5 M HCl and the solvents
were evaporated. Ethanol was added and filtered. The filtrate was evaporated. 176
mg of the title compound was obtained. The two isomers formed in the previous
reaction were still present. Isomer 1: 1H-NMR (400 MHz, DMSO-d6): d 2.25 (s, 3H),
4.67-4.80 (m, 2H), 6.09-6.44 (m, 1H), 6.94 (s, 1H). Isomer 2: 1H-NMR (400 MHz,
DMSO-d6): d 2.27 (s, 3H), 4.32-4.44 (m, 2H), 6.17-6.47 (m, 1H), 7.15 (s, 1H).
c) (S)-N-( 1 -(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-1 -(2,2-difluoroethyl)-2-methyl-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in Example
3(h) using l-(2,2-difluoro-ethyl)-2-methyl-1H-imidazole-4-carboxylic acid (0.926
mmol, 176 mg), (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzo-
nitrile (0.617 mmol, 172 mg) and only a catalytic amount of HOBt (0.062 mmol,
8.34 mg). DMF was used as the solvent. Water was added to the reaction mixture and
the mixture was extracted it three times with DCM. The combined organics were
washed twice with water. The organic phase was evaporated and the residue was
purified by flash chromatography and preparative HPLC, respectively. 15.5 mg of the
title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): d 1.07 (d, 3H), 2.36
(s, 3H), 4.23-4.55 (m, 5H), 6.19-6.51 (m, 1H), 7.02 (d, 1H), 7.53 (s, 1H), 7.86 (d,
1H), 7.90-7.95 (m, 1H), 8.00 (s, 1H), 8.12 (d, 1H).
Example 16.
N-((S)-1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)-propan-2-
yl)-1 -((R)-2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxamide
a) (R)-Ethyl 1 -(2-hydroxypropyl)-2-methyl-1 H-imidazole-4-carboxylate
Ethyl 2-methyl-lH-imidazole-4-carboxylate (3.24 mmol, 500 mg) and
potassium carbonate (32.4 mmol, 4482 mg) were dissolved in DMF (10 ml). (R)-(+)-
propylene oxide (48.6 mmol, 3.41 ml) was added and the resulting mixture was
stirred at 60 °C for 5.5 h. More (R)-(+)-propylene oxide (1.5 ml) was added and the
heating continued for another hour. The mixture was evaporated and the residue was
purified by flash chromatography. 525 mg of the title compound was obtained. 'H-
NMR (400 MHz, DMSO-d6): d 1.06 (d, 3H), 1.25 (t, 3H), 2.30 (s, 3H), 3.68-4.00 (m,
3H), 4.18 (q, 2H), 4.95 (d, 1H), 7.73 (s, 1H).
b) (R)-1 -(2-Hydroxypropyl)-2-methyl-1H-imidazole-4-carboxylic acid
(R)-Ethyl 1 -(2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxylate (2.474
mmol, 525 mg) was dissolved in methanol (1 ml) and THF (8 ml). NaOH 2 M (7.42
mmol, 3.71 ml) was added and the resulting mixture was stirred overnight at RT. The
pH of the mixture was adjusted to about 5 with 1M HCl and the solvents were
evaporated. Ethanol was added and the salts were removed by filtration. The filtrate
was evaporated. 393 mg of the title compound was obtained. 1H-NMR (400 MHz,
DMSO-d6): d 1.03 (m, 6H), 2.30 (s, 3H), 3.71-3.80 (m, 1H), 3.81-3.97 (m, 2H), 4.95
(bs), 7.67 (s, 1H).
c) N-((S)-1 -(3-(3-Chloro-4-cyano-5-fluorophenyl)-1 H-pyrazol-1 -yl)propan-2-
yl)-1 -((R)-2-hydroxypropyl)-2 -methyl-1 H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in Example
3(h) starting from (R)-l -(2-hydroxypropyl)-2-methyl-1 H-imidazole-4-carboxylic acid
(1.059 mmol, 195 mg) and (S)-4-(l-(2-aminopropyl)-lH-pyrazol-3-yl)-2-chloro-6-
fluorobenzonitrile (0.882 mmol, 246 mg) and using dry DMF (2 ml) as the solvent.
After the reaction was finished, DCM was added and the reaction mixture was
concentrated. The crude product was purified by flash chromatography and
preparative HPLC, respectively. 177.8 mg of the title compound was obtained. lH-
NMR (400 MHz, DMSO-d6): d 1.00-1.10 (m, 6H), 2.34 (s, 3H), 3.69-3.90 (m, 3H),
4.22-4.48 (m, 3H), 4.91 (d, 1H), 7.02 (d, 1H), 7.47 (s, 1H), 7.86 (d, 1H), 7.91-7.96
(m, 1H), 8.00 (s, 1H), 8.06 (d, 1H).
Example 17.
(S)-N-( 1 -(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-1'-methyl-1'H-1,4'-bipyrazole-3-carboxamide
a) Methyl r-methyl-rH-l,4'-bipyrazole-3-carboxylate
Into a solution of methyl 1H-pyrazole-3-carboxylate (10 g, 79.3 mmol) in
DMF (80 ml), cuprous oxide (0.567 g, 3.96 mmol), salicylaldoxime (1.08 g, 7.93
mmol), Cs2CO3 (64.4 g, 198.4 mmol) and l-methyl-4-iodo pyrazole (16.5 g, 79.9
mmol) were added and the mixture was stirred at 110 °C for 48 h. The reaction
mixture was quenched with saturated solution of aqueous NaHCO3 and extracted
with EtOAc. The organic layer was concentrated and purified by flash-chromato-
graphy. Yield 2.9 g. 1H-NMR (400 MHz; DMSO-d6): d 3.83 (s, 3H), 3.88 (s, 3H),
7.90 (s, 1H), 8.29 (d, 2H). LC-MS: [M+H] = 207.
b) 1'-Methyl-1'H-1, 4'-bipyrazole-3-carboxylic acid
The title compound was prepared using the procedure described in Example
33(c) starting from methyl 1 '-methyl-1'H-1,4'-bipyrazole-3-carboxylate (2.9 g, 13.5
mmol). Yield 1.4 g. 1H-NMR (400 MHz; DMSO-d6): d 3.88 (s, 3H), 6.87 (d, 1H),
7.88 (s, 1H), 8.25 (d, 2H), 12.8 (bs, 1H). LC-MS: [M+1] = 193.19.
c) (S)-N-( 1 -(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-1 '-methyl-1'H-1,4'-bipyrazole-3 -carboxamide
The title compound was prepared using the procedure described in Example
3(h) starting from 1'-methyl-1'H-[1,4'-bipyrazole]-3-carboxylic acid (0.861 mmol,
165 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzo-
nitrile (0.718 mmol, 200 mg) and using DMF (2 ml) as the solvent. DCM was added
and the reaction mixture was evaporated. The residue was purified by flash chroma-
tography. The purified product was dissolved in DCM and washed three times with 1
M NaHCO3. The combined organics were evaporated. 134 mg of the title compound
was obtained. 1H-NMR (400 MHz, DMSO-d6): d 1.15 (d, 3H), 3.88 (s, 3H), 4.28-
4.42 (m, 2H), 4.42-4.52 (m, 1H), 6.75 (d, 1H), 7.01 (d, 1H), 7.81-7.88 (m, 3H), 7.94
(s, 1H), 8.13-8.17 (m, 2H), 8.18 (s, 1H).
Example 18.
(S)-N-( 1 -(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-lH,2'H-3,3'-bipyrazole-5-carboxamide
a) Ethyl 1H,2'H-3,3'-bipyrazole-5-carboxylate
Pieces of sodium (0.26 g) were slowly added to ethanol (12 ml) with stirring
until all sodium had dissolved. l-(lH-Pyrazol-5-yl)ethanone (8.61 mmol, 0.948 g)
and diethyl oxalate (8.61 mmol, 1.258 g) was added. The mixture was heated to 75
°C for 3 h after which the stirring continued at RT overnight. Hydrazine hydro-
chloride (8.61 mmol, 0.590 g) dissolved in water (6 ml) was added. The resulting
mixture was again heated to 75 °C for 3 h. The mixture was cooled to RT and
neutralized by adding 2 M NaOH. The mixture was extracted twice with EtOAc and
the combined organics were washed with water and brine. The organic phase was
dried, filtered and evaporated. The crude product was purified by flash chromato-
graphy. 0.404 g of the title compound was obtained. 1H-NMR (400 MHz, MeOH-d4):
d 1.39 (t, 3H), 4.38 (q, 2H), 6.69 (d, 1H), 7.10 (bs, 1H), 7.70 (bs, 1H).
b) 1H,2'H-3,3'-Bipyrazole-5-carboxylic acid
Ethyl 1H,2'H-3,3'-bipyrazole-5-carboxylate (1.959 mmol, 0.404 g) was
dissolved in ethanol (5 ml) and cooled in an ice bath. NaOH 1 M solution (1.959
mmol, 4 ml) was slowly added. The solution was heated to 60 °C for 1 h. Ethanol
was removed under vacuum and the residue was diluted with tert-butyl methyl ether.
The solution was again cooled with an ice bath and acidified with 2 N HCl solution.
The solution was allowed to warm to ambient temperature and stirred overnight.
Water and DCM was added and the phases were separated. Both phases were
evaporated and combined. 0.551 g of the title compound was obtained. 1H-NMR
(400 MHz, DMSO-d6): d 6.70 (d, 1H), 7.04 (s, 1H), 7.77 (d, 1H).
c) (S)-N-( 1 -(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-1H,2'H-3,3'-bipyrazole-5-carboxamide
The title compound was prepared using the procedure described in Example
3(h) starting from lH,2'H-3,3'-bipyrazole-5-carboxylic acid (2.245 mmol, 0.4 g) and
(S)-4-( 1 -(2-aminopropyl)-1H-pyrazol-3 -yl)-2-chloro-6-fluorobenzonitrile (1.871
mmol, 0.521 g) and using DMF (10 ml) as the solvent. Water was added and the
mixture was extracted with EtOAc. The organic phase was washed with 2M Na2CO3,
water and brine. The organic phase was dried, filtered and evaporated. The crude
product was purified by flash chromatography and preparative HPLC, respectively.
0.1277 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): d
1.19 (d, 3H), 4.27-4.56 (m, 3H), 6.64 (bs, 1H), 6.84 (bs, 1H), 6.98 (d, 1H), 7.77 (bs,
1H), 7.81-7.87 (m, 2H), 7.93-7.6 (m, 1H), 8.07 (br. s, 1H), 12.57-13.78 (m, 2H).
Example 19.
N-((S)-1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)-propan-2-
yl)-1 -((S)-2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxamide
a) (S)-Ethyl 1 -(2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxylate
Ethyl 2-methyl-1H-imidazole-4-carboxylate (1.622 mmol, 250 mg) and
potassium carbonate (16.22 mmol, 2241 mg) were dissolved in dry DMF (5 ml)
under nitrogen atmosphere. (S)-2-methyloxirane (24.32 mmol, 1.723 ml) was added
and the resulting mixture was heated to 60 °C and stirred for 5.5 h. More (S)-2-
methyloxirane (1 ml) was added and the stirring continued at 60 °C for one
additional hour. The solvent was evaporated. The crude product was purified by flash
chromatography. 139 mg of the title compound was obtained. 1H-NMR (400 MHz,
DMSO-d6): d 1.06 (d, 3H), 1.24 (t, 3H), 2.30 (s, 3H), 3.71-3.89 (m, 4H), 4.18 (q,
2H), 7.73 (s, 1H).
b) (S)-1 -(2-Hydroxypropyl)-2-methyl-1H-imidazole-4-carboxylic acid
(S)-Ethyl 1 -(2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxylate (0.655
mmol, 139 mg) was dissolved in methanol (0.5 ml) and THF (4 ml). NaOH 2 M
(1.965 mmol, 0.982 ml) was added and the resulting mixture was stirred overnight at
RT. The mixture was acidified (pH~5) with 1 M HCl and evaporated. Ethanol was
added and the salts were removed by filtration. The filtrate was evaporated. 112 mg
of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): d 1.06 (d, 3H),
2.30 (s, 3H), 3.70-3.91 (m, 4H), 7.59 (s, 1H).
b) N-((S)-1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-1 -((S)-2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in Example
3(h) starting from (S)-1-(2-hydroxypropyl)-2-methyl- 1H-imidazole-4-carboxylic acid
(0.608 mmol, 112 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-
fluorobenzonitrile (0.507 mmol, 141 mg) using DMF (2 ml) as the solvent. After the
reaction had stopped, DCM was added and the reaction mixture was evaporated. The
residue was purified by flash chromatography. The purified product was dissolved in
a mixture of MeOH/DCM and washed twice with 1M NaHCO3. The organic phase
was dried, filtered and evaporated. The product was further purified by trituration
from diethyl ether, filtered and dried with vacuum. 31 mg of the title compound was
obtained. 1H-NMR (400 MHz, DMSO-d6): d 1.01-1.08 (m, 6H), 2.33 (s, 3H), 3.68-
3.91 (m, 3H), 4.22-4.48 (m, 3H), 4.91 (d, 1H), 7.02 (d, 1H), 7.47 (s, 1H), 7.86 (d,
1H), 7.94 (d, 1H), 8.01 (s, 1H), 8.06 (d, 1H).
Example 20.
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-3,3 '-bipyridine-6-carboxamide
a) ter/-Butyl 5-bromopicolinate
5-Bromopicolinic acid (5 g, 24.8 mmol) was dissolved in t-BuOH (100 ml).
To the solution, DMAP (0.303 g, 2.47 mmol), (Boc)2O (8.1 g, 37.12 mmol) were
added and stirred at 50 °C overnight. The solvent was concentrated under reduced
pressure. The residue was diluted with H2O and extracted with EtOAc. The organic
layer was concentrated. Yield 3.6 g. 1H-NMR (400 MHz; DMSO-d6): d 1.55 (s, 9H),
7.92 (d, 1H), 8.23 (dd, 1H), 8.83 (d, 1H).
b) tert-Butyl 3,3'-bipyridine-6-carboxylate
Into a solution of tert-butyl 5-bromopicolinate (3.5 g, 13.56 mmol) in DMF
(40 ml) Pd(OAc)2 (0.152 g, 0.68 mmol), dppf (0.753 g, 1.37 mmol), CuCl (1.4 g,
13.57 mmol), Cs2CO3 (8.9 g, 27.13 mmol) and pyridin-3-yl boronic acid (3.4 g,
27.13 mmol) were added under inert atmosphere. The mixture was stirred at 110 °C
overnight and diluted with H2O. The mixture was filtered through a celite bed, and
the filtrate was extracted with EtOAc. The organic layer was concentrated. Yield 1.75
g. 1H-NMR (400 MHz; CDCl3): d 1.67 (s, 9H), 7.43-7.47 (m, 1H), 7.91 (d, J= 8.0
Hz, 1H), 8.01 (dd, 1H), 8.17 (d, 1H), 8.70 (dd, 1H), 8.88 (d, 1H), 8.97 (d, 1H).
c) 3,3'-Bipyridine-6-carboxylic acid
A solution of tert-butyl 3,3'-bipyridine-6-carboxylate (3.2 g, 12.5 mmol) in 4
M HCl in dioxane (100 ml) was stirred at 110 °C overnight. The reaction mixture
was evaporated completely under reduced pressure and triturated twice from diethyl
ether. Yield 3.2 g. 1H-NMR (400 MHz; D2O): d 8.23-8.27 (m, 1H), 8.50 (d, 1H),
8.84 (d, 1H), 8.93 (d, 1H), 8.98 (d, 1H), 9.16 (s, 1H), 9.26 (s, 1H).
d) (S)-N-(1 -(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-3,3 '-bipyridine-6-carboxamide
The title compound was prepared using the procedure described in Example
3(h) starting from 3,3'-bipyridine-6-carboxylic acid (0.861 mmol, 172 mg) and (S)-4-
(l-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.718 mmol,
200 mg) using DMF (2 ml) as the solvent. After the reaction had stopped, DCM was
added and the mixture was evaporated. The residue was purified by flash chromato-
graphy and trituration from methanol, respectively. 75 mg of the title compound was
obtained. 1H-NMR (400 MHz, DMSO-d6): d 1.18 (d, 3H), 4.35-4.59 (m, 3H), 7.02
(d, 1H), 7.55-7.62 (m, 1H), 7.87-7.93 (m, 2H), 7.98 (s, 1H), 8.06-8.10 (m, 1H), 8.19-
8.25 (m, 1H), 8.35 (dd, 1H), 8.68 (dd, 1H), 8.99 - 9.05 (m, 2H), 9.13 (d, 1H).
Example 21.
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5 -fluorophenyl)-1H-pyrazol-1 -yl)-propan-2-
yl)-6-(3,3-dimethylureido)imidazo[1,2-a]pyridine-2-carboxamide
a) Ethyl 6-(3,3-dimethylureido)imidazo[ 1,2-a]pyridine-2-carboxylate
Ethyl 6-aminoimidazo[1,2-a]pyridine-2-carboxylate (0.975 mmol, 0.2 g) was
dissolved in THF (10 ml). Triethylamine (2.92 mmol, 0.296 g) was added and the
reaction mixture was cooled to 0 °C. Dimethylcarbamyl chloride (1.462 mmol, 0.135
ml) was added carefully and the mixture was allowed to warm to ambient
temperature with stirring. More of dimethylcarbamyl chloride (1.462 mmol, 0.135
ml) was added and the stirring continued for another hour. The solvent was
evaporated, DCM was added and the resulting mixture was washed with NaHCO3
solution and water. The organic phase was dried, filtered and evaporated. The crude
product was purified by flash chromatography. 0.066 g of the title compound was
obtained. 1H-NMR (400 MHz, DMSO-d6): d 1.31 (t, 3H), 2.95 (s, 6H), 4.29 (q, 2H),
7.39-7.44 (m, 1H), 7.50-7.54 (m, 1H), 8.41 (s, 1H), 8.54 (s, 1H), 8.89-8.93 (m, 1H).
b) 6-(3,3-Dimethylureido)imidazo[1,2-a]pyridine-2-carboxylic acid
Ethyl 6-(3,3-dimethylureido)imidazo[1,2-a]pyridine-2-carboxylate (0.239
mmol, 0.066 g) was dissolved in ethanol (5 ml). The solution was cooled to 0 °C and
NaOH 2 M solution (0.478 mmol, 0.239 ml) was added. The resulting mixture was
stirred at 0 °C. Ethanol was evaporated and water was added. The pH of the water
phase was adjusted to ~4 with HC1. The mixture was extracted with EtOAc and the
organic phase was dried, filtered and evaporated. The residue was triturated with
MeOH/DCM 1/9. The filtered precipitate was dried under vacuum. 0.067 g of the
title compound was obtained. LC-MS: [M-1] = 247.24.
c) (S)-N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-6-(3,3-dimethylureido)imidazo[1,2-a]pyridine-2-carboxamide
The title compound was prepared using the procedure described in Example
3(h) starting from 6-(3,3-dimethylureido)imidazo[1,2-a]pyridine-2-carboxylic acid
(0.270 mmol, 0.067 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-
fluorobenzonitrile (0.108 mmol, 0.04 g) using DMF (4 ml) as the solvent. HBTU
(0.027 mmol, 10.24 mg) was used instead of HOBt. The product precipitated into the
water phase and was separated by filtration. The organic phase also contained the
product. The organic phase was dried, filtered and evaporated. The combined
precipitates were purified by preparative HPLC. 0.0192 g of the title compound was
obtained. 1H-NMR (400 MHz, DMSO-d6) d ppm 1.13 (d, 3H), 2.95 (s, 6H), 4.30-
4.54 (m, 3H), 7.01 (d, 1H), 7.40-7.45 (m, 1H), 7.47-7.52 (m, 1H), 7.87 (d, 1H), 7.93
(dd, 1H), 7.97 (s, 1H), 8.30 (s, 1H), 8.39 (bs, 1H), 8.49 (d, 1H), 8.87-8.91 (m, 1H).
Example 22.
(S)-N-(1 -(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2-
yl)-6-(methylsulfonamido)imidazo[ 1,2-a]pyridine-2-carboxamide
a) Ethyl 6-(N-(methylsulfonyl)methylsulfonamido)imidazo[1 ,2-a]pyridine-2-
carboxylate
Ethyl 6-aminoimidazo[1,2-a]pyridine-2-carboxylate (0.975 mmol, 0.2 g) was
dissolved in THF (10 ml). Triethylamine (9.75 mmol, 0.986 g) was added and the
mixture was cooled to 0 °C. Methanesulfonyl chloride (9.75 mmol, 1.116 g) was
slowly added and the mixture was allowed to cool to RT. The stirring continued at
RT until the reaction was finished. The solvent was evaporated, DCM was added and
washed with NaHCO3 solution and water. The organic phase was dried, filtered and
evaporated. The crude product was purified with flash chromatography. 0.149 g of
the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): d 1.33 (t, 3H),
3.61 (s, 6H), 4.34 (q, 2H), 7.50 (dd, 1H), 7.69-7.74 (m, 1H), 8.54-8.56 (m, 1H), 9.00-
9.02 (m, 1H).
b) 6-(Methylsulfonamido)imidazo[1,2-a]pyridine-2-carboxylic acid
Ethyl 6-(N-(methylsulfonyl)methylsulfonamido)imidazo[1,2-a]pyridine-2-
carboxylate (0.412 mmol, 0.149 g) was dissolved in ethanol (10 ml) and cooled to 0
°C with an ice bath. NaOH 2 M solution (0.825 mmol, 0.412 ml) was added and
stirred at 0 °C for 3.5 h after which the temperature was allowed to warm to RT. The
stirring continued overnight. The temperature was raised to 50 °C and stirred for 5 h.
The mixture was again stirred at RT overnight. Ethanol was evaporated and water
was added. The pH was adjusted to 4 with 1 M HCl after which the product started to
precipitate. The precipitate was removed by filtration and dried under vacuum. 0.057
g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): d 3.05 (s,
3H), 7.22-7.29 (m, 1H), 7.60-7.66 (m, 1H), 8.49-8.53 (m, 1H), 8.55 (s, 1H), 9.81 (s,
1H).
c) (S)-N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-6-(methylsulfonamido)imidazo[1,2-a]pyridine-2-carboxamide
The title compound was prepared using the procedure described in Example
3(h) starting from 6-(methylsulfonamido)imidazo[1,2-a]pyridine-2-carboxylic acid
(0.215 mmol, 0.055 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-
fluorobenzo-nitrile (0.179 mmol, 0.050 g) using DCM (10 ml) as the solvent. HBTU
(0.018 mmol, 6.80 mg) was used instead of HOBt. The mixture was diluted with
DCM and washed with Na2CO3 solution and water. The organic phase was
evaporated. The water phase and Na2CO3 phase were washed with EtOAc. The
evaporated organic phases were combined and purified by preparative HPLC. 0.0174
g of the title compound was obtained. !H-NMR (400 MHz, DMSO-d6): d 1.14 (d,
3H), 3.04 (s, 3H), 4.27-4.58 (m, 3H), 7.00 (d, 1H), 7.27 (dd, 1H), 7.57-7.62 (m, 1H),
7.87 (d, 1H), 7.91 (dd, 1H), 7.95-7.97 (m, 1H), 8.36 (d, 1H), 8.49-8.51 (m, 1H), 8.55
(d, 1H), 9.77 (s, 1H).
Example 23.
N-((S)-1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-5-(1-hydroxy-2-methylpropyl)isoxazole-3-carboxamide
a) Ethyl 5-(1-hydroxy-2-methylpropyl)isoxazole-3-carboxylate
Ethyl chlorooximidoacetate (6.79 mmol, 1.029 g) and 4-methyl-1-pentyn-3-ol
(20.38 mmol, 2 g) were dissolved in toluene (20 ml). Et3N (6.79 mmol, 0.947 ml)
dissolved in toluene was added dropwise. The mixture was stirred overnight at RT.
The mixture was diluted with EtOAc and washed with water. The organic phase was
dried, filtered and evaporated. The crude product was purified by flash chromato-
graphy. 0.828 g of the title compound was obtained. 1H-NMR (400 MHz, MeOH-d4):
5 0.92 (d, 3H), 0.97 (d, 3H), 1.39 (t, 3H), 2.03-2.16 (m, 1H), 4.41 (q, 2H), 4.58 (d,
1H), 6.65 (s, 1H).
b) 5-(1-Hydroxy-2-methylpropyl)isoxazole-3-carboxylic acid
Ethyl 5-(1-hydroxy-2-methylpropyl)isoxazole-3-carboxylate (2.345 mmol, 0.5
g) was dissolved in ethanol (5 ml) and cooled to 0 °C. NaOH 1 M solution (5 ml)
was slowly added and the resulting mixture was allowed to warm to RT. The solution
was heated to 60 °C for 3 h. Ethanol was removed by evaporation and the residue
was diluted with tert-butyl methyl ether. The mixture was cooled to 0 °C and
acidified with 2 N HCl solution. The mixture was allowed to warm to ambient
temperature and stirred overnight. The mixture was extracted with DCM. Both
organic and aqueous phases contained the product so both they were combined and
evaporated. 0.691 g of the title compound was obtained. 1H-NMR (400 MHz,
DMSO-d6): d 0.85 (d, 3H), 0.91 (d, 3H), 2.03 (qd, 1H), 4.54 (d, 1H), 6.66 (s, 1H).
c)N-((S)-1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-5-(1-hydroxy-2-methylpropyl)isoxazole-3-carboxamide
The title compound was prepared using the procedure described in Example
3(h) starting from 5-(1-hydroxy-2-methylpropyl)isoxazole-3-carboxylic acid (2.160
mmol, 0.4 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluoro-
benzonitrile (1.800 mmol, 0.502 g) using DMF (10 ml) as the solvent. The reaction
mixture was diluted with water and EtOAc, the phases were separated and the
organic phase was washed with 2 M Na2CO3, water and brine. The organic phase was
dried, filtered and evaporated. The crude product was purified by flash chromato-
graphy and preparative HPLC, respectively. 0.0146 g of the title compound was
obtained. 1H-NMR (400 MHz, MeOH-d4): d 0.89 (d, 3H), 0.92-0.98 (m, 3H), 1.26 (d,
3H), 2.01-2.13 (m, 1H), 4.28-4.45 (m, 2H), 4.51-4.64 (m, 2H), 6.53 (d, 1H), 6.79 (d,
1H), 7.68-7.77 (m, 2H), 7.91 (s, 1H).
Example 24.
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5 -fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-5-(l ,5-dimethyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole-3-carboxamide
a) Ethyl 5-( 1,5-dimethyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole-3-carboxylate
Ethyl aminohydroxyiminoacetate (3.78 mmol, 0.5 g), 1,5-dimethyl- 1H-
pyrazole-3-carboxylic acid (95 %, 3.78 mmol, 0.530 g) and 1,3-diisopropylcarbodi-
imide (4.16 mmol, 0.525 g) were suspended in DCM (70 ml) under nitrogen
atmosphere. The mixture was stirred at RT for a day. The solvent was evaporated and
pyridine was added to the residue. The resulting mixture was refluxed for 6 h and
stirred at RT overnight. Pyridine was evaporated and the residue diluted with DCM
and water. The phases were separated and the water phase was extracted four times
with DCM. The combined organics were washed with aqueous HCl solution,
saturated NaHCO3, water and brine. The organic phase was dried, filtered and
evaporated. The crude product was purified by flash chromatography. 0.285 g of the
title compound was obtained. 1H-NMR (400 MHz, MeOH-d4): d 1.43 (t, 3H), 2.30 (s,
3H), 4.23 (s, 3H), 4.49 (q, 2H), 6.96 (s, 1H).
b) 5-(l,5-Dimethyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole-3-carboxylic acid
Ethyl 5-(l,5-dimethyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole-3-carboxylate
(1.206 mmol, 0.285 g) was dissolved in ethanol (7 ml) and cooled to 0 °C with an ice
bath. NaOH 1 M solution (3 ml) was added, the ice bath was removed and the
mixture was heated to 60 °C for 1.5 h. Ethanol was evaporated and the residue was
diluted with MTBE. The mixture was again cooled with an ice bath and acidified
with 2 M HC1. The mixture was warmed to RT and stirred overnight. Water, MTBE
and DCM were added, but the precipitate did not dissolve. The organic phase and the
water phase were combined and evaporated. 0.336 g of the title compound was
obtained. 1H-NMR (400 MHz, DMSO-d6): d 2.27 (s, 3H), 4.16 (s, 3H), 7.01 (s, 1H).
c) (S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5 -fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-5-(1,5-dimethyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole-3-carboxamide
The title compound was prepared using the procedure described in Example
3(h) starting from 5-(1,5-dimethyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole-3-carboxylic
acid (1.614 mmol, 0.336 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-
6-fluoro-benzonitrile (1.345 mmol, 0.375 g) using DMF (10 ml) as the solvent. The
reaction mixture was diluted with water and EtOAc, the phases were separated and
the organic phase was washed with 2 M Na2CO3, water and brine. The organic phase
was dried, filtered and evaporated. The crude product was purified by flash chroma-
tography and preparative HPLC, respectively. 0.003 g of the title compound was
obtained. 1H-NMR (400 MHz, CDCl3): d 1.29 (d, 3H), 2.34 (s, 3H), 4.24 (s, 3H),
4.30 (dd, 1H), 4.49 (dd, 1H), 4.61-4.72 (m, 1H), 6.65 (d, 1H), 6.88 (s, 1H), 7.53 (d,
1H), 7.61 (dd, 1H), 7.78-7.82 (m, 1H), 8.01 (d, 1H).
Example 25.
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-5-(isoxazol-3-yl)-1,2,4-oxadiazole-3-carboxamide
a) Ethyl 5-(isoxazol-3-yl)-1,2,4-oxadiazole-3-carboxylate
Ethyl aminohydroxyiminoacetate (3.78 mmol, 0.5 g), 3-isoxazolecarboxylic
acid (3.78 mmol, 0.428 g) and 1,3-diisopropylcarbodiimide (4.16 mmol, 0.525 g)
were dissolved in DCM (70 ml) under nitrogen atmosphere. The mixture was stirred
at RT for a day. The solvent was evaporated to dryness and the residue was dissolved
in pyridine and refluxed for 6 h and overnight at RT. Pyridine was evaporated and the
residue was diluted with DCM and water. The aqueous phase was extracted four
times with DCM. The combined organics were washed with aqueous HCl solution,
saturated NaHCO3, water and brine. The organic phase was dried, filtered and
evaporated. The crude product was purified by flash chromatography. 0.396 g of the
title compound was obtained. Rotamers were obtained in 1H-NMR and analysis was
repeated at elevated temperature. 1H-NMR (400 MHz, DMSO-d6, +60°C): 8 1.38 (t,
3H), 4.49 (q, 2H), 7.21 (d, 1H), 9.05 (d, 1H).
b) 5-(Isoxazol-3-yl)-1,2,4-oxadiazole-3-carboxylic acid
Ethyl 5-(isoxazol-3-yl)-1,2,4-oxadiazole-3-carboxylate (1.893 mmol, 0.396 g)
was dissolved in ethanol (5 ml) and cooled to 0 °C with an ice bath. NaOH 1 M
solution (4 ml) was slowly added and the mixture was heated to 60 °C for 3 h.
Ethanol was evaporated and the residue was diluted with MTBE. The mixture was
cooled to 0 °C and acidified by adding 2 M HCl. The mixture was stirred at RT
overnight. Water was added and the phases were separated and the water phase was
evaporated. 0.533 g of the title compound was obtained. 1H-NMR (400 MHz,D2O): d
6.68 (d, 1H), 8.65 (d, 1H).
c) (S)-N-( 1 -(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-5-(isoxazol-3-yl)-1,2,4-oxadiazole-3-carboxamide
The title compound was prepared using the procedure described in Example
3(h) starting from 5-(isoxazol-3-yl)-1,2,4-oxadiazole-3-carboxylic acid (1.933 mmol,
0.35 g) and (S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzo-
nitrile (1.610 mmol, 0.449 g) using DMF (10 ml) as the solvent. The reaction mixture
was diluted with water and EtOAc, the phases were separated and the organic phase
was washed with 2M Na2CO3, water and brine. The organic phase was dried, filtered
and evaporated. The crude product was purified by flash chromatography and
preparative HPLC, respectively. 0.0065 g of the title compound was obtained. 1H-
NMR (400 MHz, CDCl3): d 1.26 (d, 3H), 4.28 (dd, 1H), 4.46 (dd, 1H), 4.56-4.66 (m,
1H), 6.63 (d, 1H), 6.82 (d, 1H), 7.51 (d, 1H), 7.64 (dd, 1H), 7.84-7.86 (m, 1H), 7.88
(d, lH),8.51(d, 1H).
Example 26.
(S)-N-(1 -(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)-propan-2-
yl)-3-(lH-imidazol-4-yl)-1H-pyrazole-5-carboxamide
a) Lithium (Z)-4-( 1 -benzyl-1H-imidazol-4-yl)-1 -ethoxy-1,4-dioxobut-2-en-2-
olate
5-Acetyl-1-benzylimidazole (24.97 mmol, 5 g) was dissolved in dry diethyl
ether (100 ml) under nitrogen atmosphere. The mixture was cooled to -75 °C and
lithium bis(trimethylsilyl)amide (27.5 mmol, 27.5 ml) was added dropwise. The
resulting mixture was stirred at -75 °C for an hour. Diethyl oxalate (32.5 mmol, 4.74
g) was added and the mixture was allowed to warm to ambient temperature after
which the mixture was stirred for a day at RT. The formed precipitate was removed
by filtration and the precipitate was washed with diethyl ether. The precipitate was
dried under vacuum. 7.38 g of the title compound was obtained. 1H-NMR (400 MHz,
DMSO-d6): d 1.22 (t, 3H), 4.11 (q, 2H), 5.61 (s, 2H), 6.17 (s, 1H), 7.15 - 7.31 (m,
5H), 7.48 (d, 1H), 7.88 (d, 1H).
b) Ethyl 3-(1-benzyl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxylate
Lithium (Z)-4-( 1 -benzyl-1H-imidazol-4-yl)-1 -ethoxy-1,4-dioxobut-2-en-2-
olate (9.80 mmol, 3.0 g) was suspended in dry ethanol (20 ml). Hydrazine dihydro-
chloride (12.74 mmol, 1.337 g) was added and the resulting mixture was refluxed for
2 h. The mixture was cooled to ambient temperature and evaporated. The sticky oil
was purified by trituration from ethanol. The precipitate was separated by filtration
and flushed with cold ethanol. 2.614 g of the title compound was obtained. 1H-NMR
(400 MHz, DMSO-d6): d 1.31 (t, 3H), 4.33 (q, 2H), 5.81 (bs, 2H), 7.11-7.39 (m, 6H),
8.16 (bs, 1H), 9.31 (bs, 1H), 14.50 (bs, 1H).
c) Ethyl 3-(lH-imidazol-4-yl)-1H-pyrazole-5-carboxylate
Ethyl 3-(1-benzyl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxylate (8.77 mmol,
2.6 g) was dissolved in a mixture of acetic acid (10 ml) and ethanol (190 ml). The
mixture was run through H-Cube (10% Pd/C CatCart (8.77 mmol) flow 1.5 ml/min,
+80 °C, Full hydrogen mode). The collected fractions were combined and evaporated.
The acquired solid was stirred in toluene and evaporated. This was repeated once
more. 1.837 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): d 1.33 (t, 3H), 4.35 (q, 2H), 7.38 (s, 1H), 8.07 (d, 1H), 9.14 (bs, 1H), 14.44 (bs, 1H).
LC-MS:[M-1]= 205.0.
d) Ethyl 3-(1-trityl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxylate
Ethyl 3-(lH-imidazol-4-yl)-1H-pyrazole-5-carboxylate (6.79 mmol, 1.4 g)
was suspended in DCM (20 ml) under nitrogen atmosphere. Triphenylmethyl
chloride (8.15 mmol, 2.271 g) was added and stirred for 10 min at RT. Triethylamine
(8.15 mmol, 1.136 ml) was added and the resulting mixture was stirred for 20 h at
RT after which DCM (10 ml) and triphenylmethyl chloride (1 g) was added. The
stirring was continued for another 4.5 days. More triphenylmethyl chloride (1.14 g)
and triethylamine (0.6 ml) was added and the mixture was stirred for another day.
The mixture was diluted with DCM and washed with NaHCO3. The organic phase
was dried, filtered and evaporated. The residue was was purified by trituration from
ACN. 1.837 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6):
8 1.28 (t, 3H), 4.25 (q, 2H), 6.89 (s, 1H), 7.09-7.18 (m, 6H), 7.18-7.33 (m, 6H), 7.36-
7.47 (m, 3H), 7.50 (s, 1H), 7.55 (s, 1H), 13.63 (bs, 1H).
e) 3-(1-Trityl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxylic acid
Ethyl 3-(1-trityl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxylate (4.01 mmol,
1.8 g) was dissolved in ethanol (20 ml) and cooled to 0 °C. NaOH 2 M solution (8.03
mmol, 4.01 ml) was added and the mixture was stirred at RT for an hour. The
mixture was heated to 60 °C and stirred for 10 h. Ethanol was evaporated and the
residue was diluted with water. The pH was adjusted to 4 with 1 M HCl solution
which precipitated the product. The precipitate was removed by filtration and washed
with water. The solid was dried under vacuum. 1.5 g of the title compound was
obtained. 1H-NMR (400 MHz, DMSO-d6): d 6.75 (bs, 1H), 7.08-7.17 (m, 6H), 7.18 -
7.34 (m, 5H), 7.36 - 7.49 (m, 8H). LC-MS: [M-l] = 419.1.
f) (S)-N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-3 -(1 -trityl-1H-imidazol-4-yl)-1H-pyrazole-5 -carboxamide
The title compound was prepared using the procedure described in Example
3(h) starting from 3-(1-trityl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxylic acid
(0.875 mmol, 0.368 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-
fluorobenzonitrile (0.673 mmol, 0.250 g) using HBTU (0.067 mmol, 0.026 g) instead
of HOBt. DCM (4 ml) was used as the solvent. The mixture was diluted with DCM
and washed with 1 M Na2CO3 and water. The separated organic phase was dried,
filtered and evaporated to give 0.511 g of crude product. Another crude batch (931
mg) was combined here and purified first by trituration in ACN and then by flash
chromatography to give 0.095 g of the product. 1H-NMR (400 MHz, DMSO-d6): d 1.18 (d, 3H), 4.13-4.53 (m, 3H), 6.64 (s, 1H), 6.98 (d, 1H), 7.09-7.19 (m, 4H), 7.35-
7.51 (m, 9H), 7.52-7.57 (m, 1H), 7.70-7.76 (m, 1H), 7.79-7.86 (m, 2H), 7.92 (s, 1H),
7.95 (s, 1H), 8.06-8.10 (m, 1H), 8.14 -8.18 (m, 1H), 13.35 (bs, 1H).
g) (S)-N-( 1 -(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-3 -(1 H-imidazol-4-yl)-1H-pyrazole-5-carboxamide
Into (S)-N-( 1 -(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-
2-yl)-3-(1-trityl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxamide (0.139 mmol, 0.095
g) was added 4 ml of a solution containing formic acid (41.8 mmol, 1.926 g), THF
(20 ml) and water (1 ml). The resulting mixture was stirred first at RT after which the
temperature was raised to 50 °C for 2 h. The solvent was evaporated, ACN was
added and evaporated again. This was repeated once more. The crude product was
purified by preparative HPLC. 0.0169 g of the title compound was obtained. 1H-
NMR (400 MHz, CDCl3): d 1.27 (d, 3H), 4.14 (dd, 1H), 4.45 (dd, 1H), 4-57-4.64 (m,
1H), 6.29 (bs), 6.63 (d, 1H), 6.90 (s, 1H), 7.32 (d, 1H), 7.51(d, 1H), 7.52 (s, 1H),
7.63 (dd, 1H), 7.73 (d, 1H), 7.84-7.86 (m, 1H) LC-MS: [M+1] = 439.0.
Example 27.
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5 -fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-2-(chloropropan-2-yl)oxazole-4-carboxamide
a) (S)-N-( 1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-2-(2-hydroxypropan-2-yl)oxazole-4-carboxamide
The title compound was prepared using the procedure described in Example
3(h) starting from 2-(2-hydroxypropan-2-yl)oxazole-4-carboxylic acid (2.153 mmol,
0.368 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluoroberizo-
nitrile (2.153 mmol, 0.6 g) and using HBTU (0.215 mmol, 0.082 g) instead of HOBt.
DCM (15 ml) was used as the solvent. During the reaction a new batch of starting
materials was added to the reaction mixture. The batch contained half the amount of
starting materials used in the beginning of the reaction with the exception that (S)-4-
(l-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fiuorobenzonitrile was not added at
all. The resulting mixture was stirred for 2 days. The mixture was diluted with DCM
and washed with Na2CO3 solution and water. The organic phase was dried, filtered
and evaporated. The crude product was purified by flash chromatography. 0.669 g of
the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): d 1.13 (d, 3H),
1.52 (s, 6H), 4.27-4.54 (m, 3H), 5.63 (s, 1H), 7.02 (d, 1H), 7.83-7.89 (m, 2H), 7.98
(s, 1H), 8.10 (d,1H), 8.48 (s,1H).
b) (S)-N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-2-(chloropropan-2-yl)oxazole-4-carboxamide
(S)-N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-2-(2-hydroxypropan-2-yl)oxazole-4-carboxamide (0.116 mmol, 0.05 g) was
dissolved in DMF (5 ml) and triethylamine (0.255 mmol, 0.026 g) was added.
Diethyl chlorophosphate (0.232 mmol, 0.040 g) was carefully added with a syringe.
The resulting mixture was stirred at RT overnight. A mixture of ice and water was
added and the mixture was neutralized with 1 M NaOH. The mixture was extracted
twice with DCM. The combined organics were washed with water, dried, filtered and
evaporated. The crude product was purified by preparative HPLC. 0.0047 g of the
title compound was obtained. 1H-NMR (400 MHz, CDCl3): d 1.26 (d, 3H), 2.04 (d,
6H), 4.29-4.36 (m, 1H), 4.38-4.46 (m, 1H), 4.54-4.66 (m, 1H), 6.64 (d, 1H), 7.39 (d,
1H), 7.51 (d, 1H), 7.61 (dd, 1H), 7.72-7.75 (m, 1H), 8.17 (s, 1H).
Example 28.
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)-propan-2-
yl)-2-(2-propen-2-yl)oxazole-4-carboxamide
The title product was a by-product from the reaction in which (S)-N-(1-(3-(3-
chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-2-(chloro-propan-2-
yl)oxazole-4-carboxamide was synthesized. This compound was separated from the
main product during preparative HPLC purification. 0.008 g of the title compound
was obtained. 1H-NMR (400 MHz, CDCl3): d 1.27 (d, 3H), 2.13-2.18 (m, 3H), 4.31
dd, 1H), 4.42 (dd, 1H), 4.54-4.65 (m, 1H), 5.45-5.50 (m, 1H), 5.98-6.02 (m, 1H),
6.62 (d, 1H), 7.45 (d, 1H), 7.51 (d, 1H), 7.61 (dd, 1H), 7.71-7.74 (m, 1H), 8.11 (s,
1H).
Example 29.
(S)-N-(1-(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-N5-cyclopropylisoxazole-3,5-dicarboxamide
a) 3-(Ethoxycarbonyl)isoxazole-5-carboxylic acid
Ethyl chlorooximidoacetate (3.30 mmol, 0.5 g) and propiolic acid (33.0
mmol, 2.311 g) were dissolved in diethyl ether (10 ml) with stirring. Triethylamine
(3.30 mmol, 0.334 g) dissolved in diethyl ether (5 ml) was added dropwise to the
previous mixture. The reaction mixture was stirred for three days at RT during which
more triethylamine (2 x 0.668 g dissolved in 5 ml diethyl ether) was added dropwise.
The pH of the reaction mixture was adjusted to 2. The organic phase was washed
twice with water. The organic phase was dried, filtered and evaporated. The residue
was dried under vacuum. 369 mg of the title compound was obtained. 1H-NMR (400
MHz, CDCl3): d 1.44 (t, 3H), 4.49 (q, 2H), 7.41 (s, 1H), 10.59 (bs, 1H).
b) Ethyl 5-(cyclopropylcarbamoyl)isoxazole-3-carboxylate
The title compound was prepared starting from 3-(ethoxycarbonyl)isoxazole-
5-carboxylic acid (3.78 mmol, 0.7 g) and cyclopropyl-amine (2.91 mmol, 0.166 g)
using DCM (10 ml) as the solvent. The mixture was diluted with DCM and washed
with 1 M Na2CO3 and water. The organic phase was dried, filtered and evaporated.
The crude product was purified by flash chromatography. 0.284 g of the title
compound was obtained. 1H-NMR (400 MHz, DMSO-d6) d 0.58-0.64 (m, 2H), 0.70-
0.77 (m, 2H), 1.33 (t, 3H), 2.80-2.90 (m, 1H), 4.38 (q, 2H), 7.39 (s, 1H), 9.04 (bs,
1H).
c) 5-(Cyclopropylcarbamoyl)isoxazole-3-carboxylic acid
Ethyl 5-(cyclopropylcarbamoyl)isoxazole-3-carboxylate (1.267 mmol, 0.284
g) was dissolved in ethanol (10 ml). The mixture was cooled in an ice bath and
NaOH 2 M solution (2.53 mmol, 1.267 ml) was added. The resulting mixture was
stirred in cold until the reaction was complete. Ethanol was evaporated and water
was added. The pH of the mixture was adjusted to 4 with HC1. The precipitate was
removed by filtration. The filtrate was evaporated and purified by trituration from 1/9
MeOH/DCM. 0.058 g of the title compound was obtained. 1H-NMR (400 MHz,
DMSO-d6): d 0.57-0.66 (m, 2H), 0.67-0.75 (m, 2H), 2.77-2.88 (m, 1H), 6.97 (s, 1H),
8.85 (m, 1H).
d) (S)-N-3-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-
2-yl)-N5-cyclopropylisoxazole-3,5-dicarboxamide
The title compound was prepared using the procedure described in Example
3(h) starting from 5-(cyclopropyl-carbamoyl)isoxazole-3-carboxylic acid (0.377
mmol, 0.074 g) and (S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chloro-6-fluoro-
benzonitrile (0.377 mmol, 0.14 g) using DMF (4 ml) as the solvent. HBTU (0.038
mmol, 0.014 g) was used instead of HOBt. The crude product was purified by
preparative HPLC. 0.0011 g of the title compound was obtained. 1H-NMR (400
MHz, CDCl3): d 0.69-0.75 (m, 2H), 0.91-0.98 (m, 2H), 1.26 (d, 3H), 2.87-2.96 (m,
1H), 4.26 (dd, 1H), 4.46 (dd, 1H), 4.55-4.65 (m, 1H), 6.58-6.63 (m, 1H), 6.64 (d,
1H), 7.30 (s, 1H), 7.51 (d, 1H), 7.63-7.69 (m, 1H), 7.82 (s, 1H), 7.93 (d, 1H).
Example 30.
(S)-2-Bromo-N-(1 -(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)-
propan-2-yl)-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in Example
3(h) starting from 2-bromo-1H-imidazole-4-carboxylic acid (4.31 mmol, 0.822 g)
and (S)-4-( 1 -(2-aminopropyl)-1H-pyrazol-3 -yl)-2-chloro-6-fluorobenzonitrile (3.59
mmol, 1 g) using DMF (10 ml) as the solvent. DCM and water was added to the
mixture, the layers were separated and the water phase was extracted with DCM. The
combined organics were washed three times with water. The DCM phase was dried,
filtered and evaporated. The crude product was purified by flash chromatography and
preparative HPLC, respectively. 30.5 mg of the title compound was obtained. 1H-
NMR (400 MHz, DMSO-d6): d 1.10 (d, 3H), 4.24- 4.49 (m, 3H), 7.00 (d, 1H), 7.62
(s, 1H), 7.83 (d, 1H), 7.87 (d, 1H), 7.96 (s, 1H), 8.11 (d, 1H), 13.23 (bs, 1H).
Example 31.
(S)-N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-1 -(2-methylprop-1 -enyl)-1H-pyrazole-3 -carboxamide
a) Methyl 1-(2-methylprop-1-enyl)-1H-pyrazole-3-carboxylate
The title compound was prepared using the procedure described in Example
17(a) starting from methyl 1 H-pyrazole-3-carboxylate (8 g, 63.4 mmol) and 1-bromo-
2-methyl propene (12.7 g, 95.2 mmol). The product was purified with flash
chromatography. Yield 2.4 g. 1H-NMR (400 MHz; CDCl3): d 1.81 (d, 3H), 1.87 (d,
3H), 3.93 (s, 3H), 6.70 (d, 1H), 6.87 (d, 1H), 7.47 (d, 1H).
b) l-(2-Methylprop-1-enyl)-1H-pyrazole-3-carboxylic acid
The title compound was prepared using the procedure described in Example
32(d) starting from methyl 1-(2-methylprop-1-enyl)-1H-pyrazole-3-carboxylate (2.4
g, 13.3 mmol). Yield 1.6 g. 1H-NMR (400 MHz; DMSO-d6): d 1.84 (s, 6H), 6.77 (d,
1H), 6.82 (s, 1H), 7.87 (d, 1H), 12.7 (bs, 1H).
c) (S)-N-( 1 -(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-1 -(2-methylprop-1 -enyl)-1H-pyrazole-3 -carboxamide
The title compound was prepared using the procedure described in Example
3(h) starting from l-(2-methyl-prop-1-en-1-yl)-1H-pyrazole-3-carboxylic acid (1.076
mmol, 179 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluoro-
benzonitrile (0.897 mmol, 250 mg) using DCM (5 ml) as the solvent. The mixture
was diluted with DCM, washed with 1M Na2CO3 and water. The organic phase was
dried, filtered and evaporated. The product was purified by flash chromatography.
298 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): d 1.12
(d, 3H), 1.80 (d, 3H), 1.84 (d, 3H), 4.27-4.50 (m, 3H), 6.66 (d, 1H), 6.77-6.80 (m,
1H), 7.01 (d, 1H), 7.83 (d, 1H), 7.85-7.89 (m, 2H), 7.95-7.98 (m, 1H), 8.15 (d, 1H).
Example 32.
(S)-N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-1 -cyclopropyl-1H-pyrazole-3 -carboxamide
a) lH-Pyrazole-3-carboxylic acid
3-Methylpyrazole (20 g, 243.5 mmol) was dissolved in water (500 ml). Into
the solution, aqueous KMnO4 (96.2 g, 608.9 mmol in 900 ml of water) was added
and the resulting mixture was refluxed for 12 h. The reaction mixture was filtered
through a celite bed and concentrated. The white residue was dissolved in water and
made to pH 2 using concentrated HC1. The precipitated solids were filtered under
vacuum. Yield 15 g. LC-MS: [M+1] = 112.98.
b) Methyl lH-pyrazole-3-carboxylate
1H-Pyrazole-3-carboxylic acid (15 g, 133.8 mmol) was dissolved in MeOH
(250 ml). Concentrated H2SO4 (30 ml) was added to the solution. The resulting
mixture was refluxed for 12 h and concentrated. The residue obtained was quenched
by saturated aqueous solution of NaHCO3 and extracted with EtOAc. The organic
layer was concentrated. Yield 12.05 g. 1H-NMR (400 MHz; CDCl3): d 3.98 (s, 3H),
6.86 (d, 1H), 7.85 (d, 1H), 11.9 (bs, 1H).
c) Methyl l-cyclopropyl-1H-pyrazole-3-carboxylate
Methyl lH-pyrazole-3-carboxylate (4 g, 31.7 mmol) was dissolved in di-
chloroethane (160 ml). Na2CO3 (6.72 g, 63.4 mmol) and cyclopropylboronic acid
(5.44 g, 63.4 mmol) were added to the solution. The resulting mixture was heated to
70 °C and a hot solution of bipyridine (4.92 g, 31.6 mmol) and Cu(OAc)2 (5.72 g,
31.6 mmol) in dichloroethane (40 ml) was added. The mixture was stirred at 70 °C
under an oxygen atmosphere overnight. Saturated aqueous solution of NaHCO3 was
added to the reaction mixture and extracted with EtOAc. The organic layer was
evaporated and the residue was purified by flash chromatography. Yield 2.5 g. !H-
NMR (400 MHz; DMSO-d6): d 1.04-1.09 (m, 2H), 1.17-1.23 (m, 2H), 3.64-3.69 (m,
1H), 3.91 (s, 3H), 6.78 (d, 1H), 7.46 (d, 1H).
d) l-Cyclopropyl-1H-pyrazole-3-carboxylic acid
Methyl l-cyclopropyl-1H-pyrazole-3-carboxylate (2.5 g, 15 mmol) was
dissolved in THF (40 ml) and H2O (10 ml). LiOHH2O (1.50 g, 22.5 mmol) was
added and the mixture was stirred at RT overnight. The reaction mixture was
concentrated and acidified to pH 2 using 1 N HC1. The mixture was extracted with
EtOAc and the organic layer was concentrated. Yield 1.6 g. 1H-NMR (400 MHz;
DMSO-d6): d 0.96-1.02 (m, 2H), 1.04-1.09 (m, 2H), 3.79-3.84 (m, 1H), 6.66 (d, 1H),
7.88 (d, 1H), 12.6 (bs, 1H).
e) (S)-N-( 1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-1 -cyclopropyl-1H-pyrazole-3-carboxamide
l-Cyclopropyl-1H-pyrazole-3-carboxylic acid (0.30 g, 1.29 mmol) was
dissolved in DCM (20 ml). EDCI (0.692 g, 3.61 mmol), HOBt (0.487 g, 3.61 mmol)
and DIPEA (0.932 g, 7.22 mmol) were added at 0 °C to the solution. The resulting
mixture was stirred at 0 °C for 15 min. (S)-4-(1-(2-Aminopropyl)-1H-pyrazol-3-yl)-
2-chloro-6-fluorobenzonitrile (0.502 g, 1.8 mmol) dissolved in DCM (2 ml) was
added and the mixture was stirred overnight. The reaction mixture was quenched by
the addition of water and extracted with DCM. The organic layer was evaporated and
the residue was purified by flash chromatography. Yield: 400 mg. 1H-NMR (400
MHz; DMSO-d6): d 0.97-1.17 (m, 7H), 3.74-3.80 (m, 1H), 4.26-4.41 (m, 3H), 6.53
(d, 1H), 7.01 (d, 1H), 7.82-7.87 (m, 3H), 7.96 (s, 1H), 8.14 (d, 1H).
Example 33.
N-((S)-1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-2-( 1 -hydroxyethyl)-1H-imidazole-4-carboxamide
a) Methyl 2-( 1 -ethoxyvinyl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-
imidazole-4-carboxylate
Methyl-2-bromo-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-
carboxylate (10 g, 29.9 mmol) was dissolved in dioxane (200 ml). Tributyl(l-ethoxy-
vinyl)stannane (16.2 g, 44.8 mmol) was added to the solution. The resulting mixture
was degassed and purged with argon for 20 min. Then Pd(PPh3)4 (3.45 g, 2.99 mmol)
was added and the mixture was refluxed overnight. The reaction mixture was cooled
to RT and diluted with cold water. The mixture was extracted with EtOAc and
washed with aqueous KF solution. The organic layer was concentrated to give the
desired product. Yield 12.1 g. LC-MS: [M+1] = 327.78.
b) Methyl 2-acetyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-
carboxylate
Into a flask containing a solution of methyl-2-(1-ethoxyvinyl)-1-((2-(tri-
methylsilyl)-ethoxy)methyl)-1H-imidazole-4-carboxylate (3.5 g, 10.7 mmol) in THF
(25 ml), 2 N HCl (25 ml) was added at RT and stirred for 3 h. The reaction mixture
was concentrated and extracted with DCM. The organic layer was evaporated and the
residue was purified by flash chromatography. Yield 2.6 g. 1H-NMR (400 MHz;
CDCl3): d -0.016 (s, 9H), 0.94 (t, 2H), 2.73 (s, 3H), 3.58 (t, 2H), 3.94 (s, 3H), 5.76 (s,
2H), 7.93 (s, 1H).
c) 2-Acetyl-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic
acid
The title compound was prepared using the procedure described in Example
32(d) starting from methyl-2-acetyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imi-
dazole-4-carboxylate (2.5 g, 8.3 mmol). Yield 2 g. 1H-NMR (400 MHz; DMSO-d6):
d -0.06 (s, 9H), 0.83 (t, 2H), 2.57 (s, 3H), 3.53 (t, 2H), 5.68 (s, 2H), 8.23 (s, 1H),
12.76 (s,lH).
d) (S)-2-Acetyl-N-( 1 -(3 -(3 -chloro-4-cyano-5 -fluorophenyl)-1H-pyrazol-1 -yl)-
propan-2-yl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in Example
32(e) starting from 2-acetyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-
carboxylic acid (400 mg, 1.4 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-
2-chloro-6-fluoro-benzonitrile (389 mg, 1.4 mmol). The product was purified with
flash chromatography. Yield 260 mg. 1H-NMR (400 MHz; DMSO-d6): d -0.09 (s,
9H), 0.81 (t, 2H), 1.15 (d, 3H), 2.61 (s, 3H), 3.48 (t, 2H), 4.33-4.48 (m, 3H), 5.66 (s,
2H), 7.02 (d, 1H), 7.84-7.87 (m, 2H), 7.95 (s, 1H), 8.06 (s, 1H), 8.15 (d, 1H).
e) N-((S)-1 -(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-2-( 1 -hydroxyethyl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-
carboxamide
(S)-2- Acetyl-N-( 1 -(3 -(3 -chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)-
propan-2-yl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxamide (290
mg, 0.53 mmol) was dissolved in MeOH (20 ml). NaBH4 (30 mg, 0.79 mmol) was
added to the solution in portions at 0 °C and the mixture was stirred at RT for 3 h.
The reaction mixture was concentrated and dluted with water. The mixture was
extracted with DCM and the organic layer was concentrated. The product was
purified by column chromatography. Yield 245 mg. 1H-NMR (400 MHz; DMSO-d6):
d -0.05 (s, 9H), 0.81-0.86 (m, 2H), 1.07-1.1 (m, 3H), 1.49 (d, 3H), 3.47-3.51 (m, 2H),
4.29-4.43 (m, 3H), 4.88-4.91 (m, 1H), 5.4-5.45 (m, 3H), 7.03 (d, 1H), 7.68 (d, 1H),
7.86-8.00 (m, 4H).
f) N-((S)-1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-2-( 1 -hydroxyethyl)-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in Example
52(h) starting from N-((S)-1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-
yl)propan-2-yl)-2-( 1 -hydroxyethyl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-imi-
dazole-4-carboxamide (0.65 g, 1.2 mmol). Yield 124 mg. 1H-NMR (400 MHz;
DMSO-d6): d 1.07 (d, 3H), 1.41 (d, 3H), 4.27-4.41 (m, 3H), 4.73-4.78 (m, 1H), 5.51
(d, 1H), 7.03 (d, 1H), 7.41 (s, 1H), 7.86 (d, 1H), 7.92 (d, 1H), 8.01 (d, 2H), 12.28 (s,
1H).
Example 34.
(S)-2-acetyl-N-( 1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-
propan-2-yl)-1H-imidazole-4- carboxamide
a) (S)-2-Acetyl-N-( 1 -(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -
yl)propan-2-yl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in Example
32(e) starting from starting from 2-acetyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-
imidazole-4-carboxylic acid (400 mg, 1.4 mmol) and (S)-4-(1-(2-aminopropyl)-1H-
pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (389 mg, 1.4 mmol). The product was
purified with flash chromatography. Yield: 260 mg. 1H-NMR (400 MHz; DMSO-d6): d -0.09 (s, 9H), 0.81 (t, 2H), 1.15 (d, 3H), 2.61 (s, 3H), 3.48 (t, 2H), 4.33-4.48 (m,
3H), 5.66 (s, 2H), 7.02 (d, 1H), 7.84-7.87 (m, 2H), 7.95 (s, 1H), 8.06 (s, 1H), 8.15 (d,
1H).
b) (S)-2-Acetyl-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-
propan-2-yl)-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in Example
52(h) starting from (S)-2-acetyl-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-
pyrazol-1 -yl)propan-2-yl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-
carboxamide (250 mg, 0.45 mmol). Yield 124 mg. 1H-NMR (400 MHz; DMSO-d6):
d 1.14 (d, 3H), 2.57 (s, 3H), 4.31-4.5 (m, 3H), 7.02 (d, 1H), 7.78 (d, 1H), 7.84-7.87
(m, 2H), 7.94 (s, 1H), 8.11 (d, 1H), 13.62 (s, 1H).
Example 35.
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-2-(2-hydroxypropan-2-yl)-1H-imidazole-4-carboxamide
a) Methyl 2-(2-hydroxypropan-2-yl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-
imidazole-4-carboxylate
The title compound was prepared using the procedure described in Example
2(d) starting from methyl 2-acetyl-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-
imidazole-4-carboxylate (3 g, 10 mmol). The product was purified by flash-
chromatography. Yield 1.5 g. 1H-NMR (400 MHz; DMSO-d6): d -0.03 (s, 9H), 0.86
(t, 2H), 1.52 (s, 6H), 3.56 (t, 2H), 3.73 (s, 3H), 5.64 (s, 2H), 7.94 (s, 1H).
b) 2-(2-Hydroxypropan-2-yl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-
imidazole-4-carboxylic acid
The title compound was prepared using the procedure described in Example
32(d) starting from methyl 2-(2-hydroxypropan-2-yl)-1-((2-(trimethylsilyl)ethoxy)-
methyl)-1H-imidazole-4-carboxylate (1.5 g, 4.7 mmol). Yield 1 g. 1H-NMR (400
MHz; DMSO-d6): d -0.02 (s, 9H), 0.86 (t, 2H), 1.52 (s, 6H), 3.56 (t, 2H), 5.44 (s,
1H), 5.62(s, 2H), 7.83 (s, 1H).
c) (S)-N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-2-(2-hydroxypropan-2-yl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-
carboxamide
The title compound was prepared using the procedure described in Example
32(e) starting from 2-(2-hydroxypropan-2-yl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-
lH-imidazole-4-carboxylic acid (400 mg, 1.33 mmol) and (S)-4-(1-(2-amino-propyl)-
1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (370 mg, 1.33 mmol). The product
was purified with flash-chromatography. Yield 305 mg. LC-MS: [M+1] = 561.17.
d) (S)-N-(1 -(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-2-(2-hydroxypropan-2-yl)-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in Example
52(h) starting from (S)-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-
yl)propan-2-yl)-2-(2-hydroxy-propan-2-yl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-
imidazole-4-carboxamide (370 mg, 0.66 mmol). Yield 136 mg. 1H-NMR (400 MHz;
DMSO-d6): d 1.09 (d, 3H), 1.46 (s, 6H), 4.28-4.42 (m, 3H), 5.35 (s, 1H), 7.04 (d,
1H), 7.38 (d, 1H), 7.75-7.99 (m, 4H), 12.15 (s, 1H).
Example 36.
(S)-N-( 1 -(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)-propan-2-
yl)-2-cyclopropyl-1 -methyl-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in Example
32(e) starting from 2-cyclopropyl-1-methyl-1H-imidazole-4-carboxylic acid (260 mg,
1.56 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzo-
nitrile (435 mg, 1.56 mmol). Yield 123 mg. 1H-NMR (400 MHz; DMSO-d6): d 0.81-
0.91 (m, 4H), 1.08 (d, 3H), 1.95 (m, 1H), 3.65 (s, 3H), 4.27-4.38 (m, 3H), 7.01 (s,
1H), 7.46 (s, 1H), 7.69 (d, 1H), 7.87 (d, 2H), 7.96 (s, 1H).
Example 37.
(S)-N4-(1 -(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-1H-imidazole-2,4-dicarboxamide
a) Methyl 2-cyano-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-
carboxylate
Into a flask containing a solution of methyl 2-formyl-1-((2-(trimethylsilyl)-
ethoxy)-methyl)-1H-imidazole-4-carboxylate (9 g, 31.6 mmol) in MeOH (200 ml),
50 % aqueous NH2OH.HCl solution (2.5 ml) was added and stirred at RT for 3 h. The
reaction mixture was concentrated and extracted with EtOAc. The organic layer was
concentrated and the resulting residue was dissolved in DCM (200 ml). Pyridine (12
ml) and trifluoroacetic anhydride (18 ml) were added to the above mixture and stirred
for 12 h. The reaction mixture was quenched with aqueous NaHCO3 solution and
extracted with DCM. The organic layer was concentrated and purified with flash
chromatography. Yield 4.1 g. 1H-NMR (400 MHz; DMSO-d6): d -0.04 (s, 9H), 0.87
(t, 2H), 3.56 (t, 2H), 3.81 (s, 3H), 5.29 (s, 2H), 8.28 (s, 1H).
b) 2-Carbamoyl-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-
carboxylic acid
Methyl 2-cyano-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-
carboxylate (3 g, 10.7 mmol) was dissolved in THF (30 ml) and H2O (8 ml).
LiOH.H2O (1.1 g, 16.1 mmol) was added to the solution and the mixture was stirred
at RT overnight. The reaction mixture was concentrated and acidified to pH 2 using 1
N HC1. The mixture was extracted with EtOAc and the organic layer was
concentrated. Yield 2.2 g. 1H-NMR (400 MHz; DMSO-d6): d -0.06 (s, 9H), 0.85 (t,
2H), 2.57 (s, 3H), 3.52 (t, 2H), 5.79 (s, 2H), 7.66(s, 1H), 7.96(s, 1H), 8.09 (s, 1H),
12.68 (s, 1H).
c) (S)-N4-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-
2-yl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2,4-dicarboxamide
The title compound was prepared using the procedure described in Example
32(e) starting from 2-carbamoyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-
4-carboxylic acid (500 mg, 1.7 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-
yl)-2-chloro-6-fluorobenzonitrile (472 mg, 1.7 mmol). The product was purified with
flash-chromatography. Yield 420 mg. LC-MS: [M+1] = 546.19.
d) (S)-N4-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-
2-yl)-1H-imidazole-2,4-dicarboxamide
The title compound was prepared using the procedure described in Example
52(h) starting from (S)-N4-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-
yl)propan-2-yl)-1 -((2-(trimethylsilyl)ethoxy)-methyl)-1H-imidazole-2,4-dicarbox-
amide (0.45 g, 0.82 mmol) Yield 310 mg. 1H-NMR (400 MHz; DMSO-d6): d 1.14 (d,
3H), 4.28-4.24 (m, 3H), 7.01 (s, 1H), 7.63-7.67 (m, 3H), 7.84-7.94 (m, 4H), 13.39 (s,
1H).
Example 38.
4-( 1 -(3 -((S)-1 -(3 -(3-Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl-
carbamoyl)-1H-pyrazol-5-yl)ethoxy)-4-oxobutanoic acid
a) 2-Chloro-4-(1 -(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile
4-Bromo-2-chlorobenzonitrile (30 g, 139 mmol), 90 ml of THF and 360 ml of
toluene were placed in reaction vessel under nitrogen athmosphere. Bis(triphenyl-
phosphine)-palladium(II) chloride (4.57g, 6.51 mmol), Na2CO3 (33.1 g, 312 mmol),
180 ml of water and tetrabutylammonium bromide (0.894 g, 2.77 mmol) were added.
The reaction mixture was heated up to 42 °C. 1-(Tetrahydro-2H-pyran-2-yl)-1H-
pyrazole-5-boronic acid pinacol ester (42.4 g; 152 mmol) was added in three portions
within one hour. The reaction was agitated at 42 °C for one hour followed with
addition of 180 ml of water and cool down. The reaction mixture was filtered and
layers separated. Organic phase was washed with 400 ml of water. The layers were
separated and the toluene phase was distilled close to dryness. 180 ml of ethanol was
added to the warm residue and the mixture was cooled down to 5 °C for three hours.
The precipitate was filtered and washed with cold ethanol. 36.4 g of the title
compound was obtained after vacuum drying. 1H-NMR (400 MHz, DMSO-d6): d
1.48-1.70 (m, 3H), 1.78-1.86 (m, 1H), 1.90-2.00 (m, 1H), 2.29-2.46 (m, 1H), 3.55-
3.68 (m, 1H), 3.93-4.04 (m, 1H), 5.29 (dd, 1H), 6.72 (d, 1H), 7.65 (d, 1H), 7.72 (dd,
1H), 7.92 (d,lH), 8.13 (d,lH).
b) 2-Chloro-4-(1H-pyrazol-3-yl)benzonitrile hydrochloride
*************HCl/EtOH -10 % (35.1 ml, 115 mmol) was set into the reaction flask under
nitrogen athmosphere. 2-Chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-
benzonitrile (12 g, 46.2 mmol) was added. The mixture was cooled to 10 °C and
agitated for 2 h. Temperature was set to 0°C and the mixture was stirred additional 2
h. The precipitation was filtered, washed with ethanol and dried under vacuum
overnight to obtain 9.24 g of the title compound. 1H-NMR (400 MHz, DMSO-d6): d 6.99 (d, 3H), 7.86 (d, 1H), 7.96-8.02 (m, 2H), 8.14-8.17 (m, 1H).
c) 2-Chloro-4-( 1 H-pyrazol-3 -yl)benzonitrile
2-Chloro-4-(lH-pyrazol-5-yl)benzonitrile hydrochloride (8 g, 33.3 mmol) was
charged to the reaction flask and methanol (74 ml), activated charcoal (0.36 g) and
celite (0.46 g) were added. The reaction mixture was refluxed for 1 h, filtered, and
the solid was washed with warm methanol. A half of the methanol was distilled out
and water (40 ml) was added at 55 °C slowly. 50 % NaOH solution (1.916 ml, 36.7
mmol) was added slowly, the mixture was stirred for 10 min and cooled to RT.
MeOH was evaporated and residue cooled to RT. Water (49 ml) was added and the
precipitate was filtered and washed with water and dried under vacuum overnight at
60°C to obtain 6.21 g of the title compound. 1H-NMR (400 MHz, DMSO-J6): 5 6.99
(d, 1H), 7.86 (d, 1H), 7.96-8.01 (m, 2H), 8.24-8.16 (m, 1H).
d) (S)-4-( 1 -(2-Aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile
(2-Chloro-4-(l H-pyrazol-3-yl)benzonitrile (30 g, 145 mmol), (S)-ter/-butyl-1-
hydroxypropan-2-ylcarbamate (51.4 g, 291 mmol), triphenylphosphine (77 g, 291
mmol) and 210 ml of EtOAc were place in to the reaction vessel under nitrogen
atmosphere and stirred for 15 min. DIAD (57.8 ml, 291 mmol) was added slowly in
1.5 h at RT keeping the temperature stable and the reaction was stirred overnight at
RT. Concentrated HCl (134 ml, 1453 mmol) was added and the mixture was stirred
at RT overnight. Water (165 ml) and DCM (240 ml) were added, the mixture was
stirred for 30 minand layers were separated. Organic phase was washed with 2 x 270
ml of acidic water (pH~l). Water phases were combined and washed with 2 x 120 ml
of dichloromethane. Dichloromethane (150 ml) was added, pH set to 11.5 by 50 %
NaOH and the mixture was stirred for 75 min. The solution was filtered through the
celite, layers were separated and organic phase was washed with 171 ml of water.
DCM was distilled out at 33°C under reduced pressure and 60 ml of heptanes was
added. Precipitation was started, 60 ml of heptane added and the mixture was stirred
overnight. Some DCM was evaporated, 60 ml heptanes was added and the mixture
was cooled to 10°C. The precipitate was filtered, washed with 20 ml of IPA:heptane
(10:90) and dried under vacuum to obtain 24.55 g of the title compound. 1H-NMR
(400 MHz, DMSO-J6): 5 1.03 (d, 3H), 3.34-3.43 (d, 2H), 4.14 (d, 2H), 6.99 (d, 1H),
7.89 (d, 1H), 7.96 (dd, 1H), 7.99 (dd, 1H), 8.12-8.14 (m, 1H).
e) (S)-5-Acetyl-N-( 1 -(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-1H-pyrazole-3 -carboxamide
3-Acetyl-1H-pyrazole-5-carboxylic acid (10.20 g, 66.2 mmol), DCM (195 ml)
and DIPEA (11.52 ml, 66.2 mmol) were placed in to the reaction flask under nitrogen
athmosphere. HBTU (3.27 g, 8.63 mmol), EDCI (12.68 g, 66.2 mmol) and (S)-4-(1-
(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (15 g, 57.5 mmol) were
added in this order and the mixture was stirred overnight at RT. The solvent was
distilled close to dryness under vacuum, 2-propanol (25 ml) was added and the
mixture was distilled to dryness. 2-Propanol (127 ml) was added, heated to reflux,
water (23 ml) was added and the mixture was stirred for 15 min. The mixture was
cooled to RT, stirred overnight and cooled to 5°C. The precipitate was filtered,
washed with 2 x 10 ml of cold 2-propanol: water (70:30) and dried under vacuum to
obtain 18.7 g of the title compound. *H-NMR (400 MHz, DMSO-<4): 5 1.17 (d, 3H),
2.50 (s, 3H), 4.21-4.53 (m, 3H), 6.93 (d, 1H), 7.31 (s, 1H), 7.81 (d, 1H), 7.86-8.07
(m, 3H), 8.40-8.54 (bs, 1H), 14.14 (bs., 1H).
f)N-((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-
hydroxyethyl)-1H-pyrazole-3-carboxamide
Sodium borohydride (0.930 g, 24.57 mmol) and EtOH (105 ml) were placed
in to the reaction flask under nitrogen athmosphere. (S)-3-acetyl-N-(1-(3-(3-chloro-4-
cyano-phenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide (15 g, 37.8
mmol) was added in small portions to keep temperature below 25°C. After 3.5 h
sodium borohydride (0.07 g, 1.85 mmol) was added and the mixture was stirred for
additional 60 min to complete the reaction. 16 ml of ~10 % HCl in EtOH was added
carefully to set pH to 3.5 and the mixture was stirred overnight at RT. Water (30 ml)
was added and the stirring was continued for 3 h. The precipitate was filtered,
washed with 2 x 10 ml of cold watenEtOH (1:1) and dried under vacuum to obtain
12.2 g of the title compound. 1H-NMR (400 MHz, DMSO-d6): d 1.12 (d, 3H), 1.39
(d, 3H), 4.24-4.52 (m, 3H), 4.76-4.86 (m, 1H), 5.42 (d, 1H), 6.42 (bs., 1H), 6.94 (d,
1H), 7.82 (d, 1H), 8.00 (bs, 2H), 8.09 (bs, 1H), 8.20 (d, 1H), 13.05 (bs, 1H).
g) 4-( 1 -(3-((S)-1 -(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-
ylcarbamoyl)-1H-pyrazol-5-yl)ethoxy)-4-oxobutanoic acid
N-((S)-1 -(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-5-( 1 -
hydroxy-ethyl)-1H-pyrazole-3-carboxamide (1.254 mmol, 0.5 g), dihydrofuran-2,5-
dione (1.504 mmol, 0.151 g) and 4-dimethylaminopyridine (0.1254 mmol, 0.015 g)
were dissolved in THF (10 ml) and DMF (1 ml). The resulting mixture was stirred at
RT for one day after which the temperature was raised to 50 °C for one day. The
mixture was stirred at RT over the weekend. During the reaction more dihydrofuran-
2,5-dione (50 mg) was added. The solvents were evaporated and the residue was
dissolved in EtOAc. The organic phase was washed with 1 M HC1, separated, dried,
filtered and evaporated. The crude product was purified by flash chromatography.
352 mg of the title compound was obtained. 1H-NMR (400 MHz, CDCl3): d 1.22-
1.28 (m, 3H), 1.61-1.69 (m, 3H), 2.54-2.79 (m, 4H), 4.29-4.45 (m, 2H), 4.52-4.64
(m, 1H), 5.97-6.06 (m, 1H), 6.58-6.62 (m, 1H), 6.76-6.80 (m, 1H), 7.50-7.53 (m,
1H), 7.62-7.68 (m, 1H), 7.70-7.77 (m, 1H), 7.90-8.04 (m, 2H).
Example 39.
(S)-5 -Chloro-N-( 1 -(3 -(3 -chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)-propan-2-
yl)pyrazine-2-carboxamide
a) 5-Chloropyrazine-2-carbonyl chloride
5-Chloropyrazine-2-carboxylic acid (3.15 mmol, 500 mg) was dissolved in
DCM (55 ml). Oxalyl dichloride (6.62 mmol, 841 mg) was added slowly and the
resulting mixture was refluxed for 2 h. After the reaction had stopped the mixture
was concentrated. 580 mg of the title compound was obtained. 1H-NMR (400 MHz,
CDCl3) 5 8.78 (d, 1H), 9.09 (d, 1H).
b) (S)-5 -Chloro-N-( 1 -(3 -(3 -chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)pyrazine-2-carboxamide
5-Chloropyrazine-2-carbonyl chloride (3.28 mmol, 580 mg) was dissolved in
dry THF (40 ml). Triethylamine (9.83 mmol, 995 mg) and (S)-4-(1-(2-aminopropyl)-
lH-pyrazol-3-yl)-2-chlorobenzonitrile (3.28 mmol, 854 mg) were added and the
resulting mixture was stirred for one day at RT. The crude product was purified by
recrystallization from DCM. 900 mg of the title compound was obtained. 1H-NMR
(400 MHz, CDCl3): d 1.25 (d, 3H), 4.29 (dd, 1H), 4.47 (dd, 1H), 4.59-4.71 (m, 1H),
6.66 (d, 1H), 7.51 (d, 1H), 7.68-7.73 (m, 1H), 7.75-7.80 (m, 1H), 8.12 (d, 1H), 8.64
(d, 1H), 8.77 (d, 1H), 9.17 (d, 1H).
Example 40.
N-((S)-1 -(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-1 -((S)-
2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxamide
a) (S)-N-( 1 -(3 -(3-chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-2-
methyl-1H-imidazole-4-carboxamide
2-Methyl-1H-imidazole-4-carboxylic acid (29.0 g, 230 mmol), 335 ml of
DMF and 165 ml of DCM were placed in to the reaction vessel under nitrogen.
HBTU (7.27 g, 19.18 mmol), EDCI (44.1 g, 230 mmol) and 66.8 ml of DIPEA were
added. (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (50 g, 192
mmol) was added and the reaction stirred overnight at RT. 600 ml of water was
slowly added and water phase was washed with 335 ml and 500 ml of DCM. DCM
phases were combined, washed with 3 x 600 ml of water and distilled to dryness.
Acetonitrile (300 ml) was added and the mixture was heated up to 75°C. Water (300
ml) was added at >60 °C, solution was allowed to cool to RT for precipitation and
the mixture was stirred overnight at RT. Stirring was continued for additional 2 h at
<10 °C. The precipitate was filtered, washed with cold ACN:water and dried under
vacuum to obtain 47 g of crude product. The title compound was recrystallized from
EtOH with 75 % yield. 1H-NMR (400 MHz, DMSO-c/6): 8 1.08 (d, 3H), 2.30 (s, 3H),
4.23-4.48 (m, 3H), 6.95 (d, 1H), 7.41 (s, 1H), 7.82 (d, 1H), 7.95-8.07 (m, 3H), 8.09-
8.12 (m, 1H), 12.12 (bs, 1H).
b) N-((S)-1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-1 -
((S)-2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxamide
(S)-N-( 1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-2-
methyl-1H-imidazole-4-carboxamide (0.271 mmol, 100 mg) and potassium
carbonate (2.71 mmol, 375 mg) were dissolved in dry DMF (3 ml) under nitrogen
atmosphere. (S)-2-methyl-oxirane (0.298 mmol, 0.021 ml) was added and the
resulting mixture was stirred for 2.5 h at RT. The mixture was heated to 60 °C for
two days during which more (S)-2-methyloxirane (0.252 ml) was added. The solvent
was evaporated and the residue was purified by flash chromatography. 63 mg of the
title compound was obtained. 1H-NMR (400 MHz, DMSO-<4): 8 1.05 (d, 3H), 1.07
(d, 3H), 2.34 (s, 3H), 3.67-3.93 (m, 3H), 4.20 - 4.50 (m, 3H), 4.92 (bs, 1H), 6.95 (d,
1H), 7.47 (s, 1H), 7.83 (d, 1H), 7.98-8.00 (m, 2H), 8.04 (d, 1H), 8.11-8.12 (m, 1H).
Example 41.
(S)-1 -Butyl-N-( 1 -(3 -(3 -chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
2-methyl-1H-imidazole-4-carboxamide
(S)-N-(1-(3-(3-Chloro-4-cyanophenyl)-l H-pyrazol-1-yl)propan-2-yl)-2-
methyl-1H-imidazole-4-carboxamide (0.407 mmol, 150 mg), triphenylphosphine
(0.610 mmol, 160 mg) and 1-butanol (0.610 mmol, 45.2 mg) were dissolved in dry
THF (5 ml) under nitrogen atmosphere. DIAD (0.610 mmol, 123 mg) was slowly
added. The resulting mixture was stirred overnight at RT. At this point the amounts
of 1-butanol, triphenylphosphine and DIAD were doubled and the stirring continued
for another day. The solvent was evaporated and the residue was purified by flash
chromatography and preparative HPLC, respectively. 22.8 mg of the title compound
was obtained. 1H-NMR (400 MHz, DMSO-J6): 5 0.88 (t, 3H), 1.07 (d, 3H), 1.18-
1.29 (m, 2H), 1.57-1.67 (m, 2H), 2.33 (s, 3H), 3.88 (t, 2H), 4.17-4.48 (m, 3H), 6.95
(d, 1H), 7.50 (s, 1H), 7.82 (d, 1H), 7.95-8.00 (m, 2H), 8.02 (d, 1H), 8.10 (s, 1H).
Example 42.
(S)-N-( 1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-5 -(2-
hydroxypropan-2-yl)-1H-pyrazole-3 -carboxamide
The title compound was prepared using the procedure described in Example
3(h) starting from 5-(2-hydroxypropan-2-yl)-1H-pyrazole-3-carboxylic acid (0.646
mmol, 110 mg) and (S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile
(0.539 mmol, 140 mg) using DMF (2 ml) as the solvent. Water was added and the
mixture was extracted three times with DCM. The combined organics were washed
twice with water. The separated organic phase was evaporated and the residue was
purified by flash chromatography and preparative HPLC, respectively. 44.6 mg of the
title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): d 1.11 (d, 3H), 1.45
(s, 6H), 4.22-4.52 (m, 3H), 5.31 (s, 1H), 6.37 (s, 1H), 6.94 (d, 1H), 7.81 (d, 1H),
7.88-8.03 (m, 2H), 8.09 (s, 1H), 8.16 (d, 1H), 12.96 (s, 1H).
Example 43.
(S)-N-( 1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-1 '-
methyl-l'H-1,4'-bipyrazole-3-carboxamide
The title compound was prepared using the procedure described in Example
3(h) starting from l'-methyl-rH-[l,4'-bipyrazole]-3-carboxylic acid (0.921 mmol,
177 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.767
mmol, 200 mg) using DMF (2 ml) as the solvent. DCM was added and evaporated.
The residue was purified by flash chromatography. The product was further purified
by dissolving it in DCM and washing three times with 1 M NaHCO3 and evaporating
the separated DCM phase. 220 mg of the title compound was obtained. 1H-NMR
(400 MHz, DMSO-J6): 5 1.14 (d, 3H), 3.89 (s, 3H), 4.27-4.42 (m, 2H), 4.42-4.53 (m,
1H), 6.76 (d, 1H), 6.95 (d, 1H), 7.83-7.87 (m, 3H), 7.94 (dd, 1H), 8.06 (d, 1H), 8.16
(d, 1H), 8.18 (s,lH), 8.21 (d,lH).
Example 44: N-((S)-1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-
2-yl)-1 -((R)-2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in Example
3(h) starting from (R)-1-(2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxylic acid
(1.059 mmol, 195 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-
benzonitrile (0.882 mmol, 230 mg) using DMF (2 ml) as the solvent. DCM was
added and evaporated. The residue was purified by flash chromatography. The
product was further purified by dissolving it in MeOH/DCM and washing twice with
1 M NaHCC<3. The separated organic phase was dried, purified and evaporated. 289
mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-<4): 8 1.02-1.10
(m, 6H), 2.34 (s, 3H), 3.70-3.91 (m, 3H), 4.22-4.48 (m, 3H), 4.92 (d, 1H), 6.95 (d,
1H), 7.47 (s, 1H), 7.83 (d, 1H), 7.97-8.00 (m, 2H), 8.04 (d, 1H), 8.09-8.13 (m, 1H).
Example 45.
(S)-2-Bromo-N-( 1 -(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)-propan-2-
yl)-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in Example
3(h) starting from 2-bromo-1H-imidazole-4-carboxylic acid (5.75 mmol, 1.099 g)
and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (3.84 mmol, 1
g) using DMF (10 ml) as the solvent. DCM and water were added, the phases were
separated and the water phase was extracted with DCM. The combined organics were
washed three times with water. The DCM phase was dried, filtered and evaporated.
The crude product was purified by flash chromatography and preparative HPLC,
respectively. 37.8 mg of the title compound was obtained. 1H-NMR (400 MHz,
DMSO-ck): 8 1.09 (d, 3H), 4.23-4.48 (m, 3H), 6.95 (d, 1H), 7.64 (s, 1H), 7.82 (d,
1H), 7.94-8.05 (m, 2H), 8.08 (s, 1H), 8.21 (d, 1H), 13.22 (bs, 1H).
Example 46.
N-((S)-1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-5 -(1 -
hydroxy-2-methylpropyl)isoxazole-3-carboxamide
The title compound was prepared using the procedure described in Example
3(h) starting from 5-(1-hydroxy-2-methyl-propyl)isoxazole-3-carboxylic acid (1.566
mmol, 290 mg) and (S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile
(1.044 mmol, 272 mg) using a mixture of DCM (5 ml) and DMF (1 ml) as the
solvent. DCM and water were added, the phases were separated and the water phase
was extracted with DCM. The combined organics were washed twice with water. The
DCM phase was dried, filtered and evaporated. The crude product was purified by
flash chromatography and preparative HPLC, respectively. 23.4 mg of the title
compound was obtained. 1H-NMR (400 MHz, CDCl3): d 0.94 (d, 3H), 0.98 (d, 3H),
1.23 (d, 3H), 2.06-2.21 (m, 1H), 4.21-4.30 (m, 1H), 4.37-4.46 (m, 1H), 4.51-4.67 (m,
2H), 6.57-6.65 (m, 2H), 7.50 (d, 1H), 7.68 (d, 1H), 7.78-7.86 (m, 1H), 7.97 (d, 1H),
8.04 (s, 1H).
Example 47.
(S)-N-( 1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-1 -(2-
cyanoethyl)-2-methyl-1H-imidazole-4-carboxamide
Sodium hydroxide, 5 M (1.085 mmol, 0.217 ml) and (S)-N-(1-(3-(3-chloro-4-
cyano-phenyl)-1H-pyrazol-1 -yl)propan-2-yl)-2-methyl-1H-imidazole-4-carboxamide
(0.542 mmol, 200 mg) were dissolved in DMF (2 ml). The mixture was cooled to
~10 °C with an ice bath and 3-bromopropionitrile (0.813 mmol, 109 mg) was slowly
added. The reaction mixture was allowed to warm to RT and it was stirred overnight.
The liquids were evaporated. DCM was added and washed twice with water. The
separated organic phase was dried, filtered and evaporated. The crude product was
purified by flash chromatography and preparative HPLC, respectively. 73.1 mg of the
title compound was obtained. 1H-NMR (400 MHz, DMSO-rf6): 6 1.07 (d, 3H), 2.38
(s, 3H), 3.02 (t, 2H), 4.22 (t, 2H), 4.24-4.47 (m, 3H), 6.95 (d, 1H), 7.61 (s, 1H), 7.83
(d, 1H), 7.96-8.02 (m, 2H), 8.07-8.13 (m, 2H).
Example 48.
N-((S)-1 -(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-1 -(1 -
cyanoethyl)-2-methyl-1H-imidazole-4-carboxamide
Sodium hydroxide, 5 M (1.085 mmol, 0.217 ml) and (S)-N-(1-(3-(3-chloro-4-
cyano-phenyl)-1H-pyrazol-1 -yl)propan-2-yl)-2-methyl-1H-imidazole-4-carboxamide
(0.542 mmol, 200 mg) were dissolved in DMF (2 ml). The mixture was cooled to
-10 °C with an ice bath and 2-bromopropanenitrile (0.813 mmol, 109 mg) was
slowly added. The mixture was allowed to warm to RT and it was stirred for 2 h.
Solvent was evaporated, DCM was added and the mixture was washed twice with
water. The organic phase was dried, filtered and evaporated. The crude product was
purified by flash chromatography and trituration from diethyl ether. 63 mg of the title
compound was obtained. 1H-NMR (400 MHz, DMSO-d6): d 1.04-1.12 (m, 3H), 1.77
(d, 3H), 2.42 (s, 3H), 4.23-4.49 (m, 3H), 5.72 (q, 1H), 6.92-6.97 (m, 1H), 7.79-7.85
(m, 2H), 7.95-8.01 (m, 2H), 8.08-8.11 (m, 1H), 8.15 (d, 1H).
Example 49: (S)-N-( 1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-
2-yl)-1 -(2-methylprop-1 -enyl)-1H-pyrazole-3 -carboxamide
The title compound was prepared using the procedure described in Example
3(h) starting from 1-(2-methylprop-1-en-1-yl)-l H-pyrazole-3-carboxylic acid (1.151
mmol, 191 mg) and (S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile
(0.959 mmol, 250 mg) using DCM (5 ml) as the solvent. The mixture was diluted
with DCM and washed with 1 M Na2CO3. The organic phase was dried, filtered and
evaporated. The crude product was purified flash chromatography. 297 mg of the title
compound was obtained. 1H-NMR (400 MHz, DMSO-d6): d 1.12 (d, 3H), 1.80 (d,
3H), 1.85 (d, 3H), 4.25-4.52 (m, 3H), 6.66 (d, 1H), 6.77-6.81 (m, 1H), 6.95 (d, 1H),
7.83 (t, 2H), 7.94-7.97 (m, 2H), 8.06-8.10 (m, 1H), 8.18 (d, 1H).
Example 50.
(S)-N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(lH-
imidazol-4-yl)-1H-pyrazole-5-carboxamide
a)(S)-N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-
trityl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxamide
The title compound was prepared using the procedure described in Example
3(h) starting from 3-(1-trityl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxylic acid
(2.493 mmol, 1048 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-
benzonitrile (1.918 mmol, 500 mg) using a mixture of DCM (10 ml) and DMF (1 ml)
as the solvent. HBTU (0.384 mmol, 145 mg) was used instead of HOBt. The reaction
mixture was diluted with DCM and washed with 1 M Na2CC«3 and water. The
separated organic phase was dried, filtered and evaporated. 1.637 g of the title
compound was obtained. 1H-NMR (400 MHz, DMSO-d6): d 1.12 (d, 3H), 4.17-4.52
(m, 3H), 6.75 (bs., 1H), 6.92 (d, 1H), 7.12-7.19 (m, 7H), 7.35-7.53 (m, 12H), 7.80 (d,
1H), 7.97 (bs, 1H), 8.04 (s, 1H), 8.21 (d, 1H), 13.38 (bs., 1H).
b) (S)-N-( 1 -(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-3-
(1 H-imidazol-4-yl)-1H-pyrazole-5 -carboxamide
Formic acid (452 mmol, 20.82 g) was dissolved in a mixture of water (2 ml)
and THF (40 ml). (S)-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-3-(1-trityl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxamide (1.508 mmol, lg) was
added and the resulting mixture was heated to 50 °C for 3 h. The stirring continued
for 2 days at RT. The mixture was concentrated. ACN was added and evaporated.
This was repeated once more. The crude product was purified by flash chromato-
graphy. 0.371 g of the title compound was obtained. *H-NMR (400 MHz, DMSO-
de): 5 1.14 (d, 3H), 4.23-4.56 (m, 3H), 6.76 (bs, 1H), 6.94 (d, 1H), 7.53 (bs, 1H), 7.76
(s, 1H), 7.83 (d, 1H), 7.95-8.04 (m, 2H), 8.07 - 8.10 (m, 1H), 8.27 (d, 1H), 12.30 (bs,
1H), 13.40 (bs, 1H).
Example 51.
(S)-N-( 1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-1 -cyclo-
propyl-1H-pyrazole-3 -carboxamide
The title compound was prepared using the procedure described in Example
32(e) starting from 1-cyclopropyl-1H-pyrazole-3-carboxylic acid (0.300 g, 1.8 mmol)
and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-benzonitrile (0.471 g, 1.8
mmol). The product was purified by flash-chromatography. Yield: 400 mg. 1H-NMR
(400 MHz; DMSO-d6): d 0.98-1.11 (m, 7H), 3.75-3.80 (m, 1H), 4.25-4.48 (m, 3H),
6.54 (d, 1H), 6.96 (d, 1H), 7.82 (d, 2H), 7.93-7.99 (m, 2H), 8.07 (s, 1H), 8.16 (d,
1H), LC-MS: [M+1] = 395.15.
Example 52.
(S)-N-( 1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-1 -(6-
(dimethylamino)pyridin-3-yl)-1H-pyrazole-3-carboxamide
a) Methyl lH-imidazole-4-carboxylate
lH-Imidazole-4-carboxylic acid (5 g, 44.6 mmol) was dissolved in MeOH
(100 ml). Into the solution, H2SO4 (10 ml) was added at 0 °C. The resulting mixture
was stirred at 80 °C for overnight. The solvent was concentrated under reduced
pressure. The pH was adjusted to 9 with aqueous NaHCO3 solution and extracted
with EtOAc. The organic layer was concentrated to give the product. Yield 5.2 g. *H-
NMR (400 MHz; DMSO-d6): d 3.74 (s, 3H), 7.79 (bs, 2H), 12.75 (bs, 1H). LC-MS:
[M+1] = 127. 23.
b) Methyl 1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate
Into a flask containing methyl lH-imidazole-4-carboxylate (5 g, 39.7 mmol)
in DMF (70 ml), K2CO3 (13.7 g, 99.1 mmol), SEM-Cl (9.3 ml, 51.6 mmol) were
added and stirred at 80 °C overnight. The reaction mixture was quenched by the
addition of H2O and extracted with EtOAc. The organic layer was concentrated and
purified by column chromatography. Yield 3.8 g. 1H-NMR (400 MHz; DMSO-d6): d 0.05 (s, 9H), 0.80 (t, 2H), 3.47 (t, 2H), 3.74 (s, 3H), 5.30 (s, 2H), 7.91 (s, 1H), 8.01
(s, 1H). LC-MS: [M+1] = 257.27.
c) Methyl 2-bromo-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-
carboxylate
Into a flask containing methyl l-((2-(trimethylsilyl)ethoxy)methyl)-1H-
imidazole-4-carboxylate (4.0 g; 15.6 mmol) in CC14 (100 ml), catalytic AIBN, NBS
(3.1 g, 17.1 mmol) were added and stirred at 65 °C for 3 h. The reaction mixture was
quenched with aqueous solution of NaHCCh and extracted with EtOAc. The organic
layer was concentrated and purified by column chromatography. Yield 3.5 g. *H-
NMR (400 MHz; DMSO-d6): d 0.04 (s, 9H), 0.84 (t, 2H), 3.53 (t, 2H), 3.75 (s, 3H),
5.30 (s, 2H), 8.25 (s, 1H). LC-MS: [M+1] = 335.01.
d) Methyl 2-formyl-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-
carboxylate
Into a flask containing methyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-
lH-imidazole-4-carboxylate (5 g, 14.9 mmol) in THF (20 ml), 2 M solution of i-
PrMgCl in THF (22.4 ml, 44.9 mmol) was added at -40 °C under nitrogen
atmosphere. The resulting mixture was allowed to stir for 10 min at -40° C and
cooled to -78 °C. The reaction mixture was treated with DMF (7.29 ml, 89.8 mmol)
and slowly warmed to RT. The mixture was stirred for 1 h at RT and quenched with
saturated aqueous solution of NaHCO3. The crude was extracted with EtOAc. The
organic layer was concentrated under reduced pressure. Yield 3 g. LC-MS: [M+1] -
285.15.
e) Methyl 2-(hydroxymethyl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-
imidazole-4-carboxylate
Into a flask containing a solution of methyl 2-formyl-1 -((2-(trimethylsilyl)-
ethoxy)-methyl)-1H-imidazole-4-carboxylate (3 g, 10.5 mmol) in MeOH (20 ml),
NaBH4 (0.401 g, 10.5 mmol) was added in portions at 0 °C. The resulting mixture
was allowed to stir at 0 °C for 30 min followed by RT for 1 hour. The reaction
mixture was concentrated and the crude was diluted with water and extracted with
EtOAc. The organic layer was concentrated under reduced pressure. Yield 1.5 g. LC-
MS: [M+1] =287.17.
f) Methyl 2-((/er/-butyldimethylsilyloxy)methyl)-1 -((2-(trimethylsilyl)ethoxy)
methyl)-1H-imidazole-4-carboxylate
Into a flask containing a solution of methyl 2-(hydroxymefhyl)-1-((2-(tri-
methylsilyl)-ethoxy)methyl)-1H- imidazole-4-carboxylate (1 g, 3.49 mmol) in DMF
(25 ml), imidazole (0.490 g, 6.91 mmol), catalytic DMAP and TBDMSC1 (0.790 g,
5.27 mmol) were added. The resulting mixture was stirred at RT for 12 h. The
reaction mixture was quenched with saturated aqueous solution of NaHCO3 and
extracted with EtOAc. The organic layer was concentrated and purified by flash
column chromatography. Yield 800 mg. 1H-NMR (400 MHz; DMSO-d6): d -0.04 (s,
9H), 0.05 (s, 6H), 0.80 (t, 2H), 0.86 (s, 9H), 3.49 (t, 2H), 3.74 (s, 3H), 4.71 (s, 2H),
5.41 (s, 2H), 8.02 (s, 1H). LC-MS: [M+1] = 401.10.
g) (S)-2-((terNButyldimethylsilyloxy)methyl)-N-(1-(3-(3-chloro-4-cyano
phenyl)-1H-pyrazol-1 -yl)propan-2-yl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-
imidazole-4-carboxamide
Into a flask containing a solution of (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-
yl)-2-chlorobenzonitrile (0.4 g, 17.5 mmol) in toluene (20 ml), 2 M solution of
trimethyl aluminium in heptane (2.62 ml, 52.6 mmol) was added at 0 °C. The
resulting mixture was stirred at 0 °C for 10 min and a solution of methyl 2-{{tert-
butyldimethyl-silyloxy)methyl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-
carboxylate (0.7 g, 17.5 mmol) in toluene (20 ml) was added at 0 °C. The reaction
mixture was heated at 110 °C for 4 h and diluted with water. The mixture was filtered
through a celite bed and the filtrate was extracted with EtOAc. The organic layer was
concentrated under reduced pressure. The product was purified by flash column
chromatography. Yield 400 mg. 1H-NMR (400 MHz; DMSO-<4): 5 -0.05 (s, 9H),
0.05 (s, 6H), 0.82-0.84 (s, 11H), 1.14 (d, 3H), 3.47 (t, 2H), 4.26-4.40 (m, 3H), 4.74
(s, 2H), 5.38 (s, 2H), 6.94 (d, 1H), 7.73 (s, 1H), 7.83 (d, 1H), 7.99 (d, 2H), 8.10 (d,
2H). LC-MS: [M+1] = 629.38.
h) (S)-N-( 1 -(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-2-
(hydroxymethyl)-1H-imidazole-4-carboxamide hydrochloride
(S)-2-((tert-Butyldimethylsilyloxy)methyl)-N-(1-(3-(3-chloro-4-cyanophenyl)-
1 H-pyrazol-1 -yl)propan-2-yl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-
carboxamide (0.4 g, 15.9 mmol) in 6 N HCl (25 ml) was stirred at 45 °C for 24 h.The
resulting mixture was evaporated completely and triturated twice from diethyl ether.
In the end all precipitates were combined. Yield 200 mg. 1H-NMR (400 MHz;
DMSO-d6): d 1.19 (d, 3H), 4.31-4.34 (m, 3H), 4.68 (s, 2H), 6.93 (s, 1H), 7.89-7.95
(m, 3H), 8.05 (s, 1H), 8.30 (s, 1H), 9.15 (d, 1H), 14.8 (bs, 1H).
Example 53.
(S)-N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-4,5,6,7-
tetrahydropyrazolo[ 1,5-a]pyridine-2-carboxamide)
a) (S)-2-Acetyl-N-( 1 -(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in Example
32(e) starting from 2-acetyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-
carboxylic acid (300 mg, 1.05 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-
yl)-2-chlorobenzo-nitrile (273 mg, 1.05 mmol). The product was purified with flash-
chromatography. Yield 366 mg. 1H-NMR (400 MHz; DMSO-d6): d -0.09 (s, 9H),
0.81 (t, 2H), 1.15 (d, 3H), 2.6 (s, 3H), 3.49 (t, 2H), 4.31-4.47 (m, 3H), 5.66 (s, 2H),
6.95 (s, 1H), 7.85 (d, 1H), 7.92-7.97 (m, 2H), 8.06 (s, 2H), 8.17 (d, 1H).
b) (S)-2-Acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-l H-pyrazol-1-yl)propan-2-
yl)-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in Example
52(h) starting from (S)-2-acetyl-N-(1 -(3 -(3 -chloro-4-cyanophenyl)-l H-pyrazol-1-
yl)propan-2-yl)-1 -((2-(trimethylsilyl)ethoxy)-methyl)-1H-imidazole-4-carboxamide
(350 mg, 0.66 mmol). Yield 135 mg. 1H-NMR (400 MHz; DMSO-d6): d 1.13 (d,
3H), 2.56 (s, 3H), 4.3-4.5 (m, 3H), 6.96 (s, 1H), 7.78 (d, 1H), 7.85 (d, 1H), 7.96 (s,
2H), 8.06 (s, 1H), 8.13 (d, 1H), 13.61 (s, 1H).
Example 54.
N-((S)-1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-2-( 1 -
hydroxyethyl)-1H-imidazole-4-carboxamide
a) N-((S)-1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-2-( 1 -
hydroxyethyl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in Example
33(e) starting from (S)-2-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-l H-pyrazol-1-
yl)propan-2-yl)-1 -((2-(trimethylsilyl)ethoxy)-methyl)-1H-imidazole-4-carboxamide
(300 mg, 0.57 mmol). The product was purified with flash chromatography. Yield
270 mg. 1H-NMR (400 MHz; DMSO-d6): d -0.05 (s, 9H), 0.84 (t, 2H), 1.08 (d, 3H),
1.49 (d, 3H), 3.45-3.5 (m, 2H), 4.27-4.31 (m, 1H), 4.37-4.46 (m, 2H), 4.87-4.93 (m,
1H), 5.4-5.5 (m, 3H), 6.96 (s, 1H), 7.68 (s, 1H), 7.84 (d, 1H), 7.95-8.03 (m, 3H), 8.11
(d, 1H).
b) N-((S)-1 -(3-(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-2-( 1-
hydroxyethyl)-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in Example
52(h) starting from N-((S)-1 -(3 -(3 -chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-2-( 1 -hydroxyethyl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carbox-
amide (260 mg, 0.49 mmol). The product was purified by flash chromategraphy.
Yield 166 mg. 1H-NMR (400 MHz; DMSO-d6): d 1.07 (d, 3H), 1.41 (d, 3H), 4.27-
4.46 (m, 3H), 4.78 (s, 1H), 5.51 (d, 1H), 6.96 (d, 1H), 7.42 (d, 1H), 7.84 (d, 1H),
7.90-8.01 (m, 3H), 8.11 (s, 1H), 12.27 (s, 1H).
Example 55.
(S)-N-(1 -(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-2-iso-
propyl-1H-imidazole-4-carboxamide
a) Methyl 2-isopropyl-1H-imidazole-4-carboxylate
A solution of methyl lH-imidazole-4-carboxylate (5.0 g, 39.68 mmol),
AgN03 (4.0 g, 23.81 mmol), isobutyric acid (10.4 g, 119.1 mmol) in 10 % H2SO4
(150 ml) was heated at 80 °C for 15 min. An aqueous solution of (NH4)2S2O8 (28.0 g,
119.1 mmol) was added to the mixture dropwise in 15 minat 80 °C. The reaction
mixture was cooled to RT and poured into ice. The mixture was basified with
aqueous ammonia (pH 9) and extracted with EtOAc (500 ml). The organic layer was
concentrated and the residue was purified by flash chromatography. Yield 1.5 g. 1H-
NMR (400 MHz; CDCl3): d 1.36 (d, 6H), 3.05-3.14 (m, 1H), 3.87 (s, 3H), 7.62 (s,
1H).
b) Methyl 2-isopropyl-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-
carboxylate
Into a flask containing a solution of methyl 2-isopropyl-1H-imidazole-4-
carboxylate (2.7 g, 16.1 mmol) in DMF (20 ml), K2CO3 (5.5 g, 40.2 mmol) and
SEM-C1 (3.5 g, 21.0 mmol) were added. The resulting mixture was heated at 80 °C
for 18 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The
product was purified with flash chromatography. Yield 830 mg. 1H-NMR (400 MHz;
CDCl3):5 0.04 (s, 9H), 0.85-0.89 (m, 2H), 1.28 (d, 6H), 3.15-3.20 (m,
1H), 3.57 (t, 2H), 3.83 (s, 3H), 5.74 (s, 2H), 7.69 (s, 1H).
c) 2-Isopropyl-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-
carboxylic acid
The title compound was prepared using the procedure described in Example
32(d) starting from methyl 2-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imi-
dazole-4-carboxylate (830 mg, 27.8 mmol). The product was triturated from ether
and pentane. Yield 430 mg. 1H-NMR (400 MHz; DMSO-d6): d 0.04 (s, 9H), 0.83 (t,
2H), 1.21 (s, 6H), 3.10-3.16 (m, 1H), 3.41-3.50 (m, 2H), 5.34 (s, 2H), 5.35 (s, 1H),
7.85 (s, 1H).
d) (S)-N-( 1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-2-iso-
propyl-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in Example
32(e) starting from 2-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-
carboxylic acid (0.430 g, 1.5 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-
2-chlorobenzonitrile (0.395 g, 1.5 mmol). Yield 360 mg. 1H-NMR (400 MHz;
DMSO-d6): d 0.06 (s, 9H), 0.80-0.85 (m, 2H), 1.10 (d, 3H), 1.21-1.24 (m, 6H), 3.08-
3.15 (m, 1H), 3.43-3.47 (m, 2H), 4.30-4.44 (m, 3H), 5.32 (s, 2H), 6.96 (d, 1H), 7.63
(s, 1H), 7.85-7.87 (m, 2H), 7.93-7.95 (m, 2H), 8.09 (s, 1H).
e) (S)-N-( 1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-2-iso-
propyl-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in Example
52(h) starting from (S)-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-2-isopropyl-1 -((2-(trimethylsilyl)-ethoxy)methyl)-1H-imidazole-4-carboxamide
(0.36 g, 0.6 mmol). Yield 127 mg. 1H-NMR (400 MHz; DMSO-d6): d 1.08 (t, 3H),
1.23 (d, 6H), 2.94- 3.01 (m, 1H), 4.27- 4.44 (m, 3H), 6.96 (bs, 1H), 7.44 (s, 1H),
7.84 (s, 1H), 7.90- 8.02 (m, 3H), 8.10 (s, 1H).
Example 56.
(S)-2-Butyl-N-(1 -(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
1 -methyl-1H-imidazole-4-carboxamide
a) Methyl 2-butyl-1H-imidazole-4-carboxylate
The title compound was prepared using the procedure described in Example
55(a) starting from methyl 1H-imidazole-4-carboxylate (5 g, 39.7 mmol) and n-
valeric acid (13 ml, 119 mmol). Yield: 1.2 g. 1H-NMR (400 MHz; CDCl3): d 0.92 (t,
3H), 1.24-1.29 (m, 2H), 1.68-1.76 (m, 2H), 2.76 (t, 2H), 3.87 (s, 3H), 7.62 (s, 1H),
9.92 (bs, 1H).
b) Methyl 2-butyl-1-methyl-1H-imidazole-4-carboxylate
Into flask containing a solution of methyl 2-butyl-l H-imidazole-4-carboxylate
(1.2 g, 6.6 mmol) in acetone (40 ml), Cs2CO3 (6.5 g, 19.8 mmol) and methyl iodide
(0.5 ml, 6.6 mmol) were added. The reaction mixture was stirred at RT for 4 h and
the solvent was evaporated. The residue was diluted with water and extracted with
EtOAc. The organic layer was concentrated and purified with flash chromatography.
Yield 500 mg. 1H-NMR (400 MHz; CDCl3): d 0.937 (t, 3H), 1.35-1.44 (m, 2H),
1.68-1.75 (m, 2H), 2.69 (t, 2H), 3.62 (s, 3H), 3.86 (s, 3H), 7.50 (s, 1H).
c) (S)-2-Butyl-N-( 1 -(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-1 -methyl-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in Example
52(g) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzo-nitrile
(664 mg, 2.55 mmol) and methyl 2-butyl-l -methyl-1H-imidazole-4-carboxylate (500
mg, 2.55 mmol). The product was purified with flash chromatography. Yield 291 mg.
1H-NMR (400 MHz; DMSO-d6): d 0.88 (t, 3H), 1.09 (t, 3H), 1.28-1.36 (m, 2H),
1.54-1.61 (m, 2H), 2.62 (t, 2H), 3.57 (s, 3H), 4.26-4.39 (m, 3H), 6.95 (bs, 1H), 7.47
(s, 1H), 7.82 (d, 1H), 7.90 (d, 1H), 7.96 (s, 2H), 8.09 (s, 1H).
Example 57.
(S)-N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(2-
hydroxypropan-2-yl)-1 -methyl-1H-imidazole-4-carboxamide
a) Methyl 2-(2-hydroxypropan-2-yl)-1 -methyl-1H-imidazole-4-carboxylate
The title compound was prepared using the procedure described in Example
2(d) starting from methyl 2-acetyl-1-methyl- 1H-imidazole-4-carboxylate (400 mg,
2.19 mmol). The product was purified with flash-chromatography. Yield 255 mg. *H-
NMR (400 MHz; DMSO-d6): d 1.51 (s, 6H), 3.70 (s, 3H), 3.83 (s, 3H), 5.40 (s, 1H),
7.81 (s, 1H).
b)(S)-N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(2-
hydroxypropan-2-yl)-1 -methyl-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in Example
52(g) starting from methyl 2-(2-hydroxypropan-2-yl)-1-methyl-1H-imidazole-4-
carboxylate (200 mg, 1 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-
(trifluoromethyl)benzonitrile (264 mg, 1 mmol). Yield 140 mg. 1H-NMR (400 MHz;
DMSO-d6): d 1.08 (d, 3H), 1.50 (s, 6H), 3.80 (s, 3H), 4.28-4.41 (m, 3H), 5.36 (s,
1H), 6.97 (d, 1H), 7.51 (s, 1H), 7.73 (d, 1H), 7.84 (d, 1H), 7.96 (s, 2H), 8.10 (d, 1H).
Example 58.
(S)-N-( 1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-1 -
methyl-2-( 1 -methyl-1H-pyrazol-4-yl)-1H-imidazole-4- carboxamide
a) Benzyl-2-bromo-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-
carboxylate.
Silver oxide (12.7 g, 54.8 mmol) was added to a solution of 2-bromo-1-((2-
(trimethyl-silyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid (11.7 g, 36.5 mmol)
in ACN (200 ml) and stirred at RT for 10 min. Benzyl bromide (4.2 ml, 36.5 mmol)
was added to the mixture and stirred at RT for 12 h. The reaction mixture was
filtered through a celite bed and the filtrate was concentrated under reduced pressure.
The product was purified by flash chromatography. Yield 10 g. 1H-NMR (400 MHz;
CDCl3): d -0.04 (s, 9H), 0.92 (t, 2H), 3.54 (t, 2H), 5.29 (s, 2H), 5.35 (s, 2H), 7.30-
7.44 (m, 5H), 7.76 (s, 1H).
b) Benzyl 2-bromo-1H-imidazole-4-carboxylate hydrochloride.
The title compound was prepared using the procedure described in Example
52(h) starting from benzyl-2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-
imidazole-4-carboxylate (16.2 g, 39.5 mmol). Yield 9.0 g. LC-MS: [M+1] = 281.
c) Benzyl 2-bromo-1-methyl-1H-imidazole-4-carboxylate
The title compound was prepared using the procedure described in Example
56(b) starting from benzyl 2-bromo-1H-imidazole-4-carboxylate hydrochloride (8.3
g, 29.4 mmol). The product was purified by flash chromatography. Yield 1.6 g. H-
NMR (400 MHz; CDCl3): d 3.66 (s, 3H), 5.33 (s, 2H), 7.26-7.43 (m, 5H), 7.63 (s,
1H).
d) Benzyl 1-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-imidazole-4-
carboxylate
Into a flask containing a solution of benzyl 2-bromo-1-methyl-1H-imidazole-
4-carboxylate (2 g, 6.77 mmol) in 1,2-dimethoxyethane (40 ml), potassium phosphate
(2.3 g, 20.3 mmol) and l-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-
pyrazole (1.41 g, 6.77 mmol) were added at RT under argon atmosphere. The
resulting mixture was degassed and purged with argon for 10 minutes. Then
Pd(PPh3)4 (0.310 g, 0.2 mmol) was added to the reaction mixture and heated at 90 °C
for 12 h. The reaction mixture was filtered through a celite bed and the filtrate was
diluted with water and extracted with EtOAc. The organic layer was concentrated and
purified by flash chromatography. Yield 1.1 g. 1H-NMR (400 MHz; CDCl3): d 3.77
(s, 3H), 3.95 (s, 3H), 5.36 (s, 2H), 7.30-7.37 (m, 3H), 7.45 (d, 2H), 7.59 (s, 1H), 7.79
(s, 1H), 7.89 (s, 1H).
e) 1 -Methyl-2-(1 -methyl-1H-pyrazol-4-yl)-1H-imidazole-4-carboxylic acid
Into a flask containing a solution of benzyl 1-methyl-2-(1 -methyl-1H-pyrazol-
4-yl)-1H-imidazole-4-carboxylate (1 g, 3.4 mmol) in EtOH (25 ml), 10 % Pd/C (100
mg) was added at RT. The resulting mixture was stirred at RT under H2 atmosphere
for 3 h. The reaction mixture was filtered through a celite bed and the filtrate was
concentrated. The residue was triturated twice from diethyl ether. Yield 500 mg. LC-
MS:[M+1] = 207.04.
f) (S)-N-( 1 -(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-1 -
methyl-2-( 1 -methyl-1H-pyrazol-4-yl)-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in Example
32(e) starting from l-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-imidazole-4-
carboxylic acid (0.3 g, 1.44 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-
chlorobenzonitrile (0.377 g, 1.44 mmol). The product was purified by flash
chromatography. Yield 200 mg. 1H-NMR (400 MHz; DMSO-d6): d 1.10 (d, 3H),
3.72 (s, 3H), 3.91 (s, 3H), 4.23-4.45 (m, 3H), 6.95 (d, 1H), 7.63 (d, 1H), 7.83 (t, 2H),
7.99 (d, 1H), 8.03 (d, 1H), 8.07 (s, 1H), 8.17 (s, 1H).
Example 59.
(S)-N-(1-(3-(3-Chloro-4-cyanophenyl)-l H-pyrazol-1-yl)propan-2-yl)-2-
cyclopropyl-1 -methyl-1H-imidazole-4-carboxamide
a) Benzyl 2-cyclopropyl-1-methyl-1H-imidazole-4-carboxylate
Into a solution of benzyl 2-bromo-1-methyl-1H-imidazole-4-carboxylate (2.8
g, 9.49 mmol) in THF (40 ml) and water (20 ml), cesium carbonate (7.71 g, 23.7
mmol) and cyclopropyl boronic acid (1.22 g, 14.2 mmol) were added under argon
atmosphere at RT. The resulting mixture was degassed and purged with argon for 10
min. Pd(PPh3)2Cl2 (0.332 g, 0.04 mmol) was added to the mixture and heated at 100
°C for 12 h. The reaction mixture was filtered through a celite bed and the filtrate was
diluted with water and extracted with EtOAc. The organic layer was concentrated and
purified by flash chromatography. Yield 1.1 g. 1H-NMR (400 MHz; CDCl3): d 0.95-
1.02 (m, 2H), 1.07-1.11 (m, 2H), 1.72-1.78 (m, 1H), 3.70 (s, 3H), 5.32 (s, 2H), 7.29
(s, 1H), 7.42-7.62 (m, 5H), LC-MS: [M+1] = 257.
b) 2-Cyclopropyl-1-methyl-1H-imidazole-4-carboxylic acid
The title compound was prepared using the procedure described in Example
58(e) starting from benzyl 2-cyclopropyl-1-methyl-1H-imidazole-4-carboxylate (1.1
g, 1.95 mmol). Yield 400 mg. LC-MS: [M+1] = 167.06.
c)(S)-N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-
cyclopropyl-1 -methyl-1H-imidazole-4-carboxamide
The title compound was prepared using the procedure described in Example
32(e) starting from 2-cyclopropyl-1-methyl-1H-imidazole-4-carboxylic acid (0.160 g,
0.96 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro benzonitrile
(0.251 g, 0.96 mmol). The product was purified with flash chromatography. Yield
166 mg. 1H-NMR (400 MHz; DMSO-d6): d 0.80-0.92 (m, 4H), 1.07 (d, 3H), 1.94-
1.98 (m, 1H), 3.65 (s, 3H), 4.26-4.38 (m, 3H), 6.95 (s, 1H), 7.47 (s, 1H), 7.75 (d,
1H), 7.81 (s, 1H), 7.96 (s, 2H), 8.08 (s, 1H). LC-MS: [M+1] = 409.28.
Example 60.
(S)-N4-( 1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-1H-
imidazole-2,4-dicarboxamide
a) (S)-N4-( 1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-1 -
((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2,4-dicarboxamide
The title compound was prepared using the procedure described in Example
32(e) starting from 2-carbamoyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-
4-carboxylic acid (400 mg, 1.4 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-
yl)-2-chlorobenzonitrile (366 mg, 1.4 mmol). The product was purified with flash-
chromatography. Yield 410 mg. LC-MS: [M+1] = 528.24.
b) (S)-N4-( 1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-1H-
imidazole-2,4-dicarboxamide
The title compound was prepared using the procedure described in Example
52(g) starting from (S)-N4-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl)propan-
2-yl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2,4-dicarboxamide (0.41 g,
0.77 mmol). Yield 310 mg. 1H-NMR (400 MHz; DMSO-d6): d 1.13 (d, 3H), 4.32-
4.50 (m, 3H), 6.96 (s, 1H), 7.64 (s, 2H), 7.72 (s, 1H), 7.85 (s, 1H), 7.93-7.98 (m, 3H),
8.06 (s,lH), 13.40 (s, 1H).
Example 61.
(S)-N-(1 -(3-(4-Cyano-3-(trifluoromethyl)phenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-2-(2-hydroxypropan-2-yl)oxazole-4-carboxamide
The title compound was prepared using the procedure described in Example
32(e) starting from 2-(2-hydroxypropan-2-yl)-oxazole-4-carboxylic acid (0.3 g, 1.75
mmol) and (S)-4-( 1 -(2-aminopropyl)-1H-pyrazol-3 -yl)-2-(trifluoromethyl)benzo-
nitrile (0.516 mg, 1.75 mmol). The product was purified by column chromatography.
Yield 270 mg. 1H-NMR (400MHz; DMSO-d6): d 1.13 (d, 3H), 1.51 (s, 6H), 4.30-
4.52 (m, 3H), 5.67 (s, 1H), 7.05 (s, 1H), 7.86 (d, 1H), 8.17 (d, 2H), 8.28 (d, 2H), 8.47
(s, 1H).
Abbreviations
ACN - Acetonitrile
AIBN - Azobisisobutyronitrile
(Boc)2O - Di-t-butyl dicarbonate
DCM - Dichloromethane
DIAD - Di-tert-butyl azodicarboxylate
DIPEA - N,N-diisopropylethylamine
DME - Ethylene glycol dimethyl ether
DMF - N,N-Dimethylformamide
DMSO - Dimethylsulfoxide
DMAP - 4-Dimethylaminopyridine
Dppf -1,1'- bis( diphenylphosphanyl) ferrocene
EDCI - l-(3-Dimethylaminopropyl)-3-ethylcarbodi-imide hydrochloride
EtOAc - Ethyl acetate
EtOH - Ethanol
HBTU - 0-(benzotriazol-1 -yl)-N,N,N',N'-tetramethyluroniumhexafluorophosphate
HOBt- 1-Hydroxybenzotriazole
MeOH - Methanol
MTBE - Methyl-tert-butyl ether
NBS - N-bromosuccinimide
NMP - N-methylpyrrolidone
RT - Room temperature
SEM-C1 - 2-(Trimethylsilyl)ethoxymethyl chloride
TBME - tert-Butylmethyl ether
TBDMSC1 - tert-Butyldimethylchlorosilane
THF - Tetrahydrofuran
Claims
1. A compound of formula (I) or (II)

wherein ring A is any one of the following groups or tautomers thereof

wherein
Rx is halogen or CF3;
Rz is hydrogen or halogen;
R1 is hydroxy C3-7 alkyl, imidazolyl or -Ra-OC(O)-Rb;
RA is C1-7 alkyl;
Rb is C1-7 alkyl, hydroxy C1-7 alkyl or carboxy C1-7 alkyl;
R2 is C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1-7 alkyl,
methylpyrazolyl or pyrimidinyl;
R3 is halogen or pyridinyl;
R4 is pyridinyl;
R5 is C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1-7 alkyl, cyano,
hydroxy C1-7 alkyl, oxo C1-7 alkyl, halogen or methylpyrazolyl;
R6 is C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1-7 alkyl,
hydroxy, hydroxy C1-7 alkyl, cyano C1-7 alkyl or C1-7 alkoxycarbamoyl C1-7 alkyl;
R7 is hydroxy C4 alkyl;
R8 is halogen, C2-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1-7
alkyl, cyano, carboxy, oxo C1-7 alkyl, halo C1-7 alkyl, hydroxy C1-7 alkyl, tetrahydro-
2H-thiopyran or -C(O)-NHR20;
R9 is hydrogen, hydroxy, halogen, nitro, amino, cyano, oxo, C1-7 alkyl, C2-7
alkenyl, C3-7 cycloalkyl, C1-7 alkoxy, halo C1-7 alkyl, hydroxy C1-7 alkyl, cyano C1-7
alkyl, amino C1-7 alkyl, oxo C1-7 alkyl, C1-7 alkoxy C1-7 alkyl, C1-7 alkylamino,
hydroxy C1-7 alkylamino, C1-7 alkoxy C1-7 alkylamino, C1-7 alkylamino C1-7 alkyl,
hydroxy C1-7 alkylamino C1-7 alkyl, hydroxyimino C1-7 alkyl, C1-7 alkoxycarbamoyl
C1-7 alkyl, -C(O)Rn, -OC(O)R17 , -NH-C(O)R18 -NH-SO2-R19 or an optionally
substituted 5-12 membered carbocyclic or heterocyclic ring, each group linked to
B-ring via a bond or via a C1-7 alkylene linker;
R10 is hydrogen, halogen, C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, C3-7 cyclo-
alkyl C1-7 alkyl, oxo, hydroxy C1-7 alkyl, oxo C1-7 alkyl or an optionally substituted 5
or 6 membered carbocyclic or heterocyclic ring;
R11 is hydrogen, hydroxy, C1-7 alkyl, hydroxy C1-7 alkyl, C2-7 alkenyl, C3-7
cycloalkyl, halo C1-7 alkyl, C1-7 alkoxy, NR12R13, or an optionally substituted 5-12
membered carbocyclic or heterocyclic ring;
R12 is hydrogen, C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1-7
alkyl, C1-7 alkoxy, hydroxy C1-7 alkyl, amino C1-7 alkyl or C1-7 alkyl amino C1-7 alkyl;
R13 is hydrogen or C1-7 alkyl;
R14 and R15 are, independently, hydrogen or C1-7 alkyl;
R14' and R15 are, independently, hydrogen or C1-7 alkyl, or R14' and R15'
together form a bond;
R17 is C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1-7 alkyl, C1-7
alkoxy, amino C1-7 alkyl, C1-7 alkylamino or C1-7 alkylamino C1-7 alkyl;
R18 is C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1-7 alkyl, amino
C1-7 alkyl, C1-7 alkylamino or C1-7 alkylamino C1-7 alkyl;
R19 is C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl or C3-7 cycloalkyl C1-7 alkyl;
R20 is hydrogen, C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1-7
alkyl or C1-7 alkoxy;
R21 is cyano C1-7 alkyl or, in case Rx is CF3, R21 can also be hydroxy C1-7
alkyl;
R22 is hydroxy C1-7 alkyl;
R23 is C1-7 alkyl or hydroxy C1-7 alkyl;
R24 is hydroxy, halogen or C1-7 alkoxy;
ring B is any one of the following groups or tautomers thereof
and pharmaceutically acceptable salts thereof;
with the proviso that the compound of formula (II) is not any of the following
compounds:
(5)-3 -acetyl-N-( 1 -(3 -(3 -chloro-4-cyano-5 -fluorophenyl)-1H-pyrazol-1 -yl)-
propan-2-yl)-1H-pyrazole-5-carboxamide;
(S)-N-( 1 -(3 -(3 -chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
1-(pyridin-4-yl)-1H-pyrazole-3-carboxamide;
(S)-N-( 1 -(3 -(3 -chloro-4-cyano-5-fiuorophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
1 -(2-fluoroethyl)-2-methyl-1H-imidazole-4-carboxamide;
(S)-N-( 1 -(3 -(3 -chloro-4-cyano-5 -fluorophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
3-( 1 H-imidazol-4-yl)-1,2,4-oxadiazole-5-carboxamide;
(S)-5-acetyl-N-(1 -(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -
yl)propan-2-yl)isoxazole-3-carboxamide;
N-((S)-1 -(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
5-(1-hydroxyethyl)isoxazole-3-carboxamide;
(S)-5-acetyl-N-(2-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-
yl)propyl)isoxazole-3 -carboxamide;
(S)-N-(2-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propyl)-2-
methyl-1H-imidazole-4-carboxamide;
N-((S)-1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-
3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide;
(R)-N-( 1 -(3 -(3 -chloro-4-cyano-5 -fluorophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
2-methyl-1H-imidazole-4-carboxamide;
(S)-N-{l-[3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl]propan-2-
yl} -2-methyl-1H-imidazole-4-carboxamide;
(S)-N-{ 1 -[3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl]propan-2-
yl} -1 -methyl-1H-imidazole-4-carboxamide;
(S)-N-(1 -(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
3H-imidazo[4,5-b]pyridine-5-carboxamide;
(S)-N-( 1 -(3 -(3 -chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
2-(pyridin-3-yl)thiazole-4-carboxamide;
(S)-N-(1 -(3-(3-chloro-4-cyano-5-fluorophenyl)-l H-pyrazol-1 -yl)propan-2-yl)-
1 -(pyridin-3 -yl)-1H-pyrazole-3 -carboxamide;
(S)-N-( 1 -(3 -(3 -chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
2-methyl-1 -(3 -oxobutyl)-1H-imidazole-4-carboxamide;
(S)-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-
l-(3-hydroxy-3-methylbutyl)-2-methyl-1H-imidazole-4-carboxamide;
(S)-N-( 1 -(3 -(3 -chloro-4-cyano-5 -fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)imidazo[ 1,2-a]pyridine-2-carboxamide;
(S)-N-( 1 -(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
1 -(pyridin-3 -yl)-1H-imidazole-4-carboxamide;
(S)-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-
2-(2-hydroxypropan-2-yl)oxazole-4-carboxamide;
(S)-N-( 1 -(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)imidazo [ 1,2-a]pyrimidine-2-carboxamide;
(S)-N-( 1 -(3 -(3 -chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
3-fluoroimidazo[1,2-a]pyridine-2-carboxamide;
(S)-N-( 1 -(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
4,5,6,7-tetrahydro-2H-indazole-3-carboxamide;
(S)-N-(1 -(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
6,7-dihydro-5H-pyrazolo[5,1 -b] [ 1,3]oxazine-2-carboxamide;
(S)-N-( 1 -(3 -(3 -chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
2,4,6,7-tetrahydropyrano [4,3-c]pyrazole-3-carboxamide;
(S)-N-(1 -(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
1 -(6-methylpyridin-2-yl)-1H-imidazole-4-carboxamide;
(S)-N-( 1 -(3 -(3 -chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
6,7-dihydro-4H-pyrano [3,4-d] isoxazole-3 -carboxamide;
(S)-N-(1 -(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-
5-(2-hydroxypropan-2-yl)isoxazole-3-carboxamide.
2. A compound according to claim 1, wherein the compound is of formula (I)
wherein Rx is halogen, R14 is C1-7 alkyl, and ring A is any of groups (1), (2), (3), (5),
(6), (7) or (8).
3. A compound according to claim 2, wherein Rx is chloro, R14 is methyl, and
ring A is any of groups (1), (2), (5), (6) or (7), R1 is hydroxy C3-7 alkyl, imidazolyl or
carboxy C1-7 alkyl carbonyloxy C1-7 alkyl, R2 is C1-7 alkyl, C2-7 alkenyl or
methylpyrazolyl, R5 is C1-7 alkyl, C3-7 cycloalkyl, hydroxy C1-7 alkyl or methyl-
pyrazolyl, R6 is C1-7 alkyl, cyano C1-7 alkyl or hydroxy C1-7 alkyl and R8 is C1-7 alkyl,
halogen, oxo C1-7 alkyl or hydroxy C1-7 alkyl.
4. A compound according to claim 1, wherein the compound is of formula (II)
wherein R14 is C1-7 alkyl, R14', R15 and R15' is hydrogen, ring B is any of groups (1'),
(2'), (3'), (4'), (8'), (16'), (17'),(21'), (23'), (24'), (25'), (26'), (29'), (39'), (40'),
(42') or (43'), R9 is hydrogen, halogen, cyano, oxo, C1-7 alkyl, C2-7 alkenyl, C3-7
cycloalkyl, halo C1-7 alkyl, cyano C1-7 alkyl, hydroxy C1-7 alkyl, oxo C1-7 alkyl,
-NH-SO2-R19 or an optionally substituted 5-12 membered heterocyclic ring, each
R9 group linked to B-ring via a bond or via a C1-7 alkylene linker, R10 is hydrogen,
C1-7 alkyl or C3-7 cycloalkyl, and R19 is C1-7 alkyl.
5. A compound according to claim 4, wherein the 5 - 12 membered
heterocyclic ring is pyrazole, pyridine, isoxazole or imidazole ring, which is attached
to B-ring via a bond or via C1-7 alkylene linker.
6. A compound according to claim 5, wherein the 5-12 membered
heterocyclic ring contains 1-3 substituents selected from C1-7 alkyl, C3-7 cycloalkyl,
halogen or hydroxy C1-7 alkyl.
7. A compound according to claim 4, wherein Rz is hydrogen or fluoro, R14 is
methyl, R14', R15 and R15' is hydrogen, ring B is any of groups (1'), (2'), (4'), (17'),
(21') or (25'), R9 is hydrogen, halogen, cyano, oxo, C1-7 alkyl, C2-7 alkenyl, C3-7
cycloalkyl, halo C1-7 alkyl, hydroxy C1-3 alkyl, cyano C1-7 alkyl, pyrazolyl, N-methyl
pyrazolyl, pyridinyl, isoxazolyl, imidazolyl or imidazolyl methyl, and R10 is
hydrogen, C1-7 alkyl or C3-7 cycloalkyl.
8. A compound according to claim 1, which compound is
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-2,5 -difluorophenyl)-1H-pyrazol-1 -yl)propan-
2-yl)-2 -methyl-1H-imidazole-5-carboxamide;
(S)-N-(1-(3-(3-Chloro-4-cyano-2,5-difluorophenyl)-1H-pyrazol-1-yl)-propan-
2-yl)-2-(2-hydroxypropan-2-yl)oxazole-5-carboxamide;
(S)-N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-6-cyanoimidazo[ 1,2-a]pyridine-2-carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-7-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-2-carboxamide;
(S)-N-( 1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-3-isopropyl-1,2,4-oxadiazole-5-carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-5,7-dimethylimidazo[1,2-c]pyrimidine-2-carboxamide;
(S)-5-((lH-Imidazol-1-yl)methyl)-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)isoxazole-3-carboxamide;
(S)-N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-2-carboxamide;
(S)-N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-1,6-dihydropyrrolo[2,3-c]pyrazole-5-carboxamide;
(S)-N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)imidazo[2,1-b]thiazole-6-carboxamide;
(S)-N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-6-nitroimidazo[1,2-a]pyridine-2-carboxamide;
(S)-N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)-propan-2-
yl)-1 -isopropyl-2-methyl-1H-imidazole-4-carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-5-(2-hydroxypropan-2-yl)-1H-pyrazole-3-carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-l H-pyrazol-1-yl)-propan-2-
yl)-1 -(2,2-difluoroethyl)-2 -methyl-1H-imidazole-4-carboxamide;
N-((S)-1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)-propan-2-
yl)-1 -((R)-2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5 -fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-1 '-methyl-1 'H-1,4'-bipyrazole-3 -carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5 -fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-lH,2'H-3,3'-bipyrazole-5-carboxamide;
N-((S)-1 -(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)-propan-2-
yl)-1 -((S)-2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-3,3 '-bipyridine-6-carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)-propan-2-
yl)-6-(3,3-dimethylureido)imidazo[1,2-a]pyridine-2-carboxamide;
(S)-N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2-
yl)-6-(methylsulfonamido)imidazo[ 1,2-a]pyridine-2-carboxamide;
N-((S)-1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-5-(1-hydroxy-2-methylpropyl)isoxazole-3-carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-5-(l,5-dimethyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole-3-carboxamide;
(S)-N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-5-(isoxazol-3-yl)-1,2,4-oxadiazole-3-carboxamide;
(S)-N-(1-(3-(3 -Chloro-4-cyano-5 -fluorophenyl)-1H-pyrazol-1 -yl)-propan-2-
yl)-3 -(1 H-imidazol-4-yl)-1H-pyrazole-5 -carboxamide;
(S)-N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-2-(chloropropan-2-yl)oxazole-4-carboxamide;
(S)-N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2-
yl)-2-(2-propen-2-yl)oxazole-4-carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-N5-cyclopropylisoxazole-3,5-dicarboxamide;
(S)-2-Bromo-N-(1 -(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)-
propan-2-yl)-1H-imidazole-4-carboxamide;
(S)-N-( 1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-1 -(2-methylprop-1 -enyl)-1H-pyrazole-3-carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-1 -cyclopropyl-1H-pyrazole-3-carboxamide;
N-((S)-1 -(3 -(3 -Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-2-( 1 -hydroxyethyl)-1H-imidazole-4-carboxamide ;
(S)-2-acetyl-N-( 1 -(3 -(3 -chloro-4-cyano-5 -fluorophenyl)-1H-pyrazol-1 -yl)-
propan-2-yl)-1H-imidazole-4- carboxamide;
(S)-N-(1 -(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-2-(2-hydroxypropan-2-yl)-1H-imidazole-4-carboxamide ;
(S)-N-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2-
yl)-2-cyclopropyl-1 -methyl-1H-imidazole-4-carboxamide;
(S)-N4-(1-(3-(3-Chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-
yl)-1H-imidazole-2,4-dicarboxamide:
4-( 1 -(3-((S)-1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl-
carbamoyl)-1H-pyrazol-5-yl)ethoxy)-4-oxobutanoic acid;
(S)-5-Chloro-N-(1 -(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)-propan-2-
yl)pyrazine-2-carboxamide;
N-((S)-1 -(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-1 -((S)-
2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxamide;
(S)-1-Butyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-
2-methyl-1H-imidazole-4-carboxamide;
(S)-N-(1 -(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-5-(2-
hydroxypropan-2-yl)-1H-pyrazole-3 -carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-1'-
methyl-1'H-1,4'-bipyrazole-3-carboxamide;
N-((S)-1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-1 -((R)-
2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxamide;
(S)-2-Bromo-N-( 1 -(3 -(3-chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)-propan-2-
yl)-1H-imidazole-4-carboxamide;
N-((S)-1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-5-( 1 -
hydroxy-2-methylpropyl)isoxazole-3-carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-1 -(2-
cyanoethyl)-2-methyl-1H-imidazole-4-carboxamide;
N-((S)-1 -(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-1 -(1 -
cyanoethyl)-2-methyl-1H-imidazole-4-carboxamide;
(S)-N-(1 -(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-1 -(2-
methylprop-1 -enyl)-1H-pyrazole-3-carboxamide;
(S)-N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(lH-
imidazol-4-yl)-1H-pyrazole-5-carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-1 -cyclo-
propyl-1H-pyrazole-3 -carboxamide;
(S)-N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-(6-
(dimethylamino)pyridin-3-yl)-1H-pyrazole-3-carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-4,5,6,7-
tetrahydropyrazolo[l,5-a]pyridine-2-carboxamide);
N-((S)-1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-2-( 1 -
hydroxyethyl)-1H-imidazole-4-carboxamide;
(S)-N-( 1 -(3-(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-2-iso-
propyl-1H-imidazole-4-carboxamide;
(S)-2-Butyl-N-(1 -(3 -(3 -chloro-4-cyanophenyl)-1H-pyrazol- l-yl)propan-2-yl)-
1 -methyl-1H-imidazole-4-carboxamide;
(S)-N-(1 -(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-2-(2-
hydroxypropan-2-yl)-1 -methyl-1H-imidazole-4-carboxamide;
(S)-N-( 1 -(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-1 -
methyl-2-( 1 -methyl-1H-pyrazol-4-yl)-1H-imidazole-4- carboxamide;
(S)-N-( 1 -(3 -(3 -Chloro-4-cyanophenyl)-1H-pyrazol-1 -yl)propan-2-yl)-2-
cyclopropyl-1 -methyl-1H-imidazole-4-carboxamide;
(S)-N4-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-
imidazole-2,4-dicarboxamide;
(S)-N-(1 -(3-(4-Cyano-3-(trifluoromethyl)phenyl)-1H-pyrazol-1 -yl)propan-2-
yl)-2-(2-hydroxypropan-2-yl)oxazole-4-carboxamide
or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition comprising a compound of claim 1 together
with a pharmaceutically acceptable carrier.
10. A method for the treatment or prevention of androgen receptor dependent
conditions, comprising administering to a subject in need thereof a therapeutically
effective amount of a compound of claim 1.
11. A method according to claim 10, wherein the androgen receptor
dependent condition is prostate cancer.

Compounds of formula (I) or (II)

wherein Rx, Rz, R9, R10, R14, R14', R15, R15', A and B are as defined in the claims and
pharmaceutically acceptable salts and esters thereof, are disclosed. The compounds
possess utility as tissue-selective androgen receptor modulators (SARM) and are
particularly useful as medicaments in the treatment of prostate cancer and other AR
dependent conditions and diseases where AR antagonism is desired.